Congenital Goiter Research Articles

Clinical and Genetic Analysis of a Compound Heterozygous Mutation in the Thyroglobulin Gene in a Chinese Twin Family With Congenital Goiter and Hypothyroidism

Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype-genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype-phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype-genotype correlations in congenital hypothyroidism.

DUOX2 gene mutation in patients with congenital goiter with hypothyroidism

To identify DUOX2 gene mutation in patients with congenital goiter with hypothyroidism. Five patients who had transit congenital hypothyroidism with goiter were enrolled. The exons of DUOX2 gene were amplified and sequenced. A heterozygous missense mutation C1329T in the exon 10 of the DUOX2 gene was found in one patient, predicted to result in a Tryptophan to Arginine substitution at codon 376. However no mutation was detected in the other patients. p.Arg376Trp mutation in DUOX2 was found in newborns of congenital hypothyroidism. The alleles frequency of this mutation may contribute to the function loss of congenital hypothyroidism.

TSH Regulates Pendrin Membrane Abundance and Enhances Iodide Efflux in Thyroid Cells

Thyroid hormones are essential for normal development and metabolism. Their synthesis requires transport of iodide into thyroid follicles. The mechanisms involving the apical efflux of iodide into the follicular lumen are poorly elucidated. The discovery of mutations in the SLC26A4 gene in patients with Pendred syndrome (congenital deafness, goiter, and defective iodide organification) suggested a possible role for the encoded protein, pendrin, as an apical iodide transporter. We determined whether TSH regulates pendrin abundance at the plasma membrane and whether this influences iodide efflux. Results of immunoblot and immunofluorescence experiments reveal that TSH and forskolin rapidly increase pendrin abundance at the plasma membrane through the protein kinase A pathway in PCCL-3 rat thyroid cells. The increase in pendrin membrane abundance correlates with a decrease in intracellular iodide as determined by measuring intracellular (125)iodide and can be inhibited by specific blocking of pendrin. Elimination of the putative protein kinase A phosphorylation site T717A results in a diminished translocation to the membrane in response to forskolin. These results demonstrate that pendrin translocates to the membrane in response to TSH and suggest that it may have a physiological role in apical iodide transport and thyroid hormone synthesis.

Iodide Transport Defect: Functional Characterization of a Novel Mutation in the Na+/I− Symporter 5′-Untranslated Region in a Patient with Congenital Hypothyroidism

Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD. Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype. The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed. The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5'-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency. We described a novel mutation in the 5'-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function.

Congenital hypothyroidism with goiter

The article provides a description of congenital hypothyroidism and goiter in a newborn baby.

A newborn with neck mass.

Congenital goiter is a rare cause of neonatal neck mass and may result from a fetal defectin synthesis of thyroxine, or administration of antithyroid drugs or iodides during pregnancy. The thyroid dysfunction often accompanies it. This report describes a case of a male term newborn with congenital goiter and primary hypothyroidism. Hormonal replacement treatment was started leading to normal levels of free thyroxine and triiodothyronine. In face of a maternal negative investigation, dyshormonogenesis was considered to be the most probable cause of hypothyroidism.

Diagnosis of Iodide Transport Defect: Do We Need to Measure the Saliva/Serum Radioactive Iodide Ratio to Diagnose Iodide Transport Defect?

Iodide transport defect (ITD) is an infrequent condition associated with congenital dyshormonogenetic goiter due to mutations in the Na(+)/I(-) symporter (NIS) gene transmitted in an autosomal recessive manner. Herein, we describe a patient with ITD and discuss the features important for the diagnosis, focusing on whether or not measuring the saliva/serum radioactive iodide ratio is useful. A 42-year-old Japanese man attended our hospital in 2010. At that time, he had been off L-thyroxine for several months. He had no obvious mental retardation. His parents were cousins and his sister also had a goiter. Since thyroid dyshormonogenesis could not be ruled out, thyroid function tests, scintigraphy, and ultrasonography were performed. The results showed marked hypothyroidism with a high thyroglobulin level of 627 ng/mL. The results for thyroglobulin antibody and thyroid peroxidase antibody were both negative. Ultrasonography showed an enlarged thyroid gland. Neither the thyroid nor the salivary gland was visualized by (99m)TcO(4)(-) scintigraphy. Therefore, we performed genetic testing for the NIS gene without measuring the saliva/serum radioactive iodide ratio. A homozygous mutation, T354P, was identified in the NIS gene. On the basis of this finding, we could make the definitive diagnosis of ITD due to an NIS mutation. We recommend confirming the presence of the thyroid by ultrasonography of the neck first and then performing (99m)TcO(4)(-) scintigraphy. If neither the salivary gland nor the thyroid is visualized, screening for NIS mutations should be undertaken. This approach obviates the need to undertake measurement of the saliva/serum radioactive iodide ratio to diagnose ITD.

Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism

We describe the clinical, biochemical, and molecular findings of a cohort of Argentinean patients with congenital hypothyroidism (CH) and goiter studied to characterize iodide organification and thyroglobulin (TG) defects. 20 CH patients (16 unrelated) were grouped according to serum TG levels and a perchlorate discharge test (PDT) in: group 1 (G1): nine patients with high TG and PDT > 10% who were studied for tiroperoxidase (TPO), dual oxidase 2 (DUOX2), and dual oxidase A2 (DUOXA2) defects and group 2 (G2): 11 patients with low TG and PDT < 10% studied for TG defects. Goiter characteristics, outcome, and TT₄ and TT₃ levels without treatment were compared between groups. 6/9 G1 patients harbored mutations in TPO gene and 3/9 in DUOX2 gene. In G2, mutations of TG gene were found in 3/11 homozygous, 5/11 compound heterozygous, and 3/11 heterozygous patients. Goiter was only evidenced by thyroid scan in the neonatal period in both groups; was moderately enlarged in patients diagnosed during infancy. In the late detected patients, goiter was big and nodular in G1 while diffuse and moderate in G2. Early detected patients grew and developed normally while those diagnosed late were severely mentally retarded in G1 and only mildly retarded in G2. Thyroid hormone levels of G1 were significantly lower than those of G2 P < 0.01. Molecular approach to characterize defects in organification and TG defects was optimized by TG measurements and PDT. Clinical and biochemical differences based on molecular findings will allow further investigations on genotype-phenotype relationships.

Thyroglobulin gene is associated with premature ovarian failure

Variants of the thyroglobulin gene were significantly associated with premature ovarian failure in a Korean population. Three single nucleotide polymorphisms and one haplotype were found to be associated with a significant increase in the risk for premature ovarian failure.

New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

Congenital goitrous hypothyroidism, deafness and Iodide organification defect in four siblings: Pendred or pseudo-pendred syndrome?

Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect. Presence of inner ear malformations is essential for the clinical diagnosis. Most individuals with PDS are clinically and biochemically euthyroid. Mutations in the PDS gene encoding pendrin protein have been shown to be associated with PDS. It has been recently demonstrated that some families with features of PDS do not have the inner ear malformations and mutations in the PDS gene. This condition has been named as “pseudo−Pendred syndrome” (pseudo−PDS), and has been hypothesized to be of autoimmune origin. Here we report four siblings who have goiter, severe hypothyroidism, a positive perchlorate discharge test and sensorineural deafness, but not the inner ear abnormality which is diagnostic for PDS. We suggest that thyroid peroxidase (TPO) gene should be analyzed in pseudo−PDS patients with congenital goitrous hypothyroidism and deafness.Conflict of interest:None declared.

New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Locations included primary care and university hospitals. Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C-->T (p.R277X) and g.IVS35+1delG. For c.886C-->T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes, and together with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility that some cases were introduced to South America from Galicia cannot be excluded.

Congenital goitre with hypothyroidism caused by a novel compound heterozygous mutations in the thyroglobulin gene

Clinical EndocrinologyVolume 72, Issue 5 p. 716-718 Congenital goitre with hypothyroidism caused by a novel compound heterozygous mutations in the thyroglobulin gene Héctor M. Targovnik, Héctor M. Targovnik Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaSearch for more papers by this authorPierre F. Souchon, Pierre F. Souchon Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorGloria A. Machiavelli, Gloria A. Machiavelli Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaSearch for more papers by this authorAnne S. Salmon-Musial, Anne S. Salmon-Musial Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorPierre L.A. Mauran, Pierre L.A. Mauran Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorVéronique Sulmont, Véronique Sulmont Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorMartine Doco-Fenzy, Martine Doco-Fenzy Service de Génétique, CHU-Reims, UFR de Médecine IFR53, Reims, FranceSearch for more papers by this authorCarina M. Rivolta, Carina M. Rivolta Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaSearch for more papers by this author Héctor M. Targovnik, Héctor M. Targovnik Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaSearch for more papers by this authorPierre F. Souchon, Pierre F. Souchon Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorGloria A. Machiavelli, Gloria A. Machiavelli Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaSearch for more papers by this authorAnne S. Salmon-Musial, Anne S. Salmon-Musial Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorPierre L.A. Mauran, Pierre L.A. Mauran Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorVéronique Sulmont, Véronique Sulmont Service de Pédiatrie, American Memorial Hospital, CHU-Reims, Reims, FranceSearch for more papers by this authorMartine Doco-Fenzy, Martine Doco-Fenzy Service de Génétique, CHU-Reims, UFR de Médecine IFR53, Reims, FranceSearch for more papers by this authorCarina M. Rivolta, Carina M. Rivolta Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaSearch for more papers by this author First published: 25 March 2010 https://doi.org/10.1111/j.1365-2265.2009.03702.xCitations: 12 Héctor M. Targovnik, Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.Tel.: +54 11 4964 8296; Fax: +54 11 4964 8296; E-mail: htargovn@ffyb.uba.ar Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume72, Issue5May 2010Pages 716-718 RelatedInformation

Mutations of the thyroglobulin gene and its relevance to thyroid disorders

To perform an update review on thyroglobulin gene mutations associated with congenital hypothyroidism, thyroid cancer, and autoimmunity. Forty-two thyroglobulin mutations have been identified in dyshormonogenetic congenital hypothyroidism. Clinical and laboratory criteria defining defective thyroglobulin synthesis are mostly related to thyroglobulin mutations, generally caused by intracellular thyroglobulin transport defects to the colloid rather than defects in thyroid hormones synthesis. Some mutated thyroglobulin may escape the rigorous chaperone control and reach the colloid, allowing a wide phenotypic spectrum that includes euthyroidism in an adequate iodine environment. In some patients, continuous levothyroxine treatment does not reduce elevated serum thyroid-stimulating hormone (TSH) levels that may lead to goiter development. Prenatally, inactive mutant thyroglobulin will not be able to synthesize thyroid hormones and may increase pituitary thyrotroph threshold for thyroid hormone feedback. Congenital goiter is a risk factor for thyroid cancer and some thyroglobulin variants may confer susceptibility to thyroid autoimmunity. Advances in the understanding of thyroglobulin genetic defects and its severity should allow researchers to perform adequate molecular diagnosis, genetic counseling, and intrauterine treatment to prevent subtle deficits in central nervous system development. This knowledge should improve the understanding of physiological functions of the thyroid and influence of nutritional iodine.

Congenital goitre with hypothyroidism caused by a novel compound heterozygous mutations in the thyroglobulin gene

Congenital goitre with hypothyroidism caused by a novel compound heterozygous mutations in the thyroglobulin gene

Identification of a novel mutation in the SLC26A4 gene in an Italian with fluctuating sensorineural hearing loss

Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goitre and defective iodide organification. Congenital and profound hearing loss is the hallmark of the syndrome, while goitre and thyroid dysfunction are highly variable even within the same family. Clinical features are due to altered formation of pendrin, a chloride/iodide transporter protein expressed in the inner ear, thyroid gland and kidney. A novel substitution was found in exon 7 of the pendrin encoding gene ( SLC26A4) that leads to a stop codon, S314X. The new variation was found in compound heterozygosity with L445W mutation in a hearing impaired patient with bilateral Mondini's dysplasia and goitre.

Results of the Screening program for congenital hypothyroidism in Berlin (1978–1995)

Screening for congenital hypothyroidism for all newborns of the former western parts of the city of Berlin was instituted in 1978 by determination of the TSH levels in dried filter paper blood spots of the 3rd to 5th day of life. Since 1991 the newborns of the former eastern parts have been also included in the same screening program. From 1978 to 1995 a total number of 104 newborns with permanent congenital hypothyroidism have been detected resulting in a prevalence of congenital hypothyroidism of 1:3800. The etiological diagnosis of hypothyroidism was made by imaging studies (ultrasonography or 99mTc scintigraphy) and assessment of serum thyroglobulin and thyroid hormone levels. Using this approach in 37 children (30 female, 7 male) the diagnosis of athyrosis, in 20 children (15 female, 5 male) the diagnosis of ectopy and in 21 children (18 female, 3 male) the diagnosis of thyroid hypoplasia was made, 16 children (8 female, 8 male) had a normally sized gland and 4 (1 female, 3 male) had congenital goiter. In 86% of all patients the age at onset of thyroxine (L-T4) replacement therapy was 8 or 9 days of life (3-42 days) and the median initial L-T4 dose was 14 micrograms/kg/day (10-16 micrograms/kg/day). The intellectual outcome of 77 children (2-16 years) was studied and normal scores for the intelligence (IQ) and developmental (DQ) quotients were found in 71 (92%). Outcome was not correlated to the age at onset of treatment, the initial dose and the severity of hypothyroidism, but there was a positive correlation of the socioeconomic status of the family and the IQ of the patients. The results of the screening program in Berlin document that an early and efficient thyroxine replacement can normalize the intellectual outcome of patients with congenital hypothyroidism independent of the severity of the disease as assessed by the residual thyroid function detectable at diagnosis.

The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted alpha-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.

Genetic Causes of Goiter and Deafness: Pendred Syndrome in a Girl and Cooccurrence of Pendred Syndrome and Resistance to Thyroid Hormone in Her Sister

Goiter and deafness can be associated in some genetic syndromes, e.g. Pendred syndrome (PS) and resistance to thyroid hormone (RTH). PS is an autosomal recessive disorder characterized by goiter and sensorineural hearing impairment with an enlarged vestibular aqueduct bilaterally. RTH is an autosomal dominant condition of reduced tissue sensitivity to thyroid hormone in which goiter is very frequent and hearing loss occurs in about 20% of patients. OBJECTIVE, PATIENTS, AND DESIGN: The objective of this study was to identify the cause of goiter and deafness in two sisters born to healthy unrelated parents. We present their history, clinical presentation, and follow-up and report the results of molecular genetic investigations. The elder sister had an elevated TSH level at newborn screening followed by subclinical hypothyroidism, childhood-onset goiter, and bilateral progressive sensorineural hearing impairment with enlarged vestibular aqueducts, consistent with a diagnosis of PS. Her younger sister had congenital goiter, elevated free T3 and free T4 concentrations with unsuppressed TSH, sinus tachycardia, and bilateral progressive sensorineural hearing impairment with enlarged vestibular aqueducts. This clinical presentation was consistent with a diagnosis of RTH, in which, however, inner ear malformations are uncommon. Interestingly, molecular genetic testing showed that, whereas the elder sister is affected by PS, the younger sister has both PS (due to compound heterozygous SLC26A4 mutations) and RTH (due to a novel de novo heterozygous THRB mutation). This is the first report of the cooccurrence, in the same individual, of PS and RTH, two genetic syndromes both associated with goiter and hearing impairment.