Vascular malformations Q28.88

Frequent, syndromic or non-syndromic, benign, monotopic or polytopic vascular malformations as a result of abnormal embryonic tissue development. The clinical pictures summarized under the term "vascular malformation" can include vascular malformations in different tissues (skin, muscle, bone) or in different organs (e.g. skin and CNS).

In contrast to hemangiomas in infants, vascular malformations are always present at the time of birth, even if they initially only manifest themselves discreetly over the years or may go completely unnoticed clinically.

Vascular malformations initially show an increase in size proportional to body growth, do not regress and can, however, show autonomous proliferation (overgrowth) in the course of life (see also nevus flammeus - port-wine stain).

The sometimes confusing morphological diversity of true vascular tumors and vascular malformations (depending on which type of vessel is affected: capillary, vein, artery, mixed?), their localization in different parts of the skin-subcutaneous-muscle compartment, their often difficult pathogenetic classification (malformation, true tumor?) makes a universally satisfactory classification difficult, but unavoidable. When attempting a systematic classification of vascular malformations, one can proceed according to the following aspects:

Etiologic classification:

• malformation (nevus/hamartoma of the skin)
• true neoplasia

Classification according to hemodynamic criteria (low-flow and high-flow lesions):

• High-flow: AV fistulas, arterial and arteriovenous malformations.
• Low-flow: Capillary (e.g. nevus flammeus) and lymphatic malformations (lymphangiomas) show low or no flow velocities.

Histopathologic classification:

• capillary (capillary malformations - syn. capillary nevi), KM - port-wine stain - nevus flammeus)
• venous (venous malformation or mixed, VM - or CM/VM - e.g. angiokeratoma circumscriptum)
• arterial (AM or mixed CM/VM/AM/AVM)
• lymphatic (LM)
• mixed CM/VM/AM/LM)

Hemodynamic/functional classification:

• low-flow
• high-flow

Classification of vascular malformations according to pathological-anatomical aspects:

• Arterial malformations (rarely isolated; mostly truncular malformations with hypo- and aplasia of peripheral arteries)
• Arterio-venous malformations (mostly in the context of complex malformations):
  • Hemangioma, arteriovenous malformation
• Venous malformations (VM/dysplasia of deep venous complexes - often affecting the vessels of the extremities, more rarely other body regions, venous aneurysms):
  • Dysplasia of deep veins of the extremities (clinical: picture of chronic venous insufficiency)
  • Dysplasia of the venous valves (avalvulia, hypovalvulia) (clinical: picture of chronic venous insufficiency)
  • Venous malformations, multiple cutaneous and mucosal (familial) (VMCM-familial/mutations in the TEK gene).
  • Venous malformations, multiple cutaneous and mucosal (sporadic) (VMCM-sporadic/mutations in the TEK gene)
  • Venous malformations, unifocal (isolated) (VM/mutations in theTEK gene)
  • Nevus venosus segmental (flat and reticular phlebectasia/mutations in the TEK gene?)
  • Phlebectasia genuine diffuse, Bockenheimer (deep/extrafascial venous systems or combination; mutation in the TEK gene)
• Capillary and postcapillary malformations (CM):
  • Non-syndromal capillary malformations:
    • Nevus flammeus (asymmetric)/ non-syndromic port wine stain/mutation in the GNAQ/GNA11 genes)
    • Cutis marmorata teleangiectatica congenita (van Lohuizen syndrome/postzygotic mutation in early embryogenesis in the GNA11 gene?)
    • Angioma serpiginosum (diffuse and segmental/mutationsin the PORCN gene areto be assumed)
    • Naevus vascularis mixtus (combination of a naevus flammeus with a naevus anaemicus; lesional mutations in the GNA11 gene)
  • Syndromic capillary malformations + syndromic capillary/venous malformations
    • Sturge-Weber syndrome ( an activating somatic GNAQ mutation is the most common somatic mutation/ somatic GNA11 and GNB2 mutations may also be associated with SWS (Yeom S et al. 2022).
    • Microcephaly-capillary malformation syndrome (mutation in the STAMBP gene)
    • Megalencephaly-capillary malformation-polymicrogyria syndrome (mutation in the PIK3CA gene)
    • Capillarymalformation-arteriovenous malformation syndrome 1 (skin manifestation: rhodoid nevus; mutation in the RASA1 gene)
    • Capillary mal formation-arteriovenous malformation syndrome 2 - (skin manifestation: rhodoid nevus; mutation in the EPHB4 gene)
    • Cobb syndrome (neurocutaneous angiodysplasia syndrome): Combination of a nevus flammeus with vascular malformation of the spinal cord vessels. No familial occurrence, genetic defect unknown!
    • Klippel-Trénaunay syndrome (capillary/venous/osteogenic) Skin:Unilateral nevus flammeus, primary varicosis, giant growth of the lesional extremity (mutations in the AGGF1 gene)
    • Parkes Weber syndrome (capillary/venous/osteogenic with arteriovenous shunts) Skin: Quadrant-related nevus flammeus. Associations with mutations in the RASA1 gene.
    • Von Hippel-Lindau syndrome (VHS) (capillary): Neuro-cutaneous systemic disease; skin: nevus flammeus; most frequently retinal, cerebellar and spinal hemangioblastomas, renal cell carcinomas (RCC) and pheochromocytomas (germline mutations) in the VHL gene).
• Phacomatosis pigmentovascularis
  • Type I (CM + epidermal nevus)
  • Type II (phacomatosiscaesioflammea) (CM + Mongolian spot +/- anaemic nevus)
  • Type III (Phakomatosisspilorosea-Naevus-rhodoides syndrome) (CM + Naevus spilus+Naevus anaemicus; mutation in the PTPN11 gene (Polubothu S et al. 2019)
  • Type IV (CM + Mongolian spot + naevus anaemicus + naevus spilus)
  • Type V(phacomatosis caesiomarmorata) (CM - type cutis marmorata teleagiectatica + Mongolian spot +/- blue sclerae, hypertrophy of the leg, asymmetry of the cerebral hemispheres; mutations in the GNAQ/GNA11 genes)
• Naevus vascularis mixtus syndrome (mutation in GNA11)
• Proteus synd rome (port wine nevus of the Proteus type/ point mutations in the AKT1 gene)
• CLOVES synd rome (port wine nevus of the CLOVES type/mutations in the PIK3CA gene)
• Teleangiectatic malformations (see below telangiectasia)
  • Teleangiectasia hereditaria haemorrhagica (M.Osler)
  • Ataxia teleangiectatica (Louis-Bar syndrome, mutation in ATM gene)
  • Unilateral naevoid telangiectasia syndrome of the patchy type (probably not a postzygotic mosaic)
  • Unilateral punctate telangiectasia (probably not a postzygotic mosaic)
  • Maffucci synd rome (complex vascular malformations with enchondromas. Mutations in the IDH1/IDH2 genes)
• So-called Angiokeratomas (etiopathogenetically unrelated)
  • Group of lysosomal storage diseases (dermatologically: angiokeratoma corporis diffusum; clinical pictures: Fabry's disease; fucosidosis; Kanzaki's disease and others)
• Angiokeratomacircumscriptum (segmental vascular verrucous nevus)
• Angiokeratoma mibelli
• Angiokeratoma scroti/vulvae (Fordyce)
• Angiokeratoma, solitary.
• Lymphatic (partly syn. with lymphangioma - see below lymphatic malformation)
  • Lymphangiomas, superficial and deep:
    • Lymphoedema
    • Lymphangioma cavernosum (macrocystic lymphatic malformation)
    • Lymphangioma circumscriptum (microcystic lymphatic malformation)
    • Hemangioma targetoid hemosiderotic (lymphatic cocardial malformation)
    • Lymphatic superficial reticular mal formation (nevus lymphangioreticularis)
    • Lymphangiomatosis.
• Other:
  • Unna spot (salmon spot or stork bite/no vascular hamartoma/nevus)
  • Blue-Rubber-Bleb nevus syndrome (mutation in the TEK gene, disruption of the receptor tyrosine kinase TIE-2)
  • Naevus anaemicus (functional constriction of the capillaries/syndromal associations with phacomatosis caesioflammea)
  • Hamartoma, eccrine, angiomatous (nevus syringocapillaris)- proliferation of capillaries and eccrine sweat glands/lesional hyperhidrosis

  • PIK3CA-associated overgrowth syndromes(PROS) - as complex overgrowth syndromes (PROS) comprising a range of clinical findings with segmental/focal overgrowth (including vascular malformations).

There are no exact figures for the number of affected people worldwide. In Germany itself, less than 0.5% of people suffer from this rare disease. According to estimates, this affects about 450,000 people.

In sporadic nonfamilial patients with venous malformations, somatic mutations in the TEK gene associated with the presence of activating PIK3ca (phosphatidylinositol 3-kinase) mutations are detected in about half of the cases (Castillo P et al. 2016).

People with vascular anomalies often go through many stages before their condition is correctly diagnosed and treated due to its rarity and diversity.

The care of patients with vascular anomalies should take place in specialized centers. It should be ensured that the necessary experts from different specialist groups work closely and interactively with each other across their specialist boundaries and that clinical and scientific knowledge is exchanged at regular intervals.

Therapy depends on the individual type and severity of the vascular anomaly, which must be successfully eliminated either minimally invasively or surgically. Symptomatic treatment of vascular malformations includes, among other things, compression therapy as well as orthopedic and physical measures in addition to individual pain therapy.

The majority of vascular anomalies can be treated minimally invasively with sclerotherapy or catheter procedures. Surgical interventions alone are less common, but are possible and useful, especially in combination with minimally invasive techniques.

The clinical subclassification of vascular malformations can be based not only on the patient's medical history and clinical course but also on the clinical examination.

Venous and lymphatic malformations are soft and compressible; "high-flow" lesions appear firm. While lymphangiomas show a sudden increase in size during infections, venous malformations increase in volume when pressure is increased (pressing, bending forward). "High-flow" lesions can be accompanied by an increase in temperature over the affected area and a palpable pulsation.

The group of so-called angiokeratomas is listed under capillary/postcapillary malformations. The diseases listed under 1-5 are based on metabolic diseases that appear dermatologically under the clinical picture of "angiokeratoma corporis diffusum".

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