Cutis laxa

Cutis laxa is genetically heterogeneous and is associated with pathogenic variants in multiple genes. The implicated genes encode proteins involved in elastic fibre structure and assembly (e.g. ELN, FBLN5, EFEMP2, LTBP4, EMILIN1), intracellular vesicular trafficking and proton transport (e.g. ATP6V0A2, ATP6V1A, ATP6V1E1), and mitochondrial proline biosynthesis (e.g. PYCR1, ALDH18A1). In addition, pathogenic variants in ATP7A underlie the occipital horn syndrome subtype. The autosomal dominant and autosomal recessive forms show considerable clinical overlap despite differences in severity, making distinction between subtypes based on clinical features alone challenging.

Cutis laxa shows genetic heterogeneity with multiple modes of inheritance, including autosomal recessive, autosomal dominant, and X-linked forms. Autosomal recessive forms are the most common, whereas autosomal dominant inheritance is observed in ELN-related and some FBLN5-related cases, and X-linked inheritance occurs in ATP7A-related occipital horn syndrome.

The diagnosis of cutis laxa is established by molecular genetic testing, as no universally applicable clinical diagnostic criteria have been defined due to the marked heterogeneity of the disorder. In ATP6V0A2-related cutis laxa, abnormal serum transferrin and apolipoprotein CIII glycosylation patterns on isoelectric focusing provide a biochemical signature of an underlying congenital disorder of glycosylation. Histopathological examination of skin biopsy specimens, including orcein staining and electron microscopy, may demonstrate fragmentation and rarefaction of elastic fibres and can support the diagnosis.

Main differential diagnoses include:

• Geroderma osteodysplastica: wrinkling confined to the dorsum of hands and feet and the abdomen, normal cognition, osteopenia/osteoporosis with vertebral compression and long-bone fractures
• Arterial tortuosity syndrome: generalised arterial tortuosity with aneurysms and stenoses, droopy facial appearance, high palate, dental crowding
• De Barsy syndrome: characterised by progeroid appearance, cutis laxa, severe developmental delay, and neurological impairment

• Establishing the diagnosis: molecular genetic testing confirms the clinical suspicion by identifying the underlying pathogenic variant and provides the basis for accurate diagnosis and genetic counselling.
• Clinical management: a confirmed molecular diagnosis can inform clinical follow-up and support management of condition-specific complications, with surveillance and treatment guided by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variant enables predictive testing of at-risk relatives and supports informed reproductive decision-making.

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• Van Maldergem L, Loeys B. FBLN5-related cutis laxa. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Loeys B, De Paepe A, Urban Z. EFEMP2-related cutis laxa. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Callewaert BL, Urban Z. ELN-related cutis laxa. 2022 Sep 29. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Callewaert BL, Urban Z. LTBP4-related cutis laxa. 2016 Feb 11 [updated 2023 Feb 23]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .