Identification of southern Taiwan genetic variants in thyroid dyshormonogenesis through whole-exome sequencing.

Thyroid dyshormonogenesis (TDH) is responsible for 15%-25% of congenital hypothyroidism (CH) cases. Pathogenetic variants of this common inherited endocrine disorders vary geographically. Unraveling the genetic underpinnings of TDH is essential for genetic counseling and precise therapeutic strategies. This study aims to identify genetic variants associated with TDH in Southern Taiwan using whole exome sequencing (WES). We included CH patients diagnosed through newborn screening at a tertiary medical center from 2011 to 2022. Permanent TDH was determined based on imaging evidence of bilateral thyroid structure and the requirement for continuous medication beyond 3 years of age. Genomic DNA extracted from blood was used for exome library construction, and pathogenic variants were detected using an in-house algorithm. Of the 876 CH patients reviewed, 121 were classified as permanent, with 47 (40%) confirmed as TDH. WES was conducted for 45 patients, and causative variants were identified in 32 patients (71.1%), including DUOX2 (15 cases), TG (8 cases), TSHR (7 cases), TPO (5 cases), and DUOXA2 (1 case). Recurrent variants included DUOX2 c.3329G>A, TSHR c.1349G>A, TG c.1348delT, and TPO c.2268dupT. We identified four novel variants based on genotype, including TSHR c.1135C>T, TSHR c.1349G>C, TG c.2461delA, and TG c.2459T>A. This study underscores the efficacy of WES in providing definitive molecular diagnoses for TDH. Molecular diagnoses are instrumental in genetic counseling, formulating treatment, and developing management strategies. Future research integrating larger population cohorts is vital to further elucidate the genetic landscape of TDH.

Genotype-Phenotype Correlations in Thirty Japanese Patients with Congenital Hypothyroidism Attributable to TG Defects.

CONTEXT: Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS). OBJECTIVE: We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period. SUBJECTS AND METHODS: We screened 1061 patients with CH for thirteen CH-related genes and identified thirty patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into two groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the seven missense variants using HEK293 cells. RESULTS: Twenty-seven rare TG variants were detected, including fifteen nonsense, three frameshift, two splice-site, and seven missense variants. Patients were divided into two groups: thirteen patients with biallelic truncating variants and seventeen patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with TSH stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the seven missense variants was confirmed in vitro. CONCLUSION: To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement.

Contactin 6, A Novel Causative Gene for Congenital Hypothyroidism, Mediates Thyroid Hormone Biosynthesis Through Notch Signaling.

Background: Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. In patients with CH in China, thyroid dyshormonogenesis is more common than thyroid dysgenesis; however, the genetic causes of CH due to thyroid dyshormonogenesis remain largely unknown. Therefore, we aimed at identifying novel candidate causative genes for CH. Methods: To identify novel CH candidate genes, a total of 599 patients with CH were enrolled and next-generation sequencing was performed. The functions of the identified variants were confirmed using HEK293T and FTC-133 cell lines in vitro and in a mouse model organism in vivo. Results: Three pathogenic contactin 6 (CNTN6) variants were identified in two patients with CH. Pedigree analysis showed that CH caused by CNTN6 variants was inherited in an autosomal recessive pattern. The CNTN6 gene was highly expressed in the thyroid in humans and mice. Cntn6 knockout mice presented with thyroid dyshormonogenesis and CH due to the decreased expression of crucial genes for thyroid hormone biosynthesis (Slc5a5, Tpo, and Duox2). All three CNTN6 variants resulted in the blocking of the release of the Notch intracellular domain, which could not translocate into the nucleus, impaired NOTCH1 transcriptional activity, and decreased expression of SLC5A5, TPO, and DUOX2. Further, we found that DTX1 was required for CNTN6 to promote thyroid hormone biosynthesis through Notch signaling. Conclusions: This study demonstrated that CNTN6 is a novel causative gene for CH through the mediation of thyroid hormone biosynthesis via Notch signaling, which provides new insights into the genetic background and mechanisms involved in CH and thyroid dyshormonogenesis.

Outcomes of lowered newborn screening thresholds for congenital hypothyroidism.

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.

Adult Thyroid Outcomes of Congenital Hypothyroidism.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

Genetic Factors Causing Thyroid Dyshormonogenesis as the Major Etiologies for Primary Congenital Hypothyroidism: Clinical and Genetic Characterization of 33 Patients.

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.

Association of recessive c.430G>A (p.(Gly144Arg)) thyroid peroxidase variant with primary congenital hypothyroidism in cats.

BACKGROUND: Primary congenital hypothyroidism (CH) is a rare endocrine disorder in cats with a largely unknown genetic cause. OBJECTIVES: Describe the clinical presentation of CH in 11 affected cats and identify the causal genetic variant. ANIMALS: Eleven CH-cats from 10 unrelated families, 11 CH-free family members, 21 unrelated CH-free cats, and 155 unrelated nondiagnosed cats from different breeds. METHODS: Case control study of CH-cats and their siblings (2019-2021). Diagnosis was based on low to low-normal serum thyroxine (T4) concentrations, high thyroid-stimulating hormone (TSH) concentrations and clinical signs compatible with CH. We identified the causal variant using Sanger sequencing, genotyping via PCR-RFLP and variant interpretation using ACMG/AMP guidelines. RESULTS: All CH-cats (5 weeks-8 years) had disproportionate dwarfism. A goiter was not palpable in all. Thyroid scintigraphy with radiopertechnetate showed abnormally high uptake by thyroid glands, whereas scintigraphy with radioiodine showed abnormally low uptake, compatible with a defect in iodine organification by thyroid peroxidase (TPO). All cases were homozygous for TPO variant XM_006930524.4:c.430G>A(p.(Gly144Arg)), while none of the CH-free cats were. All sampled parents were heterozygous for this recessive variant. This variant was found in 15 cat breeds with an estimated allele frequency of 9%. CONCLUSIONS AND CLINICAL IMPORTANCE: Disproportionate dwarfism, abnormally high TSH and abnormally low to low-normal T4 concentrations are diagnostic for CH in cats. All cases had dyshormonogenesis demonstrated by thyroid scintigraphy. This novel TPO missense variant (not described in humans) causes CH in cats and awareness of it can assist in diagnosis and breeding.

Approach to the Patient With Congenital Hypothyroidism.

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.

Incidence tendency, etiological classification and outcome of congenital hypothyroidism in Guangzhou, China: an 11-year retrospective population-based study.

OBJECTIVES: An increased incidence of congenital hypothyroidism (CH) has been described worldwide over the years. In this study, we aimed to investigate the epidemiologic characteristics of CH, the iodine status in Guangzhou, China and to investigate which factors might influence the CH incidence during the period 2010-2020. METHODS: We retrospectively reviewed all cases of CH detected by newborn screening during the period 2010-2020. CH was classified as either suspected thyroid dyshormonogenesis (SDH) or thyroid dysgenesis (TD) based on thyroid ultrasound at first diagnosis. Patients were re-evaluated after 4 weeks of L-thyroxine withdrawal at age of 2-3 years to confirm the diagnosis of permanent CH (PCH) or transient CH (TCH). RESULTS: From 2010 to 2020, 1,655 patients with CH were confirmed from 2,400,383 newborns (1:1,450). The CH incidence increased from 1:2,584 in period [2010-2014] to 1:1,086 in period [2015-2020]. Among the 1,337 patients with thyroid ultrasound, 84.29% were SDH whereas 15.71% had TD. Further analysis revealed that more SDH (78.32%) were TCH whereas more TD (87.12%) turned to be PCH. The proportion of blood spot thyrotropin values >5 mIU/L ranged from 8.03 to 20.46%, indicating iodine deficiency. The prevalence of preterm infants increased from 5.50% in period [2010-2014] to 7.06% in period [2015-2020] (p<0.001). CONCLUSIONS: In the past decade, the CH incidence has increased progressively. SDH was the majority of CH, most of which were TCH, while most patients with TD were PCH. The increased incidence might be mainly due to iodine deficiency and increased rates of preterm infants in our study.

Goiter in a 6-year-old patient with novel thyroglobulin gene variant (Gly145Glu) causing intracellular thyroglobulin transport disorder: Correlation between goiter size and the free T3 to free T4 ratio.

Thyroglobulin gene abnormalities cause thyroid dyshormonogenesis. A 6-yr-old boy of consanguineous parents presented with a large goiter and mild hypothyroidism (thyroid-stimulating hormone [TSH] 7.2 µIU/mL, free T3 [FT3] 3.4 pg/mL, free T4 [FT4] 0.6 ng/dL). Despite levothyroxine (LT4) administration and normal TSH levels, the goiter progressed slowly and increased rapidly in size at the onset of puberty. Thyroid scintigraphy revealed a remarkably high 123I uptake of 75.2%, with a serum thyroglobulin level of 13 ng/ml, which was disproportionately low for the goiter size. DNA sequencing revealed a novel homozygous missense variant, c.434G>A [p.Gly145Glu], in the thyroglobulin gene. Goiter growth was suppressed by increasing the LT4 dose. Thyroidectomy was performed at 17-yr-of-age. Thyroglobulin analysis of the thyroid tissue detected mutant thyroglobulin present in the endoplasmic reticulum, demonstrating that thyroglobulin transport from the endoplasmic reticulum to the Golgi apparatus was impaired by the Gly145Glu variant. During the clinical course, an elevated FT3/FT4 ratio was observed along with thyroid enlargement. A high FT3/FT4 ratio and goiter seemed to be compensatory responses to impaired hormone synthesis. Thyroglobulin defects with goiter should be treated with LT4, even if TSH levels are normal.

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect.

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.

Genetics of congenital hypothyroidism: Modern concepts.

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.

Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

PURPOSE: Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). METHODS: Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. RESULTS: Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively. CONCLUSIONS: 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

Clinical characteristics and genetics analysis for the ITD of congenital hypothyroidism.

OBJECTIVES: Iodide transport defect (ITD) is one of the principal causes of congenital hypothyroidism (CH) and its primary molecular mechanism is a mutation of the sodium/iodide symporter (NIS) gene. This study aims to analyse the clinical characteristics and genetic mutations of ITD. METHODS: The participants were a pair of siblings diagnosed with congenital hypothyroidism. Inductively coupled plasma mass spectrometry was used to determine the concentration of salivary iodine and serum iodine and to calculate their ratio. At the same time, next-generation sequencing (NGS) was applied to detect all exons of congenital hypothyroidism-related genes. All suspicious variants were further validated in the patients and their parents by PCR and Sanger sequencing. RESULTS: Both patients were conclusively diagnosed with thyroid iodine transport defect (ITD). NGS identified two variants of the NIS gene in the siblings: c.1021G>A (p.Gly341Arg) with paternal origin and c.1330-2A>C with maternal origin. Both of these variants have not been reported to date. They are predicted to be pathogenic based on these clinical symptoms and comprehensive software analysis. CONCLUSIONS: This is the first reported family study of congenital hypothyroidism with SLC5A5 mutation in China. Next-generation sequencing technology is an effective means of studying the genetics of congenital hypothyroidism. The therapeutic effect of potassium iodide needs to be further evaluated.

Insights of Noncanonical Splice-site Variants on RNA Splicing in Patients With Congenital Hypothyroidism.

CONTEXT: Congenital hypothyroidism (CH) is caused by mutations in the genes for thyroid hormone synthesis. In our previous investigation of CH patients, approximately 53% of patients had mutations in either coding exons or canonical splice sites of causative genes. Noncanonical splice-site variants in the intron were detected but their pathogenic significance was not known. OBJECTIVE: This work aims to evaluate noncanonical splice-site variants on pre-messenger RNA (pre-mRNA) splicing of CH-causing genes. METHODS: Next-generation sequencing data of 55 CH cases in 47 families were analyzed to identify rare intron variants. The effects of variants on pre-mRNA splicing were investigated by minigene RNA-splicing assay. RESULTS: Four intron variants were found in 3 patients: solute carrier family 26 member 4 (SLC26A4) c.1544+9C>T and c.1707+94C>T in one patient, and solute carrier family 5 member 5 (SLC5A5) c.970-48G>C and c.1652-97A>C in 2 other patients. The c.1707+94C>T and c.970-48G>C caused exons 15 and 16 skipping, and exon 8 skipping, respectively. The remaining variants had no effect on RNA splicing. Furthermore, we analyzed 28 previously reported noncanonical splice-site variants (4 in TG and 24 in SLC26A4). Among them, 15 variants (~ 54%) resulted in aberrant splicing and 13 variants had no effect on RNA splicing. These data were compared with 3 variant-prediction programs (FATHMM-XF, FATHMM-MKL, and CADD). Among 32 variants, FATHMM-XF, FATHMM-MKL, and CADD correctly predicted 20 (63%), 17 (53%), and 26 (81%) variants, respectively. CONCLUSION: Two novel deep intron mutations have been identified in SLC26A4 and SLC5A5, bringing the total number of solved families with disease-causing mutations to approximately 45% in our cohort. Approximately 46% (13/28) of reported noncanonical splice-site mutations do not disrupt pre-mRNA splicing. CADD provides highest prediction accuracy of noncanonical splice-site variants.

Screening of 23 candidate genes by next-generation sequencing of patients with permanent congenital hypothyroidism: novel variants in TG, TSHR, DUOX2, FOXE1, and SLC26A7.

PURPOSE: To date, many genes have been associated with congenital hypothyroidism (CH). Our aim was to identify the mutational spectrum of 23 causative genes in Turkish patients with permanent CH, including thyroid dysgenesis (TD) and dyshormonogenesis (TDH) cases. METHODS: A total of 134 patients with permanent CH (130 primary, 4 central) were included. To identify the genetic etiology, we screened 23 candidate genes associated with CH by next-generation sequencing. For confirmation and to detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. RESULTS: Possible pathogenic variants were found in 5.2% of patients with TD and in 64.0% of the patients with normal-sized thyroid or goiter. In all patients, variants were most frequently found in TSHR, followed by TPO and TG. The same homozygous TSHB variant (c.162 + 5G > A) was identified in four patients with central CH. In addition, we detected novel variants in the TSHR, TG, SLC26A7, FOXE1, and DUOX2. CONCLUSION: Genetic causes were determined in the majority of CH patients with TDH, however, despite advances in genetics, we were unable to identify the genetic etiology of most CH patients with TD, suggesting the effect of unknown genes or environmental factors. The previous studies and our findings suggest that TSHR and TPO mutations is the main genetic defect of CH in the Turkish population.

Brief Report: A Novel Sodium/Iodide Symporter Mutation, S356F, Causing Congenital Hypothyroidism.

The sodium-iodide symporter (NIS, SLC5A5) is expressed at the basolateral membrane of the thyroid follicular cell, and facilitates the thyroidal iodide uptake required for thyroid hormone biosynthesis. Biallelic loss-of-function mutations in NIS are a rare cause of dyshormonogenic congenital hypothyroidism. Affected individuals typically exhibit a normally sited, often goitrous thyroid gland, with absent uptake of radioiodine in the thyroid and other NIS-expressing tissues. We report a novel homozygous NIS mutation (c.1067 C>T, p.S356F) in four siblings from a consanguineous Indian kindred, presenting with significant hypothyroidism. Functional characterization of the mutant protein demonstrated impaired plasma membrane localization and cellular iodide transport.

Intra-amniotic levothyroxine infusions in a case of fetal goiter due to novel Thyroglobulin gene variants.

Indications and administration of intra-amniotic infusions of L-thyroxine in the context of non-immune fetal hypothyroidism with goiter lack of standardization. Systematic follow-up of clinical features related to thyroid hormonal homeostasis may be useful to evaluate their efficiency and develop standardized management guidelines.

Long-Term Outcome of Patients with TPO Mutations.

INTRODUCTION: Thyroid peroxidase (TPO) deficiency is the most common enzymatic defect causing congenital hypothyroidism (CH). We aimed to characterize the long-term outcome of patients with TPO deficiency. METHODS: Clinical and genetic data were collected retrospectively. RESULTS: Thirty-three patients with primary CH caused by TPO deficiency were enrolled. The follow-up period was up to 43 years. Over time, 20 patients (61%) developed MNG. Eight patients (24%) underwent thyroidectomy: one of them had minimal invasive follicular thyroid carcinoma. No association was found between elevated lifetime TSH levels and the development of goiter over the years. CONCLUSIONS: This cohort represents the largest long-term follow up of patients with TPO deficiency. Our results indicate that elevated TSH alone cannot explain the high rate of goiter occurrence in patients with TPO deficiency, suggesting additional factors in goiter development. The high rate of MNG development and the risk for thyroid carcinoma indicate a need for long-term follow up with annual ultrasound scans.

Transient congenital hypothyroidism - too short to be transient.

Congenital hypothyroidism (CH) occurs due to thyroid dysgenesis, thyroid ectopy, and dyshormonogenesis. A proportion of CH is transient which might be due to iodine deficiency/excess or maternal antibody-mediated. Certain forms of dyshormonogenetic defects may cause transient hypothyroidism. Here is a report of a neonate with overt clinical and biochemical hypothyroidism, who on evaluation was found to have dyshormonogenesis with a homozygous mutation in dual oxidase 2 (DUOX2) gene. During infancy, she became euthyroid. Severe in utero deficiency of thyroid hormone, very short duration of hypothyroidism and first-reported mutation of the DUOX2 gene in the Indian subcontinent were interesting features in this infant.