A Novel LHX3 Variant Associated With Combined Pituitary Hormone Deficiency in an Indian Kindred

LHX3, a LIM-homeodomain transcription factor, is crucial in pituitary development. Mutations of LHX3 are infrequently described in the Indian subcontinent. We report two siblings born of consanguineous marriage with combined pituitary hormone deficiency (CPHD) who presented with short stature and extra-pituitary skeletal abnormalities. Whole-exome sequencing (WES) of both siblings revealed an identical novel in-frame deletion variant in the LHX3 gene c.634_636del (p.Glu212del). Both parents of the patients were heterozygous carriers of the same LHX3 variant. The genetic sequencing data did not reveal any other potentially causal variants of other candidate genes that could be associated with CPHD. Furthermore, the conservation of the reference region across species and the expression of LHX3 in pituitary tissue provide additional evidence supporting its pathogenic role. This in-frame deletion, according to theoretical models, could potentially disrupt protein-protein interactions, DNA binding, and protein stability, ultimately disrupting the specification of pituitary cell types. Both patients exhibited a remarkable response to recombinant growth hormone therapy. This novel variant provides a foundation for future functional studies and contributes to the expanding genetic spectrum of LHX3 variants in CPHD.