{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:04:07Z","timestamp":1780549447524,"version":"3.54.1"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["RC 2026"],"award-info":[{"award-number":["RC 2026"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pathogenic variants in the CLCN4 gene are associated with a rare X-linked neurodevelopmental disorder, Raynaud\u2013Claes syndrome, characterized by intellectual disability, epilepsy, language impairment, motor deficits, stereotypies, and structural brain abnormalities. Although heterozygous females are often considered to be only mildly affected, severe phenotypes have also been reported, and the clinical presentation shows considerable heterogeneity. The present study aims to summarize the current knowledge on CLCN4-related neurodevelopmental disorders through a review of the available literature and to describe two additional patients carrying pathogenic CLCN4 variants, one male and one female. The female patient was found to carry a de novo heterozygous variant (c.2152C &gt; T), while the male patient harbored a de novo hemizygous variant (c.949G &gt; A). Clinical data were compared with those reported in the literature in order to identify phenotypic similarities and differences among patients previously described with the same mutations. Furthermore, in light of the literature review and the clinical data collected from our patients, we propose considering Raynaud\u2013Claes syndrome as a Rett-like condition. This perspective expands the scope of differential diagnosis and underscores the importance of multidisciplinary and longitudinal diagnostic evaluation to improve clinical characterization, therapeutic management, and genetic counseling.<\/jats:p>","DOI":"10.3390\/genes17060623","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:17:31Z","timestamp":1780467451000},"page":"623","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the Phenotypic Spectrum of Raynaud\u2013Claes Syndrome: A Rett-like Presentation with Two New Cases"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7557-6598","authenticated-orcid":false,"given":"Roberta","family":"Milone","sequence":"first","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5256-6573","authenticated-orcid":false,"given":"Alessandro","family":"Orsini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Marinella","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rea","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Pasquariello","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1142-5656","authenticated-orcid":false,"given":"Lorenza","family":"Marini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7889-1355","authenticated-orcid":false,"given":"Roberta","family":"Battini","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, S., Zhang, W., Liang, P., Zhu, M., Zheng, B., Zhou, W., Wang, C., and Zhao, X. (2023). Novel variants in the CLCN4 gene associated with syndromic X-linked intellectual disability. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1096969"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4933","DOI":"10.1007\/s00415-024-12383-4","article-title":"Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients","volume":"271","author":"He","year":"2024","journal-title":"J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1111\/epi.12201","article-title":"Exome sequencing reveals new causal mutations in children with epileptic encephalopathies","volume":"54","author":"Veeramah","year":"2013","journal-title":"Epilepsia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/mp.2014.193","article-title":"X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes","volume":"21","author":"Hu","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Xu, X., Lu, F., Zhang, L., Li, H., Du, S., and Tang, J. (2021). Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: A case report. BMC Pediatr., 21.","DOI":"10.1186\/s12887-021-02860-4"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41380-022-01852-9","article-title":"Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition","volume":"28","author":"Palmer","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_7","first-page":"1280","article-title":"Analysis of CLCN4 gene variant in a child with Raynaud-Claes syndrome","volume":"40","author":"Li","year":"2023","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00439-024-02668-z","article-title":"Genotype\u2013phenotype correlation in CLCN4-related developmental and epileptic encephalopathy","volume":"143","author":"Sahly","year":"2024","journal-title":"Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tettey-Matey, A., Picollo, A., Sbrana, F., Coppola, M.A., Rubino, E., Giusto, A., Festa, M., Angeli, E., Picco, C., and Barbieri, R. (2025). Dominant action of CLCN4 neurodevelopmental disease variants in heteromeric endosomal ClC-3\/ClC-4 transporters. Cells, 14.","DOI":"10.3390\/cells14241973"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1111\/epi.16906","article-title":"The molecular and phenotypic spectrum of CLCN4-related epilepsy","volume":"62","author":"He","year":"2021","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/mp.2016.135","article-title":"De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females","volume":"23","author":"Palmer","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/(SICI)1096-8628(19960712)64:1<97::AID-AJMG17>3.0.CO;2-N","article-title":"X-linked mental retardation with neonatal hypotonia in a French family (MRX15): Gene assignment to Xp11.22\u2013Xp21.1","volume":"64","author":"Raynaud","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/(SICI)1096-8628(19960712)64:1<137::AID-AJMG24>3.0.CO;2-N","article-title":"Linkage analysis in three families with nonspecific X-linked mental retardation","volume":"64","author":"Claes","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_15","unstructured":"Green, E., Stroud, L., O\u2019Connell, R., Bloomfield, S., Cronje, J., Foxcroft, C., Hurter, K., Lane, H., Marais, R., and Marx, C. (2016). Griffiths Scales of Child Development, Part II: Administration and Scoring, Hogrefe. [3rd ed.]."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bayley, N. (2005). Bayley Scales of Infant and Toddler Development, Giunti Psychometrics. [3rd ed.].","DOI":"10.1037\/t14978-000"},{"key":"ref_17","unstructured":"Sparrow, S.S., Cicchetti, D.V., and Balla, D.A. (2016). Vineland Adaptive Behavior Scales, Giunti Psychometrics. [2nd ed.]."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e12456","DOI":"10.1111\/gbb.12456","article-title":"Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies","volume":"17","author":"Zhou","year":"2018","journal-title":"Genes Brain Behav."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e64192","DOI":"10.1002\/ajmg.a.64192","article-title":"CLCN4-related neurodevelopmental condition: Characterization of speech and language abilities","volume":"197","author":"Garrett","year":"2025","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.21037\/tp-2025-157","article-title":"Clinical features and genetic analysis of epilepsy caused by CLCN4 gene mutation: A case report and literature review","volume":"14","author":"Mao","year":"2025","journal-title":"Transl. Pediatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.braindev.2023.05.004","article-title":"Developmental and epileptic encephalopathy in a young Italian woman with a de novo missense variant in the CLCN4 gene: A case report","volume":"45","author":"Rossi","year":"2023","journal-title":"Brain Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1002\/pd.6404","article-title":"Prenatal diagnosis of CLCN4-related neurodevelopmental disorder in fetuses with congenital brain anomalies","volume":"43","author":"Lam","year":"2023","journal-title":"Prenat. Diagn."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/cge.13153","article-title":"Clinician\u2019s guide to genes associated with Rett-like phenotypes-Investigation of a Danish cohort and review of the literature","volume":"95","author":"Bisgaard","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Spagnoli, C., Fusco, C., and Pisani, F. (2021). Rett Syndrome Spectrum in Monogenic Developmental-Epileptic Encephalopathies and Epilepsies: A Review. Genes, 12.","DOI":"10.3390\/genes12081157"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/623\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T04:23:49Z","timestamp":1780547029000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/623"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":24,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["genes17060623"],"URL":"https:\/\/doi.org\/10.3390\/genes17060623","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]}}}