Clinical and Molecular Analysis of Thyroid Hypoplasia: A Population-Based Approach in Southern Brazil

Ramos, Helton Estrela; Nesi-França, Suzana; Boldarine, Valter Tadeu; Pereira, Rosana Marques; Chiamolera, Maria Izabel; Camacho, Cleber; Graf, Hans; Lacerda, Luiz de; Carvalho, Gisah Amaral de; Maciel, Rui M. B.

doi:10.1089/thy.2008.0116

Cited by 38 publications

(33 citation statements)

References 33 publications

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“…THA results in congenital hypothyroidism only sporadically, which is detected by TSH neonatal screening (20). On the other hand, it has been observed that people with THA have significantly higher TSH and FT 3 concentrations when compared to those with fully developed thyroid, which is in accordance with our observations and suggests an impaired functional reserve of the unilobate thyroid (6).…”

Section: Discussionsupporting

confidence: 91%

Increased risk of thyroid pathology in patients with thyroid hemiagenesis: results of a large cohort case–control study

Ruchała

Szczepanek

Szaflarski

et al. 2010

European Journal of Endocrinology

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Objective: Thyroid hemiagenesis (THA) is an anomaly resulting from the developmental failure of one thyroid lobe. Etiopathogenesis, clinical significance, and management of patients in whom THA is diagnosed are still a matter of debate. The aim of the study is to provide the first systematic analysis of a large cohort of subjects with THA. Design: Forty patients with THA are described in comparison to a control group of 80 subjects with fully developed thyroid gland. Methods: Serum concentrations of thyrotropin (TSH), free thyroxine (FT 4 ), free triiodothyronine (FT 3 ), and thyroid autoantibodies were measured. In 37 patients, thyroid ultrasonography and Tc-99m thyroid scintiscan were performed, followed by fine-needle aspiration biopsy if indicated. The remaining archival three cases were diagnosed with the use of I-131 scintiscan under basal conditions and after TSH stimulation. Results: Patients with THA, while usually clinically euthyroid, presented with significantly higher levels of TSH and FT 3 as well as with higher FT 3 /FT 4 concentration in comparison to the control group. Furthermore, a higher incidence of associated functional, morphological, and autoimmune thyroid disorders in patients with THA was observed when compared to subjects with bilobate thyroid (P!0.05). Conclusions: Our results revealed that individuals with THA are more likely to develop thyroid pathology. The observed high incidence of associated pathologies is presumably due to long-lasting TSH overstimulation. Therefore, THA diagnosis should be followed by systematic observation and adequate levothyroxine treatment in patients with elevated TSH level.

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Section: Discussionsupporting

confidence: 91%

Increased risk of thyroid pathology in patients with thyroid hemiagenesis: results of a large cohort case–control study

Ruchała

Szczepanek

Szaflarski

et al. 2010

European Journal of Endocrinology

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“…Furthermore, PAX8 and TTF1 synergistically activate the promoter of human TG (3). So far, 13 different mutations in the PAX8 gene have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and the phenotypes of affected individuals vary considerably. Even within the same family, heterozygous individuals with PAX8 mutations can have no thyroid gland abnormality, have thyroid hypoplasia or TD (6), making it very difficult to identify individuals harboring a PAX8 gene mutation (1).…”

Section: Introductionmentioning

confidence: 99%

Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA Binding Region: In vitro studies reveal different pathogenic mechanisms.

Hermanns¹,

Grasberger²,

Cohen³

et al. 2012

Thyroid

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Background: Mutations in PAX8, a transcription factor gene, cause thyroid dysgenesis (TD). The extreme variability of the thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. Methods: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)-and the thyroperoxidase (TPO)-promoters. Results: S54R had an impaired binding to DNA and a negligible activity on the TG-and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it also exhibited dramatically impaired activation of the TGand TPO-promoters. However, R133Q has no dominant negative effect on the WT protein in vitro. Thus, the underlying molecular mechanism by which the function of R133Q is impaired remains to be elucidated. Conclusions: We identified and functionally characterized two novel mutations of the PAX8 gene that lead to TD by distinct mechanisms. A structural defect of the mutant R133Q leading to a reduced capability for induced fit upon DNA interaction might explain the disparity between its apparently normal binding to DNA, but lack of promoter activation.

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“…In recent years, there have been reports of families with multiple affected cases and molecular biology studies have demonstrated the involvement of genes (TTF1 and 2, PAX8, TSH-R), which encode highly conserved transcription factors that result in agenesis, ectopia and thyroid hypoplasia, when inactivated (27,28).…”

Section: Discussionmentioning

confidence: 99%

Timing of thyroid ultrasonography in the etiological investigation of congenital hypothyroidism

Borges

Sedassari

et al. 2017

Arch. Endocrinol. Metab.

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Objectives: To describe the findings of thyroid ultrasonography (T-US), its contribution to diagnose congenital hypothyroidism (CH) and the best time to perform it. Subjects and methods: Forty-four patients with CH were invited to undergo T-US and 41 accepted. Age ranged from 2 months to 45 years; 23 patients were females. All were treated with L-thyroxine; 16 had previously undergone scintigraphy and 30 had previous T-US, which were compared to current ones. Results: At the current T-US, the thyroid gland was not visualized in its normal topography in 10 patients (24.5%); 31 T-US showed topic thyroid, 17 with normal or increased volume due to probable dyshormonogenesis, 13 cases of hypoplasia and one case of left-lobe hemiagenesis. One patient had decreased volume due to central hypothyroidism. Scintigraphy scans performed 3-4 years earlier showed 100% agreement with current results. Comparisons with previous T-US showed concordant results regarding thyroid location, but a decrease in current volume was observed in eight due to the use of L-thyroxine, calling the diagnosis of hypoplasia into question. Conclusions: The role of T-US goes beyond complementing scintigraphy results. It allows inferring the etiology of CH, but it must be performed in the first months of life. An accurate diagnosis of CH will be attained with molecular study and the T-US can guide this early assessment, without therapy withdrawal. Arch Endocrinol Metab. 2017;61(5):432-7

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Clinical and Molecular Analysis of Thyroid Hypoplasia: A Population-Based Approach in Southern Brazil

Cited by 38 publications

References 33 publications

Increased risk of thyroid pathology in patients with thyroid hemiagenesis: results of a large cohort case–control study

Increased risk of thyroid pathology in patients with thyroid hemiagenesis: results of a large cohort case–control study

Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA Binding Region: In vitro studies reveal different pathogenic mechanisms.

Timing of thyroid ultrasonography in the etiological investigation of congenital hypothyroidism

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