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 haematological findings in a Turkish family.

MATERIALS AND METHODS: We performed clinical, genetic and histological analyses on 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 the SNP genotype data yielded a maximal multipoint LOD score of 2.59 at 12q24.21-24.32. Exome sequence analysis for 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 sibs.

CONCLUSION: Our patients do not have gross structural brain defects besides microcephaly, strabismus, myopia, growth or developmental delay. Large platelets were observed in patients and unusual electron-dense intracytoplasmic inclusions in fibroblasts and epidermal basal cells were observed in both affected and unaffected family members. Patients do not have any genetic defect in VWF gene but vWF 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.