Cases Of Congenital Hypothyroidism Research Articles

Congenital and acquired hypothyroidism: Temporal and spatial trends in France from 2014 to 2019

PurposeTo assess the incidence of congenital hypothyroidism (CH) and acquired hypothyroidism (AH) between 2014 and 2019 in continental France. MethodsNew cases of CH and AH were identified using the French National Health Data System (Système Nationale des Données de Santé, SNDS). Temporal trends were studied using linear regression models. Spatial distributions were studied using Moran's global index (I) and the statistical method and local indicators of spatial association. ResultsThe incidence of permanent CH in females increased by 8.9 % per year (2014: 36.9 [31.1–43.7] per 100,000 birth-years vs. 2019: 51 [43.9–59.3] per 100,000 birth-years, p < 0.01). The incidence of AH decreased between 2014 and 2019 for both females (2014: 535.7 [533.2–538.2] per 100,000 person-years vs 2019: 335.5 [333.6–337.4] per 100,000 person-years, p < 0.01) and males (2014: 197.5 [195.9–199] per 100,000 person-years vs 2019: 141.7 [140.4–142.9] per 100,000 person-years, p < 0.01). The incidence of hypothyroidism was high in the Nord-Pas-De-Calais and Lorraine regions (CH and AH). ConclusionsThe incidence of permanent CH in females has increased over time. AH incidence decreased. It seems necessary to investigate environmental factors in the disparity of incidence distribution.

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

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

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

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

Revealing the genetic complexity of hypothyroidism: integrating complementary association methods.

Hypothyroidism is a common endocrine disorder whose prevalence increases with age. The disease manifests itself when the thyroid gland fails to produce sufficient thyroid hormones. The disorder includes cases of congenital hypothyroidism (CH), but most cases exhibit hormonal feedback dysregulation and destruction of the thyroid gland by autoantibodies. In this study, we sought to identify causal genes for hypothyroidism in large populations. The study used the UK-Biobank (UKB) database, reporting on 13,687 cases of European ancestry. We used GWAS compilation from Open Targets (OT) and tuned protocols focusing on genes and coding regions, along with complementary association methods of PWAS (proteome-based) and TWAS (transcriptome-based). Comparing summary statistics from numerous GWAS revealed a limited number of variants associated with thyroid development. The proteome-wide association study method identified 77 statistically significant genes, half of which are located within the Chr6-MHC locus and are enriched with autoimmunity-related genes. While coding GWAS and PWAS highlighted the centrality of immune-related genes, OT and transcriptome-wide association study mostly identified genes involved in thyroid developmental programs. We used independent populations from Finland (FinnGen) and the Taiwan cohort to validate the PWAS results. The higher prevalence in females relative to males is substantiated as the polygenic risk score prediction of hypothyroidism relied mostly from the female group genetics. Comparing results from OT, TWAS, and PWAS revealed the complementary facets of hypothyroidism's etiology. This study underscores the significance of synthesizing gene-phenotype association methods for this common, intricate disease. We propose that the integration of established association methods enhances interpretability and clinical utility.

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

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

JAG1 Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis in 813 Congenital Hypothyroidism in China.

Congenital hypothyroidism (CH) is indeed a prevalent neonatal endocrine disorder, affecting approximately 1 in 2000-3000 newborns worldwide, and 1 in 2400 newborns in China. Despite its high incidence, the genetic causes of CH, particularly those related to thyroid dysgenesis (TD), are still not well understood. However, previous studies have suggested that JAG1 may be a potential susceptibility gene for congenital thyroid defects. To explore the association between JAG1 and CH, we screened JAG1 variants in a large cohort of 813 CH patients. We performed genetic analysis of JAG1 using next-generation sequencing in 813 CH cases. The pathogenicity of the variants was assessed by bioinformatics softwares, protein sequence conservation analysis, and hydrophobic analysis. Further genetic analysis was conducted targeting 20 CH-related genes in these 25 JAG1 variant carriers. We identified 10 pathogenic missense mutations (p.V45L, p.V272I, p.P552L, p.G610E, p.G852D, p.A891T, p.E1030K, p.R1060W, p.A1131T, p.P1174L) carried by 25 patients, the mutation rate of JAG1 in CH was 3.08%. Among these 25 patients, 16 with 1 variant, 6 with 2 variants, and the other 3 with 3 variants. Our findings indicated that JAG1 variants confer genetic susceptibility to both TD and DH, but with different inheritance models. JAG1 variants lead to TD mainly through monogenic model, while for DH cases, both monogenic mechanisms and oligogenic mechanisms play a pivotal role. Oligogenicity may contribute to the disease severity of DH. JAG1 is a shared genetic factor in TD and DH, with a detection rate of 3.08% in Chinese individuals with CH. A comparison between the oligogenic and monogenic groups suggests a gene dosage effect in CH. Patients with the same JAG1 mutation exhibit diverse clinical phenotypes, indicating complex mechanisms underlying phenotypic heterogeneity.

A literature review on the redundancy of additional thyroid function tests in neonates of mothers with hypothyroidism.

Newborn thyroid screening tests are carried out during the first days after birth in many parts of the world. The aim of this review was to assess whether additional thyroid function tests of neonates born to mothers with hypothyroidism are necessary to diagnose newborns with congenital hypothyroidism (CH) missed by the usual screening test. A search in PubMed and Google Scholar databases was conducted for pertinent studies, using relevant keywords. All studies that were published in any language from 1 January 2000 to 30 June 2023 were included. Observational cohort studies were included in the analysis, while case reports and studies not referring to neonates were excluded. Thirteen studies were identified comprising more than 4400 infants with CH. Studies with the larger study populations recommended against additional testing in healthy infants of hypothyroid mothers. Similar were the results of some smaller retrospective studies. Few studies identified in total 16 infants with CH that were missed on neonatal screening without, though, a definite causative link between the mother's and the infant's thyroid dysfunction. Based on available data, additional thyroid function tests seem redundant in identifying undiagnosed cases of CH. Larger studies are needed to reach a definite conclusion.

Results of neonatal screening for congenital hypothyroidism and hyperphenylalaninemia in Zhejiang province from 1999 to 2022.

To analyze the results of neonatal screening for congenital hypothyroidism (CH) and hyperphenylalaninemia (HPA) in Zhejiang province from 1999 to 2022. A total of 11 922 318 newborns were screened from September 1999 and December 2022 in Zhejiang province. The blood thyroid stimulating hormone (TSH) levels were measured by a fluorescence method and blood phenylalanine (Phe) levels were measured by fluorescence method or tandem mass spectrometry. TSH≥9 μIU/mL was considered positive for CH, while Phe>120 μmol/L and/or Phe/Tyr ratio>2.0 were considered positive for HPA. The positive newborns in screening were recalled, and the gene variations were detected by high-throughput sequencing and MassARRAY tests. The overall neonatal screening rate during 1999-2022 was 89.41% (11 922 318/13 333 929) and the screening rate was increased from 6.46% in 1999 to 100.0% in 2022. A total of 8924 cases of CH were diagnosed among screened newborns with an incidence rate of 1/1336. A total of 563 cases of HPA were diagnosed, including 508 cases of classic phenylketonuria (cPKU) and 55 cases of tetrahydrobiopterin deficiency (BH4D), with an incidence rate of 1/21 176. Ninety-seven out of 8924 cases of CH underwent genetic analysis. Gene mutations were detected in 9 CH related genes, the highest frequency mutations were found in DUOX2 gene (69.0%) with c.3329G>A (p.R1110Q) (18.2%) and c.1588A>T (p.K530X) (17.3%) as the hotspot mutations. There were 81 PAH gene variants detected in a total of 250 cases of cPKU, and c728G>A (p.R243Q) (24.4%), c.721C>T (p.R241C) (15.0%) were the hotspot mutations. Meanwhile 7 novel variants in PAH gene were detected: c.107C>A (p.S36*), c.137G>T (p.G46V), c.148A>G(p.K50E), c.285C>T (p.I95I), c.843-10delTTCC, exon4-7del and c.1066-2A>G. There were 12 PTS gene variants detected in 36 cases of BH4D, and c.259C>T (p.P87S) (31.9%) was the hotspot mutation. The incident of CH has increased from 1999 to 2022 in Zhejiang province, and it is higher than that of national and global levels; while the incidence of HPA is similar to the national average. DUOX2 gene variation is the most common in CH patients; c.728G>A (p.R243Q) is the hotspot mutation in cPKU patients, while c.259C>T (p.P87S) is the hotspot mutation in BH4D patients.

Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients.

The disorder of thyroid gland development or thyroid dysgenesis accounts for 80-85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the genetic spectrum of congenital hypothyroid children in Bangladesh. Thus, an understanding of the molecular aetiology of thyroid dysgenesis is a prerequisite. The aim of the study was to investigate the effect of mutations in the TSHR gene on the small molecule thyrogenic drug-binding site of the protein. We identified two nonsynonymous mutations (p.Ser508Leu, p.Glu727Asp) in the exon 10 of the TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, the TSHR368-764 protein was modeled by the I-TASSER server for wild-type and mutant structures. The model proteins were targeted by thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants was explored by molecular docking and molecular dynamics simulations. The binding affinity of wild-type protein was much higher than the mutant cases for both of the drug ligands (MS437 and MS438). Molecular dynamics simulates the dynamic behavior of wild-type and mutant complexes. MS437-TSHR368-764MT2 and MS438-TSHR368-764MT1 showed stable conformations in biological environments. Finally, Principle Component Analysis revealed structural and energy profile discrepancies. TSHR368-764MT1 exhibited much more variations than TSHR368-764WT and TSHR368-764MT2, emphasizing a more damaging pattern in TSHR368-764MT1. This genetic study might be helpful to explore the mutational impact on drug binding sites of TSHR protein which is important for future drug design and selection for the treatment of congenital hypothyroid children with dysgenesis.

Increased incidence of congenital hypothyroidism in China: An analysis of 119 million screened newborns.

Despite the lack of nationwide epidemiological studies, congenital hypothyroidism (CH) incidence in China has increased. We aimed to evaluate the trends of CH and the possible reasons behind them. Data from screened newborns from the Chinese Newborn Screening Information System from 2012 to 2019 was collected. We applied the Bayesian hierarchical Poisson regression model and meta-analysis to estimate incidence or proportion over the years. The estimated CH incidence increased from 4.01 per 10,000 births in 2012 to 5.77 per 10,000 births in 2019. The average annual growth rate (ARG) of CH incidence for all provinces varied from 0.59 to 20.96%. The most rapid rise in incidence was observed in cases with an initial thyroid stimulating hormone (TSH) concentration of < 10 mIU/L. The meta-analysis results showed that the proportion of permanent CH increased by 0.024% (95%CI: 0.011%, 0.037%) annually. Each 1 mIU/L decrease in TSH cutoff value was associated with a 2.96% increase in CH incidence. In the same period, the proportion of premature CH cases increased from 6.60 to 9.10%, which was much higher than the increase in preterm births. A significant relationship was not found between provincial growth rates in screening coverage and provincial baseline incidences of CH. Conclusion:CH incidence has substantially increased in China. The slight adjustment of the TSH cutoff value and increasing preterm birth rate contribute to such a trend; however, the contribution is limited. What is Known: • An uptrend in congenital hypothyroidism (CH) incidence has been reported in many European and American countries in the last two decades; however, no studies have been conducted in China to explain the increased CH incidence. • We provide a detailed epidemiological report on the trends of CH during 2012-2019 in China, with an attempt to explore the reasons behind it. What is New: • This first-ever national-wide epidemiological report in China showed an uptrend in CH incidence with variations over regions and CH subtypes. The mild lowering of TSH cutoff values and the increasing preterm birth rate contributed to this uptrend.

Congenital hypothyroidism in Bogotá, Colombia: acurrent description (2015-2021).

Congenital hypothyroidism (CH) is a decrease in thyroid hormone function in newborns, being one of theleading causes of neurological deficits and long-term metabolic complications. This study aims to determine the prevalence and characteristics of CH cases in Bogotá, Colombia, between 2015 and 2021, as notified through the mandatory report to the Public Health Surveillance System (PHSS). A retrospective cross-sectional study was conducted. All live births (LB) with a weight≥500 g, diagnosed with CH with or without goiter (ICD-10 codes E030 and E031, respectively) in Bogotá during 2015-2021 were analyzed. For a total of 201 cases, the prevalence rate was 3.29cases per 10,000 LB. 92.54 % were classified as isolated cases of CH, 4.48 % syndromic, and 2.98 % polymalformated. A total of 16.92 % was small for gestational age. The mean gestational age was 37.38weeks (SD 2.76), 26.87 % were preterm births. Among the mothers, 8.96 % suffered from pregnancy-related or chronic diseases, the most common being hypertensive disorders of pregnancy and pre-existant hypothyroidism (without clarity concerning etiology). Atotalof 66.67 % of cases did not receive treatment after diagnosis. Treatment was established by an average age of27days after birth (SD 36.02) and 17days after case notification to the PHSS (SD 36.13). Observed prevalence is similar to the rate reported by health authorities in Colombia but inferior to reports from high-income countries, highlighting the importance of improvements in the Colombian LB's screening program. Time to diagnosis and treatment was observed to be prolonged, suggesting that new pathways are required for timely CH treatment.

Conservative Treatment of Fetal Goitrous Hypothyroidism Due to Thyroglobulin Mutations: A Case Report and Literature Review

Abstract With the advances in fetal medicine, there will be more cases of congenital hypothyroidism (CH) diagnosed in the fetal period. However, there is no consensus on the management protocol. We present a successful case of conservatively managed fetal goitrous hypothyroidism due to compound heterozygous TG mutations. Goiter was observed in a fetus at 23 weeks of gestation. Because there was no evidence of transplacental passage of antithyroid antibody and drugs, iodine overload, and iodine deficiency, the fetus was highly suspected to have CH. Considering the potential risks of amniocentesis/cordocentesis, and lack of available parenteral levothyroxine in China, the fetus was closely monitored thereafter. A male neonate was delivered vaginally without complications at 39 weeks of gestation. We verified severe hypothyroidism in the infant and immediately initiated levothyroxine therapy. His growth and mental development were normal at the age of 8 month. Whole-exome sequencing showed that the neonate had two compound heterozygous mutations in the TG gene. We also performed a literature review of the prognosis of postnatal treatment of CH due to TG mutations and the result showed that postnatal treatment of CH due to TG mutations has a favorable prognosis. However, further prospective studies are warranted to verify this conclusion.

Comparison of developmental outcomes in children with permanent and transient congenital hypothyroidism.

Congenital hypothyroidism (CH) is still one of the most common causes of preventable cognitive impairment in children, and its early detection and treatment prevent irreversible neurodevelopmental delay. Depending on the underlying cause, cases with CH may be transient or permanent. This study aimed to compare the developmental evaluation results of transient and permanent CH patients and to reveal any differences. A total of 118 patients with CH, who were followed up jointly in pediatric endocrinology and developmental pediatrics clinics, were included. The patients' progress was evaluated per the International Guide for Monitoring Child Development (GMCD). Of the cases, 52 (44.1%) were female, and 66 (55.9%) were male. While 20 (16.9%) cases were diagnosed with permanent CH, 98 (83.1%) were diagnosed with transient CH. According to the results of the developmental evaluation made with GMCD, the development of 101 (85.6%) children was compatible with their age, while 17 (14.4%) children had delays in at least one developmental area. All 17 patients had a delay in expressive language. Developmental delay was detected in 13 (13.3%) of those with transient CH and 4 (20%) with permanent CH. There is difficulty in expressive language in all cases of CH with developmental delay. No significant difference was found between the developmental evaluations of permanent and transient CH cases. The results revealed the importance of developmental follow-up, early diagnosis and interventions in those children. GMCD is thought to be an important guide to help monitoring the development of patients with CH.

Detect delayed thyroid stimulating hormone elevation in preterm neonates at age of one month

Background: The promotion of early foetal tissue growth and development is facilitated by thyroid hormones. This study sought to examine if instances of the existing screening programme would miss cases of congenital hypothyroidism as well as to identify delayed thyroid stimulating hormone (TSH) increase with gestational age in preterm neonates (33 weeks) at age one month. Methods: In this prospective study, 50 preterm neonates with gestational ages between 33 weeks and less than ≤1.8 kg were included. They were split into two equal groups: Group 1 contained low birth weight (LBW) infants, defined as those weighing less than 1.8 kg at delivery (1.5:1.8 kg). Baby born with a very low birth weight (VLBW) of less than 1.5 kg is in group 2. During the first week after birth and again at one month, free thyroxine hormone (FT4), free triiodothyronine (FT3), and TSH were collected as part of a routine screening programme. Results: TSH levels increased in both groups at one month, with Group II having a greater TSH than the other. The relationship between TSH at one month and birth weight in the two study groups was significantly unfavourable. The level of FT4 and FT3 at birth and one month were substantially different across groups for APGAR1, APGAR 2, and other measurements. Conclusions: Thyroid issues are common in preterm babies with a gestational age of 33 weeks and birth weight of 1800 grammes. When thyroid dysfunction was present, the majority of patients exhibited CH and delayed TSH rise, which newborn blood spot screening was unable to identify (NBS).

A retrospective study on newborn screening for metabolic disorders.

The process of testing newborn infants for hormonal, genetic, metabolic, and other disorders is known as newborn screening (NSB). Newborn screening is essential for detecting, diagnosing, and treating disorders that could save serious consequences for a newborn's health. Congenital Hypothyroidism (CH), Cystic Fibrosis (CF), Glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Profound Biotinidase deficiency (BD) are common disorders in India. A retrospective analysis of the results of NBS by Cord blood spots was performed at the department of Obstetrics and Gynecology, 7 Airforce Hospital, Kanpur, Uttar Pradesh, from June 2022 to September 2022. During this period, 26 newborns were screened for four disorders, including CH, CF, G6PD deficiency, and BD. In this investigation, no cases of CH, CF, G6PD deficiency, or BD were found to be positive. The results of the current data provide a distinct opportunity to investigate the birth prevalence of inborn metabolic disorders in the area close to the city of Kanpur.

ODP378 Biliary Sludge in a Neonate with Congenital Hypothyroidism

Abstract Background Most cases of congenital hypothyroidism are asymptomatic. When signs are evident, they are nonspecific. Characteristic clinical findings, including prolonged jaundice are seen in less than 5% of affected neonates. Clinical Case Female newborn, full term, appropriate weight for gestational age, five days old, Kramer zone 3 jaundice. The laboratory ruled out hemolysis, blood group incompatibility and TORCH infections. Hepatobiliary ultrasound showed biliary sludge. The screening for congenital hypothyroidism reported a TSH value of 38 mlU/L; the free T4 value was analyzed and was low. With the diagnosis of congenital hypothyroidism, levothyroxine therapy was started. The biliary sludge disappeared two weeks after initiation of hormone therapy. Conclusion It is important to exclude other causes of biliary sludge formation, such as sepsis, parenteral nutrition, hemolytic disease, metabolic diseases, some drugs and pyloric stenosis. Congenital hypothyroidism may be associated with biliary sludge formation; thyroid hormones have an inhibitory effect on the contractility of the sphincter of Oddi. Presentation: No date and time listed

ODP374 Abdominal Distention as a Unique Sign of Congenital Hypothyroidism

Abstract Background Most neonates with congenital hypothyroidism have a normal appearance at birth. Infrequent clinical presentations have been reported, including abdominal distention as the only sign, which remit with the initiation of levothyroxine therapy. Clinical Case Female newborn, full-term, appropriate weight for gestational age, six days old, who presented abdominal distension, without vomiting and with normal meconium elimination. No visceromegaly or abdominal masses were palpated. With the diagnosis of sepsis, treatment was started with ampicillin and amikacin, decompressive nasogastric tube and intravenous fluids. Abdominal X-ray showed intestinal distension. The requested cultures were negative. On the seventh day of life a TSH level of 89 mlU/L was reported; the free T4 value was analyzed and was found to be low. With the diagnosis of congenital hypothyroidism, levothyroxine therapy was indicated, and the abdominal distension remitted one week after initiation of therapy. Conclusion Most cases of congenital hypothyroidism are asymptomatic; abdominal distension, as the only sign of congenital hypothyroidism, is caused by the lower intestinal motility frequently observed in congenital hypothyroidism. Presentation: No date and time listed

Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism

PurposeThe elevated frequency of discordance for congenital hypothyroidism (CH) phenotype between monozygotic twins suggests the involvement of non-mendelian mechanisms. The aim of the study was to investigate the role of epigenetics in CH pathogenesis.MethodsA genome-wide DNA methylation analysis was performed on the peripheral blood of 23 twin pairs (10 monozygotic and 13 dizygotic), 4 concordant and 19 discordant pairs for CH at birth.ResultsDifferential methylation analysis did not show significant differences in methylation levels between CH cases and controls, but a different methylation status of several genes may explain the CH discordance of a monozygotic twin couple carrying a monoallelic nonsense mutation of DUOX2. In addition, the median number of hypo-methylated Stochastic Epigenetic Mutations (SEMs) resulted significantly increased in cases compared to controls. The prioritization analysis for CH performed on the genes epimutated exclusively in the cases identified SLC26A4, FOXI1, NKX2-5 and TSHB as the genes with the highest score. The analysis of significantly SEMs-enriched regions led to the identification of two genes (FAM50B and MEG8) that resulted epigenetically dysregulated in cases.ConclusionEpigenetic modifications may potentially account for CH pathogenesis and explain discordance among monozygotic twins.

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

An increased incidence of congenital hypothyroidism (CH) has been described worldwide over theyears. 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. 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 4weeks of L-thyroxine withdrawal at age of 2-3years to confirm the diagnosis of permanent CH (PCH) or transient CH (TCH). 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 >5mIU/L ranged from 8.03 to 20.46%, indicating iodine deficiency. The prevalence of preterm infants increased from 5.50% inperiod [2010-2014] to 7.06% in period [2015-2020] (p<0.001). 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.

Evaluation of permanent and transient congenital hypothyroidism in cases referred from National Neonatal Screening Program.

The incidence of congenital hypothyroidism (CH) has increased world-wide. Lowering cut-off in screening programs has led to an increase in the rate of transient CH. We aimed to evaluate the rates of permanent and transient CH in cases referred from the screening program and to investigate the clinical and laboratory factors which predict transient CH. In 109 cases referred from the neonatal screening program to our hospital, from September 2015 to April 2018, 52 primarily diagnosed CH cases were prospectively evaluated. Regularly followed up, 44 CH cases were included in the study at the end of 3 years. 38.2 ± 1.31 weeks (w) and mean birthweight 3021.3 ± 389.6gram (g) in the transient CH group; both were significantly lower compared to permanent CH cases with 39.06 ± 1.33 w and 3375.3 ± 425.3g (P=0.025, P=0.007) respectively. Transient CH rate was found to be 50% (all hypoplastic) in the dysgenesis group and 73.3% in groups with normal and hyperplasic thyroid gland. While fT4 , thyroid-stimulating hormone, and thyroglobulin levels at diagnosis do not predict transient/permanent CH, levothyroxine (LT-4) dosage was significantly lower in the transient CH group in all years. The optimal cut-off value with highest sensitivity and specificity for LT-4 dosage as a predictive marker to differentiate transient CH from permanent CH was 2.27μg/kg/day (P=0.004; sensitivity: 71%, specificity: 83%) at 1st year, 1.85μg /kg/day (P=0.013; sensitivity: 66%, specificity: 72%) at 2nd year and 1.69μg /kg/day at 3rd year (P < 0.0001; sensitivity: 90%, specificity: 83%). Transient CH is more frequent than expected. Our results suggest that LT-4 requirement may be a good marker for predicting transient CH, while thyroid hormone levels at the time of diagnosis do not significantly predict permanent and transient CH. Therefore, infants with CH requiring LT-4 doses <2.27 μg/kg/day at 1st year, <1.85 μg /kg/day at 2nd year may be re-evaluated earlier to discriminate transient CH rather than at 3 years of age.