{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:42:08Z","timestamp":1792122128957,"version":"4.4.0"},"reference-count":29,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3\u2032untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30 kb deletion producing a chimeric TNXA\/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers\u2013Danlos syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.<\/jats:p>","DOI":"10.3390\/jcm11133818","type":"journal-article","created":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T22:50:46Z","timestamp":1656888646000},"page":"3818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency"],"prefix":"10.3390","volume":"11","author":[{"given":"Rosa Maria","family":"Paragliola","sequence":"first","affiliation":[{"name":"Unit of Endocrinology, Agostino Gemelli Foundation University Hospital IRCCS, 00168 Rome, Italy"},{"name":"Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, 00168 Rome, Italy"},{"name":"UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Perrucci","sequence":"additional","affiliation":[{"name":"Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), Agostino Gemelli Foundation University Hospital IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Foca","sequence":"additional","affiliation":[{"name":"Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), Agostino Gemelli Foundation University Hospital IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Urbani","sequence":"additional","affiliation":[{"name":"Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), Agostino Gemelli Foundation University Hospital IRCCS, 00168 Rome, Italy"},{"name":"Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of Sacred Heart, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0523-5744","authenticated-orcid":false,"given":"Paola","family":"Concolino","sequence":"additional","affiliation":[{"name":"Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), Agostino Gemelli Foundation University Hospital IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E379","DOI":"10.1210\/jc.2012-3148","article-title":"Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia","volume":"98","author":"Merke","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1159\/000481911","article-title":"Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome","volume":"89","author":"Miller","year":"2018","journal-title":"Horm. Res. Paediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"709758","DOI":"10.3389\/fendo.2021.709758","article-title":"Genes and Pseudogenes: Complexity of the RCCX Locus and Disease","volume":"30","author":"Carrozza","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1210\/endrev\/bnab016","article-title":"Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management","volume":"43","author":"Speiser","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s40291-018-0319-y","article-title":"Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene","volume":"22","author":"Concolino","year":"2018","journal-title":"Mol. Diagn. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s12020-011-9591-x","article-title":"Clinical outcomes in the management of congenital adrenal hyperplasia","volume":"41","author":"Falhammar","year":"2012","journal-title":"Endocrine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R127","DOI":"10.1530\/EJE-18-0712","article-title":"Management of Endocrine Disease: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency","volume":"180","author":"Falhammar","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41574-022-00655-w","article-title":"Management challenges and therapeutic advances in congenital adrenal hyperplasia","volume":"18","author":"Mallappa","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1056\/NEJMra021561","article-title":"Congenital adrenal hyperplasia","volume":"349","author":"Speiser","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ritelli, M., and Colombi, M. (2020). Molecular Genetics and Pathogenesis of Ehlers-Danlos Syndrome and Related Connective Tissue Disorders. Genes, 11.","DOI":"10.3390\/genes11050547"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. C. Semin. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"154","DOI":"10.4161\/19336918.2014.994893","article-title":"Tenascin-X: Beyond the architectural function","volume":"9","author":"Valcourt","year":"2015","journal-title":"Cell. Adh. Migr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1086\/376564","article-title":"Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome","volume":"73","author":"Zweers","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1056\/NEJMoa002939","article-title":"A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency","volume":"345","author":"Schalkwijk","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E1143","DOI":"10.1210\/jc.2015-2232","article-title":"Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia","volume":"100","author":"Morissette","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/humu.23028","article-title":"Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia","volume":"37","author":"Chen","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.jmoldx.2019.06.001","article-title":"High-Throughput Screening for CYP21A1P-TNXA\/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia","volume":"21","author":"Lao","year":"2019","journal-title":"J. Mol. Diagn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2789","DOI":"10.1210\/clinem\/dgab033","article-title":"Ehlers-Danlos Syndrome: Molecular and Clinical Characterization of TNXA\/TNXB Chimeras in Congenital Adrenal Hyperplasia","volume":"106","author":"Marino","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"dgaa199","DOI":"10.1210\/clinem\/dgaa199","article-title":"The Prevalence of the Chimeric TNXA\/TNXB Gene and Clinical Symptoms of Ehlers-Danlos Syndrome with 21-Hydroxylase Deficiency","volume":"105","author":"Gao","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/s41431-021-00870-5","article-title":"Molecular genetic testing of congenital adrenal hyperplasia due to 21-hydroxylase deficiency should include CAH-X chimeras","volume":"29","author":"Lao","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1038\/s41431-021-00869-y","article-title":"Reply to Lao Q and Merke DP","volume":"29","author":"Hoeppner","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/dvdy.220","article-title":"Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes","volume":"250","author":"Gensemer","year":"2021","journal-title":"Dev. Dyn."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O","article-title":"Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK)","volume":"77","author":"Beighton","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_24","first-page":"1777","article-title":"The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS)","volume":"27","author":"Grahame","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1007\/s00296-021-04832-4","article-title":"The Beighton Score as a measure of generalised joint hypermobility","volume":"41","author":"Malek","year":"2021","journal-title":"Rheumatol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4274\/balkanmedj.2018.1113","article-title":"Updates in Clinical and Genetics Aspects of Hypermobile Ehlers Danlos Syndrome","volume":"36","author":"Forghani","year":"2019","journal-title":"Balkan. Med. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/ajmg.c.31550","article-title":"The Ehlers-Danlos syndromes, rare types","volume":"175","author":"Brady","year":"2017","journal-title":"Am. J. Med. Genet. C. Semin. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"803226","DOI":"10.3389\/fendo.2022.803226","article-title":"Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome","volume":"13","author":"Marino","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1055\/s-0029-1225259","article-title":"Cardiovascular disease risk in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency","volume":"27","author":"Kim","year":"2009","journal-title":"Semin. Reprod. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/13\/3818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:41:39Z","timestamp":1760139699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/13\/3818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,1]]},"references-count":29,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["jcm11133818"],"URL":"https:\/\/doi.org\/10.3390\/jcm11133818","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,1]]}}}