{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:52:35Z","timestamp":1790419955020,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2017,3,15]],"date-time":"2017-03-15T00:00:00Z","timestamp":1489536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient\u2019s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions.<\/jats:p>","DOI":"10.3390\/ijms18030635","type":"journal-article","created":{"date-parts":[[2017,3,15]],"date-time":"2017-03-15T11:39:26Z","timestamp":1489577966000},"page":"635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8467-4728","authenticated-orcid":false,"given":"Ariana","family":"Kariminejad","sequence":"first","affiliation":[{"name":"Kariminejad-Najmabadi Pathology &amp; Genetics Center, #2, 4th Street, Hasan Seyf Street, Sanat Square, Tehran 14667-13713, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fariba","family":"Afroozan","sequence":"additional","affiliation":[{"name":"Kariminejad-Najmabadi Pathology &amp; Genetics Center, #2, 4th Street, Hasan Seyf Street, Sanat Square, Tehran 14667-13713, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Bozorgmehr","sequence":"additional","affiliation":[{"name":"Kariminejad-Najmabadi Pathology &amp; Genetics Center, #2, 4th Street, Hasan Seyf Street, Sanat Square, Tehran 14667-13713, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5753-8288","authenticated-orcid":false,"given":"Alireza","family":"Ghanadan","sequence":"additional","affiliation":[{"name":"Department of Dermatopathology, Razi Dermatology Hospital, Tehran University of Medical Sciences, Tehran 14167-53955, Iran"},{"name":"Department of Pathology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran 14197-33141, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5510-4673","authenticated-orcid":false,"given":"Susan","family":"Akbaroghli","sequence":"additional","affiliation":[{"name":"Clinical Genetics Division, Mofid Children\u2019s Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 15514-15468, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Khorram Khorshid","sequence":"additional","affiliation":[{"name":"Genetic Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran 19857-13834, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faezeh","family":"Mojahedi","sequence":"additional","affiliation":[{"name":"Mashhad Medical Genetic Counseling Center, Social Welfare and Rehabilitation Organization, Mashhad 91767-61999, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aria","family":"Setoodeh","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology and Inherited Metabolic Disorders, Department of Pediatrics, Tehran University of Medical Sciences, Tehran 14197-33141, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Loh","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, A*STAR, Singapore 138648, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, A*STAR, Singapore 138648, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Escande-Beillard","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, A*STAR, Singapore 138648, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fransiska","family":"Malfait","sequence":"additional","affiliation":[{"name":"Center for Metabolic Diseases, Department of Pediatrics, University Hospitals Leuven, Leuven 3000, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Reversade","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, A*STAR, Singapore 138648, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thatjana","family":"Gardeitchik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, Gelderland 9102-6500, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7441-700X","authenticated-orcid":false,"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, Gelderland 9102-6500, The Netherlands"},{"name":"Hayward Genetics Center, Tulane University Medical School, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/ng.2007.45","article-title":"Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2","volume":"40","author":"Kornak","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/ng.413","article-title":"Mutations in PYCR1 cause cutis laxa with progeroid features","volume":"41","author":"Reversade","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ajhg.2009.06.008","article-title":"Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2","volume":"85","author":"Guernsey","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/sj.ejhg.5201947","article-title":"Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation","volume":"16","author":"Morava","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1212\/WNL.0b013e3181b26daf","article-title":"Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debr\u00e9 type","volume":"73","author":"Morava","year":"2009","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1093\/hmg\/ddp148","article-title":"Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival","volume":"18","author":"Hucthagowder","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1212\/01.wnl.0000327822.52212.c7","article-title":"Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type","volume":"71","author":"Kayserili","year":"2008","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/j.1399-0004.1994.tb03988.x","article-title":"Male with type II autosomal recessive cutis laxa","volume":"45","author":"Imaizumi","year":"1994","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/sj.ejhg.5201361","article-title":"Defective protein glycosylation in patients with cutis laxa syndrome","volume":"13","author":"Morava","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.bbadis.2004.11.009","article-title":"A combined defect in the biosynthesis of N- and O-glycans in patients with cutis laxa and neurological involvement: The biochemical characteristics","volume":"1741","author":"Wopereis","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/ajmg.1352","article-title":"Gerodermia osteodysplastica and wrinkly skin syndrome: Are they the same?","volume":"101","author":"Sztriha","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/j.1365-2230.2005.01825.x","article-title":"Wrinkly skin syndrome","volume":"30","author":"Hamamy","year":"2005","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1525-1470.2007.00586.x","article-title":"Gerodermia osteodysplastica\/wrinkly skin syndrome: Report of three patients and brief review of the literature","volume":"25","author":"Nanda","year":"2008","journal-title":"Pediatr. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/ajmg.a.32143","article-title":"Geroderma osteodysplasticum hereditaria and wrinkly skin syndrome in 22 patients from Oman","volume":"146","author":"Rajab","year":"2008","journal-title":"Am. J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s10545-011-9319-3","article-title":"Defect in proline synthesis: Pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities","volume":"34","author":"Kretz","year":"2011","journal-title":"J. Inherit Metab. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1002\/ajmg.a.33747","article-title":"The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2","volume":"155A","author":"Yildirim","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ymgme.2013.08.009","article-title":"Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa","volume":"110","author":"Dimopoulou","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","first-page":"126","article-title":"Gerodermie osteodysplastique hereditaire","volume":"174","author":"Bamatter","year":"1950","journal-title":"Ann. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1002\/ajmg.a.32996","article-title":"A novel missense mutation in SCYL1BP1 produces geroderma osteodysplastica phenotype indistinguishable from that caused by nullimorphic mutations","volume":"149A","author":"Alkuraya","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/BF00272192","article-title":"Geroderma osteodysplastica. A report of two affected families","volume":"40","author":"Hunter","year":"1978","journal-title":"Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1038\/ng.252","article-title":"Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin","volume":"40","author":"Hennies","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/ejhg.2013.154","article-title":"Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa","volume":"22","author":"Gardeitchik","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1007\/s00439-012-1197-8","article-title":"Further characterization of ATP6V0A2-related autosomal recessive cutis laxa","volume":"131","author":"Fischer","year":"2012","journal-title":"Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/ajmg.a.36411","article-title":"Autosomal recessive cutis laxa type 2A (ARCL2A) mimicking Ehlers-Danlos syndrome by its dermatological manifestations: Report of three affected patients","volume":"164","author":"Greally","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_25","first-page":"203","article-title":"ATP6V0A2 mutations present in two Mexican Mestizo children with an autosomal recessive cutis laxa syndrome type IIA","volume":"1","author":"Raymond","year":"2014","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jdermsci.2014.04.004","article-title":"Identification of two novel ATP6V0A2 mutations in an infant with cutis laxa by exome sequencing","volume":"75","author":"Ritelli","year":"2014","journal-title":"J. Dermatol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"521","DOI":"10.4103\/0019-5154.164434","article-title":"The diagnostic dilemma of cutis laxa: A report of two cases with genotypic dissimilarity","volume":"60","author":"Goyal","year":"2015","journal-title":"Indian J. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s10048-016-0491-3","article-title":"Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A","volume":"17","author":"Cohen","year":"2016","journal-title":"Neurogenetics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1002\/ajmg.a.33963","article-title":"A novel mutation in PYCR1 causes an autosomal recessive cutis laxa with premature aging features in a family","volume":"155A","author":"Lin","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/pde.12065","article-title":"Cutis laxa type II with mutation in the pyrroline-5-carboxylate reductase 1 gene","volume":"30","author":"Nouri","year":"2013","journal-title":"Pediatr. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.ejmg.2013.03.006","article-title":"Mutations in PYCR1 gene in three families with autosomal recessive cutis laxa, type 2","volume":"56","author":"Scherrer","year":"2013","journal-title":"Eur. J. Med. Genet."},{"key":"ref_32","first-page":"1391","article-title":"Congenital cutis laxa type 2 associated with recurrent aspiration pneumonia and growth delay: Case report","volume":"7","author":"Rahmati","year":"2015","journal-title":"Electron. Physician"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s00439-016-1660-z","article-title":"Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue","volume":"135","author":"Alazami","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.jid.2016.10.007","article-title":"Molecular dynamics simulation of the consequences of a PYCR1 mutation (p.Ala189Val) in patients with complex connective tissue disorder and severe intellectual disability","volume":"137","author":"Vahidnezhad","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1002\/ajmg.a.32564","article-title":"Geroderma osteodysplastica maps to a 4 Mb locus on chromosome 1q24","volume":"146A","author":"Newman","year":"2008","journal-title":"Am. J. Med. Genet. A"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/3\/635\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:30:29Z","timestamp":1760207429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/3\/635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,15]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2017,3]]}},"alternative-id":["ijms18030635"],"URL":"https:\/\/doi.org\/10.3390\/ijms18030635","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,15]]}}}