X-linked isolated growth hormone deficiency: Expanding the phenotypic spectrum of SOX3 polyalanine tract expansions

Isolated growth hormone (GH) deficiency (IGHD) resulting in short stature has an estimated birth incidence of 1 out of 4000-10000 (Millar et al., 2003) and is usually sporadic, but monogenic forms are known. Involvement of a number of autosomal genes has been demonstrated, including the GH-1 (Wainrajch et al., 1996; Hess et al., 2007), GH releasing hormone receptor (Wainrajch et al., 1996), and HESX1 (Thomas et al., 2001) genes. Further molecular heterogeneity is suggested, as the inherited basis of many familial cases remains unclear (Dattani, 2005). X-linked combined pituitary hormone deficiency has been demonstrated previously to show linkage to two loci. One locus at Xq21.3q22 is associated with agammaglobulinemia (Conley et al., 1991), whereas another is associated with the learning disability and spina bifida and results from duplication of Xq26.1-q27.3 (Solomon et al., 2002). SOX3 lies in this duplicated segment, and is an SRY-related high mobility group box transcription factor expressed in the developing pituitary (Collignon et al., 1996). In a single large family, Laumonnier et al., (2002) identified an in-frame 33bp duplication, encoding 11 additional alanines, in the polyalanine tract in SOX3 as the cause for X-linked learning disability associated with GH deficiency. Woods et al., (2005) subsequently demonstrated that a seven alanine repeat duplication in SOX3 could cause congenital hypopituitarism.