What are the causes of central diabetes insipidus?
- Familial Central DI
>> Gross Trauma
>> Pituitary surgery
- Autoimmune causes
>> Stalk lesions
>> Histiocytosis X
What are the causes of nephrogenic diabetes insipidus?
- Hereditary nephrogenic DI
- Drugs: lithium
- Electrolyte disturbances
- Chronic renal failure
What are the 2 investigations for diabetes insipidus?
1. Water deprivation test to rule out psychogenic polydypsia
2. DDAVP to differentiate between central DI (concentrated urine) and nephrogenic DI (no effect)
What is the management for central diabetes insipidus?
What is the management for nephrogenic diabetes insipidus?
- Solute restriction
- Thiazide diuretics
How do thiazide diuretics work in treating nephrogenic DI?
Thiazide diuretics act on inhibiting the NaCl cotransporter to inhibit water reabsorption in the distal tubules. The subsequent renal sodium loss causes extracellular volume contraction (as water flows into the relatively hypertonic intracellular compartment), when then leads to lowered GFR and increased proximal tubular sodium and water reabsorption. Hence, less water and solutes are delivered to the distal tubule and collecting duct, and are lost as urine.
What is the physiology behind euvolemic hyponatremia in SIADH?
There is excessive inappropriate isolated water reabsorption in the collecting ductules in SIADH. A similar proportion of water is thus lost in the proximal tubules due to the expanded intravascular volume, but this is accompanied by the secretion of sodium as well. Therefore, the net effect is no change in the intravascular volume, but a loss of sodium from the PCT. The hyponatremia is initially mediated by ADH-induced water retention. The ensuing volume expansion activates secondary natriuretic mechanisms, resulting in sodium and water loss. The net effect is that, with chronic SIADH, sodium loss is as or more prominent than water retention."
What are the 5 diagnostic criteria for SIADH?
1. Hyponatremia with decreased plasma osmolality
2. Urine concentration >100mOsm/dL
3. Urine Na concentration >20mEq/L
4. Normal adrenal, renal and thyroid function
5. No signs/evidence of volume depletion
What are the possible causes of SIADH?
1. Stress: pain, nausea and post-operation
2. CNS conditons: inflammation, hemorrhage, tumour, GBS
3. Respiratory infections: TB, pneumonia, empyema
4. Neoplasms: lung, pancreas and lymphoma
What is the management of SIADH?
1. Fluid restriction +/- hypertonic saline
2. Vasopressin receptor antagonists: tolvaptan, conivaptan
What is cerebral salt wasting (CSW)?
Excessive urinary sodium and subsequent hyponatremia and dehydration in individuals with intracranial disease
What is diabetic ketoacidosis?
A state of severe metabolic derangement that results from both insulin deficiency and increased amounts of counterregulatory hormones such as catecholamines, glucagon, cortisol and growth hormone
- Hyperglycemia (serum glucose at ~16mmol/L or even higher)
- Ketonemia (serum ketones >3mmol/L)
- Acidosis (venous pH <15mEq/L)
What are the common clinical features of diabetic ketoacidosis?
From hyperglycemia and osmotic diuresis/electrolyte disturbances
- Polyuria, polydipsia and polyphagia
- Abdominal pain
From metabolic ketoacidosis
- Decreased consciousness and lethargy
- Nausea and vomiting
- Fruity-smelling breath
- Kussmaul's respiration
>> Must ask for precipitating factors
5. Insulin missed
What is the management for diabetic ketoacidosis?
- Resuscitation and stabilization
- Fluid resuscitation
>> Beware of pseudohyponatremia due to hyperglycemia
>> Add 3Na+ per 10 glucose over 5.5mmol/L
- Insulin administration
>> DO NOT give insulin if K is <3.3mmol/L
>> Add D5W when glucose <15mM to prevent hypoglycemia
>> Replace KCl
>> Essential to avoid hypokalemia
>> Cardiac monitoring if potassium levels normal or low
>> HCO3 is not given unless patient has a pH of <7.0
- Frequent monitoring of
>> Vital signs
>> Electrolytes (esp. Na and K)
>> Acid-base status
ABG is more useful in monitoring DKA than blood glucose levels
What are the indications for bicarbonate use in DKA?
1. Profound acidosis (pH <7.1)
2. Associated with hypotension, arrhythmia and/or coma
3. Life-threatening hyperkalemia with bradycardia/muscle weakness
What are the common biochemical findings of DKA?
- Normakalemia/Hyperkalemia with low total body potassium
- Creatinine increased
- BUN increased
- Plasma osmolality increased
Arterial Blood Gas
- Metabolic acidosis: decreased pH and with decreased HCO3
- Secondary respiratory alkalosis by compensation
- PO4 decreased
What is the target glucose range in children?
What are the complications of DM Type 1?
- Diabetic ketoacidosis
- Microvascular: retinopathy, neuropathy, nephropathy
- Macrovascular: metabolic syndrome
- Increased risk for other autoimmune diseases
What are the risk factors for Type II DM?
- Female gender
- Positive family history
- Certain ethnic groups
What is the management for Type II DM in children?
- Physical activity: 60min of moderate-intense exercise per day
- Weight loss
- Oral hypoglycemics (Metformin as it does not cause hypoglycemia)
What are the goals for HbA1C in children with Type I DM?
<6 years: <8.5%
6-12 years: <8%
>12 years: <7%
What is the Somogyi phenomenon?
Rebound hyperglycemia afrer an incident of hypoglycemia
- Secondary to the release of counterregulatory hormones as a natural response to hypoglycemia
- Commonly reported at night as there is a greater likelihood of unrecognized and untreated hypoglycemia when the child is sleeping
- Suspect when a child whose blood sugar is in excellent control (and thus prone to hypoglycemia) begins to have intermittent high blood glucose in the morning
- BG should be checked between 2-3AM on several nights to determine whether the hypoglycemia is occurring
What is the dawn phenomenon?
A rise of blood glucose that occurs during the early morning hours (5-8AM), particularly among patients who have normal blood glucose levels
- Normal increase of morning cortisol levels
- Cumulative effect of increased nocturnal growth hormones
- Insulinopenia due to the length of time since the last insulin injection
What are the indications for further investigations in short stature?
- Very short: height <3rd centile
- Slow growth velocity
- Growth arrest
- History or physical examination findings suggestive of endocrine or other systemic disorders
What are the 4 questions to ask when evaluating a child with short stature?
- Was there IUGR? If yes, what was the cause?
- Is the growth proportionate?
- Is the growth velocity normal?
- Is bone age delayed?
What are the possible causes of short stature in children?
- Chromosomal abnormalities: Down's, Turner's, Russell-Silver, Noonan
- Congenital infections
- Teratogen exposure
- Placental insufficiency
No IUGR with disproportionate growth (U/L ratio)
- Skeletal dysplasia, e.g. Achondroplasia
No IUGR, proportionate growth with normal growth velocity
- Constitutional growth delay (delayed bone age for chronological age)
- Familial short stature (normal bone age for chronological age)
No IUGR, proportionate growth with slow growth velocity
>> Growth hormone deficiency
>> Hypopituitarism (look for midline defects/visual field defects)
>> Adrenal insufficiency
- Chronic illnesses
>> Congenital cyanotic heart diseases
>> Respiratory: asthma, cystic fibrosis
>> GI: celiac disease, IBD
>> Renal: chronic renal failure, recurrent UTI
>> Chronic infections
- Psychosocial: child neglect, child abuse
What are the causes of congenital growth hormone deficiency?
- Genetic mutations
- Embryologic CNS malformations (look for the associated following:)
>> Midline facial anomalies
>> Neurological defects
>> Micropenis in males
- Perinatal asphyxia
What are the causes of acquired growth hormone deficiency?
- Cranial infection
- Tumours: e.g. craniopharyngioma (look for visual field defects)
- Iatrogenic causes
>> Cranial irradiation
>> Previous surgery
What are the risk factors for (especially acquired) growth hormone deficiency?
- Intracranial infection
- Head trauma
- Intracranial bleed
- Previous head surgery or irradiation
- Breech delivery
- Positive family history
What does growth hormone mainly mediate?
- Chondrocyte proliferation
- IGF-1 release (works on long bones and the liver)
When is GH stimulation testing indicated?
- Height <3rd centile
- Decreased growth velocity
- Delayed bone age
- Delayed puberty
- Midline craniofacial anomalies
- Episodes of hypoglycemia
What are the indications for growth hormone therapy?
- Positive GH stimulation tests for GH deficiency on two separate occassions
- Growth velocity <3rd percentile
- Height <<3rd centile
- Bone age X-ray shows unfused epiphyses/delayed bone age
- Chromosomal/Genetic syndromes
>> Turner syndrome
>> Noonan syndrome
>> Prader-Willi syndrome
- Chronic renal failure
- Idiopathic short stature
What is the definition of short stature?
Height <3rd centile
What is the definition of tall stature?
Height greater than two SD above the mean for a given:
>> Usually height >97th centile
How can we calculate the expected height of a child?
Boys: (Ht(mom) + Ht(dad) + 12) / 2
Girls: (Ht(mom) + Ht(dad) - 12) / 2
What are the possible causes of tall stature?
- Constitutional growth spurt
- Familial tall stature
- Genetic causes
>> Klinefelter syndrome
>> Marfan syndrome
>> Sotos syndrome
:: Excessive growth physical growth in the first 2-3 years of life
:: Associated with:
~ Protrusive forehead
~ Awkward gait
~ Unusual aggressiveness or irrtability
>> Beckwith-Wiedemann syndrome
:: Midline abdominal wall defects (omphalocele, umbilical hernia etc.)
:: Neonatal hypoglycemia
- Endocrine causes
>> Hypophyseal gigantism
>> Precocious puberty
What are the clinical features of Sotos syndrome?
A rare genetic disorder characterized by cerebral overgrowth, advanced bone age and macrodolichocephaly and intellectual impairment
B: Birth weight and length large; Bone age advanced
C: Cerebral ventricles dilated
E: Eye - antimongoloid slant (downward slanting eyes)
F: Facies coarse-looking
G: Gigantism (cerebral); Genitalia abnormal' Gait awkward
H: Hypotonia; High-arched palate
I: Intelligence -- mental retardation
J: Jaw -- Prognathism
K: Kinesics -- fine movements difficult
L: Learning difficulties
What are the clinical features of Klinefelter's syndrome?
K: Karyotpye 47XXY
L: Long bones (delayed epiphyseal fusion)
I: Intelligence -- mental subnormality
F: Feminizing features -- gynecomastia
E: Epiphyseal fusion delayed
L: Learning difficulties
T: Tall stature; Testes pea-sized/cryptorchidism/hypospadias
E: Elevated plasma and urinary gonadotropins
R: Ridge count low
S: Secondary sexual characters nil; Sterility; Sperm: Azoospermia
What are the clinical features of Marfan's syndrome?
M: Mitral valve prolapse
R: Ratio of upper to lower segment decreased
F: Father's age advanced
A: Aortic regurgitation
N: Narrow maxilla
S: Subluxation of lens
What are the clinical features of Beckwith-Wiedemann syndrome?
B: Birth weight -- large for date
E: Eyes prominent; Erythrocytes increased -- polycythemia
C: Cleft ear lobes
K: Kidneys enlarged
W: Wilm's tumour
I: Insulin increased -- hyperinsulinemia
T: Tumours -- risk increased; Tongue -- macroglossia
H: Hypoglycemia (severe neonatal hypoglycemia); Head circumference decreased (microcephaly)
>> Midline abdominal wall defects -- omphalocele, umbilical hernia etc.
>> Ear creases/ear pits
>> Neonatal hypoglycemia
What is the most common cause of congenital hyperthyroidism?
Transplacental passage of maternal TSH Ab from a mother with a history of Graves' disease
>> Antibodies are usually cleared spontaneously by 2-3 months of life
What are the presenting features of congenital hyperthyroidism?
Note: clinical manifestations may be masked if the mother is on antithyroid treatment
- Poor feeding and failure to thrive
- Tachycardia + congestive heart failure +/- heart murmur
What are the long-term complications of congenital hyperthyroidism?
Developmental and behavioural problems
What are the common causes of congenital hypothyroidism?
Permanent primary hypothyroidism
- Sporadic: thyroid dysgenesis
- Hereditary: inborn errors of thyroid hormone synthesis
- Maternal antibody
- Iodine deficiency
- Prenatal exposure to antithyroid medications
What are the presenting features of congenital hypothyroidism?
- Large fontanelles
- Coarse facial features
- Poor feeding
- Sluggish, hoarse cry
- Prolonged unconjugated neonatal jaundice beyond 2 weeks of life
- Umbilical hernia
>> Prolonged jaundice is usually the first sign of congenital hypothyroidism. Other signs such as coarse facial features and macroglossia usually appear at 2-3 months of life.
What are the long-term complications of congenital hypothyroidism?
Permanent developmental delay and disability if treatment with thyroxine replacement is started after 3-6 months of age
>> Prognosis is excellent if treatment is started at 1-2 months of age
What is the mode of inheritance of congenital adrenal hyperplasia?
What are the three types of disorders of sex differentiation?
46, XY DSD
- Inborn errors of testosterone biosynthesis
- Leydig cell hypoplasia
- 5a-reductase deficiency
- Androgen receptor deficiency/insensitivity
- LH/hCG unresponsiveness
46, XX DSD
- Virilizing congenital adrenal hyperplasia
- Maternal source
>> Virilizing ovarian/adrenal tumours
>> Untreated maternal CAH
>> Placental aromatase deficiency
Ovotesticular DSD (True hermaphrodite)
- Mixed gonadal dysgensis
What are the risk factors/triggers for Type I DM?
>> Father: 1 in 20/30
>> Mother: 1 in 40-80
>> Identical twins (20-30%)
- Personal history of autoimmune diseases
- Viral infections (esp. enteroviral infections)
- Puberty (?hormonal changes)
What is the most common enzyme defect of CAH, and what are the associated hormonal abnormalities?
>> Low aldosterone
>> High testosterone
What are the presenting features of 21-hydroxlyase deficiency CAH?
Can be any of the following:
1. Classical with salt-wasting
2. Classical without salt-wasting (simple virilizing)
3. Non-classical: Low aldosterone
- Salt-wasting crisis
>> Weight loss/FTT
>> Circulatory collapse/Hypotension
- Biochemical abnormalities
>> Metabolic acidosis
4. Non-classical: High testosterone
- Virilization in girls
>> Clitoral hypertrophy
>> Variable fusion of the labia
- Masculinization in boys
>> Enlarged penis
>> Pigmented scrotum at birth
- Other signs of androgen excess
>> Precocious puberty
>> Muscular build
>> Adult body odour
Others - Tall stature in non-salt-loser males (20%)
What are the possible investigations that can confirm the diagnosis of CAH in 21-hydroxylase deficiency?
- RFT for biochemical disturbances
- Serum hormonal levels:
>> Elevated 17-OH-progesterone is diagnostic of 21-hydroxylase deficiency
>> ACTH levels: elevated due to low cortisol
- Ultrasound abdomen for adrenal hyperplasia
- In borderline cases, a corticotropin stimulation test may be performed.
>> Failure to double within 60 minutes in CAH with hypoaldosteronism
What is the management for CAH?
- Correction of fluid/electrolyte/glucose abnormalities
- Life-long glucocorticoid and mineralocorticoid supplementation
>> Allow normal growth and maturation
>> Prevent salt-losing crises
>> Extra glucocorticoids in times of stress
>> Skeletal maturity
>> Plasma androgens
>> Clitoromegaly reduction and vaginoplasty
- Genetic counseling and future antenatal treatment
>> Dexamethasone around the time of conception and continued if the fetus is female to reduce fetal ACTH drive and hence reduce virilization
What are the complications of CAH?
- Salt-wasting crises (can be fatal from hypotension or complications of electrolyte disturbances)
What are the biochemical abnormalities in a salt-wasting individual suffering from CAH (21-hydroxylase deficiency)?
- Metabolic acidosis
What is the normal sequence of puberty in girls?
Thelarche >> Pubarche >> Growth spurt >> Menarche
What is the common age of onset of puberty?
Girls: 8-13 years old
Boys: 9-14 years old
What is the normal sequence of puberty in boys?
Testicular enlargement >> Penile enlargement >> Pubarche >> Growth spurt
What is precocious puberty?
Development of secondary sexual characteristics 2-2.5SD before the population mean
Usually constitutional in girls and more suggestive of pathology in boys - Girls: <8 years of age
Boys: <9 years of age
NB: Girls with thelarche between 7-8 years old has early puberty, NOT precocious puberty due to the downward secular trend in sexual maturation.
What is delayed puberty?
Failure to develop secondary sexual characteristics by 2-2.5SD beyond the population mean
Usually constitutional in boys and more suggestive of pathology in girls
>> Lack of breast development by 13 years of age
>> Absence of menarche by 16 years of age
>> Absence of menarche within 5 years of pubertal onset
>> Lack of testicular enlargement by 14 years of age
What are the clinical features of McCune-Albright syndrome?
Suspect if there are any 2 of the following 3 features:
- Unilateral cafe-au-lait spots
- Polyostotic fibrous dysplasia
- Autonomous endocrine abnormalities: e.g. early puberty
- Cafe-au-lait spots
- Early pubery
- Abnormal Bones
>> A genetic disorder of the bones, skin and hormonal problems associated with precocious puberty
What are the possible causes of precocious puberty?
Central (hypergonadotropic hypergonadism)
- CNS conditions
>> Previous meningitis
>> Increased intracranial pressure
- Severe primary hypothyroidism (congenital, inflammatory, infiltrative, iatrogenic causes etc.)
Peripheral (hypogonadotropic hypergonadism)
- Exogenous hormonal/steroid intake
- Adrenal diseases: e.g. virilizing CAH
- Testicular/ovarian tumours
- Gonadotropin/hCG-secreting tumours
>> Intracranial teratomas
- McCune-Albright syndrome
- Aromatase excess syndrome
What are the normal growth velocities of a child?
Pubertal girls: 6-8cm/year
Pubertal boys: 8-10cm/year
What are the possible investigations that can confirm the cause of precocious puberty?
Look at growth velocity (?growth spurt?) and Tanner staging
Blood tests: Hormones
- Testosterone and DHEA
- LH, FSH
- TSH and free T4
- Bone age on hand/foot X-ray
- MRI head (brain + orbits)
- Pelvic USG
- GnRH stimulation test
- ACTH stimulation test
What are the indications for medical intervention in precocious puberty?
- Early age
- Rapid advancement of puberty
- Risk of compromising final adult height
What are the treatment goals and common treatment for central precocious puberty?
- To preserve height
- To alleviate psychosocial stress
>> GnRH agonists (e.g. leuprolide) most effect
What are the treatment goals and common treatments for peripheral precocious puberty?
- Limit effects of elevated sex steroids
- Treat underlying causes
>> Medications to decrease production/block effects of certain sex steroids:
>> Surgical intervention
What are the possible causes of delayed puberty?
- Hypogonadotropic hypogonadism
>> Psychological stress
>> Chronic illnesses
>> Excessive exercise
>> Kallmann syndrome (look for anosmia)
>> Hypothalamic/pituitary tumours
Peripheral causes (Hypergonadotropic hypogonadism)
- Primary gonadal failure/dysgenesis
- Gonadal damage
- Syndromal causes
>> Klinefelter's syndrome
>> Turner's syndrome
- Androgen insensitivity syndrome
- Hormonal deficiency
- Metabolic causes
>> Glycogen storage disease
What are some useful investigations to help determine the causes of delayed puberty?
LH, FSH, testosterone and estradiol
- Differentiate between central and peripheral causs
Other serum hormone profiles
- TSH, fT4
Other blood tests
- IBD panel
- Celiac disease panel
- Karyotype Imaging
- MRI head
- Pelvic USG
>> Have to rule out occult chronic illness such as chronic IBD, liver disease or anorexia nervosa
What is the management for delayed puberty?
- Treat underlying cause!
- Hormone replacement
>> Girls: cyclic estradiol and progesterone
>> Boys: Testosterone
What are the symptoms of adrenal insufficiency?
- Poor weight gain
- Cardiovascular shock
- Easy fatigability
- Poor weight gain
- Vague abdominal complaints
- Hyperpigmentation (primary insufficiency)
- Vascular collapse may occur
Primary adrenal insufficiency: LOW cortisol with ELEVATED ACTH levels
Secondary adrenal insufficiency: LOW cortisol with LOW ACTH levels
What are the clinical features of primary adrenal insufficiency?
Elevated ACTH levels
- Salt-craving and muscle cramping
- Mild hypercalcemia
- Orthostatic hypotension
What are the causes of hypercalcemia?
- Hyperparathyroidism: isolated, familial, syndromic
- Idiopathic: William's syndrome
- Infantile: subcutaneous fat necrosis
- Infectious: TB
- Infiltration: malignancy, sarcoidosis
>> Milk-alkali syndrome
>> Thiazide diuretics
>> Vitamin A intoxication
>> Vitamin D intoxication
- Skeletal causes
>> Skeletal dysplasias
What are the main causes of hypocalcemia in children?
- Nutritional: vitamin D deficiency
- Renal insufficiency:
>> Increased serum phosphorus
>> Decreased activity of renal a-hydroxylase
- Nephrotic syndrome
>> Lowered serum albumin
>> Decreased intestinal absorption
>> Urinary losses of calcium with prednisone therapy
- Hypoparathyroidism (DiGeorge syndrome)
- Disorders of calcium sensor genes
Is bolus insulin recommended in DKA treatment?
This has been found to be unnecessary and may increase the risk for cerebral edema. Continuous low-dose intravenous insulin infusion is preferred.
What are the possible causes of hypoglycemia in neonates?
Reduced glucose availability
- Inadequate milk
- Maternal DM
- Islet-cell adenoma
Increased glucose consumption
Low hormonal support
- Congenital adrenal hyperplasia
How does one treat SIADH?
1. Treat underlying causes
2. Long-term fluid restriction of 1200-1800mL/day
3. Hypertonic saline for very symptomatic patients with severe confusion, convulsions or coma
5. Vasopressin receptor antagonists: conivaptan, tolvaptan
What investigations should be ordered for a child presenting with DKA?
- CBC: rule out infection
- Electrolytes/BUN and CR: RFT
- Ca, PO4, Mg
- ECG -- electrolyte disturbances may predispose to arrhythmias, and MI can be a possible precipitating factor for DKA
What are the signs of failure to thrive?
- Subcutaneous fat loss
- Muscle atrophy
- Lagging behind growth chart/schedule
- Infections (recurrent)
What is the definition of obseity?
BMI >95th centile for age and height
What are the cause sof obesity?
- Unhealthy eating habits
- Sedentary lifestyle
- Formula feeding (instead of breastfeeding)
- Genetic causes
>> Prader-Willi syndrome
>> Turner syndrome
>> Carpenter syndrome
- Hormonal causes
>> Cushing's syndrome
There is 80% that the child will be obese if BOTH his/her parents are obese.
What are the complications/associations of childhood obesity?
- Type 2 DM
- Slipped capital femoral epiphysis
- Obstructive sleep apnoea
- Polycystic ovarian disease
- Early menarche
- Irregular menses
- Decreased self-esteem
Childhood obesity is NOT a reliable predictor of adult obesity unless the child is >180% of the ideal body weight.
Adolescent obseity IS a reliable and good predictor of adult obesity.