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Four New Cases of Congenital Secondary Hypothyroidism due to a Splice Site Mutation in the Thyrotropin-ß Gene: Phenotypic Variability and Founder Effect

Children’s Hospital of the Johannes Gutenberg University (G.B., U.M., G.W., J.P.), D-55101 Mainz, Germany; Institut National de la Santé et de la Recherche Médicale U393 (G.B.), Hopital Necker-Enfants Malades, F-75015 Paris, France; Department of Pediatric Endocrinology and Metabolism (A.K.T., N.O.-M., B.Y., G.O.), Cukurova University, Faculty of Medicine, TR-01330 Adana, Turkey; Children’s Hospital Amsterdamer Strasse (E.K.), D-50735 Köln, Germany; Kinderklinik des Allgemeinen Krankenhauses Hagen GmbH (U.A., G.K.), D-58095 Hagen, Germany; Children’s Hospital (R.P.), University of Leipzig, D-04103 Leipzig, Germany; and Departments of Medicine (N.H.S., S.R.) and Pediatrics (S.R.) and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Joachim Pohlenz, M.D., Children’s Hospital, University of Mainz, Langenbeckstrasse 1, Building 109, D-55101 Mainz, Germany. E-mail: pohlenz{at}mail.uni-mainz.de; or pohlenz{at}kinder.klinik.uni-mainz.de.

Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G A) in the TSHß gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHß locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHß mutation is among the more common TSHß gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.

This work was supported in part by the University of Mainz-MAIFOR (to J.P.) and by Grants DK 00055 and 15070 from the National Institutes of Health (to S.R.). G.B. was supported by an Institut National de la Santé et de la Recherche Médicale fellowship (poste vert).

Abbreviations: CH, Congenital hypothyroidism; fT3, free T₃; fT4, free T₄; SDS, SD scores; SNP, single nucleotide polymorphism.

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