CENTRAL HYPOTHYROIDISM REVEALS COMPOUND HETEROZYGOUS MUTATIONS IN THEPIT-1 GENE

Mutations in the gene encoding the Pit-1 transcriptional activator int erfere with the embryologic determination and ultimate functions of an terior pituitary cells that produce growth hormone (GH), prolactin (Pr l) and thyroid-stimulating hormone (TSH), Central hypothyroidism is of ten the presenting feature of combined pituitary hormone deficiency (C PHD), but it is not detected in screening programs that rely upon elev ation of TSH. We report a child whose hypothyroidism was recognized cl inically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency, With thyroxine and GH replacement he has reach ed the 70th percentile for height and has normal intelligence. Molecul ar analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 an d a novel missense mutation substituting glycine for glutamate at codo n 174. This case is the first demonstration of CPHD due to compound he terozygous Pit-1 point mutations, as most reported cases of the CPHD p henotype involve either the dominant negative R271W allele or homozygo sity for recessive Pit-1 mutations, Therefore, in cases of CPHD, the p ossibilities of compound heterozygosity for two different Pit-1 mutati ons, or homozygosity for mutations in the epigenetic gene, Prop-1, sho uld be considered.