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Objective: The Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. Design & methods: NBS data and parameters of CH patients and false-positive referrals in the period 2007–2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. Results: Variables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. Conclusions: Machine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.

• An understanding of thyroid embryogenesis and the physiology of the thyroid gland in the perinatal period is important for proper interpretation of abnormal laboratory results and initiation of appropriate treatment. • Appropriate thyroid hormone function is essential for normal neurodevelopment in infancy and childhood. Hypothyroidism in the first year of life can result in significant deleterious effects on growth and neurologic injury. • Delay in treatment of congenital hypothyroidism (CH) is the most common preventable cause of mental retardation. • Neonatal screening can provide early diagnosis and can prevent delays in treatment. Newborn screening methods differ and may possibly miss rare forms of congenital hypothyroidism. • Eighty-five percent of cases of permanent CH are associated with abnormal development of the thyroid gland. • In preterm newborns, thyroid hormone levels may fall because of immaturity of the thyroid gland, but these changes may be exacerbated by complications of prematurity. • Thyroid metabolism can be affected by exogenous sources of iodine, dopamine infusions, blood transfusion, and glucocorticoid treatment. • The clinical manifestations of Graves disease in the newborn include irritability, flushing, diarrhea, vomiting, tachycardia, hypertension, poor weight gain, thyroid enlargement, and exophthalmos. • There is concern for neurologic damage in infants with hemangiomas when hypothyroidism is occult and untreated.

Congenital hypothyroidism (CH) is a common heterogeneous endocrine disorder. The thyroid-stimulating hormone receptor gene (TSHR) is one of the major candidate genes associated with CH. Studies have investigated the possible correlations between the specific clinical features and the presence of TSHR variants. However, only a few reports have focused on the long-term follow-up of patients with CH. Here we present a case of CH-associated TSHR p.Arg109Gln and p.Arg450His rare compound heterozygous variants, with a follow-up performed until adolescence. The patient had high serum TSH levels during newborn screening. Oral administration of levothyroxine (l-T4) was initiated at 1 month of age. The ultrasonogram revealed normal thyroid morphology and blood flow. Reduced uptake of I-123 and negative perchlorate test was observed. A small amount of l-T4 remained needed although l-T4 could be steadily reduced by puberty. The patient was diagnosed with orthotopic, nongoitrous, and permanent CH. He had no nonclassical TSH resistance. Patients with the TSHR p.Arg109Gln compound heterozygous variant exhibit permanent CH with high TSH levels and normal or slightly lower fT4 levels. In the future, genotype identification could help predict the long-term prognosis and reduce the requirement for detailed examinations. More case studies are needed to determine the relationship between genetic variants and clinical features in CH., This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Pseudohypoparathyroidism type 1A (PHP1A) is a disorder of multiple hormone resistance, mainly parathyroid hormone. It is associated with Albright hereditary osteodystrophy phenotypes. Patients with PHP1A may initially present with hypothyroidism during infancy and later develop typical PHP1A characteristics during their childhood. Central precocious puberty (CPP) is extremely rare among PHP1A patients in whom gonadotropin resistance is more usual. This study reported a 9.5-year-old boy with congenital hypothyroidism who developed hypocalcemia secondary to pseudohypoparathyroidism. He had relatively short stature with height standard deviation score of -0.9. Obesity had been noted since the age of 2 years. At the presentation of pseudohypoparathyroidism, pubertal-sized testes of 10 mL were observed, and CPP was documented with serum testosterone concentration of 298 ng/dL (normal for Tanner stage III, 100-320), luteinizing hormone of 3.9 IU/L (normal, 0.2-5.0), and follicle-stimulating hormone of 4.8 IU/L (normal, 1.2-5.8). Pituitary magnetic resonance imaging was unremarkable. Genetic analysis confirmed the diagnosis of PHP1A with a novel heterozygous missense variant of GNAS gene in the exon 13, c.1103A>G (p.Asp368Gly). Awareness of PHP1A diagnosis in patients with congenital hypothyroidism and early childhood-onset obesity is crucial for early diagnosis. Apart from multiple hormone resistance, CPP could be manifested in patients with PHP1A.

Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation.Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT40.8 ng/dL and/or TSH5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated.Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight.This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates.

Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH−/−) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/− mice born to TRH+/− or TRH−/− dams, and conducted S/M-opsin analysis in TRH+/+ or TRH−/− mice born to TRH+/− dams at P12, P17, and P30. M-opsin expression was lower in TRH+/− mice born to TRH−/− dams than in those born to TRH+/− dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH−/− mice born to TRH+/− dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH−/− mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.

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.

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.

We report a 10-month-old girl with familial congenital hypothyroidism harboring a novel heterozygous pathogenic variant in the paired DNA-binding domain of

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 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.

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Congenital Hypothyroidism (CH) due to dyshormonogenesis may occur due to mutations in any of the key genes involved in thyroid hormone biosynthesis (TG, TPO, DUOX2, DUOXA2, SLC5A5, IYD, SLC26A4 and SLC26A7). Mutations in the Thyroglobulin gene (TG) are frequently associated with goiter, which may present fetally or neonatally, although a spectrum of phenotypes is reported. We present the case of a woman of Eritrean origin who presented in the third trimester of pregnancy in the early stages of labor. Ultrasound at presentation revealed a fetal neck swelling consistent with a goiter. Following delivery by caesarian section with minimal respiratory support, the infant was found to be hypothyroid with undetectable serum levels of thyroglobulin. Sequencing of the thyroglobulin gene revealed a homozygous donor splice site pathogenic variant (c.5686+1delG) not previously described in the literature. Levothyroxine treatment resulted in normal growth and psychomotor development. Goitrous CH with inappropriately low thyroglobulin has previously been reported in patients harbouring homozygous single nucleotide substitutions at the same TG donor splice site which result in exon skipping and Endoplasmin Reticulum retention of TG. We conclude that the TG c.5686+1delG pathogenic variant is the likely basis for our patient's fetal goiter and congenital hypothyroidism, and that the clinical phenotype associated with TG c.5686+1delG is comparable to that seen with single nucleotide substitutions at the same site.

OBJECTIVE: : To investigate molecular and clinical characteristics of children with permanent congenital hypothyroidism (CH) in Yunnan, China. METHODS: : The clinical data of 40 children with CH diagnosed and treated in the First People’s Hospital of Yunnan Province during January 2016 and January 2019 were retrospectively analyzed. All children were followed up to 3 years old, and Gesell intelligent score was evaluated at age of 1, 2 and 3 years, respectively. Developmental status and prognosis were evaluated. Next-generation sequencing (NGS) was used to screen all exons and exon-intron boundary sequences of the 27 known CH associated genes, and the relationship between genotypes and clinical phenotypes was analyzed. RESULTS: : Among the 40 children, the thyroid related pathogenic gene mutations were detected in 23 cases with a rate of 57.5%, and a total of 32 mutations of 8 genes were detected. Mutations in DUOX2, TPO and TSHR genes were the most common ones with mutation frequencies of 65.9%(29/44), 11.4%(5/44) and 9.1%(4/44), respectively. DUOX2 gene mutations were detected in 17 children with CH, and a total of 17 mutation types were detected. p.K530* was the most common mutation in DUOX2 gene, accounting for 20.7%(6/29). There was no significant difference in physical development and intelligence assessment between children with DUOX2 heterozygous mutation and compound heterozygous mutations. None of patients could terminate medication at 3 years of the follow-up and all of them were provisionally assessed as permanent CH. The physical and mental development assessment of children with other gene mutations were also in the normal range. CONCLUSION: : The detection rate of DUOX2, TPO and TSHR pathogenic mutations are high among children with permanent CH in Yunnan area, and no correlation is observed between gene mutation types and prognosis in children with CH.

Neonatal screening for congenital hypothyroidism (CH) is based on the measurement of thyroid-stimulating hormone (TSH) in whole dried blood samples on filter paper in all newborns. The objective of screening for CH is to prevent mental retardation, which is irreversible in the event of a late diagnosis, by setting up prompt treatment (before day 15) with levothyroxine. The threshold value of TSH on filter paper on day 3 is 17 mIU/L in France in the GSP method (GSP, Genetic Screening Processor, Perkin Elmer): It is one of the highest thresholds used in the world. In many countries, the TSH threshold is between 6 and 12 mIU/L. Studies have found that a threshold of17 mIU/L may miss as much as 30% of cases of CH, with 30-80% of these being permanent CH. Recent studies suggest that mild CH (currently missed by the French TSH threshold) is associated with cognitive consequences if left untreated. An inverse relationship between TSH at screening (below the current threshold) and cognitive development at preschool or school age has been shown. These studies advocate for the evaluation of a lowering of the threshold of TSH on filter paper in France: (a) to determine the number of CH diagnoses with the new threshold and whether these "new cases" would be transitory or permanent; and (b) to analyze the cost-effectiveness of the strategy.

To understand differences in thyroid hormone replacement therapy with levo-thyroxine (l-T4) between acquired and congenital hypothyroid (CH) patients.We compared biochemical thyroid parameters between euthyroid subjects (EU) and both CH adult patients and thyroidectomized patients (TP) under replacement therapy.A retrospective analysis was performed on a series of 98 consecutive adult CH patients (27 males and 71 females) with a median age of 24 years (range 18-58). Serum TSH, FT3, FT4, l-T4 dose and body weight were assessed. For comparison purposes, large series of 461 TP for thyroid cancer and 1852 EU followed at our Thyroid Clinic were used as control groups.The daily weight-based l-T4 dose was significantly higher in CH than TP group (1.9 vs. 1.7 mcg/kg, p = .03). FT3/FT4 ratio was significantly higher in the EU group, intermediate in CH and lower in TP groups (0.32, 0.28 and 0.24, respectively). Linear regression analysis displayed an inverse correlation between FT4 and TSH in all the groups. An inverse correlation between FT3 and TSH was observed in the TP group, but not in the EU and CH group suggesting that CH patients, under replacement therapy, display biochemical thyroid parameters similar to EU subjects.Adult CH patients require a higher daily l-T4 dose than adult TP. However, the different correlation of TSH and FT3 values between CH and TP patients suggests an adaptive and different hypothalamic-pituitary-thyroid axis regulation that may depend on the early timing of the onset of hypothyroidism in CH.

The present study aimed to investigate the expression, role, and underlying mechanism of action of sirtuin 1 (SIRT1) in congenital hypothyroidism (CH). A CH model was established in rats, and neuronal cells were isolated from the hippocampal tissues of normal rats. Free thyroxine (fT4) and thyroid-Stimulating hormone (TSH) concentrations were determined to confirm CH model conduction. The cognitive behavior of rats with CH was examined using open field and forced swimming tests. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression levels of SIRT1, p53, B-cell lymphoma-extra-large (Bcl-xl), Bcl-2-associated X (Bax), and cytochrome c in the hippocampal tissues and neuronal cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry were performed to evaluate cell viability and apoptosis, respectively. The results revealed that SIRT1 was expressed at low levels in the hippocampal tissues of rats with CH. Moreover, overexpression of SIRT1 in the hippocampal tissues of rats with CH and improved rat behavior, while reducing the CH-induced nerve cell apoptosis. In addition, this overexpression increased the viability, inhibited apoptosis, and reduced the expression of p53, Bax, and cytochrome c, while increasing the expression of Bcl-xl in cultured neurons. In contrast, SIRT1-small interfering RNA exhibited the opposite effects in cultured neurons. In conclusion, SIRT1 plays a role in the occurrence and development of CH by regulating nerve cell apoptosis.

BACKGROUND: The human adrenal cortex undergoes several rapid remodeling steps during its lifetime. In rodents, similar remodeling occurs postnatally in the “X-zone” layer through unknown mechanisms. Furthermore, little is known regarding the impact of thyroid hormone (TH) on adrenal glands in humans. METHODS: To investigate the impact of TH on adrenal pathophysiology, we created two genetic murine models mimicking human nonautoimmune hypothyroidism and hyperthyroidism. Moreover, we analyzed serum thyrotropin (TSH) and steroid hormone concentrations in patients diagnosed with congenital hypothyroidism and premature adrenarche (PA). RESULTS: We found that TH receptor beta-mediated hypertrophy of the X-zone significantly elevated the adrenal weights of hyperthyroid women. In the hypothyroid model, the X-zone was poorly developed in both sexes. Moreover, large reciprocal changes in the expression levels of genes that regulate adrenal cortical function were observed with both models. Unexpectedly, up- and downregulation of several genes involved in catecholamine synthesis were detected in the adrenal glands of the hypothyroid and hyperthyroid models, respectively. Furthermore, TSH and adrenal steroid concentrations correlated positively in pediatric patients with congenital hypothyroidism and PA. CONCLUSIONS: Our results revealed that congenital hypothyroidism and hyperthyroidism functionally affect adrenal gland development and related steroidogenic activity, as well as the adrenal medulla.

BACKGROUND: Multinodular goiter (MNG) is the most common disorder of the thyroid gland. Aging and genetic mutations that impair thyroid hormone (TH) production have been implicated in the development of MNG. XB130 is an adaptor/scaffold protein predominantly expressed in the thyroid gland. XB130 deficiency leads to transient postnatal growth retardation in mice due to congenital hypothyroidism. We studied the formation of MNG and possible mechanisms in elderly mice. METHODS: Thyroid glands of male and female Xb130-knockout (Xb130(−/−)), heterozygous (Xb130(+/−)), and wild-type (Xb130(+/+)) mice at the ages of 12–20 months were harvested for visual examination, histopathological, and immunohistological analyses. Blood and thyroid samples were collected after feeding elderly mice with a low iodine diet for (125)I uptake and perchlorate discharge assay. The activity of thyroperoxidase (Tpo) was examined by spectrophotometric evaluation of iodide oxidation. RESULTS: While moderate MNG was seen in Xb130(+/+) and Xb130(+/−) mice, severe MNG, characterized by multiple nodules intermixed with dilated colloid-rich macrofollicles, was found only in Xb130(−/−) mice at 18 months. Thyrocyte cytoskeletal structure and cell adhesion molecules were disorganized, and TH production was significantly reduced. Reduced iodide organification was seen in elderly Xb130(+/+) mice and further enhanced in Xb130(−/−) mice. In Xb130(+/+) mice, Tpo shows high affinity with hydrogen peroxide (H(2)O(2)) throughout aging, but reduced affinity with iodide in an age-dependent manner. By contrast, in elderly Xb130(−/−) mice, the affinity of Tpo for iodide remained high, but the affinity of Tpo for H(2)O(2) was reduced. CONCLUSIONS: The pathophysiological features in the thyroid glands of aged Xb130(−/−) mice closely resemble the features of MNG in humans. Moderate MNG in elderly mice was dramatically aggravated by XB130 deficiency. Reduced affinity of Tpo for H(2)O(2) may contribute to MNG development via oxidative stress. This could be specific to XB130 deficiency but also could be a common mechanism in MNG. Its clinical relevance should be further investigated.

Objective Defects in the human solute carrier family 26 member 4 (SLC26A4) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC26A4 mutations in Chinese patients with CH and analyze the function of the mutations. Methods 273 patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of SLC26A4 were found and analyzed. The function of 6 missense mutation in SLC26A4 were further investigated in vitro. Results Among 273 patients with CH, 7 distinct SLC26A4 heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H,p.H723R affect the membrane location and ion transport of SLC26A4, ,while p.S49R did not.Mutation p.T485M and p.D661E only affect the ion transport, but has no effect on the membrane location. Conclusion Our study indicated that the prevalence of SLC26A4 mutations was 3.66% in the Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of SLC26A4，which revealed important role of the Ile363,Arg409, Thr485, Asp661, His723 residues in function of SLC26A4. Because these mutations are heterozygous mutations, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study.

We report a patient with congenital hypothyroidism due to athyreosis complicated by a heterozygous thyroid hormone receptor beta (THRβ) gene mutation (R320L), resulting in a severe resistance to thyroid hormone beta phenotype. The proband inherited the mutant allele from his father, presenting a very mild phenotype. While the precise reason for this discrepancy remains unknown, we postulate the possibility of de novo mutation and mosaicism in the father. Correlating thyrotropin (TSH) with free thyroxine (fT4) allowed us to predict the amount of fT4 required to normalize the proband's TSH, which supported the treatment with high dose of levothyroxine.

Family history of thyroid disease (FHTD) constitutes a possible risk factor for congenital hypothyroidism (CH) in the general population; however, FHTD possible relationship with CH in subjects with Down syndrome (DS) has not yet been explored.To determine whether FHTD is associated with an increased incidence of CH in neonates with DS.Hospital-based case-control study in 220 neonates with DS. Thyroid function tests of 37 infants with DS and positive FHTD (cases) were compared with those of 183 newborns with DS without FHTD (control group). Data were analyzed using multivariate logistic regression analysis and adjusted odds ratios (aORs) with their respective 95 % confidence intervals (CI) were calculated.Nine newborns with DS in our sample had CH (4.1 %). In the multivariate analysis, FHTD showed an association with CH in neonates with DS (aOR = 8.3, 95 % CI: 2.0-34.3), particularly in males (aOR = 9.0, 95 % CI: 1.6-49.6). In contrast, newborns with DS without FHTD were less likely to suffer from CH (aOR = 0.4, 95 % CI: 0.1-0.8).Newborns with DS and FHTD have an eight-fold higher risk for CH, particularly when the index case is male. FHTD detailed evaluation can be an easy and accessible strategy to identify those newborns with DS at higher risk for CH.La historia familiar de enfermedad tiroidea (HFET) como factor de riesgo para hipotiroidismo congénito (HC), en síndrome de Down (SD) aún no ha sido explorada.Determinar si la HFET está asociada a mayor riesgo de HC en neonatos con SD.Estudio de casos y controles en 220 neonatos con SD. Se compararon las pruebas de función tiroidea (PFT) de 37 con SD e HFET (casos), frente a las PFT de 183 recién nacidos con SD sin HFET (grupo de referencia). Se realizó análisis de regresión logística multivariante y se calculó la razón de momios (RM) y sus respectivos intervalos de confianza del 95 % (IC 95 %).Nueve casos HC (4.1 %). El HC mostró asociación con la HFET (RMa = 8.3, IC 95 %: 2.0-34.3), particularmente en los varones (RMa = 9.0, IC 95 %: 1.6-49.6). La ausencia de HFET tuvo una RM de protección para HC (RMa = 0.4, IC 95 %: 0.1-0.8).La HFET puede es una estrategia fácil y accesible para identificar pacientes con SD con mayor riesgo de HC.

BACKGROUND: The frequency of ectopia of thyroid gland among all types of dysgenesis varies from 30 to 70%, its most common localization is the root of the tongue. Otorhinolaryngologists, oncologists, pediatricians can take lingual ectopia for hypertrophy of the lingual tonsil or fibroma of the tongue root, which leads to unreasonable surgical treatment. Thyroid scintigraphy plays a key role in the diagnosis of ectopia.AIM: To assess the etiological structure of congenital hypothyroidism (CH) and demonstrate the clinical course in patients with ectopic thyroid tissue in the root of the tongue.MATERIALS AND METHODS: A group of patients with CH was examined. All patients underwent neck ultrasound and radionuclide imaging. The examination was carried out against the background of the abolition of hormone replacement therapy for 14 days or before its initiation. Patients with ectopia in the root of the tongue underwent videofibrolaryngoscopy. Some patients underwent a genetic study with using genes panel of a panel of candidate genes responsible for the development of CH using the NGS method. The molecular genetic study was conducted to some patients, next-generation sequencing with the genes panel.RESULTS: The study included 73 patients with primary CH aged from 2 weeks to 17.3 years: 69 children were diagnosed based on the results of neonatal screening, 4 children with thyroid ectopia were first examined older than 6 years. The median age of patients at the time of the examination was 6.9 years [4.8; 10.0]. By data of ultrasound aplasia was diagnosed in 47.9% of patients, one child had hemiagenesis and ectopic thyroid tissue of various localization was detected in 26.0% of children. In 24.7% of children thyroid tissue was found in a typical location. Scintigraphy confirmed thyroid aplasia in 65.7% of children. Examination revealed various variants of ectopically located thyroid tissue in 31 children (42.4%): thyroid ectopia in the root of the tongue in 25 children (80.6%), ectopia in the sublingual region in 5 children (16.2%), double ectopia was detected in 1 child. The median level of TSH in newborns with ectopic thyroid gland was 124 IU/ml and was significantly lower than in children with aplasia — 219 IU/ml, pCONCLUSION: Combination of two methods is the best diagnostic approach to determine the etiology of CH — ultrasound and scintigraphy studies compensates deficiencies of each other. Our study demonstrates the importance of scintigraphy in children with CH and patients with the formation of the root of the tongue and the anterior surface of the neck in order to avoid unnecessary removal of the thyroid gland. In case of confirmation of thyroid ectopia in the root of the tongue and in the absence of symptoms of obstruction or bleeding, it is recommended to refer the patient to an endocrinologist for conservative treatment.

Congenital hypothyroidism is an important issue of pediatric endocrinology at which timely diagnosis and treatment can prevent the development of severe cases of the disease. The developed clinical guidelines are a working tool for a practicing physician. The target audience is pediatric endocrinologists and pediatricians. They briefly and logically set out the main definition of the disease, epidemiology, classification, methods of diagnosis and treatment, based on the principles of ­evidence-based medicine.

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.

Background Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population. Methods We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes. Results PKHD1 pathogenic variants were identified in 32 patients (0–46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1–2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities. Conclusion Clinical manifestations ranged from cases of neonatal demise to those diagnosed in adulthood. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival.

Benign hereditary chorea (BHC) is a rare genetically heterogeneous movement disorder, in which conventional neuroimaging has been reported as normal in most cases. Cystic pituitary abnormalities and features of empty sella have been described in only 7 patients with BHC to date. We present 4 patients from 2 families with a BHC phenotype, 3 of whom underwent targeted pituitary MR imaging and genetic testing. All four patients in the two families displayed a classic BHC phenotype. The targeted pituitary MR imaging demonstrated abnormal pituitary sella morphology. Genetic testing was performed in three patients, and showed mutations causing BHC in three of the patients, as well as identifying a novel nonsense mutation of the TITF1/NKX2-1 gene in one of the patients. The presence of the abnormal pituitary sella in two affected members of the same family supports the hypothesis that this sign is a distinct feature of the BHC phenotype spectrum due to mutations in the TITF1 gene. Interestingly, these abnormalities seem to develop in adult life and are progressive. They occur in at least 26% of patients affected with Brain-lung-thyroid syndrome. As a part of the management of these patients we recommend to perform follow-up MRI brain with dedicated pituitary imaging also in adult life as the abnormality can occur years after the onset of chorea.

Several factors may influence newborn thyroid-stimulating hormone (TSH) concentrations and cause subclinical hypothyroidism in a newborn. A sufficient level of leptin signalling is needed for the normal production of TSH and thyroid hormones by the thyroid gland. Our study aimed to investigate the correlation between maternal serum leptin concentration during the third trimester of pregnancy and newborn screening-TSH levels.This prospective cross-sectional study was conducted in obstetrics and gynaecology clinics of a state hospital between June and August 2013. Maternal venous blood samples were collected from 270 healthy pregnant women in the third trimester just before delivery. Measurements of maternal fT3, fT4, TSH, anti-thyroid peroxidase (TPO), and anti-thyroglobulin (anti-Tg) antibodies from serum samples were performed by chemiluminescence immunoassay. Maternal serum leptin levels were determined by ELISA. Dried capillary blood spots were used to measure newborn TSH levels.Subjects were divided into two groups according to the neonatal TSH levels using a cut-point of 5.5 mIU/L. Median maternal serum leptin levels were significantly higher in newborns whose TSH levels were higher than5.5 mIU/L [13.2 μg/L (1.3 - 46.5) vs 19.7 μg/L (2.4 - 48.5), p0.05]. Serum leptin levels showed a negative correlation with maternal fT4 (r=0.32, p0.05), fT3 (r=0.23, p0.05), and a positive correlation with BMI (r=0.30, p0.05).Our results suggest that high leptin levels in the third trimester of pregnancy influence maternal thyroid functions and might cause an increase in newborn TSH levels. Detection of high maternal serum leptin levels may be a reason for subclinical hypothyroidism.Postoji nekoliko faktora koji mogu uticati na koncentraciju tiroidno-stimulišućeg hormona (TSH) kod novo - rođenčadi i na izazivanje subkliničkog hipotiroidizma. Da bi štitna žlezda normalno proizvodila TSH i tiroidne hormone potreban je dovoljan nivo signalizacije leptina. U našoj studiji smo želeli da istra'imo korelaciju između koncentracije serumskog majčinskog leptina tokom trećeg trimestra trudnoće i nivo TSH na skriningu kod novo rođenčadi.Ova prospektivna studija preseka sprovedena je na akušersko-ginekološkim klinikama jedne dr'avne bolnice u periodu od juna do avgusta 2013. Uzorci venske krvi majki prikupljeni su od 270 zdravih trudnica u trećem tromesečju neposredno pre porođaja. Merenje majčinskih fT3, fT4, TSH, antitireoidnih peroksidaza (TPO) i antitireoglobulinskih (anti-Tg) antitela iz serumskih uzoraka izvedeno je hemiluminiscentnim imunološkim testom. Nivo leptina u serumu kod majki je određen ELISA testom. Za merenje nivoa TSH kod novorođenčadi korišćene su suve kapilarne krvne tačke.Ispitanici su podeljeni u dve grupe prema neonatalnim nivoima TSH sa graničnom vrednošću od 5,5 mIU/L. Srednji nivo serumskog leptina je bio značajno veći kod novorođenčadi čiji su nivoi TSH bili veći od5,5 mIU/L [13,2 mg/L (1,3-46,5) naspram 19,7 mg/L (2,4-48,5), p0,05]. Nivo leptina u serumu je pokazao negativnu korelaciju sa majčinim fT4 (r = 0,32, p0,05), fT3 (r = 0,23, p0,05) i pozitivnu korelaciju sa BMI (r = 0,30 p0,05).Naši rezultati ukazuju da visoki nivoi leptina u trećem tromesečju trudnoće utiču na funkcije štitne žlezde majke i mogu izazvati i povećati nivo TSH kod novo - rođenčadi. Otkrivanje visokog nivoa majčinskog leptina u serumu mo'e biti razlog za subklinički hipotiroidizam.

In this study, we aimed to determine the association of neonatal/post-neonatal hypothyroidism with mother's iodine exposure, especially povidone iodine disinfection, and hysterosalpingography. Participants were mother-child pairs in a Japanese birth cohort (n = 100,286). Risk factors of hypothyroidism were supplement intake, seaweed intake, other daily iodine intake, povidone iodine disinfection at delivery, and maternal history of hysterosalpingography, thyroid disease (Graves' disease and Hashimoto's thyroiditis), and medication (thiamazole and levothyroxine). Congenital hypothyroidism (CH) at age 1 year was assessed using a questionnaire. Transient hypothyroidism was defined as elevated thyroid stimulating hormone level at birth and absence of CH at age 1 year. The incidence of CH at age 1 year per 100 children was 1.1 for those born at 22-30 weeks' gestation, 0.17 following povidone iodine disinfection, and 0.07, 0.95, 0.81, 1.17, and 1.15 with a maternal history of hysterosalpingography, Graves' disease, Hashimoto's thyroiditis, thiamazole use, and levothyroxine use, respectively. Odds ratios (95% confidence intervals) of CH at age 1 year for povidone iodine disinfection, hysterosalpingography history, maternal Graves' disease, and maternal Hashimoto's thyroiditis were 1.13 (0.71-1.79), 0.47 (0.07-3.36), 7.06 (3.70-13.5), and 5.93 (2.90-12.1), respectively. For transient hypothyroidism for povidone iodine disinfection and hysterosalpingography history, these values were 1.99 (1.51-2.62) and 0.63 (0.20-1.96), respectively. Maternal thyroid disease greatly increased neonatal/post-neonatal hypothyroidism risk. Povidone iodine disinfection may increase transient hypothyroidism risk but not the risk at 1 year of age. Hysterosalpingography does not increase hypothyroidism risk from birth to age 1 year.

Context Early treatment is essential to avoid the cardiac complication of neonatal hyperthyroidism (NH). Our results have direct implications for clinical care. Objective NH can cause potentially fatal neonatal thyrotoxicosis. Here, we have evaluated the feasibility of neonatal hyperthyroidism screening using the thyroid-stimulating hormone value in dried blood collected routinely on filter paper on the third postnatal day of life for congenital hypothyroidism screening. Methods Retrospective case–control study. Cases were identified using data from our previously published study of 280 000 infants born in 10 maternity units in France in 2007-2014. Controls were identified among the 1 362 564 infants born in the Ile-de-France region during the same period. Results A screening thyroid-stimulating hormone level below 0.18 mIU/L on the third postnatal day had 71% (95% CI 44-90%) sensitivity, 99% (95% CI 99-100%) specificity, 81% (95% CI 74-86%) positive predictive value, and 98% (95% CI 97-99%) negative predictive value for detecting severe NH. By univariate regression analysis, the screening thyroid-stimulating hormone value was the strongest predictor of NH (P < .00001), with an area under the receiver-operating characteristics curve of 0.98 (95% CI 0.95-1.0). Expected frequencies were not significantly different from observed frequencies (Hosmer–Lemeshow test, P = .99). Conclusion The screening thyroid-stimulating hormone test can be used to detect severe NH, the optimal cut-off being 0.18 mIU/L. The additional cost compared with screening for congenital hypothyroidism would be small. Infants with neonatal hyperthyroidism would benefit from an earlier diagnosis with treatment initiation at the presymptomatic stage in many cases, ensuring optimal outcomes.

Adequate thyroid hormone availability is required for normal brain development. Studies have found associations between prenatal exposure to air pollutants and thyroid hormones in pregnant women and newborns. We aimed to examine associations of trimester-specific residential exposure to common air pollutants with congenital hypothyroidism (CHT). All term infants born in Israel during 2009–2015 were eligible for inclusion. We used data on CHT from the national neonatal screening lab of Israel, and exposure data from spatiotemporal air pollution models. We used multivariable logistic regression models to estimate associations of exposures with CHT, adjusting for ethnicity, socioeconomic status, geographical area, conception season, conception year, gestational age, birth weight, and child sex. To assess residual confounding, we used postnatal exposures to the same pollutants as negative controls. The study population included 696,461 neonates. We found a positive association between third-trimester nitrogen oxide exposure and CHT (per interquartile-range change, odds ratio = 1.23, 95% confidence interval: 1.08, 1.41) and a similar association for nitrogen dioxide. There was no evidence of residual confounding or bias by correlation among exposure periods for these associations.

Objectives: Congenital hypothyroidism (CH) can be permanent (PCH) or transient (TCH). While the importance of thyroxine in myelination of the brain is undisputed, the benefits to neurodevelopmental outcomes of TCH treatment are controversial. Our objectives were to determine predictive factors for PCH and verify its prevalence changes over time. Subjects and methods: A total of 165 children were evaluated at 3 years of age to verify the diagnosis of PCH. 130 were submitted to a two-step cluster analysis, with the aim of grouping them into homogeneous clusters. The mean incidence of PCH and TCH was calculated from 2004 to 2010 and 2011 to 2015. Results: Sixty-six children were diagnosed with PCH, and 99 were diagnosed with TCH. Eighty-one percent of PCH children and all TCH children with thyroid imaging had glands in situ. Eighty children (61.5%) were in Cluster 1, 8 children (6.2%) were in Cluster 2 and 42 children (32.3%) were in Cluster 3. No children had PCH in Cluster 1, while 87.5% of children in Cluster 2 and all children in Cluster 3 had PCH. The most important predictor for PCH was the initial serum TSH, which was marginally higher in importance than the blood spot TSH, followed by the initial serum free T4. The mean incidence of PCH (odds ratio: 1.95, 95% CI 1.36 to 2.95, p < 0.0001) and TCH (odds ratio 1.33, 95%, CI 1.02 to 1.77, p = 0,038) increased over time. Conclusions: The most important PCH predictors are the initial serum TSH and the blood spot TSH. The mean incidence of both PCH and TCH in our series increased.

Primary congenital hypothyroidism (CH) is a common neonatal endocrine disorder characterized by elevated concentrations of thyroid stimulating hormone (TSH) and low concentrations of free thyroxine (FT4). PAX8 and NKX2-1 are important transcription factors involved in thyroid development. In this study, we detected three novel variants in PAX8 (c.149A > C and c.329G > A) and NKX2-1 (c.706A > G) by whole exome sequencing (WES) in three unrelated CH patients with variable phenotypes. The results of Western blot and immunofluorescence analysis showed that the three variants had no effect on protein expression and subcellular localization. However, the results of the electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay suggested that the three variants in PAX8 and NKX2-1 both affected their DNA-binding ability and reduced their transactivation capacity. Moreover, a dominant-negative effect in K236E−NKX2-1 was identified by dual-luciferase reporter assay. To sum up, our findings extend our knowledge of the current mutation spectrum of PAX8 and NKX2-1 and provide important information for diagnosing, treating, and preventing CH in these families.

The hormones of the thyroid gland exert important effects on growth and development including early effects on the development of the central nervous system (CNS), regulation of temperature, and influences on metabolism. Disorders of the thyroid gland are common forms of endocrine disease in childhood and the primary care provider will definitely encounter some of these.

Congenital hypothyroidism (CH) is the most common preventable cause of mental retardation and delayed growth in children. Several prenatal and environmental factors might be associated with the disease.To determine the prevalence and risk factors of permanent CH and transient congenital hypothyroidism (TCH) in Israel.We conducted a retrospective analysis of the Israeli national newborn screening program database from 2011 to 2015. Chi-square and logistic regression were used to assess the association of the demographic and gestational factors with the CH and TCH.Of the 889,033 live births screened between 2011 and 2015, 860 were diagnosed with CH (9.76 per 10,000 live births) and 298 with TCH (3.35 per 10,000 live births). In multivariate analyses, CH was positively associated with female sex, gestational ages38 or39 weeks, birth weight3000 grams, and winter birth. A decreased risk of TCH was detected in Arabs and neonates from high socioeconomic areas. An increased risk was independently associated with gestational ages38 weeks, low birth weight, and winter birth.Several demographic, gestational, and geographical factors are associated with the development of CH and TCH. Future studies are needed to further investigate the pathogenesis in Israel.

A 7-month-old-term male infant presented with cough, tachypnoea, hypoxaemia and post-tussive emesis. Clinical history was significant for respiratory failure and pulmonary hypertension in the neonatal period requiring assisted ventilation, congenital hypothyroidism, mild hypotonia, recurrent respiratory infections, hypoxaemia requiring supplemental oxygen and nasogastric tube feeds. Physical examination showed tachypnoea, coarse bilateral breath sounds and mild hypotonia. Chest radiograph revealed multifocal pulmonary opacities with coarse interstitial markings and right upper lobe atelectasis. Following antibiotic therapy for suspected aspiration pneumonia, chest CT scan was performed and showed multiple areas of pulmonary consolidation and scattered areas of bilateral ground-glass opacities. Genetic studies showed a large deletion of chromosome 14q13.1–14q21.1, encompassing the NK2 homeobox 1 (NKX2-1) gene consistent with a diagnosis of brain–thyroid–lung (BTL) syndrome. Our case highlights the importance of genetic studies to diagnose BTL syndrome in infants with hypothyroidism, hypotonia and lung disease.

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.

BACKGROUND: Down syndrome (DS) is the most common genetic disorder in children. Children with DS tend to have various comorbid due to developmental abnormalities of chromosome 21, such as congenital heart defects, hearing loss, otitis media, eye disorders, obstructive sleep apnea, thyroid hormone disorders, gastrointestinal atresia, hip joint dislocation, leukemia, and Hirschsprung’s disease. Moreover, they also show cognitive impairments in concentration, communication, memory, and the ability to carry out tasks. Caput Scale/Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT-CLAMS) is one of the developmental assessment instruments to screen for cognitive disorders. AIM: Hereby, we aimed to find the association of comorbid with developmental quotient in DS children. Data were obtained from medical record with sample age 0–18 years and suffering from DS. METHODS: This was observational analytic study with cross-sectional approach, conducted in DS children age 0–18 years who were treated in Sanglah Hospital in 2018. Characteristic data and comorbid were obtained from medical record, meanwhile, development status was assessed using Caput Scale/CAT-CLAMS. Chi-square was applied to determine the association between comorbidities and development quotient (DQ) in DS children. RESULTS: A total of 32 children with DS were treated in Sanglah Hospital during 2018 with median age was 2 years old and dominated by female patient (71.9%). Several comorbidities were found such as endocrine disorders in 27 children (84.3%), congenital heart disease (CHD) in 16 children (50%), and other comorbid including microcephaly, congenital cataract, palatoschizis, gastrointestinal defects, and congenital talipes equinovarus in 13 children (40.4%). The most common endocrine disorders was congenital hypothyroidism (81.25%), while the most common CHD was patent ductus arteriosus (25%). Bivariate Chi-square analysis showed significant association between comorbid and DQ (PR = 1.4 [95% CI 0.95–1.97], p = 0.03). CONCLUSION: We found an association between comorbidities and DQ in DS children.

Background: Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in THRB, causing resistance to TH (RTH-β). Methods: Clinical, genetic, and biochemical data of the proband's family were collected. Results: The 3-year-old girl was diagnosed with CH due to a homozygous pathogenic c.470del p.(Asn157Thrfs*3) SLC5A5 variant in the neonatal period. She needed a notably high levothyroxine dose to normalize TSH, leading to high free thyroxine levels. There were no signs of hyperthyroidism. Sequencing identified a heterozygous pathogenic c.947G>A p.(Arg316His) THRB variant. Conclusions: To our knowledge, this is the first report of concomitant SLC5A5 and THRB variants causing CH and RTH-β.

Background: Congenital hypothyroidism is often caused by genetic mutations that impair thyroid hormone (TH) production, resulting in growth and development defects. XB130 (actin filament associated protein 1 like 2) is an adaptor/scaffold protein that plays important roles in cell proliferation, migration, intracellular signal transduction, and tumorigenesis. It is highly expressed in thyrocytes, however, its function in the thyroid remains largely unexplored. Methods: Xb130(−/−) mice and their littermates were studied. Postnatal growth and growth hormone levels were measured, and responses to low or high-iodine diet, and levothyroxine treatment were examined. TH and thyrotropin in the serum and TH in the thyroid glands were quantified. Structure and function of thyrocytes in embryos and postnatal life were studied with histology, immunohistochemistry, immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction. Results: Xb130(−/−) mice exhibited transient growth retardation postnatally, due to congenital hypothyroidism with reduced TH synthesis and secretion, which could be rescued by exogenous thyroxine supplementation. The thyroid glands of Xb130(−/−) mice displayed diminished thyroglobulin iodination and release at both embryonic and early postnatal stages. XB130 was found mainly on the apical membrane of thyroid follicles. Thyroid glands of embryonic and postnatal Xb130(−/−) mice exhibited disorganized apical membrane structure, delayed folliculogenesis, and abnormal formation of thyroid follicle lumina. Conclusion: XB130 critically regulates folliculogenesis by maintaining apical membrane structure and function of thyrocytes, and its deficiency leads to congenital hypothyroidism.

Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay. Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Graves’ disease (GD) results from the passage of thyrotropin receptor antibodies (TRAbs) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking thyroid-stimulating hormone receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism, but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child’s prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism.

Hypothyroidism is the condition of thyroid hormone deficiency. It can be primary or acquired. Primary hypothyroidism can be congenital or late onset. The symptoms of congenital hypothyroidism may go unnoticed in newborns if undiagnosed. Untreated, hypothyroidism can lead to poor mental and intellectual development in children. Hypothyroidism’s clinical manifestations are often subtle or not present at birth. Common symptoms include decreased activity and increased sleep, feeding difficulty, and constipation. On examination, common signs include myxoedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Levothyroxine is the treatment of choice. In general, the prognosis is excellent when this condition is detected by screening and started on treatment early.

The article presents a case of congenital hypothyroidism, which was manifested by persistent hypoglycemia. Persistent hypoglycemia is a rare symptom of congenital hypothyroidism. However, when performing a differential diagnosis of persistent hypoglycemia, it is necessary to evaluate the function of the thyroid gland. The cause of persistent hypoglycemia in congenital hypothyroidism can be the reduced rate of glucose absorption by the cell, a decrease in the rate of glucose absorption in the gut, reduced insulin clearance from the blood and gluconeogenesis abnormalities.

DUOX2 is the most frequently mutated gene in patients with congenital hypothyroidism (CH) in China. However, no reliable genotype-phenotype relationship has been found in patients with DUOX2 mutations. In this study, DUOX2 mutations were screened in 266 CH patients, and the enzymatic activity of 89 DUOX2 variants was determined in vitro. Furthermore, the DUOX2 residual activity in 76 CH patients caused by DUOX2 biallelic mutations was calculated. The thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were found to be higher and lower in patients with DUOX2 residual activity ≤ 22%, respectively, compared to patients with residual enzymatic activity > 22%. Moreover, we interpreted the pathogenicity of DUOX2 variants by applying the ACMG classification criteria with or without PS3/BS3 evidence. The results indicated that residual DUOX2 enzymatic activity was closely related to the clinical phenotypes of CH patients caused by DUOX2 biallelic mutations. These findings suggest that the residual enzymatic activity of 22% may be a cutoff value for estimating the severity of hypothyroidism in CH patients with biallelic DUOX2 mutations. Well-established functional studies are useful and necessary to evaluate the pathogenicity of DUOX2 variants, improving the accuracy and scope of genetic consultations.

The aim of this study was to detect the most significant risk factors leading to disability in children with congenital hypothyroidism (CH) in the autonomous Republic of Karakalpakstan (RK) during neonatal screening (NS). Methods and Results: We used data of patients with CH registered within NS in the RK in 1998-2019 by the Center for Screening of Mother and Child. To predict and calculate the most significant risk factors for disability in children with CH, we used the method of normalizing intensive indicators by E. Shigan, based on the Bayes theorem. The study recruited 111 patients with CH aged from 2 months to 20 years. Among the patients, there were 79(71.2%) girls and 32(28.8%) boys. Additionally, 34(30.6%) children with CH had been disabled since childhood. The lack of compensation after the start of treatment had the highest and most significant degree of disability risk (RR=6.39, 95% CI: 7.4-1.2). Among patients diagnosed outside of screening, disability developed 4.1 times more often than with the results of NS (RR=4.0, 95% CI: 1.1-10.6). In CH patients diagnosed outside of screening, “absence of reagents” was a significant factor increasing the risk of disability by 6.1 times (RR=6.1, 95% CI: 1.8-11.2). Such risk factors as “home delivery” and “parental refusal of the primary test” increased the risk of disability by 3.4 times (RR=3.4, 95% CI: 2.5-8.4) and 1.6 times (RR=2.4, 95% CI: 2.93-7.12), respectively. The possible errors or false-negative answers in the “normal” secondary test and the “normal” primary test increased the risk of disability by 3.3 times (RR=4.0, 95% CI: 3.2-10.7) and 2.4 times (RR=2.42, 95% CI: 2.93-7.12), respectively. Factors such as the “late response to retesting” (RR=0.82 95% CI: 0.65-0.54), “late awareness on the part of the medical staff” (RR=0.29, 95% CI: 0.27- 0.08), and "parental refusal of treatment" (RR=1.03, 95% CI: 0.81-0.84) showed less significance in patients' disability. The “starting treatment after 1 month” factor was 4.2 times more likely to result in disability than “starting treatment before 1 month” (RR=4.2, 95% CI: 4.5 -1.1). Cancellation of levothyroxine by parents for children up to 3 years of age and cancellation of treatment by parents after 3 years more likely resulted in disability by 1.4 times (RR=1.43, 95% CI: 1.4 -2.01) and 3.3 times (RR=3.33, 95% CI: 3.3-10.9), respectively. Conclusion: the most significant risk factors for the development of disability in children with CH in the RK were (in descending order): no compensation after starting treatment, no reagents for screening, starting treatment after 1 year, diagnostics outside of screening, cancellation of L-T4 by parents before and after age 3 years, false-negative secondary TSH test, false-negative primary test, parents refusing the primary test, and childbirth at home.

Congenital hypothyroidism is an actual clinical problem in pediatric practice. Previous clinical guidelines were published in 2014. The presented clinical recommendations are based on articles published from January 2013 to early 2020. The consensus guidelines include such sections as results of neonatal screening, diagnostics and criteria for treatment, lifelong follow-up, genetics of congenital hypothyroidism, family genetic counselling. The key points of new congenital hypothyroidism guidelines were commented by pediatric endocrinologists of Russians.

Background. Diseases of the thyroid gland (TG) are ranked first among all endocrine pathologies and remain one of the most difficult problems. Objective: to evaluate the morphofunctional state of the TG in children with congenital hypothyroidism (CH). Materials and methods. The work is based on survey data of 34 children with CH: ultrasound examination of the TG, determination of thyroid hormone levels (thyroid-stimulating hormone (TSH), free thyroxine, thyroglobulin). Statistical analysis was performed by standard methods using the software package StatSoft Statistica 6.0 for Microsoft Windows XP. Results. In 67.6 % of cases, the diagnosis was established according to the screening for CH, in 32.4 % — out of the screening. In 22 patients, thyroid tissue was not visualized in a typical location, or its total volume was significantly less than normal. In 12 patients, the TG was in typical place, and its volume meet norms or exceeds its upper limit. In 55.6 % of patients, we have detected cysts (in 56 % — with dystopia of the TG, in 44 % of cases — with thyroid hypoplasia). They are located paratracheally: on the left — in 66.7 %, on the right — in 13.3 %, in 20 % — on both sides. It was found a significant degree of thyroid insufficiency in patients with thyroid defects, however, in thyroid hypoplasia, the TSH level was lower (p < 0.05) compared with that of in dystopia. Burdened heredity, mainly maternal, was detected in 11.7 % of patients; almost in a third of cases, the burdened obstetric and gynecological history was observed, more than a half of mothers had abnormal labor, and post-term pregnancy occurred 2.1 times more often than in the general population. Conclusions. The incidence of congenital abnormalities of the TG in children with CH is 64.7 %; more than in half of the cases, we have determined the cysts. Severe degree of thyroid insufficiency has been registered in cases of hypoplasia of the TG.

Background. Congenital hypothyroidism (CH) as the most common hereditary thyroid pathology is a serious social, economic and psychological burden for a family, where the sick child was born, as well as for the society. The purpose of our study was to evaluate the disease incidence and to detect the clinical features of various forms of congenital hypothyroidism in children. Materials and methods. Twenty two medical records of patients with CH (14 girls, 8 boys) aged 1 month to 6 years (experimental group) and 20 healthy children of the correspondent age were analyzed, and the further assessment of their physical and neuropsychological development was conducted. All children underwent the ultrasound examination of the neck region, indirect laryngoscopy; thyroid-stimulating hormone (TSH), thyroglobulin antibodies, free thyroxine (fT4), thyroglobulin tests were also performed. Clinical signs of CH in the neonatal period were estimated according to the Apgar scores. Statistical analysis was performed with the aid of the Statistica 6.0 program. Results. The thyroid dystopia was diagnosed in 59.1 % of cases, in particular: in the hyoid area (5), the root of the tongue (2), submandibular area (2), jugular fossa (1), unspecified (2). The median of TSH in the first stage of screening in children of the main group was 38 mU/l (24.2–122.4 mU/l), in the comparison group — 2.03 mU/l (1.7–2.6 mU/l). The fT4 level ranged from 0.49 to 14.7 pmol/l, on average — 2.37 pmol/l. The number of clinical signs was not dependent on the age neither on the form of hypothyroidism at the moment of diagnosis. With age, children’s development increasingly lags behind those of correspondent age contributing to further development of fine motor delay. In 40.9 % of patients with CH, the relatives suffered from thyroid disease. Conclusions. The thyroid dystopia is the most common among various forms of congenital hypothyroidism (59.1 %). The reliable differences in TSH and fT4 levels were not found in children with thyroid dystopia and those with typically located thyroid gland. The number of clinical signs was not dependent on the age neither on the form of hypothyroidism at the moment of diagnosis and varied from their absolute absence to presence of seven symptoms at the same time. A delayed formation of motor skills, emotional reactions, the components of cognitive activity was observed in children with congenital hypothyroidism. More than one-third of children with congenital hypothyroidism have concomitant somatic pathology. The predominant lesions of any organs and systems and dependence of the nature of comorbidity on the etiology of congenital hypothyroidism were not observed. In 13.6 % of children, the congenital malformations of other organs were found, mainly in patients with congenital hypothyroidism caused by thyroid dystopia.