Capillary malformation-aterivenous malformation syndrome Q82.5

Eerola et al. 2003

Capillary malformation-arteriovenous malformation syndrome is a rare genodermatosis with cutaneous capillary malformations and a risk of associated fast-flow malformations (Brix ATH et al. 2022).

Solitary or multiple, autosomal dominant inherited capillary malformation-arterio-venous malformation - CM-AVM syndrome. The capillary skin changes are also referred to as rhodoid nevus. The multiple occurrence of rhodoid naevi is characteristic of capillary malformation-arterio-venous malformation syndrome, which is also referred to as "naevus rhodoides syndrome".

• Capillary malformation-arteriovenous malformation syndrome 1 is caused by mutations in the RASA1 gene.

• Capillary malformation-arteriovenous malformation syndrome 2 is caused by mutations in the EPHB4 gene.

The protein encoded by the RASA1 gene (RAS p21) is located in the cytoplasm and belongs to the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of the normal RAS p21, but not of its oncogenic counterpart. The protein acts as a suppressor of RAS function by enhancing the weak intrinsic GTPase activity of RAS proteins, leading to the inactive GDP-bound form of RAS and thus enabling the control of cellular proliferation and differentiation.

Usually already present at birth.

Both gene variants have very variable phenotypes. Patients typically have several small and larger, reddish-pink capillary malformations, flat pink patches (rhoidoid naevi), often with a whitish halo. These lesions are randomly distributed on the body. About 15-20% of patients have an associated arteriovenous fistula or malformation, often located on the head and neck. The fast-flowing lesions involve skin, subcutaneous tissue, muscle and/or bone or the brain or spine. Lymphatic manifestations have also been described as part of the phenotypic spectrum of this RASA1-induced malformation.

Bi capillary malformation-arteriovenous malformation syndrome 2, a literature search of 127 patients revealed the following sympotmatics: 114 (89.76 %) patients had multiple capillary malformations and 12 (9.44 %) patients had a single capillary malformation. Arteriovenous malformations/fistulas were present in 23 (18.1 %) patients, and in 5 (3.9 %) patients they were located in the central nervous system. Epistaxis occurred frequently. Telangiectasias were reported in 28 (22%) patients and beer stains were described in 20 (15.7%) patients (Brix ATH et al. 2022).

Extraction of genomic DNA from peripheral blood; whole exome sequencing.

The syndrome of capillary malformation-aterivenous malformation/CM-AVM has several features in common with hereditary hemorrhagic telangiectasia and hereditary benign telangiectasia, but can be distinguished clinically by the morphologic appearance and distribution of cutaneous vascular lesions, the presence of internal fast-flow lesions, and genetic analysis.

According to the ISSVA terminology, the syndrome is referred to as "capillary malformation-aterivenous malformation/CM-AVM). Alternatively, the term "nevus rhoidoides" is used (Happle R 2010). In ancient Greek, rhodoides means "rose-like" or "rose-colored". Accordingly, CM-AVM could also be referred to as "rhodoid nevus syndrome".

A familial heterozygous germline variant of the pathogenic RASA1, c.1248T>G (p.Tyr416X), was identified in one affected family. The proband had capillary malformations, chylothorax, lymphedema and overgrowth, whereas her affected mother had only isolated capillary malformations. Sequence analysis of DNA obtained from a skin biopsy of a capillary malformation of the affected mother revealed a second somatic RASA1 mutation (c.2245C>T, p.Arg749X). These results and the extremely variable expressivity support the hypothesis that somatic second hits are required for the development of the vascular abnormalities associated with CM-AVM syndrome. Furthermore, the phenotypes of affected individuals illustrate that lymphatic manifestations are also part of the phenotypic spectrum of RASA1-related disorders (see Fig.).

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