A Novel ATP6V0A2 Mutation Causing Recessive Cutis Laxa with Unusual Manifestations of Bleeding Diathesis and Defective Wound Healing

Abstract

Objective: Autosomal recessive cutis laxa type IIA (ARCL2A) is a rare congenital disorder characterized by loose and elastic skin, growth and developmental delay, and skeletal anomalies. It is caused by biallelic mutations in ATP6V0A2 . Those mutations lead to increased pH in secretory vesicles and thereby to impaired glycosyltransferase activity and organelle trafficking. We aimed to identify the genetic and molecular cause of the unexpected hematological findings in a Turkish family. Materials and Methods: We performed clinical, genetic, and histological analyses of a consanguineous family afflicted with wrinkled and loose skin, microcephaly, intellectual disability, cleft lip and palate, downslanting palpebral fissures, ectopia lentis, bleeding diathesis, and defective wound healing. Results: Linkage analysis using SNP genotype data yielded a maximal multipoint logarithm of odds score of 2.59 at 12q24.21-24.32. Exome sequence analysis for the proband led to the identification of novel homozygous frameshift c.2085_2088del (p.(Ser695Argfs*12)) in ATP6V0A2 , within the linked region, in the two affected siblings. Conclusion: Our patients do not have gross structural brain defects besides microcephaly, strabismus, myopia, and growth or developmental delay. Large platelets were observed in the patients and unusual electron-dense intracytoplasmic inclusions in fibroblasts and epidermal basal cells were observed in both affected and unaffected family members. The patients do not have any genetic defect in the VW F gene but von Willebrand factor activity to antigen ratios were low. Clinical findings of bleeding diathesis and defective wound healing have not been reported in ARCL2A and hence our findings expand the phenotypic spectrum of the disease.

Review of clinical and molecular variability in autosomal recessive cutis laxa 2A

“…Literature review identified 14 articles published from 2005 to 2019 with individuals with ARCL2A or WSS due to deleterious variants in ATP6V0A2 (Medrano et al, 2019: Karacan et al, 2019; Beyens et al, 2019; Kariminejad et al, 2017; Ritelli et al, 2014; Bahena‐Bahena et al, 2014; Gardeitchik et al, 2014; Greally et al, 2014; Fischer et al, 2012; Hucthagowder et al, 2009; Kornak et al, 2008; Mohamed et al, 2011; Morava et al, 2005; Tantcheva‐Poor et al, 2012). A total of 70 affected individuals from 65 families, including ours, were found (Tables S1–S4).…”

V-ATPase V0a1 promotes Weibel–Palade body biogenesis through the regulation of membrane fission

“…Qualitative or quantitative deficiency of plasma VWF multimers causes a bleeding disorder called von Willebrand disease ( Sadler, 2005 ; Sadler, 1998 ; Sharma and Haberichter, 2019 ). A V0a2 mutation has recently been reported to cause bleeding diathesis in humans ( Karacan et al, 2019 ). Plasma VWF activity is significantly impaired in patients without any substantial loss of plasma VWF antigen level, thus exhibiting a typical sign of von Willebrand disease, although no associating mutation was found in the VWF gene.…”

The Role of Cardiovascular Surgery in the Management of a Patient Diagnosed With Congenital Cutis Laxa Syndrome Complicated by Multivalvular Heart Disease

“…In addition, our justification for using a porcine valve prosthesis instead of a mechanical valve in this patient is the social status, as this patient lives in a remote suburb area with difficult access to tertiary care centers making it difficult to comply with anticoagulant therapy. Furthermore, based on the literature, Karacan et al demonstrated CCL syndrome to be a notoriously unexpectable disorder with multiple cases reported to have abrupt bleeding diathesis and defective wound healing [ 16 ]. To the best of our knowledge, this is the first case reported in the literature with successful surgical treatment of both mitral and tricuspid valves associated with this syndrome.…”