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      Central Congenital Hypothyroidism Caused by a Novel Mutation, C47W, in the Cysteine Knot Region of TSHβ

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          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 (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 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 T<sub>4</sub> and T<sub>3</sub> 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.

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          Most cited references 10

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          Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules.

          The cystine knot three-dimensional structure is found in many extracellular molecules and is conserved among divergent species. The identification of proteins with a cystine knot structure is difficult by commonly used pairwise alignments because the sequence homology among these proteins is low. Taking advantage of complete genome sequences in diverse organisms, we used a complementary approach of pattern searches and pairwise alignments to screen the predicted protein sequences of five model species (human, fly, worm, slime mold, and yeast) and retrieved proteins with low sequence homology but containing a typical cystine knot signature. Sequence comparison between proteins known to have a cystine knot three-dimensional structure (transforming growth factor-beta, glycoprotein hormone, and platelet-derived growth factor subfamily members) identified new crucial amino acid residues (two hydrophilic amino acid residues flanking cysteine 5 of the cystine knot). In addition to the well known members of the cystine knot superfamily, novel subfamilies of proteins (mucins, norrie disease protein, von Willebrand factor, bone morphogenetic protein antagonists, and slit-like proteins) were identified as putative cystine knot-containing proteins. Phylogenetic analysis revealed the ancient evolution of these proteins and the relationship between hormones [e.g. transforming growth factor-beta (TGFbeta)] and extracellular matrix proteins (e.g. mucins). They are absent in the unicellular yeast genome but present in nematode, fly, and higher species, indicating that the cystine knot structure evolved in extracellular signaling molecules of multicellular organisms. All data retrieved by this study can be viewed at http://hormone.stanford.edu/.
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            Prediction of congenital hypothyroidism based on initial screening thyroid-stimulating-hormone

            Background In thyroid-stimulating-hormone (TSH)-based newborn congenital hypothyroidism (CH) screening programs, the optimal screening-TSH cutoff level is critical to ensuring that true cases of CH are not missed. Screening-TSH results can also be used to predict the likelihood of CH and guide appropriate clinical management. The purpose of this study is to evaluate the predictive value of various screening-TSH levels in predicting a diagnosis of CH in the Ontario Newborn Screening Program (ONSP). Methods The initial screening and follow-up data of 444,744 full term infants born in Ontario, Canada from April 1, 2006 to March 31, 2010 were analyzed. Confirmed CH cases were based on local endocrinologists’ report and initiation of thyroxine treatment. Results There were a total of 541 positive screening tests (~1/822 live births) of which 296 were true positives (~1:1,500 live births). Subjects were further subdivided based on screening-TSH and positive predictive values (PPV) were calculated. Twenty four percent in the 17–19.9 mIU/L range were true positives. In the 17–30 mIU/L range, 29 % were true positives with a significantly higher PPV for those sampled after (43 %) rather than before (25 %) 28 h of age (p < 0.02). Seventy three percent of neonates with an initial screening-TSH of ≥ 30 mIU/L and 97 % of those with ≥ 40 mIU/L were later confirmed to have CH. Conclusions Infants with modestly elevated screening positive TSH levels between 17 and 19.9 mIU/L have a significant risk (24 %) of having CH. The very high frequency of true positives in term newborns with initial TSH values ≥ 30mIU/L suggests that this group should be referred directly to a pediatric endocrinologist in an effort to expedite further assessment and treatment. Screen positives with a modestly elevated TSH values (17-19.9 mIU/L) need to be examined in more detail with extended follow-up data to determine if they have transient or permanent CH.
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              Congenital secondary hypothyroidism caused by exon skipping due to a homozygous donor splice site mutation in the TSHbeta-subunit gene.

              Isolated TSH deficiency as a cause for congenital hypothyroidism is relatively uncommon. Even more rare is the identification of mutations in the TSHbeta gene, only four of which have been identified. We here report a 4-month-old girl with isolated TSH deficiency born to consanguineous parents. Sequencing of the TSHbeta-subunit gene revealed a homozygous G to A transition at position +5 of the donor splice site of intron 2. TSHbeta gene transcript could not be obtained from fibroblasts or white blood cells by illegitimate amplification. Thus, to investigate further the mechanism leading to TSH deficiency in this patient, we used an in vitro exon-trapping system. The mutation at position +5 of the donor splicing site produced a skip of exon 2. The putative product of translation from a downstream start site is expected to yield a severely truncated peptide of 25 amino acids. Surprisingly, a missense substitution affecting the 14th amino acid of the signal peptide (SigP A14T) was found in one allele of the mother and brother. SigP 14T is polymorphic with a frequency of 1.8% and has no functional consequence.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                June 2020
                08 January 2020
                : 92
                : 6
                : 390-394
                aDepartment of Pediatrics and Child Health, Faculty of Medicine, University of Almughtaribeen, Khartoum, Sudan
                bDepartment of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
                cDepartment of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
                dDepartment of Medicine, The University of Chicago, Chicago, Illinois, USA
                eDepartment of Pediatrics, The University of Chicago, Chicago, Illinois, USA
                fCommittee on Genetics, The University of Chicago, Chicago, Illinois, USA
                Author notes
                *Roy E. Weiss, MD, PhD, Department of Medicine, University of Miami Miller School of Medicine, 1120 NW 14th St., Room 310F, Miami, FL 33136 (USA), E-Mail rweiss@med.miami.edu
                504981 Horm Res Paediatr 2019;92:390–394
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 2, Pages: 5
                Novel Insights from Clinical Practice / Case Report


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