{"paper_id":"23a33bd0-1407-48d8-b778-5eac69b47a7e","body_text":"Trisomy 21 and thyroid dysfunction: A study in a cohort of Sri Lankan children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Trisomy 21 and thyroid dysfunction: A study in a cohort of Sri Lankan children Ashangi Madhushinie Weerasinghe, Navoda Atapattu, Sumudu Seneviratne, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8270642/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2026 Read the published version in BMC Pediatrics → Version 1 posted 13 You are reading this latest preprint version Abstract Background: Thyroid dysfunctions are the most common endocrine abnormalities observed in trisomy 21 (T21). The prevalence of thyroid disorders in children with T21 varies between 4% and 40%. Dysregulation of thyroid function, which is specific to T21, is a possible etiology. Thyroid dysfunction can have a significant impact on cognitive development and growth. Transiently abnormal TFTs are frequently observed in T21 and may cause diagnostic confusion. There is a paucity of prevailing literature on transiently abnormal TFTs, gland in situ congenital hypothyroidism and thyroid dysfunctions in children with T21 in resource-limited settings. Methods: Records from the Child Development Clinic dedicated to children with T21 at the university unit of Lady Ridgeway Hospital (LRH) were reviewed retrospectively. The prevalence and patterns of different thyroid dysfunctions were studied. Results: Among the 88 children with T21 (Male: Female ratio of 1.5:1), 35 (39.7%) had thyroid dysfunction. Seventeen (20%) children were managed as congenital hypothyroidism (CH), nine (10.2%) had transiently abnormal TFTs. Acquired hypothyroidism was noted in 8 (9%) children, and two children (2.3%) had hyperthyroidism. Among the 17 children who were managed as CH, 12 (70.5%) were diagnosed during the neonatal period following newborn screening (NBS). The mean TSH level at diagnosis was 22.3 mIU/l (10.6–58). All 17 children had normal ultrasound scans of the thyroid. The average current thyroxine dose in the < 3-year-old group (n=4) was 2.1 µg/kg/day, and in the ≥ 3-year-old group, it was 2.5 µg/kg/day. The average age at diagnosis of acquired hypothyroidism was 10 years and 4 months. In those managed as transiently abnormal TFTs, the time taken for TFTs to normalise (without any treatment) ranged between 6 weeks and 8 months. Conclusion: Thyroid dysfunction is a commonly encountered challenge in managing T21. Transiently abnormal TFTs are common and require close observation. Gland-in situ (GIS) CHs are increasingly being detected among this population. The cost-effectiveness of using genetic analysis in GIS-CH in resource-limited settings needs to be studied. Differentiating transient CH from permanent CH is quite challenging in clinical practice, although the low thyroxine dose requirement, especially after 3 years of age, may provide valuable information. Further longitudinal studies are needed to delineate the prevalence of transient vs permanent CH. Trisomy 21 thyroid dysfunction congenital hypothyroidism (CH) GIS-CH transiently abnormal TFT hyperthyroidism Background The spectrum of thyroid disorders in T21 consists of congenital hypothyroidism (CH), acquired hypothyroidism (subclinical or overt) and hyperthyroidism ( 1 , 2 ). Limited information is available about transiently abnormal TFTs, although they are very common in DS ( 3 ). Differentiating between transient and permanent thyroid dysfunction remains challenging, partly because of a lack of awareness of this transient phenomenon. Gland-in situ (GIS) CH has also shown an increasing prevalence in recent studies. This rise in detection rates has been attributed to the gradual reduction in the cut-off values of newborn screening ( 4 ). Approximately 35% of patients with GIS-CH have transient thyroid dysfunction and do not require lifelong thyroxine therapy (5). CH can be transient. Thyroid dysgenesis and dyshormogenesis usually predict that CH is permanent. The latter is caused by transplacental transfer of maternal autoantibodies (TRB-Ab), exposure to antithyroid drugs, and iodine deficiency, as well as genetic causes such as DUOX2 mutations ( 6 , 7 ). A study from a general paediatric cohort in the United States reported that 24–36% of CH cases identified by newborn screening (NBS) were later classified as transient ( 8 ). In terms of disease burden, the lifetime prevalence of thyroid dysfunction at T21 is as high as 13–63% ( 1 , 2 ). However, further deterioration of cognitive function can be reduced via early detection and treatment of thyroid dysfunction ( 3 , 9 ). Research on the prevalence and patterns of thyroid dysfunction among children with T21 in resource-limited settings at both the local and regional levels is scarce. In Sri Lanka, all newborns, including neonates with T21, are subjected to screening with TSH. TFTs are then performed at 6 months, 1 year and annually thereafter in accordance with the American Academy of Pediatrics (AAP) recommendations for T21 ( 10 ). To address the aforementioned gaps in knowledge, we conducted this study at Lady Ridgeway Hospital for children, a tertiary care center where children suspected of or diagnosed with T21 are referred from all over the country for long-term follow-up by a multidisciplinary team. Our objectives were to describe the prevalence and spectrum of thyroid dysfunction in children with T21 in a resource-limited setting: Sri-Lanka. Particular emphasis has been placed on exploring congenital hypothyroidism and transiently abnormal TFTs. Methods A retrospective cross-sectional descriptive study was carried out at the Child Development Clinic dedicated to children with T21, University Paediatrics Unit, Lady Ridgeway Hospital for Children (LRH), where holistic care is offered for children referred from all over the country. The study was conducted between August 2024 and March 2025. Children up to 16 years of age with a diagnosis of T21 (phenotypically confirmed by a consultant paediatrician with or without a confirmatory karyotype) were recruited. A nonprobability consecutive sampling method was used. Our aim was to characterise thyroid dysfunctions in children with T21. Data were collected via an interviewer-administered questionnaire and by reviewing health records during routine follow-up clinic visits. The operational definitions used to classify thyroid dysfunctions are included in Table 1. Standard descriptive statistics were used to analyse the data. Table-1- Case definitions of thyroid dysfunctions Thyroid dysfunction Operational definition Congenital hypothyroidism 1. Baby with an abnormal newborn screening, who on further review has a serum TSH > 20 mIU/L ± low fT4 or 2. Baby with an abnormal newborn screening, who on further review has a serum TSH- 6–20 mIU/L and USS showing small/ectopic thyroid gland ± low fT4 or 3. If NBS not done, a serum TSH > 20 mIU/L ± low fT4 and < age 3years Acquired hypothyroidism Raised serum thyroid stimulating hormone (TSH) ± low fT4 based on age specific reference ranges, above 3years of age (and not meeting criteria for congenital hypothyroidism). Hyperthyroidism Low thyroid-stimulating hormone (TSH) concentration in combination with high free thyroxine (fT4) concentration compared with age specific reference ranges Transiently abnormal TFT Abnormal serum thyroid stimulating hormone (TSH) level compared with age specific reference ranges with normal fT4 and TSH gets normalised over time without any therapeutic intervention Results Prevalence Eighty-eight children (F:M-1.5:1) were recruited into the study. Nondysjunction was the most common finding in terms of karyotype (96%). Thyroid function was abnormal in thirty-five participants (39.8%), the majority of whom were males (F:M- 1:2). The current age of the participants varied from 7 days to 16 years. The most common thyroid dysfunction was CH (48.6%), followed by transiently abnormal TFTs (25.7%). Eight participants had acquired hypothyroidism (9%), and two children had hyperthyroidism (5.7%). The remaining participants never had abnormal TFTs among the available and recorded test results. The results are summarised in Table 2 . Congenital hypothyroidism, Gland- In Situ (GIS) CH Sixty-nine (78.4%) children had undergone NBS. Among the seventeen participants diagnosed with CH, twelve (70%) were detected by NBS. The other patients (n = 5) were diagnosed via TFTs performed during follow-up. The mean TSH level at the time of CH diagnosis was 22.3 mIU/L. Ultrasound scans of the thyroid were normal in all subjects with CH. The age at diagnosis of CH varied between day3 and 1 year. In 2 children (2/17, 11%), CH was diagnosed between 2 weeks and 6 months. Associated anomalies and comorbidities Eighty-eight percent of subjects with CH had congenital heart disease, and VSD was the most common cardiac anomaly. None of the participants with CH had associated gastrointestinal or renal anomalies. Transiently abnormal TFT Transiently abnormal TFT were observed among participants at varying ages ranging from 2 weeks to 9 years. The majority (4/9) were observed in infancy, and one was observed during the neonatal period (Day 6). Importantly, none of the patients fulfilled the abovementioned diagnostic criteria for CH (Table 1). The maximum TSH value among these patients was 21.37 mIU/L, which was associated with a normal fT4 for age (1.2 ng/dL). One of these participants who had transiently abnormal TFTs (elevated TSH) at seven years of age developed acquired hypothyroidism five years later. The child in whom transient elevation of TSH was detected on day 6 of age had abnormal NBS. She was started on thyroxine on day 6 of life after blood was drawn for venous TSH. The venous TSH level was high (26.6 mIU/L). However, the TSH level after two weeks of starting thyroxine was very low (0.32 mIU/L), and thyroxine was withheld. The results of 3 weeks of repeated TSH without thyroxine treatment were normal. Acquired thyroid dysfunctions The F:M ratio of acquired hypothyroidism patients was 1:1, and the average age at diagnosis was 10 years and 4 months. Ultrasound scan of the thyroid revealed evidence of thyroiditis in 6 (75%) participants. Hyperthyroidism was noted in two participants whose average age at diagnosis was 4 year 2 m. Type 1 diabetes was noted in only one child with acquired hypothyroidism. One participant with hyperthyroidism subsequently developed Addison's disease. Among the 35 participants with thyroid dysfunction, only 3 (8.5%) had a positive family history of thyroid disorder in a first- or second-degree relative. Table 2 Spectrum of thyroid dysfunctions Thyroid dysfunction Number % Average age at diagnosis CH 17 19.3 60 d Transiently abnormal TSH 9 10.2 3 y 2 m Acquired hypothyroidism 8 9 10 y 4 m Hyperthyroidism 2 2.2 4 y 2 m Discussion Transiently abnormal TFT One of the key findings of this cross-sectional descriptive study performed at a tertiary care center was that a significant proportion of children (10.2%) had transiently abnormal TFTs. Transiently elevated TSH has been considered a common thyroid dysfunction in children with T21 in several studies ( 3 , 11 ). Although this is a frequent encounter in follow-up, the exact mechanism or management protocols of this entity are not well established. This may lead to unwarranted burdens through frequent investigations, mislabelling as permanent hypothyroidism or even unnecessary treatment. Gland- in situ (GIS) congenital hypothyroidism Interestingly, the USS in all children with CH was normal in this group. This finding is similar to the results of a study performed in Thailand ( 12 ). This finding contrasts with the prevailing literature, which mentions thyroid dysgenesis as the most common cause of CH ( 13 ). A study performed in Turkey reported thyroid hypoplasia in 95% of children with CH among their study participants (3, 14). An increasing number of studies have recently reported gland-in situ (GIS) CH among the general population undergoing newborn screening. On the one hand, the recent increase in CH with GIS is attributed to the gradual reduction in the cut-off value of TSH used in NBS ( 4 ). On the other hand, thyroid hormone organification defects and inactivating TSH-receptor gene mutations have been suggested as possible mechanisms of this entity ( 15 , 16 ). Therefore, the role of genetic testing in this group of children to reveal molecular mechanisms needs to be studied further. Transient vs permanent CH In both the CH patient groups in our study, those younger than three years and those ≥ 3 years, the average daily thyroxine requirement was relatively low (2.1 and 2.5 µg/kg/day, respectively). Comparing the prevalence of transient vs permanent CH is beyond the scope of our cross-sectional study. However, according to a recent consensus guideline endorsed by the European Society of Pediatric Endocrinology, interrupted treatment is recommended if the daily dose of L-thyroxine (LT4) is less than 25 µg (or < 3 µg/kg/day), with stable or decreasing dose requirements without an increase in TSH during therapy. If a child with no permanent CH diagnosis and a GIS requires an LT4 dose less than 3 µg/kg per day at the age of 6 months, then re-evaluation can be performed at that time ( 4 , 17 ). TFTs during follow-up Since there were children (n = 2, 11%) who were diagnosed with CH between 2 weeks and 6 months, the necessity of an additional TFT between birth and 6 months in this at-risk population needs to be evaluated further. Prevalence Our study confirmed a higher prevalence of thyroid dysfunction in T21 patients (39.8%). This varies among studies. While the reported prevalence in another Asian cohort was 40%( 12 ), it was comparatively lower (24%) in a Caucasian cohort ( 1 ). Wide variation in prevalence data can be due to population characteristics, differences in the diagnostic criteria used and the technique used to analyse thyroid hormones (18). The most common thyroid dysfunction in our study cohort was CH. The prevalence of CH in our study was as high as 19.3%. Seventy percent of them were detected by NBS. Similarly, a high prevalence (21.5%) was reported in another study (n = 50) from Libya ( 19 ). In contrast, a study performed in Thailand reported the prevalence of CH to be 3.4% in a cohort of 140 participants ( 20 ). Local and regional prevalence data need further validation through studies involving substantially larger cohorts. Hyperthyroidism The prevalence of hyperthyroidism was greater in our study cohort than in the studies published to date. The highest reported prevalence of hyperthyroidism was 0.06% (21). Two children (2.2%) in our cohort had hyperthyroidism. Hyperthyroidism in T21 is caused mainly by Graves' disease. Thyroid autoantibodies were not detected in these study participants because of concerns about cost-effectiveness in a resource-limited setting. Associated anomalies Congenital heart diseases, particularly ventricular septal defects (VSDs), are frequently observed among children with CH. One limitation of this retrospective descriptive study was the inability to observe the impact of abnormal TFTs on growth and cognition. Since there was no control group, we could not compare the study population with children with thyroid disorders and not with those with T21. Although this study was performed at the largest paediatric centre of the island, the study population may not ideally represent the national population with T21, as the majority of the participants were referred from urban areas situated on the outskirts in proximity to the hospital. Conclusion Our study data reconfirmed the increased prevalence of thyroid dysfunction in children with DS. The inherent mechanisms that are specific to DS that predispose individuals to developing thyroid dysfunction remain unclear. Maintaining a national registry of children with T21 enables equity and optimisation of the care given in resource-limited settings. Further studies in those settings have the potential to improve patients’ lives. Transiently abnormal TFTs are common in children with T21. Although this entity is transient, it needs due attention and close follow-up with TFTs. Studies addressing its precise pathophysiology and its potential impact on cognition will lay the background for establishing specific management protocols. CH may not necessarily be due to thyroid dysgenesis and may occur while the thyroid gland is in situ. Our study further supports recent reports indicating a rise in GIS-CH. Utilisation of recent genetic advances to identify the etiology of CH with GIS is a challenge in resource-limited settings. To date, specific management of transient CH lack clear mentions in the guidelines. Many children are treated until three years of age, with careful monitoring. Thyroxine is tapered over 4‒6 weeks, and TSH monitoring is performed after 3 years of age if transient CH is suspected but unproven. Abbreviations T21- Trisomy 21/Down Syndrome, CH-congenital hypothyroidism TFT-Thyroid function tests GIS-CH-Gland-in situ congenital hypothyroidism, TSH-Thyroid stimulating hormone USS- Ultrasound scan NBS- Newborn screening, LRH-Lady Ridgeway Hospital for children, VSD - Ventricular septal defect LT4- L-thyroxine Declarations Ethics approval and consent to participate: Ethics approval was obtained from the ERC (Ethics Review Committee), Faculty of Medicine, University of Colombo, Sri Lanka. Written, informed consent to participate was obtained from the parents or legal guardians of all the participants under the age of 16. Assent was obtained from the subjects when they were appropriate. Our study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Consent for publication: Written informed consent was obtained from the parent/legal guardian for the publication of all clinical details included in this article. Availability of data and materials: The datasets used during the current study are available from the corresponding author upon reasonable request. Competing Interests: The authors declare that they have no competing interests. Funding: No funding was received for this study. Authors' contributions: AW and RD collected the data and analysed the patient data. SS and NA interpreted the data regarding thyroid dysfunction and were major contributors to the writing of the manuscript. All the authors read and approved the final manuscript. Acknowledgements: We acknowledge the support of the University Paediatrics Unit, Lady Ridgeway Hospital for children for facilitating this study. References Pierce Melinda J, LaFranchi Stephen H, Pinter Joseph D. Characterisation of Thyroid Abnormalities in a Large Cohort of Children with Down Syndrome. Hormone Res Paediatrics. 2017;87(3):170–8. Mulu B, Fantahun B. 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Thyroid Function Tests in Children and Adolescents with Trisomy 21: Definition of Syndrome-Specific Reference Ranges. J Clin Endocrinol &Metabolism 2023Jun3;108(11):2779–88. Metwalley KA, Farghaly HS. Endocrine Dysfunction in Children with Down Syndrome. Annals Pediatr Endocrinol Metabolism. 2022;27(1):15–21. Nikolina Zdraveska M, Kocova, Nicholas AK, Anastasovska V, Schoenmakers N. Genetics of Gland-in situ or Hypoplastic Congenital Hypothyroidism in Macedonia. Front Endocrinol. 2020;11. Van Trotsenburg P, Stoupa A, Léger J, Rohrer T, Peters C, Fugazzola L et al. Congenital Hypothyroidism: A 2020–2021 Consensus Guidelines Update—An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021;31(3):387–419. ‌18. Prasher V. Down Syndrome and Thyroid Disorders: A Review. Down Syndrome Research and Practice. 1999;6(1):25–42. Millad Ghawil K, Abulbeida M, Doggah. Thyroid disorders in Libyan patients with Down syndrome. Libyan J Med Res. 2021;15(2):62–8. Unachak K, Md T, Pongprot Y, Sittivangkul R, Silvilairat S, Dejkhamron P et al. Thyroid Functions in Children with Down’s Syndrome. J Med Assoc Thai. 2008;91(1). ‌21. Goday-Arno A, Cerda-Esteva M, Flores-Le-Roux JA, Chillaron-Jordan JJ, Corretger JM, Cano-Pérez JF. Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol. 2009Jul;71(1):110. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2026 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 29 Jan, 2026 Reviews received at journal 23 Jan, 2026 Reviews received at journal 22 Jan, 2026 Reviews received at journal 21 Jan, 2026 Reviewers agreed at journal 18 Jan, 2026 Reviewers agreed at journal 17 Jan, 2026 Reviewers agreed at journal 15 Jan, 2026 Reviewers agreed at journal 27 Dec, 2025 Reviewers invited by journal 25 Dec, 2025 Editor assigned by journal 11 Dec, 2025 Editor invited by journal 08 Dec, 2025 Submission checks completed at journal 05 Dec, 2025 First submitted to journal 05 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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16:26:55\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":548005,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8270642/v1/875033f3-979c-49fc-b106-b3db3901451e.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Trisomy 21 and thyroid dysfunction: A study in a cohort of Sri Lankan children\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eThe spectrum of thyroid disorders in T21 consists of congenital hypothyroidism (CH), acquired hypothyroidism (subclinical or overt) and hyperthyroidism (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e). Limited information is available about transiently abnormal TFTs, although they are very common in DS (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e). Differentiating between transient and permanent thyroid dysfunction remains challenging, partly because of a lack of awareness of this transient phenomenon.\\u003c/p\\u003e \\u003cp\\u003eGland-in situ (GIS) CH has also shown an increasing prevalence in recent studies. This rise in detection rates has been attributed to the gradual reduction in the cut-off values of newborn screening (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e). Approximately 35% of patients with GIS-CH have transient thyroid dysfunction and do not require lifelong thyroxine therapy (5).\\u003c/p\\u003e \\u003cp\\u003eCH can be transient. Thyroid dysgenesis and dyshormogenesis usually predict that CH is permanent. The latter is caused by transplacental transfer of maternal autoantibodies (TRB-Ab), exposure to antithyroid drugs, and iodine deficiency, as well as genetic causes such as DUOX2 mutations (\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e). A study from a general paediatric cohort in the United States reported that 24\\u0026ndash;36% of CH cases identified by newborn screening (NBS) were later classified as transient (\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn terms of disease burden, the lifetime prevalence of thyroid dysfunction at T21 is as high as 13\\u0026ndash;63% (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e). However, further deterioration of cognitive function can be reduced via early detection and treatment of thyroid dysfunction (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e). Research on the prevalence and patterns of thyroid dysfunction among children with T21 in resource-limited settings at both the local and regional levels is scarce. In Sri Lanka, all newborns, including neonates with T21, are subjected to screening with TSH. TFTs are then performed at 6 months, 1 year and annually thereafter in accordance with the American Academy of Pediatrics (AAP) recommendations for T21 (\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eTo address the aforementioned gaps in knowledge, we conducted this study at Lady Ridgeway Hospital for children, a tertiary care center where children suspected of or diagnosed with T21 are referred from all over the country for long-term follow-up by a multidisciplinary team. Our objectives were to describe the prevalence and spectrum of thyroid dysfunction in children with T21 in a resource-limited setting: Sri-Lanka. Particular emphasis has been placed on exploring congenital hypothyroidism and transiently abnormal TFTs.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003e A retrospective cross-sectional descriptive study was carried out at the Child Development Clinic dedicated to children with T21, University Paediatrics Unit, Lady Ridgeway Hospital for Children (LRH), where holistic care is offered for children referred from all over the country. The study was conducted between August 2024 and March 2025. Children up to 16 years of age with a diagnosis of T21 (phenotypically confirmed by a consultant paediatrician with or without a confirmatory karyotype) were recruited. A nonprobability consecutive sampling method was used.\\u003c/p\\u003e \\u003cp\\u003eOur aim was to characterise thyroid dysfunctions in children with T21. Data were collected via an interviewer-administered questionnaire and by reviewing health records during routine follow-up clinic visits.\\u003c/p\\u003e \\u003cp\\u003eThe operational definitions used to classify thyroid dysfunctions are included in Table\\u0026nbsp;1. Standard descriptive statistics were used to analyse the data.\\u003c/p\\u003e \\u003cp\\u003eTable-1- Case definitions of thyroid dysfunctions\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"No\\\" id=\\\"Taba\\\" border=\\\"1\\\"\\u003e \\u003ccolgroup cols=\\\"2\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThyroid dysfunction\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eOperational definition\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCongenital hypothyroidism\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1. Baby with an abnormal newborn screening, who on further review has a serum TSH\\u0026thinsp;\\u0026gt;\\u0026thinsp;20 mIU/L\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;low fT4 or\\u003c/p\\u003e \\u003cp\\u003e2. Baby with an abnormal newborn screening, who on further review has a serum TSH- 6\\u0026ndash;20 mIU/L and USS showing small/ectopic thyroid gland\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;low fT4 or\\u003c/p\\u003e \\u003cp\\u003e3. If NBS not done, a serum TSH\\u0026thinsp;\\u0026gt;\\u0026thinsp;20 mIU/L\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;low fT4 and \\u0026lt; age 3years\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAcquired hypothyroidism\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRaised serum thyroid stimulating hormone (TSH)\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;low fT4 based on age specific reference ranges, above 3years of age (and not meeting criteria for congenital hypothyroidism).\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHyperthyroidism\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eLow thyroid-stimulating hormone (TSH) concentration in combination with high free thyroxine (fT4) concentration compared with age specific reference ranges\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTransiently abnormal TFT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAbnormal serum thyroid stimulating hormone (TSH) level compared with age specific reference ranges with normal fT4 and TSH gets normalised over time without any therapeutic intervention\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePrevalence\\u003c/h2\\u003e \\u003cp\\u003eEighty-eight children (F:M-1.5:1) were recruited into the study. Nondysjunction was the most common finding in terms of karyotype (96%). Thyroid function was abnormal in thirty-five participants (39.8%), the majority of whom were males (F:M- 1:2). The current age of the participants varied from 7 days to 16 years. The most common thyroid dysfunction was CH (48.6%), followed by transiently abnormal TFTs (25.7%). Eight participants had acquired hypothyroidism (9%), and two children had hyperthyroidism (5.7%). The remaining participants never had abnormal TFTs among the available and recorded test results. The results are summarised in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eCongenital hypothyroidism, Gland-\\u003c/em\\u003eIn Situ \\u003cem\\u003e(GIS) CH\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003eSixty-nine (78.4%) children had undergone NBS. Among the seventeen participants diagnosed with CH, twelve (70%) were detected by NBS. The other patients (n\\u0026thinsp;=\\u0026thinsp;5) were diagnosed via TFTs performed during follow-up. The mean TSH level at the time of CH diagnosis was 22.3 mIU/L. Ultrasound scans of the thyroid were normal in all subjects with CH. The age at diagnosis of CH varied between day3 and 1 year. In 2 children (2/17, 11%), CH was diagnosed between 2 weeks and 6 months.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eAssociated anomalies and comorbidities\\u003c/h3\\u003e\\n\\u003cp\\u003eEighty-eight percent of subjects with CH had congenital heart disease, and VSD was the most common cardiac anomaly. None of the participants with CH had associated gastrointestinal or renal anomalies.\\u003c/p\\u003e\\n\\u003ch3\\u003eTransiently abnormal TFT\\u003c/h3\\u003e\\n\\u003cp\\u003eTransiently abnormal TFT were observed among participants at varying ages ranging from 2 weeks to 9 years. The majority (4/9) were observed in infancy, and one was observed during the neonatal period (Day 6). Importantly, none of the patients fulfilled the abovementioned diagnostic criteria for CH (Table\\u0026nbsp;1). The maximum TSH value among these patients was 21.37 mIU/L, which was associated with a normal fT4 for age (1.2 ng/dL). One of these participants who had transiently abnormal TFTs (elevated TSH) at seven years of age developed acquired hypothyroidism five years later.\\u003c/p\\u003e \\u003cp\\u003eThe child in whom transient elevation of TSH was detected on day 6 of age had abnormal NBS. She was started on thyroxine on day 6 of life after blood was drawn for venous TSH. The venous TSH level was high (26.6 mIU/L). However, the TSH level after two weeks of starting thyroxine was very low (0.32 mIU/L), and thyroxine was withheld. The results of 3 weeks of repeated TSH without thyroxine treatment were normal.\\u003c/p\\u003e\\n\\u003ch3\\u003eAcquired thyroid dysfunctions\\u003c/h3\\u003e\\n\\u003cp\\u003eThe F:M ratio of acquired hypothyroidism patients was 1:1, and the average age at diagnosis was 10 years and 4 months. Ultrasound scan of the thyroid revealed evidence of thyroiditis in 6 (75%) participants. Hyperthyroidism was noted in two participants whose average age at diagnosis was 4\\u0026nbsp;year 2 m. Type 1 diabetes was noted in only one child with acquired hypothyroidism. One participant with hyperthyroidism subsequently developed Addison's disease.\\u003c/p\\u003e \\u003cp\\u003eAmong the 35 participants with thyroid dysfunction, only 3 (8.5%) had a positive family history of thyroid disorder in a first- or second-degree relative.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eSpectrum of thyroid dysfunctions\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThyroid dysfunction\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNumber\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e%\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAverage age at diagnosis\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e19.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e60 d\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTransiently abnormal TSH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 y 2 m\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAcquired hypothyroidism\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10 y 4 m\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHyperthyroidism\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4 y 2 m\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eTransiently abnormal TFT\\u003c/h2\\u003e \\u003cp\\u003eOne of the key findings of this cross-sectional descriptive study performed at a tertiary care center was that a significant proportion of children (10.2%) had transiently abnormal TFTs. Transiently elevated TSH has been considered a common thyroid dysfunction in children with T21 in several studies (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e). Although this is a frequent encounter in follow-up, the exact mechanism or management protocols of this entity are not well established. This may lead to unwarranted burdens through frequent investigations, mislabelling as permanent hypothyroidism or even unnecessary treatment.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eGland-\\u003c/em\\u003ein situ \\u003cem\\u003e(GIS) congenital hypothyroidism\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003eInterestingly, the USS in all children with CH was normal in this group. This finding is similar to the results of a study performed in Thailand (\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). This finding contrasts with the prevailing literature, which mentions thyroid dysgenesis as the most common cause of CH (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e). A study performed in Turkey reported thyroid hypoplasia in 95% of children with CH among their study participants (3, 14). An increasing number of studies have recently reported gland-in situ (GIS) CH among the general population undergoing newborn screening.\\u003c/p\\u003e \\u003cp\\u003eOn the one hand, the recent increase in CH with GIS is attributed to the gradual reduction in the cut-off value of TSH used in NBS (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e). On the other hand, thyroid hormone organification defects and inactivating TSH-receptor gene mutations have been suggested as possible mechanisms of this entity (\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e). Therefore, the role of genetic testing in this group of children to reveal molecular mechanisms needs to be studied further.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eTransient\\u003c/em\\u003e vs \\u003cem\\u003epermanent CH\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003eIn both the CH patient groups in our study, those younger than three years and those\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 years, the average daily thyroxine requirement was relatively low (2.1 and 2.5 \\u0026micro;g/kg/day, respectively). Comparing the prevalence of transient vs permanent CH is beyond the scope of our cross-sectional study. However, according to a recent consensus guideline endorsed by the European Society of Pediatric Endocrinology, interrupted treatment is recommended if the daily dose of L-thyroxine (LT4) is less than 25 \\u0026micro;g (or \\u0026lt;\\u0026thinsp;3 \\u0026micro;g/kg/day), with stable or decreasing dose requirements without an increase in TSH during therapy. If a child with no permanent CH diagnosis and a GIS requires an LT4 dose less than 3 \\u0026micro;g/kg per day at the age of 6 months, then re-evaluation can be performed at that time (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e).\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eTFTs during follow-up\\u003c/h3\\u003e\\n\\u003cp\\u003eSince there were children (n\\u0026thinsp;=\\u0026thinsp;2, 11%) who were diagnosed with CH between 2 weeks and 6 months, the necessity of an additional TFT between birth and 6 months in this at-risk population needs to be evaluated further.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePrevalence\\u003c/h2\\u003e \\u003cp\\u003eOur study confirmed a higher prevalence of thyroid dysfunction in T21 patients (39.8%). This varies among studies. While the reported prevalence in another Asian cohort was 40%(\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e), it was comparatively lower (24%) in a Caucasian cohort (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e). Wide variation in prevalence data can be due to population characteristics, differences in the diagnostic criteria used and the technique used to analyse thyroid hormones (18). The most common thyroid dysfunction in our study cohort was CH.\\u003c/p\\u003e \\u003cp\\u003eThe prevalence of CH in our study was as high as 19.3%. Seventy percent of them were detected by NBS. Similarly, a high prevalence (21.5%) was reported in another study (n\\u0026thinsp;=\\u0026thinsp;50) from Libya (\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e). In contrast, a study performed in Thailand reported the prevalence of CH to be 3.4% in a cohort of 140 participants (\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e). Local and regional prevalence data need further validation through studies involving substantially larger cohorts.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eHyperthyroidism\\u003c/h2\\u003e \\u003cp\\u003eThe prevalence of hyperthyroidism was greater in our study cohort than in the studies published to date. The highest reported prevalence of hyperthyroidism was 0.06% (21). Two children (2.2%) in our cohort had hyperthyroidism. Hyperthyroidism in T21 is caused mainly by Graves' disease. Thyroid autoantibodies were not detected in these study participants because of concerns about cost-effectiveness in a resource-limited setting.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssociated anomalies\\u003c/h2\\u003e \\u003cp\\u003eCongenital heart diseases, particularly ventricular septal defects (VSDs), are frequently observed among children with CH.\\u003c/p\\u003e \\u003cp\\u003eOne limitation of this retrospective descriptive study was the inability to observe the impact of abnormal TFTs on growth and cognition. Since there was no control group, we could not compare the study population with children with thyroid disorders and not with those with T21. Although this study was performed at the largest paediatric centre of the island, the study population may not ideally represent the national population with T21, as the majority of the participants were referred from urban areas situated on the outskirts in proximity to the hospital.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eOur study data reconfirmed the increased prevalence of thyroid dysfunction in children with DS. The inherent mechanisms that are specific to DS that predispose individuals to developing thyroid dysfunction remain unclear. Maintaining a national registry of children with T21 enables equity and optimisation of the care given in resource-limited settings. Further studies in those settings have the potential to improve patients\\u0026rsquo; lives.\\u003c/p\\u003e \\u003cp\\u003eTransiently abnormal TFTs are common in children with T21. Although this entity is transient, it needs due attention and close follow-up with TFTs. Studies addressing its precise pathophysiology and its potential impact on cognition will lay the background for establishing specific management protocols.\\u003c/p\\u003e \\u003cp\\u003eCH may not necessarily be due to thyroid dysgenesis and may occur while the thyroid gland is in situ. Our study further supports recent reports indicating a rise in GIS-CH. Utilisation of recent genetic advances to identify the etiology of CH with GIS is a challenge in resource-limited settings.\\u003c/p\\u003e \\u003cp\\u003e To date, specific management of transient CH lack clear mentions in the guidelines. Many children are treated until three years of age, with careful monitoring. Thyroxine is tapered over 4‒6 weeks, and TSH monitoring is performed after 3 years of age if transient CH is suspected but unproven.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eT21- Trisomy 21/Down Syndrome,\\u003c/p\\u003e\\n\\u003cp\\u003eCH-congenital hypothyroidism\\u003c/p\\u003e\\n\\u003cp\\u003eTFT-Thyroid function tests\\u003c/p\\u003e\\n\\u003cp\\u003eGIS-CH-Gland-in situ congenital hypothyroidism,\\u003c/p\\u003e\\n\\u003cp\\u003eTSH-Thyroid stimulating hormone\\u003c/p\\u003e\\n\\u003cp\\u003eUSS- Ultrasound scan\\u003c/p\\u003e\\n\\u003cp\\u003eNBS- Newborn screening, LRH-Lady Ridgeway Hospital for children,\\u003c/p\\u003e\\n\\u003cp\\u003eVSD - Ventricular septal defect\\u003c/p\\u003e\\n\\u003cp\\u003eLT4- L-thyroxine\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate:\\u0026nbsp;\\u003c/strong\\u003eEthics approval was obtained from the ERC (Ethics Review Committee), Faculty of Medicine, University of Colombo, Sri Lanka. Written, informed consent to participate was obtained from the parents or legal guardians of all the participants under the age of 16. Assent was obtained from the subjects when they were appropriate. Our study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication:\\u0026nbsp;\\u003c/strong\\u003eWritten informed consent was obtained from the parent/legal guardian for the publication of all clinical details included in this article.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials:\\u0026nbsp;\\u003c/strong\\u003eThe datasets used during the current study are available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting Interests:\\u0026nbsp;\\u003c/strong\\u003eThe authors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding:\\u0026nbsp;\\u003c/strong\\u003eNo funding was received for this study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors' contributions:\\u003c/strong\\u003eAW and RD collected the data and analysed the patient data. SS and NA interpreted the data regarding thyroid dysfunction and were major contributors to the writing of the manuscript. All the authors read and approved the final manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements:\\u003c/strong\\u003eWe acknowledge the support of the University Paediatrics Unit, Lady Ridgeway Hospital for children for facilitating this study.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003ePierce Melinda J, LaFranchi Stephen H, Pinter Joseph D. Characterisation of Thyroid Abnormalities in a Large Cohort of Children with Down Syndrome. Hormone Res Paediatrics. 2017;87(3):170\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMulu B, Fantahun B. Thyroid abnormalities in children with Down syndrome at St. Paul\\u0026rsquo;s hospital millennium medical college. Ethiopia Endocrinol Diabetes Metabolism. 2022;5(3).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCebeci Ayşe N, Ayla G, Metin Y. Profile of Hypothyroidism in Down\\u0026rsquo;s Syndrome. J Clin Res Pediatr Endocrinol. 2013;5(2):116\\u0026ndash;204.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePaolo Cavarzere, Mancioppi V, Battiston R, Lupieri V, Morandi A, Maffeis C. Primary congenital hypothyroidism: a clinical review. Frontiers in Endocrinology., Schoenmakers N. Mechanisms in Endocrinology: The pathophysiology of transient congenital hypothyroidism. European Journal of Endocrinology.2022;187(2):R1\\u0026ndash;16.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKemper AR, Grosse SD, Baker M, Pollock AJ, Hinton CF, Shapira SK. Treatment Discontinuation within 3 Years of Levothyroxine Initiation among Children Diagnosed with Congenital Hypothyroidism. J Paediatrics. 2020;223:136\\u0026ndash;40.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRazavi Z, Mohammadi L. Permanent and Transient Congenital Hypothyroidism in Hamadan West Province of Iran. Int J Endocrinol Metabolism. 2016;14(4).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKanike N, Davis A, Shekhawat PS. Transient hypothyroidism in the newborn: to treat or not to treat. Translational Pediatr. 2017;6(4):349\\u0026ndash;58.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDalrymple RA. Thyroid disorder in children and young people with Down syndrome: DSMIG guideline review. Archives Disease Child - Educ Pract.2021 Feb7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBull MJ. Health Supervision for Children With Down Syndrome. Pediatrics. 2011;128(2):393\\u0026ndash;406.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKara C, G\\u0026uuml;nindi F, Can Yılmaz G, Aydın M. Transient Congenital Hypothyroidism in Turkey: An Analysis on Frequency and Natural Course. J Clin Res Pediatr Endocrinol. 2016;8(2):170\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eUnachak K, Tanpaiboon P, Pongprot Y, Sittivangkul R, Silvilairat S, Dejkhamron P, et al. Thyroid functions in children with Down\\u0026rsquo;s syndrome. J Med Assoc Thai. 2008;91(1):56\\u0026ndash;61.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBowden SA, Goldis M. Congenital Hypothyroidism. Nih.gov. StatPearls Publishing;2023[cited2025Aug8].\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAlessandro Cattoni, Molinari S, Giulia Capitoli N, Masera ML, Nicolosi, Barzaghi S et al. Thyroid Function Tests in Children and Adolescents with Trisomy 21: Definition of Syndrome-Specific Reference Ranges. J Clin Endocrinol \\u0026amp;Metabolism 2023Jun3;108(11):2779\\u0026ndash;88.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMetwalley KA, Farghaly HS. Endocrine Dysfunction in Children with Down Syndrome. Annals Pediatr Endocrinol Metabolism. 2022;27(1):15\\u0026ndash;21.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNikolina Zdraveska M, Kocova, Nicholas AK, Anastasovska V, Schoenmakers N. Genetics of Gland-in situ or Hypoplastic Congenital Hypothyroidism in Macedonia. Front Endocrinol. 2020;11.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eVan Trotsenburg P, Stoupa A, L\\u0026eacute;ger J, Rohrer T, Peters C, Fugazzola L et al. Congenital Hypothyroidism: A 2020\\u0026ndash;2021 Consensus Guidelines Update\\u0026mdash;An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021;31(3):387\\u0026ndash;419. \\u0026zwnj;18. Prasher V. Down Syndrome and Thyroid Disorders: A Review. Down Syndrome Research and Practice. 1999;6(1):25\\u0026ndash;42.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMillad Ghawil K, Abulbeida M, Doggah. Thyroid disorders in Libyan patients with Down syndrome. Libyan J Med Res. 2021;15(2):62\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eUnachak K, Md T, Pongprot Y, Sittivangkul R, Silvilairat S, Dejkhamron P et al. Thyroid Functions in Children with Down\\u0026rsquo;s Syndrome. J Med Assoc Thai. 2008;91(1).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003e\\u0026zwnj;21. Goday-Arno A, Cerda-Esteva M, Flores-Le-Roux JA, Chillaron-Jordan JJ, Corretger JM, Cano-P\\u0026eacute;rez JF. Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol. 2009Jul;71(1):110.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Trisomy 21, thyroid dysfunction, congenital hypothyroidism (CH), GIS-CH, transiently abnormal TFT, hyperthyroidism\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8270642/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8270642/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cu\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThyroid dysfunctions are the most common endocrine abnormalities observed in trisomy 21 (T21). The prevalence of thyroid disorders in children with T21 varies between 4% and 40%. Dysregulation of thyroid function, which is specific to T21, is a possible etiology. Thyroid dysfunction can have a significant impact on cognitive development and growth. Transiently abnormal TFTs are frequently observed in T21 and may cause diagnostic confusion. There is a paucity of prevailing literature on transiently abnormal TFTs, gland in situ congenital hypothyroidism and thyroid dysfunctions in children with T21 in resource-limited settings.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eRecords from the Child Development Clinic dedicated to children with T21 at the university unit of Lady Ridgeway Hospital (LRH) were reviewed retrospectively. The prevalence and patterns of different thyroid dysfunctions were studied.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAmong the 88 children with T21 (Male: Female ratio of 1.5:1), 35 (39.7%) had thyroid dysfunction. Seventeen (20%) children were managed as congenital hypothyroidism (CH), nine (10.2%) had transiently abnormal TFTs. Acquired hypothyroidism was noted in 8 (9%) children, and two children (2.3%) had hyperthyroidism.\\u003c/p\\u003e\\n\\u003cp\\u003eAmong the 17 children who were managed as CH, 12 (70.5%) were diagnosed during the neonatal period following newborn screening (NBS). The mean TSH level at diagnosis was 22.3 mIU/l (10.6–58). All 17 children had normal ultrasound scans of the thyroid. The average current thyroxine dose in the \\u0026lt; 3-year-old group (n=4) was 2.1 µg/kg/day, and in the ≥ 3-year-old group, it was 2.5 µg/kg/day. The average age at diagnosis of acquired hypothyroidism was 10 years and 4 months. In those managed as transiently abnormal TFTs, the time taken for TFTs to normalise (without any treatment) ranged between 6 weeks and 8 months.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003e\\u003cstrong\\u003eConclusion:\\u003c/strong\\u003e\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThyroid dysfunction is a commonly encountered challenge in managing T21. Transiently abnormal TFTs are common and require close observation. Gland-in situ (GIS) CHs are increasingly being detected among this population. The cost-effectiveness of using genetic analysis in GIS-CH in resource-limited settings needs to be studied. Differentiating transient CH from permanent CH is quite challenging in clinical practice, although the low thyroxine dose requirement, especially after 3 years of age, may provide valuable information. Further longitudinal studies are needed to delineate the prevalence of transient vs permanent CH.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Trisomy 21 and thyroid dysfunction: A study in a cohort of Sri Lankan children\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-12-26 15:35:37\",\"doi\":\"10.21203/rs.3.rs-8270642/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2026-01-29T10:03:05+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-01-23T07:32:10+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-01-23T00:06:00+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-01-21T15:37:24+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"163870893382700602013789909955000831878\",\"date\":\"2026-01-19T04:17:47+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"85630021437168030389236953908410084644\",\"date\":\"2026-01-17T13:31:12+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"94785910595221954821699731730127786944\",\"date\":\"2026-01-15T18:32:16+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"328230626575691185879934328210864805193\",\"date\":\"2025-12-27T08:26:58+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-12-25T06:56:01+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-12-11T10:40:47+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2025-12-08T07:59:25+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-12-06T01:20:50+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Pediatrics\",\"date\":\"2025-12-06T01:15:23+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"d04281e4-2670-482b-9fc1-8a5f9911d4c3\",\"owner\":[],\"postedDate\":\"December 26th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-03-30T16:21:09+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-8270642\",\"link\":\"https://doi.org/10.1186/s12887-026-06761-2\",\"journal\":{\"identity\":\"bmc-pediatrics\",\"isVorOnly\":false,\"title\":\"BMC Pediatrics\"},\"publishedOn\":\"2026-03-26 16:09:02\",\"publishedOnDateReadable\":\"March 26th, 2026\"},\"versionCreatedAt\":\"2025-12-26 15:35:37\",\"video\":\"\",\"vorDoi\":\"10.1186/s12887-026-06761-2\",\"vorDoiUrl\":\"https://doi.org/10.1186/s12887-026-06761-2\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8270642\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8270642\",\"identity\":\"rs-8270642\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}