Introduction: Thyroid function in Rett syndrome (RTT) has rarely been studied with unanimous results. However, this aspect is of great concern regarding the effect thyroid hormones (TH) have on proper mammalian brain development. Objective: To evaluate the prevalence of abnormalities of thyroid function in a cohort of children with RTT. Patients and Methods: Forty-five consecutive Caucasian girls (mean age: 8.6 ± 5.3 years, range: 2.0-26.1) meeting the clinical criteria for RTT were recruited. In all of the subjects, we evaluated the serum concentrations of free-T3 (FT3), free-T4 (FT4), thyroid-stimulating hormone (TSH), thyroperoxidase autoantibodies, thyroglobulin autoantibodies (TgA), and TSH receptor (TSHr) autoantibodies. The results were compared with a group of 146 age-matched healthy Caucasian children and adolescent girls (median age: 9.5 years, range: 1.8-14.6) from the same geographical area. Results: Mean FT3 and TSH levels were not significantly different between the RTT patients and controls. Nevertheless, FT4 levels were significantly higher in RTT patients than in controls (p < 0.005). In particular, 17.7% showed FT4 levels higher than the upper reference limit (vs. 0.7% of controls, p < 0.0001), whereas 12 patients (26.7%) showed higher FT3 levels than the upper reference limit, significantly differing in respect to controls (2.0%, p < 0.0001). Finally, 5 patients (11.1%) showed higher levels of TSH, statistically differing from the control subjects (2.0%, p < 0.0001). However, evaluating the patients on the basis of different RTT genotype subgroups, patients with CDKL5 deletions showed significantly higher FT4 values than patients with MeCP2 deletions (p < 0.05). On the other hand, patients with other types of MeCP2 mutations also showed FT4 levels significantly higher than patients with MeCP2 deletions (p < 0.05). In fact, out of 8 patients with FT4 levels higher than the upper references limit, 3 of them presented with CDKL5 deletions (3 patients, 37.5%), 4 (50%) had MeCP2 mutations, and 1 (12.5%) belonged to the subgroup of MeCP2 deletions. However, when analyzing FT3 levels of the 12 patients showing higher FT3 levels than the upper references limit, 6 (50%) belonged to the subgroup with MeCP2 mutations, 4 (33.3%) to the subgroup with MeCP2 deletions, and 2 (16.7%) to the subgroups with CDKL5 deletions. Furthermore, no patient with RTT was positive for antithyroglobulin autoantibodies, antithyroid peroxidase, or anti-TSHr, with no statistical differences in respect to the controls. L-thyroxine treatment was not necessary for any patient. Conclusions: Abnormalities of thyroid function are not rare in RTT. The possible relationship between these disorders and the RTT phenotype should be confirmed and studied. Children with RTT should be screened for potential thyroid dysfunction.

Iourov IY, Vorsanova SG, Voinova VY, Kurinnaia OS, Zelenova MA, Demidova IA, Yurov YB: Xq28 (MeCP2) microdeletions are common in mutation-negative females with Rett syndrome and cause mild subtypes of the disease. Mol Cytogenet 2013;6:53.
Rett A: On a unusual brain atrophy syndrome in hyperammonemia in childhood (in German). Wien Med Wochenschr 1966;116:723-726.
Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK; RettSearch Consortium: Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 2010;68:944-950.
Percy AK: Rett syndrome. Current status and new vistas. Neurol Clin 2002;20:1125-1141.
Vorsanova SG, Iourov IY, Yurov YB: Neurological, genetic and epigenetic features of Rett syndrome. J Pediatr Neurol 2004;2:179-190.
Vorsanova SG, Ulas VI, Iurov IB, Giovanucci-Uzielli ML, Demidova IA, Gianti L, Villard L, Iurov II, Beresheva AK, Novikov PV: Genotype-phenotype correlations in Rett syndrome: the study of Russian cohort of patients (in Russian). Zh Nevrol Psikhiatr Im S S Korsakova 2002;102:23-29.
Chahrour M, Zoghbi HY: The story of Rett syndrome: from clinic to neurobiology. Neuron 2007;56:422-437.
Matsuishi T, Yamashita Y, Takahashi T, Nagamitsu S: Rett syndrome: the state of clinical and basic research, and future perspectives. Brain Dev 2011;33:627-631.
Weaving LS, Ellaway CJ, Gécz J, Christodoulou J: Rett syndrome: clinical review and genetic update. J Med Genet 2005;42:1-7.
Trevathan E, Moser H; Rett Syndrome Diagnostic Criteria Work Group: Diagnostic criteria for Rett syndrome. The Rett Syndrome Diagnostic Criteria Work Group. Ann Neurol 1988;23:425-428.
Temudo T, Santos M, Ramos E, Dias K, Vieira JP, Moreira A, Calado E, Carrilho I, Oliveira G, Levy A, Barbot C, Fonseca M, Cabral A, Cabral P, Monteiro J, Borges L, Gomes R, Mira G, Pereira SA, Santos M, Fernandes A, Epplen JT, Sequeiros J, Maciel P: Rett syndrome with and without detected MeCP2 mutations: an attempt to redefine phenotypes. Brain Dev 2011;33:69-76.
Zappella M: The Rett girls with preserved speech. Brain Dev 1992;14:98-101.
Rolando S: Rett syndrome: report of eight cases. Brain Dev 1985;7:290-296.
Hanefeld F: The clinical pattern of the Rett syndrome. Brain Dev 1985;7:320-325.
Zhao Y, Zhang X, Bao X, Zhang Q, Zhang J, Cao G, Zhang J, Li J, Wei L, Pan H, Wu X: Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med Genet 2014;15:24.
Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, Steinhoff C, Schulz R, Lipkowitz B, Ropers HH, Holmes MC, Bird A: Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet 2005;14:2247-2256.
Cooke DW, Naidu S, Plotnick L, Berkovitz GD: Abnormalities of thyroid function and glucose control in subjects with Rett syndrome. Horm Res 1995;43:273-278.
Huppke P, Roth C, Christen HJ, Brockmann K, Hanefeld F: Endocrinological study on growth retardation in Rett syndrome. Acta Paediatr 2001;90:1257-1261.
Thompson CC, Potter GB: Thyroid hormone action in neural development. Cereb Cortex 2000;10:939-945.
Cortelazzo A, De Felice C, Guerranti R, Signorini C, Leoncini S, Pecorelli A, Zollo G, Landi C, Valacchi G, Ciccoli L, Bini L, Hayek J: Subclinical inflammatory status in Rett syndrome. Mediators Inflamm 2014;2014:480980.
Mount RH, Charman T, Hastings RP, Reilly S, Cass H: The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome. J Child Psychol Psychiatry 2002;43:1099-1110.
Stagi S, Galli L, Cecchi C, Chiappini E, Losi S, Gattinara CG, Gabiano C, Tovo PA, Bernardi S, Chiarelli F, de Martino M: Final height in patients perinatally infected with the human immunodeficiency virus. Horm Res Paediatr 2010;74:165-171.
Stagi S, Giani T, Simonini G, Falcini F: Thyroid function, autoimmune thyroiditis and coeliac disease in juvenile idiopathic arthritis. Rheumatology (Oxford) 2005;44:517-520.
Seminara S, Stagi S, Candura L, Scrivano M, Lenzi L, Nanni L, Pagliai F, Chiarelli F: Changes of thyroid function during long-term hGH therapy in GHD children. A possible relationship with catch-up growth? Horm Metab Res 2005;37:751-756.
Jellinger K, Armstrong D, Zoghbi HY, Percy AK: Neuropathology of Rett syndrome. Acta Neuropathol 1988;76:142-158.
Reiss AL, Faruque F, Naidu S, Abrams M, Beaty T, Bryan RN, Moser H: Neuroanatomy of Rett syndrome: a volumetric imaging study. Ann Neurol 1993;34:227-234.
Boggio EM, Lonetti G, Pizzorusso T, Giustetto M: Synaptic determinants of Rett syndrome. Front Synaptic Neurosci 2010;2:28.
Kron M, Howell CJ, Adams IT, Ransbottom M, Christian D, Ogier M, Katz DM: Brain activity mapping in MeCP2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J Neurosci 2012;32:13860-13872.
Singh J, Saxena A, Christodoulou J, Ravine D: MeCP2 genomic structure and function: insights from ENCODE. Nucleic Acids Res 2008;36:6035.
Stancheva I, Collins AL, Van den Veyver IB, Zoghbi H, Meehan RR: A mutant form of MECP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos. Mol Cell 2003;12:425-435.
Olson DP, Koenig RJ: Thyroid function in Rubinstein-Taybi syndrome. J Clin Endocrinol Metab 1997;82:3264-3266.
Visser TJ: Thyroid hormone transporters and resistance. Endocr Dev 2013;24:1-10.
Schwartz CE, Stevenson RE: The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Best Pract Res Clin Endocrinol Metab 2007;21:307-321.
Eayrs JT: Influence of the thyroid on the central nervous system. Br Med Bull 1960;16:122-127.
Armstrong DD: Review of Rett syndrome. J Neuropathol Exp Neurol 1997;56:843-849.
Johnston MV, Jeon OH, Pevsner J, Blue ME, Naidu S: Neurobiology of Rett syndrome: a genetic disorder of synapse development. Brain Dev 2001;23(suppl 1):S206-S213.
Meehan RR, Lewis JD, Bird AP: Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res 1992;20:5085-5092.
D'Esposito M, Quaderi NA, Ciccodicola A, Bruni P, Esposito T, D'Urso M, Brown SD: Isolation, physical mapping, and northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2. Mamm Genome 1996;7:533-535.
Shahbazian MD, Zoghbi HY: Rett syndrome and MeCP2: linking epigenetics and neuronal function. Am J Hum Genet 2002;71:1259-1272.
Leferovich JM, Lana DP, Sutrave P, Hughes SH, Kelly AM: Regulation of c-ski transgene expression in developing and mature mice. J Neurosci 1995;15:596-603.
Myron Johnson A, Merlini G, Sheldon J, Ichihara K; Scientific Division Committee on Plasma Proteins (C-PP); International Federation of Clinical Chemistry and Laboratory Medicine (IFCC): Clinical indications for plasma protein assays: transthyretin (prealbumin) in inflammation and malnutrition. Clin Chem Lab Med 2007;45:419-426.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.