Pediatric endocrine disorders Flashcards
Normal and abnormal growth
Normal growth - mediated by multiple growth factors and nutrition
- in utero –> insulin and other growth factors are most important; growth hormone is less important
- postnatally –> growth hormone becomes the predominant growth factor
Abnormal growth - any deviation from the standard normal curve –> too short or too tall
Causes of tall stature
- obesity
- precocious puberty
- growth hormone excess –> gigantism/acromegaly depending on whether or not the epiphyses have fused
- hyperthyroidism
- genetic (tall parents)
- klinefelter syndrome
- marfan syndrome/homocysteinuria –> suspect if arm span is taller than the height
- overgrowth syndromes
Overgrowth syndromes
Beckwith-wiedeman - 11p15
- macroglossia
- hypoglycemia
- macrosomia (excessive birth weight)
- abdominal wall defects
- ear creases
- neoplasms
Sotos syndrome - NSD1 gene
- cerebral gigantism (large head)
- grow quickly in childhood but normal adult height
Weaver’s syndrome
- fetal and childhood overgrowth
- dysmorphic facies
When is evaluation for short stature needed?
- child is crossing percentiles –> this is normal early in life, but after the age of 4, a child who is growing at the 75th percentile should continue to do so; would be concerning if they all of a sudden started growing at the 25th
- child is below 3rd percentile
- child is outside of genetic expectations
- child/family are having concerns
Diagnostic considerations for short stature - systemic and genetic diseases
Systemic disease
- GI/nutrition - inflammatory bowel, celiac, malnutrition
- renal - chronic renal insufficiency, RTA
- resp - CF or severe asthma
- cardiac - cyanotic disease of CHF
- ENT - obstructive sleep apnea
Genetic disease
- skeletal dysplasia –> achondrodysplasia/hypochondroplasia
- multiple syndromes/genetic diseases
- mucopolysaccharidoses
- inborn errors of metabolism
- Turner syndrome
- genetic (short parents)
- idiopathic short stature/SHOX deficiency
Diagnostic considerations for short stature - Prader willi syndrome
Association with deletion or uniparental disomy of chromosome 15q-
- occurs in 1/15,000 births
- at birth –> hypotonic, poor feeders, have failure to thrive, delayed motor skills, decreased muscle mass
- age 3-4 –> develop hyperphagia and become very obese
- developmental delay, behavioral problems
- hypogonadism/delayed puberty
- usually develop short stature
Diagnostic considerations for short stature
- constitutional delay of growth and devt
- small for gestational age
- psychological deprivation
Constitutional delay of growth and development – late bloomers
Small for Gestational age (SGA) - Birth weight and/or length at least 2 SD below mean for gestational age
- –> of the 3 % of babies born SGA, about 10 % do not show catch up growth by age 2 - 3 years
- –> these children are GH resistant and will grow in response to higher than typical doses of GH
- –> may be related to variations in the IGF-1/IGF-1 receptor haplotypes
- –> SGA children have insulin resistance and are at increased risk for Type 2 diabetes and obesity
Psychosocial deprivation – children with extensive chronic stress/neglected don’t grow as well – removal from environment stimulates normal growth
Diagnostic considerations for short stature - endocrine disease
- hypothyroidism
- cushing syndrome/adrenal insufficiency
- growth hormone deficiency
- growth hormone resistance –> laron dwarfism
- turner syndrome
- hypoparathyroidism
- Rickets
Diagnostic considerations for short stature - SHOX mutation
The SHOX (short stature homeobox containing) gene encodes isoforms of a homeodomain transcription factor important in human limb development
- SHOX “haploinsufficiency” has been implicated in 3 human growth disorders = turner syndrome, idiopathic short stature, and leri-weill dyschondrosteosis (heterozygous shox mutation)
- langer mesomelic dysplasia = homozygous form of shox mutation
- SHOX mutations were found in 2-15% of children with idiopathic short stature
- important to identify kids with short stature due to SHOX deficiency because they respond to treatment with GH
Pediatric growth hormone deficiency
- clinical features
- causes
- diagnosis
Clinical features
- normal size at birth, growth failure after 6 months, excessive adiposity, +/- hypoglycemia
Causes
- isolated - idiopathic/genetic
- multiple pituitary hormone deficiency –> genetic, traumatic delivery, midline defects
- CNS tumors
- CNS trauma
- irradiation
Pediatric growth hormone deficiency
- diagnosis
- treatment
Diagnosis
- gold standard = lack of appropriate peak GH after provocative stimuli –> hypoglycemia, arginine, L-dopa, clonidine
Treatment - GH at 0.3 mg/kg/week given subQ 6 days/week until height velocity <2cm/year or bone age = 15 in girls/17 in boys
Adult growth hormone deficiency
- diagnosed by GH stim test
- GHD adults have increased osteoporosis, hypercholesterolemia, poor lean body mass, greater cardiac risk and poorer quality of life
- problems reverse with therapy
- therapy may increase risk of cancer and diabetes
Short stature interventions
- treat underlying cause of short stature
- growth hormone treats a number of conditions but is very expensive
- options to slow puberty so that there is longer time for linear growth
Differential diagnosis of short stature
Dysmorphic appearance
- abnormal karyotype –> turners or trisomy 21
- normal karyotype –> consider other genetic causes
normal appearance
- weight > height –> GH deficiency, hypothyroidism, cushings
- weight = height –> idiopathic short stature, familial short stature, constitutional growth delay
- height > weight –> consider malnutrition states or excess energy expenditure
Normal puberty
Girls
- onset (breast bud) age 8-13
- menarche within 5 years from breast bud development
Boys
- onset (testicular enlargement) age 9-14
Recent studies have shown that early signs of puberty (breast budding in girls ages 6-8) are common and usually non-pathologic, especially in african american girls
Pubertal evaluation
Lab evaluation
- increase in 89 AM LH, FSH, estradiol/testosterone
- GnRH stimulation testing –> can differentiate central from peripheral precocious puberty
Bone age evaluation –> children with precocious puberty will have accelerate bone development
Differential diagnosis for delayed puberty in a girl
- Turners syndrome
- Primary gonadal failure
- Pituitary dysfunction
- hypothalamus - anorexia, Kallman’s syndrome (no pulses of GnRH)
- androgen insensitivity syndrome –> genotypic male but androgen receptor mutation prevents action of testosterone, so phenotypically female
- constitutional delay –> late bloomer
Differential diagnosis for delayed puberty in a boy
- constitutional delay –> more common in boys
- primary gonadal failure
- –> Kleinfelter syndrome
- –> XY gonadal dysgenesis
- –> cryptochidism/anorchism
- pituitary lesion
- hypothalamus - Kallman’s syndrome –> people with kallman also can’t smell, so this might be a clue as to this etiology
Treatment of delayed puberty
- treat underlying problem
- begin low dose estrogen in girls, then increase dose and begin cycling with added progestin
- begin low dose testosterone in boys, increase dose over time to adult dosing
Precocious puberty - terminology
True precocious puberty - gonadotropin dependent
- breasts and pubic hair in girls
- testicular enlargement and pubic hair in boys
Premature thelarche - breasts only, before age 8
Premature adrenarche - pubic hair only, before age 8
Initial evaluation of precocious puberty
- history and physical
- get bone age to determine how aggressive the process is –> if they have a lot of estrogen/testosterone, their bones will look much older than their age
- determine if gonadotropin-dependent vs. gonadotropin independent –> if you have a high estrogen level but low FSH/LH, we know the estrogen is coming from somewhere else in the body
- differentiate by 8 AM labs or GnRH stim test
Causes of central precocious puberty
- 10x more common in females
- for females - idiopathic 85-95% of time
- for males - tumor risk = 20%
- CNS lesions - trauma, hypothalamic hamartoma, cranial irradiation, craniopharyngioma, meningitis
- peripheral precocious puberty can push pituitary into starting central precocious puberty –> if the pituitary sees estrogen coming from anywhere, it will think its ok to start secreting GnRH
Causes of peripheral/gonadotropin-independent precocious puberty - girls
- exogenous sex steroids –> OCPs, estrogen creams
- ovarian cyst
- gonadal hypersecretion = McCune-albright syndrome –> triad of gonadal hypersecretion, polyostotic fibrous dysplasia, and cafe-au-lait spots
- –> can have other endocrinopathies
- –> caused by Gs-protein mutation that causes gene to be constitutively turned on
- ovarian or adrenal tumor
- ectopic estrogen secreting tumor
- hypothyroidism (severe) –> TSH subunit is the same as FSH, so appears to ovaries as FSH in high concentrations, and triggers ovarian secretion of estrogen
- –> does not spontaneously reverse when hypothyroidism is treated and TSH goes down
- –> girls only
- non-classic CAH
Causes of peripheral/gonadotropin-independent precocious puberty - boys
- non-classical CAH
- testicular hypersecretion –> familial male precocious puberty = mutation in LH receptor so it is stuck in “on” position
- exogenous steroids –> testosterone gel/cream
- testicular or adrenal tumor
- McCune albright syndrome
- ectopic tumor - androgen or hCG secreting (hepatoblastoma)
Treatment for precocious puberty - factors to consider
Factors to consider in treatment
- treat underlying pathology, if any
- preservation of adult height outcome (get height prediction from bone age) –> most of these kids have accelerated bone age, so even though they look tall now they will probably stop growing sooner than they should
- appropriate timing of menarche
- important to consider the burden and expense of therapy
Treatment of gonadotropin dependent precocious puberty
GnRH agonists
- leuprolide depot –> given as IM shot monthly or every 3 months
- histrelin –> implants last 1 year
You need gnrh to pulse in order to stimulate pituitary hormones, so if you just overwhelm it by giving a steady stream it will stop activating the pituitary from secreting LH/FSH
Treatment of gonadotropin independent/peripheral precocious puberty
- aromatase inhibitors –> testolactone, anastrazole, letrozole
- steroid pathway blockers –> ketoconazole
- androgen receptor blockers –> spironolactone
- estrogen receptor blockers –> tamoxifen
Premature thelarche
- idiopathic –> usually benign and self limited; seen in 1-3% of toddler girls
- ovarian cyst/hypersecretion –> may be episodic or progressive
- exogenous estrogens –> got into mom’s OCPs
differentiate from true precocious puberty by looking at growth pattern, bone age and other signs
Premature adrenarche
- idiopathic –> often does not lead to central precocious puberty
- non-classical CAH –> milder form of CAH, may lead to central precocious puberty, hirsutism, severe acne, altered fertility
- adrenal/gonadal tumor –> rare, usually progressive process
Differentiate from true precocious puberty by looking at growth pattern, bone age and other signs
Disorders of sexual development
Congenital Adrenal Hyperplasia - most common = virilization of female infant + under virilization of male infants
Ovotesticular DSD - both ovarian and testicular tissue in gonads, “true hermaphroditism”
Androgen Insensitivity Syndrome- complete and partial – 46XY phenotypic female
- complete will look totally female
- partial may have some tissues that respond to testosterone so may be some virilization
5 alpha reductase deficiency – may present with ambiguous genitalia, won’t have peripheral conversion of testosterone to DHT which is what is necessary to virilize the male genitalia often develop enough testosterone during puberty to have normal testicular development so should be raised as male
Pediatric presentations of other endocrinopathies
Adrenal = CAH
Thyroid = congenital hypothyroidism
Calcium = DiGeorge syndrome
CAH
Caused by a mutation in one of P450 enzymes in cholesterol to steroid pathway
- 21-hydroxylase deficiency is most common form, occurs ~ 1:10,000 births
- common cause of ambiguous genitalia
- Causes salt-wasting due to hypoaldosteronism as well as virilization
- 46 XX females appear virilized,
but 46 XY males have a typical
phenotype and can have an adrenal crisis if not identified - this is why the newborn screen is so important!
Congenital hypothyroidism
- occurs 1/4000 births, on newborn screen in every state
- since thyroid horomne participates in CNS myelinization, hypothyroidism during the first three years of life causes permanent loss of IQ points
- hallmark of hypothyroidism in children is growth failure
DiGeorge syndrome
- cardiac abnormalities
- abnormal facies
- thymic aplasia –> results in infections
- clef palate
- hypoparathyroidism/hypocalcemia
- deletion on chrom 22
