{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:04:29Z","timestamp":1785431069568,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Rett syndrome (RTT, OMIM 312750) is a complex multisystem neurodevelopmental disorder. Evidence suggests that RTT may have an autoimmune component and inflammatory activation. However, the autoimmune manifestations remain poorly described. Pemphigus foliaceus is a debilitating autoimmune blistering condition caused by IgG autoantibodies that target desmoglein-1 (Dsg1), resulting in widespread skin blistering and lesions. We report a case of pemphigus foliaceus in a 20-year-old female with RTT and discuss its clinical implications. Clinical data obtained from electronic health records were extracted and reviewed. Genetic testing was performed to identify the specific methyl-CpG-binding protein 2 (MECP2) mutation and on an expanded panel of 55 genes associated with pemphigus foliaceus and related blistering disorders. The individual had pemphigus foliaceus, which required immunosuppression, intravenous immunoglobulin (IVIg) therapy, and Rituximab. The disease trajectory was complicated by infections, aspiration pneumonia, and hypoxic cardiac arrest. There was progressive functional decline, and disease control was difficult to achieve, with frequent flares. Genetic testing confirmed a heterozygous pathogenic MECP2 variant (NM_001110792.1:c.952C&gt;T; p.(Arg318Cys)). HLA genotyping identified alleles consistent with the HLA-DRB1*04:02\u2013HLA-DQA1*03:01\u2013HLA-DQB1*03:02 (DR4\/DQ8) haplotype. Furthermore, genetic analysis identified a heterozygous DSG1 variant rs12967407. This study reports the first case of pemphigus foliaceus in RTT, expanding the clinical spectrum of RTT beyond its neurodevelopmental phenotype. The DR4\/DQ8 haplotype, previously associated with pemphigus susceptibility, supports a background of genetic susceptibility in this individual. No causal association between RTT and pemphigus foliaceus can be inferred from this single case. Rather, this case demonstrates that a rare autoimmune disorder such as pemphigus foliaceus can co-occur with a pathogenic MECP2 mutation. The coexistence of a genetic and autoimmune disease can result in a more complex clinical presentation and treatment course. The case further emphasises the need for increased vigilance in identifying new and emerging systemic pathology alongside RTT.<\/jats:p>","DOI":"10.3390\/ijms27156862","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:00Z","timestamp":1785428100000},"page":"6862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["When Neurodevelopment Meets Autoimmunity: Pemphigus Foliaceus in Rett Syndrome Expands the Clinical Spectrum\u2014A Case Report"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0205-856X","authenticated-orcid":false,"given":"Jatinder","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samiya","family":"Chishti","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashidhar","family":"Ameenpur","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-4820","authenticated-orcid":false,"given":"Federico","family":"Fiori","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leighton","family":"McFadden","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan Aziz","family":"Mirza","sequence":"additional","affiliation":[{"name":"Barking, Havering and Redbridge University Hospitals NHS Trust, Romford RM7 0AG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lovro","family":"Vidmar","sequence":"additional","affiliation":[{"name":"Institute for Genomic Literacy, 1241 Kamnik, Slovenia"},{"name":"Geneplanet d.o.o., 1210 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zvi","family":"Zahavi","sequence":"additional","affiliation":[{"name":"Myogenes Limited, Borehamwood WD6 4PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5893","authenticated-orcid":false,"given":"Paramala","family":"Santosh","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pascual-Alonso, A., Mart\u00ednez-Monseny, A.F., Xiol, C., and Armstrong, J. (2021). MECP2-Related Disorders in Males. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179610"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1159\/000337637","article-title":"Rett Syndrome","volume":"2","author":"Smeets","year":"2012","journal-title":"Mol. Syndromol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Singh, J., and Santosh, P. (2025). Molecular Insights into Neurological Regression with a Focus on Rett Syndrome\u2014A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115361"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neubiorev.2019.05.013","article-title":"Rett syndrome before regression: A time window of overlooked opportunities for diagnosis and intervention","volume":"107","author":"Cosentino","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.neubiorev.2019.01.028","article-title":"Regression in Rett syndrome: Developmental pathways to its onset","volume":"98","author":"Einspieler","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e000717","DOI":"10.1136\/bmjpo-2020-000717","article-title":"Consensus guidelines on managing Rett syndrome across the lifespan","volume":"4","author":"Fu","year":"2020","journal-title":"BMJ Paediatr. Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"Rett syndrome: Revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6169","DOI":"10.1038\/s41467-025-61092-7","article-title":"Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype","volume":"16","author":"Lou","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Singh, J., Chishti, S., and Santosh, P. (2026). Co-Occurring Genetic Mutations in Rett Syndrome and MECP2-Related Disorders-Clinical and Diagnostic Implications from a Case Series. Genes, 17.","DOI":"10.3390\/genes17030274"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sanri, A., and Mutlu, M.B. (Mol. Syndromol., 2025). Double Genetic Diagnosis Involving MECP2 and EPHB4 in a Child with Neurodevelopmental Delay and Vascular Anomalies: A Case Report, Mol. Syndromol., Online ahead of print.","DOI":"10.1159\/000549131"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Singh, J., Wilkins, G., Goodman-Vincent, E., Chishti, S., Bonilla Guerrero, R., McFadden, L., Zahavi, Z., and Santosh, P. (2024). Co-Occurring Methylenetetrahydrofolate Reductase (MTHFR) rs1801133 and rs1801131 Genotypes as Associative Genetic Modifiers of Clinical Severity in Rett Syndrome. Brain Sci., 14.","DOI":"10.3390\/brainsci14070624"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/jhg.2011.50","article-title":"Investigation of modifier genes within copy number variations in Rett syndrome","volume":"56","author":"Artuso","year":"2011","journal-title":"J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s11689-026-09680-6","article-title":"Trajectory of skill acquisition, loss, and regain in females with classic Rett syndrome","volume":"18","author":"Neul","year":"2026","journal-title":"J. Neurodev. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Morgan, A., Pham, A., Beeley, S., Dunn, E., Hite, A., and Curtin, M. (2026). MECP2-Associated Rett Syndrome Without Developmental Regression\u2014A Case Series. J. Child Neurol.","DOI":"10.1177\/08830738261420277"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.it.2012.10.002","article-title":"The role of microglia in brain maintenance: Implications for Rett syndrome","volume":"34","author":"Derecki","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nature10907","article-title":"Wild-type microglia arrest pathology in a mouse model of Rett syndrome","volume":"484","author":"Derecki","year":"2012","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/mp.2010.21","article-title":"Rett syndrome and other autism spectrum disorders--brain diseases of immune malfunction?","volume":"15","author":"Derecki","year":"2010","journal-title":"Mol. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"421624","DOI":"10.1155\/2015\/421624","article-title":"Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and \u03c9-3 PUFAs","volume":"2015","author":"Leoncini","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100008","DOI":"10.1016\/j.bbih.2019.100008","article-title":"Evidence of altered salivary cytokine concentrations in Rett syndrome and associations with clinical severity","volume":"1","author":"Byiers","year":"2019","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1378\/chest.09-3021","article-title":"Unrecognized lung disease in classic Rett syndrome: A physiologic and high-resolution CT imaging study","volume":"138","author":"Guazzi","year":"2010","journal-title":"Chest"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.resp.2013.06.022","article-title":"Breathing challenges in Rett syndrome: Lessons learned from humans and animal models","volume":"189","author":"Ramirez","year":"2013","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1111\/dmcn.12358","article-title":"Prevalence, clinical investigation, and management of gallbladder disease in Rett syndrome","volume":"56","author":"Freilinger","year":"2014","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110046","DOI":"10.1016\/j.abb.2024.110046","article-title":"Biochemical and molecular determinants of the subclinical inflammatory mechanisms in Rett syndrome","volume":"757","author":"Cordone","year":"2024","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1097\/MPG.0000000000002273","article-title":"Biliary Tract Disease in Girls and Young Women with Rett Syndrome","volume":"68","author":"Motil","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41423-025-01275-w","article-title":"NLRP3 inflammasome in neuroinflammation and central nervous system diseases","volume":"22","author":"Xu","year":"2025","journal-title":"Cell. Mol. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Neam\u021bu, M., Petreu\u0219, T., Olinici, D.T., Stoica, L., Arcan, O.D., Stoica, B.A., and Mo\u0219oiu, C. (2026). The NLRP3 Inflammasome in Neuropsychiatric Disorders: Molecular Mechanisms and Emerging Therapeutic Strategies. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27073127"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xiang, Y., Zhang, M., Jiang, D., Su, Q., and Shi, J. (2023). The role of inflammation in autoimmune disease: A therapeutic target. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1267091"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1136\/ard.2009.122903","article-title":"Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjogren\u2019s syndrome","volume":"69","author":"Cobb","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tayel, S.I., Muharram, N.M., Fotoh, D.S., Elbarbary, H.S., Abd-Elhafiz, H.I., El-Masry, E.A., Taha, A.E., and Soliman, S.E. (2021). Prognostic Impact of Genetic Variants of MECP2 and TIRAP on Clinical Outcomes of Systemic Lupus Erythematosus with and without Nephritis. Biomolecules, 11.","DOI":"10.3390\/biom11091378"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.autrev.2016.01.011","article-title":"Rett syndrome: An autoimmune disease?","volume":"15","author":"Leoncini","year":"2016","journal-title":"Autoimmun. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.3892\/etm.2021.10770","article-title":"Comprehensive review on the pathophysiology, clinical variants and management of pemphigus (Review)","volume":"22","author":"Costan","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17026","DOI":"10.1038\/nrdp.2017.26","article-title":"Pemphigus","volume":"3","author":"Kasperkiewicz","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1001\/jamadermatol.2017.5799","article-title":"Association Between Pemphigus and Neurologic Diseases","volume":"154","author":"Kridin","year":"2018","journal-title":"JAMA Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.det.2011.03.012","article-title":"Diagnosis and clinical features of pemphigus foliaceus","volume":"29","author":"James","year":"2011","journal-title":"Dermatol. Clin."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Simionescu, O., and Tudorache, S.I. (2025). Autoimmune pemphigus: Difficulties in diagnosis and the molecular mechanisms underlying the disease. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1481093"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.det.2011.03.020","article-title":"The genetics of pemphigus","volume":"29","author":"Sinha","year":"2011","journal-title":"Dermatol. Clin."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/sj.gene.6363718","article-title":"A polymorphic variant of the gene coding desmoglein 1, the target autoantigen of pemphigus foliaceus, is associated with the disease","volume":"2","author":"Martel","year":"2001","journal-title":"Genes Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"38","DOI":"10.7453\/gahmj.2013.008","article-title":"The CARE Guidelines: Consensus-based Clinical Case Reporting Guideline Development","volume":"2","author":"Gagnier","year":"2013","journal-title":"Glob. Adv. Health Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Santosh, P.J., Bell, L., Lievesley, K., Singh, J., and Fiori, F. (2016). Paradoxical physiological responses to propranolol in a Rett syndrome patient: A case report. BMC Pediatr., 16.","DOI":"10.1186\/s12887-016-0734-3"},{"key":"ref_40","unstructured":"Li, H. (2013). Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13073-025-01581-y","article-title":"Automating ACMG variant classifications with BIAS-2015 v2.1.1: Algorithm analysis and benchmark against the FDA-approved eRepo dataset","volume":"17","author":"Eisenhart","year":"2025","journal-title":"Genome Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Brito, F., Lagos, C., Cubillos, J., Orellana, J., Gajardo, M., B\u00f6hme, D., Encina, G., and Repetto, G.M. (2024). Genomic analysis in Chilean patients with suspected Rett syndrome: Keep a broad differential diagnosis. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1278198"},{"key":"ref_44","first-page":"31","article-title":"Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome","volume":"29","author":"Motil","year":"1999","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.pediatrneurol.2015.03.018","article-title":"Infrared Thermal Analysis and Individual Differences in Skin Temperature Asymmetry in Rett Syndrome","volume":"53","author":"Symons","year":"2015","journal-title":"Pediatr. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Baker, J., Seiffert-Sinha, K., and Sinha, A.A. (2023). Patient genetics shape the autoimmune response in the blistering skin disease pemphigus vulgaris. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1064073"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1006\/jaut.2000.0388","article-title":"HLA class II polymorphism contributes to specify desmoglein derived peptides in pemphigus vulgaris and pemphigus foliaceus","volume":"15","author":"Loiseau","year":"2000","journal-title":"J. Autoimmun."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ruiz-Pablos, M., Paiva, B., and Zabaleta, A. (2025). The origin of autoimmune diseases: Is there a role for ancestral HLA-II haplotypes in immune hyperactivity. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1710571"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Carver, C.A., Kalesinskas, M., and Ahmed, A.R. (2023). Current biologics in treatment of pemphigus foliaceus: A systematic review. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1267668"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6862\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:16:10Z","timestamp":1785428170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":49,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156862"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156862","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}