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
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.
Clin Endocrinol (Oxf). 2017 Mar;86(3):410-418. doi: 10.1111/cen.13149. Epub 2016 Aug 4.
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).
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.
促甲状腺激素β亚基基因（TSHB）的纯合突变会导致严重的、孤立的中枢性先天性甲状腺功能减退症（CCH）。在英国和爱尔兰基于促甲状腺激素的先天性甲状腺功能减退症（CH）筛查项目中，这种疾病难以被诊断出来。因此，能够确定家族中受影响亲属的基因诊断对于该疾病的及时诊断和治疗至关重要。
设计、患者与测量：对来自英国和爱尔兰三个无血缘关系家族的4例孤立性促甲状腺激素缺乏症患者进行TSHB突变或缺失的调查。对具有相同突变（c.373delT）的病例进行单倍型分析，以研究奠基者效应。
家系1中的两名同胞对先前描述的TSHB突变（c.373delT）呈纯合状态。在家族2和家族3中，受影响的个体为TSHB c.373delT与一个5.4kb的TSHB缺失（家族2，c.1-4389_417*195delinsCTCA）或一个新的TSHB错义突变（家族3，c. A2T>C，p.Met1?）的复合杂合子。3例患者在诊断和治疗延迟后出现神经发育迟缓。相比之下，家系1中较年幼者在出生后经基因诊断和治疗后发育正常。
本研究，包括鉴定出第二个新的TSHB缺失，扩展了TSHB缺陷的分子谱，并表明等位基因缺失可能是促甲状腺激素缺乏比先前怀疑更为常见的基础。在此类病例中，严重中枢性甲状腺功能减退症的诊断和治疗延迟会导致神经发育迟缓。在CH筛查中加入甲状腺素（T4）加甲状腺素结合球蛋白（TBG）或游离甲状腺素（FT4），并通过基因病例确诊实现更早的治疗干预，可以预防此类不良后果。
