Reham S Ebrhim1, Ryan J Bruellman2, Yui Watanabe2, Matthew K Creech2, Mohamed A Abdullah3, Alexandra M Dumitrescu4, Samuel Refetoff4,5,6, Roy E Weiss7. 1. Department of Pediatrics and Child Health, Faculty of Medicine, University of Almughtaribeen, Khartoum, Sudan. 2. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. 3. Department of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. 4. Department of Medicine, The University of Chicago, Chicago, Illinois, USA. 5. Department of Pediatrics, The University of Chicago, Chicago, Illinois, USA. 6. Committee on Genetics, The University of Chicago, Chicago, Illinois, USA. 7. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA, rweiss@med.miami.edu.
Abstract
BACKGROUND: 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 (1:1,500-1:4,000), which presents on newborn screening with elevated serum thyroid-stimulating hormone (TSH) and low thyroxine (T4) and triiodothyronine (T3), 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 TSHβ gene. PATIENT: We present a consanguineous Sudanese family where the proband was diagnosed with "atypical" CH (serum TSH was low, not high). INTERVENTION AND OUTCOME: The propositus underwent whole-exome sequencing, and the C47W TSHβ 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 TSHβ subunit. The cysteine knot region of TSHβ 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 T4 and T3 levels. Other TSHβ gene mutations causing ICCH have been reported in the "seatbelt" region, necessary for TSHβ dimerization with the alpha subunit. CONCLUSIONS: Identification of a mutation in the TSHβ gene reinforces the importance of identifying ICCH that can occur in the absence of elevated serum TSH and demonstrates the functional significance of the TSHβ cysteine knot.
BACKGROUND: 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 (1:1,500-1:4,000), which presents on newborn screening with elevated serum thyroid-stimulating hormone (TSH) and low thyroxine (T4) and triiodothyronine (T3), 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 TSHβ gene. PATIENT: We present a consanguineous Sudanese family where the proband was diagnosed with "atypical" CH (serum TSH was low, not high). INTERVENTION AND OUTCOME: The propositus underwent whole-exome sequencing, and the C47W TSHβ 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 TSHβ subunit. The cysteine knot region of TSHβ 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 T4 and T3 levels. Other TSHβ gene mutations causing ICCH have been reported in the "seatbelt" region, necessary for TSHβ dimerization with the alpha subunit. CONCLUSIONS: Identification of a mutation in the TSHβ gene reinforces the importance of identifying ICCH that can occur in the absence of elevated serum TSH and demonstrates the functional significance of the TSHβ cysteine knot.
Authors: Joachim Pohlenz; Alexandra Dumitrescu; Ulrich Aumann; Gerhard Koch; Ralph Melchior; Dirk Prawitt; Samuel Refetoff Journal: J Clin Endocrinol Metab Date: 2002-01 Impact factor: 5.958
Authors: Yui Watanabe; Ryan J Bruellman; Reham S Ebrhim; Mohamed A Abdullah; Alexandra M Dumitrescu; Samuel Refetoff; Roy E Weiss Journal: Thyroid Date: 2018-12-18 Impact factor: 6.568