79 results on '"Zwaveling-Soonawala N"'
Search Results
2. Bone Mineral Density in Children and Adolescents With Prader-Willi Syndrome: A Longitudinal Study During Puberty and 9 Years of Growth Hormone Treatment
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Bakker, N. E., Kuppens, R. J., Siemensma, E. P. C., Tummers-de Lind van Wijngaarden, R. F. A., Festen, D. A. M., Bindels-de Heus, G. C. B., Bocca, G., Haring, D. A. J. P., Hoorweg-Nijman, J. J. G., Houdijk, E. C. A. M., Jira, P. E., Lunshof, L., Odink, R. J., Oostdijk, W., Rotteveel, J., Van Alfen, A. A. E. M., Van Leeuwen, M., Van Wieringen, H., Wegdam-den Boer, M. E. J., Zwaveling-Soonawala, N., and Hokken-Koelega, A. C. S.
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- 2015
3. Intra-operative visualization of the common bile duct by ICG fluorescence imaging during a near-total pancreatectomy in an infant
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Zwanenburg, E.S., primary, Hompes, R., additional, Mooij, C., additional, Zwaveling - Soonawala, N., additional, Besselink, M., additional, and Oomen, M., additional
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- 2021
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4. Eight Years of Growth Hormone Treatment in Children With Prader-Willi Syndrome: Maintaining the Positive Effects
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Bakker, N. E., Kuppens, R. J., Siemensma, E. P. C., Tummers-de Lind van Wijngaarden, R. F. A., Festen, D. A. M., Bindels-de Heus, G. C. B., Bocca, G., Haring, D. A. J. P., Hoorweg-Nijman, J. J. G., Houdijk, E. C. A. M., Jira, P. E., Lunshof, L., Odink, R. J., Oostdijk, W., Rotteveel, J., Schroor, E. J., Van Alfen, A. A. E. M., Van Leeuwen, M., Van Pinxteren-Nagler, E., Van Wieringen, H., Vreuls, R. C. F. M., Zwaveling-Soonawala, N., de Ridder, M. A. J., and Hokken-Koelega, A. C. S.
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- 2013
5. Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening
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Naafs, J C, primary, Verkerk, P H, additional, Fliers, E, additional, van Trotsenburg, A S P, additional, and Zwaveling-Soonawala, N, additional
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- 2020
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6. Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation
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Zwaveling-Soonawala, N., Hagebeuk, E. E., Slingerland, A. S., Ris-Stalpers, C., Vulsma, T., and van Trotsenburg, A. S.
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- 2011
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7. Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data
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Naafs, J C, primary, Vendrig, L M, additional, Limpens, J, additional, van der Lee, H J, additional, Duijnhoven, R G, additional, Marchal, J P, additional, Trotsenburg, A S van, additional, and Zwaveling-Soonawala, N, additional
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- 2020
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8. Mortality in Children With Early-Detected Congenital Central Hypothyroidism
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Zwaveling-Soonawala, N., Naafs, J.C., Verkerk, P.H., and Trotsenburg, A.S.P. van
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Life ,Health ,CH - Child Health ,ELSS - Earth, Life and Social Sciences ,Healthy for Life ,Healthy Living - Abstract
Context Approximately 60% to 80% of patients with congenital central hypothyroidism (CH-C) have multiple pituitary hormone deficiencies (MPHDs), making CH-C a potentially life-threatening disease. Data on mortality in patients with CH-C are lacking. Objective To study the mortality rate in pediatric patients with early-detected and treated CH-C in the Netherlands and to investigate whether causes of death were related to pituitary hormone deficiencies. Methods Overall mortality rate, infant mortality rate (IMR), and under-5 mortality rate were calculated in all children with CH-C detected by neonatal screening between 1 January 1995 and 1 January 2013. Medical charts were reviewed to establish causes of death. Results A total of 139 children with CH-C were identified, of which 138 could be traced (82 with MPHD, 56 with isolated CH-C). Total observation time was 1414 years with a median follow-up duration of 10.2 years. The overall mortality rate was 10.9% (15/138). IMR and under-5 mortality rate were 65.2/1000 (9/138) and 101.4/1000 (14/138), respectively, compared with an IMR of 4.7/1000 and under-5 mortality of 5.4/1000 live-born children in the Netherlands during the same time period (P < 0.0001). Main causes of death were severe congenital malformations in six patients, asphyxia in two patients, and congenital or early neonatal infection in two patients. Pituitary hormone deficiency was noted as cause of death in only one infant. Conclusion We report an increased mortality rate in patients with early-detected CH-C that does not seem to be related to endocrine disease. This suggests that mortality due to pituitary insufficiency is low in patients with early-detected and early-treated CH-C.
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- 2018
9. Mutations in TBL1X Are Associated With Central Hypothyroidism
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Heinen, C.A., Losekoot, M., Sun, Y., Watson, P.J., Fairall, L., Joustra, S.D., Zwaveling-Soonawala, N., Oostdijk, W., Akker, E.L.T. van den, Alders, M., Santen, G.W.E., Rijn, R.R. van, Dreschler, W.A., Surovtseva, O.V., Biermasz, N.R., Hennekam, R.C., Wit, J.M., Schwabe, J.W.R., Boelen, A., Fliers, E., Trotsenburg, A.S.P. van, ANS - Complex Trait Genetics, Paediatric Endocrinology, Other Research, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Human Genetics, Radiology and Nuclear Medicine, APH - Amsterdam Public Health, Ear, Nose and Throat, Paediatric Genetics, Endocrinology Laboratory, Endocrinology, and Pediatrics
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Adult ,Male ,Heterozygote ,Adolescent ,Hypothalamus ,Infant ,Original Articles ,Middle Aged ,Pedigree ,Thyroxine ,Young Adult ,Hypothyroidism ,Pituitary Gland ,Mutation ,Humans ,Female ,RNA, Messenger ,Transducin ,Child ,Hearing Loss ,hormones, hormone substitutes, and hormone antagonists - Abstract
Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. Objective: The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands. Design: This was an observational study. Setting: The study was conducted at university medical centers. Patients: Nineteen individuals with and seven without a mutation participated in the study. Main Outcome Measures: Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. Results: Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%–25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary. Conclusions: TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH., By using DNA-analysis, clinical and biochemical phenotyping, and in vitro functional and expression studies, we show that TBL1X mutations are associated with central hypothyroidism and hearing loss.
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- 2016
10. Intracraniele actinomycose bij een kind met een carieus gebit
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Zwaveling-Soonawala, N., Spanjaard, L., van de Wetering, M., Winterberg, D. H., Paediatric Endocrinology, Amsterdam institute for Infection and Immunity, Medical Microbiology and Infection Prevention, and General Paediatrics
- Abstract
A diagnosis of intracranial actinomycosis was made in a 9-year-old boy with headache, cranial nerve dysfunction and ataxia. Poor dental hygiene leading to caries and an inflammation in his right upper jaw probably was the cause of cervicofacial actinomycosis with intracranial extension. A full recovery was achieved by treatment with benzylpenicillin. Actinomyces is a gram-positive bacterium belonging to the endogenous flora of the mucous membranes of the oropharynx, gastrointestinal tract, and female genital tract. Disruption of the mucous membrane is the portal of entry for an extremely destructive infective process that is effectively treated with penicillin. Good orodental hygiene is important for the prevention of actinomycosis
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- 2003
11. Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation
- Author
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Zwaveling-Soonawala, N., primary, Hagebeuk, E. E., additional, Slingerland, A. S., additional, Ris-Stalpers, C., additional, Vulsma, T., additional, and van Trotsenburg, A. S., additional
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- 2010
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12. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study
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Anina Enderli, Krishna Chatterjee, David A. Koolen, Jana Malikova, Paul Dimitri, Roelineke J. Lunsing, Patricia Crock, Charles Marques Lourenço, Corstiaan A. den Uil, Ferdy S van Geest, Jan Lebl, Christine M. Armour, Michaela Linder-Lucht, Tony Huynh, Annette Hackenberg, Zita Halász, Jan Fairchild, Francesco Porta, Adri van der Walt, Verónica Mericq, Gautem P. Ambegaonkar, Nitash Zwaveling-Soonawala, Daniel Konrad, D Barca, Barbara Castellotti, Cláudia Fernandes Lorea, Anna Dolcetta-Capuzzo, Peter J Simm, Heiko Krude, Evelien F. Gevers, Ayhan Abaci, Claudia Castiglioni, Jet van der Spek, Jolante Wierzba, Carla Moran, Serap Turan, Isabelle Oliver-Petit, Felipe Monti Lora, Amnon Zung, Klara Rozenkova, Nicola Brunetti-Pierri, Fabiano de Oliveira Poswar, W. Edward Visser, Gopinath M. Subramanian, Bianka Heinrich, Irenaeus F.M. de Coo, Milou A.M. Stals, Belinda George, Michael Wurm, Alice Dica, Amy Lawson-Yuen, Rachana Dubey, Christina Reinauer, Athanasia Stoupa, Stefan Groeneweg, Joel Vanderniet, Marjolein H G Dremmen, Marie Claire Y. de Wit, Marjo S. van der Knaap, Edna E. Mancilla, Dana Craiu, Korcan Demir, Greta Lyons, Gerarda Cappuccio, Jean Louis Wémeau, Yogen Singh, Anne McGowan, Alberto Alcantud, Praveen G. Paul, Enrico Bertini, Laura Paone, Marco Spada, Régis Coutant, Marco Cappa, Ingrid M. van Beynum, Jonathan Gallichan, Nicole I. Wolf, Michel Polak, Marieke M. van der Knoop, Christian DeGoede, Davide Tonduti, Federica Zibordi, Tuba Seven Menevse, Katalin Eszter Müller, Anna Simon, Marianna Bugiani, Priyanka Bakhtiani, Anna Kłosowska, Internal Medicine, Pediatrics, Neurology, Radiology & Nuclear Medicine, Cardiology, Intensive Care, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pathology, Pediatric surgery, Paediatric Endocrinology, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Functional Genomics, Groeneweg, S., van Geest, F. S., Abaci, A., Alcantud, A., Ambegaonkar, G. P., Armour, C. M., Bakhtiani, P., Barca, D., Bertini, E. S., van Beynum, I. M., Brunetti-Pierri, Nicola, Bugiani, M., Cappa, M., Cappuccio, G., Castellotti, B., Castiglioni, C., Chatterjee, K., de Coo, I. F. M., Coutant, R., Craiu, D., Crock, P., Degoede, C., Demir, K., Dica, A., Dimitri, P., Dolcetta-Capuzzo, A., Dremmen, M. H. G., Dubey, R., Enderli, A., Fairchild, J., Gallichan, J., George, B., Gevers, E. F., Hackenberg, A., Halasz, Z., Heinrich, B., Huynh, T., Klosowska, A., van der Knaap, M. S., van der Knoop, M. M., Konrad, D., Koolen, D. A., Krude, H., Lawson-Yuen, A., Lebl, J., Linder-Lucht, M., Lorea, C. F., Lourenco, C. M., Lunsing, R. J., Lyons, G., Malikova, J., Mancilla, E. E., Mcgowan, A., Mericq, V., Lora, F. M., Moran, C., Muller, K. E., Oliver-Petit, I., Paone, L., Paul, P. G., Polak, M., Porta, F., Poswar, F. O., Reinauer, C., Rozenkova, K., Menevse, T. S., Simm, P., Simon, A., Singh, Y., Spada, M., van der Spek, J., Stals, M. A. M., Stoupa, A., Subramanian, G. M., Tonduti, D., Turan, S., den Uil, C. A., Vanderniet, J., van der Walt, A., Wemeau, J. -L., Wierzba, J., de Wit, M. -C. Y., Wolf, N. I., Wurm, M., Zibordi, F., Zung, A., Zwaveling-Soonawala, N., and Visser, W. E.
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Male ,Pediatrics ,Endocrinology, Diabetes and Metabolism ,Bayley Scales of Infant Development ,Monocarboxylic Acid Transporter ,0302 clinical medicine ,Endocrinology ,Retrospective Studie ,Neurodevelopmental Disorder ,Medicine ,030212 general & internal medicine ,Child ,Thyroid hormone transport ,Symporters ,Mental Disorders ,Hazard ratio ,SDG 10 - Reduced Inequalities ,Middle Aged ,Prognosis ,Survival Rate ,International Agencie ,Child, Preschool ,Cohort ,Mental Disorder ,Female ,Disease characteristics ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Human ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Cohort study ,Adult ,Monocarboxylic Acid Transporters ,medicine.medical_specialty ,Adolescent ,Prognosi ,HEART-RATE ,030209 endocrinology & metabolism ,Sudden death ,Follow-Up Studie ,MONOCARBOXYLATE TRANSPORTER-8 ,Young Adult ,03 medical and health sciences ,HORMONE ,Muscular Diseases ,Internal Medicine ,Humans ,PSYCHOMOTOR RETARDATION ,Survival rate ,Aged ,Retrospective Studies ,Muscular Disease ,business.industry ,MUTATIONS ,Symporter ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Infant ,International Agencies ,Retrospective cohort study ,Biomarker ,Neurodevelopmental Disorders ,Mutation ,business ,Biomarkers ,Follow-Up Studies - Abstract
Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access) BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score
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- 2020
13. Central congenital hypothyroidism: Early diagnosis and clinical outcome during childhood and adolescence
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Naafs, J.C., van Trotsenburg, A.S.P., Fliers, E., Zwaveling-Soonawala, N., Boelen, A., and Faculteit der Geneeskunde
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This thesis focuses on improving the diagnostic process for central congenital hypothyroidism (CH) and describes the long-term outcome of early-detected patients. Central CH refers to thyroid hormone (thyroxine, T4) deficiency at birth due to insufficient hypothalamic-pituitary stimulation of the thyroid gland. It may occur in isolation or combined with multiple pituitary hormone deficiency (MPHD). Diagnosing central CH in neonates is challenging, as this relies on a low serum free T4 (FT4) concentration only. We established age-specific reference intervals for FT4 and thyrotropin (TSH) and show that the neonatal FT4 lower limit is 3 pmol/L higher than in adults. Although worldwide most neonatal screening programs do not detect central CH, the Dutch program does. We report clinical characteristics of the largest patient group described so far and show that most patients are not identified clinically, but only after receiving an abnormal screening result. A genetic diagnosis is established in most patients with isolated central CH. In a systematic review we show that robust studies on cognitive outcome are lacking. In a cross-sectional study we show that full-scale IQ (FSIQ) in early-detected patients with isolated central CH does not differ from siblings. In MPHD patients, FSIQ is significantly lower compared with siblings. We also show that self-reported health-related quality of life (HRQoL) is similar in central CH patients and siblings. Parent-reported HRQoL is significantly lower in MPHD patients compared with siblings. Finally, despite a high overall mortality among early-detected central CH patients, deaths due to pituitary insufficiency are rare.
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- 2021
14. Iodinated Contrast Induced Hypothyroidism in the Infant After Enteral Contrast Enema: A Case Report and Systematic Review.
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Pijpers AGH, Zoetelief SE, Eeftinck Schattenkerk LD, de Vries R, Onland W, van Schuppen J, van Trotsenburg ASP, van Heurn LWE, Derikx JPM, Zwaveling-Soonawala N, and Mooij CF
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Background: Excessive iodine intake triggers the Wolff-Chaikoff effect resulting in downregulation of thyroid hormone synthesis to prevent hyperthyroidism. Failure to escape the Wolff-Chaikoff effect can be seen especially in (premature born) infants and may result in prolonged iodine induced hypothyroidism. We describe a rare case of a preterm infant who developed severe iodinated contrast induced hypothyroidism after the use and prolonged stasis of enteral iodinated contrast media (ICM). In addition a systematic literature search was performed to evaluate all available data on this complication., Methods: A systematic literature search was performed in PubMed and Embase. Studies describing the effect of enteral ICM on thyroid function were considered eligible. The primary outcome was to determine the frequency of contrast induced hypothyroidism in infants after administration of enteral ICM., Results: The premature infant in our center developed severe iodinated contrast induced hypothyroidism after enteral ICM. In total, only two studies met our eligibility data, reporting eight patients. Out of these eight patients, four premature infants developed a contrast induced hypothyroidism after enteral administration of ICM., Conclusion: Data on severity, length and frequency of contrast induced hypothyroidism after exposure to enteral ICM is very scarce. The herein reported case and literature search illustrate the potential severity of the complication and underline the necessity of future studies on this topic. We recommend standardized monitoring of thyroid function after exposure to enteral ICM in newborns to prevent delayed diagnosis of severe contrast induced hypothyroidism until evidence based recommendations can be made.
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- 2024
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15. Approach to the Patient: Challenging Cases of Pediatric Thyrotoxicosis.
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Mooij CF, Zwaveling-Soonawala N, Hillebrand JJ, and van Trotsenburg ASP
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Graves' disease (GD) is the leading cause of hyperthyroidism in children. However, compared to adults GD in children is a rare condition. In a recent guideline issued by the European Thyroid Association the diagnostic evaluation and treatment of pediatric GD is described extensively. In this article we go beyond the guideline and describe the potential challenges of establishing the right etiology of thyrotoxicosis in children, illustrated by cases of thyroid hormone resistance, autonomous functioning thyroid nodules and subacute thyroiditis with a thyrotoxic phase. In addition, we report therapeutic challenges in pediatric GD such as recurrent immunological flare-ups under anti-thyroid drug (ATD) treatment, innovative ways to improve ATD compliance and the role of definitive treatment in persistent complaints of malaise under ATD treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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16. Effects and Safety of Growth Hormone Treatment in Six Children with Pycnodysostosis.
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Renes JS, Sas TCJ, Clement-de Boers A, Zwaveling-Soonawala N, Hannema SE, van der Velden JAEM, van der Kaay DCM, and Hokken-Koelega ACS
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Introduction: Pycnodysostosis is an extremely rare skeletal dysplasia caused by cathepsin K deficiency. It is characterized by extreme short stature with adult height (AH) in males typically less than 150 cm and in females less than 130 cm. Our objective was to evaluate the effect and safety of growth hormone (GH) treatment in 6 patients with pycnodysostosis treated according to the Dutch national pycnodysostosis guideline., Case Presentation: Six subjects (4 boys, 2 girls) presented with pycnodysostosis, treated with GH 1.4 mg/m2/day (∼0.046 mg/kg/day) for ≥1 year. Median (IQR) age at start of GH was 10.4 years (5.7; 12.2) and median height 113.5 cm (93.3; 129.3) (-4.2 SDS [-4.8; -3.6]). All children were prepubertal at start of GH. After 1 year of GH, median height gain was 7.6 cm (6.5; 8.5) (0.3 SDS [-0.3; 0.7]). Three children are still treated with GH, and the other three subjects reached AH: 1 boy reached an AH of 157.0 cm (-3.8 SDS) after 6.3 years of GH, and 2 girls reached an AH of 138.5 cm (-5.2 SDS) after 4.8 years of GH and 148.0 cm (-3.6 SDS) after 6.4 years of GH, respectively. This last girl received additional GnRH analogue treatment. In all subjects, height SDS remained stable or improved during and after GH treatment. No serious adverse advents were found. Serum IGF-I remained below the +2 SDS., Conclusion: Our data suggest that GH may prevent the decline in height which can be observed in children with pycnodysostosis. Further research is needed to confirm this. Also, the effect of other growth-promoting strategies such as treatment with an additional GnRH analogue warrants further investigation., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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17. Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.
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Lauffer P, Heinen CA, Goorsenberg AWM, Malekzadeh A, Henneman P, Heijboer AC, Zwaveling-Soonawala N, Boelen A, and van Trotsenburg ASP
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- Humans, Infant, Newborn, Reference Values, Thyroid Function Tests standards, Female, Thyrotropin blood, Male, Neonatal Screening methods, Thyroxine blood
- Abstract
Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies ( p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.
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- 2024
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18. Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency
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Garrelfs MR, Rinne T, Hillebrand JJ, Lauffer P, Bijlsma MW, Claahsen-van der Grinten HL, de Leeuw N, Finken MJJ, Rotteveel J, Zwaveling-Soonawala N, Nieuwdorp M, van Trotsenburg ASP, and Mooij CF
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- Infant, Newborn, Humans, Aldosterone, Phenotype, Homozygote, Cytochrome P-450 CYP11B2 genetics, Hypoaldosteronism genetics
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Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2 , resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8:NM_000498.3:c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient’s asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the biochemical and genetic work-up performed and describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1., Competing Interests: Conflict of interest: None declared., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)
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- 2024
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19. Corrigendum to "Expert management of congenital portosystemic shunts and their complications" [JHEP Reports 6 (2024)].
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McLin VA, Franchi-Abella S, Brütsch T, Bahadori A, Casotti V, de Ville de Goyet J, Dumery G, Gonzales E, Guérin F, Hascoet S, Heaton N, Kuhlmann B, Lador F, Lambert V, Marra P, Plessier DA, Quaglia A, Rougemont AL, Savale L, Sarma MS, Sitbon O, Superina RA, Uchida H, van Albada M, Johannes van der Doef HP, Vilgrain V, Wacker J, Zwaveling-Soonawala N, Debray D, and Wildhaber BE
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[This corrects the article DOI: 10.1016/j.jhepr.2023.100933.]., (© 2024 The Author(s).)
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- 2024
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20. Optimizing the Dutch newborn screening for congenital hypothyroidism by incorporating amino acids and acylcarnitines in a machine learning-based model.
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Jansen HI, van Haeringen M, Bouva MJ, den Elzen WPJ, Bruinstroop E, van der Ploeg CPB, van Trotsenburg ASP, Zwaveling-Soonawala N, Heijboer AC, Bosch AM, de Jonge R, Hoogendoorn M, and Boelen A
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- Infant, Newborn, Humans, Neonatal Screening methods, Amino Acids, Thyrotropin, Congenital Hypothyroidism diagnosis
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Objective: Congenital hypothyroidism (CH) is an inborn thyroid hormone (TH) deficiency mostly caused by thyroidal (primary CH) or hypothalamic/pituitary (central CH) disturbances. Most CH newborn screening (NBS) programs are thyroid-stimulating-hormone (TSH) based, thereby only detecting primary CH. The Dutch NBS is based on measuring total thyroxine (T4) from dried blood spots, aiming to detect primary and central CH at the cost of more false-positive referrals (FPRs) (positive predictive value (PPV) of 21% in 2007-2017). An artificial PPV of 26% was yielded when using a machine learning-based model on the adjusted dataset described based on the Dutch CH NBS. Recently, amino acids (AAs) and acylcarnitines (ACs) have been shown to be associated with TH concentration. We therefore aimed to investigate whether AAs and ACs measured during NBS can contribute to better performance of the CH screening in the Netherlands by using a revised machine learning-based model., Methods: Dutch NBS data between 2007 and 2017 (CH screening results, AAs and ACs) from 1079 FPRs, 515 newborns with primary (431) and central CH (84) and data from 1842 healthy controls were used. A random forest model including these data was developed., Results: The random forest model with an artificial sensitivity of 100% yielded a PPV of 48% and AUROC of 0.99. Besides T4 and TSH, tyrosine, and succinylacetone were the main parameters contributing to the model's performance., Conclusions: The PPV improved significantly (26-48%) by adding several AAs and ACs to our machine learning-based model, suggesting that adding these parameters benefits the current algorithm.
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- 2023
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21. Tocilizumab for the fifth progression of cystic childhood craniopharyngioma-a case report.
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de Vos-Kerkhof E, Buis DR, Lequin MH, Bennebroek CA, Aronica E, Hulleman E, Zwaveling-Soonawala N, van Santen HM, and Schouten-van Meeteren AYN
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- Humans, Female, Child, Adolescent, Hypothalamus pathology, Craniopharyngioma complications, Craniopharyngioma drug therapy, Pituitary Neoplasms complications, Pituitary Neoplasms drug therapy, Pituitary Neoplasms pathology, Hypopituitarism pathology
- Abstract
We present the case of a 15-year-old girl, with a fifth cystic progression of an adamantinomatous craniopharyngioma after multiple surgeries and previous local radiotherapy. She had severe visual impairment, panhypopituitarism including diabetes insipidus, and several components of hypothalamic damage, including morbid obesity and severe fatigue. To prevent further late effects hampering her quality of survival, she was treated biweekly with intravenous tocilizumab, an anti-interleukin-6 agent, which stabilized the cyst for a prolonged time. Based on the biology of adamantinomatous craniopharyngioma, this immune-modulating treatment seems promising for the treatment of this cystic tumor in order to reduce surgery and delay or omit radiotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Vos-Kerkhof, Buis, Lequin, Bennebroek, Aronica, Hulleman, Zwaveling-Soonawala, van Santen and Schouten-van Meeteren.)
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- 2023
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22. Neonatal screening for primary and central congenital hypothyroidism: is it time to go Dutch?
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Boelen A, Zwaveling-Soonawala N, Heijboer AC, and van Trotsenburg ASP
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- Infant, Newborn, Humans, Neonatal Screening, Thyrotropin, Thyroxine, Thyroid Hormones, Congenital Hypothyroidism diagnosis
- Abstract
Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2-3 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 characterized by low TH concentrations, while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH based and 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 the 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 probably 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.
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- 2023
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23. Further Delineation of Central Congenital Hypothyroidism due to Variants in TBL1X and IRS4 .
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Lauffer P, Naafs JC, Bikker H, Garrelfs MR, Mooij CF, Boelen A, Zwaveling-Soonawala N, and van Trotsenburg ASP
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- Humans, Congenital Hypothyroidism genetics, Insulin Receptor Substrate Proteins genetics, Transducin genetics
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- 2023
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24. Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism.
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Stroek K, Visser A, van der Ploeg CPB, Zwaveling-Soonawala N, Heijboer AC, Bosch AM, van Trotsenburg ASP, Boelen A, Hoogendoorn M, and de Jonge R
- Subjects
- Humans, Thyroxine analysis, Glycoprotein Hormones, alpha Subunit analysis, Thyroxine-Binding Globulin analysis, False Positive Reactions, Algorithms, Gestational Age, Infant, Newborn, Neonatal Screening, Congenital Hypothyroidism diagnosis, Machine Learning, Random Forest
- Abstract
Objective: The 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 & Methods: NBS 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., Results: Variables 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%., Conclusions: Machine 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., Competing Interests: Declaration of Competing Interest Annet M. Bosch has received a speaker’s fee from Nutricia and has been a member of advisory boards for Biomarin., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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25. The Effects of 5 Years of Growth Hormone Treatment on Growth and Body Composition in Patients with Temple Syndrome.
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Juriaans AF, Trueba-Timmermans DJ, Kerkhof GF, Grootjen LN, Walet S, Sas TCJ, Rotteveel J, Zwaveling-Soonawala N, Verrijn Stuart AA, and Hokken-Koelega ACS
- Subjects
- Child, Adult, Humans, Insulin-Like Growth Factor I metabolism, Growth Hormone, Body Composition, Uniparental Disomy, Body Height, Human Growth Hormone therapeutic use, Human Growth Hormone pharmacology, Prader-Willi Syndrome
- Abstract
Introduction: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal uniparental disomy of chromosome 14, paternal deletion of 14q32.2, or an isolated methylation defect. Most patients with TS14 develop precocious puberty. Some patients with TS14 are treated with growth hormone (GH). However, evidence for the effectiveness of GH treatment in patients with TS14 is limited., Methods: This study describes the effect of GH treatment in 13 children and provides a subgroup analysis of 5 prepubertal children with TS14. We studied height, weight, body composition by dual-energy X-ray absorptiometry, resting energy expenditure (REE), and laboratory parameters during 5 years of GH treatment., Results: In the entire group, mean (95% CI) height SDS increased significantly during 5 years of GH treatment from -1.78 (-2.52; -1.04) to 0.11 (-0.66; 0.87). Fat mass percentage SDS decreased significantly during the first year of GH, and lean body mass (LBM) SDS and LBM index increased significantly during 5 years of treatment. IGF-1 and IGF-BP3 levels rose rapidly during GH treatment, and the IGF-1/IGF-BP3 molar ratio remained relatively low. Thyroid hormone levels, fasting serum glucose, and insulin levels remained normal. In the prepubertal group, median (interquartile range [IQR]) height SDS, LBM SDS, and LBM index also increased. REE was normal at start and did not change during 1 year of treatment. Five patients reached adult height and their median (IQR) height SDS was 0.67 (-1.83; -0.01)., Conclusion: GH treatment in patients with TS14 normalizes height SDS and improves body composition. There were no adverse effects or safety concerns during GH treatment., (© 2023 S. Karger AG, Basel.)
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- 2023
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26. Meta-Analysis of DNA Methylation Datasets Shows Aberrant DNA Methylation of Thyroid Development or Function Genes in Down Syndrome.
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Lauffer P, Zwaveling-Soonawala N, Li S, Bacalini MG, Naumova OY, Wiemels J, Boelen A, Henneman P, de Smith AJ, and van Trotsenburg ASP
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- Humans, Epigenesis, Genetic, Thyroid Gland, Phenotype, DNA Methylation, Down Syndrome genetics
- Abstract
Background: In Down syndrome (DS), there is high occurrence of congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) early in life. The etiology of CH and early SH in DS remains unclear. Previous research has shown genome-wide transcriptional and epigenetic alterations in DS. Thus, we hypothesized that CH and early SH could be caused by epigenetically driven transcriptional downregulation of thyroid-related genes, through promoter region hypermethylation. Methods: We extracted whole blood DNA methylation (DNAm) profiles of DS and non-DS individuals from four independent Illumina array-based datasets (252 DS individuals and 519 non-DS individuals). The data were divided into discovery and validation datasets. Epigenome-wide association analysis was performed using a linear regression model, after which we filtered results for thyroid-related genes. Results: In the discovery dataset, we identified significant associations for DS in 18 thyroid-related genes. Twenty-one of 30 significant differentially methylated positions (DMPs) were also significant in the validation dataset. A meta-analysis of the discovery and validation datasets detected 31 DMPs, including 29 promoter-associated cytosine-guanine dinucleotides (CpG) with identical direction of effect across the datasets, and two differentially methylated regions. Twenty-seven DMPs were hypomethylated and promoter associated. The mean methylation difference of hypomethylated thyroid-related DMPs decreased with age. Conclusions: Contrary to our hypothesis of generalized hypermethylation of promoter regions of thyroid-related genes-indicative of epigenetic silencing of promoters and subsequent transcriptional downregulation, causing biochemical thyroid abnormalities in DS-we found an enrichment of hypomethylated DMPs annotated to promoter regions of these genes. This suggests that CH and early SH in DS are not caused by differential methylation of thyroid-related genes. Considering that epigenetic regulation is dynamic, we hypothesize that the observed thyroid-related gene DNAm changes could be a rescue phenomenon in an attempt to ameliorate the thyroid phenotype, through epigenetic upregulation of thyroid-related genes. This hypothesis is supported by the finding of decreasing methylation difference of thyroid-related genes with age. The prevalence of early SH declines with age, so hypothetically, epigenetic upregulation of thyroid-related genes also diminishes. While this study provides interesting insights, the exact origin of CH and early SH in DS remains unknown.
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- 2023
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27. Temple Syndrome: Clinical Findings, Body Composition and Cognition in 15 Patients.
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Juriaans AF, Kerkhof GF, Mahabier EF, Sas TCJ, Zwaveling-Soonawala N, Touwslager RNH, Rotteveel J, and Hokken-Koelega ACS
- Abstract
Background: Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader-Willi-like, Silver-Russell-like or as a Silver-Russell spectrum disorder., Methods: This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader-Willi-like from December 2018 to January 2022., Results: Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS -2.03 (-3.22; -1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect., Conclusions: Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.
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- 2022
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28. Mild Isolated Congenital Central Hypothyroidism Due to a Novel Homozygous Variant in TSHB : A Case Report.
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Lauffer P, Bikker H, Boelen A, Jöbsis JJ, van Trotsenburg ASP, and Zwaveling-Soonawala N
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- Female, Homozygote, Humans, Infant, Newborn, Neonatal Screening, Reference Values, Thyroid Function Tests, Thyroid Hormones, Thyroxine therapeutic use, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism genetics
- Abstract
Pathogenic variants in TSHB are known to cause severe isolated central congenital hypothyroidism (CH). In this study, we present the clinical, biochemical, and genetic features of the first patient with a mild central CH phenotype. We identified a novel homozygous variant in TSHB : (Chr1: NM_000549.5):c.290A>G p.(Tyr97Cys) in a newborn girl detected by neonatal CH screening, whose central CH was initially overlooked because of misinterpretation of her plasma-free thyroxine (fT4) concentration. This report adds to the phenotypic spectrum of TSHB variants and underlines the importance of using age-specific fT4 reference intervals to diagnose central CH.
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- 2022
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29. The Effect of Pre-Thyroidectomy Calcitriol Prophylaxis on Post-Thyroidectomy Hypocalcaemia in Children.
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Vendrig LM, Mooij CF, Derikx JPM, Fischer JC, van Trotsenburg ASP, and Zwaveling-Soonawala N
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- Child, Humans, Adolescent, Thyroidectomy adverse effects, Calcitriol therapeutic use, Calcium, Retrospective Studies, Postoperative Complications etiology, Postoperative Complications prevention & control, Parathyroid Hormone, Hypocalcemia etiology, Hypocalcemia prevention & control
- Abstract
Introduction: Transient or persistent hypoparathyroidism is one of the most well-known complications of total thyroidectomy and may lead to symptomatic hypocalcaemia. In children, treatment of post-thyroidectomy hypocalcaemia usually consists of postoperative calcium and/or vitamin D supplementation. In 2013, we implemented prophylactic pre-thyroidectomy calcitriol supplementation for all children undergoing total thyroidectomy at the Amsterdam UMC. The objective of this study was to evaluate the efficacy of this prophylactic calcitriol supplementation in preventing post-thyroidectomy hypocalcaemia in children., Methods: In a retrospective case study, we included all children (age <18 years), who underwent a total or completion thyroidectomy in the Amsterdam UMC, between 2000 and 2020. Patients were divided into two groups, patients with preoperative calcitriol supplementation and those without (controls). Hypocalcaemia was defined as total serum calcium concentration of <2.0 mmol/L. The primary outcome measure was the occurrence of hypocalcaemia in the first 72 h after surgery. Secondary outcome measures were occurrence of symptomatic hypocalcaemia, need for medical intervention within the first 72 h after surgery, and length of hospitalization., Results: A total of 51 patients were included; 26 with calcitriol prophylaxis and 25 controls. There was no significant difference in occurrence of hypocalcaemia (17/26 prophylaxis group; 18/25 control group). Median postoperative calcium concentrations in the first 72 h were significantly higher in the group with prophylaxis at 30-35 h (2.26 vs. 2.01 mmol/L) and 36-41 h (2.17 vs. 1.92 mmol/L). Occurrence of symptomatic hypocalcaemia, need for medical intervention, and length of hospitalization were not significantly different between the groups., Conclusion: Calcitriol prophylaxis resulted in somewhat higher postoperative calcium concentrations but did not reduce the occurrence of hypocalcaemia or affect clinical outcome measures such as occurrence of symptomatic hypocalcaemia and length of postoperative hospitalization., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
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- 2022
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30. Pasireotide treatment for severe congenital hyperinsulinism due to a homozygous ABCC8 mutation.
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Mooij CF, Tacke CE, van Albada ME, Barthlen W, Bikker H, Mohnike K, Oomen MWN, van Trotsenburg ASP, and Zwaveling-Soonawala N
- Abstract
ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI.
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- 2021
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31. Defective Levothyroxine Response in a Patient with Dyshormonogenic Congenital Hypothyroidism Caused by a Concurrent Pathogenic Variant in Thyroid Hormone Receptor-β.
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Lauffer P, Bikker H, Garrelfs MR, Hillebrand JJG, de Sonnaville MCS, Zwaveling-Soonawala N, and van Trotsenburg ASP
- Subjects
- Child, Preschool, Consanguinity, Female, Humans, Pedigree, Symporters, Turkey, Congenital Hypothyroidism drug therapy, Congenital Hypothyroidism genetics, Thyroid Hormone Receptors beta genetics, Thyroid Hormone Resistance Syndrome genetics, Thyroxine therapeutic use
- Abstract
Background: Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in THRB , causing resistance to TH (RTH-β). Methods: Clinical, genetic, and biochemical data of the proband's family were collected. Results: The 3-year-old girl was diagnosed with CH due to a homozygous pathogenic c.470del p.(Asn157Thrfs*3) SLC5A5 variant in the neonatal period. She needed a notably high levothyroxine dose to normalize TSH, leading to high free thyroxine levels. There were no signs of hyperthyroidism. Sequencing identified a heterozygous pathogenic c.947G>A p.(Arg316His) THRB variant. Conclusions: To our knowledge, this is the first report of concomitant SLC5A5 and THRB variants causing CH and RTH-β.
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- 2021
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32. Second-tier Testing for 21-Hydroxylase Deficiency in the Netherlands: A Newborn Screening Pilot Study.
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Stroek K, Ruiter A, van der Linde A, Ackermans M, Bouva MJ, Engel H, Jakobs B, Kemper EA, van den Akker ELT, van Albada ME, Bocca G, Finken MJJ, Hannema SE, Mieke Houdijk ECA, van der Kamp HJ, van Tellingen V, Paul van Trotsenburg AS, Zwaveling-Soonawala N, Bosch AM, de Jonge R, Heijboer AC, Claahsen-van der Grinten HL, and Boelen A
- Subjects
- Adrenal Hyperplasia, Congenital blood, Algorithms, False Positive Reactions, Humans, Infant, Newborn, Netherlands, Sensitivity and Specificity, 17-alpha-Hydroxyprogesterone blood, Adrenal Hyperplasia, Congenital diagnosis, Cortodoxone blood, Neonatal Screening methods, Pilot Projects
- Abstract
Context: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives., Objective: We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study., Methods: Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis., Results: A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days)., Conclusion: Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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33. Complications After Thyroidectomy in Children: Lymph Node Dissection Is a Risk Factor for Permanent Hypocalcemia.
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van Rooijen JJ, van Trotsenburg ASP, van de Berg DJ, Zwaveling-Soonawala N, Nieveen van Dijkum EJM, Engelsman AF, Derikx JPM, and Mooij CF
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- Adolescent, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Hypocalcemia etiology, Male, Postoperative Complications etiology, Prognosis, Retrospective Studies, Risk Factors, Hypocalcemia pathology, Lymph Node Excision adverse effects, Postoperative Complications pathology, Quality of Life, Thyroid Diseases surgery, Thyroidectomy adverse effects
- Abstract
Background: Thyroidectomy is a treatment option in some benign thyroid disorders and the definitive treatment option for thyroid cancer. As postoperative mortality is extremely rare data on postoperative complications and long-term health consequences are important., Objective: To evaluate the frequencies of short- and long-term complications, and their risk factors in pediatric patients (0-18 years) who underwent a thyroidectomy in a tertiary children's hospital., Methods: A retrospective single center study was performed including all pediatric patients who underwent a thyroidectomy between January 2013 and February 2020., Results: Forty-eight patients were included in this study (mean age 14.6 years). Twenty-nine total thyroidectomies and 19 hemithyroidectomies were conducted. Thyroid carcinoma was the indication to perform a thyroidectomy in 12 patients, 36 patients underwent a thyroidectomy because of a benign thyroid disorder. Postoperative hypocalcemia was evaluated in patients who underwent a total thyroidectomy. Rapidly resolved hypocalcemia was observed in three patients (10.3%), transient hypocalcemia in 10 patients (34.5%) and permanent hypocalcemia in six patients (20.7%). Permanent hypocalcemia was only seen in patients who underwent a thyroidectomy combined with additional lymph node dissection because of thyroid carcinoma [thyroid carcinoma: OR 43.73, 95% CI (2.11-904.95); lymph node dissection: OR 76.14, 95% CI (3.49-458.98)]. Transient and permanent recurrent laryngeal nerve injury was reported in four (8.3%) and one (2.1%) of all patients, respectively., Conclusion: Permanent postoperative complications after thyroidectomy are rare in pediatric patients undergoing a thyroidectomy without lymph node dissection. However, in this age group permanent hypocalcemia occurs more frequently after thyroidectomy with additional lymph node dissection because of thyroid cancer. With respect to quality of life, especially of pediatric thyroid cancer patients, reducing this complication is an important goal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Rooijen, van Trotsenburg, van de Berg, Zwaveling-Soonawala, Nieveen van Dijkum, Engelsman, Derikx and Mooij.)
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- 2021
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34. Health-Related Quality of Life in Patients With Early-Detected Central Congenital Hypothyroidism.
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Naafs JC, Marchal JP, Verkerk PH, Fliers E, van Trotsenburg ASP, and Zwaveling-Soonawala N
- Subjects
- Adolescent, Child, Child, Preschool, Congenital Hypothyroidism diagnosis, Cross-Sectional Studies, Early Diagnosis, Fatigue congenital, Female, Humans, Hypopituitarism congenital, Hypopituitarism diagnosis, Male, Parents psychology, Self Report, Congenital Hypothyroidism psychology, Fatigue psychology, Hypopituitarism psychology, Quality of Life, Siblings psychology
- Abstract
Context: Central congenital hypothyroidism (CH) requires lifelong medical treatment. The majority of children with central CH have multiple pituitary hormone deficiencies (MPHD), but in some cases central CH is isolated. Most pituitary hormone deficiencies are associated with impaired health-related quality of life (HRQoL). However, studies on HRQoL in central CH are lacking., Objective: To evaluate HRQoL and fatigue in children and young adults with central CH, as well as parent perspectives., Design: Nationwide cross-sectional study comparing HRQoL between early-detected central CH patients and unaffected siblings with the Pediatric Quality of Life inventory (PedsQL™) and PedsQL Multidimensional Fatigue Scale. Participants ≥ 8 years old filled in self-reports; parents of participants aged 3 to 18 years filled in parent reports. Isolated central CH patients, MPHD patients, and siblings were compared using a linear mixed model and Tukey's post hoc test., Results: Eighty-eight patients and 52 siblings participated, yielding 98 self-reports and 115 parent reports. Isolated central CH patients (n = 35) and siblings showed similar scores on all subscales, both in the self-reports and parent reports. For MPHD patients (n = 53), self-reported scores were similar to those of siblings. Parent reported total HRQoL and fatigue scores were significantly poorer in MPHD patients compared with siblings (mean differences -10.2 and -9.4 points; P < 0.01), as were scores for physical functioning, social functioning and general fatigue., Conclusion: Self-reported HRQoL scores in isolated central CH and MPHD patients were similar to siblings. However, parents reported significantly lower HRQoL and fatigue scores for MPHD patients, suggesting a difference in perceived limitations between MPHD patients and their parents., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2021
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35. Diagnosis and Management of Central Congenital Hypothyroidism.
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Lauffer P, Zwaveling-Soonawala N, Naafs JC, Boelen A, and van Trotsenburg ASP
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- Congenital Hypothyroidism drug therapy, Congenital Hypothyroidism genetics, Hormone Replacement Therapy, Humans, Immunoglobulins genetics, Infant, Newborn, Insulin Receptor Substrate Proteins genetics, Membrane Proteins genetics, Neonatal Screening, Prognosis, Thyrotropin, beta Subunit genetics, Transducin genetics, Congenital Hypothyroidism diagnosis, Thyroxine therapeutic use
- Abstract
Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered ( IGSF1 , TBL1X , IRS4 ), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lauffer, Zwaveling-Soonawala, Naafs, Boelen and van Trotsenburg.)
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- 2021
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36. Methimazole-induced remission rates in pediatric Graves' disease: a systematic review.
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van Lieshout JM, Mooij CF, van Trotsenburg ASP, and Zwaveling-Soonawala N
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- Adolescent, Child, Humans, Remission Induction methods, Treatment Outcome, Antithyroid Agents therapeutic use, Graves Disease diagnosis, Graves Disease drug therapy, Methimazole therapeutic use
- Abstract
Objective: Comparison of studies on remission rates in pediatric Graves' disease is complicated by lack of uniformity in treatment protocols, remission definition, and follow-up duration. We performed a systematic review on remission rates in pediatric Graves' disease and attempted to create uniformity by recalculating remission rates based on an intention-to-treat analysis., Methods: PubMed and Embase were searched in August 2020 for studies on patients with Graves' disease: (i) 2 to 18 years of age, (ii) initially treated with methimazole or carbimazole for at least 18 months, (iii) with a follow-up duration of at least 1 year after cessation of methimazole or carbimazole. All reported remission rates were recalculated using an intention-to-treat analysis., Results: Of 1890 articles, 29 articles consisting of 24 patient cohorts were included with a total of 3057 patients (82.6% female). Methimazole or carbimazole was initially prescribed in 2864 patients (93.7%). Recalculation based on intention-to-treat analysis resulted in an overall remission rate of 28.8% (829/2880). Pooled remission rates based on treatment duration were 23.7, 31.0, 43.7, and 75% respectively after 1.5-2.5 years, 2.5-5 years, 5-6 years (two studies), and 9 years (single study) treatment duration. The occurrence of adverse events was 419 in 2377 patients (17.6%), with major side effects in 25 patients (1.1%)., Conclusions: Using a standardized calculation, the overall remission rate in methimazole-treated pediatric GD is 28.8%. A few small studies indicate that longer treatment increases the remission rate. However, evidence is limited and further research is necessary to investigate the efficacy of longer treatment durations.
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- 2021
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37. The Efficacy and Short- and Long-Term Side Effects of Radioactive Iodine Treatment in Pediatric Graves' Disease: A Systematic Review.
- Author
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Lutterman SL, Zwaveling-Soonawala N, Verberne HJ, Verburg FA, van Trotsenburg ASP, and Mooij CF
- Abstract
Background: Graves's disease (GD) is the most common cause of hyperthyroidism. Maximal 30% of pediatric GD patients achieve remission with antithyroid drugs. The majority of patients therefore require definitive treatment. Both thyroidectomy and radioactive iodine (RAI) are often used as definitive treatment for GD. However, data on efficacy and short- and long-term side effects of RAI treatment for pediatric GD are relatively scarce., Methods: A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting the efficacy or short- and long-term side effects of RAI treatment in pediatric GD., Results: Twenty-three studies evaluating 1,283 children and adolescents treated with RAI for GD were included. The treatment goal of RAI treatment changed over time, from trying to achieve euthyroidism in the past to aiming at complete thyroid destruction and subsequent hypothyroidism in the last 3 decades. The reported efficacy of a first RAI treatment when aiming at hypothyroidism ranged from 42.8 to 97.5%, depending on the activity administered. The efficacy seems to increase with higher RAI activities. When aiming at hypothyroidism, both short- and long-term side effects of treatment are very rare. Long-term side effects were mainly seen in patients in whom treatment aimed at achieving euthyroidism., Conclusion: RAI is a safe definitive treatment option for pediatric GD when aiming at complete thyroid destruction. When aiming at hypothyroidism, the efficacy of treatment seems to increase with a higher RAI activity. Prospective studies are needed to determine the optimal RAI dosing regimen in pediatric GD., Competing Interests: The authors report that they have no conflicts of interest to disclose., (Copyright © 2021 by S. Karger AG, Basel.)
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- 2021
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38. Low free thyroxine and normal thyroid-stimulating hormone in infants and children: possible causes and diagnostic work-up.
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Lauffer P, van Trotsenburg ASP, and Zwaveling-Soonawala N
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- Adult, Child, Humans, Infant, Thyroid Function Tests, Thyrotropin, Thyroxine, Congenital Hypothyroidism diagnosis, Thyroid Diseases diagnosis
- Abstract
Screening for hypo- or hyperthyroidism in adults is generally done by measuring the serum thyrotropin (thyroid-stimulating hormone, TSH) concentration. This is an efficient approach in case of suspected acquired thyroid disease. However, in infants and children, congenital hypothalamus-pituitary-thyroid (HPT) axis disorders also need to be considered, including primary and central congenital hypothyroidism, and even rarer thyroid hormone receptor and transporter defects. In primary congenital hypothyroidism, TSH will be elevated, but in the other congenital HPT axis disorders, TSH is usually within the normal range. Free thyroxine (FT4) assessment is essential for the diagnosis in these conditions.Conclusion: Here we discuss a number of rare congenital HPT axis disorders in which TSH is normal, but FT4 is low, and provide a clinical algorithm to distinguish between these disorders. What is Known: • A single thyroid-stimulating hormone (TSH) measurement is an appropriate screening method for primary hypothyroidism. • For central hypothyroidism and rare thyroid hormone receptor and transporter defects a free thyroxine (FT4) measurement is essential for the diagnosis because TSH is usually normal. What is New: • Here we present a new problem-oriented clinical algorithm including a diagnostic flow-chart for low FT4 and normal TSH in infants and children.
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- 2021
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39. Improving the Dutch Newborn Screening for Central Congenital Hypothyroidism by Using 95% Reference Intervals for Thyroxine-Binding Globulin.
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Stroek K, Heijboer AC, van Veen-Sijne M, Bosch AM, van der Ploeg CPB, Zwaveling-Soonawala N, de Jonge R, van Trotsenburg ASP, and Boelen A
- Abstract
Introduction: Newborn screening (NBS) for congenital hypothyroidism (CH) in the Netherlands consists of thyroxine (T4), thyroid-stimulating hormone (TSH), and T4-binding globulin (TBG) measurements to detect thyroidal CH and central CH (CH-C). CH-C is detected by T4 or a calculated T4/TBG ratio, which serves as an indirect measure of free T4. TSH and TBG are only measured in the lowest 20 and 5% of daily T4 values, respectively. A recent evaluation of the Dutch NBS for CH showed that the T4 and T4/TBG ratio contribute to the detection of CH-C but also lead to a low positive predictive value (PPV). Dried blood spot (DBS) reference intervals (RIs) are currently unknown and may contribute to improvement of our NBS algorithm., Materials and Methods: RIs of T4, TSH, TBG, and the T4/TBG ratio were determined according to Clinical & Laboratory Standards Institute guidelines in heel puncture cards from routine NBS in both sexes and at the common NBS sampling ages. Scatter plots were used to compare the healthy reference population to previously published data of CH-C patients and false positives., Results: Analyses of 1,670 heel puncture cards showed small differences between subgroups and led to the formulation of total sample DBS RIs for T4 (56-118 nmol/L), TSH (<2.6 mIU/L), TBG (116-271 nmol/L), and the T4/TBG ratio (>20). 46% of false-positive referrals based on T4 alone had a TBG below the RI, indicating preventable referral due to partial TBG deficiency. One case of CH-C also had partial TBG deficiency (TBG 59 and T4 12 nmol/L blood)., Discussion/conclusion: Established DBS RIs provided possibilities to improve the PPV of the Dutch CH NBS algorithm. We conclude that by taking partial TBG deficiency into account, approximately half of T4 false-positive referrals may be prevented while maintaining NBS sensitivity at the current level., Competing Interests: Annet M. Bosch has received a speaker's fee from Nutricia and has been a member of advisory boards for Biomarin. All other authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)
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- 2021
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40. Cognitive and Motor Outcome in Patients with Early-Detected Central Congenital Hypothyroidism Compared with Siblings.
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Naafs JC, Marchal JP, Fliers E, Verkerk PH, Luijten MAJ, Boelen A, van Trotsenburg ASP, and Zwaveling-Soonawala N
- Subjects
- Adolescent, Child, Child, Preschool, Cognition drug effects, Cognition Disorders diagnosis, Cognition Disorders etiology, Congenital Hypothyroidism drug therapy, Cross-Sectional Studies, Early Diagnosis, Early Medical Intervention, Female, Hormone Replacement Therapy, Humans, Infant, Newborn, Intelligence Tests, Male, Motor Activity drug effects, Motor Disorders diagnosis, Motor Disorders etiology, Neonatal Screening, Netherlands, Prognosis, Retrospective Studies, Siblings, Thyroxine pharmacology, Thyroxine therapeutic use, Treatment Outcome, Cognition physiology, Congenital Hypothyroidism diagnosis, Motor Activity physiology
- Abstract
Context: Early treatment of primary congenital hypothyroidism (CH) prevents irreversible brain damage. Contrary to primary CH, outcome studies on central CH are scarce. Most patients with central CH have multiple pituitary hormone deficiencies (MPHD); these patients are also at risk for neonatal hypoglycemia., Objective: To assess cognitive and motor outcome in patients with early-treated central CH detected by the Dutch neonatal screening., Methods: In this cross-sectional study, primary outcome full-scale intelligence quotient (FSIQ) was measured in patients with MPHD and patients with isolated central CH born between January 1, 1995, and January 1, 2015, with siblings as controls. Secondary outcomes were intelligence test subscales and motor function. Linear mixed models were used to compare both patient groups and siblings, followed by post hoc tests in case of significant differences., Results: Eighty-seven patients (52 MPHD; 35 isolated central CH) and 52 siblings were included. Estimated marginal means for FSIQ were 90.7 (95% CI 86.4-95.0) in patients with MPHD and 98.2 (95% CI 93.0-103.5) in patients with isolated central CH. While patients with MPHD scored lower FSIQs than siblings (mean difference -7.9 points, 95% CI -13.4 to -2.5; P = .002), patients with isolated central CH did not. Processing speed was lower in both patient groups than in siblings (mean differences -10.5 and -10.3 points). Motor difficulties occurred significantly more often in patients (33%) versus siblings (5%; P = .004)., Conclusion: In early-treated central CH, FSIQ is comparable with siblings in patients with isolated central CH, while patients with MPHD have a significantly lower FSIQ. This may be explained by disease-specific consequences of MPHD, such as neonatal hypoglycemia and more severe hypothyroidism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2021
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41. Thyroidectomy in Pediatric Patients with Graves' Disease: A Systematic Review of Postoperative Morbidity.
- Author
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Zaat AS, Derikx JPM, Zwaveling-Soonawala N, van Trotsenburg ASP, and Mooij CF
- Abstract
Background: Graves' disease (GD) is the most common cause of hyperthyroidism. In children, the overall relapse frequency after treatment with antithyroid drugs is high. Therefore, many pediatric GD patients eventually require thyroidectomy as definitive treatment. However, the postoperative complications of thyroidectomy in pediatric GD patients are poorly reported., Objective: To identify the frequency of short- and long-term postoperative morbidities after thyroidectomy in pediatric GD patients., Methods: A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting short- and long-term postoperative morbidities after thyroidectomy in pediatric GD patients according to the PRISMA guidelines., Results: Twenty-two mainly retrospective cohort studies were included in this review evaluating short- and long-term morbidities in 1,424 children and adolescents. The frequency of transient hypocalcemia was 22.2% (269/1,210), with a range of 5.0-50.0%. The frequency of permanent hypocalcemia was 2.5% (36/1,424), with a range of 0-20.0%. Two studies reported high frequencies of permanent hypocalcemia, 20.0 (6/30) and 17.4% (9/52), respectively. The 20% frequency could be explained by low-volume surgeons in poorly controlled GD patients. Only 21 cases of permanent hypocalcemia were reported in the 1,342 patients included in the other 20 studies (1.6%). Transient and permanent recurrent laryngeal nerve injury were reported less frequently, with frequencies between 0-20.0 and 0-7.1%, respectively. Infection, hemorrhage/hematoma, and keloid development were only rarely reported as postoperative complications., Conclusion: The results of this systematic review suggest that thyroidectomy is a safe treatment option for pediatric GD patients. The minority of patients will experience transient and benign morbidities, with hypocalcemia being the most common transient postoperative morbidity. Permanent postoperative morbidities are relatively rare., Competing Interests: The authors report that they have no conflicts of interest to disclose., (Copyright © 2020 by European Thyroid Association Published by S. Karger AG, Basel.)
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- 2021
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42. A Newborn Falsely Suspected of Congenital Hypothyroidism due to Mutated Thyroxine-Binding Globulin with Low Binding Affinity.
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Hengeveld RCC, Albersen M, Hadders MAH, Hellinga I, Bikker H, Heijboer AC, Paul van Trotsenburg AS, Hillebrand JJ, Boelen A, and Zwaveling-Soonawala N
- Subjects
- Congenital Hypothyroidism genetics, Diagnostic Errors, Genetic Diseases, X-Linked genetics, High-Throughput Nucleotide Sequencing, Humans, Infant, Newborn, Male, Neonatal Screening, Thyroid Function Tests, Congenital Hypothyroidism diagnosis, Genetic Diseases, X-Linked diagnosis, Mutation, Missense, Thyroxine-Binding Globulin deficiency, Thyroxine-Binding Globulin genetics
- Abstract
Introduction: Neonatal screening programs for congenital hypothyroidism (CH) have been implemented worldwide to facilitate early diagnosis and treatment. The Dutch neonatal CH screening is primarily based on the measurement of thyroxine (T4). When T4 is low, an additional thyroxine-binding globulin (TBG) measurement is performed to reduce the number of false-positive screening results due to harmless TBG deficiency. Here, we present a case of a rare functional TBG deficiency leading to a false suspicion of CH., Case Presentation: Neonatal screening in this patient revealed a decreased T4, normal TSH, and normal TBG concentration, suggesting central CH. However, free T4 was normal. DNA sequencing analysis revealed a novel, hemizygous mutation (c.139G>A) in SERPINA7, the gene encoding TBG, resulting in the substitution of the conserved amino acid alanine to threonine at position 27. Crystal structure analyses showed that this substitution has a detrimental effect on binding of T4 to TBG., Conclusions: The novel SERPINA7 variant in this patient led to a false suspicion of central hypothyroidism in the Dutch T4-based neonatal screening program. It is important to recognize patients with such TBG defects to prevent unnecessary additional testing and treatment., (© 2021 The Author(s). Published by S. Karger AG, Basel.)
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- 2021
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43. Age-Specific Reference Intervals for Plasma Free Thyroxine and Thyrotropin in Term Neonates During the First Two Weeks of Life.
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Naafs JC, Heinen CA, Zwaveling-Soonawala N, van der Schoor SRD, van Tellingen V, Heijboer AC, Fliers E, Boelen A, and van Trotsenburg ASP
- Subjects
- Adult, Congenital Hypothyroidism blood, Female, Humans, Immunoassay, Infant, Newborn, Linear Models, Male, Maternal Age, Neonatal Screening, Netherlands, Pregnancy, Pregnancy Complications, Term Birth, Thyroid Function Tests, Thyroid Hormones, Age Factors, Reference Values, Thyrotropin blood, Thyroxine blood
- Abstract
Background: Congenital hypothyroidism (CH) is a common and preventable cause of mental retardation, which is detected in many neonatal screening programs. Upon suspicion of CH, plasma free thyroxine (fT4) and thyrotropin (TSH) concentrations are measured. CH can be of thyroidal or central origin (CH-T and CH-C, respectively). While CH-T diagnosis is based on an elevated TSH with a low fT4, CH-C diagnosis is based on a low fT4 without a clearly elevated TSH. Currently, reliable neonatal reference intervals (RIs) for plasma fT4 and TSH are lacking. Age-specific RIs would greatly improve the diagnostic process for CH, especially for CH-C. Our aim was to establish neonatal RIs for plasma fT4 and TSH in term neonates at day 3-7 ( t = 1) and day 13-15 ( t = 2). The study was particularly designed to provide a reliable fT4 lower limit of the RI to facilitate the diagnosis of CH-C. In the Netherlands, neonates are screened at day 3-7 of life. After a screening result suggestive for CH-C, pediatric consultation takes place on average at day 14. Thus, the time points were chosen accordingly. Methods: Venous blood was collected from 120 healthy neonates at each time point (94 participants provided blood samples at two time points; 52 participants provided a sample at t = 1 or t = 2). fT4 and TSH were measured using an immunoassay (Cobas; Roche Diagnostics). RIs were calculated using the 95% confidence interval for normally distributed data and the nonparametric percentile method if data were not normally distributed. Results: From 146 participants (49% female), ≥1 measurement was available. Ninety-five percent RIs for fT4 were 20.5-37.1 pmol/L (day 3-7) and 15.3-26.5 pmol/L (day 13-15). Ninety-five percent RIs for TSH were 1.0-8.4 mU/L (day 3-7) and 1.4-8.6 mU/L (day 13-15). Conclusions: Our results indicate an fT4 lower limit of the RI of 20.5 pmol/L at day 3-7 and 15.3 pmol/L at day 13-15. These lower limits are considerably higher than this assay's lower limit of the adult RI for fT4. In case CH is suspected, we recommend measuring fT4 and TSH using an assay with an established neonatal RI, taking into account the child's age in days.
- Published
- 2020
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44. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.
- Author
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Groeneweg S, van Geest FS, Abacı A, Alcantud A, Ambegaonkar GP, Armour CM, Bakhtiani P, Barca D, Bertini ES, van Beynum IM, Brunetti-Pierri N, Bugiani M, Cappa M, Cappuccio G, Castellotti B, Castiglioni C, Chatterjee K, de Coo IFM, Coutant R, Craiu D, Crock P, DeGoede C, Demir K, Dica A, Dimitri P, Dolcetta-Capuzzo A, Dremmen MHG, Dubey R, Enderli A, Fairchild J, Gallichan J, George B, Gevers EF, Hackenberg A, Halász Z, Heinrich B, Huynh T, Kłosowska A, van der Knaap MS, van der Knoop MM, Konrad D, Koolen DA, Krude H, Lawson-Yuen A, Lebl J, Linder-Lucht M, Lorea CF, Lourenço CM, Lunsing RJ, Lyons G, Malikova J, Mancilla EE, McGowan A, Mericq V, Lora FM, Moran C, Müller KE, Oliver-Petit I, Paone L, Paul PG, Polak M, Porta F, Poswar FO, Reinauer C, Rozenkova K, Menevse TS, Simm P, Simon A, Singh Y, Spada M, van der Spek J, Stals MAM, Stoupa A, Subramanian GM, Tonduti D, Turan S, den Uil CA, Vanderniet J, van der Walt A, Wémeau JL, Wierzba J, de Wit MY, Wolf NI, Wurm M, Zibordi F, Zung A, Zwaveling-Soonawala N, and Visser WE
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, International Agencies, Male, Mental Disorders etiology, Middle Aged, Monocarboxylic Acid Transporters genetics, Muscular Diseases etiology, Mutation, Neurodevelopmental Disorders etiology, Prognosis, Retrospective Studies, Survival Rate, Symporters genetics, Young Adult, Biomarkers analysis, Mental Disorders pathology, Monocarboxylic Acid Transporters deficiency, Muscular Diseases pathology, Neurodevelopmental Disorders pathology, Symporters deficiency
- Abstract
Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency., Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings., Findings: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients., Interpretation: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies., Funding: Netherlands Organisation for Health Research and Development, and the Sherman Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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45. Reforming the male Tanner genital scale.
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Lauffer P, Mooij CF, Zwaveling-Soonawala N, and van Trotsenburg ASP
- Subjects
- Adolescent, Child, Humans, Male, Genitalia, Male growth & development, Puberty physiology, Sexual Maturation physiology
- Published
- 2020
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46. The Use of the Iodine-Rich Drug Amiodarone in the Rapid Preoperative Preparation for Thyroidectomy because of Persistent Hyperthyroidism.
- Author
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Mooij CF, Zwaveling-Soonawala N, Fliers E, and van Trotsenburg ASP
- Published
- 2019
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47. Thiamazole-Associated Neuropathy.
- Author
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den Besten M, Engelen M, Sas TCJ, van Trotsenburg ASP, and Zwaveling-Soonawala N
- Subjects
- Adolescent, Child, Female, Humans, Male, Antithyroid Agents adverse effects, Methimazole adverse effects, Peripheral Nervous System Diseases chemically induced
- Published
- 2019
- Full Text
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48. Mutations in IRS4 are associated with central hypothyroidism.
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Heinen CA, de Vries EM, Alders M, Bikker H, Zwaveling-Soonawala N, van den Akker ELT, Bakker B, Hoorweg-Nijman G, Roelfsema F, Hennekam RC, Boelen A, van Trotsenburg ASP, and Fliers E
- Subjects
- Adolescent, Adult, Animals, Child, Child, Preschool, Female, Heterozygote, Humans, Hypothalamus metabolism, Infant, Male, Mice, Middle Aged, Mutation, Pedigree, Pituitary Gland metabolism, Young Adult, Hypothyroidism genetics, Insulin Receptor Substrate Proteins genetics, Leptin metabolism, Signal Transduction, Thyroxine blood
- Abstract
Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern., Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice., Results: We found mutations in the insulin receptor substrate 4 ( IRS4 ) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion . IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations., Conclusions: Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2018
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49. Mortality in Children With Early-Detected Congenital Central Hypothyroidism.
- Author
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Zwaveling-Soonawala N, Naafs JC, Verkerk PH, and van Trotsenburg ASP
- Subjects
- Child, Child Mortality, Child, Preschool, Early Diagnosis, Female, Follow-Up Studies, Humans, Hypothyroidism diagnosis, Hypothyroidism mortality, Infant, Infant Mortality, Infant, Newborn, Male, Mortality, Neonatal Screening, Netherlands epidemiology, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism mortality
- Abstract
Context: Approximately 60% to 80% of patients with congenital central hypothyroidism (CH-C) have multiple pituitary hormone deficiencies (MPHDs), making CH-C a potentially life-threatening disease. Data on mortality in patients with CH-C are lacking., Objective: To study the mortality rate in pediatric patients with early-detected and treated CH-C in the Netherlands and to investigate whether causes of death were related to pituitary hormone deficiencies., Methods: Overall mortality rate, infant mortality rate (IMR), and under-5 mortality rate were calculated in all children with CH-C detected by neonatal screening between 1 January 1995 and 1 January 2013. Medical charts were reviewed to establish causes of death., Results: A total of 139 children with CH-C were identified, of which 138 could be traced (82 with MPHD, 56 with isolated CH-C). Total observation time was 1414 years with a median follow-up duration of 10.2 years. The overall mortality rate was 10.9% (15/138). IMR and under-5 mortality rate were 65.2/1000 (9/138) and 101.4/1000 (14/138), respectively, compared with an IMR of 4.7/1000 and under-5 mortality of 5.4/1000 live-born children in the Netherlands during the same time period (P < 0.0001). Main causes of death were severe congenital malformations in six patients, asphyxia in two patients, and congenital or early neonatal infection in two patients. Pituitary hormone deficiency was noted as cause of death in only one infant., Conclusion: We report an increased mortality rate in patients with early-detected CH-C that does not seem to be related to endocrine disease. This suggests that mortality due to pituitary insufficiency is low in patients with early-detected and early-treated CH-C.
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- 2018
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50. TSH and FT4 Concentrations in Congenital Central Hypothyroidism and Mild Congenital Thyroidal Hypothyroidism.
- Author
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Zwaveling-Soonawala N, van Trotsenburg ASP, and Verkerk PH
- Subjects
- Case-Control Studies, Congenital Hypothyroidism diagnosis, Diagnosis, Differential, Humans, Infant, Newborn, Neonatal Screening methods, Thyroxine-Binding Globulin deficiency, Thyroxine-Binding Globulin metabolism, Congenital Hypothyroidism blood, Thyrotropin blood, Thyroxine blood
- Abstract
Context: In central hypothyroidism (CeH), free thyroxine (FT4) concentrations are low, whereas thyrotropin (TSH) concentrations may be low, normal, or even slightly elevated due to reduced bioactivity. Congenital CeH (CCeH) may be isolated or part of multiple pituitary hormone deficiencies (MPHD)., Objective: We tested our hypotheses that (1) TSH concentrations have a more U-shaped distribution in children with CCeH compared with children with a normally functioning hypothalamic-pituitary-thyroid axis and (2) TSH concentrations in children with CCeH with MPHD are higher compared with children with isolated CCeH. We also studied whether FT4 levels are helpful in distinguishing CCeH from mild congenital hypothyroidism of thyroidal origin (CH-T)., Methods: Dutch neonatal screening TSH and first diagnostic TSH and FT4 were analyzed in all children diagnosed with permanent CCeH between 1995 and 2012. Controls were children with T4-binding globulin deficiency. FT4 concentrations in CCeH were compared with those in CH-T with TSH values in the same range as those of CCeH., Results: We studied 120 children with CCeH (isolated CCeH, n = 50; MPHD, n = 70) and 350 control subjects. Screening TSH concentrations were not significantly different (P = 0.055), but diagnostic TSH values were significantly different between the CCeH group and the control group (P = 0.037). TSH was significantly higher in MPHD compared with isolated CCeH (P = 0.004). FT4 concentrations were significantly lower in CCeH compared with mild CH-T (P < 0.0005)., Conclusion: TSH values in CCeH have a more U-shaped distribution compared with controls with the highest TSH concentrations in MPHD. FT4 levels were significantly lower in CCeH compared with CH-T.
- Published
- 2018
- Full Text
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