Tall stature and abnormally rapid growth

Tall stature is defined as a height of more than 2 standard deviations above the population mean or exceeding the 97^th percentile for age and sex. In most cases, tall stature represents an acceptable normal variation in growth. However, tall stature can also be the result of an underlying disorder (i.e., endocrine or genetic abnormalities). Differentiating between normal or pathological growth variations involves a thorough medical history and clinical examination. Bone age tests, karyotyping, and endocrinological tests can confirm the diagnosis of a pathological cause.

• Definition: A height of more than 2 standard deviations above the population mean or exceeding the 97^thpercentile on the normal growth curve for age and sex.
• Most tall children do not have a pathological cause.

Evaluation of growth

• History
  • Assess milestones (exclude developmental delay)
  • Determine midparental height
• Physical examination
  • Accurate serial measurements of individual body areas
    • Proportional vs disproportional growth (e.g., disproportionately long extremities usually indicate Marfan syndrome)
    • Length or height
    • Growth velocity
  • Exclude the following:
    • Secondary sexual characteristics
    • Neurological lesions
    • Dysmorphisms
• Further diagnostic measures (if a pathological cause is suspected)
  • Bone age
  • Karyotyping
  • Endocrine laboratory tests (depends on which pathology is suspected e.g., insulin-like growth factor for excess growth hormone, or TSH and T₄ hormone for hyperthyroidism)

Etiology of tall stature

References:^{[2][3][4][5][6]}

Gigantism

• Definition: : rare disorder characterized by abnormal linear growth during childhood due to growth hormone excess while the epiphyseal growth plates are still open
• Pathophysiology
  • Most common: ↑ growth hormone (GH) secretion from the anterior pituitary; (i.e., adenoma ) → ↑ IGF-1 synthesis → ↑ cell growth and proliferation (for more details see the “Acromegaly” article)
  • ↑ GHRH secretion from the hypothalamus (i.e., tumors)
  • ↑ Production of IGF-binding protein → ↑ half-life of IGF-1
• Risk factors (associated with an ↑ incidence of pituitary tumors)
  • Multiple endocrine neoplasia type 1 (MEN 1)
  • McCune-Albright syndrome
  • Carney complex
  • Neurofibromatosis
  • Tuberous sclerosis
• Clinical features
  • Tall stature
  • ↑ Growth of distal limbs (i.e., hands, feet, fingers, toes)
  • Tumor mass symptoms: headaches, visual changes , features of hypopituitarism
  • Progressive macroencephaly
  • Coarse facial features, frontal bossing, prognathism
  • Obesity
• Diagnosis
  • ↑ Serum IGF-1
  • ↑ GH after oral glucose tolerance test confirms pituitary gigantism.
  • After a biochemical diagnosis is established
    • MRI: pituitary mass
    • CT if MRI is negative: exclude other GH-secreting tumors (e.g., pancreas, adrenal glands, ovarian, bronchial)
• Treatment
  • Transsphenoidal surgery: pituitary adenoma excision
  • Medical therapy
    • Somatostatin analogs; (e.g., octreotide )
    • GH receptor antagonists (e.g., pegvisomant)
• Complications
  • Carpal tunnel syndrome
  • Cardiovascular disease
    • Heart failure (the most common cause of death)
    • Hypertension
  • Osteoarthritis
  • Endocrine disorders (i.e., hypogonadism, diabetes, hyperprolactinemia)
  • Benign tumors (i.e., uterine leiomyomas, prostatic hypertrophy, colonic polyps)

Other causes

• Precocious puberty
• Hyperthyroidism

References:^[7]

Beckwith-Wiedemann syndrome ^[8]

• Definition: congenital disorder of growth with a predisposition to tumor development
• Epidemiology
  • ∼ 1/15,000 newborns in the US
  • Increased risk of nephroblastoma, hepatoblastoma, neuroblastoma, adrenal tumors
• Etiology: associated with WT2 gene mutation on chromosome 11 (∼ 80% of cases)
• Pathophysiology: defect in genetic imprinting → overexpression of genes
• Clinical features
  • Macrosomia; , omphalocele (i.e., exomphalos)
  • Macroglossia, organ enlargement (heart, liver, kidney, etc.)
  • Hemihypertrophy (hemihyperplasia): One side or a part of one side of the body is larger than the other.
  • Features of neonatal hypoglycemia : irritability, intellectual disability
  • Genitourinary abnormalities
  • Facies: midface hypoplasia, infraorbital and earlobe creases
  • Cleft palate (rare)
• Diagnosis
  • ↓ Blood glucose, ↑ serum insulin, IGF-2 (hypoglycemia)
  • Screening options for embryonal tumors ^[9]
    • Abdominal ultrasound every 3 months until 8 years of age
    • Alpha-fetoprotein levels every 3 months until 4 years of age
• Treatment
  • Frequent feedings to maintain sufficient blood glucose levels
  • Resection of embryonal tumors

Sotos syndrome (cerebral gigantism) ^[10]

• Epidemiology: 1/10,000–14,000 newborns ^[11]
• Etiology: autosomal dominant mutation in the NSD1 gene on chromosome 5 ^[10]
• Symptoms ^[10]
  • Tall stature
  • Macrocephalus
  • Facies
    • High forehead
    • Elongated face
    • Hypertelorism
    • Pointed chin
    • Receding hairline
  • Psychomotor retardation
  • Hypotonia
  • Delays in achieving milestones (e.g., walking, talking, clumsiness)
• Diagnosis
  • Usually clinical
  • DNA studies (5q35 microdeletions and partial NSD1 deletions in 10–15% of cases)
  • Prenatal diagnosis possible
• Treatment
  • Only symptomatic treatment is possible.
  • Multiprofessional approach
• Course
  • Normal growth rate from 3–5 years of age (only moderately increased adult height)
  • Permanent cognitive-developmental impairments are common.

Other causes

• Marfan syndrome
• Homocystinuria
• Fragile X syndrome
• Neurofibromatosis type 1
• Klinefelter syndrome (47,XXY)
• Weaver syndrome