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Background: Permanent congenital hypothyroidism (CH) is usually a more severe type of CH. However, the molecular etiology and clinical features of permanent CH remain unclear., Methods: We recruited 42 patients who were diagnosed with CH and followed-up after diagnosis. Demographic information and data at diagnosis and treatment were recorded. Genetic analyses were performed using whole exome sequencing. Based on the presence or absence of variants and differences in clinical features, we grouped the study participants and analyzed their characteristics., Results: A total of 29 patients (69.0 %) were identified as having variants potentially related to their disease. Among the 24 patients with normal-sized thyroid gland-in-situ (GIS) or goiter, 23 (95.8 %, P < 0.001) had variants. This is compared to 18 patients with thyroid dysgenesis (TD), of which six (33.3 %) had genetic variants. We detected 55 variants in six genes, the most frequently mutated gene being DUOX2 (70.9 %). Biallelic DUOX2 variants were detected in 14 of 24 (58.3 %) GIS or goiter patients. Compared to the cases with variants, the L-T4 dose at 2 and 3 years of age and current dose were higher in the unmutated cases. At 2 years of age, patients with TD required higher doses of L-T4 supplementation. Patients with DUOX2 variants showed lower doses of L-T4 being required at 2 and 3 years of age and current. Furthermore, patients with GIS or goiter with DUOX2 variants showed lower doses of L-T4., Conclusions: Patients with CH, whether TD or GIS or goiter, are at risk of developing a permanent condition. Compared with patients with TD, the detection of variants was higher in patients with GIS or goiter. The most frequently mutated gene was DUOX2, with a biallelic type. Patients with TD required higher doses of L-T4 supplementation with age, whereas those patients with the DUOX2 variant required relatively lower doses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Congenital hypothyroidism (CH) is a common congenital endocrine disorder in humans. CH-related diseases such as athyreosis, thyroid ectopy, and hypoplasia are primarily caused by dysgenic thyroid development. However, the underlying molecular mechanisms remain unknown., Methods: To identify novel CH candidate genes, 192 CH patients were enrolled, and target sequencing of 21 known CH-related genes was performed. The remaining 98 CH patients carrying no known genes were subjected to exome sequencing (ES). The functions of the identified variants were confirmed using thyroid epithelial cells in vitro and in zebrafish model organisms in vivo., Results: Four pathogenic GBP1 variations from three patients were identified. In zebrafish embryos, gbp1 knockdown caused defective thyroid primordium morphogenesis and hypothyroidism. The thyroid cells were stuck together and failed to dissociate from each other to form individual follicles in gbp1-deficient embryos. Furthermore, defects were restored with wild-type human GBP1 (hGBP1) messenger RNA (mRNA) except for mutated hGBP1 (p.H150Y, p.L187P) overexpression. GBP1 promoted β-catenin translocation into the cytosol and suppressed the formation of cellular adhesion complexes. Suppression of cell-cell adhesion restored the thyroid primordium growth defect observed in gbp1-deficient zebrafish embryos., Conclusion: This study provides further understanding regarding thyroid development and shows that defective cellular remodeling could cause congenital hypothyroidism., (© 2021. The Author(s).)

Background: Congenital hypothyroidism (CH), the most common neonatal endocrine disorder worldwide, can be caused by variants in thyroid transcription factor (TTF) genes including NKX2-1, FOXE1, PAX8, NKX2-5 and HHEX. This study aims to perform targeted next-generation sequencing (NGS) panel for comprehensive mutation screening on these genes in a cohort of 606 CH patients with various types from Henan Province, China, to investigate the mutation rate of TTF genes, and to analyze the clinical, biochemical and molecular characteristics of our CH cohort., Methods: High-throughput sequencing combined with statistical calculation were applied for mutation screening and analyses of the clinical data., Results: Twenty-two likely disease-causing monoallelic mutations in the TTF genes were identified in our cohort (3.63%, 22/606). Mutated PAX8 was the most predominant genetic alteration among these TTF mutations. Interestingly, PAX8 defects were only found in TD cases and variants in the five TTF genes were detected in gland in situ (GIS) patients. CH patients with the same genotype may have significant phenotypic variability and permanent CH (PCH) patients in the GIS group were significantly fewer than those in the TD group., Conclusions: Our study showed the estimated TTF mutation rate among CH cases was 3.63% in Henan Province and genetic alternations in TTF genes played a role not only in TD but also in GIS, especially in goiter. Although we speculated that the five TTF genes may be involved in certain steps of thyroid hormone biosynthesis, more researches are needed to verify the conclusions of the present study., (Copyright © 2021. Published by Elsevier B.V.)

Branchial cleft cysts are the most common lesions in the lateral neck with ectopic thyroid tissue found only rarely within these cysts. Over the years, multiple cases of papillary thyroid carcinoma arising from these ectopic thyroid tissues have been described in the literature with these cases sharing a normal thyroid gland on surgical and histological evaluation. Recently, however, there are three cases of papillary thyroid carcinoma in a branchial cleft cyst reported to be the result of metastasis from a thyroid primary. We present a 49-year-old female with a rare case of papillary thyroid carcinoma metastasis to a branchial cleft cyst with imaging characteristics that may prospectively suggest metastatic involvement., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Developmental anomalies of the thyroid gland, defined as thyroid dysgenesis, underlie the majority of cases of congenital hypothyroidism. Thyroid dysgenesis is predominantly a sporadic disorder although a reported familial enrichment, variation of incidence by ethnicity and the monogenic defects associated mainly with athyreosis or orthotopic thyroid hypoplasia, suggest a genetic contribution. Of note, the most common developmental anomaly, thyroid ectopy, remains unexplained. Ectopy may result from multiple genetic or epigenetic variants in the germline and/or at the somatic level. This review provides a brief overview of the monogenic defects in candidate genes that have been identified so far and of the syndromes which are known to be associated with thyroid dysgenesis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism in iodine-sufficient regions and includes a spectrum of developmental anomalies. The genetic components of TD are complex. Although a sporadic disease, advances in developmental biology have revealed monogenetic forms of TD. Inheritance is not based on a simple Mendelian pattern and additional genetic elements might contribute to the phenotypic spectrum. This article summarizes the key steps of normal thyroid development and provides an update on responsible genes and underlying mechanisms of TD. Up-to-date technologies in genetics and biology will allow us to advance in our knowledge of TD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The most frequent cause of congenital hypothyroidism is thyroid dysgenesis. Thyroid dysgenesis summarizes a spectrum of developmental abnormalities of the embryonic thyroid ranging from complete absence of the thyroid gland (athyreosis), to a normally located but too small thyroid (hypoplasia), or an abnormally located thyroid gland (ectopy). Although considered a sporadic disease, distinct genetic forms of isolated or syndromic thyroid dysgenesis have been described in recent years. However, genetics of thyroid dysgenesis (TD) are mostly not following simple Mendelian patterns, and beside monogenic, multigenic and epigenetic mechanisms need to be considered. The review will highlight the molecular mechanisms of thyroid organogenesis, clinical and genetic features of the different monogenetic forms of thyroid dysgenesis, the aspects relevant for diagnosis and counseling of affected families and current research strategies to get more insight into the non-Medelian mechanisms of normal and abnormal thyroid development., (Copyright © 2013 Elsevier Ltd. All rights reserved.)