Congenital Hypothyroidism Patients Research Articles

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.

Quality of life and socioeconomic and educational status in patients with congenital hypothyroidism.

The aim of this study was to investigate the influence of primary congenital hypothyroidism (CH) on quality of life, level of education and socioeconomic status (SES). Two independent study cohorts, a national and a regional, were collected from Finnish national registers and patient records. Data on social security benefits, SES, marital status, and education were collected from Statistics Finland. Health-related quality of life (HRQoL) was studied in the regional patient cohort with the standardized 15D and 16D instruments. There were no statistically significant differences in education level, marital status, or SES between CH patients (n = 40) and their matched controls at the age of 25 years. The mean 15D score was both statistically significantly and clinically importantly lower in CH patients (n = 29) than controls (0.904 vs. 0.953, p = 0.008). CH patients reported significantly lower scores across various dimensions of physical and mental HRQoL, including breathing, sleeping, speech, excretion, mental function, distress, and vitality. The mean 16D score was lower in CH patients compared to controls (0.917, vs. 0.947), but without statistical significance. SES of CH patients did not differ from matched controls. Thus, most CH patients integrate well into society, but their HRQoL is impaired. Most patients with primary congenital hypothyroidism integrate well into society. In the current study, their socioeconomic and marital status did not differ from matched controls at the age of 25 years. However, health-related quality of life measured using 15D instrument was impaired. Every fourth patient reported that congenital hypothyroidism influenced everyday life.

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.

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.

Intelligence quotient (IQ) outcome in children with early-treated congenital hypothyroidism: a systematic review and meta-analysis

Background Congenital hypothyroidism (CH) is the most common congenital endocrine disorder in childhood and is one of the most preventable causes of intellectual disability (ID). Late initiation of thyroid hormone substitution therapy has a negative impact on intellectual abilities in CH patients.
 Objective To compare Intelligence Quotient (IQ) between children with CH who underwent early treatment among the children without CH.
 Methods We performed online literature searches of ScienceDirect, Pubmed, Cochrane Library, and Google Scholar. We included clinical studies that examined IQ scores in patients with early-treated CH and without CH. Review Manager 5.4 was used to perform the meta-analysis.
 Results Twelve studies comparing pediatric patients with and without CH were included in this meta-analysis, for a total of 808 patients. Based on data analysis, IQ levels of verbal IQ [mean difference (MD) -9.05; (95%CI -14.51 to -3.59); (P<0.00001)], performance IQ [MD -11.70; (95%CI -17.41 to -5.99); (P<0.00001)], and total IQ [MD -10.78; (95%CI -14.03 to -7.54); (P<0.00001)]. While verbal, performance, total, of the early-treated CH group were within the normal range, they were each significantly lower than those in the non-CH group.
 Conclusion This meta-analysis reveals that IQ scores in early-treated CH subjects were within normal limits, but significantly lower than that of normal controls.

Neonatal screening for primary and central congenital hypothyroidism: is it time to go Dutch?

Thyroid hormone (TH) is indispensable for brain development in utero and during the first two to three years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage. Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterised by low TH concentrations while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH-based thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4-TSH-thyroxine-binding globulin (TBG) NBS algorithm for CH which enables detection of primary and central CH. Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild, and that early detection of central CH by NBS problably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.

Comorbidity in Congenital Hypothyroidism-A Nationwide, Population-based Cohort Study.

Patients with congenital hypothyroidism (CH) are affected more often than the general population by other chronic diseases and neurological difficulties. The aim of this nationwide population-based register study was to investigate the incidence of congenital malformations, comorbidities, and the use of prescribed drugs in patients with primary CH. The study cohort and matched controls were identified from national population-based registers in Finland. All diagnoses from birth until the end of 2018 were collected from the Care Register, and subject-specific prescription drug purchases were identified from The Prescription Register from birth until the end of 2017. Diagnoses of neonatal and chronic diseases were collected for 438 full-term patients and 835 controls (median follow-up time 11.6 years; range, 0-23 years). Newborns with CH were more often found to have neonatal jaundice (11.2% and 2.0%; P < .001), hypoglycemia (8.9% and 2.8%; P < .001), metabolic acidemia (3.2% and 1.1%; P = .007), and respiratory distress (3.9% and 1.3%; P < .003) as compared to their matched controls.Congenital malformations were diagnosed in 66 of 438 (15.1%) CH patients and in 62 of 835 (7.4%) controls (P < .001). The most commonly affected extrathyroidal systems were the circulatory and musculoskeletal systems. The cumulative incidence of hearing loss and specific developmental disorders was higher among CH patients than controls. The use of antidepressant and antipsychotic drugs was similar in CH patients and their controls. CH patients have more neonatal morbidity and congenital malformations than their matched controls. The cumulative incidence of neurological disorders is higher in CH patients. However, our results do not support the existence of severe psychiatric comorbidity.

Adult Thyroid Outcomes of Congenital Hypothyroidism.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

Genetic testing can change diagnosis and treatment in children with congenital hypothyroidism.

Guidelines on congenital hypothyroidism (CH) recommend that genetic testing should aim to improve diagnosis, treatment or prognosis, but it is unclear which patients would benefit most from the genetic investigation. We aimed to investigate the genetic etiology of transient CH (TCH) and permanent CH (PCH) in a well-characterized cohort, and thereby evaluate the impact of genetic testing on the management and prognosis of children with CH. A total of 48 CH patients with normal, goitrous (n 5) or hypoplastic thyroid (n 5) were studied by high-throughput sequencing using a custom-designed 23-gene panel. Patients initially categorized as TCH (n 15), PCH (n 26) and persistent hyperthyrotropinemia (PHT, n 7) were re-evaluated after genetic testing. Re-evaluation based on genetic testing changed the initial diagnoses from PCH to PHT (n 2) or TCH (n 3) and from PHT to TCH (n 5), which resulted in a final distribution of TCH (n 23), PCH (n 21) and PHT (n 4). Genetic analysis also allowed us to discontinue treatment in five patients with monoallelic TSHR or DUOX2, or no pathogenic variants. The main reasons for changes in diagnosis and treatment were the detection of monoallelic TSHR variants and the misdiagnosis of thyroid hypoplasia on neonatal ultrasound in low birthweight infants. A total of 41 (35 different, 15 novel) variants were detected in 65% (n 31) of the cohort. These variants, which most frequently affected TG, TSHR and DUOX2, explained the genetic etiology in 46% (n 22) of the patients. The molecular diagnosis rate was significantly higher in patients with PCH (57%, n 12) than TCH (26%, n 6). Genetic testing can change diagnosis and treatment decisions in a small proportion of children with CH, but the resulting benefit may outweigh the burden of lifelong follow-up and treatment.

Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism

ObjectiveThe 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 & methodsNBS 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. ResultsVariables 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%. ConclusionsMachine 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.

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.

Genetic mutation profiles for children with congenital hypothyroidism in Fujian province

Objective: To explore the mutation characteristics of pathogenic genes in children with congenital hypothyroidism (CH) in Fujian. Methods: The clinical data of 116 unrelated CH children diagnosed in Fujian Provincial Maternal and Child Health Hospital from January 2019 to September 2020 were retrospectively analyzed, including 50 females and 66 males, with an average age of (20±10) days at diagnosis. Targeted exome sequencing technology was used to detect the mutation frequency, type and distribution characteristics of 29 genes related to thyroxine synthesis or thyroid development. Results: Three hundred and fifty-one potential functional mutations were detected in 105 of 116 CH patients, with a detection rate of 90.5% (105/116). DUOX2 (66.4%, 77/116) was the most frequent mutated gene, followed by TG (23.3%, 27/116), DUOXA1 (23.3%, 27/116), and TPO (12.1%, 14/116), which were all involved in thyroid hormone synthesis. Among the 105 children with CH, 70 cases carried double allele mutation. Except for 3 cases of thyroid dysplasia related genes (2 cases of TSHR and 1 case of GLIS3), the rest were also related to thyroid hormone synthesis. The gene with the highest carrier rate was DUOX2 (68.8%, 59/70), followed by TG (8.6%, 6/70), TPO (4.3%, 3/70), DUOXA2 (1.4%, 1/70) and DUOXA1 (1.4%, 1/70). Conclusion: The main mutated genes in CH children in Fujian are the key genes involved in thyroid hormone synthesis, such as DUOX2, TG and TPO.

Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism.

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.

Guidelines for Newborn Screening of Congenital Hypothyroidism (2021 Revision)

Purpose of developing the guidelines: Newborn screening (NBS) for congenital hypothyroidism (CH) was started in 1979 in Japan, and early diagnosis and treatment improved the intelligence prognosis of CH patients. The incidence of CH was once about one in 5,000-8,000 births, but has been increased with diagnosis of subclinical CH. The disease requires continuous treatment and specialized medical facilities should conduct differential diagnosis and treatment in patients who are positive by NBS to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, the guidelines were revised in 2014. Here, we have added minor revisions to the 2014 version to include the most recent findings. Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Physical Development at School Entry in Children with Congenital Hypothyroidism Diagnosed by the National Program of Newborn Screening in Iran.

The newborn screening program for diagnosing and treating children with congenital hypothyroidism (CH) in Iran was established in 2004. This study aimed to evaluate the national program's success in maintaining the physical development and anthropometric indexes of children with CH. This historical cohort study was carried out in five provinces located in five different geographical regions of Iran. The anthropometric indexes, including weight, height, and head circumference of 240 children diagnosed with transient congenital hypothyroidism (TCH) (n = 131) and permanent congenital hypothyroidism (PCH) (n = 109) were measured and compared with those of 240 healthy children aged six. Mean ± standard deviation (SD) of weight, height, and head circumference of children with CH aged six were 20304.8 ± 4457.9 g, 115.6 ± 5.9 cm, and 50.8 ± 1.7 cm, respectively. Mean ± SD of height (116.7 ± 6.1 cm) and head circumference (51.1 ± 1.7 cm) in the control (healthy) group were significantly higher than those of the CH children group (P < 0.05). Mean ± SD weight in the control group (20741.2 ± 4337.3 g) was higher than that in the CH group (20304.8 ± 4457.9 g). However, the difference was not statistically significant (P = 0.3). No significant difference was observed between TCH and PCH children in the subgroup analysis (P > 0.05). Although the mean of anthropometric indexes in CH patients was slightly lower than that in healthy children aged six, the difference between the two groups was insignificant. The physical development of children with CH was evaluated as good. Our results suggested that the newborn screening program for identifying and treating children with CH in Iran may have improved the growth outcomes.

Genetic Factors Causing Thyroid Dyshormonogenesis as the Major Etiologies for Primary Congenital Hypothyroidism: Clinical and Genetic Characterization of 33 Patients.

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. 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. 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. 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.

Treatment of Congenital Hypothyroidism: Impact of Secular Changes in Levothyroxine Initial Dose on Early Growth

Introduction: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. Methods: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 μg/kg/day), 1990s (n = 50, 7.4 μg/kg/day), 2000s (n = 59, 9.7 μg/kg/day), and 2010s (n = 44, 10.8 μg/kg/day). Results: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. Discussion: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation.

ODP391 Neurodevelopmental and Growth Outcome of Congenital Hypothyroidism: A National Investigation of Birth Cohort Study

Abstract 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

ODP459 Adiposity Rebound in Japanese Patients with Congenital Hypothyroidism Detected by Neonatal Screening

Abstract Background More than 40 years have passed since the introduction of newborn screening programs (NBS) for congenital hypothyroidism (CH), and there have been many reports on the long-term outcome of CH identified by NBS. There are some reports that CH is associated with early adiposity rebound and adult obesity. On the other hand, the association between AR and CH has not been revealed in Japan. Objective The aim of this study was to evaluate the timing of AR in individuals with CH detected by NBS in our institution, furthermore, to find out the risk factors of early AR in CH individuals. Patients and Methods The study included 212 CH children (105 female/107 males) who were ten years of age or older as of September 2021. We retrospectively collected height and weight data from one to ten years of age, and the timing of AR was visually determined. We examined the association between the AR age and the severity of hypothyroidism at NBS and at the first visit. Results The median AR age was 5.6 years for boys and 6.2 years for girls, which was unexpectedly not unexpectedly younger than that of the general Japanese population reported by Koyama (4.8 ± 1.4 years for boys, 4.7 ± 1.5 years for girls). Data from 115 patients (107 males, 105 females) whose physique data between the age of 15 and 18 were available showed that body mass index (BMI) was 21.1±3.2 kg/m2 for males and 20.6±2.7 kg/m2 for females, positively correlated with AR age, and not significantly different from BMI at 15-19 years of age (21.1±3.6 for males and 20.2±2.2 for females) in the 2019 National Nutrition and Health Survey (p=0.790, p=0.619). NBS-FT4 was slightly positively correlated to AR age (r=0.234, p=0. 0315). We found that the AR age may be earlier and adult BMI may be higher in CH patients without ossification of the distal femoral epiphyseal nucleus at first evaluation. Discussion Severe fetal hypothyroidism may cause an absence of mineralization of the distal femoral epiphyses in the neonatal period. Our results indicate that severe fetal hypothyroidism, even if diagnosed and treated at neonatal, contributes to the development of adult obesity. Conclusion The AR age and BMI at 15-18 years of CH are not significantly different from the general population. However, severe fetal hypothyroidism could result in adult obesity. Presentation: No date and time listed

Mutation screening of eight genes and comparison of the clinical data in a Chinese cohort with congenital hypothyroidism.

Congenital hypothyroidism (CH) is a common neonatal endocrine disorder, characterized by irreversible intellectual disability and short stature if left untreated. It can be divided into thyroid dysgenesis (TD), including athyreosis, ectopy and hypoplasia, and dyshormonogenesis (DH), also referring to gland in situ (GIS), in which patients have eutopic thyroids with normal size or goiter. This study aims to analyze the clinical and genetic data of 375 Chinese CH patients without DUOX2 and thyroid transcription factor (TTF) variants, and to explore the mutation frequencies of the eight genes and the inheritance pattern of CH. Targeted next generation sequencing (NGS) and statistical analysis were performed for mutation screening on eight CH-related genes and the comparison of clinical data in a cohort of 606 Chinese CH patients from Henan Province. A total of 104 variants were detected in genes required for thyroid formation (TSHR, GLIS3, BOREALIN, NTN1, JAG1 and TUBB1) and thyroid hormone synthesis (TG and TPO) in 83 subjects. Monogenic variants were the most prevalent with a percentage of 75.00% (78/104) followed by oligogenic variants (25.00%, 26/104). No differences were found in various clinical data between patients with and without variants. However, it should be noted that only initial L-T4 dose was statistically different between patients with monogenic variants and oligogenic variants. Our results suggested that apart from Mendelian monogenic inheritance, oligogenic inheritance of CH could not be excluded and also involves other factors, such as penetrance, epigenetic mechanisms and environmental factors.