Pathogenesis Of Congenital Hypothyroidism Research Articles

Deciphering the mystery of CHNG3.

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

Identification of Eukaryotic Translation Initiation Factor 4B as a Novel Candidate Gene for Congenital Hypothyroidism.

Congenital hypothyroidism (CH) is the most common endocrine disorder in neonates, but its etiology is still poorly understood. We performed whole exome sequencing to identify novel causative gene for CH and functional studies to validate its role in the occurrence of CH. Whole exome sequencing in 98 CH patients not harboring known CH candidate genes and bioinformatic analysis were performed. Functional analysis was performed using morpholino, a synthetic short antisense oligonucleotide that contains 25 DNA bases on a methylene morpholine backbone, in zebrafish and CRISPR‒Cas9-mediated gene knockout in mice. Eukaryotic translation initiation factor 4B (EIF4B) was identified as the most promising candidate gene. The EIF4B gene was inherited in an autosomal recessive model, and one patient with thyroid dysgenesis carried EIF4B biallelic variants (p.S430F/p.P328L). In zebrafish, the knockdown of eif4ba/b expression caused thyroid dysgenesis and growth retardation. Thyroid hormone levels were significantly decreased in morphants compared with controls. Thyroxine treatment in morphants partially rescued growth retardation. In mice, the homozygous conceptuses of Eif4b+/- parents did not survive. Eif4b knockout embryos showed severe growth retardation, including thyroid dysgenesis and embryonic lethality before E18.5. These experimental data supported a role for EIF4B function in the pathogenesis of the hypothyroid phenotype seen in CH patients. Our work indicated that EIF4B was identified as a novel candidate gene in CH. EIF4B is essential for animal survival, but further studies are needed to validate its role in the pathogenesis of CH.

The length of FOXE1 polyalanine tract in congenital hypothyroidism: Evidence for a pathogenic role from familial, molecular and cohort studies.

FOXE1 is required for thyroid function and its homozygous mutations cause a rare syndromic form of congenital hypothyroidism (CH). FOXE1 has a polymorphic polyalanine tract whose involvement in thyroid pathology is controversial. Starting from genetic studies in a CH family, we explored the functional role and involvement of FOXE1 variations in a large CH population. We applied NGS screening to a large CH family and a cohort of 1752 individuals and validated these results by in silico modeling and in vitro experiments. A new heterozygous FOXE1 variant segregated with 14-Alanine tract homozygosity in 5 CH siblings with athyreosis. The p.L107V variant demonstrated to significantly reduce the FOXE1 transcriptional activity. The 14-Alanine-FOXE1 displayed altered subcellular localization and significantly impaired synergy with other transcription factors, when compared with the more common 16-Alanine-FOXE1. The CH group with thyroid dysgenesis was largely and significantly enriched with the 14-Alanine-FOXE1 homozygosity. We provide new evidence that disentangle the pathophysiological role of FOXE1 polyalanine tract, thereby significantly broadening the perspective on the role of FOXE1 in the complex pathogenesis of CH. FOXE1 should be therefore added to the group of polyalanine disease-associated transcription factors.

Génétique de l’hypothyroïdie congénitale

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). DH accounts for about 35% of CH and a genetic cause is identified in 50% of patients. However, TD accounts for about 65% of CH, and a genetic cause is identified in less than 5% of patients. The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development and function. We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.

New genetics in congenital hypothyroidism.

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

Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats.

EphA5 and its ligand ephrin-A5 interaction can trigger synaptogenesis during early hippocampus development. We have previously reported that abnormal EphA5 expression can result in synaptogenesis disorder in congenital hypothyroidism (CH) rats. To better understand its precise molecular mechanism, we further analyzed the characteristics of ephrin-A5 expression in the hippocampus of CH rats. Our study revealed that ephrin-A5 expression was downregulated by thyroid hormone deficiency in the developing hippocampus and hippocampal neurons in rats. Thyroxine treatment for hypothyroid hippocampus and triiodothyronine treatment for hypothyroid hippocampal neurons significantly improved ephrin-A5 expression but could not restore its expression to control levels. Hypothyroid hippocampal neurons in-vitro showed synaptogenesis disorder characterized by a reduction in the number and length of neurites. Furthermore, the synaptogenesis-associated molecular expressions of NMDAR-1 (NR1), PSD95 and CaMKII were all downregulated correspondingly. These results suggest that ephrin-A5 expression may be decreased in CH, and abnormal activation of ephrin-A5/EphA5 signaling affects synaptogenesis during brain development. Such findings provide an important basis for exploring the pathogenesis of CH genetically.

JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects.

The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.

Etiology of congenital hypothyroidism in Isfahan: Does it different?

Background:Considering the higher prevalence of congenital hypothyroidism (CH) in Iran and the importance of determination of the etiology of CH for assessing appropriate treatment strategies, understanding the pathogenesis of CH and the implications of its inheritance and prognosis, the aim of this study was to determine the etiology of CH 7 years after initiation of the program in Isfahan province.Materials and Methods:In this cross-sectional study, children with a primary diagnosis of CH studied. They clinically examined and their medical files were reviewed by a Pediatric Endocrinologist. Considering screening and follow-up lab data and radiologic findings the etiology of CH was determined. Screening properties of different etiologies of CH was compared.Results:In this study, 437 patients with permanent CH (PCH) were studied. Etiology of PCH in 316 (72.3%) and 121 (27.7%) of cases was thyroid dyshormonogenesis and thyroid dysgenesis, respectively. Prevalence of agenesis, ectopia, hypoplasia and hemiagenesis in thyroid dysgenetic patients was 13.3%, 6.4%, 4.3% and 3.7% respectively. Mean of thyroid stimulating hormone in screening, recall and after discontinuing treatment at 3 years of age was significantly lower in dyshormonogenetic CH patients than dysgenetic ones(P < 0.01).Conclusion:Seven years of our experiences in CH screening program indicated that the etiology of CH in Isfahan, with a higher rate of CH, with a predominance of thyroid dyshormonogenesis is different from most of the studies world-wide and similar to other reports from Iran. The findings of the current study provide us baseline information for determination of CH pathogenesis in this region.

Risk factors for congenital hypothyroidism in Egypt: results of a population case-control study (2003–2010)

BACKGROUND AND OBJECTIVESAlthough the prevention of the neuropsychological consequences of congenital hypothyroidism (CH) through the use of replacement therapy represents an important public health success, knowledge about the modifiable risk factors could reduce the number of infants affected by this disease. This study was carried out to identify risk factors for CH at Fayoum Governorate, Egypt.DESIGN AND SETTINGSThis was a population-based case-control study, which started in 2003 and was carried out for 8 years through Fayoum center of the Egyptian Ministry of Health and Population screening program for CH.METHODSThis study was a population-based case-control study carried out by using national project for CH. One control was enrolled for each new CH infant; 320 cases and 320 controls were enrolled in 8 years. Maternal and neonatal influences were investigated.RESULTSA statistically significant association of CH was observed with birth defects, female gender, gestational age >40 weeks, and gestational diabetes. An increased risk for CH was detected in twins by a multivariate analysis.CONCLUSIONOur results suggest a multifactorial origin of CH in which genetic (high frequency of additional malformations) and environmental factors (especially maternal diabetes) play a role in the development of the disease.

Delayed onset congenital hypothyroidism in a patient with DUOX2 mutations and maternal iodine excess

Congenital hypothyroidism (CH), one of the most common congenital endocrine disorders, causes irreversible intellectual disability in untreated patients. Today, the vast majority of patients receive early diagnosis and treatment in the context of newborn screening for CH, and achieve satisfactory cognitive development. However, a subset of patients with delayed onset are undetectable by newborn screening, and miss benefit from early intervention. Here, we report on a delayed-onset CH patient that had two contributing factors in the pathogenesis of CH simultaneously, i.e., a genetic defect and iodine excess. The patient was exposed to excessive iodine in utero because her mother consumed massive amounts of seaweed during pregnancy. Surprisingly, the patient had a negative result in newborn screening, but developed overt CH at age 3 months. She received thyroxine supplementation until when normalization of the thyroid function was confirmed at age 3 years (i.e., transient CH). Mutation screening for DUOX2, a causative gene for transient CH, showed biallelic mutations (p.[E327X] + [H678R]). This report provides a new example of environmental modification of phenotypes of CH due to a genetic defect, which can potentially distort screening results.

High prevalence of congenital hypothyroidism in Isfahan: Do familial components have a role?

Background:Despite elimination of iodine deficiency, the rates of both permanent and transient congenital hypothyroidism (CH) in our study were higher than the comparable worldwide rates, which emphasize the major role of genetic factors in the pathogenesis of CH and many studies in this regard confirm this possibility.Materials and Methods:In this review, we report all studies that established during CH screening program regarding familial and genetic component of the disease.Results:Although we could not entirely ignore the possible role of environmental and autoimmune factors in the development and function of thyroid gland, our findings strongly suggest the role of genetic factors as dominant etiologic factor in CH.Conclusion:The studies support the existence of a familial component of CH involving dominant genetic predisposition factors with a low penetrance. Considering the polygenic/multifactorial basis of CH, they suggest the possible involvement of other unknown genes in the pathogenesis of the disease, which may also follow non-Mendelian pattern of inheritance.

Mutation analysis of thyroid peroxidase gene in 20 Chinese patients with congenital hypothyroidism

Thyroid peroxidase(TPO) gene was detected in 20 patients with congenital hypothyroidism. An insertion c. 2268insT of TPO gene was found in one of them, and c. 2268insT combined with c. 1477G＞C mutation in another. TPO gene mutation may be related to pathogenesis of congenital hypothyroidism in Chinese. Key words: Congenital hypothyroidism; Thyroid peroxidase gene; Mutation

Von Willebrand Factor, and Soluble Intercellular and Vascular Cell Adhesion Molecules as Indices of Endothelial Activation in Patients with Congenital Hypothyroidism

Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan, the possible involvement of endothelial dysfunction in the pathogenesis of CH and the lack of studies in this field, the aim of this study was to determine the endothelial function in CH patients. Methods: During this case-control study, the endothelial function in CH neonates and in those with normal screening results was evaluated during a CH screening program in Isfahan. Peripheral blood samples were obtained for measurement of the von Willebrand factor (vWf), and intercellular and vascular cell adhesion molecule (ICAM and VCAM). In CH patients these biomarkers were measured twice: before and 4 weeks after treatment. Results: In this study, 56 neonates were evaluated: 30 of them were neonates with normal screening results and 26 were diagnosed with CH and classified into two groups according to their TSH levels. The mean ICAM and VCAM were higher in CH patients than in the control group (p < 0.05). The mean ICAM and VCAM decreased significantly after treatment in CH patients (p < 0.05). There is no significant relationship between TSH, ICAM, VCAM and vWf (p > 0.05). Conclusion: The findings of this study demonstrate the possible involvement of the endothelial system in the pathogenesis of CH and its cardiovascular complications. Further studies with a larger sample size and with the measurement of other endothelial function markers are needed.

Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia

To establish the role of new TSH receptor (TSHr) variants (P27T, E34 K, R46P, D403N, W488R and M527T) recently identified in children with congenital hypothyroidism (CH) or subclinical hypothyroidism (SH) with a thyroid gland of normal size. TSHr variants were obtained by mutagenesis. Wild-type (wt) and TSHr mutants were expressed in COS cells and cAMP assay, (125)I-TSH binding and microchip flow cytometry analyses were performed. D403N and M527T mutants showed a lower cAMP response to bovine TSH (bTSH) with respect to the wtTSHr. R46P and W488R mutants did not show any response to bTSH stimulation in terms of cAMP production. The E34 K mutant showed a significantly lower cAMP response to stimulation with bTSH, while P27T had a lower cAMP response only to the highest dose of bTSH used. P27T, E34 K, D403N and M527T mutants showed a lower TSH binding capacity with respect to the wtTSHr. R46P and W488R mutants did not show any TSH binding. E34 K, D403N, M527T, R46P and W488R TSHr variants seem to cause a functional abnormality of the receptor which is responsible for the observed phenotype. The P27T TSHr variant does not seem to play a functional role in the pathogenesis of CH and should be considered as a polymorphism.

Effects of hyper- and hypothyroid on expression of thyroid hormone receptor mRNA in rat myocardium

Thyroid dysfunction is classified into hyperthyroidism and congenital hypothyroidism (CH). Both hyperthyroidism and CH can cause heart lesions; however, the mechanisms involved remain unclear. The left ventricle was collected from eu-, hyper-, and hypothyroid rat. RNA was extracted and reverse-transcripted to cDNA. Real-time fluorescence quantitation-PCR was used to quantify the differential expression of thyroid hormone receptor (TR) subtype mRNA among eu-, hyper-, and hypothyroid rat myocardium. Here, we show that compared with the normal myocardium, TRalpha1 mRNA expression was upregulated by 51% (P<0.01), TRalpha2 mRNA expression was downregulated by 58% (P<0.01), and TRbeta1 mRNA expression remained unchanged in hyperthyroid rat myocardium (P>0.05). TRalpha1, TRalpha2, and TRbeta1 were expressed in normal and hypothyroid rat myocardium throughout the developmental process. In hypothyroid rats, myocardial TRalpha1 mRNA expression was generally downregulated and the expression peak appeared late. Myocardial TRalpha2 mRNA expression was generally upregulated and the expression peak appeared late. Myocardial TRbeta1 mRNA expression was generally downregulated and changed similarly with the control group. In addition, the hypogenetic myocardium can be seen in the hypothyroid rat by pathology study. Taken together, the abnormal expression of TR subtype mRNA may have a close relationship with the pathogenesis of CH and hyperthyroidism heart disease.

Identification of Novel Genes Involved in Congenital Hypothyroidism Using Serial Analysis of Gene Expression

Part of the molecular basis of congenital hypothyroidism (CH) has been elucidated by the identification of molecular defects in pituitary- and thyroid-specific genes in patients with various subtypes of hypothyroidism. So far identified genetic defects only explain a small proportion of cases of hypothyroidism. Thus novel research strategies are required to isolate more tissue-specific genes involved in the pathogenesis of CH at present considered ‘idiopathic’ from a molecular perspective. We applied serial analysis of gene expression to human thyroid tissue and developed a computational substraction method to identify tissue-specific genes. The result has been the identification of three genes preferentially expressed in the thyroid gland. The first one encodes part of the thyroid oxidase (THOX2) system. We linked mutations in the THOX2 gene with idiopathic cases of transient and permanent CH. The second transcript identified, DEHAL1, encodes the protein responsible for the recycling of iodine in the thyroid gland and represents the candidate gene for a specific subtype of CH. The third one encodes NM41, a protein currently under investigation which shows features characteristic of the cystine-knot family of proteins, typically involved in early development.

Cytogenetic analysis in congenital hypothyroidism

In order to evaluate the possible role of genetic factors in the pathogenesis of congenital hypothyroidism (CH), we investigated the occurrence of chromosome aberrations in a consecutive series of 47 patients with CH and 208 matched healthy controls. No abnormal karyotype was found in CH patients. In 5 CH patients and in 3 healthy controls a number of heterochromatin variants was detected. Although chromosomal variants are devoid of phenotypic effects, the frequency of these variants was higher in CH patients than in the control group (10.6% vs 1.4%, p less than 0.005). These findings suggest that the association of congenital hypothyroidism with chromosomal variants may reflect more than chance concurrence.

Cytotoxic antibodies in congenital hypothyroidism.

Antibody-dependent cell-mediated cytotoxicity was determined in serum samples from 61 patients with congenital hypothyroidism (CH) and 46 of their mothers, using a 51chromium release assay with human thyroid cells. Such cytotoxic antibodies were found in 31% of the children and 24% of their mothers. In the 12 (of 37) newborn infants with hypothyroidism (group 1) who had positive tests, the median cell lysis was 20.1% compared to 4% in healthy newborns. In the 7 (of 29) mothers who had positive tests, the median lysis was 21.3%. In 24 older children with CH (group 2), cytotoxic activity was found in 6, and in them the median lysis was 19.7%; 4 of their mothers had increased lytic activity (median, 20.6%). In 96% of the mother-infant pairs concordance existed between the cytotoxic activity in mothers and their children. Increased thyroid cell lysis was found in 6 of 20 children with athyrosis (30%) and in 6 of 23 children with an ectopic gland (50%), but in only 1 of 14 children with a normal gland. Thyroglobulin antibodies were detected in 2 and antithyroid microsomal antibodies in 3 children-mother pairs. TSH receptor antibodies were present in 5 children and 3 of their mothers. The results indicate that intrauterine autoimmune thyroiditis could be involved in the pathogenesis of CH in some patients.

HLA typing and congenital, primary hypothyroidism

An association has been demonstrated between HLA-antigens and thyroid diseases such as Graves' disease, Hashimoto's thyroiditis and subacute thyroiditis.The significance of HLA types in the pathogenesis of congenital hypothyroidism has not been clarified. Recently, a study from Japan showed an increased frequency of HLA-Aw24 in congenital hypothyroidism (N Engl J Med 1980; 303:226). An American study did not confirm this finding, but could not exclude the possibiloty that HLA-B18 may be increased in patients with congenital hypothyroidism (N Engl J Med 1980;303: 1177).In a study of HLA-A, B and C types in - so far - 24 Danish patients with congenital hypothyroidism we did not find any association between the HLA types and the congenital dysplasia of the thyroid gland. In particular, the frequencies of Aw24 and B18 antigens were both lower in the patients than in the controls.