title: Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland.
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.
  
  
  METHODS
  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 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 (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Nicholas
authors.affiliation: Department of Paediatric Endocrinology & Diabetes, National Children's Hospital, AMNCH, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Jaleel
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Lyons
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Schoenmakers
authors.affiliation: 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.
authors.forename: M T
authors.initials: MT
authors.lastname: Dattani
authors.affiliation: Department of Paediatric Endocrinology & Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
authors.forename: E
authors.initials: E
authors.lastname: Crowne
authors.affiliation: Department of Clinical Genetics, North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK.
authors.forename: B
authors.initials: B
authors.lastname: Bernhard
authors.affiliation: Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Kirk
authors.affiliation: Department of Paediatric Endocrinology & Diabetes, National Children's Hospital, AMNCH, Dublin, Ireland.|University of Dublin, Trinity College Dublin, Dublin, Ireland.
authors.forename: E F
authors.initials: EF
authors.lastname: Roche
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: V K
authors.initials: VK
authors.lastname: Chatterjee
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: N
authors.initials: N
authors.lastname: Schoenmakers
mesh_terms: D003409:Congenital Hypothyroidism / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D057210:Delayed Diagnosis / Q000009:adverse effects; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D007231:Infant, Newborn; D007494:Ireland; D008297:Male; D015997:Neonatal Screening / Q000379:methods*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D037322:Thyrotropin, beta Subunit / Q000235:genetics*; D006113:United Kingdom
chemical_list: D037322:Thyrotropin, beta Subunit