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Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland

I suspect the idea of including Free T4 testing in the heel test done shortly after birth is highly desirable. TSH-only is nonsense. (This is far from the first paper to come to that conclusion.) Timing is also important - too soon after birth potentially means that the mother's thyroid hormones and baby's low TSH generation capability are together sufficient to keep TSH down.

Recognition of the genetic issues is potentially very important - but likely to be too late in many cases.

Clin Endocrinol (Oxf). 2017 Mar;86(3):410-418. doi: 10.1111/cen.13149. Epub 2016 Aug 4.

Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland.

Nicholas AK1, Jaleel S2, Lyons G1, Schoenmakers E1, Dattani MT3, Crowne E4, Bernhard B5, Kirk J6, Roche EF2,7, Chatterjee VK1, Schoenmakers N1.

Author information

1 University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

2 Department of Paediatric Endocrinology & Diabetes, National Children's Hospital, AMNCH, Dublin, Ireland.

3 University College London Institute of Child Health, Developmental Endocrinology Research Group, Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, London, UK.

4 Department of Paediatric Endocrinology & Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

5 Department of Clinical Genetics, North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK.

6 Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK.

7 University of Dublin, Trinity College Dublin, Dublin, Ireland.



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.


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).


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 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.


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 (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.

© 2016 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

PMID: 27362444

PMCID: PMC5324561

DOI: 10.1111/cen.13149


Full text freely accessible here:


5 Replies

Thanks for link. So much needs to be done still....


Thank you for posting! Where would we get to know about these things if it wasn't for this forum so thank you to all those you go the extra mile to keep us informed.


Helvella thanks for posting. It is so much easier now to do genetic testing and it is the way forward for so many intractable health problems but how long will it be before NHS latches on to the fact that it might save them a lot of money on unnecessary testing and a lot of GP appointments and angst about things being "all in your head"


Well said, crimple! Just how many genes ARE there than can be causing hypo symptoms but 'normal' blood results?!

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Thanks for the research and the post, as always we're all appreciative :-) Just wish I understood half!

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