{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T12:16:46Z","timestamp":1771244206215,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T00:00:00Z","timestamp":1771113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Duplications involving Xp22.33, particularly within the pseudoautosomal region 1 (PAR1), are rare. While copy number variants (CNVs) involving SHOX, a dosage-sensitive gene in PAR1, are known to cause growth disorders, large duplications encompassing the entire PAR1 region and beyond show variable associations with skeletal and neurodevelopmental abnormalities. Duplication of the near-complete, isolated PAR1 with a comprehensive clinical description has not been reported. Case Presentation: We report a male patient with a 2.49 Mb duplication encompassing nearly the entire PAR1 region (chrX:200854\u20132692897, GRCh37). Clinical features included global developmental delay (GDD), autism spectrum disorder (ASD), recurrent seizures, hypotonia with joint hypermobility, dysmorphic features, and proportionate tall stature. The duplicated segment contains 30 genes, including 15 protein-coding genes that escape X-inactivation. Among these, SHOX, DHRSX, ASMT, and CSF2RA are notable candidates contributing to the observed phenotype. Conclusions: This report presents a detailed clinical characterization of a rare, near-complete, isolated PAR1 duplication in a male individual. The co-occurrence of tall stature, GDD, ASD, and seizures raises the possibility of a dosage-related phenotypic effect involving one or more genes within the duplicated interval. While causality cannot be definitively established, these observations contribute to the emerging understanding of the functional consequences of Xp22.33 duplications and suggest that increased copy number within this region may be associated with a clinically significant neurodevelopmental phenotype.<\/jats:p>","DOI":"10.3390\/genes17020238","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T11:11:28Z","timestamp":1771240288000},"page":"238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Xp22.33 Duplication Encompassing PAR1 in a Male with Syndromic Neurodevelopmental Disorder and Tall Stature"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8537-2515","authenticated-orcid":false,"given":"Dibyendu","family":"Dutta","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1941-2318","authenticated-orcid":false,"given":"Xi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Baylor Genetics, Houston, TX 77021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ria","family":"Garg","sequence":"additional","affiliation":[{"name":"Center of Development, Behavior, and Genetics, State University of New York Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1016\/j.ajhg.2024.09.005","article-title":"Where Is the Boundary of the Human Pseudoautosomal Region?","volume":"111","author":"Bellott","year":"2024","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1086\/449313","article-title":"A Novel Class of Pseudoautosomal Region 1 Deletions Downstream of SHOX Is Associated with Leri-Weill Dyschondrosteosis","volume":"77","author":"Thomas","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/1750-1172-6-53","article-title":"Evaluation of SHOX Copy Number Variations in Patients with M\u00fcllerian Aplasia","volume":"6","author":"Sandbacka","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/jhg.2015.53","article-title":"Rare Pseudoautosomal Copy-Number Variations Involving SHOX and\/or Its Flanking Regions in Individuals with and without Short Stature","volume":"60","author":"Fukami","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref_5","first-page":"634","article-title":"SHOX Duplications Found in Some Cases with Type I Mayer-Rokitansky-Kuster-Hauser Syndrome","volume":"12","author":"Gervasini","year":"2010","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/jhg.2016.18","article-title":"Systematic Molecular Analyses of SHOX in Japanese Patients with Idiopathic Short Stature and Leri-Weill Dyschondrosteosis","volume":"61","author":"Shima","year":"2016","journal-title":"J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1159\/000530171","article-title":"SHOX Whole Gene Duplications Are Overrepresented in SHOX Haploinsufficiency Phenotype Cohorts","volume":"162","author":"Bunyan","year":"2022","journal-title":"Cytogenet. Genome Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1136\/jmedgenet-2020-106842","article-title":"Rare and de Novo Duplications Containing SHOX in Clubfoot","volume":"57","author":"Sadler","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.4103\/0366-6999.167369","article-title":"A Rare Novel Copy Number Variation of Xp22.33-P11.22 Duplication Is Associated with Congenital Heart Defects","volume":"128","author":"Zhang","year":"2015","journal-title":"Chin. Med. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1159\/000443232","article-title":"Xp22.33p22.12 Duplication in a Patient with Intellectual Disability and Dysmorphic Facial Features","volume":"6","author":"Lintas","year":"2016","journal-title":"Mol. Syndromol."},{"key":"ref_11","first-page":"405","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. Off. J. Am. Coll. Med. Genet."},{"key":"ref_12","first-page":"245","article-title":"Technical Standards for the Interpretation and Reporting of Constitutional Copy-Number Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev-genom-102822-100509","article-title":"DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data","volume":"24","author":"Foreman","year":"2023","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/AOG.0000000000006112","article-title":"Neurodevelopmental Outcomes of 3-Year-Old Children Exposed to Maternal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Utero","volume":"147","author":"Shook","year":"2026","journal-title":"Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2439792","DOI":"10.1001\/jamanetworkopen.2024.39792","article-title":"In Utero Exposure to Maternal COVID-19 and Offspring Neurodevelopment Through Age 24 Months","volume":"7","author":"Jaswa","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2443697","DOI":"10.1001\/jamanetworkopen.2024.43697","article-title":"Neurodevelopment in the First 2 Years of Life Following Prenatal Exposure to Maternal SARS-CoV-2 Infection","volume":"7","author":"Vrantsidis","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"P\u0103curar, D., Dinulescu, A., Prejmereanu, A., Palc\u0103u, A.C., Dijm\u0103rescu, I., and Pavelescu, M.-L. (2025). Neurodevelopmental Outcomes in Children Born to Mothers Infected with SARS-CoV-2 During Pregnancy: A Narrative Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176202"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"129","DOI":"10.2174\/138920207780368141","article-title":"The Human Pseudoautosomal Region (PAR): Origin, Function and Future","volume":"8","author":"Morris","year":"2007","journal-title":"Curr. Genomics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1093\/hmg\/9.5.695","article-title":"The Short Stature Homeobox Gene SHOX Is Involved in Skeletal Abnormalities in Turner Syndrome","volume":"9","author":"Schiller","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1002\/ajmg.a.33334","article-title":"Increased Number of Sex Chromosomes Affects Height in a Nonlinear Fashion: A Study of 305 Patients with Sex Chromosome Aneuploidy","volume":"152A","author":"Ottesen","year":"2010","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1159\/000309418","article-title":"Trisomy of the Short Stature Homeobox-Containing Gene (SHOX) Due to Duplication\/Deletion of the X Chomosome: Clinical Implications on the Stature","volume":"74","author":"Jasper","year":"2010","journal-title":"Horm. Res. Paediatr."},{"key":"ref_22","first-page":"159","article-title":"Unexpected Phenotype in a Boy with Trisomy of the SHOX Gene","volume":"23","author":"Iughetti","year":"2010","journal-title":"J. Pediatr. Endocrinol. Metab. JPEM"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Turan, B., Arslan, G., \u00c7inleti, T., Ar\u0131kan, \u015e., Y\u0131lmaz, \u0130.T., Saka G\u00fcven\u00e7, M., and D\u00fcndar, B.N. (2025). Duplication in the SHOX Gene as a Rare Genetic Cause of Short Stature and\/or Skeletal Abnormalities: A Clinical Report and Review of the Literature. J. Clin. Res. Pediatr. Endocrinol.","DOI":"10.4274\/jcrpe.galenos.2025.2024-11-20"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Paprocka, J., Jezela-Stanek, A., Tylki-Szyma\u0144ska, A., and Grunewald, S. (2021). Congenital Disorders of Glycosylation from a Neurological Perspective. Brain Sci., 11.","DOI":"10.3390\/brainsci11010088"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Astro, V., Alowaysi, M., Fiacco, E., Saera-Vila, A., Cardona-Londo\u00f1o, K.J., Aiese Cigliano, R., and Adamo, A. (2021). Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs from Patients with Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.801597"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1016\/j.cell.2024.04.041","article-title":"A Pseudoautosomal Glycosylation Disorder Prompts the Revision of Dolichol Biosynthesis","volume":"187","author":"Wilson","year":"2024","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"962","DOI":"10.7150\/ijms.9529","article-title":"DHRSX, a Novel Non-Classical Secretory Protein Associated with Starvation Induced Autophagy","volume":"11","author":"Zhang","year":"2014","journal-title":"Int. J. Med. Sci."},{"key":"ref_28","first-page":"188","article-title":"47,XYY Syndrome and Male Infertility","volume":"15","author":"Kim","year":"2013","journal-title":"Rev. Urol."},{"key":"ref_29","first-page":"851","article-title":"48,XXYY, 48,XXXY and 49,XXXXY Syndromes: Not Just Variants of Klinefelter Syndrome","volume":"2011","author":"Tartaglia","year":"1992","journal-title":"Acta Paediatr. Oslo Nor."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1534\/g3.112.004689","article-title":"A Discovery Resource of Rare Copy Number Variations in Individuals with Autism Spectrum Disorder","volume":"2","author":"Prasad","year":"2012","journal-title":"G3 Bethesda Md"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/(SICI)1096-8628(19981102)80:2<103::AID-AJMG2>3.0.CO;2-1","article-title":"An Adult with 49,XYYYY Karyotype: Case Report and Endocrine Studies","volume":"80","author":"Shanske","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/ddrr.85","article-title":"An Extra X or Y Chromosome: Contrasting the Cognitive and Motor Phenotypes in Childhood in Boys with 47,XYY Syndrome or 47,XXY Klinefelter Syndrome","volume":"15","author":"Ross","year":"2009","journal-title":"Dev. Disabil. Res. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Demily, C., Poisson, A., Peyroux, E., Gatellier, V., Nicolas, A., Rigard, C., Schluth-Bolard, C., Sanlaville, D., and Rossi, M. (2017). Autism Spectrum Disorder Associated with 49,XYYYY: Case Report and Review of the Literature. BMC Med. Genet., 18.","DOI":"10.1186\/s12881-017-0371-1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1136\/adc.2009.179747","article-title":"Autism, Language and Communication in Children with Sex Chromosome Trisomies","volume":"96","author":"Bishop","year":"2011","journal-title":"Arch. Dis. Child."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1749-6632.1998.tb10107.x","article-title":"Molecular Cloning and Developmental Expression of the Xenopus Homolog of Integrin Alpha 4","volume":"857","author":"Whittaker","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1210\/en.2015-1888","article-title":"Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland","volume":"157","author":"Rath","year":"2016","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.molmet.2019.07.007","article-title":"Temporal Expression Patterns of the Melatoninergic System in the Human Thymus of Children","volume":"28","author":"Rubio","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"978","DOI":"10.2174\/1381612822666151214104624","article-title":"Melatonin in Pregnancy: Effects on Brain Development and CNS Programming Disorders","volume":"22","author":"Yen","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/j.1600-079X.2007.00435.x","article-title":"Melatonin Influences the Proliferative and Differentiative Activity of Neural Stem Cells","volume":"42","author":"Moriya","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Cai, G., Edelmann, L., Goldsmith, J.E., Cohen, N., Nakamine, A., Reichert, J.G., Hoffman, E.J., Zurawiecki, D.M., Silverman, J.M., and Hollander, E. (2008). Multiplex Ligation-Dependent Probe Amplification for Genetic Screening in Autism Spectrum Disorders: Efficient Identification of Known Microduplications and Identification of a Novel Microduplication in ASMT. BMC Med. Genomics, 1.","DOI":"10.1186\/1755-8794-1-50"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jonsson, L., Ljunggren, E., Bremer, A., Pedersen, C., Land\u00e9n, M., Thuresson, K., Giacobini, M., and Melke, J. (2010). Mutation Screening of Melatonin-Related Genes in Patients with Autism Spectrum Disorders. BMC Med. Genomics, 3.","DOI":"10.1186\/1755-8794-3-10"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1038\/ncomms4650","article-title":"Protein Interaction Network of Alternatively Spliced Isoforms from Brain Links Genetic Risk Factors for Autism","volume":"5","author":"Corominas","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1093\/hmg\/7.11.1771","article-title":"Gene Duplications as a Recurrent Theme in the Evolution of the Human Pseudoautosomal Region 1: Isolation of the Gene ASMTL","volume":"7","author":"Ried","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7019","DOI":"10.1007\/s12035-016-0202-y","article-title":"Copy Number Variants in Patients with Autism and Additional Clinical Features: Report of VIPR2 Duplication and a Novel Microduplication Syndrome","volume":"54","author":"Firouzabadi","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1084\/jem.20080759","article-title":"Pulmonary Alveolar Proteinosis Caused by Deletion of the GM-CSFRalpha Gene in the X Chromosome Pseudoautosomal Region 1","volume":"205","author":"Doan","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1084\/jem.20080990","article-title":"Familial Pulmonary Alveolar Proteinosis Caused by Mutations in CSF2RA","volume":"205","author":"Suzuki","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13740","DOI":"10.1038\/s41598-018-31780-0","article-title":"DNA Hypermethylation and Differential Gene Expression Associated with Klinefelter Syndrome","volume":"8","author":"Nielsen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E518","DOI":"10.1210\/jc.2014-2780","article-title":"Gene Expression Patterns in Relation to the Clinical Phenotype in Klinefelter Syndrome","volume":"100","author":"Zitzmann","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/SHK.0b013e3182571e46","article-title":"Sex Differences in Inflammatory Cytokines and CD99 Expression Following in Vitro Lipopolysaccharide Stimulation","volume":"38","author":"Corazza","year":"2012","journal-title":"Shock Augusta Ga"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lef\u00e8vre, N., Corazza, F., Valsamis, J., Delbaere, A., De Maertelaer, V., Duchateau, J., and Casimir, G. (2019). The Number of X Chromosomes Influences Inflammatory Cytokine Production Following Toll-Like Receptor Stimulation. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01052"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/238\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T11:36:14Z","timestamp":1771241774000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,15]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["genes17020238"],"URL":"https:\/\/doi.org\/10.3390\/genes17020238","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,15]]}}}