Endocrinology

Question 1

Growth hormone

• ____ stimulates GH release
• ____ Inhibits GH release

Answer 1

Growth hormone

• Growth hormone-releasing hormone (GHRH) stimulates GH release
• Somatostatin inhibits GH release

Question 2

LH and FSH

- ____, released primarily from the gonad, inhibits only FSH secretion.

Answer 2

LH and FSH

- Inhibin, released primarily from the gonad, inhibits only FSH secretion.

Question 3

Prolactin

• Different in that it is under tonic hypothalamic inhibition by _____ sent down the pituitary stalk.
• ____ drugs (such as metoclopramide and phenothiazines) also increase prolactin, as does ____. Thus, prolactin elevates with primary ____ and with any inhibition in the production of dopamine from the hypothalamus (most commonly, medications).

Answer 3

Prolactin

• Different in that it is under tonic hypothalamic inhibition by dopamine sent down the pituitary stalk.
• Antidopaminergic drugs (such as metoclopramide and phenothiazines) also increase prolactin, as does TRH. Thus, prolactin elevates with primary hypothyroidism and with any inhibition in the production of dopamine from the hypothalamus (most commonly, medications).

Question 4

Congenital hypopituitarism:
- Generally includes ____ deficiency along with >1 of the 5 hormones produced in the anterior pituitary

• Pt:
  
  • Predominant presenting symptom: _____
  • Small penis, undescended testes- microphallus is a clue in males to GH deficiency
  • _____ suggests septa-optic dysplasia
  • Low free thyroxine, TSH deficiency
  • Neonatal cholestasis with direct hyperbilirubinemia

Answer 4

Congenital hypopituitarism:
- Generally includes GH deficiency along with >1 of the 5 hormones produced in the anterior pituitary

• Pt:
  
  • Predominant presenting symptom: Hypoglycemia
  • Small penis, undescended testes- microphallus is a clue in males to GH deficiency
  • Wandering nystagmus suggests septa-optic dysplasia
  • Low free thyroxine, TSH deficiency
  • Neonatal cholestasis with direct hyperbilirubinemia

Question 5

Congenital defects that can present with hypopituitarism 
Septooptic dysplasia (Morsier syndrome)
- Involves abnormality of the optic nerve (absence of the optic chiasm, optic nerve hypoplasia, or both), agenesis or hypoplasia of the septum pellucidum or corpus callosum or both; and often variable degrees of hypothalamic insufficiency

Any lesion that destroys the hypothalamus, pituitary, or pituitary stalk can cause pituitary hormone deficiencies.
- Due to its location in the suprasellar region, craniopharyngioma is the most common tumor to cause acquired pituitary hormone deficiencies in children. Tumor calcifications are often noted on imaging studies

Answer 5

Congenital defects that can present with hypopituitarism 
Septooptic dysplasia (Morsier syndrome)
- Involves abnormality of the optic nerve (absence of the optic chiasm, optic nerve hypoplasia, or both), agenesis or hypoplasia of the septum pellucidum or corpus callosum or both; and often variable degrees of hypothalamic insufficiency

Any lesion that destroys the hypothalamus, pituitary, or pituitary stalk can cause pituitary hormone deficiencies.
- Due to its location in the suprasellar region, craniopharyngioma is the most common tumor to cause acquired pituitary hormone deficiencies in children. Tumor calcifications are often noted on imaging studies

Question 6

GROWTH HORMONE DEFICIENCY

• Pt:
  
  • Normal length and weight at birth.
    
    • Severe defects in GH production: Drop lower than 4 SDs below the mean by 1yo
    • Less severe defects have a variable effect on growth
  • Microphallus (or micropenis) is a clue in males
  • Hypoglycemia and prolonged direct hyperbilirubinemia in the neonatal period
  • Know: ______ anomalies, such as a solitary ______, indicate a high likelihood of GH deficiency. Pts with cleft lip or cleft palate have about a 4% chance of having GH deficiency. Bilateral or unilateral ______ hypoplasia is also associated with hypopituitarism.
• Dx:
  
  • Suspect GH deficiency with postnatal _______ (heights or lengths >3 SD below the mean) and even more importantly, a slow growth velocity.
    
    • Falling off the growth curve after 3 yo is a huge red flag and deserves evaluation.
  • CBC with diff, ESR or CRP, CMP, celiac disease screen, Free T4/TSH, IGF-1, IGF-BP3, urinalysis, karyotype (in girls)
    
    • Serum level of ________ and the GH-dependent _________ that are in the upper part of the normal range pretty much rule out GH deficiency.
  • Definitive: Lack of response to ____________ in the clinical setting of growth failure
    
    • GH levels that do not rise >10ug/L after stimulation using 2 different agents are consistent with GH deficiency.
    • Bone age must be >2 SD from the mean to be considered delayed or advanced.
• Treatment of GH Deficiency
  
  • Begin tx as soon as you make the diagnosis
  • Give recombinant ______ at a dose of 0.18-0.30mg/kg/week subcutaneously in 6-7 divided doses/week.
    
    • Side effects of GH therapy:
      
      • ____, ______, transient carbohydrate intolerance, transient hypothyroidism, and scoliosis
      • Must monitor for hypothyroidism as it occasionally occur transient during therapy
      • From careful analysis of existing databases, there appears to be no increased risk of leukemia for children with no other risk factors

Answer 6

GROWTH HORMONE DEFICIENCY

• Pt:
  
  • Normal length and weight at birth.
    
    • Severe defects in GH production: Drop lower than 4 SDs below the mean by 1yo
    • Less severe defects have a variable effect on growth
  • Microphallus (or micropenis) is a clue in males
  • Hypoglycemia and prolonged direct hyperbilirubinemia in the neonatal period
  • Know: Midfacial anomalies, such as a solitary maxillary central incisor, indicate a high likelihood of GH deficiency. Pts with cleft lip or cleft palate have about a 4% chance of having GH deficiency. Bilateral or unilateral optic nerve hypoplasia is also associated with hypopituitarism.
• Dx:
  
  • Suspect GH deficiency with postnatal growth failure (heights or lengths >3 SD below the mean) and even more importantly, a slow growth velocity.
    
    • Falling off the growth curve after 3 yo is a huge red flag and deserves evaluation.
  • CBC with diff, ESR or CRP, CMP, celiac disease screen, Free T4/TSH, IGF-1, IGF-BP3, urinalysis, karyotype (in girls)
    
    • Serum level of insulin-like growth factor-1 (IGF-1) and the GH-dependent IGF-binding protein-3 (IGF-BP3) that are in the upper part of the normal range pretty much rule out GH deficiency.
  • Definitive: Lack of response to stimulation of GH production (GH-stimulation testing) in the clinical setting of growth failure
    
    • GH levels that do not rise >10ug/L after stimulation using 2 different agents are consistent with GH deficiency.
    • Bone age must be >2 SD from the mean to be considered delayed or advanced.
• Treatment of GH Deficiency
  
  • Begin tx as soon as you make the diagnosis
  • Give recombinant human growth hormone (hGH) at a dose of 0.18-0.30mg/kg/week subcutaneously in 6-7 divided doses/week.
    
    • Side effects of GH therapy:
      
      • SCFE, pseudotumor cerebri, transient carbohydrate intolerance, transient hypothyroidism, and scoliosis
      • Must monitor for hypothyroidism as it occasionally occur transient during therapy
      • From careful analysis of existing databases, there appears to be no increased risk of leukemia for children with no other risk factors

Question 7

Congenital growth hormone deficiency

• Pt:
  
  • Linear growth deceleration after the first 6-12mo of life

Answer 7

Congenital growth hormone deficiency

• Pt:
  
  • Linear growth deceleration after the first 6-12mo of life

Question 8

Acquired growth hormone deficiency

• Path:
  
  • Pituitary hormone deficiencies are common after cranial irradiation. GH axis is the most sensitive and the first to be affected.
• Pt: Linear growth deceleration after a period of normal growth

Answer 8

Acquired growth hormone deficiency

• Path:
  
  • Pituitary hormone deficiencies are common after cranial irradiation. GH axis is the most sensitive and the first to be affected.
• Pt: Linear growth deceleration after a period of normal growth

Question 9

SHORT STATURE

Short stature is ___ STD below mean height for children of same sex and age OR height less than ____rd%ile

Answer 9

SHORT STATURE

Short stature is 2 STD below mean height for children of same sex and age OR height <2.3rd%ile

Question 10

Evaluation for child with short stature

• For children with short stature, normal growth rate, and no other symptoms
  
  • Bone age indicates a pt’s potential growth
  • A delayed bone age gives a pt more growth potential whereas an advanced bone age gives less potential growth, and a normal bone age does not allow for any additional growth when compared to age-matched peers.
  • Bone age must be >2 SD from the mean to be considered delayed or advanced.
  • Turner’s syndrome would have a concordant bone age. A declining growth velocity can be consistent with an endocrine disorder such as GH deficiency or hypothyroidism. Bone age, however, would be delayed in these endocrine disorders.
• For children with severe short stature (height less than -2.5 SD / 0.6th%ile) or growth failure
  
  • Falling off the growth curve after 3 yo is a huge red flag and deserves evaluation.
  • CBC with diff, ESR or CRP, CMP, celiac disease screen (tTG, IgA), Free T4/TSH, IGF-1, IGF-BP3, urinalysis, karyotype (in girls)
    
    • Karyotype to rule out Turner syndrome

Answer 10

Evaluation for child with short stature

• For children with short stature, normal growth rate, and no other symptoms
  
  • Bone age indicates a pt’s potential growth
  • A delayed bone age gives a pt more growth potential whereas an advanced bone age gives less potential growth, and a normal bone age does not allow for any additional growth when compared to age-matched peers.
  • Bone age must be >2 SD from the mean to be considered delayed or advanced.
  • Turner’s syndrome would have a concordant bone age. A declining growth velocity can be consistent with an endocrine disorder such as GH deficiency or hypothyroidism. Bone age, however, would be delayed in these endocrine disorders.
• For children with severe short stature (height

Question 11

Familial/ Genetic short stature (Normal growth velocity, normal bone age, family hx of short stature)
- CA __ BA ___ HA.

Answer 11

Familial/ Genetic short stature (Normal growth velocity, normal bone age, family hx of short stature)
- CA = BA > HA.

Question 12

Constitutional delay of growth and puberty (Normal growth velocity, delayed bone age, typically family hx of delayed puberty)

• Pt:
  
  • Birth weight and height are normal with normal growth during initial 4-12mo.
  • Followed by decreased linear growth at 4-6 months and continuing until 2-3 years old.
  • By 2-3yo, linear growth resumes at a normal growth velocity at >5cm/year
  • Puberty is delayed
  • Family hx of “late bloomers”
• Dx
  
  • Diagnosis of exclusion
    
    • ___ bone age radiography.
      
      • CA __ BA __ HA
    • If height is plotted for bone age, it falls within the target height range percentiles
• Tx:
  
  • Providing reassurance regarding final height with follow-up in 6-12 months

Answer 12

Constitutional delay of growth and puberty (Normal growth velocity, delayed bone age, typically family hx of delayed puberty)

• Pt:
  
  • Birth weight and height are normal with normal growth during initial 4-12mo.
  • Followed by decreased linear growth at 4-6 months and continuing until 2-3 years old.
  • By 2-3yo, linear growth resumes at a normal growth velocity at >5cm/year
  • Puberty is delayed
  • Family hx of “late bloomers”
• Dx
  
  • Diagnosis of exclusion
    
    • Delayed bone age radiography.
      
      • CA > BA = HA
    • If height is plotted for bone age, it falls within the target height range percentiles
• Tx:
  
  • Providing reassurance regarding final height with follow-up in 6-12 months

Question 13

Arrest/slow in height and increasing/maintained weight, think endocrine causes.

Answer 13

Arrest/slow in height and increasing/maintained weight, think endocrine causes.

Question 14

Growth Hormone Deficiency (decrease in growth velocity, delayed bone age, family hx of hormone deficiency is sometimes seen in these pts)

Answer 14

Growth Hormone Deficiency (decrease in growth velocity, delayed bone age, family hx of hormone deficiency is sometimes seen in these pts)

Question 15

Russell-Silver syndrome

• Short stature, frontal bossing, triangular facies, shortened and incurved 5th fingers (clinodactyly), and asymmetry. With NORMAL head circumference
• Low birth weights (SGA) and FTT
• Hemihypertrophy. Cafe au lait spots. Delayed bone age. Reflux is major issue.

Answer 15

Russell-Silver syndrome

• Short stature, frontal bossing, triangular facies, shortened and incurved 5th fingers (clinodactyly), and asymmetry. With NORMAL head circumference
• Low birth weights (SGA) and FTT
• Hemihypertrophy. Cafe au lait spots. Delayed bone age. Reflux is major issue.

Question 16

Growth hormone is approved for the following indications

• Idiopathic short stature
  
  • Children with idiopathic short stature whose height is >___ STDs below the mean (less than __%) and who are unlikely to catch up in height.
• Children born SGA who have not achieved a height >2 SDs below the mean (about __%) by age 2yo
• ____ deficiency
• ____ syndrome
• ___ syndrome
• ____ syndrome
• SHOX gene haploinsufficiency (short stature homeobox)
• Chronic renal insufficiency (pretransplantation only)

Answer 16

Growth hormone is approved for the following indications

• Idiopathic short stature
  
  • Children with idiopathic short stature whose height is >2.25 STDs below the mean (<1.2%) and who are unlikely to catch up in height.
  • Children born SGA who have not achieved a height >2 SDs below the mean (about 2%) by age 2yo
• Growth hormone deficiency
• Turner syndrome
• Noonan syndrome
• Prader-Willi syndrome
• SHOX gene haploinsufficiency (short stature homeobox)
• Chronic renal insufficiency (pretransplantation only)

Question 17

DIABETES INSIPIDUS

• Classifications:
  
  • Think of Central DI (inadequate ADH production) in the pt with high Na and high urine volume who also has a hx of recent neurosurgery, head trauma, or brain cancer/metastasis. Some pts have idiopathic central DI, but most endocrinologists would still rule-out pituitary etiologies, esp adenomas, with appropriate imaging.
  • A pt with nephrogenic DI has renal ADH insensitivity.
• Pt: Polyuria and polydipsia are the classic symptoms (but these sx may be discounted or not noticed), in which case chronic dehydration is likely to be the presenting finding.
  
  • New-onset enuresis may be the 1st sign seen in older children.
• Dx:
  
  • Serum osmolality >___mOsm/kg with urine osmolality less than __ mOsm/kg is pathognomonic for DI.
  • Extremely low or absent serum ADH strongly supports the dx of central DI.
  • Administer _______ to determine whether the pt can respond to ADH.
    
    • Central DI: Giving desmopressin increases urine osmolality and therefore decreases plasma osmolality back toward normal values (~280mOsm/kg)
    • Nephrogenic DI, giving desmopressin does not increase urine osmolality
  • Water restriction test distinguishes primary polydipsia from central DI.
    
    • Uosm increases = ______
    • No change in Uosm, Dilute urine - give ADH
      
      • Uosm increases =_____
      • No change in Uosm = _____
  • A 2015 study found that a ______ level >21.4 pmol/L has a 100% sensitivity and 100% specificity for nephrogenic DI! If this test is available, do it when nephrogenic DI is a possibility to immediately rule it out.

Answer 17

DIABETES INSIPIDUS

• Classifications:
  
  • Think of Central DI (inadequate ADH production) in the pt with high Na and high urine volume who also has a hx of recent neurosurgery, head trauma, or brain cancer/metastasis. Some pts have idiopathic central DI, but most endocrinologists would still rule-out pituitary etiologies, esp adenomas, with appropriate imaging.
  • A pt with nephrogenic DI has renal ADH insensitivity.
• Pt: Polyuria and polydipsia are the classic symptoms (but these sx may be discounted or not noticed), in which case chronic dehydration is likely to be the presenting finding.
  
  • New-onset enuresis may be the 1st sign seen in older children.
• Dx:
  
  • Serum osmolality >300mOsm/kg with urine osmolality <300 mOsm/kg is pathognomonic for DI.
  • Extremely low or absent serum ADH strongly supports the dx of central DI.
  • Administer 1-desamino-8-D-arginine vasopressin (aka desmopressin or DDAVP) to determine whether the pt can respond to ADH.
    
    • Central DI: Giving desmopressin increases urine osmolality and therefore decreases plasma osmolality back toward normal values (~280mOsm/kg)
    • Nephrogenic DI, giving desmopressin does not increase urine osmolality
  • Water restriction test distinguishes primary polydipsia from central DI.
    
    • Uosm increases = psychogenic polydipsia.
    • No change in Uosm, Dilute urine - give ADH
      
      • Uosm increases = central diabetes insipidus
      • No change in Uosm = nephrogenic diabetes insipidus
  • A 2015 study found that a copeptin level >21.4 pmol/L has a 100% sensitivity and 100% specificity for nephrogenic DI! If this test is available, do it when nephrogenic DI is a possibility to immediately rule it out.

Question 18

Nephrogenic Diabetes Insipidus

• Lack of response to ADH by the kidney collecting tubules.
• _____ is the most widely known drug to induce nephrogenic DI.
• Tx: _______
  
  • Requires sufficient intake of water.
  • If applicable, discontinue any drug that is the cause of DI.
  • Low-sodium (specifically, low-solute-load) diets
  • ____
  • _____

Answer 18

Nephrogenic Diabetes Insipidus

• Lack of response to ADH by the kidney collecting tubules.
• Lithium is the most widely known drug to induce nephrogenic DI.
• Tx: Gentle diuresis
  
  • Requires sufficient intake of water.
  • If applicable, discontinue any drug that is the cause of DI.
  • Low-sodium (specifically, low-solute-load) diets
  • Thiazides
  • Amiloride

Question 19

Central (Neurogenic) Diabetes Insipidus

• Decreased antidiuretic hormone
• Path:
  
  • Idiopathic (most common)
  • Primary/inherited forms are very rare
  • Second/acquired forms are much more common. Injury to the hypothalamus and posterior pituitary gland:
    
    • CNS tumors (most common cause)
      
      • Craniopharyngioma
    • Infiltrative lesions (histiocytosis)
    • Head trauma (surgical or nonsurgical)
• Tx: Responds well to ______

Answer 19

Central (Neurogenic) Diabetes Insipidus

• Decreased antidiuretic hormone
• Path:
  
  • Idiopathic (most common)
  • Primary/inherited forms are very rare
  • Second/acquired forms are much more common. Injury to the hypothalamus and posterior pituitary gland:
    
    • CNS tumors (most common cause)
      
      • Craniopharyngioma
    • Infiltrative lesions (histiocytosis)
    • Head trauma (surgical or nonsurgical)
• Tx: Responds well to desmopressin

Question 20

Syndrome of Inappropriate Antidiuretic Hormone Secretion

• Causes: SIADH results from either excess secretion of ADH or the production of ADH-like molecules by tumors or other tissues.
  
  • Ex: Brain lesion (tumor close to posterior pituitary results in transient SIADH)
• Pt: Dilutional hyponatremia due to water retention
• Dx:
  
  • ____ serum sodium, ____ serum osmolality due to water retention
  • High Urine osmolality (UOsm), high urine specific gravity due to water retention in kidney
  • High urine sodium (UNa) due to sodium excretion in the kidney from hypervolemia suppressing aldosterone
  • Rule out ____ or ____ before making diagnosis of SIADH as both can have low serum osmolalities and high urine osmolalities
• Tx:
  
  • _____
  • Severe symptoms/hyponatremia require immediate tx with hypertonic 3% NaCl
  • Antibiotic _____ has been shown to interfere with ADH receptor and can be used to tx pts with chronic low Na concentrations due to SIADH.

Answer 20

Syndrome of Inappropriate Antidiuretic Hormone Secretion

• Causes: SIADH results from either excess secretion of ADH or the production of ADH-like molecules by tumors or other tissues.
  
  • Ex: Brain lesion (tumor close to posterior pituitary results in transient SIADH)
• Pt: Dilutional hyponatremia due to water retention
• Dx:
  
  • Low serum sodium, low serum osmolality due to water retention
  • High Urine osmolality (UOsm), high urine specific gravity due to water retention in kidney
  • High urine sodium (UNa) due to sodium excretion in the kidney from hypervolemia suppressing aldosterone
  • Rule out hypothyroidism or glucocorticoid deficiency before making diagnosis of SIADH as both can have low serum osmolalities and high urine osmolalities
• Tx:
  
  • Fluid restriction.
  • Severe symptoms/hyponatremia require immediate tx with hypertonic 3% NaCl
  • Antibiotic demeclocycline has been shown to interfere with ADH receptor and can be used to tx pts with chronic low Na concentrations due to SIADH.

Question 21

Cerebral Salt Wasting
- Path: Due to oversecretion of ______ that is normally released in response to hypervolemia states and promotes ___ and ___ excretion and lowers BP.

• Pt:
  
  • Increased UOP with resultant hypovolemia
• Labs:
  
  • Low plasma sodium
  • High urinary sodium excretion (>150 mEq/L)
  • Low ___
  • High ___ concentrations
  • (vs SIADH with low UOP, low plasma sodium, high vasopressin, normal ANP concentrations)
• Tx:
  
  • Replacement of UOP with IV solutions - NS Isotonic fluid hydration to 3% sodium, depending on the clinical situation

Answer 21

Cerebral Salt Wasting
- Path: Due to oversecretion of atrial natriuretic peptide (ANP) that is normally released in response to hypervolemia states and promotes salt and water excretion and lowers BP.

• Pt:
  
  • Increased UOP with resultant hypovolemia
• Labs:
  
  • Low plasma sodium
  • High urinary sodium excretion (>150 mEq/L)
  • Low vasopressin
  • High ANP concentrations
  • (vs SIADH with low UOP, low plasma sodium, high vasopressin, normal ANP concentrations)
• Tx:
  
  • Replacement of UOP with IV solutions - NS Isotonic fluid hydration to 3% sodium, depending on the clinical situation

Question 22

ACTH-Adrenal-Cortisol Axis Deficiency

• Different from SIADH in that, with cortisol deficiency, there is dilute urine with low urine osmolality (vs decreased UOP and high urine osmolality with SIADH).
• In addition, cortisol deficiency causes hypoglycemia.

Answer 22

ACTH-Adrenal-Cortisol Axis Deficiency

• Different from SIADH in that, with cortisol deficiency, there is dilute urine with low urine osmolality (vs decreased UOP and high urine osmolality with SIADH).
• In addition, cortisol deficiency causes hypoglycemia.

Question 23

Tall stature = >__SD above the mean height for age

Answer 23

Tall stature = >2SD above the mean height for age

Question 24

3 genetic causes of tall stature include ___ syndrome (XXY; 1/600 males), ___ syndrome (AD; 1/5000), and ___ (AR; 1/200,000)

Answer 24

3 genetic causes of tall stature include Klinefelter syndrome (XXY; 1/600 males), Marfan syndrome (AD; 1/5000), and homocystinuria (AR; 1/200,000)

Question 25

Evaluation of tall stature - Lab and further testing should be directed by history and physical exam findings. - If hx is suggestive of a genetic disorder or the physical exam is abnormal, screen for GH excess with a random ___ level and serum ___ and ____ concentrations. - If there is increased GH, order a brain/sella MRI - An oral glucose tolerance test can also be useful, bc a large glucose load should suppress GH levels but typically does not in the setting of excess GH production. - Chromosomal analysis is helpful in males if Klinefelter syndrome is suspected. - Tx: - Can give height-limiting therapy if predicted adult height is >77” for boys and >72” for girls or if significant psychosocial impairment exists bc of the height. However, this is highly controversial. - Sex steroids (estrogens for girls, testosterone for boys) can be helpful but only if given early enough in puberty to accelerate epiphyseal fusion and limit further growth. - Remember estrogen fuses the growth plates.

Answer 25

Evaluation of tall stature - Lab and further testing should be directed by history and physical exam findings. - If hx is suggestive of a genetic disorder or the physical exam is abnormal, screen for GH excess with a random GH level and serum IGF-1 and IGF-BP3 concentrations. - If there is increased GH, order a brain/sella MRI - An oral glucose tolerance test can also be useful, bc a large glucose load should suppress GH levels but typically does not in the setting of excess GH production. - Chromosomal analysis is helpful in males if Klinefelter syndrome is suspected. - Tx: - Can give height-limiting therapy if predicted adult height is >77” for boys and >72” for girls or if significant psychosocial impairment exists bc of the height. However, this is highly controversial. - Sex steroids (estrogens for girls, testosterone for boys) can be helpful but only if given early enough in puberty to accelerate epiphyseal fusion and limit further growth. - Remember estrogen fuses the growth plates.

Question 26

PUBERTY - Normally, about 1-3 years before puberty is clinically evidence, LH levels become detectable during sleep. - ____ is pulsatile in nature and increases as clinical puberty approaches. - ____ is the most useful gonadotropin to assess for the onset of puberty - ____ secretion is responsible for the onset and progression of puberty. ___ - and not androgens - lead to epiphyseal fusion and cessation of growth.

Answer 26

PUBERTY - Normally, about 1-3 years before puberty is clinically evidence, LH levels become detectable during sleep. - LH is pulsatile in nature and increases as clinical puberty approaches. - LH is the most useful gonadotropin to assess for the onset of puberty - GnRH secretion is responsible for the onset and progression of puberty. Estrogens - and not androgens - lead to epiphyseal fusion and cessation of growth.

Question 27

Female: No SRY gene - causes gonads to develop into ovaries Testosterone → ( aromatase) → Estrogen → _____ Adrenal gland → Androgen (DHEA) → ____

Answer 27

Female: No SRY gene - causes gonads to develop into ovaries Testosterone → ( aromatase) → Estrogen → breast development (gonadal) Adrenal gland → Androgen (DHEA) → pubic/axillary/odor

Question 28

Male: SRY gene - causes formation of testes FSH → ___ cells → ___ & ____ → Inhibit mullerian duct formation LH → ____ cells → ____ → Wolffian duct virilize into epididymis, vas deferens, seminal vesicle → Secondary sex characteristics (hair/voice) → Estrogen -- (5a-reductase) → DHT → _____ (gonadal) Adrenal gland → Androgen (DHEA) → _____

Answer 28

Male: SRY gene - causes formation of testes FSH → Sertoli cells → Estrogens & MIS → Inhibit mullerian duct formation LH → Leydig cells → Testosterone → Wolffian duct virilize into epididymis, vas deferens, seminal vesicle → Secondary sex characteristics (hair/voice) → Estrogen -- (5a-reductase) → DHT → external genitalia (gonadal) Adrenal gland → Androgen (DHEA) → hair/acne/odor

Question 29

PUBERTY STAGES Female - Stage I (0-15yo) - Stage 2 (8-15yo) - *Height increases at accelerated rate 7-8cm/year* - Stage 3 (10-15yo) - P3: Adult type pubic hair (coarse, dark, curly) with distribution limited to symphysis pubis and labia majora - *Peak growth velocity occurs 8cm/year* - Menarche occurs in 2% of girls in late stage 3 - Stage 4 (10-17yo) - B4: Projection of areola from secondary breast mound at a different angle - *Menarche occurs in most girls 1-3 years after thelarche in Tanner stage 3 or 4* - Stage 5 (12.5-15yo)

Answer 29

PUBERTY STAGES Female - Stage I (0-15yo) - Stage 2 (8-15yo) - *Height increases at accelerated rate 7-8cm/year* - Stage 3 (10-15yo) - P3: Adult type pubic hair (coarse, dark, curly) with distribution limited to symphysis pubis and labia majora - *Peak growth velocity occurs 8cm/year* - Menarche occurs in 2% of girls in late stage 3 - Stage 4 (10-17yo) - B4: Projection of areola from secondary breast mound at a different angle - *Menarche occurs in most girls 1-3 years after thelarche in Tanner stage 3 or 4* - Stage 5 (12.5-15yo)

Question 30

Male - Stage 1 (0-15yo) - Stage 2 (10-15yo) - Enlargement and reddening of testes - Stage 3 (11.5-16.5yo) - *Lengthening of phallus begins in SMR 3*. - *Height increases at accelerated rate: 7-8 cm/year* - *Gynecomastia may occur (age 13.2yo)* - *Voice breaks (age 13.5yo)* - Ejaculation and spermarche - SMR 3. Occurs one year after testes enlarge - Change of voice at SMR 3-4 pubic - Stage 4 (12-17yo) - Pubic hair adult in type but not in distribution (extends across the pubis but spares the medial surface of the thighs) - *Darker scrotal skin* - *Axillary hair, acne, and deepening of voice* - *Height increases at peak rate 10cm/year (13.8yo)* - Stage 5 (13-18yo) - *Facial hair* - Testes >__mL, >___cm

Answer 30

Male - Stage 1 (0-15yo) - Stage 2 (10-15yo) - Enlargement and reddening of testes - Stage 3 (11.5-16.5yo) - *Lengthening of phallus begins in SMR 3*. - *Height increases at accelerated rate: 7-8 cm/year* - *Gynecomastia may occur (age 13.2yo)* - *Voice breaks (age 13.5yo)* - Ejaculation and spermarche - SMR 3. Occurs one year after testes enlarge - Change of voice at SMR 3-4 pubic - Stage 4 (12-17yo) - Pubic hair adult in type but not in distribution (extends across the pubis but spares the medial surface of the thighs) - *Darker scrotal skin* - *Axillary hair, acne, and deepening of voice* - *Height increases at peak rate 10cm/year (13.8yo)* - Stage 5 (13-18yo) - *Facial hair* - Testes >25mL, >4.5cm

Question 31

Tanner 1 less than __cm, Tanner 2: __-___cm length of testes, Tanner 3: ___-___cm length of testes; Tanner 4: __-___cm length of tests, Tanner 5: >__cm

Answer 31

Tanner 1 <2.5cm, Tanner 2: 2.5-3.3cm length of testes, Tanner 3: 3.4-4cm length of testes; Tanner 4: 4.1-4.5cm length of tests, Tanner 5: >4.5cm

Question 32

Workup is recommended for onset of puberty in boys less than __yo or absence by __yo and girls less than __yo and absence by __yo

Answer 32

Workup is recommended for onset of puberty in boys <9yo or absence by 14yo and girls <8yo and absence by 13yo

Question 33

Normal female puberty is considered late if there are no secondary sexual characteristics after __yo or if >__ years have passed between the beginning and completion of puberty.

Answer 33

Normal female puberty is considered late if there are no secondary sexual characteristics after 13yo or if >5 years have passed between the beginning and completion of puberty.

Question 34

Average time to complete puberty is _ years

Answer 34

Average time to complete puberty is 4 years

Question 35

Order for girls: Breast, hair, growth, menarche (TPGM) (BHHP) - Thelarche = Breast bud (___yo), first sign of puberty - Adrenarche/Pubarche = Pubic hair. Follows thelarche by 0.5-1 year - Growth = Peak height velocity (SMR 2-3 breast) (___yo) - Initiation of growth spurt (IGS) typically begins at around 9.5yo, with average peak height velocity of 9cm/yr (6-10cm/year) achieved at 11.5 years of age when most girls are at sexual maturity rating SMR 2-3 roughly 6 months before menarche. - Menarche = Period (SMR breast Stage 3-4) (Mean age ___yo) - Occurs about 2-2.5 years after thelarche, but can be as long as 5 years. - Once menarche has started, most girls have about 3 inches (7cm) of growth left - Physiologic leukorrhea precedes menarche by 6-12 months

Answer 35

Order for girls: Breast, hair, growth, menarche (TPGM) (BHHP) - Thelarche = Breast bud (10yo), first sign of puberty - Adrenarche/Pubarche = Pubic hair. Follows thelarche by 0.5-1 year - Growth = Peak height velocity (SMR 2-3 breast) (11.5yo) - Initiation of growth spurt (IGS) typically begins at around 9.5yo, with average peak height velocity of 9cm/yr (6-10cm/year) achieved at 11.5 years of age when most girls are at sexual maturity rating SMR 2-3 roughly 6 months before menarche. - Menarche = Period (SMR breast Stage 3-4) (Mean age 12.5yo) - Occurs about 2-2.5 years after thelarche, but can be as long as 5 years. - Once menarche has started, most girls have about 3 inches (7cm) of growth left - Physiologic leukorrhea precedes menarche by 6-12 months

Question 36

Order for boys: penis/testicular enlargement, hair/pubarche, growth/peak height velocity, spermarche (development of sperm) - Gonadarche / Testicular enlargement (SMR Genital 2, >4mL testicular volume or >2.5cm in long axis) (__yo) - Adrenarche/Pubarche = Pubic hair growth - Growth spurt (SMR 3-4) (__yo) - Initiation of growth spurt at 11.5 years, and reach PHV 10.3cm/year (5.8-13.1cm) at 13.5 year of age - Compared to girls, boys have an additional 2 years of growth (at a rate of 5 cm/year) before growth spurt initiation. As a result, girls are about 10cm shorter than boys at IGS

Answer 36

Order for boys: penis/testicular enlargement, hair/pubarche, growth/peak height velocity, spermarche (development of sperm) - Gonadarche / Testicular enlargement (SMR Genital 2, >4mL testicular volume or >2.5cm in long axis) (10yo) - Adrenarche/Pubarche = Pubic hair growth - Growth spurt (SMR 3-4) (13.5yo) - Initiation of growth spurt at 11.5 years, and reach PHV 10.3cm/year (5.8-13.1cm) at 13.5 year of age - Compared to girls, boys have an additional 2 years of growth (at a rate of 5 cm/year) before growth spurt initiation. As a result, girls are about 10cm shorter than boys at IGS

Question 37

PRECOCIOUS PUBERTY - Girls <8yo, boys <9yo - An earlier initiation of growth spurt means earlier cessation of growth that may result in shorter adult height. - _________ is an important discriminator between central and peripheral precocious puberty. - Workup: Measurement of LH, FSH, TSH, DHEAS, estradiol in girls, and testosterone in boys, and a bone age radiograph. - Look for elevated LH and FSH for central sources of precocious puberty, 17-OHP to evaluate for CAH, DHEAS to evaluate for the possibility of adrenal tumors, and testosterone and estradiol for gonadal sources.

Answer 37

PRECOCIOUS PUBERTY - Girls <8yo, boys <9yo - An earlier initiation of growth spurt means earlier cessation of growth that may result in shorter adult height. - Size of the testes is an important discriminator between central and peripheral precocious puberty. - Workup: Measurement of LH, FSH, TSH, DHEAS, estradiol in girls, and testosterone in boys, and a bone age radiograph. - Look for elevated LH and FSH for central sources of precocious puberty, 17-OHP to evaluate for CAH, DHEAS to evaluate for the possibility of adrenal tumors, and testosterone and estradiol for gonadal sources.

Question 38

CENTRAL PRECOCIOUS PUBERTY (Gonadotropin-dependent precocious puberty) - Path: Early activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in increased LH and FSH levels - CPP is much more common in girls than boys. - Approx 95% of true precocity in females are sporadic and idiopathic. - _______ is much more common in boys (25-75%) with central precocious puberty than in girls - Pt: - In boys and girls, height and weight are advanced, typically with marked linear growth acceleration. - Bone maturation is accelerated, as evidenced by an advanced bone age. - Because of early closure of the epiphyses, a majority of those who do not receive tx end up being <5%ile for height. - Physical exam: - Testes are _____ in volume (>__ ml) in central precocious puberty as they are stimulated by LH. Or an increase in size in ovaries (by US) - Testicular size is an important discriminator bw central and peripheral precocious puberty in boys - Labs: Detect by pubertal LH level, basal or stimulated - __level > __ IU/L (pubertal level) is consistent with central precocious puberty - Use of GnRH as a stimulation test can be helpful - Elevated peak LH can be diagnostic. - Bone age is typically quite advanced. - Diagnosis- confirm with elevated serum __ - Be careful how you diagnose CPP - it is very specific. - In girls, there must be ____ AND ____ involvement manifested by clinical features of both estrogen and androgen secretion - In boys, all you need is____ - Need to rule out organic CNS etiologies with an MRI of brain - As a rule, males with central precocious puberty have a ____ until proven otherwise. - Tx: - For almost all boys and girls with the rapidly progressive form of CPP, use long-acting _____ to interrupt the endogenous pulsatile GnRH from stimulating progression of sexual maturity. - Because you want to have a constant level (depot preparations work well), _____ acetate

Answer 38

CENTRAL PRECOCIOUS PUBERTY (Gonadotropin-dependent precocious puberty) - Path: Early activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in increased LH and FSH levels - CPP is much more common in girls than boys. - Approx 95% of true precocity in females are sporadic and idiopathic. - CNS pathology is much more common in boys (25-75%) with central precocious puberty than in girls - Pt: - In boys and girls, height and weight are advanced, typically with marked linear growth acceleration. - Bone maturation is accelerated, as evidenced by an advanced bone age. - Because of early closure of the epiphyses, a majority of those who do not receive tx end up being <5%ile for height. - Physical exam: - Testes are pubertal/larger in volume (>4 ml) in central precocious puberty as they are stimulated by LH. Or an increase in size in ovaries (by US) - Testicular size is an important discriminator bw central and peripheral precocious puberty in boys - Labs: Detect by pubertal LH level, basal or stimulated - LH level > 0.3 IU/L (pubertal level) is consistent with central precocious puberty - Use of GnRH as a stimulation test can be helpful - Elevated peak LH can be diagnostic. - Bone age is typically quite advanced. - Diagnosis- confirm with elevated serum LH - Be careful how you diagnose CPP - it is very specific. - In girls, there must be adrenal AND gonadal involvement manifested by clinical features of both estrogen and androgen secretion - In boys, all you need is gonadal involvement - Need to rule out organic CNS etiologies with an MRI of brain - As a rule, males with central precocious puberty have a brain tumor until proven otherwise. - Tx: - For almost all boys and girls with the rapidly progressive form of CPP, use long-acting GnRH analogs (GnRHa) to interrupt the endogenous pulsatile GnRH from stimulating progression of sexual maturity. - Because you want to have a constant level (depot preparations work well), leuprolide acetate

Question 39

Common Organic Brain Lesions Causing Central Precocious Puberty - ________ is the most common brain lesion that causes CPP. - This lesion contains ectopic neural tissue that contains GnRH-secretory neurons - Pt: - If it is a rapidly progressive precocity, hypothalamic hamartoma is the most likely etiology. - Can cause _____, frequently manifested by inappropriate laughter. - Tx: Traditional surgical intervention is not recommended for hypothalamic hamartomas, except for those pts with intractable seizures - Other lesions causing CPP include postencephalitic scars, tuberculous brain involvement, hydrocephalus, tuberous sclerosis, head trauma, and neoplasms (about 50% are germinomas or astrocytomas)

Answer 39

Common Organic Brain Lesions Causing Central Precocious Puberty - Hypothalamic hamartoma is the most common brain lesion that causes CPP. - This lesion contains ectopic neural tissue that contains GnRH-secretory neurons - Pt: - If it is a rapidly progressive precocity, hypothalamic hamartoma is the most likely etiology. - Can cause gelastic seizures, frequently manifested by inappropriate laughter. - Tx: Traditional surgical intervention is not recommended for hypothalamic hamartomas, except for those pts with intractable seizures - Other lesions causing CPP include postencephalitic scars, tuberculous brain involvement, hydrocephalus, tuberous sclerosis, head trauma, and neoplasms (about 50% are germinomas or astrocytomas)

Question 40

PERIPHERAL PRECOCIOUS PUBERTY (Gonadotropin-independent precocious puberty) - Pt: - A clue to a gonadotropin-independent cause of precocious puberty in a boy is virilization without ________ bc the testis grows from FSH stimulation. - Dx: - In girls with signs of excess exposure and in boys with prepubertal sized testes, measurement of 17-hydroxyprogesterone (for CAH), DHEA-S marker of adrenal androgen production), and testosterone (in girls) is indicated. Testicular US is indicated if a testicular tumor is suspected. Tumors - Rare tumors exist that can secrete androgen, estrogen, or gonadotropin (such as hCG), thereby causing gonadotropin-independent precocious puberty. - A boy with an hCG-secreting tumor has testicular enlargement bc the hCG acts as LH. Therefore, you can recognize an hCG-secreting tumor bc the boy has testicular enlargement with a suppressed LH level (and a detectable hCG) - The majority of tumors that cause peripheral precocious puberty are germ cell tumors.

Answer 40

PERIPHERAL PRECOCIOUS PUBERTY (Gonadotropin-independent precocious puberty) - Pt: - A clue to a gonadotropin-independent cause of precocious puberty in a boy is virilization without increase in testicular size bc the testis grows from FSH stimulation. - Dx: - In girls with signs of excess exposure and in boys with prepubertal sized testes, measurement of 17-hydroxyprogesterone (for CAH), DHEA-S marker of adrenal androgen production), and testosterone (in girls) is indicated. Testicular US is indicated if a testicular tumor is suspected. Tumors - Rare tumors exist that can secrete androgen, estrogen, or gonadotropin (such as hCG), thereby causing gonadotropin-independent precocious puberty. - A boy with an hCG-secreting tumor has testicular enlargement bc the hCG acts as LH. Therefore, you can recognize an hCG-secreting tumor bc the boy has testicular enlargement with a suppressed LH level (and a detectable hCG) - The majority of tumors that cause peripheral precocious puberty are germ cell tumors.

Question 41

McCune-Albright - Path - Due to a missense mutation in the _____ gene that encodes for the protein cAMP formation, - Any receptors that operate with a cAMP-dependent mechanism can be affected (TSH, FSH, LH, GHRH, and ACTH receptors). - Starts as GnRH independent and becomes GnRH dependent precocious puberty - Pt: - P___, p___ (cafe au lait Coast of ___) (vs “coast of California” in NF1), P____ - Usually, vaginal bleeding becomes evident by 3yo - ______, by itself, is the classic endocrine presentation for MAS in girls! - (Classic exam question is a female toddler with clearly developed breasts and a large, irregular CALM) - LH and FSH are low, and there is no response to GnRH. - Tx: Management varies depending on endocrine abnormalities present. - GnRH agonists can be used if the puberty has switched to the gonadotropin-dependent form. - For GH excess, _____ is useful. - Prognosis is good, but significant bone deformities and fractures can result from the bony lesions.

Answer 41

McCune-Albright - Path - Due to a missense mutation in the GNAS1 gene that encodes for the protein cAMP formation, - Any receptors that operate with a cAMP-dependent mechanism can be affected (TSH, FSH, LH, GHRH, and ACTH receptors). - Starts as GnRH independent and becomes GnRH dependent precocious puberty - Pt: - Precocious puberty, patchy pigmentation (cafe au lait Coast of Maine) (vs “coast of California” in NF1), Polyostotic fibrous dysplasia of the skeletal system - Usually, vaginal bleeding becomes evident by 3yo - Vaginal bleeding, by itself, is the classic endocrine presentation for MAS in girls! - (Classic exam question is a female toddler with clearly developed breasts and a large, irregular CALM) - LH and FSH are low, and there is no response to GnRH. - Tx: Management varies depending on endocrine abnormalities present. - GnRH agonists can be used if the puberty has switched to the gonadotropin-dependent form. - For GH excess, octreotide is useful. - Prognosis is good, but significant bone deformities and fractures can result from the bony lesions.

Question 42

Benign premature thelarche - Isolated breast development that occurs in the first 2 years of life. - No involvement of the adrenal glands (no body odor, pubic hair, axillary hair development, acne) - Dx: Diagnosis of exclusion - You must rule out excessive exposure to estrogen (such as estrogen cream or estrogen- or placenta-containing shampoo, ingestion of OCPs, ingestion of excessive soy products, or excessive use of lavender or tea tree oil). - Consider evaluating with an estradiol level, FSH level, LH level, and a bone age. Labs are normal for age. - Isolated premature thelarche does not require further evaluation and workup. Evidence of true puberty such as signs of adrenarche, acne, and vaginal discharge in combination with thelarche points to an increased likelihood of central precocious puberty which requires further work up. - Benign condition. Breast tissue usually persists for 3-5 years but can regress during this time. - What appears to be benign premature thelarche may be the 1st sign of actual precocious puberty, so you must follow the child. - If isolated breast development occurs after 3yo, it is almost always due to some other condition.

Answer 42

Benign premature thelarche - Isolated breast development that occurs in the first 2 years of life. - No involvement of the adrenal glands (no body odor, pubic hair, axillary hair development, acne) - Dx: Diagnosis of exclusion - You must rule out excessive exposure to estrogen (such as estrogen cream or estrogen- or placenta-containing shampoo, ingestion of OCPs, ingestion of excessive soy products, or excessive use of lavender or tea tree oil). - Consider evaluating with an estradiol level, FSH level, LH level, and a bone age. Labs are normal for age. - Isolated premature thelarche does not require further evaluation and workup. Evidence of true puberty such as signs of adrenarche, acne, and vaginal discharge in combination with thelarche points to an increased likelihood of central precocious puberty which requires further work up. - Benign condition. Breast tissue usually persists for 3-5 years but can regress during this time. - What appears to be benign premature thelarche may be the 1st sign of actual precocious puberty, so you must follow the child. - If isolated breast development occurs after 3yo, it is almost always due to some other condition.

Question 43

Benign Premature Adrenarche - Pt: - Any combination of pubic or axillary hair, body odor, or acne before 8yo in girls and before 9yo in boys. - There is no gonadal involvement (no breast development in girls and no testicular enlargement in boys). - Dx: Rule out other causes of androgen excess, which can be exogenous or endogenous. - A common cause of exogenous androgen exposure is accidental exposure. - An example is when an adult male in the family uses transdermal androgen gel for testosterone replacement - Endogenous causes of premature adrenarche include tumors or late-onset congenital adrenal hyperplasia. - Evaluation: Measure testosterone, DHEAS, androstenedione, 17-OHP, and bone age - If any of the screening tests are abnormal, the pt must be evaluated for pathological conditions including late-onset CAH and adrenal tumors.

Answer 43

Benign Premature Adrenarche - Pt: - Any combination of pubic or axillary hair, body odor, or acne before 8yo in girls and before 9yo in boys. - There is no gonadal involvement (no breast development in girls and no testicular enlargement in boys). - Dx: Rule out other causes of androgen excess, which can be exogenous or endogenous. - A common cause of exogenous androgen exposure is accidental exposure. - An example is when an adult male in the family uses transdermal androgen gel for testosterone replacement - Endogenous causes of premature adrenarche include tumors or late-onset congenital adrenal hyperplasia. - Evaluation: Measure testosterone, DHEAS, androstenedione, 17-OHP, and bone age - If any of the screening tests are abnormal, the pt must be evaluated for pathological conditions including late-onset CAH and adrenal tumors.

Question 44

Premature Menarche - Pt: Most girls have only 1-3 episodes of bleeding; then puberty occurs at the normal time, and subsequent menstrual cycles are normal - In a child with isolated vaginal bleeding, first rule out more common causes such as foreign body, vulvovaginitis, or sexual abuse.

Answer 44

Premature Menarche - Pt: Most girls have only 1-3 episodes of bleeding; then puberty occurs at the normal time, and subsequent menstrual cycles are normal - In a child with isolated vaginal bleeding, first rule out more common causes such as foreign body, vulvovaginitis, or sexual abuse.

Question 45

There is no such thing as benign premature testelarche! - If you see a boy <9yo with enlarged testes, the pt has a 27-75% chance of having a brain tumor. Order a brain MRI promptly!

Answer 45

There is no such thing as benign premature testelarche! - If you see a boy <9yo with enlarged testes, the pt has a 27-75% chance of having a brain tumor. Order a brain MRI promptly!

Question 46

Pubertal Gynecomastia - Occurs at puberty. Reaching peak prevalence at 14yo and SMR stages 2-3 or 3-4. - Is a very specific diagnosis - you must evaluate pubertal status with a genital exam prior to diagnosing pubertal gynecomastia. If you diagnosed pubertal gynecomastia, the pt must be in puberty! - Can occur in boys in SMR genital Stage 2, 3, or 4 puberty. - If they are Stage __ or Stage ___, this is abnormal and requires evaluation! - Tx: - Breast size almost always reduces in a few months but can persist for up to __ years. No further workup or treatment but should be followed in subsequent exams. - Pubertal gynecomastia generally measures <4cm and does not require specific workup or therapy - Gynecomastia measuring >___cm (similar to SMR 2-3 female) commonly does not regress.

Answer 46

Pubertal Gynecomastia - Occurs at puberty. Reaching peak prevalence at 14yo and SMR stages 2-3 or 3-4. - Is a very specific diagnosis - you must evaluate pubertal status with a genital exam prior to diagnosing pubertal gynecomastia. If you diagnosed pubertal gynecomastia, the pt must be in puberty! - Can occur in boys in SMR genital Stage 2, 3, or 4 puberty. - If they are Stage 1 or Stage 5, this is abnormal and requires evaluation! - Tx: - Breast size almost always reduces in a few months but can persist for up to 2 years. No further workup or treatment but should be followed in subsequent exams. - Pubertal gynecomastia generally measures <4cm and does not require specific workup or therapy - Gynecomastia measuring >5cm (similar to SMR 2-3 female) commonly does not regress.

Question 47

Pathologic gynecomastia - Occurs in pts who are SMR genital Stage 1 or 5 and who have an abnormal estrogen:testosterone ratio - Evaluate any boy who falls outside of the normal pubertal gynecomastia diagnosis. This includes - Atypical SMR genital stage (1 or 5) - Atypical age (<10 or >16yo) - Chronic illness of liver, thyroid, or renal - Abnormal pubertal progression - Pts requesting surgery - Pts with macrogynecomastia (breast sizes greater than SMR 3), which does not resolve with time - Evaluation - Estradiol, estrone, testosterone, DHEAS, LH to rule out an LH-secreting tumor, and hCG to screen for a germ cell tumor.

Answer 47

Pathologic gynecomastia - Occurs in pts who are SMR genital Stage 1 or 5 and who have an abnormal estrogen:testosterone ratio - Evaluate any boy who falls outside of the normal pubertal gynecomastia diagnosis. This includes - Atypical SMR genital stage (1 or 5) - Atypical age (<10 or >16yo) - Chronic illness of liver, thyroid, or renal - Abnormal pubertal progression - Pts requesting surgery - Pts with macrogynecomastia (breast sizes greater than SMR 3), which does not resolve with time - Evaluation - Estradiol, estrone, testosterone, DHEAS, LH to rule out an LH-secreting tumor, and hCG to screen for a germ cell tumor.

Question 48

Thyroxine-binding globulin (TBG) - Increased TBG can cause a clinically irrelevant and often incidentally found high TOTAL T4, and decreased TBG can similarly cause low TOTAL T4 - 2 common clinical scenarios and possible questions: - 1) Newborn boy with TBG deficiency fails the newborn screen with a low total T4. What to do? These pts are euthyroid and have a normal free T4 and a normal TSH and so do not require levothyroxine. No further follow-up is indicated. Occasionally, there is an affected brother due to the X-linked inheritance of this condition. - 2) A teenage girl has an elevated total T4 on labs but is not clinically hyperthyroid. What to know? This may be due to OCPs with resultant elevated estrogen causing an increase in TBG. If so, labs will show a high T4 but a normal free T4 and a normal TSH. These pts are clinically euthyroid and do not require medication.

Answer 48

Thyroxine-binding globulin (TBG) - Increased TBG can cause a clinically irrelevant and often incidentally found high TOTAL T4, and decreased TBG can similarly cause low TOTAL T4 - 2 common clinical scenarios and possible questions: - 1) Newborn boy with TBG deficiency fails the newborn screen with a low total T4. What to do? These pts are euthyroid and have a normal free T4 and a normal TSH and so do not require levothyroxine. No further follow-up is indicated. Occasionally, there is an affected brother due to the X-linked inheritance of this condition. - 2) A teenage girl has an elevated total T4 on labs but is not clinically hyperthyroid. What to know? This may be due to OCPs with resultant elevated estrogen causing an increase in TBG. If so, labs will show a high T4 but a normal free T4 and a normal TSH. These pts are clinically euthyroid and do not require medication.

Question 49

Interpretation of thyroid function studies - High TSH - Low Free T4 - Primary hypothyroidism - Normal Free T4 - Compensated/subclinical hypothyroidism - High Free T4 - Pituitary resistant hyperthyroidism; nonadherence to thyroid hormone replacement with recent adherence - Low TSH - High Free T4 - Hyperthyroidism - Normal Free T4 - Incipient / Subclinical hyperthyroidism - Low Free T4 - Secondary / Central hypothyroidism

Answer 49

Interpretation of thyroid function studies - High TSH - Low Free T4 - Primary hypothyroidism - Normal Free T4 - Compensated/subclinical hypothyroidism - High Free T4 - Pituitary resistant hyperthyroidism; nonadherence to thyroid hormone replacement with recent adherence - Low TSH - High Free T4 - Hyperthyroidism - Normal Free T4 - Incipient / Subclinical hyperthyroidism - Low Free T4 - Secondary / Central hypothyroidism

Question 50

Drugs and conditions that affect thyroid function - Increased TBG - Estrogen: Supplements, OCP, pregnancy - Tamoxifen, clofibrate, narcotics (heroin), hepatitis, biliary cirrhosis - Decreased TBG - Androgens - Glucocorticoids - Nephrotic syndrome - Inherited TBG deficiency - Slow release nicotine - Blocks peripheral conversion of T4 to T3 - Propranolol - Glucocorticoids - Propylthiouracil - Amiodarone

Answer 50

Drugs and conditions that affect thyroid function - Increased TBG - Estrogen: Supplements, OCP, pregnancy - Tamoxifen, clofibrate, narcotics (heroin), hepatitis, biliary cirrhosis - Decreased TBG - Androgens - Glucocorticoids - Nephrotic syndrome - Inherited TBG deficiency - Slow release nicotine - Blocks peripheral conversion of T4 to T3 - Propranolol - Glucocorticoids - Propylthiouracil - Amiodarone

Question 51

``` Radioiodine uptake (RAIU) - Useful in differentiating nonpituitary thyrotoxic states (low TSH, high free thyroxine) ``` - Has NO use in diagnosing causes of hypothyroidism - RAIU is increased in association with: - Graves disease - Hot nodules (eg multinodular goiter, toxic solitary nodule, hCG-secreting tumor) - RAIU is decreased in association with: - Self-limited, thyroiditis-induced thyrotoxic states (painless chronic thyroiditis, postpartum thyroiditis, subacute, thyroiditis, and the potential hyperthyroid phase of Hashimotor’s) - Thyroiditis factitia - Amiodarone - RAIU is low bc the thyroid is already saturated with iodine prior to the 123I dose.

Answer 51

``` Radioiodine uptake (RAIU) - Useful in differentiating nonpituitary thyrotoxic states (low TSH, high free thyroxine) ``` - Has NO use in diagnosing causes of hypothyroidism - RAIU is increased in association with: - Graves disease - Hot nodules (eg multinodular goiter, toxic solitary nodule, hCG-secreting tumor) - RAIU is decreased in association with: - Self-limited, thyroiditis-induced thyrotoxic states (painless chronic thyroiditis, postpartum thyroiditis, subacute, thyroiditis, and the potential hyperthyroid phase of Hashimotor’s) - Thyroiditis factitia - Amiodarone - RAIU is low bc the thyroid is already saturated with iodine prior to the 123I dose.

Question 52

Thyroid scan (aka scintiscan or radionuclide scan) - The thyroid scan is used only for nodular disease - in determining whether a nodule is hot (functioning) or cold (nonfunctioning). - On a thyroid scan, cold nodules are more likely to be malignant than hot nodules. Thyroid scan produces a picture

Answer 52

Thyroid scan (aka scintiscan or radionuclide scan) - The thyroid scan is used only for nodular disease - in determining whether a nodule is hot (functioning) or cold (nonfunctioning). - On a thyroid scan, cold nodules are more likely to be malignant than hot nodules. Thyroid scan produces a picture

Question 53

Tests for evaluation of symmetric goiter - Hypothyroid - Free T4, TSH, ATA, Anti-TPO - Hyperthyroid - Free T4, TSH, ATA, Anti-TPO, TSI - Euthyroid - Free T4, TSH, ATA, Anti-TPO

Answer 53

Tests for evaluation of symmetric goiter - Hypothyroid - Free T4, TSH, ATA, Anti-TPO - Hyperthyroid - Free T4, TSH, ATA, Anti-TPO, TSI - Euthyroid - Free T4, TSH, ATA, Anti-TPO

Question 54

Congenital Hypothyroidism - Path: - Thyroid dysgenesis (including dysgenesis, agenesis, and ectopic thyroid) is the most common cause (90%) - Note that thyroid dysgenesis and inadvertent administration of radioiodine during pregnancy are causes of permanent hypothyroidism. - Or rarely 2nd most prevalent cause is dyshormonogenesis (defect in intrathyroid metabolism and hormone production). - Transient congenital hypothyroidism occurs in geographic regions with endemic iodine deficiency when the mother, and consequently the fetus, are iodine deficient. - Another cause is central hypothyroidism (hypopituitarism), which would not be detected by newborn screens that use TSH detection methodology. - Transient hypothyroidism can occur with excess iodine exposure (topical betadine for a procedure) causing suppression of the thyroid gland (Wolff-Chaikoff effect), with maternal thyroid hormone receptors blocking antibodies that are are associated with Graves disease (transplacentally passed), or with anti-thyroid medication (taken for maternal Graves disease) - Transient hypothyroidism persists until the antibody disappears, typically by 3 months of age. - Maternal Hashimoto thyroiditis does NOT cause congenital hypothyroidism - Pt: - Most infants appear normal/asymptomatic at birth (as there is some placental transfer of maternal thyroxine T4). However, this vertical transmission of thyroxine provides only 33% of normal levels; so, neonatal screening still finds a high TSH and a low T4. - If symptoms are present, large anterior fontanelle, large posterior fontanelle, prolonged jaundice, umbilical hernia. - Look particularly for an enlarged posterior fontanelle. Only 3% of normal infants have an opening wider than 0.5cm. - Dentition is delayed, and the tongue is large and thick. - Myxedema - Present during the 1st month of life with feeding problems, sluggishness, lack of interest, choking spells when nursing, somnolence, respiratory difficulties caused by enlargement of the tongue due to myxedema, and constipation. - Developmental delay - Most children have hypotonic muscles, but a few have pseudohypertrophy, known as Kocher-Debre-Semelaigne syndrome - Bone maturation is slowed, and this is demonstrated on XR in about 60% of those affected - A good example is the distal femoral epiphysis, which is normally present at birth. In hypothyroid infants, it is absent. - Screening for all states: TSH with reflex to total T4 or T4 with reflex to TSH - Newborn screening is important for detecting congenital hypothyroidism bc neonates are often asymptomatic due to placental passage of some maternal thyroid hormone. - Goal of screening programs is to identify children with neonatal hypothyroidism early and to begin tx as close to 2 weeks of age as possible. - The ideal time for screening for congenital hypothyroidism is day 3 (but most babies are home by then). - Dx: low T4 and high TSH. When TSH >40 mIU/L on filter paper newborn screening, confirmatory venous TSH and free thyroxine should be drawn - Thyroid scan can be used to pinpoint the underlying absence of thyroid tissue or to locate ectopic thyroid. - Be aware there are 2 other conditions in which a scan showing no thyroid tissue is possible: - 1) In neonates with a blocking TSH-receptor antibody (similar to neonatal Graves’ but blocking instead of stimulating) - 2) With an iodine-trapping defect - These are both rare conditions. A thyroid US shows thyroid tissue in these settings. - Tx: If filter paper TSH is >40 mIU/L, Start on thyroid replacement therapy levothyroxine immediately - When tx is initiated within 1mo or less after birth, the prognosis is normal intellectual development is excellent - Do NOT give T3 and do NOT give liquid preparations - stable thyroxine liquid preparations are not consistently reliable in the commercial US markets - give tablets only! - Levothyroxine is best absorbed in a fasted state; many foods decrease its absorption, esp those high in dietary fiber - Prognosis: - Is good for those started on replacement therapy in the first few weeks of life. - About 20%, however, have a neurosensory hearing deficit. - Without therapy, affected infants progress to global developmental delay with significantly poor linear growth. Affected infants <3yo lose IQ points for every week they are not treated.

Answer 54

Congenital Hypothyroidism - Path: - Thyroid dysgenesis (including dysgenesis, agenesis, and ectopic thyroid) is the most common cause (90%) - Note that thyroid dysgenesis and inadvertent administration of radioiodine during pregnancy are causes of permanent hypothyroidism. - Or rarely 2nd most prevalent cause is dyshormonogenesis (defect in intrathyroid metabolism and hormone production). - Transient congenital hypothyroidism occurs in geographic regions with endemic iodine deficiency when the mother, and consequently the fetus, are iodine deficient. - Another cause is central hypothyroidism (hypopituitarism), which would not be detected by newborn screens that use TSH detection methodology. - Transient hypothyroidism can occur with excess iodine exposure (topical betadine for a procedure) causing suppression of the thyroid gland (Wolff-Chaikoff effect), with maternal thyroid hormone receptors blocking antibodies that are are associated with Graves disease (transplacentally passed), or with anti-thyroid medication (taken for maternal Graves disease) - Transient hypothyroidism persists until the antibody disappears, typically by 3 months of age. - Maternal Hashimoto thyroiditis does NOT cause congenital hypothyroidism - Pt: - Most infants appear normal/asymptomatic at birth (as there is some placental transfer of maternal thyroxine T4). However, this vertical transmission of thyroxine provides only 33% of normal levels; so, neonatal screening still finds a high TSH and a low T4. - If symptoms are present, large anterior fontanelle, large posterior fontanelle, prolonged jaundice, umbilical hernia. - Look particularly for an enlarged posterior fontanelle. Only 3% of normal infants have an opening wider than 0.5cm. - Dentition is delayed, and the tongue is large and thick. - Myxedema - Present during the 1st month of life with feeding problems, sluggishness, lack of interest, choking spells when nursing, somnolence, respiratory difficulties caused by enlargement of the tongue due to myxedema, and constipation. - Developmental delay - Most children have hypotonic muscles, but a few have pseudohypertrophy, known as Kocher-Debre-Semelaigne syndrome - Bone maturation is slowed, and this is demonstrated on XR in about 60% of those affected - A good example is the distal femoral epiphysis, which is normally present at birth. In hypothyroid infants, it is absent. - Screening for all states: TSH with reflex to total T4 or T4 with reflex to TSH - Newborn screening is important for detecting congenital hypothyroidism bc neonates are often asymptomatic due to placental passage of some maternal thyroid hormone. - Goal of screening programs is to identify children with neonatal hypothyroidism early and to begin tx as close to 2 weeks of age as possible. - The ideal time for screening for congenital hypothyroidism is day 3 (but most babies are home by then). - Dx: low T4 and high TSH. When TSH >40 mIU/L on filter paper newborn screening, confirmatory venous TSH and free thyroxine should be drawn - Thyroid scan can be used to pinpoint the underlying absence of thyroid tissue or to locate ectopic thyroid. - Be aware there are 2 other conditions in which a scan showing no thyroid tissue is possible: - 1) In neonates with a blocking TSH-receptor antibody (similar to neonatal Graves’ but blocking instead of stimulating) - 2) With an iodine-trapping defect - These are both rare conditions. A thyroid US shows thyroid tissue in these settings. - Tx: If filter paper TSH is >40 mIU/L, Start on thyroid replacement therapy levothyroxine immediately - When tx is initiated within 1mo or less after birth, the prognosis is normal intellectual development is excellent - Do NOT give T3 and do NOT give liquid preparations - stable thyroxine liquid preparations are not consistently reliable in the commercial US markets - give tablets only! - Levothyroxine is best absorbed in a fasted state; many foods decrease its absorption, esp those high in dietary fiber - Prognosis: - Is good for those started on replacement therapy in the first few weeks of life. - About 20%, however, have a neurosensory hearing deficit. - Without therapy, affected infants progress to global developmental delay with significantly poor linear growth. Affected infants <3yo lose IQ points for every week they are not treated.

Question 55

Acquired Hypothyroidism - Path: Many pts have high levels of circulating antithyroid antibodies - ____ antibody and _____ usually indicate hypothyroidism - Causes: - Most common cause is autoimmune thyroiditis - Pt: - Weight for age is proportionately greater than height for age. - ____ is a hallmark - growth practically ceases! - ____, which is a fracture of the growth plate in the femoral head, is associated with any disorder that slows or speeds up growth, and hypothyroidism is such a disorder. - Dx: - Expect a high TSH and a low free T4 with hypothyroidism due to a thyroid deficiency state. - Low TSH and low free T4 levels indicate either a hypothalamic problem (tertiary hypothyroidism) or a pituitary problem (secondary hypothyroidism) - Tx: L-thyroxine

Answer 55

Acquired Hypothyroidism - Path: Many pts have high levels of circulating antithyroid antibodies (antithyroglobulin antibody and antithyroperoxidase antibody) - Thyroid peroxidase antibody and antithyroglobulin usually indicate hypothyroidism - Causes: - Most common cause is autoimmune thyroiditis - Pt: - Weight for age is proportionately greater than height for age. - Growth failure is a hallmark - growth practically ceases! - SCFE, which is a fracture of the growth plate in the femoral head, is associated with any disorder that slows or speeds up growth, and hypothyroidism is such a disorder. - Dx: - Expect a high TSH and a low free T4 with hypothyroidism due to a thyroid deficiency state. - Low TSH and low free T4 levels indicate either a hypothalamic problem (tertiary hypothyroidism) or a pituitary problem (secondary hypothyroidism) - Tx: L-thyroxine

Question 56

Chronic Autoimmune Thyroiditis (Hashimoto disease or chronic lymphocytic thyroiditis) - Hashimoto thyroiditis is the most common cause of acquired hypothyroidism and the most common cause of thyroid enlargement in children >6yo. - Occurs with the increased frequency in children with ______ - Pt: - Can occur with normal thyroid function - Hashitoxicosis: - 5-10% of children with autoimmune thyroiditis develop tachycardia, nervousness, and other signs of thyroid excess with elevations in free T4 and suppression of TSH early in the course of illness. - But in most adolescents, this phase does not develop or goes unnoticed, and they present initially with euthyroid goiter or goiter with mild hypothyroidism. - Poor linear growth, mild weight gain, relative bradycardia, and delayed return of deep tendon reflexes. - A firm rubbery enlarged thyroid gland with heterogeneous texture is typical of Hashimoto thyroiditis. - Associations: - Annually screen all children with ______ for autoimmune thyroid disease. - Also appears with increased incidence in pts with trisomy 21, Turner syndrome, or Klinefelter syndrome. - Dx: - Elevated TSH is the best initial test - Most pts have antithyroperoxidase antibodies and anti-thyroglobulin antibodies. - Be aware that these are not specific to autoimmune thyroiditis and can also develop in Graves’ and in normal individuals. Still, consider Hashimoto disease in pts with these antibodies - esp if there is a family hx of thyroid disease. - Biopsy confirms the diagnosis and shows lymphocytes, but it is rarely indicated. - Tx: - Levothyroxine replacement - Use FNA to biopsy a nodule that remains prominent bc thyroid cancer has developed in pts with autoimmune thyroiditis.

Answer 56

Chronic Autoimmune Thyroiditis (Hashimoto disease or chronic lymphocytic thyroiditis) - Hashimoto thyroiditis is the most common cause of acquired hypothyroidism and the most common cause of thyroid enlargement in children >6yo. - Occurs with the increased frequency in children with Trisomy 21 - Pt: - Can occur with normal thyroid function - Hashitoxicosis: - 5-10% of children with autoimmune thyroiditis develop tachycardia, nervousness, and other signs of thyroid excess with elevations in free T4 and suppression of TSH early in the course of illness. - But in most adolescents, this phase does not develop or goes unnoticed, and they present initially with euthyroid goiter or goiter with mild hypothyroidism. - Poor linear growth, mild weight gain, relative bradycardia, and delayed return of deep tendon reflexes. - A firm rubbery enlarged thyroid gland with heterogeneous texture is typical of Hashimoto thyroiditis. - Associations: - Annually screen all children with Type 1 diabetes for autoimmune thyroid disease. - Also appears with increased incidence in pts with trisomy 21, Turner syndrome, or Klinefelter syndrome. - Dx: - Elevated TSH is the best initial test - Most pts have antithyroperoxidase antibodies and anti-thyroglobulin antibodies. - Be aware that these are not specific to autoimmune thyroiditis and can also develop in Graves’ and in normal individuals. Still, consider Hashimoto disease in pts with these antibodies - esp if there is a family hx of thyroid disease. - Biopsy confirms the diagnosis and shows lymphocytes, but it is rarely indicated. - Tx: - Levothyroxine replacement - Use FNA to biopsy a nodule that remains prominent bc thyroid cancer has developed in pts with autoimmune thyroiditis.

Question 57

Low T3 Syndrome (Nonthyroidal illness) (aka “____ sick”) - Low T3 syndrome occurs in critically ill pts (such as DKA) and in anorexia nervosa. - Path: T4 is converted into inactive reverse T3 instead of the biologically active T3, likely as a way to conserve proteins from metabolism in times of severe stress. - Pt has low total and free T3, normal/low total T4, low/normal/high free T4, and normal TSH. - ________ is used to confirm the diagnosis - Tx directed at primary illness. No replacement of T3 or T4 is necessary.

Answer 57

Low T3 Syndrome (Nonthyroidal illness) (aka “Euthyroid sick”) - Low T3 syndrome occurs in critically ill pts (such as DKA) and in anorexia nervosa. - Path: T4 is converted into inactive reverse T3 instead of the biologically active T3, likely as a way to conserve proteins from metabolism in times of severe stress. - Pt has low total and free T3, normal/low total T4, low/normal/high free T4, and normal TSH. - Reverse T3 is used to confirm the diagnosis - Tx directed at primary illness. No replacement of T3 or T4 is necessary.

Question 58

Subacute (de Quervain) Thyroiditis - Self-limited inflammation of the thyroid, typically following a URI - Pt: - Fever, thyroid gland pain, tenderness - Labs - Initially, there are signs and symptoms of ___thyroidism, with release of T4 and T3 from the damaged gland. This is usually followed by a more prolonged period of hypothyroidism.

Answer 58

Subacute (de Quervain) Thyroiditis - Self-limited inflammation of the thyroid, typically following a URI - Pt: - Fever, thyroid gland pain, tenderness - Labs - Initially, there are signs and symptoms of hyperthyroidism, with release of T4 and T3 from the damaged gland. This is usually followed by a more prolonged period of hypothyroidism.

Question 59

Suppurative Thyroiditis - Bacterial infection of the thyroid gland - Most common organisms are Staph aureus, Strep pyogenes, and Strep pneumoniae. - Thyroid function tests are normal. - Can be difficult to differentiate from subacute thyroiditis, but hyperthyroidism is uncommon, pts tend to be more ill-appearing, and the duration of illness is usually only 2-4 weeks. - Tx with antibiotics aimed at the primary cause.

Answer 59

Suppurative Thyroiditis - Bacterial infection of the thyroid gland - Most common organisms are Staph aureus, Strep pyogenes, and Strep pneumoniae. - Thyroid function tests are normal. - Can be difficult to differentiate from subacute thyroiditis, but hyperthyroidism is uncommon, pts tend to be more ill-appearing, and the duration of illness is usually only 2-4 weeks. - Tx with antibiotics aimed at the primary cause.

Question 60

Myxedema Coma - Very rare, is a medical emergency - Severe _______ leading to slowing of multiple organ functions. - Pt: - Diminished mental status and hypothermia. - Hypotension, bradycardia, hypoglycemia, hyponatremia. - Tx: Thyroid hormone, glucocorticoids

Answer 60

Myxedema Coma - Very rare, is a medical emergency - Severe hypothyroidism leading to slowing of multiple organ functions. - Pt: - Diminished mental status and hypothermia. - Hypotension, bradycardia, hypoglycemia, hyponatremia. - Tx: Thyroid hormone, glucocorticoids

Question 61

Thyroid-Binding Globulin (TBG) deficiency - Inherited in X-linked manner - Pt: Clinically euthyroid. - It is important to identify these children so they are NOT tx with thyroxine! - Labs: TSH level normal, Total thyroxine (T4) level is low. Free T4 level normal. TBG level, if measured, would be low. - Dx: Confirm by measuring a TBG level.

Answer 61

Thyroid-Binding Globulin (TBG) deficiency - Inherited in X-linked manner - Pt: Clinically euthyroid. - It is important to identify these children so they are NOT tx with thyroxine! - Labs: TSH level normal, Total thyroxine (T4) level is low. Free T4 level normal. TBG level, if measured, would be low. - Dx: Confirm by measuring a TBG level.

Question 62

HYPERTHYROIDISM - Dx: Low TSH and elevated free T4 and T3 levels - Elevated ______ / thyrotropin receptor antibodies confirms Graves disease (90% patients)

Answer 62

HYPERTHYROIDISM - Dx: Low TSH and elevated free T4 and T3 levels - Elevated thyroid-stimulating immunoglobulins (TSI) / thyrotropin receptor antibodies confirms Graves disease (90% patients)

Question 63

(Juvenile) Graves Disease - Most common cause of hyperthyroidism and thyrotoxicosis in children and adolescents. Girls are more frequently affected. - Path: TSH receptor-stimulating antibodies (TSI; TSHR-Ab), which activate TSH receptors in the thyroid gland, causing increased production of thyroid hormones. - Pt: - Children with thyrotoxicosis present with muscle weakness as well as increasing anxiety, palpitations, and appetite - Many have weight loss, but some have weight increase. - Behavior problems (which can be mistaken for ADHD), declining school performance, and decreased exercise tolerance are common. - Frequently have cardiac signs/symptoms by the time of diagnosis, with cardiomegaly, tachycardia, widened pulse pressure (or frank HTN), and gallop rhythms. - Remember to listen for a thyroid bruit; it is heard in 50% of pts with hyperthyroidism - Tremor, excessive perspiration, and rapid tendon reflex relaxation times are also possible. - Labs - First do a serum TSH, free T4, and T3 to confirm hyperthyroidism - The serum TSH should be suppressed below the limit of detection. - Then, measure TSI (thyrotropin receptor antibodies) / thyroid receptor antibodies to confirm Graves’ as the etiology

Answer 63

(Juvenile) Graves Disease - Most common cause of hyperthyroidism and thyrotoxicosis in children and adolescents. Girls are more frequently affected. - Path: TSH receptor-stimulating antibodies (TSI; TSHR-Ab), which activate TSH receptors in the thyroid gland, causing increased production of thyroid hormones. - Pt: - Children with thyrotoxicosis present with muscle weakness as well as increasing anxiety, palpitations, and appetite - Many have weight loss, but some have weight increase. - Behavior problems (which can be mistaken for ADHD), declining school performance, and decreased exercise tolerance are common. - Frequently have cardiac signs/symptoms by the time of diagnosis, with cardiomegaly, tachycardia, widened pulse pressure (or frank HTN), and gallop rhythms. - Remember to listen for a thyroid bruit; it is heard in 50% of pts with hyperthyroidism - Tremor, excessive perspiration, and rapid tendon reflex relaxation times are also possible. - Labs - First do a serum TSH, free T4, and T3 to confirm hyperthyroidism - The serum TSH should be suppressed below the limit of detection. - Then, measure TSI (thyrotropin receptor antibodies) / thyroid receptor antibodies to confirm Graves’ as the etiology

Question 64

(Juvenile) Graves Disease - Tx: - Aimed at 2 actions: - 1) Blunting the toxic effects of the circulating T4/T3 - _______ are useful for - Controlling many of the manifestations of Graves’ until the thyroid can be “turned off” - Preventing “thyroid storm” when administered preoperatively for surgical maneuvers that can cause massive leakage of thyroid hormones into the circulation. - 2) Stopping further increased production of T4/T3 - 3 ways: - 1) Ablation of the thyroid with radioactive iodine - Some specialists are using it as the preferred initial therapy. - 2) Surgical thyroidectomy - Biggest concerns are post-op hypoparathyroidism and recurrent laryngeal nerve damage - 3) Blocking thyroid hormone biosynthesis with drugs - Both ____ and ____ - However, bc of increased risk of ____ and death, the FDA recommends against using PTU in pediatric pts - unless they cannot tolerate methimazole. - Side effects: - Skin rashes are the most common side effect of these drugs, whereas ____ is the most worrisome side effect. - Counsel pts to go to the ED immediately with occurrence of a sore throat and mouth ulcers; this can indicate agranulocytosis, which needs immediate attention!

Answer 64

(Juvenile) Graves Disease - Tx: - Aimed at 2 actions: - 1) Blunting the toxic effects of the circulating T4/T3 - Beta-blockers are useful for - Controlling many of the manifestations of Graves’ until the thyroid can be “turned off” - Preventing “thyroid storm” when administered preoperatively for surgical maneuvers that can cause massive leakage of thyroid hormones into the circulation. - 2) Stopping further increased production of T4/T3 - 3 ways: - 1) Ablation of the thyroid with radioactive iodine - Some specialists are using it as the preferred initial therapy. - 2) Surgical thyroidectomy - Biggest concerns are post-op hypoparathyroidism and recurrent laryngeal nerve damage - 3) Blocking thyroid hormone biosynthesis with drugs - Both methimazole and propylthiouracil (PTU) - However, bc of increased risk of hepatotoxicity and death, the FDA recommends against using PTU in pediatric pts - unless they cannot tolerate methimazole. - Side effects: - Skin rashes are the most common side effect of these drugs, whereas \granulocytopenia is the most worrisome side effect. - Counsel pts to go to the ED immediately with occurrence of a sore throat and mouth ulcers; this can indicate agranulocytosis, which needs immediate attention!

Question 65

Neonatal Graves / Neonatal Thyrotoxicosis - Path: Transplacental passage of maternal TSH receptor stimulating immunoglobulin (TSI / thyroid-stimulating immunoglobulins aka thyrotropin receptor antibodies) acting at the baby’s thyroid gland. - It is the maternal level of TSI, not her thyroid function tests, that correlates with the risk and severity of thyrotoxicosis in the infant. - Remember, the TSI may never go away, even with definitive therapy for Graves’ (ie surgery or radioactive iodine ablation). So, if you are called to a delivery for a baby whose mom is on levothyroxine, always ask: Why? If it is due to Graves disease, even though mom was ablated years before, the TSI may still be in her system and is being transferred to her baby! - Pt: - Death rates approach 25% due to high-output cardiac failure. - Dx: Finding high levels of total T4, free T4, T3, and TSI in postnatal blood is the diagnostic factor. TSH is low. - Low TSH and elevated free T4 and T3 levels - Elevated _____ confirms Graves disease - Tx: - 1st line is ______ - Add propranolol (1-2mg/kg/day divided into 2-4 doses) if sympathetic overstimulation is severe. Are used as adjunctive therapy until symptoms of hyperthyroidism are controlled. - Iodine is also often used, bc it rapidly inhibits hormone release

Answer 65

Neonatal Graves / Neonatal Thyrotoxicosis - Path: Transplacental passage of maternal TSH receptor stimulating immunoglobulin (TSI / thyroid-stimulating immunoglobulins aka thyrotropin receptor antibodies) acting at the baby’s thyroid gland. - It is the maternal level of TSI, not her thyroid function tests, that correlates with the risk and severity of thyrotoxicosis in the infant. - Remember, the TSI may never go away, even with definitive therapy for Graves’ (ie surgery or radioactive iodine ablation). So, if you are called to a delivery for a baby whose mom is on levothyroxine, always ask: Why? If it is due to Graves disease, even though mom was ablated years before, the TSI may still be in her system and is being transferred to her baby! - Pt: - Death rates approach 25% due to high-output cardiac failure. - Dx: Finding high levels of total T4, free T4, T3, and TSI in postnatal blood is the diagnostic factor. TSH is low. - Low TSH and elevated free T4 and T3 levels - Elevated thyroid-stimulating immunoglobulins (TSI) / thyrotropin receptor antibodies confirms Graves disease - Tx: - 1st line is Methimazole - Add propranolol (1-2mg/kg/day divided into 2-4 doses) if sympathetic overstimulation is severe. Are used as adjunctive therapy until symptoms of hyperthyroidism are controlled. - Iodine is also often used, bc it rapidly inhibits hormone release

Question 66

Thyroid Nodules - The vast majority (90%) of thyroid nodules are benign and, on average, only 10% are malignant. About 50% of solitary thyroid nodules are cystic lesions or benign adenomas. - Of those that are cancerous, >90% are well-differentiated follicular carcinoma. - About 26% of thyroid nodules in children and adolescents are malignant (vs 5% on adults) - Evaluation - 1) Order thyroid ultrasonography, which is the preferred imaging modality for thyroid nodules. Tells you solid vs cystic. - 2) Check TSH, to see if nodule is hyperfunctioning - If TSH is suppressed, thyroid uptake scan (nuclear thyroid scintigraphy) to evaluate if the nodule is hyperfunctioning / a hot nodule vs cold. - 3) If nodule is present and not hyperfunctioning, do FNA under US guidance, which is the most definitive test or the best test to determine the cause of the nodule. Will give cause and diagnosis of cancer if present. - Indications for FNA: nodule >__cm - _____ is best option to establish diagnosis - 4) If the FNA is: - Benign: repeat US in 6-12 months - Inadequate or nondiagnostic: repeat US and FNA in 3-6 months - Indeterminate or suspicious: perform surgery - If pt with a thyroid nodule has a total thyroidectomy, follow _____ level bc this is a reliable tumor marker.

Answer 66

Thyroid Nodules - The vast majority (90%) of thyroid nodules are benign and, on average, only 10% are malignant. About 50% of solitary thyroid nodules are cystic lesions or benign adenomas. - Of those that are cancerous, >90% are well-differentiated follicular carcinoma. - About 26% of thyroid nodules in children and adolescents are malignant (vs 5% on adults) - Evaluation - 1) Order thyroid ultrasonography, which is the preferred imaging modality for thyroid nodules. Tells you solid vs cystic. - 2) Check TSH, to see if nodule is hyperfunctioning - If TSH is suppressed, thyroid uptake scan (nuclear thyroid scintigraphy) to evaluate if the nodule is hyperfunctioning / a hot nodule vs cold. - 3) If nodule is present and not hyperfunctioning, do FNA under US guidance, which is the most definitive test or the best test to determine the cause of the nodule. Will give cause and diagnosis of cancer if present. - Indications for FNA: nodule >1cm - Fine needle aspiration is best option to establish diagnosis - 4) If the FNA is: - Benign: repeat US in 6-12 months - Inadequate or nondiagnostic: repeat US and FNA in 3-6 months - Indeterminate or suspicious: perform surgery - If pt with a thyroid nodule has a total thyroidectomy, follow thyroglobulin level bc this is a reliable tumor marker.

Question 67

Thyroid Cancer - Thyroid cancer occurs in about 26% of thyroid nodules in children and adolescents - A solitary nodule in the first 20 years of life is much more likely to be malignant than in an older person. - Risk factors/symptoms of thyroid cancer include: - Hx of radiation to the neck or head - A solitary nodule >1cm with fixed, hard, and/or irregular borders - A solitary nodule with calcifications - A family hx of MEN - Rapidly growing nodule that is firm or hard - Satellite lymph nodes - Hoarseness or dysphagia - Evidence of distant metastasis

Answer 67

Thyroid Cancer - Thyroid cancer occurs in about 26% of thyroid nodules in children and adolescents - A solitary nodule in the first 20 years of life is much more likely to be malignant than in an older person. - Risk factors/symptoms of thyroid cancer include: - Hx of radiation to the neck or head - A solitary nodule >1cm with fixed, hard, and/or irregular borders - A solitary nodule with calcifications - A family hx of MEN - Rapidly growing nodule that is firm or hard - Satellite lymph nodes - Hoarseness or dysphagia - Evidence of distant metastasis

Question 68

____ - Most common thyroid cancer type in both children and adults. More aggressive in childhood than adulthood but survival is better.

Answer 68

Papillary thyroid carcinoma - Most common thyroid cancer type in both children and adults. More aggressive in childhood than adulthood but survival is better.

Question 69

Medullary thyroid carcinoma - Special because of its production of _____, which comes from the parafollicular or C cells of the thyroid gland (C cells = Calcitonin)

Answer 69

Medullary thyroid carcinoma - Special because of its production of calcitonin, which comes from the parafollicular or C cells of the thyroid gland (C cells = Calcitonin)

Question 70

Parathyroid hormone - Increases serum calcium (release from bone), decreases serum phosphate (inhibit phosphate reabsorption from kidneys) Vitamin D - Moves calcium and phosphate in same direction Physiology - 1) High calcium and high phosphorus are due to high levels of _____ - 2) Low calcium and low phosphorus are due to low levels of _____ - 3) High calcium and low phosphorus are due to _____ - 4) Low calcium and high phosphorus are due to _____ Calcitonin - Can be considered a ___ antagonist - Slows down the osteoClasts, causing a decrease in bone resorption (C = Chew bone) and increases renal calcium clearance.

Answer 70

Parathyroid hormone - Increases serum calcium (release from bone), decreases serum phosphate (inhibit phosphate reabsorption from kidneys) Vitamin D - Moves calcium and phosphate in same direction Physiology - 1) High calcium and high phosphorus are due to high levels of vitamin D - 2) Low calcium and low phosphorus are due to low levels of vitamin D - 3) High calcium and low phosphorus are due to hyperparathyroidism - 4) Low calcium and high phosphorus are due to hypoparathyroidism Calcitonin - Can be considered a PTH antagonist - Slows down the osteoClasts, causing a decrease in bone resorption (C = Chew bone) and increases renal calcium clearance.

Question 71

HYPOPARATHYROIDISM - Causes: - Ex: 22q11.2 deletion DiGeorge syndrome - Pt: Positive Chvostek or Trousseau signs may be present. - Labs: Low serum calcium (5-7mg/dL), low PTH, high phosphorus (7-12mg/dL) - Tx: - IV calcium while monitoring heart rates closely - After stabilization, tx pts with hypoparathyroidism with calcitriol

Answer 71

HYPOPARATHYROIDISM - Causes: - Ex: 22q11.2 deletion DiGeorge syndrome - Pt: Positive Chvostek or Trousseau signs may be present. - Labs: Low serum calcium (5-7mg/dL), low PTH, high phosphorus (7-12mg/dL) - Tx: - IV calcium while monitoring heart rates closely - After stabilization, tx pts with hypoparathyroidism with calcitriol

Question 72

Autoimmune Polyglandular (polyendocrine) Syndromes (APSs) - Affect function of several endocrine glands; and nonendocrine organs can be affected - APS1 and APS2 are NOT MEN syndromes! - Suspect autoimmune hypoparathyroidism in a child with hypocalcemia and parathyroid antibodies and another type of autoimmune disorder or other organ-specific antibodies. - Autoimmune hypoparathyroidism is usually associated with Addison disease and chronic mucocutaneous candidiasis. - If you find 2 out of 3 symptoms, then you have found autoimmune polyglandular syndrome Type 1 (APS1) - Classified according to the type of glands affected. - APS Type 1 (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Whitaker syndrome) - AR disorder - Pt: - Characterized by _____, _____, and ______ - Candidiasis typically starts first; hypoparathyroidism is next, and finally Addison’s occurs. - APS Type 2 (Schmidt syndrome) - Pt: Primarily autoimmune thyroiditis /thyroid disease, diabetes mellitus type 1, and adrenal cortical insufficiency (Addison’s)

Answer 72

Autoimmune Polyglandular (polyendocrine) Syndromes (APSs) - Affect function of several endocrine glands; and nonendocrine organs can be affected - APS1 and APS2 are NOT MEN syndromes! - Suspect autoimmune hypoparathyroidism in a child with hypocalcemia and parathyroid antibodies and another type of autoimmune disorder or other organ-specific antibodies. - Autoimmune hypoparathyroidism is usually associated with Addison disease and chronic mucocutaneous candidiasis. - If you find 2 out of 3 symptoms, then you have found autoimmune polyglandular syndrome Type 1 (APS1) - Classified according to the type of glands affected. - APS Type 1 (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Whitaker syndrome) - AR disorder - Pt: - Characterized by candidiasis, hypoparathyroidism, and adrenal failure - Candidiasis typically starts first; hypoparathyroidism is next, and finally Addison’s occurs. - APS Type 2 (Schmidt syndrome) - Pt: Primarily autoimmune thyroiditis /thyroid disease, diabetes mellitus type 1, and adrenal cortical insufficiency (Addison’s)

Question 73

Pseudohypoparathyroidism - Typical theme is PTH resistance: - Clinical hypoparathyroidism (low Ca, high P) but high _____, indicating resistance to hormone

Answer 73

Pseudohypoparathyroidism - Typical theme is PTH resistance: - Clinical hypoparathyroidism (low Ca, high P) but high PTH, indicating resistance to hormone

Question 74

Pseudohypoparathyroidism type 1a (Albright’s Hereditary Osteodystrophy (AHO)) - Pt: - Tetany - These children have ____ faces and ____ builds. - Those affected typically have short fingers with dimpling of the dorsum of the hand (due to a 4th metacarpal bone). - Albright hereditary osteodystrophy (AHO) phenotype: - Think of a family presenting to your clinic - all of them are short and stocky and have calcium problems. They can also have hypothyroidism. Their hands and feet are small due to a brachymetacarpals and brachymetatarsals. - Path: ____ imprinting of the GNAS mutation - Labs: ____ calcium, ___ phosphorus, and ___ PTH

Answer 74

Pseudohypoparathyroidism type 1a (Albright’s Hereditary Osteodystrophy (AHO)) - Pt: - Tetany - These children have round faces and short stocky builds. - Those affected typically have short fingers with dimpling of the dorsum of the hand (due to a 4th metacarpal bone). - Albright hereditary osteodystrophy (AHO) phenotype: - Think of a family presenting to your clinic - all of them are short and stocky and have calcium problems. They can also have hypothyroidism. Their hands and feet are small due to a brachymetacarpals and brachymetatarsals. - Path: Maternal imprinting of the GNAS mutation - Labs: Low calcium, high phosphorus, and high PTH

Question 75

Pseudopseudohypoparathyroidism - Present with phenotype (AHO) of pseudohypoparathyroidism but NOT with the hormone resistance - Path: ____ imprinting of the GNAS mutation - Pt: Similar to those of a pt with pseudohypoparathyroidism - short, stocky, brachymetacarpals and brachymetatarsals with a round face. - BUT _______! - Must follow these pts bc, as they age, they frequently develop hypocalcemia.

Answer 75

Pseudopseudohypoparathyroidism - Present with phenotype (AHO) of pseudohypoparathyroidism but NOT with the hormone resistance - Path: Paternal imprinting of the GNAS mutation - Pt: Similar to those of a pt with pseudohypoparathyroidism - short, stocky, brachymetacarpals and brachymetatarsals with a round face. - BUT labs are normal! - Must follow these pts bc, as they age, they frequently develop hypocalcemia.

Question 76

RICKETS - Bony malformation due to any abnormality in the production or excretion of calcium and phosphate in growing bone. It is a disease of the growth plate. Rickets results in under-mineralization of the growth plate, and it occurs only in children with open growth plates. - Pt: - An infant with advanced rickets presents with frontal bossing, craniotabes, widened sutures nodules on the ribs (aka “rachitic rosary”), and flared wrists - Older child presents with flared wrists or ankles, genu valgum, or genu varum. - Diagnosis is made by lab and XR. - Labs: - All pts with rickets have an abnormality in their calcium and/or phosphorus, and all have elevated alkaline phosphatase! - Decreased 25-OH vit D. - Check calcium, phosphorus, PTH. Elevated ______________ in both calcipenic and phosphopenic rickets. - All have XR changes at their growth plates. - They have irregularity of calcification, cupping of the metaphysis, fraying and widening of the growth plate, and diffuse osteomalacia. They may have rachitic rosary. - Ddx: Vitamin-D deficient rickets, familial hypophosphatemic rickets (FHR), deficiency of enzymes in vitamin D metabolism (25-hydroxylase or 1-alpha-hydroxylase), or resistance of 1,25-dihydroxy vitamin D. - Note that FHR does not result in hyperparathyroidism!

Answer 76

RICKETS - Bony malformation due to any abnormality in the production or excretion of calcium and phosphate in growing bone. It is a disease of the growth plate. Rickets results in under-mineralization of the growth plate, and it occurs only in children with open growth plates. - Pt: - An infant with advanced rickets presents with frontal bossing, craniotabes, widened sutures nodules on the ribs (aka “rachitic rosary”), and flared wrists - Older child presents with flared wrists or ankles, genu valgum, or genu varum. - Diagnosis is made by lab and XR. - Labs: - All pts with rickets have an abnormality in their calcium and/or phosphorus, and all have elevated alkaline phosphatase! - Decreased 25-OH vit D. - Check calcium, phosphorus, PTH. Elevated Alkaline phosphatase in both calcipenic and phosphopenic rickets. - All have XR changes at their growth plates. - They have irregularity of calcification, cupping of the metaphysis, fraying and widening of the growth plate, and diffuse osteomalacia. They may have rachitic rosary. - Ddx: Vitamin-D deficient rickets, familial hypophosphatemic rickets (FHR), deficiency of enzymes in vitamin D metabolism (25-hydroxylase or 1-alpha-hydroxylase), or resistance of 1,25-dihydroxy vitamin D. - Note that FHR does not result in hyperparathyroidism!

Question 77

Nutritional Rickets / Vitamin D Deficient Rickets - Vitamin D or calcium deficiency - Labs: - ____ 25-hydroxyvitamin D level, ____ PTH level (caused by total body calcium depletion), normal or low calcium level, low phosphorus level (caused by PTH-induced renal phosphate wasting), and ____ alkaline phosphatase level. - Tx: ____

Answer 77

Nutritional Rickets / Vitamin D Deficient Rickets - Vitamin D or calcium deficiency - Labs: - Low 25-hydroxyvitamin D level, high PTH level (caused by total body calcium depletion), normal or low calcium level, low phosphorus level (caused by PTH-induced renal phosphate wasting), and high alkaline phosphatase level. - Tx: Daily oral supplement with liquid vitamin D2

Question 78

Deficiency of 1-alpha-hydroxylase (Vitamin D-Dependent Rickets Type 1) - Labs: ____ 1,25-dihydroxyvitamin D and leads to secondary hyperPTH, 25 vit D is ____, low calcium level, ____ PTH level, low phosphorus level - Tx: _______

Answer 78

Deficiency of 1-alpha-hydroxylase (Vitamin D-Dependent Rickets Type 1) - Labs: Low 1,25-dihydroxyvitamin D and leads to secondary hyperPTH, 25 vit D is normal, low calcium level, high PTH level, low phosphorus level - Tx: Calcium and calcitriol (1,25-dihydroxyvitamin D)

Question 79

Familial Hypophosphatemic Rickets - It is actually a kidney disease - a phosphorus-wasting disease due to decreased renal tubular resorption of phosphorus. - Labs: Extremely _____ serum phosphorus, ___ urine phosphorus, an ____ alkaline phosphatase level, ____ PTH and calcium levels, an inappropriate normal 1,25-dihydroxyvitamin D (calcitriol) level for the degree of hypophosphatemia. - Tx: _____

Answer 79

Familial Hypophosphatemic Rickets - It is actually a kidney disease - a phosphorus-wasting disease due to decreased renal tubular resorption of phosphorus. - Labs: Extremely low serum phosphorus, high urine phosphorus, an elevated alkaline phosphatase level, NORMAL PTH and calcium levels, an inappropriate normal 1,25-dihydroxyvitamin D (calcitriol) level for the degree of hypophosphatemia. - Tx: Lifelong treatment of phosphorus and calcitriol

Question 80

Transient Hyperphosphatasemia of Childhood - Frequently an incidental finding in young children (typically 1-2 years of age) who have a marked _______ of their serum alkaline phosphatase level. Other bone markers, including calcium, PTH, 25-hydroxyvitamin D, and liver markers, are normal. -______

Answer 80

Transient Hyperphosphatasemia of Childhood - Frequently an incidental finding in young children (typically 1-2 years of age) who have a marked elevation of their serum alkaline phosphatase level. Other bone markers, including calcium, PTH, 25-hydroxyvitamin D, and liver markers, are normal. - No tx or further follow-up is indicated.

Question 81

HYPERPARATHYROIDISM - Causes: Due to either a primary defect (eg adenoma, hyperplasia) or increased PTH production (usually secondary compensatory increase aimed at reversing a hypocalcemia state). - Pt: - Manifestations of hypercalcemia - Most frequently seen as muscular weakness, nausea, vomiting, constipation, and fever. Can also present with __________ - Classic question portrays a child in bed immobilized in a cast with nausea, emesis, and bedwetting who has hypercalcemia. - Bone pain can occur, and height can be affected by vertebral fractures. - Abdominal pain is a classic finding on exam and can be due to acute pancreatitis. - Labs: High serum calcium (>12mg/dL), serum PTH, and urine calcium. - Dx: Elevated serum PTH, elevated serum calcium, low serum phosphorus - Tx: Use bisphosphonates or calcitonin to tx hypercalcemia

Answer 81

HYPERPARATHYROIDISM - Causes: Due to either a primary defect (eg adenoma, hyperplasia) or increased PTH production (usually secondary compensatory increase aimed at reversing a hypocalcemia state). - Pt: - Manifestations of hypercalcemia - Most frequently seen as muscular weakness, nausea, vomiting, constipation, and fever. Can also present with bed-wetting and polyuria. - Classic question portrays a child in bed immobilized in a cast with nausea, emesis, and bedwetting who has hypercalcemia. - Bone pain can occur, and height can be affected by vertebral fractures. - Abdominal pain is a classic finding on exam and can be due to acute pancreatitis. - Labs: High serum calcium (>12mg/dL), serum PTH, and urine calcium. - Dx: Elevated serum PTH, elevated serum calcium, low serum phosphorus - Tx: Use bisphosphonates or calcitonin to tx hypercalcemia

Question 82

MEN I - ____inheritance? - Hyperplasia or neoplasia of the ____, ____, ____ (ZE (ulcers), insulinoma (hypoglycemia))

Answer 82

MEN I - AD - Hyperplasia or neoplasia of the anterior Pituitary (functional), parathyroid (hypercalcemia; hyperparathyroidism is typically the presenting finding), endocrine pancreas (ZE (ulcers), insulinoma (hypoglycemia))

Question 83

MEN 2A - ____ inheritance - ____ oncogene - ______, _____, ______

Answer 83

MEN 2A - AD inheritance - RET oncogene - Pheochromocytoma, medullary thyroid cancer, hyperparathyroidism

Question 84

MEN 2B - Inherited in an ___ fashion - ___ oncogene - ____, ____, ____. ___ - Best next step is to evaluate for medullary thyroid carcinoma.

Answer 84

MEN 2B - Inherited in an AD fashion - RET oncogene - Pheochromocytoma, medullary thyroid cancer (occurs in 100% of individuals), mucosal neuronal tumors. Marfanoid body habitus - Best next step is to evaluate for medullary thyroid carcinoma.

Question 85

``` ADRENAL HPA axis (Hypothalamus, anterior pituitary, and adrenal gland) ``` - In pts with a low cortisol level, testing for the ACTH level helps determine which part of the HPA axis has a problem: - If ACTH is high, the problem is in the adrenal gland (ie primary adrenal insufficiency) - If ACTH is low, the problem is in the HTH or anterior pituitary (ie secondary adrenal insufficiency). Further define the problem area by testing the CRH level: - If the CRH is low, it is an HTH problem - If CRH is high, it is an anterior pituitary problem

Answer 85

``` ADRENAL HPA axis (Hypothalamus, anterior pituitary, and adrenal gland) ``` - In pts with a low cortisol level, testing for the ACTH level helps determine which part of the HPA axis has a problem: - If ACTH is high, the problem is in the adrenal gland (ie primary adrenal insufficiency) - If ACTH is low, the problem is in the HTH or anterior pituitary (ie secondary adrenal insufficiency). Further define the problem area by testing the CRH level: - If the CRH is low, it is an HTH problem - If CRH is high, it is an anterior pituitary problem

Question 86

Adrenal gland has 2 distinct structures: - Outer adrenal cortex - 1) Outer zone glomerulosa (_____ [salt]) - 2) Middle zone fasciculata (____l [sugar] but some androgens) - 3) Inner zone reticularis (_____ [sex] but some cortisol) - Inner adrenal medulla - Chromaffin cells manufacture norepinephrine

Answer 86

Adrenal gland has 2 distinct structures: - Outer adrenal cortex - 1) Outer zone glomerulosa (mineralocorticoids (aldosterone) [salt]) - 2) Middle zone fasciculata (mainly cortisol [sugar] but some androgens) - 3) Inner zone reticularis (mainly androgens [sex] but some cortisol) - Inner adrenal medulla - Chromaffin cells manufacture norepinephrine

Question 87

Renin-angiotensin-aldosterone system - Primary and secondary causes of aldosterone excess. Pts develop HTN and hypokalemia metabolic alkalosis. - Primary and secondary causes of aldosterone deficiency cause sodium and water loss, volume depletion, and hyperkalemia metabolic acidosis.

Answer 87

Renin-angiotensin-aldosterone system - Primary and secondary causes of aldosterone excess. Pts develop HTN and hypokalemia metabolic alkalosis. - Primary and secondary causes of aldosterone deficiency cause sodium and water loss, volume depletion, and hyperkalemia metabolic acidosis.

Question 88

ADRENAL INSUFFICIENCY - Most common cause of adrenal insufficiency of any type in North America is secondary adrenal insufficiency caused by withdrawal or omission of glucocorticoid therapy in pts who have been on chronic glucocorticoid therapy. - Most common cause of primary adrenal insufficiency in children is CAH. - Most common cause of primary adrenal insufficiency in adults is Addison disease (autoimmune destruction of the adrenal cortex). Worldwide, destruction of the adrenal glands by tuberculosis is a common cause. - Pt: Symptoms are nonspecific, and the diagnosis if often missed. Children frequently are symptomatic for several years before being diagnosed. Know the spectrum of findings bc it can be acutely fatal! - Nausea and vomiting (without diarrhea) - Suspect primary adrenal insufficiency - Suspect primary AI In any pt with hyperpigmentation - Pts with primary adrenal insufficiency usually have salt craving (love to drink pickle juice!) due to salt loss from the aldosterone deficiency. - Pts with secondary adrenal insufficiency do not have the salt loss bc the associated low ACTH level has little effect on mineralocorticoid production.

Answer 88

ADRENAL INSUFFICIENCY - Most common cause of adrenal insufficiency of any type in North America is secondary adrenal insufficiency caused by withdrawal or omission of glucocorticoid therapy in pts who have been on chronic glucocorticoid therapy. - Most common cause of primary adrenal insufficiency in children is CAH. - Most common cause of primary adrenal insufficiency in adults is Addison disease (autoimmune destruction of the adrenal cortex). Worldwide, destruction of the adrenal glands by tuberculosis is a common cause. - Pt: Symptoms are nonspecific, and the diagnosis if often missed. Children frequently are symptomatic for several years before being diagnosed. Know the spectrum of findings bc it can be acutely fatal! - Nausea and vomiting (without diarrhea) - Suspect primary adrenal insufficiency - Suspect primary AI In any pt with hyperpigmentation - Pts with primary adrenal insufficiency usually have salt craving (love to drink pickle juice!) due to salt loss from the aldosterone deficiency. - Pts with secondary adrenal insufficiency do not have the salt loss bc the associated low ACTH level has little effect on mineralocorticoid production.

Question 89

Secondary Adrenal Insufficiency ACTH (Corticotropin) Deficiency - Most common cause of ACTH deficiency (and adrenal insufficiency overall) is stopping or missing glucocorticoid therapy (without proper weaning) in people who have been on chronic steroid therapy. - A tx course that lasts a little as 2 weeks can suppress the adrenal glands. - Chronic use of high-dose inhaled corticosteroids can cause HPA suppression. - Disease of the HTH or pituitary can also cause ACTH deficiency - most commonly from idiopathic hypopituitarism or a destructive lesion, such as craniopharyngioma (which decreases HTH production and release of CRH). Most destructive lesions result in the loss of multiple pituitary hormones.

Answer 89

Secondary Adrenal Insufficiency ACTH (Corticotropin) Deficiency - Most common cause of ACTH deficiency (and adrenal insufficiency overall) is stopping or missing glucocorticoid therapy (without proper weaning) in people who have been on chronic steroid therapy. - A tx course that lasts a little as 2 weeks can suppress the adrenal glands. - Chronic use of high-dose inhaled corticosteroids can cause HPA suppression. - Disease of the HTH or pituitary can also cause ACTH deficiency - most commonly from idiopathic hypopituitarism or a destructive lesion, such as craniopharyngioma (which decreases HTH production and release of CRH). Most destructive lesions result in the loss of multiple pituitary hormones.

Question 90

Primary Adrenal Insufficiency - Marked elevation of ACTH; so measurement of ACTH is very helpful in differentiating between primary and secondary adrenal insufficiency - The most definitive tests as plasma/serum levels of cortisol before and after ACTH is given. - With adrenal insufficiency, resting levels of cortisol are low, and no increase is seen with exogenous ACTH. (Over time, the cortisol-producing cells of the adrenal gland atrophy without ACTH stimulation) - ACTH-stimulating testing is useful to diagnose both primary and secondary adrenal insufficiency bc neither responds adequately to ACTH. - Aldosterone levels can be helpful, particularly if you suspect an isolated defect or in infants whom you suspect have congenital adrenal hyperplasia. - Aldosterone levels are low in pts with salt-wasting CAH, adrenal hypoplasia, and Addison disease.

Answer 90

Primary Adrenal Insufficiency - Marked elevation of ACTH; so measurement of ACTH is very helpful in differentiating between primary and secondary adrenal insufficiency - The most definitive tests as plasma/serum levels of cortisol before and after ACTH is given. - With adrenal insufficiency, resting levels of cortisol are low, and no increase is seen with exogenous ACTH. (Over time, the cortisol-producing cells of the adrenal gland atrophy without ACTH stimulation) - ACTH-stimulating testing is useful to diagnose both primary and secondary adrenal insufficiency bc neither responds adequately to ACTH. - Aldosterone levels can be helpful, particularly if you suspect an isolated defect or in infants whom you suspect have congenital adrenal hyperplasia. - Aldosterone levels are low in pts with salt-wasting CAH, adrenal hypoplasia, and Addison disease.

Question 91

Addison Disease - Is one of the acquired forms of adrenal insufficiency. - Path: Autoimmune destruction of the adrenal cortex. Therefore, deficiency of both _____ and ______. - The increased levels of MSH cause hyperpigmentation. - Pt: - Dehydration and salt craving (due to mineralocorticoid deficiency) + skin _______(due to high ACTH) - Hyperpigmentation is an important clue. Hyperpigmentation can be generalized (be esp suspicious about areas without sun exposure, such as axilla or areas normally covered by underwear) and may be seen in creases on the palms and in the gums. - Labs: - Low serum cortisol concentration - In response to low cortisol levels, ACTH levels are high - Hyponatremia, hyperkalemia (due to lack of aldosterone), hypoglycemia (due to lack of cortisol), metabolic acidosis - Hyperkalemia occurs bc of mineralocorticoid deficiency

Answer 91

Addison Disease - Is one of the acquired forms of adrenal insufficiency. - Path: Autoimmune destruction of the adrenal cortex. Therefore, deficiency of both glucocorticoid (cortisol) and mineralocorticoid (aldosterone). - The increased levels of MSH cause hyperpigmentation. - Pt: - Dehydration and salt craving (due to mineralocorticoid deficiency) + skin hyperpigmentation “tan” (due to high ACTH) - Hyperpigmentation is an important clue. Hyperpigmentation can be generalized (be esp suspicious about areas without sun exposure, such as axilla or areas normally covered by underwear) and may be seen in creases on the palms and in the gums. - Labs: - Low serum cortisol concentration - In response to low cortisol levels, ACTH levels are high - Hyponatremia, hyperkalemia (due to lack of aldosterone), hypoglycemia (due to lack of cortisol), metabolic acidosis - Hyperkalemia occurs bc of mineralocorticoid deficiency

Question 92

Adrenoleukodystrophy - Be aware of the teenage boy with new-onset clumsiness - think about obtaining long-chain fatty acids to make the diagnosis! - Consider this in any male with adrenal insufficiency.

Answer 92

Adrenoleukodystrophy - Be aware of the teenage boy with new-onset clumsiness - think about obtaining long-chain fatty acids to make the diagnosis! - Consider this in any male with adrenal insufficiency.

Question 93

Adrenal Hemorrhage - Hemorrhage into the adrenal glands - Be on the lookout for scrotal hematoma! - Frequently, the hemorrhage is asymptomatic and picked up only later with calcifications seen in the adrenal. - Waterhouse-Friderichsen syndrome causes bilateral adrenal hemorrhage

Answer 93

Adrenal Hemorrhage - Hemorrhage into the adrenal glands - Be on the lookout for scrotal hematoma! - Frequently, the hemorrhage is asymptomatic and picked up only later with calcifications seen in the adrenal. - Waterhouse-Friderichsen syndrome causes bilateral adrenal hemorrhage

Question 94

Congenital Adrenal Hypoplasia - Can be confused with more common CAH. - Pt: - Increased pigmentation, symptoms related to salt wasting, and symptoms due to low levels of adrenal steroids - Cryptorchidism is common.

Answer 94

Congenital Adrenal Hypoplasia - Can be confused with more common CAH. - Pt: - Increased pigmentation, symptoms related to salt wasting, and symptoms due to low levels of adrenal steroids - Cryptorchidism is common.

Question 95

Adrenal Crisis - Life-threatening condition caused by inadequate levels of cortisol and aldosterone - Pt: Hypotension and electrolyte disturbances are the primary clinical features. - Must quickly and aggressively tx - IVF and correction of hypoglycemia - Subsequently, a IV stress dose of hydrocortisone 50-100mg/m2 of body surface area. Then continue IV hydrocortisone at 100mg/m2 per day, either as continuous infusion or divided q6h, until clinical status is improved.

Answer 95

Adrenal Crisis - Life-threatening condition caused by inadequate levels of cortisol and aldosterone - Pt: Hypotension and electrolyte disturbances are the primary clinical features. - Must quickly and aggressively tx - IVF and correction of hypoglycemia - Subsequently, a IV stress dose of hydrocortisone 50-100mg/m2 of body surface area. Then continue IV hydrocortisone at 100mg/m2 per day, either as continuous infusion or divided q6h, until clinical status is improved.

Question 96

CONGENITAL ADRENAL HYPERPLASIA - _____Inheritance?? - Most common 46, XX DSD - Causes of CAH that have salt-wasting manifestations (result in loss of both cortisol and aldosterone): - 21-hydroxylase deficiency - 3Beta-hydroxysteroid dehydrogenase deficiency - Lipoid CAH - Types of CAH that cause decreased cortisol but do not affect aldosterone (so no salt wasting) are: - 11Beta-hydroxylase deficiency - 17alpha-hydroxylase deficiency - Dx: - 1st clue to diagnosis is a prior hx of a sibling with CAH! - Younger siblings are much more likely to be affected. - Always suspect CAH in a child or infant with FTT, and esp in a female with ambiguous external genitalia. - Male infants have no clinical signs at birth, whereas female infants are virilized. - Classic presentation is of an XY infant presenting in adrenal crisis at 2 weeks of age. - In males with CAH, the testes are small compared to the degree of virilization - Whereas in precocious puberty and in Leydig cell tumors, the testes are enlarged for age. - In girls with ambiguous external genitalia, CAH is the only thing to cause elevated adrenal cortical steroid levels. - Most state screening programs use the level of 17-OHP to screen for CAH due to 21-hydroxylase deficiency. If a high level is reported it is important to repeat a serum 17-OHP measurement and begin replacement doses of hydrocortisone, and, if salt wasting is present, 9alpha-fludrocortisone. - Postdelivery Tx - Give glucocorticoids (hydrocortisone) to tx adrenal insufficiency and to inhibit excessive production of androgens and progression of the virilization. - Hydrocortisone must be continued for life with classic CAH. Increasing the dose during episodes of stress or surgery is required. - If neonates have salt-wasting disease and/or elevated renin levels, administer a mineralocorticoid (fludrocortisone) and oral sodium. - You must use sex hormone replacement for 17-OHP and 3B-HSD defiiencies to induce or maintain normal puberty.

Answer 96

CONGENITAL ADRENAL HYPERPLASIA - AR - Most common 46, XX DSD - Causes of CAH that have salt-wasting manifestations (result in loss of both cortisol and aldosterone): - 21-hydroxylase deficiency - 3Beta-hydroxysteroid dehydrogenase deficiency - Lipoid CAH - Types of CAH that cause decreased cortisol but do not affect aldosterone (so no salt wasting) are: - 11Beta-hydroxylase deficiency - 17alpha-hydroxylase deficiency - Dx: - 1st clue to diagnosis is a prior hx of a sibling with CAH! - Younger siblings are much more likely to be affected. - Always suspect CAH in a child or infant with FTT, and esp in a female with ambiguous external genitalia. - Male infants have no clinical signs at birth, whereas female infants are virilized. - Classic presentation is of an XY infant presenting in adrenal crisis at 2 weeks of age. - In males with CAH, the testes are small compared to the degree of virilization - Whereas in precocious puberty and in Leydig cell tumors, the testes are enlarged for age. - In girls with ambiguous external genitalia, CAH is the only thing to cause elevated adrenal cortical steroid levels. - Most state screening programs use the level of 17-OHP to screen for CAH due to 21-hydroxylase deficiency. If a high level is reported it is important to repeat a serum 17-OHP measurement and begin replacement doses of hydrocortisone, and, if salt wasting is present, 9alpha-fludrocortisone. - Postdelivery Tx - Give glucocorticoids (hydrocortisone) to tx adrenal insufficiency and to inhibit excessive production of androgens and progression of the virilization. - Hydrocortisone must be continued for life with classic CAH. Increasing the dose during episodes of stress or surgery is required. - If neonates have salt-wasting disease and/or elevated renin levels, administer a mineralocorticoid (fludrocortisone) and oral sodium. - You must use sex hormone replacement for 17-OHP and 3B-HSD defiiencies to induce or maintain normal puberty.

Question 97

Salt-Wasting CAH (More common) - 21-hydroxylase deficiency - Females are usually detected at birth due to their ambiguous genitalia and thus generally do not present in shock at 2 weeks. - If you see a male in the nursery with bilateral undescended testes, obtain a 17-OHP and karyotype prior to assigning a gender! - Males appear normal at birth. Classic presentation is of an XY infant presenting in adrenal crisis at 2 weeks of age. - 3B-HSD deficiency typically causes salt wasting with less virilization. - Girls have only mild-moderate clitoral enlargement. - Whereas males have incomplete virilization - various degrees of hypospadias - The ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone is markedly high compared to the ratio in 21-hydroxylase deficiency, where it is low

Answer 97

Salt-Wasting CAH (More common) - 21-hydroxylase deficiency - Females are usually detected at birth due to their ambiguous genitalia and thus generally do not present in shock at 2 weeks. - If you see a male in the nursery with bilateral undescended testes, obtain a 17-OHP and karyotype prior to assigning a gender! - Males appear normal at birth. Classic presentation is of an XY infant presenting in adrenal crisis at 2 weeks of age. - 3B-HSD deficiency typically causes salt wasting with less virilization. - Girls have only mild-moderate clitoral enlargement. - Whereas males have incomplete virilization - various degrees of hypospadias - The ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone is markedly high compared to the ratio in 21-hydroxylase deficiency, where it is low

Question 98

Non-Salt Wasting CAH (Less common) - Males with 21-hydroxylase deficiency - Boys appear normal at birth. By 6 months of age, they have signs of sexual precocity. There is adrenal involvement only! - The testes are prepubertal (remember this is an adrenal problem, not a testicular problem!) and appear small compared to the penis. - Females with 21-hydroxylase deficiency

Answer 98

Non-Salt Wasting CAH (Less common) - Males with 21-hydroxylase deficiency - Boys appear normal at birth. By 6 months of age, they have signs of sexual precocity. There is adrenal involvement only! - The testes are prepubertal (remember this is an adrenal problem, not a testicular problem!) and appear small compared to the penis. - Females with 21-hydroxylase deficiency

Question 99

Classic: neonatal period w adrenal insufficiency +/- ambiguous genitalia; salt wasting 21-Hydroxylase Deficiency - Path: AR inheritance of 21-hydroxylase deficiency - Deficiency leads to underproduction of cortisol and aldosterone and overproduction of androgens. - Pt: 2 biggest concerns are life-threatening salt-wasting crises and female virilization. - Females: Most infants have the salt-wasting + virilizing forms - Ambiguous genitalia - Males: No clinical signs at birth. Lethargy, poor feeding, hypotension, hypoglycemia, and hyperpigmentation - Classic presentation is of an XY infant is adrenal crisis in an untreated pt at 1-2 weeks of life - Laboratory findings include hyponatremia, hyperkalemia (from lack of aldosterone), hypoglycemia (from lack of cortisol), and hyperreninemia, metabolic acidosis (from lack of aldosterone) - Dx: Increased 17-hydroxyprogesterone

Answer 99

Classic: neonatal period w adrenal insufficiency +/- ambiguous genitalia; salt wasting 21-Hydroxylase Deficiency - Path: AR inheritance of 21-hydroxylase deficiency - Deficiency leads to underproduction of cortisol and aldosterone and overproduction of androgens. - Pt: 2 biggest concerns are life-threatening salt-wasting crises and female virilization. - Females: Most infants have the salt-wasting + virilizing forms - Ambiguous genitalia - Males: No clinical signs at birth. Lethargy, poor feeding, hypotension, hypoglycemia, and hyperpigmentation - Classic presentation is of an XY infant is adrenal crisis in an untreated pt at 1-2 weeks of life - Laboratory findings include hyponatremia, hyperkalemia (from lack of aldosterone), hypoglycemia (from lack of cortisol), and hyperreninemia, metabolic acidosis (from lack of aldosterone) - Dx: Increased 17-hydroxyprogesterone

Question 100

11 Beta-Hydroxylase- distinguish by presence of HTN - Pt: - Virilization + HTN = 11B-hydroxylase deficiency - Differentiate 11B- from 21-hydroxylase deficiency by observing no salt wasting.

Answer 100

11 Beta-Hydroxylase- distinguish by presence of HTN - Pt: - Virilization + HTN = 11B-hydroxylase deficiency - Differentiate 11B- from 21-hydroxylase deficiency by observing no salt wasting.

Question 101

17alpha-Hydroxylase Deficiency | - Pt: Salt retention, HTN, hypokalemia, suppression of renin and aldosterone

Answer 101

17alpha-Hydroxylase Deficiency | - Pt: Salt retention, HTN, hypokalemia, suppression of renin and aldosterone

Question 102

``` BP/Na Virilization 21 __ ___ 11 ___ ___ 17 ___ ____ (Arrows look like the numbers; 1 is always up) ```

Answer 102

``` BP/Na Virilization 21 Down ^ 11 ^ ^ 17 ^ Down (Arrows look like the numbers; 1 is always up) ```

Question 103

3B-HSD - Salt wasting with less virilization - Pt: - Classic forms with salt wasting occur in both boys and girls - With boys, incomplete virilization with hypospadias develops - Labs: - Huge increase in the delta5 steroids occurring upstream from the block, like 17-hydroxypregnenolone but also elevated 17-OHP (due to extraadrenal 3B-HSD activity that occurs in peripheral tissue; making it easily confused with 21-hydroxylase deficiency) - It is necessary to check ratios of delta5 to delta4 steroids in plasma and urine for a definitive diagnosis! - Ratio of ____ to ____ is markedly high compared to the ratio in 21-hydroxylase deficiency, where it is low.

Answer 103

3B-HSD - Salt wasting with less virilization - Pt: - Classic forms with salt wasting occur in both boys and girls - With boys, incomplete virilization with hypospadias develops - Labs: - Huge increase in the delta5 steroids occurring upstream from the block, like 17-hydroxypregnenolone but also elevated 17-OHP (due to extraadrenal 3B-HSD activity that occurs in peripheral tissue; making it easily confused with 21-hydroxylase deficiency) - It is necessary to check ratios of delta5 to delta4 steroids in plasma and urine for a definitive diagnosis! - Ratio of delta 5 steroid (17-hydroxypregnenolone) to delta4 (17-hydroxyprogesterone) is markedly high compared to the ratio in 21-hydroxylase deficiency, where it is low.

Question 104

Lipoid Adrenal Hyperplasia - Most severe form of CAH. - Path: There is no production of gonadal or adrenal steroid hormones.

Answer 104

Lipoid Adrenal Hyperplasia - Most severe form of CAH. - Path: There is no production of gonadal or adrenal steroid hormones.

Question 105

Adrenocortical tumors - Almost always unilateral - Pt: - Virilization is the presenting symptom. - In addition to virilization, about 20-40% of these children have Cushing syndrome - Labs: - Urinary 17-ketosteroids, serum DHEA, serum DHEAS, and serum androstenedione are elevated. - Tx: Treat surgically.

Answer 105

Adrenocortical tumors - Almost always unilateral - Pt: - Virilization is the presenting symptom. - In addition to virilization, about 20-40% of these children have Cushing syndrome - Labs: - Urinary 17-ketosteroids, serum DHEA, serum DHEAS, and serum androstenedione are elevated. - Tx: Treat surgically.

Question 106

Suppress = not Cushing’s Fail to suppress = Cushing’s syndrome. Get ACTH - Normal ACTH = Adrenal tumor. CT/MRI, resect - Increased ACTH = ACTH-dependent. Do high dose dex suppression - Fails to suppress = ectopic tumor. Pan-scan - Suppress = Cushing’s Disease (pituitary tumor). Resect

Answer 106

Suppress = not Cushing’s Fail to suppress = Cushing’s syndrome. Get ACTH - Normal ACTH = Adrenal tumor. CT/MRI, resect - Increased ACTH = ACTH-dependent. Do high dose dex suppression - Fails to suppress = ectopic tumor. Pan-scan - Suppress = Cushing’s Disease (pituitary tumor). Resect

Question 107

CUSHING SYNDROME - Path: Results from sustained glucocorticoid levels and manifests with obesity, poor height progression, and associated HTN. - Can result from either excess exogenous or endogenous glucocorticoid. - Exogenous glucocorticoid by any route can have a profound effect on linear growth. - The overproducing adrenal can be ACTH independent or ACTH dependent (Cushing disease) - Causes: - ACTH-Independent Cushing Syndrome (increased cortisol level suppresses CRH and ACTH secretion) - Iatrogenic: Most common cause is exogenous steroid exposure (including inhaled and topical steroids) - Adrenocortical tumors (most common cause in infancy) - Primary pigmented nodular adrenocortical disease - It is part of the Carney complex - an AD disease with blue nevi, cardiac and skin myxomas, and in boys, sexual precocity. Frequently, thyroid tumors, pituitary tumors, and melatonin schwannomas are part of the syndrome. - McCune-Albright syndrome - ACTH-Dependent Cushing Syndrome (elevated ACTH pushing overproduction of cortisol) - Pituitary hypersecretion of ACTH (Cushing disease) - most due to pituitary adenomas - Ectopic secretion of CRH or ACTH by tumors - Pt: - HTN is part of the syndrome and can cause heart failure - Weight gain with linear growth failure - These pts are HTNive with poor height velocity. If a pt has normal growth/height velocity, then the pt does not have Cushing’s. - Screening: - Best screen is ________ which is elevated. Urinary excretion of free cortisol is increased in Cushing’s. - Midnight salivary cortisol is also a good initial screen. - Conduct a 1-mg overnight dexamethasone suppression test if diagnosis is unclear: - When you give a dose of dexamethasone at 11pm and again the following morning at 8am, look for a plasma cortisol level <5ug/dl. A higher level confirms Cushing syndrome. - A morning cortisol level that does not suppress to dexamethasone is consistent with endogenous Cushing syndrome - If you have determined that cortisol levels are inappropriately elevated, you next need to determine if it is ACTH independent or dependent. Perform a high-dose (or 2-step) dexamethasone suppression test. - Clue: - Children with Cushing syndrome are usually short with poor growth velocities, while those with obesity are generally tall for their age with accelerated growth velocities. - Dexamethasone markedly decreases the urinary excretion of corticosteroids in exogenous obesity. - Tx: Depends on the lesion and location.

Answer 107

CUSHING SYNDROME - Path: Results from sustained glucocorticoid levels and manifests with obesity, poor height progression, and associated HTN. - Can result from either excess exogenous or endogenous glucocorticoid. - Exogenous glucocorticoid by any route can have a profound effect on linear growth. - The overproducing adrenal can be ACTH independent or ACTH dependent (Cushing disease) - Causes: - ACTH-Independent Cushing Syndrome (increased cortisol level suppresses CRH and ACTH secretion) - Iatrogenic: Most common cause is exogenous steroid exposure (including inhaled and topical steroids) - Adrenocortical tumors (most common cause in infancy) - Primary pigmented nodular adrenocortical disease - It is part of the Carney complex - an AD disease with blue nevi, cardiac and skin myxomas, and in boys, sexual precocity. Frequently, thyroid tumors, pituitary tumors, and melatonin schwannomas are part of the syndrome. - McCune-Albright syndrome - ACTH-Dependent Cushing Syndrome (elevated ACTH pushing overproduction of cortisol) - Pituitary hypersecretion of ACTH (Cushing disease) - most due to pituitary adenomas - Ectopic secretion of CRH or ACTH by tumors - Pt: - HTN is part of the syndrome and can cause heart failure - Weight gain with linear growth failure - These pts are HTNive with poor height velocity. If a pt has normal growth/height velocity, then the pt does not have Cushing’s. - Screening: - Best screen is 24-hour urine free cortisol, which is elevated. Urinary excretion of free cortisol is increased in Cushing’s. - Midnight salivary cortisol is also a good initial screen. - Conduct a 1-mg overnight dexamethasone suppression test if diagnosis is unclear: - When you give a dose of dexamethasone at 11pm and again the following morning at 8am, look for a plasma cortisol level <5ug/dl. A higher level confirms Cushing syndrome. - A morning cortisol level that does not suppress to dexamethasone is consistent with endogenous Cushing syndrome - If you have determined that cortisol levels are inappropriately elevated, you next need to determine if it is ACTH independent or dependent. Perform a high-dose (or 2-step) dexamethasone suppression test. - Clue: - Children with Cushing syndrome are usually short with poor growth velocities, while those with obesity are generally tall for their age with accelerated growth velocities. - Dexamethasone markedly decreases the urinary excretion of corticosteroids in exogenous obesity. - Tx: Depends on the lesion and location.

Question 108

HYPERALDOSTERONISM - Path: - Primary hyperaldosteronism - Conn syndrome - presence of ______ - Labs: - Hypokalemia, suppressed plasma renin levels. - Dx - HTN, hypokalemia, and low renin with elevated aldosterone indicate the diagnosis of primary hyperaldosteronism. - ___________ is usually given first. - If it results in marked suppression of aldosterone levels, the pt has a glucocorticoid-suppressible hyperaldosteronism. - If there is no response, use CT or MRI to look for an adrenal adenoma. - If imaging is negative, perform adrenal vein catheterization and check for aldosterone. - High concentrations of aldosterone are found in one adrenal vein when an adenoma is present and in both when bilateral adrenal hyperplasia is the culprit. - If the adrenal vein catheterization is not successful, an exploratory laparotomy must be considered. - Elevated aldo, elevated renin. Aldo:renin<10 = renovascular HTN (secondary hyperaldosteronism). For FMD, stent. For atherosclerotic disease, no stent - Elevated aldo, decreased renin. Aldo:renin>20 = Conn’s (primary hyperaldosteronism). Do adrenal/salt suppression test - Tx: - Tx glucocorticoid-suppressible, hyperaldosteronism with________ - Tx aldosteronoma with surgical removal - Tx bilateral adrenal hyperplasia with ______, which returns blood pressure and potassium levels to normal. Try _____ if the pt cannot tolerate spironolactone. If the condition cannot be controlled medically, a unilateral adrenalectomy may be helpful.

Answer 108

HYPERALDOSTERONISM - Path: - Primary hyperaldosteronism - Conn syndrome - presence of adrenal aldosteronoma (aldosterone-secreting benign adrenal neoplasm) - Labs: - Hypokalemia, suppressed plasma renin levels. - Dx - HTN, hypokalemia, and low renin with elevated aldosterone indicate the diagnosis of primary hyperaldosteronism. - Dexamethasone is usually given first. - If it results in marked suppression of aldosterone levels, the pt has a glucocorticoid-suppressible hyperaldosteronism. - If there is no response, use CT or MRI to look for an adrenal adenoma. - If imaging is negative, perform adrenal vein catheterization and check for aldosterone. - High concentrations of aldosterone are found in one adrenal vein when an adenoma is present and in both when bilateral adrenal hyperplasia is the culprit. - If the adrenal vein catheterization is not successful, an exploratory laparotomy must be considered. - Elevated aldo, elevated renin. Aldo:renin<10 = renovascular HTN (secondary hyperaldosteronism). For FMD, stent. For atherosclerotic disease, no stent - Elevated aldo, decreased renin. Aldo:renin>20 = Conn’s (primary hyperaldosteronism). Do adrenal/salt suppression test - Tx: - Tx glucocorticoid-suppressible, hyperaldosteronism with hydrocortisone or prednisone - Tx aldosteronoma with surgical removal - Tx bilateral adrenal hyperplasia with spironolactone, which returns blood pressure and potassium levels to normal. Try amiloride if the pt cannot tolerate spironolactone. If the condition cannot be controlled medically, a unilateral adrenalectomy may be helpful.

Question 109

PHEOCHROMOCYTOMA - Path: Catecholamine-secreting tumor that originates from the chromaffin cells. Typically, it develops in the adrenal medulla - About 1 in 5 is bilateral - Pt: Episodic Paroxysmal, pain (headache), pressure (HTN), palpitations (tachy), perspirations - HTN is almost always present in children with pheo and is usually sustained - Dx: - Children differ from adults in that primary catecholamine is norepinephrine rather than epinephrine. - Measurement of ______ is the best test for detection of pheos in children. - Urinary vanillylmandelic acid (VMA) and metanephrine, the major metabolites of epinephrine and norepinephrine, respectively, are increased. - (Children with neuroblastoma can also have elevated levels, but not as high as seen with pheo; HTN is usually not seen with neuroblastoma) - Imaging - Do not forget that bilateral disease is relatively common. - Tx: - Removal of the tumor, a serious and dangerous surgery. - Preoperatively, it is very important to give both ___- (prevents HTN) and ___.

Answer 109

PHEOCHROMOCYTOMA - Path: Catecholamine-secreting tumor that originates from the chromaffin cells. Typically, it develops in the adrenal medulla - About 1 in 5 is bilateral - Pt: Episodic Paroxysmal, pain (headache), pressure (HTN), palpitations (tachy), perspirations - HTN is almost always present in children with pheo and is usually sustained - Dx: - Children differ from adults in that primary catecholamine is norepinephrine rather than epinephrine. - Measurement of plasma free metanephrines is the best test for detection of pheos in children. - Urinary vanillylmandelic acid (VMA) and metanephrine, the major metabolites of epinephrine and norepinephrine, respectively, are increased. - (Children with neuroblastoma can also have elevated levels, but not as high as seen with pheo; HTN is usually not seen with neuroblastoma) - Imaging - Do not forget that bilateral disease is relatively common. - Tx: - Removal of the tumor, a serious and dangerous surgery. - Preoperatively, it is very important to give both alpha- (prevents HTN) and beta-blockers.

Question 110

PRIMARY HYPOGONADISM - MALE - Causes: A whole list - Clinical manifestations - Suspect primary hypogonadism if the testes and penis are abnormally small. - Diagnosis - Confirm the diagnosis by finding low testosterone level in the setting of high LH and FSH levels.

Answer 110

PRIMARY HYPOGONADISM - MALE - Causes: A whole list - Clinical manifestations - Suspect primary hypogonadism if the testes and penis are abnormally small. - Diagnosis - Confirm the diagnosis by finding low testosterone level in the setting of high LH and FSH levels.

Question 111

SECONDARY HYPOGONADOTROPIC HYPOGONADISM (MALES) - Deficiency of LH, FSH, or both. - Causes: - Hypopituitarism can result in hypogonadotropic hypogonadism if it causes a decrease in FSH or LH. - Microphallus (<2.5cm) in the newborn male with GH deficiency and undescended testes suggests that gonadotropin deficiency also exists. - Isolated deficiency of gonadotropin - affects the hypothalamus (GnRH deficiency) instead of the pituitary

Answer 111

SECONDARY HYPOGONADOTROPIC HYPOGONADISM (MALES) - Deficiency of LH, FSH, or both. - Causes: - Hypopituitarism can result in hypogonadotropic hypogonadism if it causes a decrease in FSH or LH. - Microphallus (<2.5cm) in the newborn male with GH deficiency and undescended testes suggests that gonadotropin deficiency also exists. - Isolated deficiency of gonadotropin - affects the hypothalamus (GnRH deficiency) instead of the pituitary

Question 112

``` PRIMARY HYPOGONADISM (FEMALES) XX Gonadal Dysgenesis (Pure ovarian dysgenesis) - Pt: - Normal external genitalia, normal growth, and are normal otherwise. - At puberty, however, sexual maturation does not happen. - Streak ovaries only. ``` - Perrault syndrome = ___ + ____

Answer 112

``` PRIMARY HYPOGONADISM (FEMALES) XX Gonadal Dysgenesis (Pure ovarian dysgenesis) - Pt: - Normal external genitalia, normal growth, and are normal otherwise. - At puberty, however, sexual maturation does not happen. - Streak ovaries only. ``` - Perrault syndrome = XX gonadal dysgenesis + sensorineural hearing loss

Question 113

In a girl >16yo with primary amenorrhea, the single most useful study is a _____.

Answer 113

In a girl >16yo with primary amenorrhea, the single most useful study is a karyotype.

Question 114

POLYCYSTIC OVARY SYNDROME (PCOS aka Stein-Leventhal syndrome) - Pt: Irregular menses with symptoms or biochemical evidence of hyperandrogenism (hirsutism, acne) +/- bilaterally enlarged polycystic ovaries - Lab findings: 1 or more elevated androgens: total testosterone, (esp) free testosterone, dehydroepiandrosterone, or androstenedione. Elevated ___ levels relative to ____ ( ratio) occur in only ½ of PCOS patients - Dx: Both of following features not otherwise explainable: - Evidence of hyperandrogenism (eg hirsutism, persistent acne, male pattern alopecia, persistent testosterone elevation above adult normal), particularly if confirmed by an elevated serum testosterone, and - Finding elevated levels of testosterone (especially free testosterone) with an elevated LH:FSH ratio (3-5:1) helps diagnosis. - Menstrual pattern lasting >1 year that is abnormal for gynecologic age (years since menarche) - Can consider US of polycystic ovaries (at least 12 follicles measuring 2-9mm or increased ovarian volume >10cc) - Tx: - Tx ovarian hyperandrogenism with ___ - Tx hirsutism with electrolysis and _____ - an antiandrogenic agent that works by competing at the androgen receptor site and by inhibiting 5-alpha-reductase, thus reducing conversion of testosterone to dihydrotestosterone.

Answer 114

POLYCYSTIC OVARY SYNDROME (PCOS aka Stein-Leventhal syndrome) - Pt: Irregular menses with symptoms or biochemical evidence of hyperandrogenism (hirsutism, acne) +/- bilaterally enlarged polycystic ovaries - Lab findings: 1 or more elevated androgens: total testosterone, (esp) free testosterone, dehydroepiandrosterone, or androstenedione. Elevated LH levels relative to FSH (LH:FSH ratio) occur in only ½ of PCOS patients - Dx: Both of following features not otherwise explainable: - Evidence of hyperandrogenism (eg hirsutism, persistent acne, male pattern alopecia, persistent testosterone elevation above adult normal), particularly if confirmed by an elevated serum testosterone, and - Finding elevated levels of testosterone (especially free testosterone) with an elevated LH:FSH ratio (3-5:1) helps diagnosis. - Menstrual pattern lasting >1 year that is abnormal for gynecologic age (years since menarche) - Can consider US of polycystic ovaries (at least 12 follicles measuring 2-9mm or increased ovarian volume >10cc) - Tx: - Tx ovarian hyperandrogenism with oral contraceptives - Tx hirsutism with electrolysis and spironolactone - an antiandrogenic agent that works by competing at the androgen receptor site and by inhibiting 5-alpha-reductase, thus reducing conversion of testosterone to dihydrotestosterone.

Question 115

46, XX DSD - Differential diagnosis is easy - too many androgens! - _______ is the most common cause of 46, XX DSD. - Virilizing maternal tumors producing androgens - Maternal drugs - Maternal exposure to androgens (such as testosterone or 17-methyltestosterone, use of danazol to tx endometriosis has androgen effects) can produce virilization in the female fetus: - If the mom is exposed during 8-13 weeks of gestation, the baby can have labial fusion - If exposure is after the 13th week, the baby can have clitoral enlargement - If mom is exposed continually from week 8 until delivery, the baby has labial fusion and clitoral enlargement.

Answer 115

46, XX DSD - Differential diagnosis is easy - too many androgens! - CAH is the most common cause of 46, XX DSD. - Virilizing maternal tumors producing androgens - Maternal drugs - Maternal exposure to androgens (such as testosterone or 17-methyltestosterone, use of danazol to tx endometriosis has androgen effects) can produce virilization in the female fetus: - If the mom is exposed during 8-13 weeks of gestation, the baby can have labial fusion - If exposure is after the 13th week, the baby can have clitoral enlargement - If mom is exposed continually from week 8 until delivery, the baby has labial fusion and clitoral enlargement.

Question 116

``` Mullerian Agenesis (Mayer-Rokitansky-Kurter Syndrome) - Path: Idiopathic loss of mullerian ducts (XX). Mullerian agenesis with primary amenorrhea and absence/hypoplasia of the vagina, cervix, and/or uterus ``` - Pt: Secondary sex characteristics, female external genitalia, ovaries. No uterus or tubes - Can look like androgen insensitivity, but individuals with Mullerian agenesis will have normal axillary and pubic hair development, 46 XX karyotype, and female levels of testosterone - Dx: karyotype and US - Tx: elevate vagina surgically, can’t have kids bc no uterus

Answer 116

``` Mullerian Agenesis (Mayer-Rokitansky-Kurter Syndrome) - Path: Idiopathic loss of mullerian ducts (XX). Mullerian agenesis with primary amenorrhea and absence/hypoplasia of the vagina, cervix, and/or uterus ``` - Pt: Secondary sex characteristics, female external genitalia, ovaries. No uterus or tubes - Can look like androgen insensitivity, but individuals with Mullerian agenesis will have normal axillary and pubic hair development, 46 XX karyotype, and female levels of testosterone - Dx: karyotype and US - Tx: elevate vagina surgically, can’t have kids bc no uterus

Question 117

46, XY DSD DSDs Due to Defects in Testicular Differentiation Denys-Drash Syndrome - Pt: Triad: ____, ___, and ____ - At high risk for XY gonadal dysgenesis with ambiguous genitalia. - Pts have a total deficiency of testicular function that is so complete that Mullerian ducts are found.

Answer 117

46, XY DSD DSDs Due to Defects in Testicular Differentiation Denys-Drash Syndrome - Pt: Triad: Nephropathy, ambiguous genitalia, and Wilms tumor. - At high risk for XY gonadal dysgenesis with ambiguous genitalia. - Pts have a total deficiency of testicular function that is so complete that Mullerian ducts are found.

Question 118

Swyer Syndrome (XY Pure Gonadal Dysgenesis) (think SRY) - “Pure” gonadal dysgenesis bc it is not of chromosomal origin (although origin is genetic) and is not associated with physical or growth findings. - The dysgenesis results in a pt with no Leydig cells, so there is no testosterone to support the Wolffian structures; and the Sertoli cells do not form, so the Mullerian structures develop. - Path: Most pts have a mutation in the SRY gene, but the Y chromosome is cytogenetically normal. - Pt: - Complete female phenotype at birth, with vagina, uterus, and uterine tubes. - The gonads are undifferentiated streaks - Testosterone levels are low.

Answer 118

Swyer Syndrome (XY Pure Gonadal Dysgenesis) (think SRY) - “Pure” gonadal dysgenesis bc it is not of chromosomal origin (although origin is genetic) and is not associated with physical or growth findings. - The dysgenesis results in a pt with no Leydig cells, so there is no testosterone to support the Wolffian structures; and the Sertoli cells do not form, so the Mullerian structures develop. - Path: Most pts have a mutation in the SRY gene, but the Y chromosome is cytogenetically normal. - Pt: - Complete female phenotype at birth, with vagina, uterus, and uterine tubes. - The gonads are undifferentiated streaks - Testosterone levels are low.

Question 119

Leydig Cell Aplasia - Path: Mutation in LHCG receptor (which responds to hCG and LH) - Pt: - Female phenotypes, but there can be mild virilization. - Uterus and uterine tubes are absent (Sertoli cells are present, so MIS is present; the Leydig cells are absent, so there is no testosterone to support the Wolffian structures)

Answer 119

Leydig Cell Aplasia - Path: Mutation in LHCG receptor (which responds to hCG and LH) - Pt: - Female phenotypes, but there can be mild virilization. - Uterus and uterine tubes are absent (Sertoli cells are present, so MIS is present; the Leydig cells are absent, so there is no testosterone to support the Wolffian structures)

Question 120

Persistent Mullerian Duct Syndrome - Path: Problem with Sertoli cells: They do not make MIS, so the Mullerian ducts survive. - Pt: Phenotypic males that are virilized but have Mullerian ducts - (ie pt has surgery to correct cryptorchidism or inguinal hernia, and surgeon discovered uterine tubes and uterus) - Karyotype is ____!

Answer 120

Persistent Mullerian Duct Syndrome - Path: Problem with Sertoli cells: They do not make MIS, so the Mullerian ducts survive. - Pt: Phenotypic males that are virilized but have Mullerian ducts - (ie pt has surgery to correct cryptorchidism or inguinal hernia, and surgeon discovered uterine tubes and uterus) - Karyotype is XY! (NOT XX/XY)

Question 121

5alpha-Reductase Deficiency - Path: Cannot convert testosterone to DHT. Decreased production of DHT causes severe ambiguity of the external genitalia.

Answer 121

5alpha-Reductase Deficiency - Path: Cannot convert testosterone to DHT. Decreased production of DHT causes severe ambiguity of the external genitalia.

Question 122

Androgen Insensitivity Syndrome /Testicular feminization - Insensitivity to androgens constitutes the most common cause of 46,XY DSD - Normal male genotype (X,Y) - Pt: Variety of presentations, from complete phenotypic females, to males with various forms of ambiguous genitalia, to males with normal genitalia but infertility. - All of these infants have testes (often undescended) and normal or elevated testosterone. High LH, testosterone, and DHT levels.

Answer 122

Androgen Insensitivity Syndrome /Testicular feminization - Insensitivity to androgens constitutes the most common cause of 46,XY DSD - Normal male genotype (X,Y) - Pt: Variety of presentations, from complete phenotypic females, to males with various forms of ambiguous genitalia, to males with normal genitalia but infertility. - All of these infants have testes (often undescended) and normal or elevated testosterone. High LH, testosterone, and DHT levels.

Question 123

Complete androgen insensitivity - 1-2% of girls who go for inguinal hernia repair have this disorder! - Pt: - Infant is phenotypical female at birth and is raised as such. - External genitalia are female, and the vagina ends in a blind pouch (“blind pouch” is buzzword for androgen insensitivity). - Pt for complete androgen insensitivity syndrome - Primary amenorrhea, normal breast development, lack of axillary and pubic hair, blind vaginal pouch on exam. - US may reveal intra-abdominal testes and a lack of all Mullerian structures - Labs will show male levels of testosterone - The clue for this disorder, unlike others (Swyer syndrome, true agonadism, Leydig cell aplasia) is that testosterone levels are normal or high, and girls have normal breast development due to aromatization of testosterone to estrogen (have a normal estrogen receptor) - Know how to differentiate Swyer syndrome from androgen insensitivity syndrome. Both are XY genotype with female phenotype, but there are definitive differences in etiology and labs - Important points are that, with Swyer syndrome, the gonads are undifferentiated streaks and the testosterone levels are low; with androgen insensitivity, the gonads are testes and the testosterone levels are high.

Answer 123

Complete androgen insensitivity - 1-2% of girls who go for inguinal hernia repair have this disorder! - Pt: - Infant is phenotypical female at birth and is raised as such. - External genitalia are female, and the vagina ends in a blind pouch (“blind pouch” is buzzword for androgen insensitivity). - Pt for complete androgen insensitivity syndrome - Primary amenorrhea, normal breast development, lack of axillary and pubic hair, blind vaginal pouch on exam. - US may reveal intra-abdominal testes and a lack of all Mullerian structures - Labs will show male levels of testosterone - The clue for this disorder, unlike others (Swyer syndrome, true agonadism, Leydig cell aplasia) is that testosterone levels are normal or high, and girls have normal breast development due to aromatization of testosterone to estrogen (have a normal estrogen receptor) - Know how to differentiate Swyer syndrome from androgen insensitivity syndrome. Both are XY genotype with female phenotype, but there are definitive differences in etiology and labs - Important points are that, with Swyer syndrome, the gonads are undifferentiated streaks and the testosterone levels are low; with androgen insensitivity, the gonads are testes and the testosterone levels are high.

Question 124

OVOTESTICULAR DISORDER OF SEXUAL DIFFERENTIATION (DSD) (previously known as true hermaphroditism) - Occurs when both ovarian and testicular tissues are present. - Majority of pts are 46, XX.

Answer 124

OVOTESTICULAR DISORDER OF SEXUAL DIFFERENTIATION (DSD) (previously known as true hermaphroditism) - Occurs when both ovarian and testicular tissues are present. - Majority of pts are 46, XX.

Question 125

HYPERCHOLESTEROLEMIA - Universal nonfasting screening (total and HDL-C levels) for lipid disorders should occur between 9-11 years of age and then again at age 17-21 years - Children ages 2-8 years and 12-16 years should have measured 2x fasting lipid profiles (average results) IF: - Positive family hx: - Early _____disease (<55yo for man or <65 for woman) in a 1st degree relative (parent, grandparent, aunt/uncle, or sibling) - A parent ever had a total cholesterol >____mg/dL or known familial dyslipidemia - For children between ages 2-8yo who have a parent with a total cholesterol of >240 mg/dL, a fasting lipid profile should be obtained and then repeated after 2 weeks-3 months - Child has BMI >85%ile, or an underlying medical condition associated with cardiovascular disease (eg DM, HTN, chronic renal disease, significant tobacco smoke exposure) - Moderate risk conditions - Kawasaki disease with regressed coronary aneurysms - Chronic inflammatory disease (SLE, juvenile rheumatoid arthritis) - HIV infection - Nephrotic syndrome - High risk conditions - T1DM and G2DM - CKD/ESRD/post-renal transplant - Post-orthopedic heart transplant - Kawasaki disease with current aneurysms - Screening results: - Calculate non-HDL-C by subtracting HDL-C from total cholesterol. If non-HDL-C >___ mg/dL and/or HDL-C 1 less than ___mg/dL, obtain 2 fasting lipid panels and average the results. - Tx: - Pharmacotherapy is not indicated in children less than ___yo unless there is >1 associated RF for cardiovascular disease (eg diabetes, HTN requiring drug therapy, BMI >97%ile) or a hx of familial hypercholesterolemia or hypertriglyceridemia. - Pharmacotherapy in children >___yo with dyslipidemia is indicated only when dietary and lifestyle changes fail to improve lipid and cholesterol levels. - Consider pharmacotherapy in children >_yo with an LDL-C >___ mg/dL who do not respond to lifestyle changes after 6mo

Answer 125

HYPERCHOLESTEROLEMIA - Universal nonfasting screening (total and HDL-C levels) for lipid disorders should occur between 9-11 years of age and then again at age 17-21 years - Children ages 2-8 years and 12-16 years should have measured 2x fasting lipid profiles (average results) IF: - Positive family hx: - Early coronary heart disease (<55yo for man or <65 for woman) in a 1st degree relative (parent, grandparent, aunt/uncle, or sibling) - A parent ever had a total cholesterol >240mg/dL or known familial dyslipidemia - For children between ages 2-8yo who have a parent with a total cholesterol of >240 mg/dL, a fasting lipid profile should be obtained and then repeated after 2 weeks-3 months - Child has BMI >85%ile, or an underlying medical condition associated with cardiovascular disease (eg DM, HTN, chronic renal disease, significant tobacco smoke exposure) - Moderate risk conditions - Kawasaki disease with regressed coronary aneurysms - Chronic inflammatory disease (SLE, juvenile rheumatoid arthritis) - HIV infection - Nephrotic syndrome - High risk conditions - T1DM and G2DM - CKD/ESRD/post-renal transplant - Post-orthopedic heart transplant - Kawasaki disease with current aneurysms - Screening results: - Calculate non-HDL-C by subtracting HDL-C from total cholesterol. If non-HDL-C >145 mg/dL and/or HDL-C <40mg/dL, obtain 2 fasting lipid panels and average the results. - Tx: - Pharmacotherapy is not indicated in children <10yo unless there is >1 associated RF for cardiovascular disease (eg diabetes, HTN requiring drug therapy, BMI >97%ile) or a hx of familial hypercholesterolemia or hypertriglyceridemia. - Pharmacotherapy in children >10yo with dyslipidemia is indicated only when dietary and lifestyle changes fail to improve lipid and cholesterol levels. - Consider pharmacotherapy in children >8yo with an LDL-C >190 mg/dL who do not respond to lifestyle changes after 6mo

Question 126

Familial Combined Hyperlipidemia - _____ is usually elevated but LDL receptor activity is normal - Types - Type 2a: Elevated LDL alone - Type 2b: Elevated LDL and triglyceride - Type 4: Normal LDL and elevated triglyceride - Pt: - Presents in adults with early coronary artery disease - Corneal arcus (ie deposition of lipid in the peripheral corneal stroma) can occur, but xanthomas do NOT - Tx: Diet changes, exercise, statin drugs to lower LDL cholesterol

Answer 126

Familial Combined Hyperlipidemia - LDL is usually elevated but LDL receptor activity is normal - Types - Type 2a: Elevated LDL alone - Type 2b: Elevated LDL and triglyceride - Type 4: Normal LDL and elevated triglyceride - Pt: - Presents in adults with early coronary artery disease - Corneal arcus (ie deposition of lipid in the peripheral corneal stroma) can occur, but xanthomas do NOT - Tx: Diet changes, exercise, statin drugs to lower LDL cholesterol

Question 127

Familial Hypercholesterolemia (FH) - ______ Inheritance? - Path: Mutations at the gene locus for LDL receptor protein - Pt: - Achilles tendonitis or tenosynovitis can be the 1st clue in a teenage pt. - Tendon and tuberous xanthomas occur between 5-15yo. - Homozygous children develop planar xanthomas (flat, orange-colored skin lesions from birth - 5yo. - Look for a child with parents who have ________. - Serum cholesterol is usually 600-1000 mg/dL. - Tx: Diet, exercise changes, cholesterol-lowering statins. In severe cases, LDL apheresis. - Prognosis: - Untreated FH male heterozygotes have a 100% risk of developing coronary heart disease by 70 yo

Answer 127

Familial Hypercholesterolemia (FH) - AD - Path: Mutations at the gene locus for LDL receptor protein - Pt: - Achilles tendonitis or tenosynovitis can be the 1st clue in a teenage pt. - Tendon and tuberous xanthomas occur between 5-15yo. - Homozygous children develop planar xanthomas (flat, orange-colored skin lesions from birth - 5yo. - Look for a child with parents who have tendon xanthomas or with many 1st degree relatives with highly elevated LDL cholesterol levels. - Serum cholesterol is usually 600-1000 mg/dL. - Tx: Diet, exercise changes, cholesterol-lowering statins. In severe cases, LDL apheresis. - Prognosis: - Untreated FH male heterozygotes have a 100% risk of developing coronary heart disease by 70 yo

Question 128

Lipoprotein Lipase (LPL) deficiency - ___inheritance? - Path: Children with this disorder have impaired chylomicron clearance, resulting in huge increases of chylomicrons with marked _______ (up to 10,000mg/dL) in the plasma, giving it a milky or lipemic appearance. - Pt: - Presents before 10yo with _______ as the initial complaints - Management: - Symptoms will abates with strict nutrition therapy; a total dietary restriction of fat

Answer 128

Lipoprotein Lipase (LPL) deficiency - AR - Path: Children with this disorder have impaired chylomicron clearance, resulting in huge increases of chylomicrons with marked hypertriglyceridemia (up to 10,000mg/dL) in the plasma, giving it a milky or lipemic appearance. - Pt: - Presents before 10yo with abdominal pain as the initial complaints - Management: - Symptoms will abates with strict nutrition therapy; a total dietary restriction of fat

Question 129

Familial Hypertriglyceridemia - Normal total cholesterol and LDL levels. Elevated VLDL and triglyceride levels (Type 4 pattern). - Pt: If triglyceride level >2,000 mg/dL, pt can present with pancreatitis

Answer 129

Familial Hypertriglyceridemia - Normal total cholesterol and LDL levels. Elevated VLDL and triglyceride levels (Type 4 pattern). - Pt: If triglyceride level >2,000 mg/dL, pt can present with pancreatitis

Question 130

Dysbetalipoproteinemia (Hyperlipoproteinemia Type 3) | - Elevated ___ AND ____ levels.

Answer 130

Dysbetalipoproteinemia (Hyperlipoproteinemia Type 3) | - Elevated cholesterol AND triglyceride levels.

Question 131

Abetalipoproteinemia (Bassen-Kornzweig Syndrome) - AR - Chylomicrons, VLDL, and LDL are absent from plasma. Cholesterol and triglycerides are low. - Clinically important bc the fat-soluble vitamins (ADEK) are dependent and cannot be absorbed or transported properly. However, only vitamin E deficiency is clinically apparent - Dx: Jejunal biopsy, failure to form chylomicrons after a fatty meal, or demonstration of the absence of apoB in plasma

Answer 131

Abetalipoproteinemia (Bassen-Kornzweig Syndrome) - AR - Chylomicrons, VLDL, and LDL are absent from plasma. Cholesterol and triglycerides are low. - Clinically important bc the fat-soluble vitamins (ADEK) are dependent and cannot be absorbed or transported properly. However, only vitamin E deficiency is clinically apparent - Dx: Jejunal biopsy, failure to form chylomicrons after a fatty meal, or demonstration of the absence of apoB in plasma

Question 132

Smith-Lemli-Opitz Syndrome - ____ inheritance? - Path: Mutation in enzyme necessary for cholesterol synthesis. Defect in cholesterol biosynthesis resulting from deficient activity of 7-dehydrocholesterol reductase - Pt: Range from isolated parietal 2-3-toe syndactyly with developmental delay to severely malformed fetuses that die in utero. - Severe form: - Facial features: Microcephaly, hypertelorism, broad nasal tip, cleft palate, low-set ears, narrow bifrontal diameter, ptosis, anteverted nostrils, micrognathia - Postaxial polydactyly - Overlapping fingers - Abnormal thumbs - Partial _______ - Hypospadias - Ambiguous genitalia - Genotypic males commonly have genital ambiguity. Mullerian ducts are absent. - Syndrome has 2 types: - Type I - Classic form as above. Associated with pyloric stenosis - Type II - Postaxial polydactyly and extremely abnormal external genitalia. It is associated with Hirschsprung disease and is fatal within a year. - Serum levels of _____ will be elevated due to deficient enzyme that leads to backup (level inversely correlates with severity of disease). Cholesterol will be normal/low. - Tx: No proven effective tx.

Answer 132

Smith-Lemli-Opitz Syndrome - AR - Path: Mutation in enzyme necessary for cholesterol synthesis. Defect in cholesterol biosynthesis resulting from deficient activity of 7-dehydrocholesterol reductase - Pt: Range from isolated parietal 2-3-toe syndactyly with developmental delay to severely malformed fetuses that die in utero. - Severe form: - Facial features: Microcephaly, hypertelorism, broad nasal tip, cleft palate, low-set ears, narrow bifrontal diameter, ptosis, anteverted nostrils, micrognathia - Postaxial polydactyly - Overlapping fingers - Abnormal thumbs - Partial 2-3-toe syndactyly - Hypospadias - Ambiguous genitalia - Genotypic males commonly have genital ambiguity. Mullerian ducts are absent. - Syndrome has 2 types: - Type I - Classic form as above. Associated with pyloric stenosis - Type II - Postaxial polydactyly and extremely abnormal external genitalia. It is associated with Hirschsprung disease and is fatal within a year. - Serum levels of 7-dehydrocholesterol will be elevated due to deficient enzyme that leads to backup (level inversely correlates with severity of disease). Cholesterol will be normal/low. - Tx: No proven effective tx.

Question 133

Screening - ADA recommends screening for type 2 DM in at-risk children and adolescents at least every 3 years. Screening is recommended in pts who are overweight (BMI 85%ile) and have at least 1 of the following risk factors ADA Diagnosis 2017 Diagnosis made by using 1 of 4 criteria - 1) Fasting plasma glucose >___mg/dL - 2) Classic symptoms of hyperglycemia (eg polyuria, polydipsia) and a random plasma glucose >___mg/dL - 3) A 2-hour plasma glucose >___mg/dL during a standard oral glucose tolerance test (75g) - 4) Hemoglobin A1c >___ - ADA-recommended Hgb A1c is <7.5% for all pediatric age groups. - Note: Any abnormal value of testing must be repeated on a different day before the diagnosis of diabetes is confirmed.

Answer 133

Screening - ADA recommends screening for type 2 DM in at-risk children and adolescents at least every 3 years. Screening is recommended in pts who are overweight (BMI 85%ile) and have at least 1 of the following risk factors ADA Diagnosis 2017 Diagnosis made by using 1 of 4 criteria - 1) Fasting plasma glucose >126mg/dL - 2) Classic symptoms of hyperglycemia (eg polyuria, polydipsia) and a random plasma glucose >200mg/dL - 3) A 2-hour plasma glucose >200mg/dL during a standard oral glucose tolerance test (75g) - 4) Hemoglobin A1c >6.5 - ADA-recommended Hgb A1c is <7.5% for all pediatric age groups. - Note: Any abnormal value of testing must be repeated on a different day before the diagnosis of diabetes is confirmed.

Question 134

Type 1 Diabetes Mellitus - Children with congenital rubella have an increased risk of DM. - Type 1 DM is linked to certain HLAs, particularly HLA-DR3, HLA-DR4, HLA-B8, HLA-BW15 - Pt: - Classically presents with polyuria, polydipsia, and weight loss. Normally, this continues for <1 months - Clues to think about: - Enuresis in a previously toilet-trained child - Lethargy or weakness - Weight loss - In adolescent girls, look for skin infections or vaginal candidiasis. - A candida diaper dermatitis that does not respond to therapy provides a possible clue to the presence of glycosuria in an infant. - Ketoacidosis is the presenting finding in about 25% of children with diabetes. - Regular screening of asymptomatic child or family members of a pt with Type 1 DM is NOT recommended. - Work-up - If necessary, obtain pancreatic autoantibodies - islet cell, insulin glutamic acid decarboxylase (GAD), and insulinoma-associated antigen-2 (IA-2 / tyrosine phosphatase - to differentiate DM1 from DM2 - Screening guidelines: 2017 ADA guidelines recommend starting at 5 years after diagnosis of Type 1 DM: - At time of diagnosis (once glycemic control is established), American Diabetes Association recommends screening for thyroid disease with TSH, free T4, and thyroid antibody (thyroid peroxidase, antithyroglobulin antibodies) and every 1-2 years - Celiac disease: Check at diagnosis with tissue transglutaminase or antiendomysial antibodies + IgA, and then any time with symptoms - Screening for retinopathy with ophthalmologic examination when at least 10yo and at least 3-5 years of diabetes - Begin yearly screening for urine albumin excretion (nephropathy) in DM 1 patients 3-5 years after initial diagnosis and is at least 10 yo - Fasting lipids (once metabolic control is normalized): if there is a high-risk family hx check at diagnosis or 2 years of age, otherwise check at age 10yo - Long-term complications of DM1 - Retinopathy - Present in 20% of DM1 pts after only 10 years of disease and in 45-60% after 20 years - Nephropathy - affects nearly 40% of those with DM1 for 25+ years - Tx persistent micro- or macroalbuminuria (albuminuria 30-300 mg/24hr) with ACE inhibitors or angiotensin II receptor blockers (ARBs) - Neuropathy - Autoimmune thyroid disease is the most common associated autoimmune disease seen in children with T1D - Celiac disease - 2nd most common associated autoimmune condition after autoimmune thyroid disease. - Celiac disease has increased incidence in type 1 diabetics, presents as recurrent hypoglycemia in children with type 1 diabetes - Maintenance therapy for DM1 - ADA 2017 guidelines recommend the use of intensive insulin therapy for all pts with DM1. - Other treatment considerations - For patients not following check/medication schedule, the action most likely to help is to give instructions to check and record at least 4 glucose levels per day and conduct a follow-up review of his glucose log in 1 week. - Honeymoon Period - Time during which there is residual B-cell function, esp in the early months after diagnosis of diabetes. - These children with DM1 demonstrate good glycemic control with minimal insulin requirements - the “honeymoon” effect. - Dawn Phenomenon - Normal occurrence in which there is increased blood glucose 4-7am with no preceding hypoglycemia. - Management of DM1 during infections - During intercurrent illnesses, whether infection or trauma, children with diabetes require more insulin than their baseline. - A good rule is to add 10-20% to each dose to the rapid-acting insulin given for meal coverage or glucose correction, if ketones are present. - Pts also need to drink plenty of fluids during an illness - about 8 ounces of a nonsugary fluid an hour.

Answer 134

Type 1 Diabetes Mellitus - Children with congenital rubella have an increased risk of DM. - Type 1 DM is linked to certain HLAs, particularly HLA-DR3, HLA-DR4, HLA-B8, HLA-BW15 - Pt: - Classically presents with polyuria, polydipsia, and weight loss. Normally, this continues for <1 months - Clues to think about: - Enuresis in a previously toilet-trained child - Lethargy or weakness - Weight loss - In adolescent girls, look for skin infections or vaginal candidiasis. - A candida diaper dermatitis that does not respond to therapy provides a possible clue to the presence of glycosuria in an infant. - Ketoacidosis is the presenting finding in about 25% of children with diabetes. - Regular screening of asymptomatic child or family members of a pt with Type 1 DM is NOT recommended. - Work-up - If necessary, obtain pancreatic autoantibodies - islet cell, insulin glutamic acid decarboxylase (GAD), and insulinoma-associated antigen-2 (IA-2 / tyrosine phosphatase - to differentiate DM1 from DM2 - Screening guidelines: 2017 ADA guidelines recommend starting at 5 years after diagnosis of Type 1 DM: - At time of diagnosis (once glycemic control is established), American Diabetes Association recommends screening for thyroid disease with TSH, free T4, and thyroid antibody (thyroid peroxidase, antithyroglobulin antibodies) and every 1-2 years - Celiac disease: Check at diagnosis with tissue transglutaminase or antiendomysial antibodies + IgA, and then any time with symptoms - Screening for retinopathy with ophthalmologic examination when at least 10yo and at least 3-5 years of diabetes - Begin yearly screening for urine albumin excretion (nephropathy) in DM 1 patients 3-5 years after initial diagnosis and is at least 10 yo - Fasting lipids (once metabolic control is normalized): if there is a high-risk family hx check at diagnosis or 2 years of age, otherwise check at age 10yo - Long-term complications of DM1 - Retinopathy - Present in 20% of DM1 pts after only 10 years of disease and in 45-60% after 20 years - Nephropathy - affects nearly 40% of those with DM1 for 25+ years - Tx persistent micro- or macroalbuminuria (albuminuria 30-300 mg/24hr) with ACE inhibitors or angiotensin II receptor blockers (ARBs) - Neuropathy - Autoimmune thyroid disease is the most common associated autoimmune disease seen in children with T1D - Celiac disease - 2nd most common associated autoimmune condition after autoimmune thyroid disease. - Celiac disease has increased incidence in type 1 diabetics, presents as recurrent hypoglycemia in children with type 1 diabetes - Maintenance therapy for DM1 - ADA 2017 guidelines recommend the use of intensive insulin therapy for all pts with DM1. - Other treatment considerations - For patients not following check/medication schedule, the action most likely to help is to give instructions to check and record at least 4 glucose levels per day and conduct a follow-up review of his glucose log in 1 week. - Honeymoon Period - Time during which there is residual B-cell function, esp in the early months after diagnosis of diabetes. - These children with DM1 demonstrate good glycemic control with minimal insulin requirements - the “honeymoon” effect. - Dawn Phenomenon - Normal occurrence in which there is increased blood glucose 4-7am with no preceding hypoglycemia. - Management of DM1 during infections - During intercurrent illnesses, whether infection or trauma, children with diabetes require more insulin than their baseline. - A good rule is to add 10-20% to each dose to the rapid-acting insulin given for meal coverage or glucose correction, if ketones are present. - Pts also need to drink plenty of fluids during an illness - about 8 ounces of a nonsugary fluid an hour.

Question 135

Type 2 Diabetes Mellitus - Genetic component is much stronger in Type 2 than in Type 1. - RFs and recommendations for DM2 screening from ADA include: - 1) Overweight with BMI >85%ile for age and sex, weight for height >85%ile, or weight >120% of ideal for height, and - 2) Any 2 of the following RFs: - Family hx of DM2 in 1st or 2nd degree relative - Race/ethnicity: Native American, African American, Latino, Asian American, Pacific Islander - Signs of insulin resistance or conditions associated with insulin resistance: acanthosis nigricans, HTN, dyslipidemia, PCOS, or SGA birth weight - Maternal hx of DM or gestation DM during the pregnancy - Recommended screening at 10yo or puberty (if that occurs at <10yo), and follow every 3 years if normal. - Tx: - If the child is not metabolically decompensated at presentation, Metformin is the 1st line therapy for those who do not meet criteria for insulin - Insulin should be initiated when ketosis is present, when the plasma glucose is >250 mg/dl or HgA1c is >9%, or when diagnosis of type 1 DM vs type 2 DM is not clear. - ADA recommends that insulin should be initiated at diagnosis for youth with DM2 if the blood glucose is >250 mg/dL (13.9mmol/L) or HgbA1c >8.5%. - Screening: Screening for comorbidites and long-term complications should begin at diagnosis as hyperglycemia is present for an undetermined amount of time prior as DM2 has a more insidious progression - Urine microalbumin at diagnosis and then yearly - Begin yearly screening with spot urine albumin-to-creatinine ratio for albuminuria/nephropathy - Serum fasting lipid panel as soon as metabolically stable and then yearly (uncontrolled hyperglycemia can cause abnormal lipids) - Blood pressure screening at every visit - Retinal dilated eye exams for retinopathy at diagnosis and yearly - Screening for nonalcoholic liver disease at diagnosis and yearly

Answer 135

Type 2 Diabetes Mellitus - Genetic component is much stronger in Type 2 than in Type 1. - RFs and recommendations for DM2 screening from ADA include: - 1) Overweight with BMI >85%ile for age and sex, weight for height >85%ile, or weight >120% of ideal for height, and - 2) Any 2 of the following RFs: - Family hx of DM2 in 1st or 2nd degree relative - Race/ethnicity: Native American, African American, Latino, Asian American, Pacific Islander - Signs of insulin resistance or conditions associated with insulin resistance: acanthosis nigricans, HTN, dyslipidemia, PCOS, or SGA birth weight - Maternal hx of DM or gestation DM during the pregnancy - Recommended screening at 10yo or puberty (if that occurs at <10yo), and follow every 3 years if normal. - Tx: - If the child is not metabolically decompensated at presentation, Metformin is the 1st line therapy for those who do not meet criteria for insulin - Insulin should be initiated when ketosis is present, when the plasma glucose is >250 mg/dl or HgA1c is >9%, or when diagnosis of type 1 DM vs type 2 DM is not clear. - ADA recommends that insulin should be initiated at diagnosis for youth with DM2 if the blood glucose is >250 mg/dL (13.9mmol/L) or HgbA1c >8.5%. - Screening: Screening for comorbidites and long-term complications should begin at diagnosis as hyperglycemia is present for an undetermined amount of time prior as DM2 has a more insidious progression - Urine microalbumin at diagnosis and then yearly - Begin yearly screening with spot urine albumin-to-creatinine ratio for albuminuria/nephropathy - Serum fasting lipid panel as soon as metabolically stable and then yearly (uncontrolled hyperglycemia can cause abnormal lipids) - Blood pressure screening at every visit - Retinal dilated eye exams for retinopathy at diagnosis and yearly - Screening for nonalcoholic liver disease at diagnosis and yearly

Question 136

DIABETIC KETOACIDOSIS (DKA0 - Most common cause of recurrent DKA is insulin omission from medication noncompliance. - Labs: Hyperglycemia, glucosuria, ketonuria, ketonemia, and high anion gap metabolic acidosis. - Hyperkalemia is due to decreased intracellular potassium shift - Dx criteria: - Blood glucose >___ mg/dL - required for diagnosis - Acidosis: Venous pH <7.__ or bicarbonate less than ___ mmol/L - Ketonemia plus ketonuria on serum or urine - ketonuria required for diagnosis - Tx: - ____ at ___ml/kg. - Subsequent fluid therapy of NS at rate of 1.5-2x maintenance requirements. - Include _____ in fluid therapy. - The pt is total body potassium depleted (despite initial lab evaluation often demonstrating normal or even high potassium) bc of the acidosis, driving potassium extracellularly. - Once the serum glucose has fallen <300mg/dL, you must add ____ to the fluids (started with D5). - After the initial fluid bolus is complete (typically after an hour), begin a continuous IV ____ of 0.1 units/kg/hr of regular insulin (an initial bolus insulin dose is not recommended). - Continue IV insulin until the acidosis corrects, even if glucose infusions must be increased. - Once the acidosis is corrected, you can stop the continuous infusion and start subcutaneous insulin. - It is important to give the 1st dose of subcutaneous insulin before you stop the insulin drip or the pt can have recurrent ketosis. - DKA is the leading cause of morbidity and mortality in children with Type 1 diabetes, primarily due to cerebral edema. - Complication: _____ is an important potential complication of DKA. Can cause significant morbidity and mortality

Answer 136

DIABETIC KETOACIDOSIS (DKA0 - Most common cause of recurrent DKA is insulin omission from medication noncompliance. - Labs: Hyperglycemia, glucosuria, ketonuria, ketonemia, and high anion gap metabolic acidosis. - Hyperkalemia is due to decreased intracellular potassium shift - Dx criteria: - Blood glucose >200 mg/dL - required for diagnosis - Acidosis: Venous pH <7.3 or bicarbonate <15 mmol/L - Ketonemia plus ketonuria on serum or urine - ketonuria required for diagnosis - Tx: - NS Fluid bolus at 10ml/kg. - Subsequent fluid therapy of NS at rate of 1.5-2x maintenance requirements. - Include potassium in fluid therapy. - The pt is total body potassium depleted (despite initial lab evaluation often demonstrating normal or even high potassium) bc of the acidosis, driving potassium extracellularly. - Once the serum glucose has fallen <300mg/dL, you must add glucose to the fluids (started with D5). - After the initial fluid bolus is complete (typically after an hour), begin a continuous IV infusion of 0.1 units/kg/hr of regular insulin (an initial bolus insulin dose is not recommended). - Continue IV insulin until the acidosis corrects, even if glucose infusions must be increased. - Once the acidosis is corrected, you can stop the continuous infusion and start subcutaneous insulin. - It is important to give the 1st dose of subcutaneous insulin before you stop the insulin drip or the pt can have recurrent ketosis. - DKA is the leading cause of morbidity and mortality in children with Type 1 diabetes, primarily due to cerebral edema. - Complication: Encephalopathy from cerebral edema is an important potential complication of DKA. Can cause significant morbidity and mortality

Question 137

HYPEROSMOLAR HYPERGLYCEMIC STATE - More common in DM2, rare in DM1. - Pt: - Severe hyperglycemia (serum glucose >___mg/dL) - Hyperosmolality (osmolality >330 mOsm/kg) - Minimal or no ketosis - Nonketotic acidosis (arterial pH >7.3 or venous pH >7.25, serum bicarb >15mmol/L) - Marked dehydration - Coma or markedly depressed sensorium - Neurologic complications (eg seizures, hemiparesis, present Babinski signs) - Tx: Fluids and IV insulin - Directed at rapid correction of the vascular volume deficit (much more aggressively than DKA) and very slow correction of the hyperosmolality. - Give initial bolus of 20ml/kg normal saline. - Give insulin by continuous IV infusion 0.025-0.05 unit/kg/hr when the glucose stops decreasing (by at least 50mg/dL/hr) secondary to fluid resuscitation; this typically occurs in the 2nd hour of therapy.

Answer 137

HYPEROSMOLAR HYPERGLYCEMIC STATE - More common in DM2, rare in DM1. - Pt: - Severe hyperglycemia (serum glucose >600mg/dL) - Hyperosmolality (osmolality >330 mOsm/kg) - Minimal or no ketosis - Nonketotic acidosis (arterial pH >7.3 or venous pH >7.25, serum bicarb >15mmol/L) - Marked dehydration - Coma or markedly depressed sensorium - Neurologic complications (eg seizures, hemiparesis, present Babinski signs) - Tx: Fluids and IV insulin - Directed at rapid correction of the vascular volume deficit (much more aggressively than DKA) and very slow correction of the hyperosmolality. - Give initial bolus of 20ml/kg normal saline. - Give insulin by continuous IV infusion 0.025-0.05 unit/kg/hr when the glucose stops decreasing (by at least 50mg/dL/hr) secondary to fluid resuscitation; this typically occurs in the 2nd hour of therapy.

Question 138

DIABETES INSIPIDUS - Classifications: - Think of Central DI (inadequate ADH production) in the pt with high Na and high urine volume who also has a hx of recent neurosurgery, head trauma, or brain cancer/metastasis. Some pts have idiopathic central DI, but most endocrinologists would still rule-out pituitary etiologies, esp adenomas, with appropriate imaging. - A pt with nephrogenic DI has renal ADH insensitivity. - Pt: Polyuria and polydipsia are the classic symptoms (but these sx may be discounted or not noticed), in which case chronic dehydration is likely to be the presenting finding. - New-onset enuresis may be the 1st sign seen in older children. - Dx: - Serum osmolality >____mOsm/kg with urine osmolality less than ___ mOsm/kg is pathognomonic for DI. - Extremely low or absent serum ADH strongly supports the dx of central DI. - Administer____ to determine whether the pt can respond to ADH. - Central DI: Giving desmopressin increases urine osmolality and therefore decreases plasma osmolality back toward normal values (~280mOsm/kg) - Nephrogenic DI, giving desmopressin does not increase urine osmolality - Water restriction test distinguishes primary polydipsia from central DI. - A 2015 study found that a ____ level >21.4 pmol/L has a 100% sensitivity and 100% specificity for nephrogenic DI! If this test is available, do it when nephrogenic DI is a possibility to immediately rule it out.

Answer 138

DIABETES INSIPIDUS - Classifications: - Think of Central DI (inadequate ADH production) in the pt with high Na and high urine volume who also has a hx of recent neurosurgery, head trauma, or brain cancer/metastasis. Some pts have idiopathic central DI, but most endocrinologists would still rule-out pituitary etiologies, esp adenomas, with appropriate imaging. - A pt with nephrogenic DI has renal ADH insensitivity. - Pt: Polyuria and polydipsia are the classic symptoms (but these sx may be discounted or not noticed), in which case chronic dehydration is likely to be the presenting finding. - New-onset enuresis may be the 1st sign seen in older children. - Dx: - Serum osmolality >300mOsm/kg with urine osmolality <300 mOsm/kg is pathognomonic for DI. - Extremely low or absent serum ADH strongly supports the dx of central DI. - Administer 1-desamino-8-D-arginine vasopressin (aka desmopressin or DDAVP) to determine whether the pt can respond to ADH. - Central DI: Giving desmopressin increases urine osmolality and therefore decreases plasma osmolality back toward normal values (~280mOsm/kg) - Nephrogenic DI, giving desmopressin does not increase urine osmolality - Water restriction test distinguishes primary polydipsia from central DI. - A 2015 study found that a copeptin level >21.4 pmol/L has a 100% sensitivity and 100% specificity for nephrogenic DI! If this test is available, do it when nephrogenic DI is a possibility to immediately rule it out.

Question 139

Nephrogenic Diabetes Insipidus - Lack of response to ADH by the kidney collecting tubules. - Path: - Ex: Lithium is the most widely known drug to induce nephrogenic DI. - Tx: - Requires sufficient intake of water. - If applicable, discontinue any drug that is the cause of DI. - Low-sodium (specifically, low-solute-load) diets - Thiazides reduce UOP in nephrogenic DI, as do prostaglandin synthesis inhibitors (eg indomethacin). - Amiloride, esp in lithium-induced DI, is useful.

Answer 139

Nephrogenic Diabetes Insipidus - Lack of response to ADH by the kidney collecting tubules. - Path: - Ex: Lithium is the most widely known drug to induce nephrogenic DI. - Tx: - Requires sufficient intake of water. - If applicable, discontinue any drug that is the cause of DI. - Low-sodium (specifically, low-solute-load) diets - Thiazides reduce UOP in nephrogenic DI, as do prostaglandin synthesis inhibitors (eg indomethacin). - Amiloride, esp in lithium-induced DI, is useful.

Question 140

Central (Neurogenic) Diabetes Insipidus - Decreased antidiuretic hormone - Path: - Idiopathic (most common) - Primary/inherited forms are very rare - Second/acquired forms are much more common. Injury to the hypothalamus and posterior pituitary gland: - CNS tumors (most common cause) - Craniopharyngioma - Infiltrative lesions (histiocytosis) - Head trauma (surgical or nonsurgical) - Tx: Responds well to ____

Answer 140

Central (Neurogenic) Diabetes Insipidus - Decreased antidiuretic hormone - Path: - Idiopathic (most common) - Primary/inherited forms are very rare - Second/acquired forms are much more common. Injury to the hypothalamus and posterior pituitary gland: - CNS tumors (most common cause) - Craniopharyngioma - Infiltrative lesions (histiocytosis) - Head trauma (surgical or nonsurgical) - Tx: Responds well to desmopressin

Question 141

Normal urine sodium is __ mEq/L

Answer 141

Normal urine sodium is 10-20 mEq/L

Question 142

BMI less than __% = Underweight BMI __-__%ile = Healthy weight __%ile BMI = overweight >__%ile BMI = obese

Answer 142

BMI <5%ile = Underweight BMI 5-85%ile = Healthy weight >85%ile BMI = overweight >95%ile BMI = obese

Question 143

METABOLIC SYNDROME - Dx: >3 of the following 6 fulfills criteria for metabolic syndrome. In children, there is no agreement on the definition. - 1) Obesity, BMI >__%ile - 2) HTN: SBP/DBP >__%ile (>130 mmHg systolic and/or >85mmHg diastolic) - 3) Triglycerides >__mg/dl - 4) HDL less than ___ - 5) Glucose intolerance: Fasting glucose >___ mg/dL, or oral glucose tolerance test >__ mg/dL - 6) Waist circumference >90%ile (>35 inches for women, >40 inches for men)

Answer 143

METABOLIC SYNDROME - Dx: >3 of the following 6 fulfills criteria for metabolic syndrome. In children, there is no agreement on the definition. - 1) Obesity, BMI >97%ile - 2) HTN: SBP/DBP >90%ile (>130 mmHg systolic and/or >85mmHg diastolic) - 3) Triglycerides >110mg/dl - 4) HDL <40mg/dL - 5) Glucose intolerance: Fasting glucose >110 mg/dL, or oral glucose tolerance test >140 mg/dL - 6) Waist circumference >90%ile (>35 inches for women, >40 inches for men)

Question 144

HYPOGLYCEMIA - Without evidence of ketosis (B-hydroxybutyric acid), a fatty acid oxidation disorder must be strongly considered. - Hypoglycemia without ketosis = ____ OR _____ - Ketotic hypoglycemia - Classic presentation is the lean 3-5yo pt who has an acute illness. They skip dinner, sleep all night and through breakfast, and then wake up at about 10am with hypoglycemia seizure. - Elevated serum and urine ketone levels are characteristic of ketotic hypoglycemia and represent activation of fat metabolism as an alternative fuel source. - Tx: - For an alert patient, the rule of 15: - Eat 15 grams of carbohydrates, wait 15 minute and recheck blood sugar, and repeat as needed until glucose is >70mg/dL. - In the unconscious pt, give glucagon or IV glucose. - ______ is effective in diabetics with hypoglycemia due to insulin therapy or other causes of hyperinsulinism - When using glucagon, be careful bc it is a GI hormone that can cause emesis, so protect the airway!

Answer 144

HYPOGLYCEMIA - Without evidence of ketosis (B-hydroxybutyric acid), a fatty acid oxidation disorder must be strongly considered. - Hypoglycemia without ketosis = hyperinsulinemia OR fatty acid oxidation disorder - Ketotic hypoglycemia - Classic presentation is the lean 3-5yo pt who has an acute illness. They skip dinner, sleep all night and through breakfast, and then wake up at about 10am with hypoglycemia seizure. - Elevated serum and urine ketone levels are characteristic of ketotic hypoglycemia and represent activation of fat metabolism as an alternative fuel source. - Tx: - For an alert patient, the rule of 15: - Eat 15 grams of carbohydrates, wait 15 minute and recheck blood sugar, and repeat as needed until glucose is >70mg/dL. - In the unconscious pt, give glucagon or IV glucose. - Glucagon is effective in diabetics with hypoglycemia due to insulin therapy or other causes of hyperinsulinism - When using glucagon, be careful bc it is a GI hormone that can cause emesis, so protect the airway!

Question 145

Insulinoma - BOTH insulin and C-peptide are elevated Factitious disorder - With exogenous administration of insulin, the insulin level is high, but the C-peptide level is low (the analog insulins are not always picked up by lab assays)

Answer 145

Insulinoma - BOTH insulin and C-peptide are elevated Factitious disorder - With exogenous administration of insulin, the insulin level is high, but the C-peptide level is low (the analog insulins are not always picked up by lab assays)

Question 146

``` MONOGENIC DIABETES (more traditionally called maturity-onset diabetes of youth (MODY) - Refers to several hereditary forms of diabetes that are AD in inheritance and present as a primary defect in insulin secretion ``` - MODY 1- due to a mutation in the hepatocyte nuclear factor-4a gene (HNF4A), located on chromosome 20 - Responds to sulfonylurea therapy, which is the only time this is the 1st line therapy in a child - MODY 2- due to a mutation in the gene for glucokinase (GCK), located on chromosome 7 - MODY 3- due to a gene mutation for hepatic nuclear factor-1a (HNF1A), located on chromosome 12 (most common form) - Responds to sulfonylurea therapy, which is the only time this is the 1st line therapy in a child - MODY 4 - mutation for hepatic nuclear factor 18; has to be treated with insulin - Dx: - ________

Answer 146

``` MONOGENIC DIABETES (more traditionally called maturity-onset diabetes of youth (MODY) - Refers to several hereditary forms of diabetes that are AD in inheritance and present as a primary defect in insulin secretion ``` - MODY 1- due to a mutation in the hepatocyte nuclear factor-4a gene (HNF4A), located on chromosome 20 - Responds to sulfonylurea therapy, which is the only time this is the 1st line therapy in a child - MODY 2- due to a mutation in the gene for glucokinase (GCK), located on chromosome 7 - MODY 3- due to a gene mutation for hepatic nuclear factor-1a (HNF1A), located on chromosome 12 (most common form) - Responds to sulfonylurea therapy, which is the only time this is the 1st line therapy in a child - MODY 4 - mutation for hepatic nuclear factor 18; has to be treated with insulin - Dx: - Document DM in at least 3 generations (with AD transmission), and the diagnosis has to be made in at least 1 individual before 25yo.

Question 147

INSULIN-RESISTANCE SYNDROMES Donohue Syndrome (Leprechaunism) - Path: Insulin resistance caused by mutation of both insulin receptor genes - Rare syndrome of intrauterine growth retardation, fasting hypoglycemia, and postprandial hyperglycemia in association with profound insulin resistance - Serum ______ levels are 100x normal and result in significant acanthosis nigricans - Death is common before 1yo

Answer 147

INSULIN-RESISTANCE SYNDROMES Donohue Syndrome (Leprechaunism) - Path: Insulin resistance caused by mutation of both insulin receptor genes - Rare syndrome of intrauterine growth retardation, fasting hypoglycemia, and postprandial hyperglycemia in association with profound insulin resistance - Serum insulin levels are 100x normal and result in significant acanthosis nigricans - Death is common before 1yo

Question 148

Rabson-Mendenhall Syndrome - Rare disorder in which affected children have severe insulin resistance, acanthosis nigricans, teeth and nail abnormalities, and pineal hyperplasia - Females often have hyperandrogenism. - These children are very similar to Donohue syndrome-affected children but (statistically) live longer. - Despite the significant insulin resistance, they are at increased risk for postprandial hypoglycemia. They often require several hundred units of insulin per day. - Newer research protocols use leptin therapy to decrease the insulin requirement.

Answer 148

Rabson-Mendenhall Syndrome - Rare disorder in which affected children have severe insulin resistance, acanthosis nigricans, teeth and nail abnormalities, and pineal hyperplasia - Females often have hyperandrogenism. - These children are very similar to Donohue syndrome-affected children but (statistically) live longer. - Despite the significant insulin resistance, they are at increased risk for postprandial hypoglycemia. They often require several hundred units of insulin per day. - Newer research protocols use leptin therapy to decrease the insulin requirement.

Question 149

Primary amenorrhea is defined by the absence of menarche by age ___ in the presence of normal sexual maturation, by age ___ in the absence of normal sexual maturation, and by ___ years following completed sexual maturation. Secondary amenorrhea is cessation of menstruation for >____ consecutive months any time after the onset of menarche.

Answer 149

Primary amenorrhea is defined by the absence of menarche by age 16 in the presence of normal sexual maturation, by age 14 in the absence of normal sexual maturation, and by 2 years following completed sexual maturation. Secondary amenorrhea is cessation of menstruation for >3 consecutive months any time after the onset of menarche.