Abstract
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*195delinsCTCA), or a novel missense TSHB missense (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 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 results in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.
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