Mutations

GHRH Receptor Mutations

Even though isolated GHRH deficiency has not been identified, genetic mutations in pituitary GHRH receptors have been identified i2n humans and mice (18,20,42). The little (lit/lit) dwarf mouse has postnatal growth failure and delayed pubertal maturation with biochemical evidence of GHD and high GHRH levels (20,42). Pituitary histology reveals somatotroph hypoplasia with absent secretory granules (43). This condition is inherited in an autosomal recessive manner. These mice have a single nucleotide substitution that produces a missense mutation by changing Asp60^Gly in the GHRH receptor and prevents hypothalamic GHRH binding (20).

In 1996, the first human GHRH receptor defect resulting in profound GHD was described by Wajnrajch et al. (44). They identified an autosomal recessive form of GHD in a consanguineous Indian Moslem kindred. A G^T transversion at position 265 produces a nonsense mutation (Glu72^Stop) in the GHRH receptor. This yields a truncated receptor that lacks membrane spanning regions and a G-protein binding site. In a presumably separate Pakistani kindred, an autosomal recessive form of extreme dwarfism, the Dwarfism of Sindh, is now attributed to an identical mutation in the GHRH receptor gene (45). Patients with GHRH receptor mutations respond well to exogenous GH therapy without antibody formation. Although these loss of function mutations demonstrate the importance of GHRH and its receptor in growth, the current investigative data suggest that GHRH receptor defects will be an uncommon cause of human GHAD (46).

Pituitary Transcription Factor Mutations

To date, human defects in the pituitary transcription factors Rpx, PROP-1, and pit1 have been described. These are associated with heritable combined pituitary hormone deficiencies, characterized by GHD in addition to deficiency of one or more of the following: adrenocorticotropic hormone, follicle stimulating hormone, luteinizing hormone, or TSH (Table 3).

Rpx defects in mice cause variable anterior central nervous system (CNS) defects and pituitary dysplasia (26). The spectrum of defects is not unlike those seen in septo-optic dysplasia (SOD). Recently it was confirmed that a homozygous loss of function mutationin Rpx results in human familial SOD. The defect is a missense mutation in a highly conserved amino acid arginine 53, converting it to cysteine. Some sporadic cases of SOD have since been confirmed as also having defects in Rpx (47). However, mutations in Rpx only account for a small portion of patients with SOD.

Loss of function of PROP-1 results in the Ames dwarfism mouse paradigm (27). Defects of PROP-1 have now been described in humans with familial multiple pituitary

Table 3

Traditional Classification System for Multiple Pituitary Hormone Deficiencies

Table 3

Traditional Classification System for Multiple Pituitary Hormone Deficiencies

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