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Molecular spectrum of TSH β subunit gene defects in central hypothyroidism in the UK and Ireland
Author(s) -
Nicholas A.K.,
Jaleel S.,
Lyons G.,
Schoenmakers E.,
Dattani M.T.,
Crowne E.,
Bernhard B.,
Kirk J.,
Roche E.F.,
Chatterjee V.K.,
Schoenmakers N.
Publication year - 2017
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.13149
Subject(s) - congenital hypothyroidism , missense mutation , sibling , endocrinology , allele , medicine , haplotype , mutation , compound heterozygosity , genetics , thyroid , gene , biology , psychology , developmental psychology
Summary Objective Homozygous mutations in the TSH beta subunit gene ( TSHB ) result in severe, isolated, central congenital hypothyroidism ( CCH ). This entity evades diagnosis in TSH ‐based congenital hypothyroidism ( CH ) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. Design, Patients and Measurements Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB . Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). Results Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4‐ kB TSHB deletion (kindred 2, c.1‐4389_417*195delins CTCA ) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. Conclusions This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine‐binding globulin ( TBG ), or free thyroxine ( FT 4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.