Deciphering the mystery of CHNG3

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.

Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients

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.

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.

Congenital hypothyroidism (CH) develops a or functional defect of the thyroid gland; hypothalamic-pituitary axis malformations; or altered action, transport, or of thyroid hormones. 1) In the majority of cases (65%), primary CH is due to a developmental defect of the thyroid gland or thyroid dysgenesis. When the thyroid gland is normal sized or hyperplasic (goiter), hypothyroidism occurs due to a defect in thyroid hormone synthesis or dyshormonogenesis. 2) New genetic approaches such as high-throughput sequencing (next-generation sequencing) and the detailed phenotypic description of patients and/or families affected by CH have provided new genetic avenues for CH research. Furthermore, they have made it possible to extend the thyroid phenotype associated with certain mutated genes. 1) Recently, Narumi 3) revealed distinct mutation patterns in the CHNG3 gene affecting a TTTG microsatellite in a noncoding region from the undiagnosed CH pedigree through whole genome sequencing (WGS). They also reported that CHNG3 accounted for 13.9% (95% confidence interval, 11.9-16.1) of the Japanese CH cohort and is one of the leading genetic causes of CH in Japan. 4) A microsatellite is defined as a tract of a repetitive DNA motif composed of short repeating units of 1-6 nucleotides. 5) Microsatellites are observed in almost all known eukaryotic and prokaryotic genomes and are present in both coding and noncoding regions. 6) This makes microsatellites powerful genetic markers for a variety of applications, such as genetic linkage mapping, population genetics, quantitative trait loci-based selection breeding, and evolutionary studies. 7) The mutation rate of microsatellites is higher than that of other genomic regions owing to DNA polymerase slippage during DNA replication and repair. 5) In this study. a novel CH caused by a noncoding region variant in the CHNG3 gene was discovered by combined linkage analysis and WGS. Large-scale WGS has several advantages over whole exome sequencing for discovering noncoding or regulatory regions, copy number variations, repeat expansions, and DNA methylation. WGS is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases. It can also aid in uncovering potential genetic causes and guide treatment. The CHNG3 gene plays a crucial role in the regulation of thyroid hormone metabolism, influencing various physiological processes. Recent studies have highlighted its importance in thyroid function and the broader implications for metabolic health. 4) Dysregulation of CHNG3 has been linked to thyroid disorders, which can lead to significant systemic effects including alterations in energy expenditure and growth. However, many questions remain about how specific mutations influence disease susceptibility and phenotype variations, particularly in diverse populations. Understanding the mechanisms behind the interaction of CHNG3 with thyroid hormones may be vital for developing targeted therapies for thyroid-related conditions. The findings underscore the need for further research to elucidate the mechanisms by which CHNG3 mutations affect thyroid health in the Asian demographic, a vital study area.

Purpose We compared the age at menarche and standard deviation score (SDS) of final height (FH) in permanent congenital hypothyroidism (CH) patients with those of healthy female adolescents and assessed their associations with CH screening-related variables or demographic factors.Methods In this cross-sectional study, we included 207 female CH patients and 598 healthy age-matched female adolescents. Ages at puberty onset and menarche, height at puberty and menarche, and the FH and its SDS were evaluated in the 2 groups and compared. Associations between screening variables and anthropometric data with age at menarche and SDS of FH were also assessed in CH patients.Results In the included population, 113 patients with CH and 453 healthy girls attained their FH. The mean ages at puberty onset and menarche in CH patients were higher than those in the healthy population (P<0.05). The mean height at menarche and the FH and its SDS were not different between the 2 groups (P>0.05). There was no significant association between FH SDS in CH patients and age of treatment (P=0.30). Age at menarche was significantly higher in CH patients with delayed age at treatment initiation (P=0.04). The difference between FH and target height was not significantly different among CH patients (P=0.83).Conclusions While CH patients had a significantly higher age at menarche compared to the healthy population, appropriate treatment changed this age to be similar to that in the healthy group. However, CH patients who experienced delayed treatment had a higher age at menarche. Age at treatment initiation was the only screening-related variable related to age at onset of menarche and puberty.

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.

Thyroid Disorders.

Next‐generation Sequencing Facilitates the Diagnosis in a Child With Twinkle Mutations Causing Cholestatic Liver Failure

Objectives The purpose was to investigate the neurodevelopmental and growth status of Congenital hypothyroidism (CH) patients compared to normal children using population-based cohort study. Methods The National Investigation of Birth Cohort in Korea study 2008 (NICKs-2008) consisted of the Korean National Health Insurance System (NHIS) and the National Health Screening Program for Infants and Children (NHSPIC) databases comprising children born in 2008 (n=469,248) and 2009 (n=448,459). The CH patients were enrolled with International Classifications of Diseases-10 codes and drug classification (levothyroxine over 5 years) codes. We investigated their developmental outcomes using the Korean-Ages and Stages Questionnaire (K-ASQ), and serial changes of BMI (BMI-z) and height (height -z) were compared in children with and without CH. Risk ratios were obtained using a modified Poisson regression and weighted risk differences using binomial regression. Results Of the 919,707 newborns, 433 children (boys, 47.7%) were diagnosed as CH (1: 2,124 of prevalence). The risk ratio (RR) for delayed development based on the results from the 5th–7th K-ASQ was higher for the total developmental area (adjusted RR = 2.77, 95% CI: 1.507-5.118) in CH patients. There was significant difference between patients with CH and controls in the assessment of gross motor, fine motor and problem-solving areas (P &amp;lt; . 0001). At 66-71 months of age, short stature (height-z &amp;lt; -1.63) were increased in the CH group compared with normal children (adjusted RR 2.27, 95% CI 1.328-3.865). Obese children (BMI-z &amp;gt; 1.63) were not increased. Conclusions The adequate large cohort data showed that prevalence of developmental delay and short stature were higher in CH patients than normal. Careful and early intervention is needed. Presentation: No date and time listed

Hypospadias

The relationship between nonalcoholic fatty liver disease and pediatric congenital hypothyroidism patients

Next-generation sequencing analysis of DUOX2 in 192 Chinese subclinical congenital hypothyroidism (SCH) and CH patients

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.

Background: This report provides a molecular cytogenetic characterization of an Omani girl with 19p13.12 microdeletion and compares her clinical features of global developmental delay (GDD) and multiple congenital anomalies with the gene mutations and disorders associated with this locus. Case Presentation: The 4-year-old Omani girl presented to the National Genetic Center with the following clinical features: GDD, hypotonia, multiple congenital anomalies, facial dysmorphism, and skeletal anomalies. Array comparative genomic hybridization (CGH) identified a 1.913 Mb de novo microdeletion in the patient within 19p13.12. The deletion includes 53 genes, of which 35 are Online Mendelian Inheritance in Man (OMIM) genes. The deleted region includes NFIX (OMIM #164005), CACNA1A (OMIM # 601011) and NACC1 (OMIM # 610672) genes which are previously reported to be associated with the presented clinical features. Conclusion: 19p13.12 microdeletion syndrome is a rare condition for which only one prenatal and 5 postnatal cases have been reported previously. This case of 19p13.12 microdeletion syndrome is the first case to be reported in Oman as well as in the Gulf Cooperation Council countries (GCC) and in the Middle East and North Africa (MENA).