Cutis laxa, autosomal recessive, type 1bQ82.8

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. Apart from 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 organisation of elastic fibres. In principle, autosomal dominant forms can be distinguished from autosomal recessive forms, independent of the gene system. 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.

Cutis laxa, autosomal recessive, type 2B is caused by a mutation in the EFEMP2 gene (gene location 11q13.1). The EFEMP2 gene (EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 2) encodes fibulin 4.

Cutis laxa, autosomal recessive, type 2B is a clinically severe form with life-threatening complications such as emphysema and pulmonary artery stenosis. Fibulins comprise a group of extracellular matrix proteins or matricellular proteins that are composed of a tandem of an epidermal-growth factor-like domain with a C-terminal fibulin-typical module. The family consists of 7 members, fibulins 1 to 7 (de Vega S et al. 2014). For functional and molecular reasons, the fibulin group can be divided into long fibulins, fibulins 1/2/6, and short fibulins, fibulins 3/4/5/7 (Papke CL et al. 2014). Chemically, all fibulins are glycoproteins that are embedded in the fibrillar extracellular matrix of different organ systems in varying densities. For example, fibulin 4 is essential for the structure and function of the walls of large vessels (Papke CL et al. 2014).

The clinical spectrum of EFEMP2 mutations is relatively large and affects skin, vessels, lungs and the skeletal system. Most of the time, they are severe courses. In addition to a pronounced cutis laxa, severe life-threatening dysfunctions of the lungs due to cystic and atelectatic changes, atropical diaphragm with hiatus hernias are predominantly found (Urban Z et al. 2009). Furthermore:

Skeleton: retrognathia, arachnodactyly, hypermobility of the joints; microcephaly;

Ophthalmological: Keratoglobus (Mauger TF et al. 2019)

Cardiovascular changes: pulmonary artery stenosis, aneurysms, vascular stenosis

Symptomatic; if necessary surgical correction of aortic aneurysms, phospho-therapy.

Mutations of the EFEMP2 gene can also cause severe cadiovascular and severe intrauterine skeletal changes (skeleton: arachnodactyly, clubfoot, intrauterine flexures of the long bones, rib fractures) without signs of cutis laxa (Al-Hassnan ZN et al. 2012).

1. Al-Hassnan ZN et al (2012) Recessively inherited severe aortic aneurysm caused by mutated EFEMP2. At J Cardiol 109:1677-1680. https://www.ncbi.nlm.nih.gov/pubmed/22440127
2. de Vega S et al (2014) A C-terminal fragment of fibulin-7 interacts with endothelial cells and inhibits their tube formation in culture. Arch Biochem Biophys 545:148-153.
3. Kouwenberg D et al (2011) Recognizable phenotype with common occurrence of microcephaly, psychomotor retardation, but no spontaneous bone fractures in autosomal recessive cutis laxa type IIB due to PYCR1 mutations.Am J Med Genet A 155A:2331-2332
4. Letard P et al (2018) Severe Phenotype of Cutis Laxa Type 1B with Antenatal Signs due to a Novel Homozygous Nonsense Mutation in EFEMP2. Mol syndrome 9:190-196.
5. Mauger TF et al (2019) Keratoglobus with ARCL1B (EFEMP2 gene) cutis laxa. On J Ophthalmol Case Rep 15:100477.
6. 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.