Growth hormone deficiency pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Pathophysiology
Genetics
MOLECULAR GENETICS OF GROWTH HORMONE DEFICIENCY
30 percent of GHD is genetic [9,10].
The POU1F1 gene
is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone releasing hormone (GHRH) receptor [11,12].
PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia and/or familial multiple pituitary hormone deficiency [17]; paradoxical cystic hyperplasia of the pituitary also has been reported [18]. This is the most common known genetic cause of combined pituitary hormone deficiency [19,20].
GHRH receptor gene defects
Children with mutations in the GHRH receptor gene have undetectable GH release during standard provocative tests and after exogenous GHRH administration, but they respond to GH treatment.
Deletions and mutations of GH1
GH1 is the gene encoding GH, located on chromosome 17. Gene deletions, frameshift mutations, and nonsense mutations of GH1 have been described as causes of familial GHD [25].
Syndrome of bioinactive GH
A diagnosis of the syndrome of bioinactive GH has been proposed for short children with a phenotype that resembles that of isolated GHD, with normal or slightly elevated basal GH levels in combination with low insulin-like growth factor I (IGF-I) concentrations that increase after treatment with exogenous GH. True molecular abnormalities involving a mutant GH molecule have rarely been reported [26,27]
Laron syndrome
It is caused by homozygous or compound heterozygous mutations in the growth hormone (GH) receptor gene; a variety of mutations have been identified, most of which affect the extracellular GH-binding region of the receptor [2-4].
GH receptor signal transduction
a homozygous missense mutation in the gene encoding signal transducer and activator transcription 5B (STAT5B) which is essential for normal signaling of the GH receptor [15-18].
IGF-I gene mutations
Mutations in the gene encoding IGF-I cause a unique syndrome of GHD 21-23
patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, sensorineural hearing loss 21
Defective stabilization of circulating IGF-I
deficiency of acid-labile subunit (ALS) which is important for the stabilization of the IGF-I-IGFBP-3 complex, forming a three-part (ternary) complex in the circulation. [25,26].
IGF-I receptor mutations
Mutations in the gene encoding the receptor for IGF-I have been reported in infants presenting with pre- and postnatal growth failure [27-30].
These mutations are thought to result in partial loss of function of the IGF-I receptor