deck 4 Flashcards
(133 cards)
1
Q
Grave’s disease
A
pretty much causes almost all hyperthyroidism in childhood
peak age 11-15
5x more in females than males
most have family history of autoimmune gyroid disease
Findings:
1. enlarged thymus
2. splenomegaly
3. lymphadenopathy
4. infiltration of thyroid gland and retroorbital space with lymphocytes/plasma cells
5. peripheral lymphocytosis
2
Q
Why do you get thyroid hyperplasic
A
TRSab binds to TSH receptor and leads to thyroid hyperplasia and overproduction of thyroid hormone
antigens are shared between the eye and the thyroid
associated with HLAB8
3
Q
Associated conditions with Graves disease
A
Addison DM1 Myasthenia gravis Celiac SLE RA vitiligo ITP pernicius anemia
4
Q
Clinical features of Grave’s/hyperthyroidism
A
emotional disturbances motor hyperactivity restless sleepers poor schoolwork finger tremor eat lots and either lose or don't gain weight accelerate height velocity thyroid can be enlarged exopthalmos lid lag eye pain, etc sweaty skin tachycardia Brisk Reflexes, increased sympathetic nervous system
5
Q
What is thyroid storm
A
acute onset hyperthermia severe tachycardia heart failure restlessness can lead to delirium, coma and death
6
Q
Precipitating factors for thyroid crisis/storm
A
trauma
infection
radioactive iodine treatment
surgery
Treatment of thyroid storm in teens:
1. Inhibit thyroid hormone formation and secretion - PTU/NaI
2. Sympathtetic blockate - propanolol
3. steroids
4. supprotive therapy: IV fluids, temp control (cool blankets, tylenol), O2 if needed, pentobarbital for sedation
treat the precipitating event
7
Q
Labs in hyperthyroidism
A
increased T3 and T4, suppressed TSH
antithyroid antibodies - including thyroid peroxidase antibodies are often present
MOST patients have TRSAb measurable (if new especially)
reduced bone density at diagnosis but returns with treatment
acceleration of growth and bone maturation
8
Q
Cause sof hyperthyroidism in chilren
A
1 (BY FAR): Graves disease
Other causes uncommon:
- functional thyroid nodule - if palpable nodule or T3>T4
- Toxic multinodular goiter - TSH receptr activation mutation or McCUne Albright
- thyroiditis is rare in children
Exogenous thyroid hormone: T4 and TSH
9
Q
hyperthyroid from exogenous thyroid hormone, labs
A
T4 and TSH are same as Graves, but low Thyroglobulin (whereas elevated in Graves)
10
Q
thyroid hormone synthesis
A
- thyroid gland function : make T4 and T3
- iodine needed to synthesize these hormones
- thyroid tissue traps and transports the iodine
- thyroidal peroxides – oxidizes the iodine so it can react with tyrosine to make thyroid hormone (T4 and T3)
- T3 and T4 stored as thyroglobulin until they are delivered to the body cells
- T3 physiologically active hormone, but most of the circulating thyroid hormone is T4 (we usually measure T4)
- T4 and T3- most of it is bound to carriers (mostly thyroxine binding globulin (TBG) ,
11
Q
Treatment of hyperthyroidism
A
1st line: medical treatment using anti-thyroid drugs - methimazole (don’t use PTU in kids because of liver disease risk)
2nd line - if have adverse effects or doesn’t work:
radio iodine (dont need to do pre-treatment) , will take 1-6 months to work completely, need lower dose of antithyroid drugs and betal blocker usually; a few studies say increased risk of neoplasms in adults (although other place says no) so a few docs prefer surgery
or thyroidectomy
- do after patient is euthyroid
complciations: rare - hypPOTH, vocal cord paralysis
Adjunt treatments:
beta blocker
opthalmopathy - steroids
12
Q
Side effects of antithyroid medication:
A
transient granulocytopenia
transient urticardial rashes (stop the med then restart)
severe: agranulocytosis, hepatitis, lupus like polyarthritis, GN and vasculitis (rare)
severe liver disease with PTU
13
Q
How to monitor treatment with antithyroid medication
A
TSH - if it is rising greater than normal then you are over treating
takes 3-6 weeks to start seeing effect, adequate control in 3-4 months
14
Q
neonatal graves disease
A
cause is TRSAb crosses the placenta (mom has grave’s disease, or past history of treat meed surgically, rarely can have hypoT or Hashimotoonly in 2% of mothers with Graves
usually improves on its own by age 6-12 weeks
Clinical manifestations: IUGR, goiters, microcephaly, ventricular enlargement
hypertension and cardiac decompensation
have high T4 and low TSH
advanced bone age, frontal bossing with triangular facies and cranial synostosis
Treatment: propanolol, methimazole
Can occasionally persist
If delayed treatment: advanced osseous maturation, microcephaly, and MR
15
Q
Solitary thyroid nordule in chilren causes
A
Benign causes:
adenomas, cyst, hashimoto, abscess, thyroglossal duct cyst, hemiagenesis
**suddenly appearing or rapidly enlarging thyroid - cyst or benign adenoma
16
Q
true or false - most thyroid nodules in children are benign
A
true
although some studies show that the proportion that are cancerous is higher than adults (from 2-40%)
investigations for thyroid nodule: serum thyroid function tests, antithyroid antibody determinations, US thyroid exam, FNA
17
Q
thyroid nodule with suppressed serum TSH
A
suggests an autonomous hot nodule
should do radio iodine uptake and scan
FNA is helpful to avoid surgery for benign nodules
if hard or grown rapidly, should do surgery
18
Q
inheritance of multiple endocrine neoplasia
A
autosomal dominant
19
Q
Kid with hypocalcemia at 48 hours of life, common or uncommon?
A
common
between 12-72 hours of life
especially in premature infants, in infants with asphyxia and in infants of diabetic mothers (early neonatal hypocalcemia)
after the first week of life, the type of feeding is also a determinant of the level of calcium
20
Q
Causes of hypocalcemia
A
- PTH deficiency
- PTH receptor defects (pseudohypoparathyroidism
- mitochondrial DNA mutations
- magnesium deficiency
- phosphate excess
- vitamin D deficiency
21
Q
Causes of hypoparathyroidism
A
- PTH hypoplasia - ie DiGeorge syndrome, X linked recessive, autosomal recessive, HDR syndrome, suppression due to maternal hyper PTH, AD hypoPTH, mitochondrial, surgical, autoimmune, idiopathic
most common after first few years of life are autoimmune
22
Q
idiopathic hypoparathyroidism
A
spectrum clinical: muscular pain and cramps early->then to numbness, stiffness and tingling of the hands and feet positive Chvostek or Trousseau sign can get convulsions hypocalcemia - dlayed teeth eruption mucucutaneous cadidiasis cataracts after long term other autoimmune diseases
23
Q
labs in hypoPTH
A
calcium is low phosphorus is elevated ALP normal or low level of 1,25OH2D is usually low prolongation of QT from hypocalcemia
24
Q
Treatment of hypoPTH
A
IV 10% calcium gluconate
calcitriol should be given
adequate calcium intake
25
Ddx of unexplained hypocalcemia
magnesum deficiency should be considered
hypoMg can also be from Crohn and CF
associated with TLS (hypocalcemia and hyper phosphate)
Keey-Caffey syndrome - can have episodic hypocalcemia
26
Albright Hereditary Osteodystrophy
```
aka pseudohypoparathyroidism
clinical signs:
can have tetany as presenting sign
short, stocky children
brachydactyly
index finger longer than middle finger
other skeletal abnormalities
MR, calcification of the basal ganglia and cataracts
```
27
hyperparathyroidism
usually is compensatory
sometimes have a primary problem with PTH production
usually secondary to vitamin D deficient ricket sand malabsorption
can be associate dwith MEN I
28
Clinical manifestations of hyperparathyroidism
```
1. hypercalcemia
muscular weakness, fatigue, headache, anorexia, abdo pain, nausea vomiting, constipation, polydipsia, polyuria, weight loss and weever
can get nephrocalcinosis after some time
acute psi - can be with pancreatitis
Treatment: surgery for PTH glands
```
29
Causes of hypercalcemia
1. PTH excess
PTH receptor excess
Can sensing inactivated
vitamin D excess - iatrogenic, ectopic production (sarcoid, TB granulomatous lesions, SC fat necrosis, excessively fortified milk)
unknown cause - williams syndrome
Other: hypophosphatasia, prolonged immobilization, thyrotoxicosis, hypervitaminosis A, leukemia, acquired hypocalciuric hypercalcemia
30
kid with long term rickets on vitamin D, about to have a surgery of the back, what to do about vitamin D
should stop or decrease the dose since they are at risk of hypercalcemia after surgery where there is immobilization
31
zones where different hormones are made
glomerulosa - aldo
fasciculata - cortisol
reticularis - DHEAS/testosterone
32
Effects of glucocoricoids
increase in stress situation
1. metabolic effects:
- increase glucose production by increasing hepatic gluconeogensis
- increase insulin resistance
- stimulate glycogen deposition and production in the liver
- increase lipolysis and FFAs - leads to unequal fat deposition - i.e. increased in trunk, neck and face (moon facies)
catabolic/antianabolic effect on protein metabolism
2. circulatory and renal effects:
- positive effect on heart
3. growth: inhibit linear growth and skeletal maturation
excess can impair growth but need some to help with normal growth and development
help with development of hepatic and GI system, as well as lung maturation
4. immunological: inhibit inflammatory process
increased PMNs, high levels decrease inflammatory and cellular immune responses and increase susceptibility to certain bacterial, viral, fungal and parasitic infections
5. skin/ bone and calcium
decrease serum calcium, can cause osteoporosis (long term)
6. CNS effects: insomnia/impair sleep
33
Actions of mineralocorticoids:
na/k/fluid balance
34
actions of adrenal androgens
women 50% of androgens are adrenal, in men <2% are from the adrenal
synthetic steroids: ie prednison
35
order the following steroids by strength:
weak to stronger
prednisone/prednisolone - 4-5 x more potent
betamethasone/dexamethasone- 25-40 x more potent
fluodrocortisone - lots of mineralocorticoid activity
36
Adrenal medulla - what do they make
dopamine, norepi, and epi
37
Causes of adrenal insufficiency - primary, inherited
1. Primary - problem of the adrenal cortex
a) inherited:
- inborn defects, adrenal hypoplasia congenita, adrenoleukodystrophy, familial glucocorticoid deficiency, type I autoimmune polyendocrinopathy (APS 1: chronic mucocutaneous candidiasis, then hypoPTH then addison), disorders of cholesterol synthesis and metabolism (i.e. smith lemli)
38
causes of adrenal insufficiency, primary acquired
acquired primary
1. Addison disease - autoimmune addison disease - most common
2. infection - TB used to be most common, now is meningococcemia, AIDS
3. drugs - ketoconazole , rifamin, phenytoin, phenobarbitol, etomidate (can last for 4-8 hours, can be a problem in super sick kids!)
4. adrenal gland hemorrhage
39
Addison disease most common cause
autoimmune Addison disease, destruction of glands
most have anti adrenal cytoplasmic antibodies
can be part of APS 1 and 2
40
A newborn baby is breech and then presents with abdo mass, anemia, jaundice , scrotal hematoma and hypoglycaemia
what is the diagnosis
hemorrhage into adrenal glands
(can also happen post nattily with anticoagulants, child abuse)
often asymptomatic initially and detected later with calcification
41
Clinical manifestations of adrenal insufficiency
cortisol deficiency
- decrease cardiac output and vascular tone - leads to orthostatic hypotension in oler chilren
aldosterone deficiency
- hypovolemia due to decreased resorption of sodium in the distal nephron and hyperkalemia from decreased potassium excursion
**cortisol deficiency on its own doesn't cause hyperkalemia
42
Why do you get hyper pigmentation in adrenal insufficiency
increased ACTH - which stimulates POMV
43
Presentation of adrenal insufficiency
infancy: hyperkalemia, hyponatremia, hypoglycemia, don't always have ketones because infants don't always make detones as well as oleo kids, don't get hyper pigmentation
older kids: muscles weakness, malaise, anorexia, vomiting, weight loss and orthostatic hypotension - can be insidious onset
can have decompensation during minor illness
44
Labs in adrenal insufficiency
cortisol can be low normal - but low considering how sick they are
increased urinary excretion of sodium and chloride
most definitive - ACTH stimulation test **
45
Ddx of adrenal insufficiency
first need to Ddx between addison disease and gastroenteritis with dehydration or sepsis
cause: 17OHP, cortisol, ACTH stim test
elevated very long chain fatty acids - adrenoleukodystrophy
antiadrenal antibodies
hypoparathyroidism most commonly associated disorders
46
Treatment of adrenal insufficiency
fluids
treat electrolyte abnormalities
chronic replacement after:
hydrocortisone daily orally
ACTH to monitor the adequacy of glucocorticoid replacement in primary adrenal insufficiency
don't need to normalize the ACTH levels (high normal to 2-3 x normal is okay)
fludrocortisone (fluorinef) if aldo deficiency present
47
treatment of adrenoleukodystrophy
lorenzo's oil
bm transplant
lovastatin
48
Causes of adrenal insufficiency - secondary
1. Abrupt cessation of corticosteroids - can give high dose for 1 week without needing to taper the dose
most likely if infection/surgery right after
2. corticotropin deficiency
- pituitary or hypothalamic dysfunction; most common cause is destructive lesions in the area of the pituitary
congenital lesions of the pituitary - septo-optic dysplasia
- Prader-Willi (some endocrinologists suggest treating these kids with hydrocortisone during severe illness)
**in secondary adrenal insufficiency - don't get aldosterone secretion affected
these happen because of suppression of the HPA axis by the steroids
49
true or false, both primary and secondary adrenal insufficiency get aldo affected
false - don't usually get aldo affected because the gland itself is intact and the RAS system is not involved
50
Diagnosis of secondary adrenal insufficiency
can be hard to diagnose sometimes because the glands themselves are okay
most commonly used test now: low dose ACTH stimulation testing - can have false negative especially when very acute (since the though is that there will be some atrophy of the gland if ACTH stimulation is lacking)
51
physiologic and stress dossing of hydrocortisone
10 mg/m2/24 hour physiology
| 50 is the stress dose
52
treatment of secondary adrenal insufficiency
hydrocortisone, don't need mineralocorticoid replacement usually
53
adrenal insufficiency in the critical care setting, differential
1. shock (especially meningococcemia)
2. etomidate
3. neurosurgical patients or tumours of hypothalamus or pituitary
4. previous treatment with steroids
5. NICU - immature HPA axis
54
most common form of congenital adrenal hyperplasia
21OHP
| when this is defective you get accumulation of 17OHP (the precursor that the hormone converts)
55
CAH
most severe form with 21OHP
1. cortisol deficienc
2. aldo deficient
therefore have salt wasting form
weight loss, anorexia, vomiting, dehydration, weakness, hypotension, hypoglycaemia, hyponatremia and hyperkalemia
deelop at 10-14 days of age
can die - electrolyte abnormalities (i.e. hyperkalemia, and also hypotension)
because of cortisone deficiency - get increased ACTH
56
what are the clinical signs of prenatal androgen excess from CAH
get increased androgen because 17OHP is shunted into androgen pathy
females- will have masculinized external genitalia - enlargement of the clitoris and labial fusion, vagina has a common opening with the urethra
some females may be thought to be males with hypospadias and cryptoorchidism
salt losing form - most virilizatio
internal organs are normal - females have normal ovaries
brain: "sexually dimorphic behaviurs"
boys: appear normal at birth - may not have diagnosis until adrenal insufficiency develops
newborn screening saves the boys
57
genetics of CAH
deletions in the 21 hydroxyls genes
can be inherited
to do prenatal diagnosis can do CVS or amnio
58
signs of postnatal androgen excess
after birth
boys - normal, and boys with simple virilizing form - delayed diagnosis because they look normal and rarely develop adrenal insufficiency
signs of androgen excess: rapi growth, accelerated skeletal maturation 9tall in childhood but have premature closure of epiphyses and shooter adult stature)
might be pubic/axillary hair and acne and a deep voice
penis/scrotum and prostate may become enlarged, testes usually prepubertal
internal organs are female but may not get periods unless suppress the excess androgen
59
non classical 21 OH deficiency
cortisol and aldo are normal
affected females have normal genitals at birth
males and females may present with precocious pubarche and early development of pubic and axillary hair, might get hirsutism, acne, menstrual disorders and infertility later in life
60
labs in salt losing CAH
hyponatremia, hyperkalemia, metaolic acidosis and often hypoblycemia
can take 10-14 days for these to develop
17OHP (17 hydroxyprogesterone) are elevated
however, this hormone is high in the 1st 2-3 days of life even if unaffected, and especially if sick or perm
after infantcy, 17OHP circadian rhythm (highest in the AM)
cortisol low in patients with salt losing type, can be normal in simple virilizing (but inappropriately low in relation to ACTH and 17OHP levels)
renin high, with inappropriately low aldo
61
Diagnosis of 21OHP best diagnosis
meausre 17OHP before and 30-60min after IV bolus of 0.125-0.25 mg of cosyntropin
62
Physical exam, most useful finding to suggest that baby with ambiguous genitalia is a genetic male?
palpable gonads almost always suggest genetic male and presence of testicular tissues
US can help to look for uterus/gonads
karyotype
hormonal testing also to determine the genetic sex and anatomy of reproductive structures
63
Newborn screening for CAH
analyse 17OHP
if potentially affected, come back for lutes and repeat at 2 weeks of age
infants with salt-wasting disease may have abnormal lutes at this age but usually not severely ill
non classical not reliably detected by newborn screening (but not a big deal, since don't get adrenal insufficiency)
cut off is lo - lots of false positive (positive predictive value of 1%) problem is worst in PREM babies
can improve the PPV by using cut offs based on GA and other methods
64
Treatment of CAH
1. Glucocorticoids - to treat cortisol deficiency
also suppresses excess androgen production
dose is 15-20 mg/m2/24 hr (higher than other types of adrenal insufficiency) of hydrocortisone orally divided TID ; double or triple stress dosing
need the treatment forever
need to monitor puberty, growth, skeletal maturation
hormones 17OHP and androstenedione should be measured (want to have in high nomal or several times normal)
menarche in girls at appropriate age if good control
Simple virilizing disease - usually not diagnosed till later - can have skeletal maturation 5 year or more in advance of chronological age, can also sometimes have precocious puberty
2. if have salt wasting disease - also need mineralocorticoid - i.e. fludrocotrisone
other treatments sometimes used:
- antiandrogen/aromatase inhibiter
- GH
65
What are males with 21 hydroxyls defecieicny ncy with inadequate steroid therapy be at risk of?
adrenal rest testicular tumors - usually regress with increased steroids
testicular MRI/US and doppler to look at them
66
Surgical management of ambiguous genital in CAH
significantly virilized famles - usually undergo surgery between 2-6 months of age
Limited long term follow up of kids who had surgery - some sexual dysfunction
sex assignment: usually based on expected sexual functioning and fertility in adulthood with early correction of the external genitals
67
Prenatal treatment of CAH
give the mothers steroids - supposes the secretion of steroids by fetal adrenal, therefore less androgens , then do CVS
only continue the therapy if the baby is female (since we don't want virilization, and we want the boys to have androgens
may have lower birth weight
68
Types of CAH
1. 21 hydroxyls deficiency (most common) - classic and non classic form
classic is glucocorticoid and mineralocorticoid deficiency , non classic is mainly increased androgen effects , can be asymptomatic
2. 11 beta hydroxylase deficiency (5%) - glucocorticoid deficiency, aldo is normal (therefore don't get the same dramatic presentation) can actually have HYPERtension, can get ambiguous genitalia (females) and virilization (treatment is glucocorticoids)
3. others: 3beta- same as 21OHP classical; 17 alph hydroxilase (m not learning (table 570-1)
69
What is Antley Bixler syndrome?
```
P450 oidoreductase have some defect in 17hydroxylase and/or 21 hydroxylse ; leads to:
1. virilizaton of female fetuses, may virilize mother
2. associated findings:
- craniosynostosis
- brachycephaly
- frontal bossing
- severe midface hypoplasia
- humeroradial synostosis
boying ulnas/ femurs
hear thad kidney malformation
```
70
What is Cushing syndrome?
abnormally high levels of cortisol or other steroids
causes:
1. Excess glucocorticoid hormones - can cause hyperglycaemia, hypertension, weight gain, linear growth retardation and osteoporosis
2. Endogenous Cushing syndrome - adrenocortical tumor (most common in infants), Cushing disease (in >7 year old) where excess ACTH leads to bilateral adrenal hyperplasia
3. ectopic production of ACTH - most likely to have hypertension
4. McCune Albright - rarely with this
71
Clinical manifestations of Cushing syndrome - more severe in infants < 1 year
rounded face
prominent cheeks
flushed appearance (moon facies)
generalized obesity - common
abnormal masculization with adrenal tumours -
growth can be impaired
older kids: striae, delayed puberty, weakness, hadeachd and emotional lability
hypertension and hyperglycaemia can happen
osteoporosis can cause pathological raptures
72
Labs in Cushin syndrome
lose the circadian rhythm of corisol (normally high and decrease at midnight)
elevated nightime cortisol
increased urinary cortisol
dexamethasone suppression test - won't suppress the cortisol that well
glucose tolerance - often abnormal
73
elevated cortisol but no clinical evidence of cushing?
glucocorticoid resistance
74
Treatment of Cushing disease
pituitary Cushin disease - microsurgery
if ectopic steroid production, may need to remove adrenals
pre op and post op steroid
post op complications: sepsis, pancreatitis, thrombosis, poor wound healing, sudden collapse
after treatment have catch up gown and puberty, but still have abnormal bone density and compromised adult height
75
Pheochromocytomas
from chromatin cells
most common site is the adrenal medulla
can happen anywhere in the sympathetic chain
Clinical : hypertension - all patients have it at some point
paroxysmal hypertension, can be sustained
between attacks of hypertension can have normal BP
during episodes have headache, palpitations, abdo pain, dizziness, pallor/vomiting and sweating also occur
can get convulsions (from hypertensive encephalopathy)
symptoms can be worse with exercise
polyuria and polydipsia can occur
growth failure may be striking
optho may show papilledema, hemorrhages, exudate, arterial constriction
can have enlarged heart
HTN can be HIGH 180-260/120-210
76
genetic syndromes associated with pheochromocytoma
```
von Hippel Lindau
MEN
neurofibromatosis
Tuberous Sclerosis
Sturge Weber
Ataxia Telangiectasia
```
77
Diagnosis of phenochromocytoma
diagnosis: elevated bloor or urinary levels of catecholamines and metabolites
increased urinary excretion of vanillylmandelic acid (VMA) - major metabolite of epi and norepi
(can get false elevated with vanilla and fruits) therefore no longer routinely measured!
best sensitivity and specific: plasma normetanephrine with plasma norepinephrine the best test (need to avoid caffeine, tylenol)
urinary metanephrines are increased
urinary findings: protein, casts, glucose, gross hematuria suggests bladder tumour
78
Treatment of pheochromocytoma
remove the tumour, need to monitor the BP and heart rate closely
79
age at menarche
average is 12.5-13 years, range of normal
| usually mecharche correlates closely with skeletal age
80
Male hypogonadism - can be primary or secondary
primary hypogonadism - hypergonadotropic (i.e. the testes themselves fail)
secondary - have low gonadotropes
81
Causes of male hypogonadism
Primary hypergonadotropic hypogonadism : aka primary
- need to have some degree of testicular function to be a phenotypical male infant
Causes:
1) Genetic Defects
FSH/LH resistance, mutations in steroid synthetic pathways, gonadal dysgenesis, Klinefelter syndrome (47 XXY), Noonan, CF
2) Acquired defects;
crytorchidism, vanishing testes (have normal external genitalia and no uterus or fallopian tubes, therefore had testes at some point ) , chemo (cyclophosphamide and ifosfamide), cisplatin /radiation, infection (ie mumps), infarction (testicular torsion), trauma
Secondary hypogonadotropic hypogonadism
1. Hypothalamic:
a) genetic defects: X linked Kallman syndrome, AD Kallman syndrome, Inherited syndromes: Prader-Willi, Bardet-Biedl, Laurence-Moon Biedl, Alstrom, Constitutional Growth delay?
b) Acquired (reversible): anorexia, drug use, malnutrition, chronic illness, hyperprolactinemia
2. Pituitary:
a) genetic defects: isolated hypogonadotropic hypogonadism at pituitary level, septo-optic dysplasia
b) Acquired defects: pituitary tumours, infarction, infiltration, hemosiderosis and hemochromatosis, radiation, unknown
82
Congenital anorchia
disappearance of testes at some point after development (since they don't have uterus and fallopian tubes and normal external genitalia)
Labs; low levels of testosterone, and elevated levels of LH and FSH
83
Labs in primary hypogonadism
FSH and LH are increased (because less negative feedback)
testosterone doesn't help in prepubertal since we know will be low
during puberty - testosterone levels correlate better with testicular size, stage of sexual maturity and bone age than chronological age
testosterone will be low post puberty in primary hypogonadism
attenuated rise after hCG administration
elevated Antimullerian hormone (normally testosterone will block AMH)
bone age - delayed bone age
84
Noonan syndrome
nomal karyotype
20% are familial - autosomal dominant inheritance
missense mutations
Clinical manifestations:
1. Most common: short stature, webbing of the neck, pectus carinatum, cubits valgus, right sided congenital heart disease
2. Common: hypertelorism, epicanthus, downward slanting palpebral fissues, ptosis, micrognathia, and ear abnormalities
3. Less common: clinodactyly, hernias, vertebral anomalies
IQ is 86 (verbal>performance)
high frequency sensorineural hearing loss
most common cardiac : pulmonary valvular stenosis, hypertrophic cardiomyopathy, ASD
HSM
heme disorders: low clotting factors XI and XII, ALL, and chronic myelomonocytic leukaemia
males: cryptorchidism and small testes
low or normal testosterone secretion
delayed puberty
adult height in 20s
prenatal: nomal karyotype, edema or hydrops and short femur length
85
Treatment of Noonan:
growth hormone
86
Klinefelter syndrome
most common sex chromosomal aneuploidy
associated with infertile/oligospermia
80% will have 47 XXY chromosome complement
Clinical findings: rarely made before puberty since not that many features
1. behavioural psych, may have normal IQ with delayed verbal IZ , later in high school have learning difficulties (mostly language based)
2. Build: tal, slim and underweight , very long legs (lower limb>upper segment)
3. small testes
4. small phallus
5. cryptorchidis more common
6. low bone mineral density
7. pubertal development may be delayed
labs: elevated Lh/FSH and responses to gnRH stimultion
gynecomastic - 80% of adults, shave less than usual
sex chromosome aneuploidy
infertility in most
87
Risks in boys with Klinefelter
```
pulmonary disease
varicose veins
breast cancer
mediastinal germ cell tumours
leukemia, lymphoma and other heme cancers
```
88
Treatment of Klinefelter
testosterone - either long acting infections or gel
will help with secondary sex characteristics but will not improve fertility
gynecomastia - treat with aromatase inhibitors
89
hypogonadotropic hypogonadism (see above for causes)
hypothalamic if deficiency GnRH or if deficiency in pituitary FSH/LH production
Isolated - more likely to be from hypothalamus - one common is Kallman syndrome - when anosmia and hypogonadotropic
90
Kallman syndrome
most common form of hypogonadotropic hpogonadism and is genetically heterogeneous ( linked, AR and AD forms)
associated with anosmia/hyposmia
most cases are autosomal, 15% are X linked
Associated findings: synkinesia (mirror movements, hearing loss, mid facial defects and renal a genesis
can also have isolated hypogonadotropic hypogonadism (without anosmia) most are idiopathic, a few genetic conditions
91
Diagnosis of hypogonadotropin hypogonadism
low gonadotropins and gonadal steroids
constititusional delay can look similar to it
anosmia is a key question in patients with delayed puberty since can have family history of it
should check prolactin (since hyperprolctinemia can cause delayed puberty also)
MRI brain to look for hp abnormalities
92
Hypogonadotroc hypogonadism treatment
1. rule out constitutional delay of puberty
testosterone (injections or gel) can be treatment - secondary characteristics but will not lead to fertility
treatment with gonadotropins (i.e. HcG, or HMG) can also try pulse GnRH - lead o testicuar developmentincludinr spermatogenesis
93
Testicular cause of precocious puberty
Leydig cell timor
94
Gynecomastia differential
True (breast tissue) vs false (adipose tissue)
true is fibroglandular mass at least 0.5 cm in diameter, concentrated beneath the nipple and areola
Phsiologic forms:
Newborn: transient in male newborns (60-90%) from estrogens in pregnancy, asymmetrical can be and galactorrhea in 5%; most cases resolve in 4-8 weeks of birth, a few can last 12 months
Prepubertal: NOT physiologic, need to investigate
Pubertal: early to mid puberty
peak at: tanner stage 3-4, at age 14 and at testicular volume of 5-10 ml; breast can be tender
95
pubertal gynecomastia
Pubertal: early to mid puberty
peak at: tanner stage 3-4, at age 14 and at testicular volume of 5-10 ml; breast can be tender , can be unequal breasts
Course: spontaneous regression can occur in a few months, rarely longer than 2 years, psychosocial distress
cause: imbalance of estrogen and androgen
96
Pathological causes of gynecomastia -
1. genetic forms (rare but exist) - i.e. aromatase activation
2. exogenous estrogen - consider in prepubertal chilren - can have accidental ingestion or percutaneous absorption or ingestion ; in workers who make estrogen and even in their children
Medications that decrease androgen, increase estradiol or displace androgens from breast androgen receptors:
- spironolactone, alkylating agents, anabolic steroids, HCG, ketoconazol, cimetidine and androgen inhibitors
- weaker associations: opiates/alcohol, marijuana, lavender/certain tea oils
- Klinefelter syndrome, Androgen insensitivity syndromes , CAH (11 hydroxylase), Peutz-Jeghers , hyperthyroidism, malnourished patients who are well nourished
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Evaluation of gynecomastia
pubertal cases: history and physical
family history, history of liver/renal disease, meds/drugs of abuse, herbal and cosmetic products with estrogens
P/E: look at breasts: skin changes, fixation, LN , and nipple discharge, as well as a testicular exam
no lab in pubertal cases if not suspicious
ALL pre-pubertal cases (as well as pubertal cases with suspected features);
Thyroid functon
testosterone
estradiol
HcG and LH levels
if galactorrhea then do a prolactin level
do in the AM
select cases : karyotype, DHEAS, and liver and renal function tests
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Treatment of gynecomastia:
if physiologic only treat if emotional problems/striking (may consider androgens, aromatase inhibitors, and estrogen antagonists (i.e. tamoxifen) ) but don't work treat
if big breasts and refractory - then can do surgery
99
Hypofunction of the ovaries Differential
Primary -congenital failure of development, postnatal destruction (aka premature ovarian failure, arrest of ovaries by age 40) , can also have drugs (i.e. cyclophosphamid, procarbazine, etoposide and exposure of ovaries to irradiation) ; teenagers more likely to keep some function
Secondary - lack of stimulation by pituitary or hypothalamus
100
Primary hypogonadism in the female (Primary hypogonadism) clinical manifestations and differential
hard to diagnose pre-puberty - other than Turner, the other causes don't have any pre-puberty manifestations
Hypergonadotropic hypogonadism:
1) genetic: FSH/LH resistance, mutations in steroidogenic pathways, 46 XX gonadal dysgenesis, Turner syndrome, Noonan syndrome, Galactosemia, Fragile X associated disorders, Bloom syndrome, Werner syndrome, ataxia telangiectasia, Fanconi anemia
2) Acquired: chemo, radiation, autoimmune ovarian failure from autoimmune polyendocrin syndromes 1 and 2
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Turner syndrome
webbed neck, sexual infantilism (what a terrible word) and cubitus valgus in adult females
Chromosomes: 45X
ovaries have disappearance of oocytes by 2 years of age
eventually have streak ovaries - only connective tissue
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Clinical manifestations
edema f dorsa of the hands and feet and loose skin folds at the nape of the neck
low birthweight
decreased length
in childhood: webbing of the neck, low posterior hairline, small mandible, prominent ears, epicentral folds, high arched palate, broad chest, cubits valgus and hyper convex fingernails
at puberty: breast development fails to occur
Short stature - with linear growth deceleration is key
Cardiac anomalies: bicuspid aortic valve, aortic dilation, partial anomalous pulmonary venous connections, coarctations
should monitor BP
Renal U/S at diagnosis - can have renal malformations
ovaries - decrease in percentage of detectable ovaries
sexual maturation fails to occur, can have primary gonadal failure
autoimmune thyroid disease
IBD Crohn nd UC are possible, should screen for celiac
sternal malformations
congenitl hip displasia
recurrent OM
hearing defects
may be a bit delayed with GM and FM development but intelligence is normal
increased risk of learning disabilities, social isolation, anxiety
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Turner syndrome labs
chromosomes in short girls - since can be shot without tons of other findings
Shortened 4th metatarsal and metacarpal bones
FSH elevated
should check the thyroid antiperoxidase antibodies, if present check T4 and TSH
measure TTG IgA for celiac
Growht hormone deficiency plays a part in growth
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Treatment of Turner
```
growth hormone
estrogen replacement (but need to optimize timing to help with height)
```
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Secondary hypogonadism (hypogonadotropic)
1) hypothalamic:
a) genetic defects: kallman (although hypogonadism more likely in males rather than females) , other gens, Inherited (Prader-Willi, Bardet-Biedl), constitutional growth delay (she very marked
b_ Acquired: anorexia, drug use, malnutrition, chronic illness (i.e. crohn), hyperprolactinemia
2) Pituitary:
a) genetic defects: gonadotropin deficiency, septo-optic dysplasia
b) acquired: pituitary tumors/infarction, infiltrative, hemosiderosis, radiation
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Ovarian tumors in kids
overall they are rare, but a few can be malignant
#1 most common: germ cell tumours
#2: epithelial cell tumours
#3: sex cord/stromal tumors
tumor markers in ovarian tumors: alpha fetoprotein, HCG, carcinoembryonic antigen
most synthesize estrogens, a few synthesize androgens
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most common estrogen producing ovarian tumour causing precocious puberty
granulosa cell tumor although only 1-10% of ovarian tumours
Clinical manifestations - premature puberty but mainly estrogen manifestations, don't usually have pubic hair
may have mass in the lower portion of the abdomen
imaging: US or CT
Labs:elevated estradiol, suppressed gonadotropins
Treatment and Prognosis: should remove it surgically when diagnosed
other tumours: sex cord timor, chorioepithelioma (makes lots of hCG)
108
follicular cysts
can be associated with premature puberty
| McCune Albright similar mechanism
109
virilizing ovatian bumors
types of tumours - rare in general, especially in pre-pubertal
110
Differential of disorders of sex development
1) 46 XX DSD:
a) Androgen Exposure
- Fetal/fetoplacental source (includes CAH, aromatase deficiency, glucocorticoid receptor gene mutation)
- Maternal source ( virilizing ovarian tumor, adrenal tumor, androgenic drugs)
b) Disorder of ovarian development
- gonadal dysgenesis
- testicular DSD
c) Undetermined Origin
- associated with GU and GI tract defects
2) 46 XY DSD
a) Defects in Testicular Development:
- Denys Drash syndrome, WAGR syndrome, campomelic syndrome, XY pure gonadal dysgenesis, SRY gene mutation, XY gonadal agenesis, unknown cause
b) Deficiency of Testicular Hormones:
- leydig cell aplasia
- mutation in LH receptor
- Lipoid adrenal hyperplasia
- CAH
- persistent mullerian duct syndrome
c) Defect in Androgen Action
- 5alpha reductase, androgen receptor defects, Smith Lemli Opitz
3) Ovotesticular DSD
Sex Chromosome DSD
- Turner syndrome, Klinefelter syndrome, mixed gonadal dysgenesis, chimeric /ovotesticular
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Diagnostic tests for disorder of sex differentiation
1. Karyotype: with rapid determination of sex chromosomes
2. Other blood tests:
- screen for CAH
- screen for androgens and precursors
- screen for geonadal response to gonadotropin in patients suspected of having testicular gonads, simulation with infections of HCG, measure testosterone and dihydrotestosterone before and after HCG
- molecular genetics for SRY
- gonadotropin levels
3. Internal anatomy of patients with ambiguous genitalie (with imaging)
- VCUG, endoscopic exam, US, renal/adrenal US, CT or MRI if needed
112
Denys Drash Syndrome
nephropathy - proteinuria to nephrotic syndrome and end stage renal failure
ambiguous genitalia
bilateral Wilms tumor
most cases are XY
113
WAGR syndrome
Wilms tumor
aniridia
GU malformations
retardation
114
most common male DSD
androgen insensitivity syndrome:
- X linked recessive disorders
Clinical manifestations:
Complete AIS: extreme form of failure of virilization, genetic males female at birth, external genitalia are female, vagina is a pouch and uterus is absent
testes are usually intra-abdominal
at puberty normal breast development but no periods
height are similar to normal males
Partial AIS: can have wider range of manifestations
Diagnosis of AIS:
diminished surge of testosterone and LH in infancy;
decrease in IGF fibroblasts
Treatment:
remove the testes
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management of patient with ambiguous genitalia
1. tell the family about the condition - early, completely, compassionately; avoid guilt, shame, discomfort
2. multiD team
3. pelvic US to look for uterus and ovaries
if there is uterus and no gonades, suggests XX ; virilized XX females usually reared as females even when highly virilized
absence of uterus, with or without gonades
116
present uterus and no gonads, chromosomes?
XX - virilized XX females
| generally reared as females even when highly virilized (although not always)
117
no uterus with or without gonads
most likely XY undervirilized male
depending on the condition and what will happen in puberty, determine whether to raise as male or female
previously used to have surgery, this is more controversial
118
Diabetes Mellitus Type 1
autoimmune destruction of beta cells
genetic and environmental factors susceptibility
o Major environmental effect, possible association with viral infections (controversial)-congenital rubella infection
o Seasonal associations – more diagnosis in winter months
o Dietary factors – cow’s milk, heavier young children, chemicals
119
What does insulin do: (from Julie)
```
o glycogen synthesis
o increase lipid synthesis ->makes adipose tissue make fat
o decrease proteolysis
o decrease gluconeogenesis
o increase K uptake by the cell
o causes arterial wall muscles to relax
```
120
Definition of Diabetes (see written notes for more details)
impaired glucose tolerance: FBG >6.0 mmol/L or 2 hour plasma glucose 7.0 mmol/L or 2 hour glucose >11.1mmol/L
121
true or false - impaired glucose tolerance predicts future diabetes and cardiovascular risk
false - no it doesn't
except in pregnancy
state between normal and diabetes
122
HgA1C and pre meal glucose targets in different age groups
- < 6 year old: HgA1C12 year old: HgA1c<7.0 FBG 4-7
123
starting insulin for diabetes
- Starting Regimen:
o 2 or more bolus, 1 or more basal
o Dose to start with (based on CHEO handouts):
• Total daily dose 0.5 units/kg/day (toddlers 0.25-0.5 units/kg/day)
• 2/3 in the AM, 1/3 in the PM
• in AM, 2/3 of each dose as basal and 1/3 as fast acting
124
guideline for monitoring of diabetes type 1 (canadian guidelines)
- Hypertension (16% with DM1 have it)
o Q6 months
- Nephropathy
o 1st morning albumin/Cr yearly screening starting at age 12 if >5 years of diabetes; helps detect microalbuminuria
o random Alb/Cr : may be compromised in adolescents because of exercise induced proteinuria and benign postural proteinuria, if abnormal (>2.5 mg/mmol) see then do morning ACR
o Treatment of nephropathy (based on adult evidence)
• 1st line ACEi
• 2nd line HCTZ
- Autoimmune Thyroiditis
o At diagnosis, TSH, anti thyroid antibodies- anti-thyroidperoxide antibodies, anti thyroglobulin antibodies, anti TSH receptor antibody
o 15-30% of DM1 have autoimmune thyroiditis, most at puberty have hypothyroidism, can get hyperthyroidism also
o IF positive screen q6 months -1 year, if negative, screen every 2 years
- Dyslipidemia
o Fasting triglycerides, cholesterol, LDL and HDL -> at 12 year old and 17 year old
o RFs (test even if 5 years, then yearly
o If haven’t had for 5 years, then start after >5 years diabetes
o Refer to optho
o More leeway if good control and no retinopathy initially
- Check for comorbidities (at diagnosis):
o Celiac disease – as clinically indicated hx/exam/anti TTG if suspicious; symptomatic 60-70% test would be anti TTGand IgA levels
o Adrenal insufficiency – as clinically indicated, suspect if recurrent hypoglycemia with decreased insulin need, Addison disease is rare, even in DM1, test would be 8am serum cortisol and sodium/potassium
o Eating disorder
o Neuropathy (usually subclinical)– only post puberty
125
high AM glucose in DM1 two potential causes
Dawn phenomenon - higher growth hormone overnight
Somogyi phenomenon - rebound from late night/or early morning hypoglycaemia
126
surgery in patient with diabetes type I
IV insulin and fluids
table 583-9 goes over the IV insulin coverage during surgery
if the surgery is brief and supposed to have full oral intake shortly after - monitor the glucose hourly
give insulin according to child' home glucose correction scale
glargine/detemir - full dose
NPH or LEnte - one half to eh morning dose before surgery
don't discharge until stable glucose and baby eating well
127
which type of diabetes more likely to have genetics?
type 2
128
Who should you screen for type 2 diabetes:
overweight and at least 2 other risk factors for T2DM - start at age 10 or at puberty and every 2 years
risk factors:
1) family history in 1st or second degree relatives
2) mom with gestational diabetes
3) ethic groups
4) insulin resistance
fasting blood glucose usually used (although some are now saying to use HgA1C)
129
management of type 2 diabetes
diet and exercise are type 1
oral hypoglycaemia if doesn't work
metformin most commonly used - need to assess renal function before starting, can also get hepatic dysfunction
others:thizolidinediones, sulfonylureas, acarbose, pramlintide, incretin mimetics
130
Complications of T2DM
hypertension and lipid abnormalities
screening for microalbuminuria and retinopathy
sleep apnea
fatty liver diesease
131
neonatal in type 2 DM
often IUGR and little - hypothesis that they then try to conserve energy later in life, predisposes them to type 2
132
CF related diabetes
associated with pancreatic insufficiency
females higher risk than males
pancreatic damage leads to slowly progressive insulin deficiency
progressive delayed response
eventually get some insulin resistance
microvascular complications but slower, macro vascular complications (less likely, potentially because they die first)
course: can wax and wane
associated with poor weight gain - treatment with insolent helps with weight gain, slows down lung deterioration
133
drugs which can cause diabetes
steroids - glucose intolerance
| immunosuppression: cyclosporine and tacrolimus
