New GH-1 gene mutations: expanding the spectrum of causes of isolated growth hormone deficiency.

Estimates of the frequency of growth hormone deficiency (GHD) range from 1:4,000 to 1:10,000. Most cases are sporadic and presumed to be secondary to one of a wide variety of causes. However, in families with consanguinity, or when a second case occurs in the same family, a genetic cause may be suspected. Four distinct familial types of isolated GHD (IGHD) have been well differentiated on the basis of inheritance, hormonal deficiencies, and molecular analyses. Two forms are inherited autosomal recessively (IGHD type IA and IB); one is inherited autosomal dominantly (IGHD type II); and one is inherited in an X-linked manner. This review focuses on the secretory pathway of GH and the possible mechanisms causing IGHD type II. In IGHD type II, the apparently same phenotype results from several distinct GH-1 gene alterations leading to different blockades within the secretory pathway. This type of IGHD, in addition to some other specific GH-1 gene mutations, provides the most important opportunity for shedding light on cellular biological mechanisms beyond its description at the DNA/RNA level.