A case report on congenital hypothyroidism and alpha thalassemia in children with anemia and muscle damage as the main manifestation.

RATIONALE: This study reports the first case of congenital hypothyroidism (CH) and alpha thalassemia in a child in China, with anemia and muscle damage as the main manifestations. Analyzing and studying this case is of great significance in reducing missed and misdiagnosed CH and will provide a clinical strategy for treating these patients. PATIENT CONCERNS: Child, female, 2 years and 7 months old, the child appeared dispirited, had poor appetite, shallow complexion, reduced activities with anemia, elevated muscle enzymes, height, and growth retardation. DIAGNOSES: The child was diagnosed with CH with alpha thalassemia. INTERVENTIONS: The patient was treated with levothyroxine sodium and anemia correction. OUTCOMES: The children's current spirit, appetite, red face, normal limb activity, physical development, and intelligence were significantly better than those of normal children of the same age. CONCLUSIONS: CH with alpha thalassemia, especially anemia and muscle damage as the main manifestations, has not been reported. Administration of levothyroxine sodium is effective in correcting anemia in patients with CH and alpha thalassemia. LESSON: Due to CH and alpha thalassemia, there are no specific symptoms and they are prone to missed diagnosis and misdiagnosis. Therefore, patients with anemia and elevated muscle enzyme levels should be routinely tested for thyroid function to diagnose them early and provide proper treatment to avoid negative consequences.

Normal Values for the fT3/fT4 Ratio: Centile Charts (0-29 Years) and Their Application for the Differential Diagnosis of Children with Developmental Delay.

Primary congenital hypothyroidism is easily diagnosed on the basis of elevated plasma levels of thyroid-stimulating hormone (TSH). In contrast, in the rare disorders of thyroid hormone resistance, TSH and, in mild cases, also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and can have the same serious consequences for child development as congenital hypothyroidism. A total of n = 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free triiodothyronine (T3) to free thyroxine (T4), the fT3/fT4 ratio. The aim was to determine whether individuals with developmental delay and genetically confirmed thyroid hormone resistance, carrying defects in Monocarboxylate Transporter 8 (MCT8), Thyroid Hormone Receptor alpha (THRα), and Selenocysteine Insertion Sequence-Binding Protein 2 (SECISBP2), had abnormal fT3/fT4 ratios. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend using the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be easily plotted on centile charts using our free online tool, which accepts various SI and non-SI units for fT3, fT4, and TSH.

Systematic review of thyroid function in NKX2-1-related disorders: Screening and diagnosis.

BACKGROUND: NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated. OBJECTIVES: The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD. METHODS: This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers. RESULTS: Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging. CONCLUSION: This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.

Genetic etiology in patients diagnosed with congenital hypothyroidism with new-generation sequencing: A single-center experience.

AIM: Congenital hypothyroidism (CH) is the most common endocrine disorder of the newborn; it is seen in every 3000-4000 births. Genetic features can guide treatment for patients with in situ glands. The present study aimed to contribute to the literature on CH variants and to show the benefit that genetic analysis can provide to patients in follow-up. METHOD: A total of 52 patients (47 families) diagnosed with CH were included in the study. Overall, 32 target genes involved in thyroid physiology were investigated by next-generation sequencing (NGS). RESULTS: In total, 29 (55 %) of the patients were male, and the rate of dysgenesis was 19.2 %. In this study, 29 of 52 patients had at least one variant in one gene involved in CH (n = 29, 33 different variants) (Including likely benign variants and variants of unknown significance). There were 21 patients (40.3 %) with gland in situ. The most common variant was DUOX2 (20 %). The second most common variants were those in the TPO and TG genes (15 % and 15 %, respectively); 41.1 % of these were variants of uncertain significance (VUS), 26.4 % were pathogenic, 23.5 % were likely benign, and 11.7 % were likely pathogenic. On the basis of their zygosity, we identified 73.5 % heterozygous, 17.6 % homozygous, and 8.9 % combined heterozygous variants. There were mutant variants in two genes in six patients and three in one patient. CONCLUSION: This study found a variant in 55 % of the patients and shed light on the etiology of some cases of CH. The frequency of VUS was high. Although variants were identified in this study, their implication in the etiology of CH is not certain and, for most of the patients, it is also not sufficient for explaining the pathology with the current state of knowledge.

The longitudinal growth trajectory of children with congenital hypothyroidism during the first 3 years of life.

Congenital hypothyroidism (CH) is detected through a newborn screening program in Iran, enabling early detection and prompt treatment. This study addresses the longitudinal growth trajectory of Iranian children with CH and explores associated factors during the first 3 years of life. Data from 1474 children with CH in Isfahan, Iran (2002-2022), were analyzed. Weight, height, and head circumference were measured, and z-scores for age were calculated. Group-based trajectory modeling was applied to distinct growth trajectories. Factors influencing growth patterns, including gender, treatment initiation age, delivery method, parental consanguinity, history of familial hypothyroidism, and thyroid-stimulating hormone (TSH) levels at 3-7 days, were investigated. Thirty-seven percent of children diagnosed with CH faced a delay in weight, while 36.6% experienced stunted height, and 25.7% showed a retardation in head circumference growth. The initiation of treatment, parental consanguinity, and family history of hypothyroidism varied among these groups. Children exhibiting an optimal growth pattern in the initial 3 years of life demonstrated lower average TSH levels. CONCLUSION: This research emphasizes the complexity of managing CH and stresses the importance of tailoring interventions based on individualized characteristics and the ongoing growth patterns of the children. Future research is required to understand the intricate relationships between growth patterns and various determinants and optimize the growth and developmental outcomes of children with CH. WHAT IS KNOWN: • Iran has a higher prevalence of congenital hypothyroidism (CH) with a nationwide screening program. • There are concerns about delayed growth in CH children, but limited research on long-term patterns and contributing factors. WHAT IS NEW: • Distinct patterns in weight, height, and head circumference among children with CH were identified. • Factors such as consanguinity, parental hypothyroidism, and TSH levels impact growth outcomes. • CH management is complicated, and there is a need for individualized interventions.

Paediatric thyroid disease.

The spectrum of thyroid disorders presenting to paediatricians is different to that seen by adult physicians. Referrals reflect cases detected by the neonatal screening programme for congenital hypothyroidism and many of the inherited defects of thyroid hormone generation or action will be manifest in early life. Autoimmune thyroid disease can be particularly challenging to manage in the young and the potential impact of thyroid status on neurodevelopment and schooling are key considerations throughout childhood and adolescence.

Clinical efficacy of multigene panels in the management of congenital hypothyroidism with gland in situ.

Congenital hypothyroidism (CHT) is a diverse condition with various genetic etiologies. This study aimed to investigate the utility of next-generation sequencing (NGS) analysis in guiding treatment decisions and predicting prognosis for CHT patients with gland in situ (GIS). A retrospective analysis was conducted on 33 CHT patients with GIS who underwent NGS analysis at a single institution between 2018 and 2023. Patients were classified as having permanent (PCH), transient congenital hypothyroidism, or ambiguous congenital hypothyroidism (ACH) CHT based on their response to levothyroxine discontinuation at 3 years of age. Among the 33 patients, genetic variants were identified in 26, with the most prevalent variants found in DUOX2 (26.92%), TSHR (30.77%), TG (19.35%), and DUOXA2 (19.23%). Patients with high initial thyroid-stimulating hormone levels (>50 mIU/L) and low free thyroxine levels (<0.89 ng/dL) at diagnosis tended to have compound heterozygous or homozygous variants in DUOX2, DUOXA2, and TG, and were more likely to develop PCH. In contrast, patients with heterozygous variants in these genes often exhibited ACH. TSHR variants were associated with diverse clinical manifestations, ranging from PCH to ACH, and were more common in patients with initial thyroid-stimulating hormone levels <50 mIU/L. The study highlights the potential utility of NGS analysis in predicting the clinical course and guiding treatment decisions for CHT patients with GIS. Genetic analysis may aid in determining the appropriate duration of levothyroxine therapy and monitoring strategies, particularly in cases where traditional clinical indicators are inconclusive.

Insights from European Reference Network for rare neurological disorders study surveys on diagnosis, treatment, and management of NKX2-1-related disorders.

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea. OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists. METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item. RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts. CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

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.

Incidence and associated risk factors of congenital hypothyroidism among newborns in Hainan, China: a retrospective study.

OBJECTIVES: This study aims to investigate the incidence and risk factors of congenital hypothyroidism (CH) in newborns in Hainan Province, China, to provide a reference for early and effective prevention strategies. METHODS: Newborns born in Hainan Province from 2017 to 2021 were the subjects of this study. Time-resolved immunofluorescence was used for initial screening and chemiluminescence for confirmatory diagnosis. Based on the diagnosis, newborns were classified into CH and non-CH groups. Statistical analysis was conducted on the initial screening and confirmed CH cases in newborns in Hainan Province, and potential risk factors for CH were explored. RESULTS: From 2017 to 2021, a total of 585,886 newborns were screened, revealing 6,856 initial positive results, 614 positive rescreens, and 420 confirmed CH cases, yielding an incidence rate of 1/1,395 (420/585,886). The annual initial positive screening rate of newborns in Hainan Province showed a rising trend from 2017 to 2021 (p=0.000). No significant differences were found regarding gender (p=0.400) and ethnicity (p=0.836). Multivariate logistic regression analysis indicated that residing in coastal areas, especially those with salt fields (OR=2.151, 95 % CI: 1.364-3.390), was risk factors for the development of CH in newborns. CONCLUSIONS: The incidence of CH in newborns showed a year-on-year increase in Hainan Province from 2017 to 2021. Residing in coastal areas, particularly those with salt fields, was identified as a risk factor for the development of CH.

Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

Late-onset dyshormonogenic goitrous hypothyroidism due to a homozygous mutation of the SLC26A7 gene: a case report.

BACKGROUND: In this study, we used targeted next-generation sequencing (NGS) to investigate the genetic basis of congenital hypothyroidism (CH) in a 19-year-old Tunisian man who presented with severe hypothyroidism and goiter. CASE PRESENTATION: The propositus reported the appearance of goiter when he was 18. Importantly, he did not show signs of mental retardation, and his growth was proportionate. A partial organification defect was detected through the perchlorate-induced iodide discharge test. NGS identified a novel homozygous mutation in exon 18 of the SLC26A7 gene (P628Qfs*11), which encodes for a new iodide transporter. This variant is predicted to result in a truncated protein. Notably, the patient's euthyroid brother was heterozygous for the same mutation. No renal acid-base abnormalities were found and the administration of 1 mg of iodine failed to correct hypothyroidism. CONCLUSIONS: We described the first case of goitrous CH due to a homozygous mutation of the SLC26A7 gene diagnosed during late adolescence.

Newborn screening in Colombia: The experience of a private program in Bogotá / Tamizaje neonatal en Colombia: la experiencia de un programa privado en Bogotá.

Introduction. The first neonatal screening program in Colombia ­ PREGEN ­ was set up in the medical private sector of Bogotá in 1988. We report the results from recent years that, given the scarcity of similar information in our country, may help estimate the frequency of the evaluated neonatal disorders and which ones should be included in the neonatal screening programs in our country. Objective. To describe the results of PREGEN´s newborn screening program between 2006 and 2019. Materials and methods. We analyzed databases and other informative documents preserved in PREGEN from the 2006-2019 period. Results. One in every 164 newborns screened in our program had an abnormal hemoglobin variant, and one in every 194 carried some hemoglobin S variant. Glucose-6- phosphate dehydrogenase deficiency and congenital hypothyroidism are next as the more common disorders. Conclusions. Abnormal hemoglobin causes the most frequent monogenic disorder in the world. Glucose-6-phosphate dehydrogenase deficiency is the most common enzymopathy affecting nearly 400 million individuals worldwide. Since both disorders are more common in people of African descent and confer some resistance to malaria, we believe that screening for both disorders may be more relevant in the areas with African ancestry in our country.

Introducción. En Colombia, el primer programa de tamizaje neonatal, PREGEN, inició labores en el sector privado de Bogotá en 1988. En este artículo se presentan los resultados obtenidos en los últimos años, que, dada la carencia de estos estudios en el país, pueden servir para evaluar la frecuencia de aparición de los trastornos congénitos evaluados y estimar cuáles de ellos deben ser objeto de tamizaje neonatal a nivel nacional. Objetivos. Reportar los resultados del programa de tamizaje PREGEN entre el 2006 y el 2019. Materiales y métodos. Para este análisis se examinaron las bases de datos y otros documentos informativos de PREGEN para el periodo 2006-2019. Resultados. Uno de cada 164 recién nacidos tamizados en el programa PREGEN en Bogotá presentó una variante anormal de la hemoglobina y uno de cada 194 es portador de hemoglobina S. Los siguientes dos trastornos más frecuentes encontrados fueron la deficiencia de la enzima glucosa-6-fosfato deshidrogenasa (frecuencia 1:2.231) y el hipotiroidismo congénito (frecuencia 1:3.915). Conclusiones. Las hemoglobinopatías mostraron ser uno de los desórdenes monogénicos más comunes, seguidos por la deficiencia de glucosa-6-fosfato deshidrogenasa y el hipotiroidismo congénito. Se calcula que cerca de 400 millones de personas en el mundo están afectadas por la deficiencia de glucosa-6-fosfato deshidrogenasa, por lo cual es la enzimopatía más común en el mundo. Como ambos desórdenes son más frecuentes en poblaciones de origen africano y confieren algún grado de resistencia a la malaria, es de prever que su tamizaje debe ser de mayor importancia en las zonas con ancestros africanos en Colombia.

A novel useful marker in the early discrimination of transient hyperthyrotropinemia/hypothyroxinemia and congenital hypothyroidism in preterm infants: thyroid-stimulating hormone/free thyroxine ratio.

OBJECTIVES: Transient hyperthyrotropinemia/transient hypothyroxinaemia and congenital hypothyroidism (CH) have completely different treatment and clinical outcomes. However, a powerful, highly sensitive and cost-effective marker for the differentiation of these clinical entities in the early postnatal period is not available. Therefore, we aimed to test the potential, early predictive, diagnostic power of the thyroid-stimulating hormone (TSH)/free thyroxine (fT4) ratio for differentiation of the two clinical entities in the early period of life. METHODS: TSH and fT4 levels were recorded on the postnatal day 7 of premature infants<32 weeks of gestational age. TSH/fT4 ratio was calculated. The significance degree of TSH/fT4 ratio was analyzed for the differentiation of transient hyperthyrotropinemia or transient hypothyroxinaemia and CH. RESULTS: The study included 1,204 preterm infants<32 weeks of gestational age. Of the 1,204 infants, 978 (81.2 %) had normal thyroid function. Eighty-eight infants (7.3 %) were diagnosed with CH and 138 (11.5 %) with transient hyperthyrotropinemia or transient hypothyroxinemia. Initial TSH/fT4 ratio>4.8 was found to be an early diagnostic warning sign with high power in favor of transient hyperthyrotropinemia or transient hypothyroxinemia (AUC value: 0.947) and TSH/fT4 ratio>12.5 (AUC value: 0.999) was found to be an early diagnostic warning sign with high power in favor of CH (p=0.0001). CONCLUSIONS: We found for the first time that the TSH/fT4 ratio can be used for the early differentiation of transient hyperthyrotropinemia/transient hypothyroxinaemia and CH in preterm infants without additional cost and with high power.

High-resolution melt curve analysis: An approach for variant detection in the TPO gene of congenital hypothyroid patients in Bangladesh.

TPO (Thyroid Peroxidase) is known to be one of the major genes involved in congenital hypothyroid patients with thyroid dyshormonogenesis. The present study aims to validate high-resolution melting (HRM) curve analysis as a substitute method for Sanger sequencing, focusing on the frequently observed non-synonymous mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in patients from Bangladesh. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood specimens were collected, and DNA was extracted followed by PCR and Sanger sequencing. Among the 36 specimens, 20 were pre-sequenced, and variants were characterized through Sanger sequencing. Following pre-sequencing, the 20 pre-sequenced specimens underwent real-time PCR-HRM curve analysis to determine the proper HRM condition for separating the three variations from the wild-type state into heterozygous and homozygous states. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method demonstrated a sensitivity and specificity of 100 percent in accurately discerning wild-type alleles from both homozygous and heterozygous states of c.1117G>T (23/36; 63.8%), c.1193G>C (30/36; 83.3%), and c.2173A>C (23/36; 63.8%) variants frequently encountered among 36 Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach for TPO gene variant detection. In conclusion, HRM-based molecular technique targeting variants c.1117G>T, c.1193G>C, and c.2173A>C could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations in TPO gene in Bangladeshi patients with dyshormonogenesis.

Clinical and molecular analyses of isolated central congenital hypothyroidism based on a survey conducted in Japan.

Central congenital hypothyroidism (CH) can occur as an isolated deficiency or as part of combined pituitary hormone deficiency. Unlike primary CH, central CH cannot be detected by newborn screening (NBS) using dry filter paper blood TSH levels, and early diagnosis remains challenging. In this study, the clinical and genetic backgrounds of patients with isolated central CH were determined through a questionnaire-based survey among members of the Japanese Society for Pediatric Endocrinology. The known causes of isolated central CH were studied in 14 patients, including six with previously reported patient data. The results revealed IGSF1 and TBL1X pathogenic variants in nine and one patient, respectively. All six patients with low free thyroxine (FT4) levels detected in NBS carried IGSF1 pathogenic variants. Five patients with isolated central CH diagnosed after 3 months of age were variant-negative, except for one female patient with a heterozygous IGSF1 variant. Two of the four variant-negative patients and a variant-positive patient were diagnosed with pituitary hypoplasia. One and two patients with IGSF1 variant had obesity and intellectual disability, respectively. Left amblyopia was identified in the patient with a TBL1X variant. The study revalidated that IGSF1 variants comprise the most frequent pathogenic variant in patients with isolated central CH in Japan. The neonatal period is the optimal time for the diagnosis of central CH, particularly IGSF1 abnormalities, and the introduction of T4 screening should be considered in the future, taking cost-effectiveness into consideration.

High frequency of transient congenital hypothyroidism among infants referred for suspected congenital hypothyroidism from the Turkish National screening program: thyroxine dose may guide the prediction of transients.

PURPOSE: We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers in Türkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. METHODS: This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by "National Newborn Screening Program" (NNSP) who were born in 2015 and followed for 6 years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). RESULTS: Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34-38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0 µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value < 45 µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1 µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. CONCLUSION: According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0 µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45 µIU/mL as the best cut-off limits to predict TCH.

TSHR Variant Screening and Phenotype Analysis in 367 Chinese Patients With Congenital Hypothyroidism.

Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype-phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between TSHR genotypes and clinical phenotypes. Methods: In total, 367 patients with CH were recruited for TSHR variant screening using whole-exome sequencing. The effects of the variants were evaluated by in-silico programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity. Results: Among the 367 patients with CH, 17 TSHR variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic TSHR variants. In vitro experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with TSHR biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with DUOX2 biallelic variants. Conclusions: We found a high frequency of TSHR variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by TSHR biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by TSHR biallelic variants is relatively mild. Our study expands the TSHR variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.