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)
