Growth Hormone-Releasing Hormone Receptor and Growth Hormone Gene Abnormalities

Abstract

In approximately 10 % of children with isolated growth hormone deficiency, a genetic defect can be found. Traditionally, familial isolated growth hormone deficiency (IGHD) has been classified into four types, depending on the inheritance pattern. We propose to use an adapted classification which is first based on the gene defect (GHRHR or GH1). For GHRHR defects (classically part of type IB), no further subclassification is needed, but GH1 defects are subclassified into an autosomal recessive form with complete lack of circulating GH (classical type 1A), an autosomal recessive form with low but detectable GH concentrations (part of classical type IB), an autosomal dominant form (with low GH peaks, part of the classical type II), and bioinactive GH syndrome (usually autosomal dominant). More than 30 pathogenic mutations in GHRHR have been reported, including nonsense, missense, and splice site mutations, in addition to deletions and regulatory mutations affecting the POU1F1-binding sites in the promoter region. The pattern of inheritance is autosomal recessive, and heterozygous carriers are asymptomatic. The mutations are dispersed throughout the GHRHR gene. The main characteristics of the first subclass of GH1 defects are very severe growth faltering and unmeasurable circulating GH concentration, as well as the frequent development of anti-GH antibodies on GH treatment. The second and third subclasses have a more variable severity of GHD. The autosomal dominant type is mostly caused by skipping of exon 3, which leads to a dominant-negative effect of the 17.5 kDa GH isoform. In bioinactive GH syndrome, circulating GH is normal or even elevated, in contrast to a low serum IGF-I.