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

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 VWF 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.