Cutis laxa (overview) Q82.8

Cutis laxa is the name given to a heterogeneous group, rare, of hereditary disorders whose leading clinical symptom is defined by drooping, wrinkled, inelastic (in contrast to Marfan syndrome and Ehlers-Danlos syndrome) skin.

The cutaneous features of hereditary cutis laxa variants, are due to loss, fragmentation or to severe disorganization of elastic fibers.

The systemic significance of this disorder of elastogenesis affects different organ systems. Besides skin involvement, lungs, vessels, skeletal system are mainly affected. The hereditary variants of cutis laxa are caused by mutations in various genes (e.g. PYCR1, LTBP4, ATP6V0A2, RIN2, PTDSS1, etc .), which are functionally involved in the formation or degradation or in the organization of elastic fibers.

Basically, autosomal dominant forms can be distinguished from autosomal recessive forms, independent of gene systematics. Acquired, "cutis-laxa-like" connective tissue diseases, which are also associated with elastolysis or elastotic degeneration of the elastic fiber systems, must be differentiated from the hereditary forms.

The following forms are distinguished according to the mode of inheritance and the clinical picture:

Autosomal recessive cutis laxa (ARCL): Autosomal recessive cutis laxa (ARCL) has, in addition to the clinically pathological skin symptoms, a pronounced systemic involvement (in contrast to autosomal dominant cutis laxa, in which skin symptoms are predominant). Autosomal recessive cutis laxa is subdivided according to the gene defect:

• ARCL1A (Cutis laxa, autosomal recessive,type 1; mutation at FBLN5 gene, gene location 14q32.12, fibulin 5) most severe form with life-threatening complications such as emphysema, pulmonary artery stenosis - OMIM: 219100
• ARCL1B (Cutis laxa, autosomal recessive,type 1B; mutation at EFEMP2 gene (EGF-containing fibulin-like extracellular matrix protein 2), gene location 11q13.1, fibulin 4) severe form with life-threatening complications such as emphysema, pulmonary artery stenosis. Fibulin 4 has been shown to be essential for the integrity of the wall structure of large vessels (Papke CL et al. 2015) - OMIM: 614437
• ARCL1C (cutis laxa, autosomal recessive, type 3; mutation at latent transforming growth factor-beta-binding protein 4 (LTBP4) gene, gene location 19q13.2, disruption of elastogenesis) with severe associated abnormalities ( of the lung, gastrointestinal tract, urinary tract - OMIM: 613177. Mutations at the LTBP4 gene also play a pathogenetically significant role in Duchenne muscular dystrophy (DMD), among other diseases (Van Dorn CS et al. 2018).
• ARCL2A (Cutis laxa, autosomal recessive,type 2A; mutation of ATP6V0A2 - C-ATPase, gene location: 12q24.31, altered gylycolysis) developmental abnormalities, microcephaly - OMIM 219200. Note: this form of cutis laxa is also called "wrinkly skin syndrome".
• ARCL2B (Cutis laxa, autosomal recessive,type 2B; mutation at the PYCR1 gene; gene location 17q25.3, mutation of a protein localized in the mitochodria involved in proline and ornithine synthesis) OMIM: 614438. Note: also named De-Barsy syndrome B or progeroid cutis laxa.
• ARCL3A (Cutis laxa, autosomal recessive, type 3A; mutation at the ALDH18A1 gene encoding a protein localized in the mitochondria involved in proline and ornithine synthesis) Cutis laxa, progeroid picture, mental retardation. OMIM: 219150. note: also referred to as de-Barsy syndrome A.
• ARCL3B (Cutis laxa, autosomal recessive, type 3B, mutations at the PYCR1 gene (pyrroline-5-carboxylate reductase 1) which encodes a protein of the same name. (Gene location 17q25.3) Cutis laxa, developmental defects, no emphysema. OMIM: 614438, also referred to as De-Barsy syndrome B or "PYCR1-related progeroid syndrome".
• RIN2-related Cut is laxa (Cutis laxa, autosomal recessive, RIN2-related; mutations at the RIN2 gene encoding a protein of the same name involved in endosome transport). Cutis laxa, preferentially occurring on the face. OMIM: 6130754.
• Geroderma osteodysplasticum (mutations at the GORAB gene, which encodes a protein of the same name, a member of the Golgin family). Characterized by wrinkled skin on the dorsum of the hands, feet, and abdomen, signs of progeria).
• Arterial tortuosity syndrome (Autosomal recessive inherited, very rare cutis laxa syndrome, the mutations in the SLC2A10 gene, which encodes a glucose transport protein). OMIM: 208050

Autosomal-dominant cutis laxa: Autosomal-dominant inherited forms of cutis laxa (ADCL) affect comparatively less severe systemic disease. However, clinically relevant systemic changes may occur, such as changes in the heart valves, aneurysms of the great vessels, diverticula in the gastrointestinal tract, hernias, or emphysema.

• ADCL1 (cutis laxa, autosomal dominant, mutations at the elastin gene, gene location 7q11.23, which codes for elastin). Cutis laxa, emphysema, and aortic aneurysm may occur. OMIM 123700
• ADCL2 (Cutis laxa, autosomal dominant, mutations at fibulin 5 gene FBLN5, gene location 14q32.12, which encodes fibulin5). Cutis laxa. OMIM 123700
• Cutislaxa, autosomal dominant (Lens-Majeweski syndrome), mutation at PTDSS1 gene encoding phosphatitserine synthetase 1) Cutis laxa, developmental delay, no emphysema. OMIM: 151050
• AGel amyloidosis, mutaion in gene with corneal opacities, POlynueropathy and cutis laxa.

X-linked cutis laxa (XRCL).

• Cutis laxa, X-linked (also called occipital horn syndrome - mild course of Menkes syndrome) is clinically similar to ARCL2. Detectable mutations are at the ATP7A gene, gene location Xq21.1). Note: Synonyms are: EDS IX (older name), Ehlers-Danlos syndrome type 9 (older name).

Overall, the hereditary Cutis laxa is very rare. Autosomal-recessive inherited forms are more common than autosomal dominant forms.

Due to the considerable clinical overlap of hereditary forms, diagnosis is often problematic. The diagnostic procedure includes a detailed physical examination, subtle family history, skeletal status, developmental diagnosis, imaging, histological analysis, liver function tests and biochemistry, renal sonography, and ophthalmological and cardiological examinations.

A causal therapy does not exist. In this respect, symptomatic therapeutic approaches should be chosen. Excess skin can be treated surgically and cosmetically. In case of systemic infestation, therapy is to be chosen according to the symptoms of the organ.

In the classic hereditary forms of cutis laxa, life expectancy is not limited in the case of skin involvement alone. If systemic involvement is present, as is the case mainly in the autosomal recessive forms, the extent of pulmonary or vascular involvement often determines the prognosis (in adulthood: pulmonary emphysema; vascular complications). Neonates (ARCL1 A-C types) may die from hypoplastic lungs.

Genetic counselling: In families with known causal mutations, prenatal diagnostics by DNA analysis is possible.

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