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Summary Table

Feature	Detail
Risk Factors	History of CNS tumor (craniopharyngioma), cranial irradiation, traumatic brain injury, perinatal insult (breech delivery, birth asphyxia), midline defects (cleft lip/palate, septo-optic dysplasia), consanguinity, family history of short stature with delayed bone age
Etiology	Congenital (genetic mutations in GH1, GHRHR, or transcription factors like PIT-1/PROP-1; midline structural defects) or acquired (craniopharyngioma, germinoma, histiocytosis, radiation, surgery, head trauma, infection)
Patient Presentation	Short stature with declining growth velocity (crossing downward on percentile lines), proportionate body habitus, delayed bone age, history of neonatal hypoglycemia or prolonged jaundice in infancy
Classic Physical Exam	Proportionate short stature, cherubic facies (doll-like face), frontal bossing, midfacial hypoplasia, increased truncal adiposity, micropenis in males, delayed dentition, high-pitched voice
Key Diagnostic Results	Low IGF-1 and IGFBP-3 for age, failed GH stimulation test (peak GH < 10 ng/mL), delayed bone age on left wrist X-ray, MRI showing pituitary hypoplasia or structural lesion
Management	Daily subcutaneous recombinant human GH (rhGH) until epiphyseal closure or adult dosing for adult GHD; monitor IGF-1 levels and growth velocity
Keywords	"Proportionate short stature," "delayed bone age," "cherubic/doll-like facies," "crossing growth percentiles downward," "neonatal hypoglycemia," "micropenis," "craniopharyngioma"

1. Pathophysiology

Growth hormone (GH) is synthesized and secreted by somatotroph cells in the anterior pituitary gland. Its release is regulated by two hypothalamic peptides: growth hormone-releasing hormone (GHRH), which stimulates secretion, and somatostatin, which inhibits it. GH acts both directly on tissues and indirectly through insulin-like growth factor 1 (IGF-1), which is produced primarily in the liver. IGF-1 mediates most of the growth-promoting effects of GH on the skeletal growth plates by stimulating chondrocyte proliferation and hypertrophy within the epiphyseal physis.

When GH secretion is insufficient, the downstream production of IGF-1 falls. This leads to reduced linear growth velocity, which is the hallmark of the disease. Because GH deficiency affects longitudinal bone growth proportionally across all segments, the child remains proportionately short, distinguishing this condition from skeletal dysplasias where limb-to-trunk ratios are abnormal.

GH also has important metabolic functions. It promotes lipolysis and opposes insulin action. In deficiency states, loss of lipolytic drive results in increased truncal adiposity. In neonates, GH contributes to hepatic gluconeogenesis and counter-regulatory glucose homeostasis; therefore, neonatal GHD can present with recurrent hypoglycemia, sometimes severe enough to cause seizures. Additionally, GH synergizes with gonadotropins during sexual development. Male neonates with combined pituitary hormone deficiency (including GH and gonadotropins) may present with micropenis and cryptorchidism.

The "cherubic" or doll-like facies is explained by midfacial hypoplasia. GH is necessary for normal development of the facial bones, particularly the midface. Without adequate GH, the forehead appears prominent (frontal bossing), the nasal bridge is depressed, and the overall facial appearance looks immature relative to chronologic age.

In congenital forms, transcription factor mutations (PIT-1, PROP-1, HESX1, LHX3) can cause combined pituitary hormone deficiency, meaning GH deficiency may coexist with deficiencies of TSH, ACTH, gonadotropins, or prolactin. This is a high-yield concept: a child with short stature, hypothyroidism, and hypocortisolism should raise suspicion for a panhypopituitary state, not isolated thyroid or adrenal disease.

2. Classification and Clinical Manifestation

Classification by Etiology

Category	Subtype	Key Features
Congenital	Isolated GHD (Types IA, IB, II, III)	Type IA: autosomal recessive, complete GH absence, develops anti-GH antibodies when treated with exogenous GH; Type IB: autosomal recessive, partial deficiency; Type II: autosomal dominant; Type III: X-linked
Congenital	Combined pituitary hormone deficiency (CPHD)	Mutations in PIT-1 (GH + TSH + prolactin), PROP-1 (GH + TSH + prolactin + gonadotropins, and sometimes ACTH over time), HESX1 associated with septo-optic dysplasia
Congenital	Structural midline defects	Septo-optic dysplasia (optic nerve hypoplasia + absent septum pellucidum + pituitary dysfunction), holoprosencephaly, cleft lip/palate with pituitary hypoplasia
Acquired	Tumors	Craniopharyngioma (most common), germinoma, glioma, Rathke cleft cyst
Acquired	Radiation	Cranial irradiation > 18 Gy; GH axis is the most radiosensitive of all pituitary axes
Acquired	Infiltrative / Inflammatory	Langerhans cell histiocytosis, lymphocytic hypophysitis, sarcoidosis
Acquired	Trauma / Surgery	Traumatic brain injury, post-surgical pituitary damage
Functional / Transient	Psychosocial deprivation	Reversible GH suppression due to emotional neglect; GH levels normalize upon removal from the adverse environment

Clinical Manifestation by Age of Onset

Age Group	Presentation
Neonate	Hypoglycemia (sometimes with seizures), prolonged conjugated jaundice, micropenis, midline facial defects; birth length is typically normal because intrauterine linear growth is driven primarily by insulin and IGF-2 rather than GH
Infant / Toddler	Growth deceleration becoming apparent after 6 to 12 months, progressive fall across length percentiles, increased subcutaneous fat
Child	Proportionate short stature, height more than 2 SD below the mean, growth velocity < 4 to 5 cm/year, delayed bone age (typically more than 2 years behind chronologic age), delayed dentition, immature facies, high-pitched voice
Adolescent	Delayed puberty if combined with gonadotropin deficiency, continued short stature with open epiphyses
Adult (acquired)	Increased visceral adiposity, reduced lean muscle mass, decreased bone mineral density, dyslipidemia (elevated LDL), fatigue, impaired quality of life, cardiovascular risk

3. Diagnostic Workup

Test	Role	Key Finding
IGF-1 and IGFBP-3	Best initial screening test	Low for age and sex (high sensitivity, but normal levels do not completely exclude GHD)
Bone age (left hand/wrist X-ray)	Supportive evidence	Delayed bone age (> 2 SD behind chronologic age); used to differentiate from familial short stature (normal bone age) and constitutional delay (delayed bone age but normal GH axis)
GH stimulation test	Confirmatory / gold standard	Peak GH < 10 ng/mL after provocation with at least two different stimuli (insulin, arginine, clonidine, glucagon, or L-DOPA) confirms GHD
Brain MRI with pituitary focus	Anatomic evaluation	Pituitary hypoplasia, ectopic posterior pituitary bright spot, absent or thin pituitary stalk, mass lesions (craniopharyngioma)
Additional pituitary hormone panel	Rule out CPHD	Free T4, cortisol (8 AM or ACTH stimulation test), LH/FSH, prolactin
Karyotype (females)	Exclude Turner syndrome	45,X or mosaic variant; always consider in any short female before diagnosing GHD
Genetic testing	Selected cases	GH1, GHRHR, or transcription factor gene panels in familial or severe congenital cases

IGF-1 and IGFBP-3 serve as the best initial screening tests because they reflect integrated GH secretion over time and are not affected by the pulsatile nature of GH release. A single random GH level is useless for diagnosis because GH is secreted in pulses (primarily during deep sleep), and between pulses, GH levels are essentially undetectable even in normal individuals. This is a classic exam trap: a random GH level cannot be used to diagnose or exclude GHD.

If screening values are low, the next step is the GH stimulation test. This is the gold standard. Two pharmacologic provocative agents must be used because no single agent has perfect sensitivity. Commonly tested stimuli include insulin-induced hypoglycemia (the insulin tolerance test, considered the most reliable but carries risk of severe hypoglycemia), arginine, clonidine, glucagon, and L-DOPA. A peak GH response of less than 10 ng/mL after stimulation is the traditional cutoff that confirms deficiency. For neonates or very young infants, a random GH level may be interpretable because neonates have elevated baseline GH; a low random GH in the neonatal period can be diagnostic.

Bone age X-ray (Greulich-Pyle method, left hand and wrist) is obtained in virtually all children evaluated for short stature. In GHD, bone age is significantly delayed, typically more than 2 standard deviations behind chronologic age. This finding is supportive but not diagnostic on its own, since constitutional delay of growth and puberty also presents with delayed bone age. The key distinguishing factor is that constitutional delay has a normal growth velocity and normal IGF-1 for bone age, while GHD has a declining growth velocity and low IGF-1.

MRI of the brain with pituitary protocol is essential in all confirmed cases to identify structural causes. The classic triad suggesting congenital GHD on MRI includes anterior pituitary hypoplasia, ectopic posterior pituitary bright spot, and thin or absent pituitary stalk. If a mass lesion is identified, craniopharyngioma is the leading differential. Craniopharyngioma classically shows suprasellar calcifications on CT and a cystic-solid mass on MRI.

In all patients diagnosed with GHD, a full anterior pituitary hormone panel must be obtained to exclude combined deficiencies. This includes thyroid function (free T4, TSH), adrenal function (morning cortisol or cosyntropin stimulation test), and gonadotropins in adolescents. Failure to detect and treat concurrent central adrenal insufficiency before initiating GH therapy can precipitate an adrenal crisis because GH enhances cortisol clearance through induction of 11-beta-hydroxysteroid dehydrogenase type 1.

4. Management and Treatment

Scenario	Treatment	Details
Pediatric GHD	Recombinant human GH (rhGH)	0.025 to 0.05 mg/kg/day subcutaneously, administered at bedtime to mimic physiologic nocturnal secretion
Neonatal hypoglycemia	Acute dextrose + GH replacement	IV dextrose bolus (D10W, 2 mL/kg) for acute hypoglycemia; initiate GH replacement promptly
Combined pituitary hormone deficiency	Replace all deficient axes	Cortisol replacement must precede thyroid replacement (to avoid precipitating adrenal crisis); GH is added after glucocorticoid and thyroid axes are stable
Adult GHD	rhGH at lower dose	0.15 to 0.3 mg/day initially, titrated based on IGF-1 levels; dose is much lower than pediatric dosing
Monitoring	IGF-1, growth velocity, bone age	IGF-1 every 3 to 6 months (target mid-normal range for age); growth velocity annually; bone age every 12 months; monitor for scoliosis, slipped capital femoral epiphysis
Discontinuation	Near-final height or epiphyseal fusion	Re-test GH axis after reaching final height; if adult GHD confirmed, continue at adult dose for metabolic benefit

Recombinant human GH (rhGH) is the cornerstone of treatment. In children, the standard dose ranges from 0.025 to 0.05 mg/kg/day, given as a single daily subcutaneous injection, preferably at bedtime to replicate the normal physiologic peak of GH during slow-wave sleep. Treatment is continued until the child has reached near-final adult height or radiographic evidence of epiphyseal closure is confirmed.

For patients with combined pituitary hormone deficiency, the sequence of hormone replacement matters and is a commonly tested concept. Glucocorticoid replacement must be initiated before levothyroxine, because thyroid hormone increases metabolic rate and cortisol clearance, which can unmask or worsen adrenal insufficiency. Similarly, GH therapy should not be started until the cortisol axis is adequately replaced, since GH increases conversion of cortisone to cortisol peripherally and can alter cortisol metabolism.

Monitoring during treatment is centered on IGF-1 levels (which should be maintained within the age-appropriate normal range; supra-physiologic IGF-1 levels increase the theoretical risk of adverse effects), growth velocity (a good first-year response is typically 10 to 12 cm/year), and periodic bone age films to track skeletal maturation. Over-treatment can accelerate bone age advancement and paradoxically reduce final adult height.

Adverse effects of GH therapy that are high-yield for exams include benign intracranial hypertension (pseudotumor cerebri), presenting with headache and papilledema shortly after initiating therapy. Slipped capital femoral epiphysis (SCFE) can occur because GH stimulates rapid growth at the proximal femoral physis; any child on GH therapy who develops hip or knee pain requires urgent evaluation. Scoliosis progression can also be exacerbated during rapid growth. GH is contraindicated in active malignancy because of its mitogenic effects through IGF-1, though evidence does not show increased de novo cancer risk with replacement doses in GHD.

Upon reaching final height, GH therapy is temporarily discontinued and the GH axis is re-tested. If stimulation testing confirms persistent GHD in adulthood, GH replacement is resumed at a lower adult dose (0.15 to 0.3 mg/day, not weight-based) for its metabolic benefits, including maintenance of lean body mass, bone mineral density, lipid profile, and cardiovascular health.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Constitutional delay of growth and puberty	Short stature with delayed bone age, family history of "late bloomers"	Normal growth velocity for bone age, normal IGF-1 for bone age, positive family history of delayed puberty with eventual normal adult height; GH stimulation test is normal
Familial short stature	Short stature with short parents	Normal bone age (bone age equals chronologic age), normal growth velocity tracking along a low but consistent percentile, normal GH axis, predicted adult height consistent with mid-parental height
Turner syndrome (45,X)	Short stature in females, can have delayed puberty	Disproportionate features (shield chest, widely spaced nipples, webbed neck, cubitus valgus), coarctation of the aorta, streak gonads; karyotype confirms
Hypothyroidism	Short stature, delayed bone age, weight gain	Weight gain is disproportionate to height (weight-for-height is elevated), constipation, dry skin, delayed relaxation of deep tendon reflexes, elevated TSH with low free T4
Cushing syndrome	Short stature with truncal obesity	Weight gain with growth arrest (height velocity drops while weight increases), striae, moon facies, buffalo hump, elevated 24-hour urinary free cortisol
Psychosocial dwarfism	Short stature with low GH levels	History of emotional deprivation or neglect; GH levels and growth normalize when the child is removed from the adverse environment
Celiac disease / chronic illness	Poor growth, can have low IGF-1	GI symptoms (diarrhea, bloating, failure to thrive), iron deficiency anemia, positive tissue transglutaminase (tTG-IgA); growth improves with gluten-free diet
Laron syndrome (GH insensitivity)	Clinically identical to GHD (same phenotype)	Elevated GH levels with low IGF-1 (GH receptor defect); does not respond to exogenous GH therapy; treated with recombinant IGF-1

6. Traps and High-Yield Pearls

The single most common mistake students make with GHD questions is confusing it with constitutional delay of growth and puberty. Both conditions present with short stature and delayed bone age. The discriminating clue is growth velocity: constitutional delay maintains a normal (though slow-for-age) growth velocity tracking along a consistent percentile, while GHD shows a declining growth velocity with progressive percentile crossing. If the vignette describes a child "falling off the growth curve," think GHD. If the vignette says "always been at the 5th percentile but growing steadily," think constitutional delay or familial short stature.

Another classic trap is the random GH level. Because GH is secreted in pulses, a single random measurement is meaningless and should never be used to diagnose or exclude GHD. The exam will tempt you with a "normal random GH" as a distractor to steer you away from the diagnosis. The correct screening test is IGF-1 (which reflects average GH activity), and the confirmatory test is the GH stimulation test.

Watch for the vignette that describes a child with GHD features plus hypothyroidism and/or adrenal insufficiency. This signals combined pituitary hormone deficiency, and the next best step in management is cortisol replacement before levothyroxine, not starting GH.

A neonatal presentation of recurrent hypoglycemia, micropenis, and prolonged jaundice is a classic triad for congenital GHD or panhypopituitarism. Do not attribute neonatal hypoglycemia to "feeding difficulties" when these other features are present.

Finally, remember Laron syndrome as the ultimate distractor: the phenotype is identical to GHD, but GH levels are high (not low). This tests whether you understand the GH-IGF-1 axis. The treatment for Laron syndrome is recombinant IGF-1 (mecasermin), not GH, because the receptor is defective.

The core competency being tested in GHD questions is the ability to distinguish proportionate short stature with pathologic growth deceleration from benign growth variants, to correctly sequence screening versus confirmatory testing, and to recognize the clinical significance of combined pituitary hormone deficiencies in guiding the order of hormone replacement.

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