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We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene  HESX1 / Hesx1  in man and mouse.   However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of  HESX1  mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the  Hesx1  null allele show a milder SOD phenocopy, implying that heterozygous mutations in human  HESX1  could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for  HESX1  mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the  HESX1  locus, indicated that only one  HESX1  mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the  HESX1  gene.

Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia