Overgrowth syndromes

Overgrowth syndromes are genetic conditions characterized by a generalized or localized increase in tissue. Generalized overgrowth can manifest with tall stature, organomegaly, macrocephaly, and/or obesity, while localized or segmental overgrowth causes dysmorphic features. Associated conditions include developmental delay and intellectual disability, and some overgrowth syndromes increase the risk of cancer. Management of overgrowth syndromes includes referral to a genetics specialist for diagnostic evaluation to identify the underlying etiology and detect overgrowth of internal organs. Periodic screening for malignancies is recommended in certain overgrowth syndromes (e.g., Beckwith-Wiedemann syndrome).

Types of overgrowth syndromes ^[1][2]

• Generalized overgrowth
  • Beckwith-Wiedemann syndrome
  • Sotos syndrome (cerebral gigantism)
  • Weaver syndrome
  • Simpson-Golabi-Behmel syndrome
• Mosaic overgrowth: PIK3CA-related overgrowth spectrum
• Both mosaic and generalized overgrowth: PTEN hamartoma tumor syndrome

Clinical features of overgrowth syndromes ^[1][2]

These features are typical of overgrowth syndromes. Specific features vary by condition.

• Generalized overgrowth
  • Tall stature
  • Organomegaly
  • Macrocephaly
  • Obesity
• Localized overgrowth
  • Dysmorphic features
  • Isolated macrodactyly
  • Hemimegalencephaly
  • Lateralized overgrowth
• Associations
  • Developmental delay
  • Intellectual disability
  • Increased cancer risk
  • Vascular malformations
  • Hyperinsulinism

Management of overgrowth syndromes ^[1][2]

The following is general guidance on management of overgrowth syndromes. Specific management varies by condition.

• Refer patients with suspected overgrowth syndromes to a genetics specialist.
• Diagnostic workup is based on suspected underlying etiology and may include:
  • Imaging, e.g.:
    • Abdominal ultrasound to evaluate for organomegaly
    • Brain MRI to assess for abnormalities
  • Tissue biopsy in patients with asymmetric overgrowth
  • Genetic testing
• Perform periodic screening for certain malignancies in patients with syndromes associated with increased risk, e.g.: ^[3]
  • Beckwith-Wiedemann syndrome and Simpson-Golabi-Behmel syndrome: Screen for Wilms tumor and hepatoblastoma.
  • PTEN hamartoma tumor syndrome: Screen for thyroid, colon, breast, renal, and skin cancer.

• 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 ^[5]
    • 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

• Epidemiology: 1/10,000–14,000 newborns ^[7]
• Etiology: autosomal dominant mutation in the NSD1 gene on chromosome 5 ^[6]
• Symptoms ^[6]
  • 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 gene 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.