Growth Hormone Deficiency

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DESCRIPTION

  • Growth hormone deficiency (GHD) is a rare cause of growth failure in children.
  • Due to a lack of growth hormone (GH) action caused by either a defect in GH synthesis (insufficient hormone) or in GH release
  • Can be associated with other pituitary hormone deficiencies

EPIDEMIOLOGY

  • U.S. prevalence is approximately 1:4,000.
  • Males are more commonly diagnosed than females.
  • Congenital GHD diagnoses are made with two peak ages:
    • Infancy (<1 year of age): usually because of associated hypoglycemia
    • Later infancy (1 to 2 years of age): identified by poor linear growth usually after the 1st year of life unless concurrent central hypothyroidism.
  • Acquired childhood GHD can occur at any age, usually identified by poor linear growth
  • Syndromal causes of congenital GHD often associated with other midline defects such as cleft palate, central incisor, holoprosencephaly, etc.

ETIOLOGY

  • Idiopathic: probably the commonest diagnosis but only made after exclusion of conditions causing GHD that require further management
  • Congenital
    • Congenital malformation of the pituitary can be associated with the following:
      • Holoprosencephaly
      • SOD
      • Midline defects: cleft lip, cleft palate, central maxillary incisor
      • Ectopic posterior pituitary, small anterior pituitary, and/or hypoplastic infundibulum
    • Genetic mutations
      • Familial multiple anterior pituitary hormone deficiency (e.g., HESX1, SOX2, SOX3, LHX3, LHX4, GHRHR, POU1F1, PROP1)
      • GH1 gene mutations (type Ia, Ib, II, III)
  • Acquired idiopathic
    • Central nervous system (CNS) tumors: craniopharyngioma, germinoma, medulloblastoma, glioma, pinealoma
    • Pituitary or hypothalamic irradiation
    • Trauma: child abuse or closed head injury
    • Surgical resection/damage of pituitary gland/stalk
    • Birth injury/perinatal insult
    • Infection: viral encephalitis, bacterial or fungal infection, tuberculosis
    • Vascular: pituitary infarction or aneurysm
    • Infiltration affecting pituitary gland or sella turcica: Langerhans cell histiocytosis, sarcoid
    • Hypophysitis

RISK FACTORS

Genetics

  • Most cases are either isolated congenital GHD with no clear genetic cause or result from nonspecific hypothalamic/pituitary damage from etiologies including infection, inflammation, tumors and their treatment (especially radiation therapy).
  • Neuromigrational defects such as septo-optic-dysplasia (SOD) are also associated with hypopituitarism.
    • Although SOD is considered a vascular disruptive sequence, it can be associated with genetic causes (e.g., HESX1, SOX2, SOX3, and OTX2 mutations).
    • However, other than SOD, neuromigrational defects are usually sporadic, not associated with genetic conditions.
  • Autosomal recessive and autosomal dominant forms of GHD occur with mutations in the GH gene (GH1) and in the GH-releasing hormone receptor (GHRHR) gene.
  • X-linked forms also occur and can be associated with immunodeficiency (e.g., BTK).

PATHOPHYSIOLOGY

  • GH has several anabolic actions. Its principal one is increasing linear growth both directly through GH action on the growth plate and indirectly via stimulation of hepatic and growth plate insulin-like growth factor 1 (IGF-1).
  • GH has important metabolic effects on glucose metabolism, in particular gluconeogenesis, and can present with both symptomatic and asymptomatic hypoglycemia.
  • GH is involved in phallus growth, and GHD is associated with male micropenis.

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