Endocrine Flashcards
What is premature adrenarche?
Early activation of HPA axis, often seen in obese children. Typical onset 4-8 yrs. Mild growth spurt. May have mildly advanced bone age. Pubic hair, axillary hair, apocrine sweat.
What is premature thelarche?
Early breast development
Typically happens between birth to 2 yrs, most regress, no long term risks.
At what tanner stage does peak height velocity occur in males?
Tanner stage 4-5
When does peak height velocity occur in girls, relative to menarche?
growth spurt occurs before menses
Definition of precocious puberty
girls < 8 yrs, boys < 9 yrs
hormone pattern in primary gonadal failure
elevated LH/FSH, low estrogen/testosterone
pubic hair, acne, body odor but no thelarche
premature adrenarche due to secretion fo adrenal androgens (DHEA)
first sign of puberty in boys
testicular growth
what is pubarche?
pubic hair growth
what testicular volume indicates puberty?
4mL = 2.5 cm
what is DHEAS
an adrenally produced androgen
what is an intervention you can take to improve growth in Turner’s syndrome?
growth hormone
incidence of Turner syndrome
1/2000
diagnosis of type 1 diabetes - fasting
fasting blood glucose > 7 mmol
diagnosis of type 1 diabetes - random
random glucose > 11.1 mmol
most common CAH mutation
21-hydroxylase enzyme deficiency
micropenis in term infant
<2.5cm
most common type of pediatric thyroid cancer
papillary carcinoma
treatment of thyroid cancer
thyroidectomy, post-operative radio-ablation to remove any remaining tissue
what is the antibody in graves disease
thyrotropin receptor stimulating antibody
causes of hyperthyroidism
graves (thyrotropin receptor stimulating antibody), subacute thyroiditis, suppurative thyroiditis, toxic adenoma, exogenous thyroid hormone
syndromes associated with pheochromocytoma
VHL, MEN2, NF1
how to screen for cushing’s disease
24 hour urinary free cortisol
definition of pathologic #s
2 or more long bone #s < 10 yrs, 3 or more long bone #s < 19 yrs, any vertebral compression # (loss of > 20% of vertebral height)
anterior pituitary hormones
TSH LH FSH prolactin GH ACTH "go find the adenoma please"
posterior pituitary hormones
ADH
oxytocin
steroids made by adrenal gland
zona glomerulosa - aldosterone
zona fasiculata - cortisol
zona reticularis - DHEA-S and androstenedione (pre-cursor to testosterone)
first sign of puberty in males
testicular enlargement (volume > 4mLs or size > 2.5cm)
first sign of puberty in females
breast bud formation
Definition of premature adrenarche
sexual hair < 8 yrs in girls, < 9 yrs in boys
What does premature adrenarche put girls at risk for?
PCOS, hyperandrogenism, +/- metabolic syndrome
DDX isolated vaginal bleeding
vulvovaginitis urethral prolapse sexual abuse sarcoma botryoides foreign body
What is the origin of a craniopharyngioma?
remnant of rathke’s pouch
stimuli for ADH release?
increased plasma osmolality (sensed by osmoreceptors in hypothalamus)
AND
hypovolemia (sensed by baroreceptors in carotid sinus of aortic arch)
What should you think of if you see a patient with a single central incisor?
Midline defects – congenital hypopituitarism and GH deficiency
DDX acquired GH deficiency
autoimmune - sarcoid irradiation idiopathic sheehan syndrome tumour (craniopharyngeoma, glioma, pinealoma, pituitary adenoma) CNS - stroke, TBI (NAI) infectious (meningitis, encephalitis)
Triad associated with multiple pituitary hormone deficiency
Anterior pituitary hypoplasia
Absent pituitary stalk
Ectopic bright spot on MRI
Definition of precocious puberty
Appearance of secondary sexual characteristics OTHER THAN PUBIC HAIR
Girls < 8 yrs
Boys < 9 yrs
DDX central precocious puberty
idiopathic CNS tumours hypothalamic hamartoma severe, untreated hypothyroidism (elevated TSH - alpha subunit is same as FSH) hydrocephalus, myelomeningocele trauma
Precocious puberty in boys - what percent have structural/CNS cause?
75%!
Evaluation of precocious puberty
Random LH
Leuprolide (GnRH) stimulation test - then measure LH after
Sex steroids (testosterone, estradiol, DHEA-S), TSH
Bone age (should be advanced)
Consider MRI brain - ALWAYS in males, in females < 6 yrs
Abdo U/S - ovaries, uterus
When to MRI if concerned about central precocious puberty
Girls with rapid breast development, girls < 6 yrs, ALL boys, girls with estradiol > 30 pg/mL
Tx of central precocious puberty (idiopathic)
GnRH agonist (Lupron)
Most common CNS lesion causing central precocious puberty
Hypothalamic hamartomas (associated with gelastic or psychomotor seizures)
Types of CNS tumous that can cause central precocious puberty
astrocytoma, ependymoma, optic tract gliomas (assoc with NF1), hypothalamic hamartoma
The alpha subunit of TSH is the same as….
FSH
Abnormally elevated TSH in boys causes…
testicular enlargement
Elevated hCG (from tumour secretion) in boys can stimulate….
LH receptors in Leydig cells, causing release of testosterone
McCune Albright - TRIAD
precocious puberty
polyostotic fibrous dysplasia
cafe au lait macules
Other clinical features of McCune Albright
multinodular goiter
cushing’s syndrome
gigantism/acromegaly
hypophosphatemic rickets
LH stimulates
Leydig cells to make testosterone
FSH stimulates
sertoli cells, resulting in stimulation of seminiferous tubules and testicular growth
Tx of familial male AD GnRH independent precocious puberty
ketoconazole
Leydig cell tumours result in….
asymmetric enlargement of testes
hCG secreting germ cell tumour in boys results in….
stimulation of LH receptor and symmetric testicular enlargement (but not to full pubertal size, due to stimulation of ONLY LH receptor) and penile growth (due to testosterone)
Denys-Drash syndrome
early onset renal failure
Wilm’s tumour
abnormal external genitalia
Definition of delayed puberty
Girls: Lack of breast development by 12 yrs
Boys: Lack of testicular enlargement by 14 yrs
At what bone age should you expect spontaneous puberty to start?
Boys: bone age 12 yrs
Girls: bone age 11 yrs
DDX hypogonadotrophic hypogonadism (secondary)
Genetic (Kallman, Prader-Willi)
Acquired (anorexia, drugs, malnutrition, chronic illness)
Pituitary (septo-optic dysplasia, tumours, infarction, infiltrative disorders, radiation)
Hypergonadotropic hypogonadism (primary)
Mutations causing FSH, LH resistance
Gonadal dysgenesis
Klinefelter syndrome (47 XXY)
Noonan syndrome (PTPN-11 mutation)
CF
Acquired: Chemo, rads, infection (mumps), torsion, trauma
Noonan syndrome mutation
PTPN11 - gene on chromosome 12q24.1
Rasopathy!
Kleinfelter genetics
47 XXY
Kleinfelters - increased risk of…
pulmonary disease
varicose veins
breast cancer
hypergonadotropic hypogonadism
Kleinfelters - increased risk of what cancers
male breast cancer
germ cell tumour
leukemia, lymphoma
Kallman syndrome
hypogonadotropic hypogonadism AND anosmia
Neonatal gynecomastia is seen in ______ % and resolves by _____
seen in 60-90% of newborns and usually resolves by 2 months
5% have galactorrhea!
what % of boys get gynecomastia during puberty?
approx 65%
gynecomastia + galactorrhea - think of what?
prolactinoma
DDX gynecomastia in teenage boy
Normal pubertal gynecomastia
Genetic predisposition
Exogenous estrogen
Kleinfelter syndrome
Peutz-Jeghers
Hyperthyroidism (mimicks FSH stimulation)
(If galactorrhea present, think of prolactinoma)
Premature ovarian failure
arrest of normal ovarian function before the age of 40yrs
aka hypergonadotropic hypogonadism
Turner syndrome - where does the single x come from?
the single x is usually maternal!
not associated with parental age
Life threatening consequence of Turner syndrome
coarctation of the aorta, bicuspid aortic valve
ALSO: ascending aortic dilation, partial anomalous pulmonary venous return
(adults: premature coronary artery disease)
How common are anti-thyroid antibodies in Turner syndrome
30-50% of patients!
thyroid peroxidase or thyroglobulin antibodies
What other autoimmune conditions should you screen for in Turner syndrome?
celiac disease (4-6%) autoimmune thyroid disease (10-30%)
Turner syndrome - MSK issues to look for
scoliosis (10%)
congenital hip dysplasia
Turner syndrome with Y chromosome material is at increased risk of…
gonadoblastoma (7-10%)
recommendation: Prophylactic gonadectomy (even if no evidence of tumours)
What is the gonadoblastoma locus on the Y chromosome
GBY
What is Perrault syndrome?
XX gonadal dysgenesis + sensorineural deafness
Definition of amenorrhea
absence of menses at age 15 OR > 3 yrs post thelarche
Top 2 causes of primary amenorrhea
gonadal dysgenesis
mullerian agenesis
45 X / 46 XY - at increased risk of?
gonadoblastoma in 25%
47XXX
1/1000 live born females, due to maternal meiotic non-disjunction
normal sexual development, menses
speech/language delay, poor academics, tall, gangly, behaviour issues
MRI - low amygdala volumes
Girls with noonan syndrome
CHD - pulmonary valvular stenosis
normal sexual maturation (may be delayed 2 yrs)
Ovarian failure - genetic/metabolic causes
45X
galactosemia
denys-drash
ataxia-telangiectasia
If you see galactorrhea and secondary amenorrhea - what should you think of?
a pituitary adenoma (elevated prolactin - suppresses GnRH, causing secondary amenorrhea)
anosmia and hypogonadotropic hypogonadism is called what?
Kallmann syndrome
47XXY and hypergonadotropic hypogonadism
Kleinfelters
What should you think about in a patient with septo-optic dysplasia and an intercurrent illness?
They have pituitary deficiencies (in 25%) - should give stress dosing hydrocortisone if they are unwell!
Production of T3
20% secreted by thyroid
80% as a result of de-iodination of T4 by liver/kidney/other tissues
where is the thyroid hormone receptor located
in the cell nucleus
Which four hormones have the same alpha subunit?
TSH
FSH
LH
hCG
How would you evaluate for ectopic thyroid tissue (or thyroid agenesis)?
Thyroid radionuclide testing with Technetium-99 or Radioiodine-123
prevalence of congenital hypothyroidism
1 in 3000
most common cause of congenital hypothyroidism in north america
thyroid dysgenesis (80-85% of cases, 1/3 of these are complete aplasia)
(#2: dyshormonogenesis, #3: thyrotropin receptor-blocking antibody)
What is Pendred syndrome?
an autosomal recessive condition w/ sensorineural deafness and goiter
(defect in chloride-iodide transport protein in both thyroid and cochlea)
Baby with congenital hypothyroidism, and mom with:
hashimoto’s, graves, hypothyroidism on replacement tx
what diagnosis to consider?
the presence of thyrotropin receptor blocking antibodies
(3rd most common cause of congenital hypothyroidism - still v. rare)
Resolves within 3-6 mos
most common cause of congenital hypothyroidism worldwide
iodine deficiency
What congenital anomaly often co-exists with congenital hypothyroidism?
cardiac anomalies in 10%
also: CNS, eye anomalies, hearing loss
what clinical finding might you see in a patient with ectopic thyroid?
thyroglossal duct cysts
ECG + ECHO findings in congenital hypothyroidism
ECG: low voltage P and T waves, low amplitude QRS
ECHO: poor left ventricular function, pericardial effusion
adverse effect of overdose of thyroxine
craniosynostosis
“temperment problems”
most common cause of acquired hypothyroidism
chronic lymphocytic thyroiditis
Conditions at increased risk of autoimmune thyroid disease
Down (20%) Turner's (30%) Kleinfelters T1DM (5%) Celiac Sjogren MS Pernicious anemia Cystinosis Vitiligo Alopecia Congenital rubella
Medication that can induce hypothyroidism
Amiodarone (due to high levels of iodine) Lithium PPU Methimazole Iodides Valproate (subclinical)
Other rare causes of acquired hypothyroidism
chronic hep C infection
large liver hemangiomas (increased conversion of T4 – T3 – T2)
first clinical manifestation of acquired hypothyroidism
deceleration of growth
what antibodies should you test for if you suspect autoimmune thyroiditis?
anti-TPO
anti-thyroglobulin
subacute granulomatous thyroiditis (de quervain disease)
possible viral cause
URTI with tenderness over thyroid - then severe pain over thyroid
inflammation causes release of T4/T3
FOUR Phases:
hyperthyroid, euthyroid, hypothyroid and then remission
Nutrient deficiencies that can cause goiter
Selenium
Iron
Vitamin A
Wolff-Chaikoff effect
administration of large doses of iodide, results in inhibition of organification of iodine and decreased synthesis of thyroid hormone
Condition associated with toxic multinodular goiter, cafe au lait macules, precocious puberty, polyostotic fibrous dysplasia
mccune albright
common causes of hyperthyroidism
Graves disease Post-partum thyroiditis Toxic multinodular goiter Toxic solitary adenoma Exogenous thyroid hormone
splenomegaly, lymphadenopathy, goiter, involvement of retro-orbital tissues, enlarged thymus - findings in what condition?
Graves disease
Antibody in Graves disease
thyrotropin receptor stimulating antibody (TRSAb)
HLA associations with Graves disease in Caucasian populations
HLA-B8, HLA-DR3
Thyrotropin receptor stimulating antibodies to measure
TBI, TBII
differentiating between exogenous thyroid hormone and Graves disease
- both have elevated T4 and suppressed TSH however thyroglobulin will be LOW in exogenous supplementation and elevated in Graves disease
Treatment of graves
Methimazole (risk of liver disease with PTU) - cure rate 30-80%
Radioiodine > 10 yrs
Subtotal thyroidectomy
Frequency of neonatal hyperthyroidism (if mom has hx of Graves)
2%
Treatment of neonatal graves disease
propanolol and methimazole
Familial hypocalciuric hypercalcemia is due to..
loss-of-function mutation of calcium sensing receptor (resulting in increased set-point for calcium homeostasis)
Mechanism of action of Calcitonin
inhibits bone resorption by affecting osteoclastic activity (tones down calcium in the blood)
Sites of action: PTH
Kidney: increase 1,25-OH-Vit D
Gut: increased Ca absorption
Bone: Increased bone resorption
Aplasia or hypoplasia of the parathyroid gland is associated with what syndrome…
DiGeorge (22q11.2)
can have neonatal hypocalcemia
What syndrome is a result of a GATA3 mutation
HDR syndrome:
hypoparathyroidism
sensorineural deafness
renal anomaly
Transient hypocalcemia of the newborn may be as a result of what (usually asymptomatic) condition in the mother
maternal hyperparathyroidism (causing suppression of neonatal parathyroid hormone), often due to a parathyroid adenoma
Common surgical cause of hypoparathyroidism
thyroidectomy (even when parathyroid glands are identified and left intact)
Two deposition/infiltrative disorders that can cause hypoparathyroidism
Thalassemia
Wilson’s disease
Autoimmune polyglandular syndrome type I
HAM syndrome:
hypoparathyroidism
Addisons
mucocutaneous candidiasis
Autosomal recessive
PE signs of hypercalcemia
Chvostek - tapping on face anterior to ear results in twitching of face
Trousseau - inflate BP cuff above SBP x several minutes, results in muscular contraction (flexcious of wrist and MCPs)
Chovstek’s sign
tapping on face in front of ear results in twitching of muscles, sign of hypercalcemia
Trousseau’s sign
inflate a BP cuff > SBP x several minutes, results in muscle contraction / wrist flexion
Sign of hypercalcemia
PE findings of long-standing hypocalcemia
irregular enamel formation, soft teeth, dry/scaly skin, cataracts, intellectual delay
ECG finding hypocalcemia
prolonged QT
What can develop if you treat patients with autosomal dominant hypocalcemic hypercalciuria with Vit D?
nephrocalcinosis, renal impairment
What other electrolytes should you check in hypocalcemia?
Magnesium - can lead to hypocalcemia (unclear mechanism, may impair release of PTH)
Phosphate - can be elevated
what causes pseudohypoparathyroidism?
genetic defect in PTH receptor
MSK changes in pseudohypoparathyroidism
- short stature
- brachydactyly (short fingers, usually first finger is longer than 2nd)
- subcutaneous calcium deposits
- bowing of bones
what is pseudopseudohypoparathyroidism?
anatomic features of pseudohypoparathyroidism with normal calcium levels - PTH may be slightly elevated, may be related to slightly reduced receptor activity
MEN I
autosomal dominant disorder
hyperplasia of pancreas, anterior pituitary and parathyroid glands
in what clinical situation could transient neonatal hyperparathyroidism occur?
maternal hypoparathyroidism (due to hypocalcemic condition for fetus) results in bone manifestations
clinical manifestations hypercalcemia
“bones, moans, stones, groans”
- muscle weakness
- fatigue
- h/a
- abdo pain, constipation
- N/V
- acute pancreatitis
characteristic x-ray finding of hyperparathyroidism
resorption of subperiosteal bone along the margins of the phalanges of the hands
hypercalcemia and elevated PTH - TWO CAUSES
hyperparathyroidism
familial hypocalciuric hypercalcemia (loss of function mutation of calcium sensing receptor, resulting in higher set point for serum calcium)
tx of hyperparathyroidism
surgical exploration for adenoma
what electrolyte abnormality can be seen in granulomatous disease?
hypercalcemia (in 30-50%) of patients with sarcoid, less often with TB
due to elevated 1,25-OH-Vit D
what is the usual cause of hypercalcemia of malignancy?
parathyroid hormone related peptide
what can cause hypercalcemia in newborn infants?
subcutaneous fat necrosis (may be due to elevated 1,25-oh-vit D)
tx: prednisone
what tissues contain ALP?
liver
bone
kidney
syndrome associated with infantile hypercalcemia?
William’s syndrome (10%)
what do you measure if you suspect hypervitaminosis D?
serum 25-OH-Vit D (not 1,25-OH-vit D) — longer half-life!
clinical features of Rickets
widened wrists/ankles (+cupping, fraying of edge of metaphysis on xray) craniotables rachitic rosary harrison groove frontal bossing delayed fontanelle closure scoliosis valgus/varus deformities leg pain etc...
medications associated with low Vit D levels
phenobarbital
phenytoin
isoniazid
rifampin
most common cause of Fanconi syndrome in children
cystinosis
lab tests - Rickets work up
calcium phosphate ALP PTH 25-OH-vit D 1,25-OH-vit D cr, lytes urine analysis (for fanconi syndrome)
what type of Vit D should you measure?
25-OH-Vit D made in liver
1,25-OH-Vit D is dependent on renal fxn and enzymes
fatal complication of hypocalcemia
laryngospasm
tx of symptomatic hypocalcemia
IV calcium bolus (on ECG monitors)
consider active Vit D (1,25-Vit D)
mutation in vit D dependent rickets type 1
mutation in enzyme 1-alpha-hydroxylase - can’t convert 25-OH-Vit D to active form (1,25-OH-Vit D!)
vitamin D dependent rickets type 2
what is the mutation, name an associated autoimmune condition, how do you treat
mutation in vit D receptor, usually have high levels of 1,25-OH-vit D
50-70% have alopecia!
tx - may respond to high doses of vit D (if partial receptor activity)
Most common cause of hypophosphatemic rickets
X-linked hypophosphatemic rickets
Due to mutation in PHEX gene, results in inhibition of phosphate resorption in kidney and inhibition of 1-alpha-hydroxylase enzyme in kidney
Females are symptomatic - x-linked DOMINANT disorder!
Clinical manifestations of hypophosphatemic rickets
abnormalities of lower extremities
poor growth
delayed dentition, tooth abscesses
lab findings hypophosphatemic rickets
high urinary phosphate hypophosphatemia increased ALP PTH, calcium levels are normal low/normal 1,25-OH-vit D
Tx of hypophosphatemic rickets
1,25-OH-vit D
phosphorus
Viral infections implicated in T1DM
Congenital rubella syndrome
others: enteroviruses, mumps
Environmental exposures that may increase risk of T1DM
cow’s milk protein
gluten
How can you risk stratify patients with 1st degree family member with type 1 diabetes in terms of their future risk?
by number of autoantibodies
low risk = single aab
moderate risk = 2 aab
high risk = > 2 aab
possible protective factors against developing T1DM
vaccination (against mumps, pertussus)
supplementing omega 3, vitamin D
breastfeeding
delaying exposure to cows-milk protein and gluten
DKA - lab values
ketonuria
glucose > 11
pH < 7.3
bicarb < 18
most common enzyme deficiency resulting in congenital adrenal hyperplasia
21-hydroxylase deficiency
What are the types of classical CAH due to 21-hydroxylase deficiency?
- Salt wasting (low cortisol and aldosterone) in 70%
2. Simple virilizing (low cortisol, adequate aldosterone) in 30%
CAH - classic salt-wasting type. Who is higher risk of mortality, boys or girls?
boys! because girls are detected earlier due to virilization, boys present very unwell (salt-wasting crisis, adrenal insufficiency)
Boys with CAH - virilizing features
pubic hair axillary hair deep voice enlarged penis PRE-PUBERTAL TESTES
Lab test - CAH
- low Na
- hyperkalemia
- elevated 17-hydroxyprogesterone in response to ACTH stimulation
- elevated renin (due to aldosterone deficiency)
when do you screen for proteinuria in T1DM?
at age 12 yrs (if T1DM for at least 5 yrs)
How do you screen for proteinuria in T1DM?
first morning albumin to creatinine ratio
if abnormal, retest at least 1 month later with either a repeat first morning ACR or a timed 24 hr urine
When do you screen for retinopathy in T1DM?
at age 15 or at least 5 yrs after diagnosis
when do you screen for dyslipidemia in T1DM?
- In children < 12 yrs with risk factors for dyslipidemia (fam hx, obesity)
- In all children > 12 yrs with T1DM
How often should you screen for hypertension in a child with T1DM?
twice per year
When do you screen a child with T1DM for thyroid antibodies?
at diagnosis, and then every 2 yrs (test TSH and thyroid peroxidase antibodies)
When should you screen a child with T1DM for celiac?
ONLY if symptomatic
Glycemic target in child with T1DM < 6 yrs old
A1C 8.0%
Glycemic target in child with T1DM 6-12 yrs old
A1C 7.5%
Glycemic target in adolescents
A1C < 7%
Osteogenesis imperfecta - triad
blue sclera
fragile bones
early deafness
Type I osteogenesis imperfecta - severity, clinical features
mild symptoms
easy bruising, joint laxity
mild short stature
childhood fractures - improves after puberty
Type II osteogenesis imperfecta - severity, clinical features
perinatal lethal
children are stillborn or die in the first yr of life, have multiple intrauterine fractures
Type III osteogenesis imperfecta
severe, progressive deforming, non-lethal
in utero fractures, macrocephaly, triangular facies
MSK: flared rib cage, scoliosis, vertebral compression, extreme short stature
xray: popcorn appearance at metaphyses
Type IV osteogenesis imperfecta
moderately severe
fractures after ambulation, improved after puberty
bowing of limbs
may be able to ambulate
