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Objective: Rare coexistence of disease or pathology Background: We present a rare case of an ectopic thyroid nodule hyperplasia, confirmed postoperatively after excision and histopathological examination of a chronic cervical mass. We discuss the different clinical and therapeutic features of this rare thyroid dysgenesis caused by a defect of migration of the gland along its normal way of descent. Case Report: A 48-year-old man with a history of hypertension and asthma presented with dysphagia and a progressively growing firm mass at the anterior part of his neck over the past 6 months. Ultrasound and computed tomography suggested that the mass was attached only to the anterior part of the larynx, without connection to the thyroid, and with a multinodular gland in normal position. A complete surgical excision was performed under general anaesthesia through an external cervical approach. The mass, measuring 60×40 mm, was sent for a histological assessment, which concluded a fully encapsulated ectopic thyroid mass attached only to the soft tissues of the anterior part of the larynx, not showing any sign of malignancy transformation. The outcome of the surgery was marked by a quick recovery, with an improvement of the initial symptoms, proper healing of the surgical scar, and durable normal thyroid functioning after a regular follow-up of 6 months. Conclusions: Nonspecific symptoms can reveal ectopic thyroid tissue growth. Appropriate neck imaging combined, when available, with fine needle aspiration help to determine the extent of the mass and predict its nature. Surgical excision and histological analysis are required to confirm the diagnosis and to exclude any thyroid neoplasm. [ABSTRACT FROM AUTHOR]

Introduction: Pathogenic variants in the genes involved in the formation of thyroid tissue and thyroid hormone secretion have been reported to cause congenital hypothyroidism (CH) in some cases. This study aimed to evaluate the clinical and genetic findings of CH cases thought to be due to genetic variants. Methods: The study included cases whose genetic analysis was performed in accordance with the Congenital Hypothyroidism: A 2020–2021 Consensus Guidelines Update Guidelines recommendations criteria and analyzed them using the next-generation sequencing panel. Results: Sixty one Turkish patients from 45 families were included in the study. The overall frequency of variant detection was 37.7% (out of 45 families, 17 had a positive mutation). Segregation was carried out for all families with positive variants. Variants in the TPO gene are the most frequently encountered, and this situation was identified in 10 families. Variants followed this in the TSHR gene in 7 families, variants in the DUOX2 gene in 5 families, and two variants in the TG and NKX2-1 genes in 2 families each, which are six novel variants. Furthermore, among the NKX2-1 cases, one had thyroid involvement only, while the other had chorea only. We did not find differences between cases with detected mutations and mutation-negative cases regarding gender, neonatal/perinatal parameters, initial thyroid function values, and thyroid morphology. Conclusion: In the current investigation, rare new variations in genes known to be related to CH were discovered, adding to the molecular genetic spectrum. When we compare the overall variant detection frequency, the selection criterion for genetic analysis based on the current guidelines is quite rational, considering the benefits and costs, on the other hand, present in new genes awaiting discovery. Also, TSHR mutations are likely to be common and may account for more than 5% of thyroid dysgenesis cases if we include nonfamilial thyroid dysgenesis. [ABSTRACT FROM AUTHOR]

Thyroid hemiagenesis (THA) is a rare congenital abnormality in which one of the thyroid lobes fails to develop normally. The prevalence rates range from 0.02% to 0.25%, with no gender preponderance and most commonly involve the left lobe. We report a case of left THA in a 37-year-old female that was found incidentally during total thyroidectomy for right papillary thyroid carcinoma. Most patients with THA are asymptomatic, however, may have subclinically raised thyroid-stimulating hormone levels or be predisposed to developing thyroid disorders such as nodular goiter, hyperthyroidism, Grave’s disease, Hashimoto’s thyroiditis, hyperparathyroidism, or malignancy. Usual imaging techniques such as ultrasonography, computed tomography, and magnetic resonance imaging allow the confirmation of diagnosis and provide clearer glandular and regional visualization. Additional modalities such as thyroid scintigraphy enable the functional assessment and identification of any suspicious nodules and aid in decision-making. THA is a very uncommon condition and the diagnosis is primarily made through imaging. Clinicians should be aware that this condition exists along with documented associations of concomitant thyroid disorders and malignancy.

Thyroid hemiagenesis (THA) is a rare congenital abnormality in which one of the thyroid lobes fails to develop normally. The prevalence rates range from 0.02% to 0.25%, with no gender preponderance and most commonly involve the left lobe. We report a case of left THA in a 37-year-old female that was found incidentally during total thyroidectomy for right papillary thyroid carcinoma. Most patients with THA are asymptomatic, however, may have subclinically raised thyroid-stimulating hormone levels or be predisposed to developing thyroid disorders such as nodular goiter, hyperthyroidism, Grave's disease, Hashimoto's thyroiditis, hyperparathyroidism, or malignancy. Usual imaging techniques such as ultrasonography, computed tomography, and magnetic resonance imaging allow the confirmation of diagnosis and provide clearer glandular and regional visualization. Additional modalities such as thyroid scintigraphy enable the functional assessment and identification of any suspicious nodules and aid in decision-making. THA is a very uncommon condition and the diagnosis is primarily made through imaging. Clinicians should be aware that this condition exists along with documented associations of concomitant thyroid disorders and malignancy. [ABSTRACT FROM AUTHOR]

Background: BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid. Methods: We characterized thyroid development and function in Borealindeficient (Borealin+/-) mice using histology, transcriptomic analysis, and quantitative PCR. Results: Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin+/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin+/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin+/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility. Conclusion: These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations. [ABSTRACT FROM AUTHOR]

BackgroundBOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid.MethodsWe characterized thyroid development and function in Borealin-deficient (Borealin+/−) mice using histology, transcriptomic analysis, and quantitative PCR.ResultsThyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin+/− mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin+/− aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin+/− thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility.ConclusionThese findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.

Background: Newborn screening (NBS) has largely eliminated the physical and neurodevelopmental effects of untreated congenital hypothyroidism (CH). Many countries, including Australia, have progressively lowered NBS bloodspot thyroid‐stimulating hormone (b‐TSH) thresholds. The impact of these changes is still unclear. Objectives: To evaluate the performance of CH NBS following the reduction of b‐TSH thresholds in New South Wales (NSW) and the Australian Capital Territory (ACT), Australia, from 15 to 8 mIU/L, and to determine the clinical outcomes of cases detected by these thresholds. Methods: NBS data of 346 849 infants born in NSW/ACT, Australia from 1 November, 2016–1 March, 2020 inclusive were analysed. A clinical audit was conducted on infants with a preliminary diagnosis of CH born between 1 January, 2016–1 December, 2020 inclusive. Results: The lowered b‐TSH threshold (≥8 mIU/L, ~99.5th centile) detected 1668 infants (0.48%), representing an eight‐fold increase in recall rate, of whom 212 of 1668 (12.7%) commenced thyroxine treatment. Of these 212 infants, 62 (29.2%) (including eight cases with a preliminary diagnosis of thyroid dysgenesis) had an initial b‐TSH 8–14.9 mIU/L. The positive predictive value for a preliminary diagnosis of CH decreased from 74.3% to 12.8% with the lowered threshold. Proportionally, more pre‐term infants received a preliminary CH diagnosis on screening with the lower threshold (16.1% of 62) than with the higher threshold (8.0% of 150). Conclusion: Clinically relevant CH was detected using the lowered threshold, albeit at the cost of an eight‐fold increase in recall rate. Further clinical and economic studies are required to determine whether benefits of lowered screening thresholds outweigh potential harms from false‐positive results on infants, their families and NBS programs. [ABSTRACT FROM AUTHOR]

Background: ISL LIM homeobox 2, also known as insulin gene enhancer protein ISL-2 (ISL2), is a transcription factor gene that participates in a wide range of developmental events. However, the role of ISL2 in the hypothalamus-pituitary-thyroid axis is largely unknown. In the present study, we characterized the expression patterns of ISL2 and revealed its regulative role during embryogenesis using zebrafish. Methods: We used the CRISPR/Cas9 system to successfully establish homozygous ISL2-orthologue (isl2a and isl2b) knockout zebrafish. Moreover, we utilized these knockout zebrafish to analyze the pituitary and thyroid phenotypes in vivo. For further molecular characterization, in situ hybridization and immunofluorescence were performed. Results: The isl2a mutant zebrafish presented with thyroid hypoplasia, reduced whole-body levels of thyroid hormones, increased early mortality, gender imbalance, and morphological retardation during maturity. Additionally, thyrotropes, a pituitary cell type, was notably decreased during development. Importantly, the transcriptional levels of pituitary-thyroid axis hormones-encoding genes, such as tshba, cga, and tg, were significantly decreased in isl2a mutants. Finally, the thyroid dysplasia in isl2a mutant larvae may be attributed to a reduction in proliferation rather than changes in apoptosis. Conclusions: In summary, isl2a regulates the transcriptional levels of marker genes in hypothalamus-pituitary-thyroid axis, and isl2a knockout causing low thyroid hormone levels in zebrafish. Thus, isl2a identified by the present study, is a novel regulator for pituitary cell differentiation in zebrafish, resulting in thyroid gland hypoplasia and phenotypes of hypothyroidism. [ABSTRACT FROM AUTHOR]

• Detection of variants was higher in patients with normal-sized gland-in-situ or goiter than those with thyroid dysgenesis. • Permanent congenital hypothyroidism patients with thyroid dysgenesis required higher doses of L-T4 supplementation with age. • Permanent congenital hypothyroidism patients with the DUOX2 variant required relatively lower doses. Permanent congenital hypothyroidism (CH) is usually a more severe type of CH. However, the molecular etiology and clinical features of permanent CH remain unclear. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background: Congenital hypothyroidism (CH) is a common neonatal endocrine disorder, characterized by irreversible intellectual disability and short stature if left untreated. It can be divided into thyroid dysgenesis (TD), including athyreosis, ectopy and hypoplasia, and dyshormonogenesis (DH), also referring to gland in situ (GIS), in which patients have eutopic thyroids with normal size or goiter. This study aims to analyze the clinical and genetic data of 375 Chinese CH patients without DUOX2 and thyroid transcription factor (TTF) variants, and to explore the mutation frequencies of the eight genes and the inheritance pattern of CH. Methods: Targeted next generation sequencing (NGS) and statistical analysis were performed for mutation screening on eight CH-related genes and the comparison of clinical data in a cohort of 606 Chinese CH patients from Henan Province. Results: A total of 104 variants were detected in genes required for thyroid formation (TSHR, GLIS3, BOREALIN, NTN1, JAG1 and TUBB1) and thyroid hormone synthesis (TG and TPO) in 83 subjects. Monogenic variants were the most prevalent with a percentage of 75.00% (78/104) followed by oligogenic variants (25.00%, 26/104). No differences were found in various clinical data between patients with and without variants. However, it should be noted that only initial L-T4 dose was statistically different between patients with monogenic variants and oligogenic variants. Conclusions: Our results suggested that apart from Mendelian monogenic inheritance, oligogenic inheritance of CH could not be excluded and also involves other factors, such as penetrance, epigenetic mechanisms and environmental factors. [ABSTRACT FROM AUTHOR]

ABSTRACT Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic‐pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high‐throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.

Aim:Congenital hypothyroidism (CH) is one of the most common endocrinological problems in the neonatal period. CH, which occurs in 1:3,000-4,000 births, is a preventable cause of mental retardation. In the literature, the most common cause of CH is dysgenesis of the thyroid gland, followed by thyroid dyshormonogenesis. We aimed to determine the prevalence of permanent (P-CH) and transient (T-CH) CH in cases followed up with a diagnosis of CH and to identify a prediction method for persistency.Materials and Methods:We retrospectively analyzed the medical records of 105 children with CH. TSH levels in a screening program, TSH and fT4 levels of the first venous sample, 10-15th day of treatment, monthly in the first 6 months, 2-3 monthly until 18th months, and 6-monthly until 3 years of age were recorded. L-T4 doses (per microgram per body weight) in each visit were also recorded.Results:From the 105 children (58 males, 47 females) enrolled in this study, 38 (36.2 %) were referred from the National Newborn Screening Program. Treatment was discontinued during the 3rd year follow-up period in 44 (41.9 %) of the cases with normal thyroid gland morphology. L-thyroxine (L-T4) therapy was discontinued at a median age of 1.9+-1.08 years.TSH levels at the time of diagnosis were higher in the P-CH group, but this difference was not statistically significant (p=0.165). At the sixth month, first and second years of follow-up, L-T4 doses were significantly higher in the P-CH than in the T-CH group (p

Background and aims: Although the significance of primary congenital hypothyroidism (CH) is supported by an increasing amount of evidence, the clinical and genetic characteristics of this condition are still poorly understood. This study aimed to explore the underlying genetic etiologies in a cohort of primary CH patients. Subjects and Methods: The clinical data of 33 patients with primary CH were collected and analyzed via a cross-sectional study. Genetic analysis was performed by high-throughput sequencing and Sanger verification, and the pathogenicity of the novel missense variants was predicted using a variety of comprehensive bioinformatic tools. Results: Among the 33 patients, 22 (22/33, 66.7%) harbored pathogenic variants in the causative genes of thyroid dysgenesis or dyshormonogenesis, with DUOX2 (15/33, 45.5%) topping the list, followed by TG, TPO, DUOXA2 and PAX8. Four novel genetic variants were detected, including a pathogenic frameshift and three likely pathogenic missense variants. Positive neonatal screening for TSH, neonatal jaundice and abnormal thyroid morphology were the main positive findings among all cases. Although 31 of the total 33 CH patients exhibited normal anthropometric and social performance, the other 2 had poor prognosis in this study. Conclusions: This study reported 33 new CH patients bearing four novel genetic variants, which enriched the variant spectrum of CH genes. In this cohort, genetic factors causing thyroid dyshormonogenesis were the main etiologies of CH development. Most patients exhibited a favorable prognosis; however, systematic management remains a challenge in achieving improved clinical outcomes for CH patients. [ABSTRACT FROM AUTHOR]

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and the most common preventable cause of development delay and growth failure if diagnosed and treated early. The thyroid is the first endocrine gland to develop during embryonic life and to be recognizable in humans. Thyroid development and maturation can be divided into 2 phases: a first phase of embryogenesis and a second phase of folliculogenesis and differentiation with thyroid hormone production at the final steps. Regulation of the thyroid function requires normal development of the hypothalamic-pituitary-thyroid axis, which occurs during the embryonic and neonatal period. Defects in any of steps of thyroid development, differentiation, and regulation lead to permanent CH. Newborn screening programs, established in only one-third of countries worldwide, detect CH and are cost-effective and highly sensitive and specific. During the last decade, epidemiology of CH has changed with increased frequency of thyroid in situ in primary CH. Advances in molecular testing have expanded knowledge and understanding of thyroid development and function. However, a molecular cause is identified in only 5% of CH due to thyroid dysgenesis. The purpose of this article is to describe the clinical approach to the child with CH, focusing on diagnostic work-up and future challenges on optimizing thyroid replacement therapy and regenerative medicine. The review is written from the perspective of the case of 2 girls referred for CH after newborn screening and diagnosed with thyroid ectopy. The genetic work-up revealed novel mutations in TUBB1 gene, associated with large platelets and abnormal platelet physiology. [ABSTRACT FROM AUTHOR]

Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate‐limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine‐containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone‐inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action. [ABSTRACT FROM AUTHOR]

Objectives: It was aimed to investigate the outcomes of babies referred to a tertiary health center in Turkey for evaluation primary congenital hypothyroidism (CH) through newborn screening., Methods: The hospital files of 328 newborns who were referred for CH from newborn screening between June 2013 and June 2020 were retrospectively reviewed. The newborns were evaluated with their clinical characteristics at admission, as well as their follow-up data and final diagnoses., Results: Sixteen (4.9 %) newborns were diagnosed with transient neonatal hyperthyrotropinemia after follow-up. Treatment was initiated in 166 (50.6 %) of the cases with a diagnosis of CH. The median age at initiation of treatment was 17 days (5-69). Treatment was initiated in 88.3 % of the cases in the first month of the life. After at least 3 years of follow-up, 30/120 (20.0 %) of the cases were diagnosed with permanent CH and 11/30 (36.7 %) of them were diagnosed with thyroid dysgenesis. All of the cases who used >37.5 µg per day levothyroxine at the age of 1 or 2 years were diagnosed with permanent CH during their follow-up. For the prediction of transient CH, the sensitivity and specificity of levothyroxine doses of ≤25 µg per day at 1 year of age were calculated as 96.2 and 46.2 %, and for 2 years of age, the sensitivity and specificity were calculated as 97.8 and 65.2 %., Conclusions: In this cohort, 10 % of all referrals result in permanent CH. Thyroid imaging with ultrasonography and levothyroxine dose during follow-up can be guiding in predicting permanent CH., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Thyroglossal duct cysts, which are the most frequently encountered congenital cervical anomalies in children, occur due to embryologic remnants of the thyroglossal duct. Although diagnosis may be challenging, clinicians can be aided by imaging and fine-needle aspiration biopsies. We describe the clinical management of a two-year-old boy with a thyroglossal duct cyst mimicking a goitre on a pertechnetate thyroid scan.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic‐pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high‐throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder. [ABSTRACT FROM AUTHOR]

Objective: Congenital hypothyroidism (CH) is known to be due to thyroid dyshormonogenesis (DH), which is mostly inherited in an autosomal recessive inheritance pattern or thyroid dysgenesis (TD), whose inheritance pattern is controversial and whose molecular etiology remains poorly understood. Design and Methods: The variants in 37 candidate genes of CH, including 25 genes related to TD, were screened by targeted exon sequencing in 205 Chinese patients whose CH cannot be explained by biallelic variants in genes related to DH. The inheritance pattern of the genes was analyzed in family trios or quartets. Results: Of the 205 patients, 83 patients carried at least one variant in 19 genes related to TD, and 59 of those 83 patients harbored more than two variants in distinct candidate genes for CH. Biallelic or de novo variants in the genes related to TD in Chinese patients are rare. We also found nine probands carried only one heterozygous variant in the genes related to TD that were inherited from a euthyroid either paternal or maternal parent. These findings did not support the monogenic inheritance pattern of the genes related to TD in CH patients. Notably, in family trio or quartet analysis, of 36 patients carrying more than two variants in distinct genes, 24 patients carried these variants inherited from both their parents, which indicated that the oligogenic inheritance pattern of the genes related to TD should be considered in CH. Conclusions: Our study expanded the variant spectrum of the genes related to TD in Chinese CH patients. It is rare that CH in Chinese patients could be explained by monogenic germline variants in genes related to TD. The hypothesis of an oligogenic origin of the CH should be considered. [ABSTRACT FROM AUTHOR]

Purpose Thyroid dysgenesis is one of the most common causes of permanent congenital hypothyroidism. Thyroid ultrasonography or scan is used to detect thyroid dysgenesis. We analyzed the sensitivity and specificity of thyroid ultrasonography and scan in diagnosing thyroid dysgenesis to determine the clinical utility of each thyroid imaging method. Methods Sixty-one patients younger than 7 years of age were investigated via thyroid scan. Nineteen patients who were initially interpreted as having thyroid dysgenesis, such as ectopia, hemiagenesis, or aplasia, by thyroid scan were included in the study. Clinical characteristics and findings of a thyroid imaging study were reviewed. Results Initially, thyroid scan results were interpreted as ectopia (n=9), hemiagenesis (n=1), and nonvisualization (n=9). In contrast, the results of thyroid ultrasonography were normal thyroid gland (n=5), ectopia (n=6), and hypoplasia (n=8). After reviewing the results of both studies, final imaging diagnoses were as follows: normal thyroid gland (n=5), hemiagenesis (n=1), ectopia (n=9) including 2 dual ectopy, hypoplasia (n=3), and aplasia (n=1). Thyroid ultrasonography showed higher sensitivity and specificity in detecting presence of normal thyroid gland. Thyroid scan was better to detect ectopia. Among 8 patients who were initially interpreted as having hypoplasia by ultrasonography, 4 were confirmed as ectopia and one as aplasia. Conclusions This study showed that thyroid ultrasonography is useful as the first-line imaging study to detect normal-sized eutopic thyroid gland. Thyroid scan should be performed to investigate the presence of ectopia if hypoplasia or aplasia is suspected by ultrasonography.

Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis. The aim of the study was to reveal genetic factors responsible for thyroid maldevelopment in two siblings with THA. None of the family members presented with congenital heart defect. The samples were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Enrichment Kit, San Diego, CA 92121, USA). An ultra-rare variant c.839C>T (p.Pro280Leu) in NKX2-5 gene (NM_004387.4) was identified in both affected children and an unaffected father. In the mother, the variant was not present. This variant is reported in population databases with 0.0000655 MAF (GnomAD v3, dbSNP rs761596254). The affected amino acid position is moderately conserved (positive scores in PhyloP: 1.364 and phastCons: 0.398). Functional prediction algorithms showed deleterious impact (dbNSFP v4.1, FATHMM, SIFT) or benign (CADD, PolyPhen-2, Mutation Assessor). According to ACMG criteria, variant is classified as having uncertain clinical significance. For the first time, NKX2-5 gene variants were found in two siblings with THA, providing evidence for its potential contribution to the pathogenesis of this type of thyroid dysgenesis. The presence of the variant in an unaffected parent, carrier of p.Pro280Leu variant, suggests potential contribution of yet unidentified additional factors determining the final penetrance and expression. [ABSTRACT FROM AUTHOR]

Aim: Congenital hypothyroidism (CH) is one of the most common endocrinological problems in the neonatal period. CH, which occurs in 1:3,000-4,000 births, is a preventable cause of mental retardation. In the literature, the most common cause of CH is dysgenesis of the thyroid gland, followed by thyroid dyshormonogenesis. We aimed to determine the prevalence of permanent (P-CH) and transient (T-CH) CH in cases followed up with a diagnosis of CH and to identify a prediction method for persistency. Materials and Methods: We retrospectively analyzed the medical records of 105 children with CH. TSH levels in a screening program, TSH and fT4 levels of the first venous sample, 10-15th day of treatment, monthly in the first 6 months, 2-3 monthly until 18th months, and 6-monthly until 3 years of age were recorded. L-T4 doses (per microgram per body weight) in each visit were also recorded. Results: From the 105 children (58 males, 47 females) enrolled in this study, 38 (36.2 %) were referred from the National Newborn Screening Program. Treatment was discontinued during the 3rd year follow-up period in 44 (41.9 %) of the cases with normal thyroid gland morphology. L-thyroxine (L-T4) therapy was discontinued at a median age of 1.9+-1.08 years. TSH levels at the time of diagnosis were higher in the P-CH group, but this difference was not statistically significant (p=0.165). At the sixth month, first and second years of follow-up, L-T4 doses were significantly higher in the P-CH than in the T-CH group (p<0.001, p<0.001, p<0.001 respectively). TSH levels were also higher in the P-CH group than in the T-CH group (p=0.123, p=0.038, p=0.049 respectively). Consistent with these results, measured fT4 levels were found to be lower in the P-CH group compared to the T-CH group (p=0.431, p=0.361, p=0.028 respectively). Conclusion: L-T4 doses at 6, 12 and 24 months may predict transient hypothyroidism in patients with normal thyroid gland morphology before 36 months. [ABSTRACT FROM AUTHOR]

Thyroid dysgenesis (TD) accounts for 80% cases of congenital hypothyroidism, which is the most common neonatal disorder. Until now, the gene mutations have been reported associated with TD can only account for 5% cases, suggesting the genetic heterogeneity of the pathology. Nicotinamide nucleotide transhydrogenase (NNT) plays a crucial role in regulating redox homeostasis, patients carrying NNT mutations have been described with a clinical phenotype of hypothyroidism. As TD risk is increased in the context of several syndromes and redox homeostasis is vital for thyroid development and function, NNT might be a candidate gene involved in syndromic TD. Therefore, we performed target sequencing (TS) in 289 TD patients for causative mutations in NNT and conducted functional analysis of the gene mutations. TS and Sanger sequence were used to screen the novel mutations. For functional analysis, we performed western blot, measurement of NADPH/NADPtotal and H2O2 generation, cell proliferation, and wounding healing assay. As a result, three presumably pathogenic mutations (c.811G > A, p.Ala271Ser; c.2078G > A, p.Arg693His; and c.2581G > A, p.Val861Met) in NNT had been identified. Our results showed the damaging effect of NNT mutations on stability and catalytic activity of proteins and redox balance of cells. In conclusion, our findings provided novel insights into the role of the NNT isotype in thyroid physiopathology and broaden the spectrum of pathogenic genes associated with TD. However, the pathogenic mechanism of NNT in TD is still need to be investigated in further study. [ABSTRACT FROM AUTHOR]

Objective: To identify the genetic etiologies of congenital primary hypothyroidism (CH) in Thai patients. Design and methods: CH patients were enrolled. Clinical characteristics including age, signs and symptoms of CH, pedigree, family history, screened thyroid-stimulating hormone results, thyroid function tests, thyroid imaging, clinical course and treatment of CH were collected. Clinical exome sequencing by next-generation sequencing was performed. In-house gene list which covered 62 potential candidate genes related to CH and thyroid disorders was developed for targeted sequencing. Sanger sequencing was performed to validate the candidate variants. Thyroid function tests were determined in the heterozygous parents who carried the same DUOX2 or DUOXA2 variants as their offsprings. Results: There were 118 patients (63 males) included. Mean (SD) age at enrollment was 12.4 (7.9) years. Forty-five of 118 patients (38%) had disea se-causing variants. Of 45 variants, 7 genes were involved (DUOX2, DUOXA2, TG, TPO, SLC5A5, PAX8 and TSHR). DUOX2, a gene causing thyroid dyshormonogenesis, was the most common defective gene (25/45, 56%). The most common DUOX2 variant found in this study was c.1588A>T. TG and TPO variants were less common. Fourteen novel variants were found. Thyroid function tests of most parents with heterozygous state of DUOX2 and DUOXA2 variants were normal. Conclusions: DUOX2 variants were most common among Thai CH patients, while TG and TPO variants were less common. The c.1588A>T in DUOX2 gene was highly frequent in this population.

Objectives: The potential of harm to infants or their parents from a false positive (FP) newborn screening (NBS) result for congenital hypothyroidism (CH) is often cited as an argument against lowering of screening thresholds for CH. This systematic review (SR) examines the evidence of harm and factors that possibly contribute. Study Design: PRISMA guidelines were followed and the protocol was registered online (Prospero, ID CRD42019123950, 20 August 2019) before the search was conducted. Multiple electronic databases and grey literature were searched. Articles were included/excluded based on predetermined eligibility criteria. Included articles were appraised for quality, using the relevant Critical Appraisal Skills Program (CASP) tool. Data were extracted and results were tabulated and summarised as part of a narrative synthesis. Results: A total of six studies met the inclusion criteria. All were qualitative and three were based on the same cohort. Studies were published between 1983 and 1996. CASP appraisals scored 2/6 studies as moderate quality and 4/6 as low quality. Studies reported that FP results on CH screening may cause initial stress for parents and poorly defined behavioural disturbance in a small number of children, though these effects were generally not long‐lasting. Poor screening processes and inadequate communication with parents, increased the risk of harm to parents and children, from FP results. Conclusion: This SR found a small number of dated, qualitative studies of low to moderate quality, conducted soon after the initiation of NBS for CH. Conclusive evidence of the risks of harm from FP results and ways to mitigate harm, awaits further, well‐designed studies. [ABSTRACT FROM AUTHOR]

Congenital hypothyroidism (CH) is a disorder of thyroid hormone deficiency which develops secondary to incomplete thyroid development or inadequate thyroid hormone production. State-mandated newborn screening throughout the United States has increased the detection rate of CH, allowing for early intervention. Although the overall mortality rate of CH is low, delayed or omitted treatment can lead to devastating neurocognitive outcomes. As such, CH is regarded as the leading cause of preventable intellectual disability in children. Early identification, facilitated by astute neonatal nursing and medical care, is contingent upon an active working knowledge of the disease process and awareness of the limitations of the newborn screen. [ABSTRACT FROM AUTHOR]

Context: Children with congenital hypothyroidism (CH) are at risk for suboptimal neurodevelopment. Objectives: To evaluate neurocognitive function and white matter microstructure in children with permanent or transient CH and to correlate these findings with disease severity. Design, participants and methods: A retrospective and prospective observational study was conducted in 39 children with permanent or transient CH, and in 39 healthy children. Cognitive function was assessed by Wechsler Intelligence Scale, Fourth Edition, and by other tests; the white matter microstructure was investigated by 3 Tesla magnetic resonance imaging. Results: Children with permanent CH have lower cognitive scores at a median age of 9.5 years than those with transient CH and controls. An IQ score between 71 and 84 was found in 28.6% of permanent CH and of <70 (P = 0.06) in 10.7%. The Processing Speed Index (PSI; P = 0.004), sustained visual attention (P = 0.02), reading speed (P = 0.0001), written calculations (P = 0.002), and numerical knowledge (P = 0.0001) were significantly lower than controls. Children born to mothers with Hashimoto's thyroiditis have significantly lower IQ values (P = 0.02), Working Memory Index (P = 0.03), and PSI (P = 0.02). Significantly lower IQ and Verbal Comprehension Index values were found in children with a family history of thyroid disorders (P = 0.004 and P = 0.009, respectively). In children with permanent CH, significant correlations between abnormalities in white matter microstructural, clinical, and cognitive measures were documented. Conclusions: These findings indicate that children with CH are at risk of neurocognitive impairment and white matter abnormalities despite timely and adequate treatment. The association between offspring cognitive vulnerability and maternal thyroid disorders requires careful consideration. [ABSTRACT FROM AUTHOR]

Thyroglossal duct cysts, which are the most frequently encountered congenital cervical anomalies in children, occur due to embryologic remnants of the thyroglossal duct. Although diagnosis may be challenging, clinicians can be aided by imaging and fine-needle aspiration biopsies. We describe the clinical management of a two-year-old boy with a thyroglossal duct cyst mimicking a goitre on a pertechnetate thyroid scan. [ABSTRACT FROM AUTHOR]

• The estimated TTF mutation rate among CH cases was 3.63% in Henan Province. • Genetic alternations in TTF genes played a role not only in TD but also in GIS, especially in goiter. • We speculated that the five TTF genes may be involved in thyroid hormone biosynthesis. 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. High-throughput sequencing combined with statistical calculation were applied for mutation screening and analyses of the clinical data. 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 p ermanent CH (PCH) patients in the GIS group were significantly fewer than those in the TD group. 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. [ABSTRACT FROM AUTHOR]

Introduction Ectopic thyroid is a rare congenital condition. Dual ectopic thyroid is rarer still with only 30 cases reported in literature. The most common location is the lingual or sublingual region followed by the hyoid region. Instances of dual ectopic thyroid with one in lingual region and the other in mediastinum are very few. Case Report A case of dual ectopic thyroid is presented with absent normal thyroid in a girl of 14 years who presented with difficulty in swallowing and lump sensation in throat. Ultrasound, MRI scan and Technetium 99m pertechnetate thyroid scan were done. She showed lingual thyroid and thyroid tissue in upper mediastinum and no thyroid tissue in the normal anatomical location. Discussion The discovery of mediastinal ectopic thyroid was incidental. She had subclinical hypothyroidism and was treated with thyroxine replacement therapy.

Ectopic thyroid is the presence of gland at any location except for its normal position in the anterior neck in front of the trachea. It may result from an early arrest of migration or migration along an abnormal path. Ectopic thyroid in the submandibular region is relatively unusual and may or may not be accompanied with the orthotopically located thyroid gland. Pathological changes reported in the literature in the ectopic gland include goitrous change, hyperplasia, malignancy, and, rarely, inflammation. Patients usually present as a palpable, mobile, and painless mass below the lateral jaw. The important differentials include salivary gland tumor, lymphoma, inflammatory lymphadenopathy, lipoma, and cysts. Ultrasonography, radionuclide scan, computed tomography, and magnetic resonance imaging are the diagnostic modalities for documenting the presence of ectopia. Evaluation of functional status with thyroid profile and histopathological examination after fine-needle aspiration cytology directs further management. Surgical removal is the preferred treatment for ectopic thyroid. Thyroidectomy predisposes the patient to iatrogenic hypothyroidism if eutopic thyroid is absent or hypofunctioning. Such patients require lifelong thyroid replacement. However, asymptomatic cases may be managed conservatively. Ectopic thyroid in the submandibular region has important clinical implications and hence, even though rare, should be considered as one of the differentials in the patient presenting with swelling below the lateral jaw.

Background: The etiology of most cases of congenital hypothyroidism (CHT) due to thyroid dysgenesis (DG) is unknown. If transient environmental factors can impact on thyroid gland development, then clustering of cases in time and/or space may occur, and this would be more likely in thyroid DG than dyshormonogenesis (DHG). Methods: The newborn screening program for CHT in Scotland is linked to a central database that includes case details such as postcode. The etiology of CHT is investigated in many cases of CHT using scintigraphy and/or ultrasonography. We looked for evidence of a change in CHT incidence with year of birth and according to season of the year. We then undertook space–time clustering analysis (using a method based on K-functions, with nearest neighbor thresholds) of CHT in Scotland between 1979 and 2015. We also looked for evidence of overall changes associated with sex and area-based birth density. Results: Of 531 cases with CHT during the study period, 290 cases had been categorized as DG (n = 229) or DHG (n = 61) following more detailed investigation. The incidence of CHT increased with year of birth and was in part linked to changing methodology, but there was no seasonality. There was no evidence of overall space–time clustering (p = 0.06), but there was evidence of clustering in babies with DG (p = 0.007). This picture appeared to be most closely linked to underlying thyroid gland hypoplasia rather than thyroid gland agenesis or ectopia. There was significant space–time clustering for both males and females, but clustering was restricted to lesser birth density areas. There was also evidence of clustering for unknown cases (p < 0.001). Clustering of these cases was restricted to females but was present for cases from both greater and lesser birth density areas. There was no evidence of clustering in cases of DHG. Conclusions: These data suggest that an unidentified environmental factor or factors may be involved in the etiology of thyroid DG in Scotland. The variation in CHT incidence observed internationally may reflect environmental as well as genetic factors. [ABSTRACT FROM AUTHOR]

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N = 116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N = 2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla > 14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients. [ABSTRACT FROM AUTHOR]

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed RTHβ. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different THRB mutations and among tissue types in the same individual due in part to differential expression of the mutant TRβ protein. As a result, management is tailored to the specific symptoms of TH excess or deprivation encountered in the affected individual as currently there is no available therapy to fully correct the TRβ defect. This focused review aims to provide a concise update on RTHβ, discuss less well recognized associations with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease, and summarize existing evidence and controversies regarding the phenotypic variability of the syndrome. Review of management addresses goiter, attention deficit disorder and “foggy brain”. Lastly, this work covers emerging areas of interest, such as the relevance of variants of unknown significance and novel data on the epigenetic effect resulting from intrauterine exposure to high TH levels and its transgenerational inheritance.

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed RTHβ. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different THRB mutations and among tissue types in the same individual due in part to differential expression of the mutant TRβ protein. As a result, management is tailored to the specific symptoms of TH excess or deprivation encountered in the affected individual as currently there is no available therapy to fully correct the TRβ defect. This focused review aims to provide a concise update on RTHβ, discuss less well recognized associations with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease, and summarize existing evidence and controversies regarding the phenotypic variability of the syndrome. Review of management addresses goiter, attention deficit disorder and "foggy brain". Lastly, this work covers emerging areas of interest, such as the relevance of variants of unknown significance and novel data on the epigenetic effect resulting from intrauterine exposure to high TH levels and its transgenerational inheritance. [ABSTRACT FROM AUTHOR]

Background: An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary: The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions: This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition. [ABSTRACT FROM AUTHOR]

Introduction: Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and one of the most common preventable forms of mental retardation worldwide. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). TD accounts for about 65% of CH, however a genetic cause is identified in less than 5% of patients. Purpose: The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development, function and pathways. Results and conclusion: We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis, affecting 0.05–0.5% population. The aim of the study was an identification of genetic factors responsible for thyroid maldevelopment in two siblings with THA. Methods: We evaluated a three-generation THA family with two sisters presenting the disorder. Proband (Patient II:3) was diagnosed at the age of 45 due to neck asymmetry. Left lobe agenesis and nontoxic multinodular goiter were depicted. Proband's sister (Patient II:6) was euthyroid, showed up at the age of 39 due to neck discomfort and left-sided THA was demonstrated. Affected individuals were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Kit) and all identified variants were evaluated for pathogenicity. Sanger sequencing was used to confirm WES data and check segregation among first-degree relatives. Results: In both siblings, a compound heterozygous mutations NM_000168.6: c.[2179G>A];[4039C>A] (NP_000159.3: p.[Gly727Arg];[Gln1347Lys]) were identified in the GLI3 gene, affecting exon 14 and 15, respectively. According to the American College of Medical Genetics, variants are classified as of uncertain significance, and were found to be very rare (GnomAD MAF 0.007131 and 0.00003187). The segregation mapping and analysis of relatives indicated causativeness of compound heterozygosity. Conclusions: We demonstrated for the first time a unique association of THA phenotype and the presence of compound heterozygous mutations p.[Gly727Arg];[Gln1347Lys] of GLI3 gene in two siblings. [ABSTRACT FROM AUTHOR]

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Objectives: Congenital hypothyroidism (CH) is the most common endocrine disorder in neonates as well as one of the few preventable causes of severe learning difficulties. Early screening, diagnosis, and treatment are mandatory to prevent later sequelae. We sought to determine the demographic and the clinical features of CH in Oman. Methods: We conducted a retrospective cross-sectional study, including all Omani children newly diagnosed with CH from January 2004 to December 2016 followed at the National Diabetes and Endocrine Center at the Royal Hospital. Those with transient hypothyroidism were excluded from the study. Data collection involved demographic data, clinical manifestations, lab investigations, thyroid scan results, and initiation date of the thyroxine (T4). Results: A total of 96 patients were newly diagnosed with CH during the study period. Out of the 96 patients, 43 were males (44.8%), and 53 were females (55.2%), and majority were asymptotic (n = 84; 87.5%). Only 78 patients had a thyroid scan. Among those who did the scan, thyroid dysgenesis was the most common (n = 40, 51.3%), followed by dyshormonogenesis (n = 35; 44.9%) and the least was central hypothyroidism (n = 3; 3.8%). The majority of patients (n = 72; 86.7%) were started on T4 therapy within 30 days of life. The remaining (n = 11; 13.3%) had a delay in starting the treatment due to compliance issues, which led to a developmental delay (p < 0.001). Conclusions: This is the first epidemiological study conducted in Oman that highlights the unique demographic and etiology features of CH. Dyshormonogenesis has a high prevalence in the Omani population compared to other nations. The neurological sequelae in our patients were higher in compression to worldwide prevalence, which was mainly due to delay in starting T4 therapy.

Introduction Aberrant thyroid is a mass of tissue having the structure of a normal or pathological thyroid gland and situated at some definite distance from normal thyroid, with which it has no connection. The prevalance of ectopic thyroid is 1 case per 100,000- 300,000 persons1 and the incidence of aberrant thyroid in parapharyngeal space is even rarer. Materials and Methods A rare case of aberrant thyroid in parapharyngeal space is reported, which presented as oropharyngeal mass and dysphagia. She also had thyroid gland in the usual position. Result She was managed surgically with transcervical approach and was euthyroid postoperatively. Conclusion Aberrant thyroid should be one of the differential diagnoses for parapharyngeal space masses.

*Visual Abstracts prepared by Dr. Carmen Carina Cabrera Introduction. The causes of congenital hypothyroidism (CHT) are thyroid dysgenesis (TD), dyshormonogenesis (TDH)or transient (TH). Methodology. This is a cross-sectional study looking at data over a period of 16 years (2000-2016). Confirmed cases had thyroid scan at the age of 3-years-old and repeated TFT (after 6 weeks off medications). Relevant data was collected retrospectively. Results. Forty (60% female) children with CHT were included in the study. Thirty (75%) children presented with high cord TSH. Nine (23%) presented after 2 weeks of life. Majority were diagnosed with TDH (42.5%) with TD and TH of 40% and 17.5% respectively. Median cord TSH of children with TD was significantly higher compared to TDH and TH (p=0.028 and p=0.001 respectively). L-thyroxine doses were not significantly different between TD, TDH and TH at diagnosis or at 3 years. Conclusions. TDH is highly prevalent in our population. TD may present after 2 weeks of life. One in five children treated for CHT had TH. Differentiating TD, TDH and TH before initiating treatment remains a challenge in Malaysia. This study provides clinicians practical information needed to understand the possible aetiologies from a patient’s clinical presentation, biochemical markers and treatment regime. Reassessing TH cases may be warranted to prevent unnecessary treatment.

Background: Thyroid dysgenesis (TD), which is caused by gland developmental abnormalities, is the most common cause of congenital hypothyroidism (CH). In addition, advances in diagnostic techniques have facilitated the identification of mild CH patients with a gland-in-situ (GIS) with normal thyroid morphology. Therefore, TD and GIS account for the vast majority of CH cases.Methods: Sixteen known genes to be related to CH were sequenced and screened for variations by next-generation sequencing (NGS) in a cohort of 377 CH cases, including 288 TD cases and 89 GIS cases.Results: In our CH cohort, we found that DUOX2 (21.22%) was the most commonly variant pathogenic gene, while DUOXA2 was prominent in TD (18.75%) and DUOX2 was prominent in GIS (34.83%). Both biallelic and triple variants of DUOX2 were found to be most common in children with TD and children with GIS. The most frequent combination was DUOX2 with DUOXA1 among the 61 patients who carried digenic variants. We also found for the first time that biallelic TG, DUOXA2, and DUOXA1 variants participate in the pathogenesis of TD. In addition, the variant p.Y246X in DUOXA2 was the most common variant hotspot, with 58 novel variants identified in our study.Conclusion: We meticulously described the types and characteristics of variants from sixteen known gene in children with TD and GIS in the Chinese population, suggesting that DUOXA2 and DUOX2 variants may confer susceptibility to TD and GIS via polygenic inheritance and multiple factors, which further expands the genotype-phenotype spectrum of CH in China.

Abstract The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.