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Unlabelled: We report four children originating from two unrelated German families with congenital hypothyroidism (CH) due to mutations in the thyroid peroxidase (TPO) gene. Three female siblings (family 1) were found to be compound heterozygous for two mutations, a known mutation in exon 9 (W527C), and a mutation in exon 8 (Q446H), which has not been described before. In the second family we identified a boy with goitrous CH, who had a novel homozygous mutation in the TPO gene in exon 16 (W873X). All children of family 1 were diagnosed postnatally by newborn screening. The case of the boy of family 2 has already been reported for the in utero treatment of a goiter with hypothyroidism., Conclusion: Our results confirm existing data on the phenotypic variability of patients with TPO gene mutations.

Unlabelled: Congenital primary hypothyroidism occurs in one out of 4,000 births. About 20% of cases are due to defects in thyroid hormonogenesis. We report on a German girl with congenital hypothyroidism due to a mutation in the thyroid peroxidase (TPO) gene who had elevated serum levels of thyroglobulin during periods of hyperthyrotropinemia., Methods: The TPO gene was sequenced directly from genomic DNA., Results: The patient had a novel homozygous mutation (R314W) in the TPO gene. The unaffected parents were non-consanguineous and both heterozygous carriers of the mutation. Fifty normal individuals did not harbor the mutation ruling out a common polymorphism., Conclusion: The identified TPO gene mutation (R314W) is very likely the genetic cause for hypothyroidism in the reported child. R314W has not been described before and codes for a presumably inactive TPO molecule.

Context and Objective: Most cases of goitrous congenital hypothyroidism (CH) from thyroid dyshormonogenesis 1) follow a recessive mode of inheritance and 2) are due to mutations in the thyroid peroxidase gene (TPO). We report the genetic mechanism underlying the apparently dominant inheritance of goitrous CH in a nonconsanguineous family of French Canadian origin., Design, Setting, and Participants: Two brothers identified by newborn TSH screening had severe hypothyroidism and a goiter with increased (99m)Tc uptake. The mother was euthyroid, but the father and two paternal uncles had also been diagnosed with goitrous CH. After having excluded PAX8 gene mutations, we hypothesized that the underlying defect could be TPO mutations., Results: Both compound heterozygous siblings had inherited a mutant TPO allele carried by their mother (c.1496delC; p.Pro499Argfs2X), and from their father, one brother had inherited a missense mutation (c.1978C-->G; p.Gln660Glu) and the other an insertion (c.1955insT; p.Phe653Valfs15X). The thyroid gland of one uncle who is a compound heterozygote for TPO mutations (p.Phe653Valfs15X/p.Gln660Glu) was removed because of concurrent multiple endocrine neoplasia type 2A. Immunohistochemistry revealed normal TPO staining, implying that Gln660Glu TPO is expressed properly. Modeling of this mutant in silico suggests that its three-dimensional structure is conserved, whereas the electrostatic binding energy between the Gln660Glu TPO and its heme group becomes repulsive., Conclusion: We report a pedigree presenting with pseudodominant goitrous CH due to segregation of three different TPO mutations. Although goitrous CH generally follows a recessive mode of inheritance, the high frequency of TPO mutations carriers may lead to pseudodominant inheritance.

Objective: Congenital primary hypothyroidism (CH) occurs in one of 4000 births and in 20% of the cases CH is due to a defect in thyroid hormonogenesis. Candidate genes were examined to determine the precise aetiology of suspected dyshormonogenesis in CH., Design: The genes that code for thyroid peroxidase (TPO), pendrin (PDS), sodium iodide symporter (NIS) and thyroid oxidase 2 (THOX2) were sequenced directly from genomic DNA., Patients: Two girls found to have CH in the neonatal screening programme and suspected of having thyroid dyshormonogenesis were investigated to identify their molecular defect., Results: Patient A had a novel heterozygous 1 bp insertion in the THOX2 gene (ins602g). This insertion results in a frameshift that predicts a premature stop at codon 300. Analysis of cDNA, transcribed from lymphocyte RNA, showed that this mutation causes skipping of exon 5, resulting in a frameshift and a premature stop at codon 254. The euthyroid mother was also a heterozygous carrier of the mutation whereas the father was homozygous for the wild-type THOX2 gene. In patient B, compound heterozygous mutations (ins602g-->fsX300 and D506N) were identified. D506N was present in one allele of the clinically unaffected mother and in a brother, whereas the euthyroid father was heterozygous for ins602g. Sixty normal individuals did not harbour the mutations. Sequencing of the TPO, PDS and NIS genes revealed no mutations., Conclusions: The identified THOX2 mutations, which have not been described previously, are the probable causes of CH in the patients. Mutations in the THOX2 gene should be considered as the molecular cause of CH in young patients with thyroid dyshormonogenesis.

Context: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses., Case Report: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected., Methods: We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro., Results: Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro., Conclusions: These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.

Objective: Congenital primary hypothyroidism occurs in 1 of 4000 births. Whereas the majority of the cases are due to developmental defects of the thyroid gland, 20% carry a defect in thyroid hormonogenesis. We report a Turkish boy who had goitrous hypothyroidism due to a mutation in the thyroid peroxidase (TPO) gene., Design: The TPO gene was sequenced directly from genomic DNA and cDNA which was transcribed from three RNA samples harvested from different parts of the patient's excised thyroid gland. Patient The boy was thyroidectomized because of continuing growth of his thyroid gland and development of multiple nodes suspected of malignancy by ultrasound examination. Histopathological examination verified a dyshormonogenetic goiter with multiple follicular adenomas., Results: The patient had a novel homozygous 10-bp deletion of the TPO gene at position 2812 in exon 16. This frame shift mutation results in a severely altered intracellular part of the protein. The deletion identified in leucocyte DNA was also found in thyroid tissue cDNA - so that instability of the transcript or a splicing defect was excluded. Both unaffected parents were heterozygous carriers of the mutation whereas 50 healthy individuals of the same ethnic background did not harbour the mutation., Conclusions: The identified TPO gene deletion is the first mutation coding for an inactive TPO molecule, which has a severely altered intracellular segment. Because the most likely reason for the enlarging goiter was poor compliance of the patient, this report underlines the importance of a careful and regular follow-up of patients with dyshormonogenesis.

Congenital primary hypothyroidism (CH) occurs in 1 of 4000 births. The majority of the cases are due to agenesis or dysgenesis of the thyroid gland, which can be caused by mutations in genes encoding for transcriptional factors that are responsible for the development of the thyroid gland. It is also known that the thyrotropin receptor (TSHR), a G-protein coupled receptor, is involved in late stages of thyroid organogenesis. Thus, mutations in the TSHR gene can cause congenital hypothyroidism. However, the clinical spectrum of thyroid abnormalities due to mutant TSHRs is wide and ranges from severe hypoplasia to an almost normal sized and structured thyroid gland. So far, 23 distinct loss-of-function mutations in the TSHR gene have been reported, occurring in families of different ethnic backgrounds and geographical areas. Here we report on a Turkish kindred in which two children were diagnosed to have very mild congenital primary hypothyroidism and one child had subclinical hypothyroidism. A novel homozygous missense mutation in codon 593 (A593 V) of the TSHR gene was identified in the affected individuals as the underlying molecular defect. This mutation substitutes a non-polar amino acid (alanine) with a non-polar amino acid (valine), so that only a minimal impairment of the TSHR function is expected. Indeed, the molecular finding is in agreement with the observed mild phenotype of the affected individuals. Our conclusion is that in mild primary hypothyroidism or subclinical hypothyroidism, mutations in the TSHR gene have to be considered as the molecular cause, especially in patients who have no detectable thyroid autoantibodies and have thyroid glands of normal size and in normal location.

Congenital primary hypothyroidism can be caused by reduced or absent responsiveness of the thyroid gland to thyrotropin (TSH), which normally binds to the thyrotropin receptor (TSHR) and exerts its effects mainly by stimulating intracellular cyclic adenosine monophosphate (cAMP). So far 22 causative loss-of-function mutations in the TSHR gene have been reported as occurring in families from different ethnic and geographical origins. We here report a family of Turkish origin in which all four children were diagnosed as having congenital primary hypothyroidism. A homozygous nonsense mutation in codon 609 (R609X) of the TSHR gene was identified in all affected individuals as the underlying molecular defect. The mutation leads to a truncated TSHR, which is likely to be biologically inactive. This mutation has been identified before to cause resistance to TSH in a large Bedouin kindred where two affected hypothyroid individuals were also resistant to adrenocorticotrophic hormone (ATCH). Interestingly none of the affected individuals in our family had symptoms consistent with hypocortisolism, which excludes a direct impact of this TSHR mutation on the hypothalamicpituitary-adrenal axis.