Cutis laxa, autosomal recessive, type 2aQ82.8

Cutis laxa is the name given to a heterogeneous group of hereditary diseases whose main symptom is a pendulous, inelastic (in contrast to Marfan's syndrome and Ehlers-Danlos syndrome) skin. These cutaneous characteristics are almost always due to loss, fragmentation or severe disorganization of the elastic fibers. The systemic significance of this disorder of elastogenesis affects different organ systems. Besides the skin, lungs and vessels are mainly affected. The hereditary forms of Cutis laxa are triggered by mutations in different genes (e.g. PYCR1, LTBP4, ATP6V0A2 and others), which are functionally involved in the build-up or breakdown or in the organisation of elastic fibres. In principle, autosomal dominant forms can be distinguished from autosomal recessive forms, independent of the gene systematics. If the clinical phenomenon "cutis laxa" or rather "cutis laxa-like skin changes" is considered in terms of differential diagnosis, further hereditary as well as acquired clinical pictures have to be taken into account.

There is a mutation in the ATP6V0A2 - C-ATPase gene, gene location: 12q24.31 which codes for a V-ATPase. The ATP6VOA2 gene is a subunit of the vacuolar ATPase (v-ATPase), a heteromultimeric enzyme present in intracellular vesicles and in the plasma membrane of specialized cells and essential for the pH gradient (acidification) and glycolysis of various cellular components (Miles AL et al. (2017). It performs an important function in the glycosylation of elastic fibres (Guillard M et al. (2009).

The clinical spectrum of autosomal recessive cutis laxa is very heterogeneous with respect to organ involvement and severity.

Type 2A autosomal recessive cutis laxa (ARCL2A) is a specific disease with different organ involvement, ranging from mild to severe. Associated are cranial anomalies (microcephaly). In contrast to other variants of autosomal recessive cutis laxa there is no lung emphysema. The electron microscopic reduction of elastic fibers in the dermis and abnormal elastin components is pathognomonic.

1. Guillard M et al (2009) Vacuolar H+-ATPase meets glycosylation in patients with cutis laxa. Biochim Biophys Acta 1792:903-914.
2. Loeys B et al (2002) Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet 11:2113-2118.
3. Miles AL et al (2017) The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels. Elife pii: e22693. doi: 10.7554/eLife.22693.
4. Papke CL et al (2015) Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations.Hum Mol Genet 24:5867-5879.