Capillary malformation-aterivenous malformation syndrome Q82.5

Last updated on: 26.05.2024

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History
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Eerola et al. 2003

Definition
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Capillary malformation-arteriovenous malformation syndrome is a rare, complex vascular malformation with cutaneous capillary vascular 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.

Etiopathogenesis
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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.

Manifestation
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The symptoms of intracranial AVMs/AVFs seem to appear early in life.

Clinical features
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Both gene variants have very variable phenotypes. Patients typically have several small and larger, reddish-pink capillary malformations, flat pink patches (rhodoid nevi), often with a whitish halo. These lesions are randomly distributed on the body. Approximately 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).

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

Differential diagnosis
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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.

Complication(s)
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Life-threatening complications of these lesions can include bleeding, congestive heart failure and/or neurological sequelae.

Note(s)
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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".

Case report(s)
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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.).

Literature
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  1. Alluhaibi R et al. (2021) Capillary Malformation-Arteriovenous Malformation Syndrome. Cureus 13:e12562.
  2. Amyere M (2017) Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation 136:1037-1048.
  3. Arnold AW et al. (2012) Phacomatosis melanorosea without extracutaneous features: an unusual type of phacomatosis pigmentovascularis. Eur J Dermatol 22:473-475.
  4. Brix ATH et al. (2022) Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review. Acta Derm Venereol 102:adv00662.
  5. Cen Q et al. (2020) Unilateral and segmental distribution of facial erythema: is it a real port-wine stain? Hereditas 157:27.
  6. Edwards LR et al. (2018) RASA1 mutation in a family with capillary malformation-arteriovenous malformation syndrome: A discussion of the differential diagnosis. Pediatr Dermatol 35:e9-e12.
  7. Gorham LW, Wright AW, Shultz HH, Maxon FC (1954) Disappearing bones: A rare form of massive osteolysis. Report of two cases, one with autopsy findings. Am J Med 17: 674-682
  8. Gorham LW, Stout AP (1955) Massive osteolysis (acute spontaneous absortion of bone, phantom bone, dissapearing bone): Its relation to hemangiomatosis. J Bone Joint Surg (Am) 37: 985-1004
  9. Happle R (2005) Nevus roseus: a distinct vascular birthmark. Eur J Dermatol 15:231-234.
  10. Macmurdo CF et al. (2016) RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet A 170:1450-1454.
  11. Panzer R et al. (2017) Rhodoid naevus syndrome: why is this name preferable to 'capillary malformation-arteriovenous malformation'? J Eur Acad Dermatol Venereol 31:e446-e448.
  12. Poliner A et al. (2022) Port-wine Birthmarks: Update on Diagnosis, Risk Assessment for Sturge-Weber Syndrome, and Management. Pediatr Rev 43: 507-516.
  13. Revencu N et al. (2013) RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat 34:1632-1641.
  14. Rujira Rujiwetpongstorn et al. (2020) Multiple lentigines in RASA1-associated capillary malformation-arteriovenous malformation syndrome: A case report. JAAD Case Reports, 10.1016/j.jdcr.2020.10.022.
  15. Tekin B et al. (2016) Phacomatosis Melanorosea: A Further Case of an Unusual Skin Disorder. Acta Derm Venereol 96:280-282.
  16. Torchia D (2021) Phacomatosis spilorosea versus phacomatosis melanorosea: a critical reappraisal of the worldwide literature with updated classification of phacomatosis pigmentovascularis. Acta Dermatovenerol Alp Pannonica Adriat 30:27-30.

Outgoing links (2)

EPHB4 gene; RASA1 gene;

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Last updated on: 26.05.2024