{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T03:30:51Z","timestamp":1747193451991,"version":"3.40.5"},"reference-count":19,"publisher":"S. Karger AG","issue":"6","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Res Paediatr"],"published-print":{"date-parts":[[2019]]},"abstract":"<b><i>Background:<\/i><\/b> Isolated central congenital hypothyroidism (ICCH) is a rare form (1:50,000 newborns) of congenital hypothyroidism, which can present with growth and neuropsychological retardation. Unlike the more common primary CH (1:1,500\u20131:4,000), which presents on newborn screening with elevated serum thyroid-stimulating hormone (TSH) and low thyroxine (T<sub>4<\/sub>) and triiodothyronine (T<sub>3<\/sub>), ICCH presents with low TSH and low thyroid hormone levels. ICCH, therefore, may be missed in most newborn screens that are based only on elevated TSH. Most cases of ICCH have been associated with mutations in the <i>TSH\u03b2<\/i> gene. <b><i>Patient:<\/i><\/b> We present a consanguineous Sudanese family where the proband was diagnosed with \u201catypical\u201d CH (serum TSH was low, not high). <b><i>Intervention and Outcome:<\/i><\/b> The propositus underwent whole-exome sequencing, and the C47W TSH\u03b2 mutation was identified. Sanger sequencing confirmed the proband to be homozygous for C47W, and both parents were heterozygous for the same mutation. The mutation was predicted by several in silico methods to have a deleterious effect (SIFT 0.0, Damaging; Polyphen2_HDIV 0.973, probably damaging; MutationTaster 1, disease causing; and CADD 3.17, 16.62). C47W affects the first cysteine of the cysteine knot of the TSH\u03b2 subunit. The cysteine knot region of TSH\u03b2 is highly conserved across species and is critical for binding to the TSH receptor. Only two other mutations were previously reported along the cysteine knot and showed consistently low or undetectable serum TSH and low T<sub>4<\/sub> and T<sub>3<\/sub> levels. Other <i>TSH\u03b2<\/i> gene mutations causing ICCH have been reported in the \u201cseatbelt\u201d region, necessary for TSH\u03b2 dimerization with the alpha subunit. <b><i>Conclusions:<\/i><\/b> Identification of a mutation in the <i>TSH\u03b2<\/i> gene reinforces the importance of identifying ICCH that can occur in the absence of elevated serum TSH and demonstrates the functional significance of the TSH\u03b2 cysteine knot.<\/jats:p>","DOI":"10.1159\/000504981","type":"journal-article","created":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T22:00:33Z","timestamp":1578520833000},"page":"390-394","source":"Crossref","is-referenced-by-count":2,"title":["Central Congenital Hypothyroidism Caused by a Novel Mutation, C47W, in the Cysteine Knot Region of TSH\u03b2"],"prefix":"10.1159","volume":"92","author":[{"given":"Reham\u00a0S.","family":"Ebrhim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan\u00a0J.","family":"Bruellman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yui","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew\u00a0K.","family":"Creech","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed\u00a0A.","family":"Abdullah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2743-770X","authenticated-orcid":false,"given":"Alexandra\u00a0M.","family":"Dumitrescu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy\u00a0E.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2020,1,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-5-17"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-016-0559-0"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1007\/s11102-008-0122-6"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-7-90"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2018.0137"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0588-7"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg509"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0810-575"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1515\/JPEM.2004.17.4.669"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000034234.88317.B1"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb08355.x"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.4595"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-0223"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0494"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2015.0096"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1159\/000362413"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1210\/mend.15.5.0639"}],"container-title":["Hormone Research in Paediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/504981","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/504981","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T16:16:40Z","timestamp":1745425000000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000504981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019]]},"references-count":19,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6,19]]},"published-print":{"date-parts":[[2020,6,23]]}},"URL":"https:\/\/doi.org\/10.1159\/000504981","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.11550051","asserted-by":"subject"}]},"ISSN":["1663-2818","1663-2826"],"issn-type":[{"type":"print","value":"1663-2818"},{"type":"electronic","value":"1663-2826"}],"subject":[],"published":{"date-parts":[[2019]]}}}