Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency

Combined pituitary hormone deficiency (CPHD) has been linked with rare abno rmalities in genes encoding transcription factors necessary for pituitary d evelopment(1). We have isolated LHX3, a gene involved in a new syndrome, us ing a candidate-gene approach developed on the basis of documented pituitar y abnormalities of a recessive lethal mutation in mice generated by targete d disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins(3), consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consangui neous families displaying a complete deficit in all but one (adrenocorticot ropin) anterior pituitary hormone and a rigid cervical spine leading to lim ited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged ant erior pituitary. These LHX3 mutations consist of a missense mutation (Y116C ) in the LIM2 domain at a phylogenetically conserved residue and an intrage nic deletion predicting a severely truncated protein lacking the entire hom eodomain. These data are consistent with function of LHX3 in the proper dev elopment of all anterior pituitary cell types, except corticotropes, and ex trapituitary structures.