title: Congenital isolated central hypothyroidism caused by a "hot spot" mutation in the thyrotropin-beta gene.
abstract: Two adult siblings presented to our practice with a known history of congenital central isolated hypothyroidism. Their growth, development, and general health had been normal. Although the disorder was known to result from thyrotropin (TSH) deficiency, providers in the past had made multiple adjustments in their levothyroxine replacement doses in attempts to normalize serum TSH levels. This suggests a need for better education of providers who care for patients with central hypothyroidism. We performed DNA sequencing of the TSHbeta gene and identified a homozygous single base deletion in codon 105, on exon 3, resulting in a frameshift and a premature termination signal at codon 114. This same mutation (C105FS114X) has been previously reported in South America and Europe and appears to be the most common genetic mutation associated with congenital isolated TSH deficiency. The identification of this mutation for the first time in the United States suggests that this disorder, now described in patients from countries on multiple continents, is more common than previously appreciated and may be a mutational "hot spot."
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Michael.mcdermott@uchsc.edu
authors.forename: Michael T
authors.initials: MT
authors.lastname: McDermott
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Haugen
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Black
authors.forename: William M
authors.initials: WM
authors.lastname: Wood
authors.forename: David F
authors.initials: DF
authors.lastname: Gordon
authors.forename: E Chester
authors.initials: EC
authors.lastname: Ridgway
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005091:Exons; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D037322:Thyrotropin, beta Subunit / Q000235:genetics*
chemical_list: D037322:Thyrotropin, beta Subunit