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Subunit Gene Defects in Central Hypothyroidism in the UK and Ireland

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Subunit Gene Defects in Central Hypothyroidism in the UK and Ireland Clinical Endocrinology (2017) 86, 410–418 doi: 10.1111/cen.13149 ORIGINAL ARTICLE Molecular spectrum of TSHb subunit gene defects in central hypothyroidism in the UK and Ireland A.K. Nicholas*, S. Jaleel†, G. Lyons*, E. Schoenmakers*, M.T. Dattani‡, E. Crowne§, B. Bernhard–, J. Kirk**, E.F. Roche†,††, V.K. Chatterjee* and N. Schoenmakers* *University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK, †Department of Paediatric Endocrinology & Diabetes, National Children’s Hospital, AMNCH, Dublin, Ireland, ‡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, §Department of Paediatric Endocrinology & Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, ¶Department of Clinical Genetics, North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, **Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, UK and ††University of Dublin, Trinity College Dublin, Dublin, Ireland such cases result in neurodevelopmental retardation. Inclusion Summary of thyroxine (T4) plus thyroxine-binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case Objective Homozygous mutations in the TSH beta subunit ascertainment enabling earlier therapeutic intervention, could gene (TSHB) result in severe, isolated, central congenital prevent such adverse sequelae. hypothyroidism (CCH). This entity evades diagnosis in TSH- based congenital hypothyroidism (CH) screening programmes in (Received 8 April 2016; returned for revision 24 June 2016; finally the UK and Ireland. Accordingly, genetic diagnosis, enabling revised 24 June 2016; accepted 28 June 2016) 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 Ire- Introduction land were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was under- Isolated congenital central hypothyroidism is rare (incidence 1 in 1 taken in cases with identical mutations (c.373delT). 65 000), with genetic causes comprising mutations in the TSH Results Two siblings in kindred 1 were homozygous for a pre- beta subunit (TSHB), the immunoglobulin superfamily member 1 2 viously described TSHB mutation (c.373delT). In kindreds 2 and (IGSF1) or, less frequently, the TRH receptor (TRHR) genes. 3, the affected individuals were compound heterozygous for Central hypothyroidism is associated with either subnormal or TSHB c.373delT and either a 5Á4-kB TSHB deletion (kindred 2, inappropriately normal TSH levels and therefore evades diagnosis c.1-4389_417*195delinsCTCA) or a novel TSHB missense muta- in the UK and Irish TSH-based newborn screening programmes tion (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retarda- for congenital hypothyroidism (CH). Unfortunately, patients may tion, following delayed diagnosis and treatment, was present in then present later in the neonatal period with overt clinical 3 cases. In contrast, the younger sibling in kindred 1 developed hypothyroidism; in TSHB mutation cases, thyroid hormone defi- 3 normally following genetic diagnosis and treatment from birth. ciency is profound, resulting in neurodevelopmental retardation. Conclusions This study, including the identification of a sec- Heterodimeric TSH, secreted by anterior pituitary thyrotroph b ond, novel, TSHB deletion, expands the molecular spectrum of cells, comprises a hormone-specific beta subunit (TSH ) and a a TSHB defects and suggests that allele loss may be a commoner common alpha subunit ( GSU) shared with other members of basis for TSH deficiency than previously suspected. Delayed the glycoprotein hormone family (luteinizing hormone, follicle- diagnosis and treatment of profound central hypothyroidism in stimulating hormone and chorionic gonadotrophin). The integ- rity and bioactivity of the heterodimer are maintained by a ‘seat belt’ structure formed by the b-subunit peptide that is stabilized Correspondence: Nadia Schoenmakers, University of Cambridge Meta- by disulphide bridges including the so-called buckle between bolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of amino acids 39 and 125.4 Metabolic Science, Box 289, Addenbrooke’s Hospital, Hills Road, The human TSHb subunit gene is organized into 3 exons: Cambridge CB2 0QQ, UK. Tel.: +44 1223 767188; Fax: +44 1223 330598; E-mail: [email protected] exon 1 is untranslated, and exons 2 and 3 encode a 138-amino 410 © 2016 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. UK and Irish TSHB mutations 411 acid peptide. The twenty N-terminal amino acids encode a sig- Patients and methods nal peptide that is cleaved to yield a 118-amino acid mature protein detectable in serum.4,5 The most frequently described Clinical phenotype, auxological parameters and biochemistry for TSHB mutation is a single-nucleotide deletion (c373delT), each case are summarized in Table 1. resulting in a cysteine 125 to valine conversion (C125V) and dis- ruption of the Cys-Cys 39–125 disulphide bridge, with a subse- Patients 1a and 1b (P1a and P1b) quent shift in reading frame and premature stop codon at position 134.6 Eight additional mutations have been described, P1a is the second son of healthy, nonconsanguineous Cau- including missense (p.C108Y, p.C105R, p.G49R) and nonsense casian (UK) parents. Although his TSH on neonatal screening – or frameshift mutations (p.E32*, p.Q69*, p.F77Sfs*6).3,7 11 Two was reported normal, he presented aged 3 weeks with a lower splice site mutations (c162G>A, IVS2 + 5G>A),3,12 and more respiratory tract infection and was noted to have clinical fea- recently a homozygous TSHB deletion, have also been tures of hypothyroidism, including somnolence, constipation reported.13 All are inherited in an autosomal recessive manner and dry skin. Thyroid function tests were consistent with sev- and are associated with severe central hypothyroidism. (The ere central hypothyroidism (total T4 < 10 nmol/l, normal range nomenclature of mutations in this paper follows the most recent 50–160; TSH 0Á1 mU/l, NR 0Á1–5), with no TSH response to HGNC guidelines to include the 20-amino acid signal peptide of TRH stimulation. Subsequent dynamic testing, showing pre- TSHb, such that codon numbering may differ from that cited in served corticotroph, somatotroph and gonadotroph function, the previously published articles). excluded combined pituitary hormone deficiency (data not We report three kindreds from the UK or Ireland in which shown), and his basal prolactin level was 554 mU/l (NR <700). four cases exhibit isolated central hypothyroidism secondary to Levothyroxine treatment was commenced at the age of 5 weeks TSHB mutations. In kindred 1, two siblings (P1a and P1b) are and 2 days, despite good compliance development was delayed. homozygous for the previously described c.373delT mutation. In Formal assessment of age 2 years revealed significantly kindred 2, the affected child (P2) is compound heterozygous for impaired hearing and speech. At age 7 years, growth is normal, c.373delT together with a maternally derived 5Á4-kb deletion and he is in mainstream education, but requires additional involving TSHB alone (c.1-4389_417*195delinsCTCA). In kin- support. dred 3, the proband (P3) is compound heterozygous for P1b, the younger brother of P1a, underwent screening for c.373delT and a novel missense mutation (c.2T>C, p.Met1?), central hypothyroidism at birth following this diagnosis in his disrupting the methionine residue from which translation is ini- older sibling. Thyroid function was consistent with TSH defi- tiated. We describe these TSHB defects and associated clinical ciency (cord blood fT4 6Á5 pmol/l, NR 10–24; TSH <0Á05 mU/l, phenotypes in the context of the wider literature. NR 0Á3–4). Levothyroxine was commenced at age 1 week, and Table 1. Clinical phenotype, auxological and biochemical parameters for each case harbouring TSHB mutations P1a P1b P2 P3 Neonatal screening TSH (mU/l) ‘Normal’ ‘Normal’ <10 Gestational length (weeks) 42 42 40 39 Birth weight (kg) 3Á71 4Á14 3Á18 2Á8 At diagnosis Age (weeks) 5 Birth 8 14 Body length (cm) and centile 56Á2 (25th) NA 51 (<3rd) <3rd Body weight (kg) and centile 5Á60 (75th) 4Á14 (75th) 3Á52 (<3rd) NA(3rd) TSH (mU/l) 0Á1(0Á1–5Á0) <0Á05(0Á3–4Á0) 2Á78 (0Á4–4Á0) 0Á45 (0Á4–3Á5) fT4 (pmol/l) <10(50–160)* 6Á5(10–24) <3Á89(10–25) <5Á1 (13Á8–22Á5) Peak TSH response to TRH 0Á09 NA 3Á21 NA MRI pituitary Normal NA Normal Normal Extrathyroidal abnormalities Neurodevelopment Mild motor and sensory Normal Mild motor delay Horizontal pendular nystagmus, processing deficits, extra bilateral sensorineural hearing support at school loss developmental delay (motor, language), Autism/Asperger spectrum Attends special school Haematological Macrocytic anaemia Macrocytic anaemia *In P1a, the T4 value refers to total T4 (nmol/l). In three cases, the absolute T4 value could not be quantified because it was significantly below the lower limit of the normal
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