The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor

Growth and function of the thyroid and adrenal glands are maintained and co ntrolled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), resp ectively. The action of these trophic hormones requires the presence of fun ctional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occur red alone or together in eight family members belonging to four nuclear fam ilies. The high serum TSH and ACTH levels in the presence of normal or hypo plastic thyroid glands and low glucocorticoid, but not mineralocorticoid co ncentrations, are characteristic of resistance to TSH and ACTH. Linkage ana lysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation w as identified in exon 10 of the TSHR that replaces the normal cytosine in n ucleotide 2024 with a thymidine. As a result the normal arginine in codon 6 09 (CGA) is replaced with a stop codon (TGA). This mutation produces a trun cated TSHR lacking the third intracellular and extracellular loops, the six th and seventh transmembrane segments, and the intracytoplasmic tail. The p resence of hypothyroidism did not affect the timing, severity, and manner o f clinical manifestation of hypoadrenocortisolism.