Growth hormone-releasing hormone receptor mutations in familial growth hormone deficiency

The proliferation of pituitary somatotroph cells and their synthesis and secretion of growth hormone (GH) are under the control of the hypothalamic factor GH-releasing hormone (GHRH), which acts by binding to a specific cell surface receptor (GHRH receptor [GHRHR]). Mutations in the GHRHR gene (GHRHR) are emerging as a relatively common cause of familial isolated GH deficiency (IGHD) type 113, the most prevalent form of familial IGHD, transmitted as an autosomal-recessive trait. Initially, GHRHR mutations have been reported in families in which the homozygously affected subjects had consanguineous parents. More recently, kindreds are being discovered in which affected subjects are compound heterozygotes for different GHRHR mutations, proving that faulty GHRHR alleles could be rather prevalent in the general population. Patients in whom both GHRHR alleles are defective have severe IGHD, with frankly low serum insulin-like growth factor-1 level and subnormal serum GH response to a variety of GH stimulation tests. Pituitary function is otherwise normal. They never present with micropenis or neonatal hypoglycemia, but they invariably have anterior pituitary hypoplasia when studied by magnetic resonance imaging. In this review, we describe the heterogeneity of the GHRHR mutations discovered so far, the phenotype of affected individuals, and the clinical characteristics that should cause the endocrinologist to suspect the existence of one of these genetic abnormalities.