Familial Growth Hormone Deficiency and Mutations in the GHRH Receptor Gene

Abstract Growth hormone (GH)-releasing hormone (GHRH) is necessary for the proliferation of the somatotropic cells of the anterior pituitary and the synthesis and secretion of GH. GHRH is released by the hypothalamus into the portal hypophysial circulation to bind to a membrane surface receptor [GHRH receptor (GHRHR)] expressed by the somatotropic cells. Because of the need of GHRH for GH secretion, it is to be expected that alterations in synthesis or action of GHRH would result in isolated GH deficiency (IGHD). Indeed, although GHRH gene mutations have never been reported, mutations in the GHRHR gene (GHRHR) are emerging as a relatively common cause of inherited autosomal recessive IGHD. The first human GHRHR mutations were discovered in families with a history of parental consanguinity. More recently, kindreds in which IGHD subjects are compound heterozygotes for two distinct mutations indicate that faulty GHRHR alleles may be prevalent and that these mutations may need to be suspected even in sporadic IGHD cases. Patients with two faulty GHRHR alleles have normal weight at birth. Growth failure becomes apparent during the first year of life. Biochemical studies show low serum insulin-like growth factor-1 level, and absent or markedly reduced GH response to a variety of stimuli. Magnetic resonance imaging shows hypoplasia of the anterior pituitary. In this chapter, we describe the GHRHR mutations reported to date and the phenotype of affected individuals.