Molecular Mechanisms in Rare and Hereditary Vascular Diseases

Dear Colleagues,

Rare (lympho)vascular diseases are an under-diagnosed and extremely heterogeneous group of disorders. The clinical spectrum is very broad, ranging from minor localized changes to generalized, sometimes life-threatening forms. These diseases may be detectable prenatally, may occur as part of a larger syndromic disease, and often require multidisciplinary therapeutic approaches. In addition to the monogenic forms of primary lymphoedema, which are caused by lymphatic dysfunction or malformation, somatic changes such as blood and lymphatic vessel malformations, which generally affect individual body regions or organs but not the whole body, represent an important group in the spectrum of lymphovascular diseases.

Venolymphatic malformations refer to vascular malformations that affect both veins and lymph vessels. When both veins and lymphatics are abnormal, the malformation may result in lymphatic cysts that contain blood, or varicose and tortuous veins, associated with lymphedema. Abnormal dermal lymphatics with associated blood often result in dark purple crusts called angiokeratomas. Patients may benefit from a combination of laser, sclerotherapy, and surgical debulking. Compression garments are often useful to control reoccurrence after treatment.

Patients with Klippel–Trenaunay syndrome, also called Klippel–Trenaunay–Weber syndrome or KT syndrome, commonly have a patchy capillary vascular malformation on the skin surface (port wine stain) as well as an underlying venolymphatic malformation, with hypertrophy of the involved region.

Patients may have involvement that extends up the leg to involve the buttock and retroperitoneum, which can result in rectal or genital bleeding. The trunk and upper extremities can also be involved, and hand involvement can lead to overgrowth of the fingers.

Parkes–Weber syndrome resembles Klippel–Trenaunay syndrome in that it is associated with a combination of abnormal vessels characterized by a patchy capillary vascular malformation (port wine stain) on the surface. Unlike KT syndrome, there is an underlying arteriovenous malformation. This means there is a high blood flow, and high blood pressure malformation may result in more significant overgrowth, a warmer skin temperature, and in severe cases, abnormal bleeding or high output heart failure.

CLOVES is an abbreviation for a collection of anatomic abnormalities that may include congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal abnormalities. What is most striking are the extensive soft tissue masses of the trunk composed of excess fat and abnormal blood vessels, usually dilated veins and lymphatics. Patients may also exhibit epidermal moles and spinal or skeletal abnormalities. CLOVES syndrome is very rare, and the cause is unknown.

Proteus syndrome is a genetic disorder that results in skin and soft tissue overgrowth, abnormal bone development and vascular malformations. Because of the many deformities characterized by asymmetric overgrowth of the extremities and soft tissue masses, the syndrome is named after the Greek god Proteus, who could change his shape. It is believed that the Elephant Man, Joseph Merrick, actually had Proteus syndrome rather than neurofibromatosis. Additional physical characteristics include thickened, wrinkled skin on the soles of the feet and skull abnormalities.

Hereditary hemorrhagic telangiectasia also known as Osler–Weber–Rendu syndrome, hereditary hemorrhagic telangiectasia is a dominant hereditary condition characterized by the formation of abnormal vessels on the skin, mucous membranes, brain, lungs, liver and intestines. Significant and repeated episodes of bleeding may require treatment. When the condition affects the nasal and oral cavity, otolaryngology is usually involved in treatment for endoscopy and cauterization. Cutaneous telangiectasias (spider veins) can respond to pulsed yellow dye laser therapy offered by dermatology or plastic surgery. When the intestines are involved, general surgery may be involved if bowel resection is indicated.

Blue rubber bleb nevus syndrome (BRBNS) is a hereditary form of venous malformations characterized by small clusters of dilated veins that occur predominantly in the skin and gastrointestinal tract. Treatment of problematic cutaneous and subcutaneous dilated veins may include sclerotherapy or direct surgical excision. Significant gastrointestinal bleeding that causes anemia is most effectively treated by bowel resection.

Many genes govern the wall of a blood vessel, and COL4A1 is one of them. Its mutation leads to vascular wall alteration, hindering proper neuronal function and causing issues with cognitive processing and innovation.

COL4A1/A2-related disorders are rare genetic disorders that affect many organs and systems of the body. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy) and kidney abnormalities (renal pathology); however, the full spectrum of this syndrome is not yet completely characterized and there are many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities that can be part of the spectrum of the disease. There are notable differences in the specific signs and symptoms (clinical heterogeneity) and different organs are affected to different degrees between patients, even among members of a family who carry the same gene variant.

The abnormal blood vessels in the brain are caused by COL4A1 and COL4A2 gene changes (variants). The health problems in affected people are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance.

Rare conditions that can be causes of stroke include the following: Fabry's disease, Sneddon syndrome (SS)CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy), CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), and Cerebrotendinous xanthomatosis.

Historically, much attention has focused on thoracic aortic aneurysm and dissection (TAAD), and numerous genes in the TGF-β signaling pathway have been implicated in many cases of TAAD. However, improved genotyping as well as more extensive phenotyping has led to greater appreciation of the involvement of additional vascular beds in TAAD and other vascular syndromes as well as the involvement of other organs and biological processes. In this review, we describe several vascular syndromes that affect both the thoracic aorta and other vascular beds and discuss their associated genes and mutations, many of which can be identified through commercially available genetic testing panels. The TAAD group of vascular disorders encompass Marfan syndrome, Familial thoracic aortic aneurysm and dissection, Vascular Ehlers-Danlos syndrome, Congenital contractural arachnodactyly, Shprintzen-Goldberg Syndrome, Arterial tortuosity syndrome, Turner Syndrome. Another clinical condition of potential interest as a vascular disease involving brain arterioles with a genetic basis is the Cerebral amyloid angiopathy (CAA). CAA is a type of cerebrovascular disorder characterized by the accumulation of amyloid beta-peptide within the leptomeninges and small/medium-sized cerebral blood vessels. The amyloid deposition results in fragile vessels that may manifest in lobar intracerebral hemorrhages (ICH). It may also present cognitive impairments, incidental microbleeds, hemosiderosis, inflammatory leukoencephalopathy, Alzheimer disease, or transient neurological symptoms. In familial CAA cases of “presenile” CAA are caused by mutations in the amyloid precursor protein (APP) gene. Examples of other mutations resulting in familiar CAA include ACys peptide, ATTR peptide, PrPSc peptide, ABri peptide, ADan peptide, and AGel peptide. In Sporadic CAAsome evidence has demonstrated a relationship with apolipoprotein E (APOE). Researchers found that patients with APOE epsilon 2 or epsilon 4 alleles seem to be at greater risk for cranial hemorrhages than the general population.

In this Special Issue, several authors will contribute to reviewing the genetic, pathologic, and clinical profile of these rare vascular diseases with a genetic basis.

Prof. Dr. Antonino Tuttolomondo
Guest Editor

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• Klippel–Trenaunay syndrome
• Parkes–Weber syndrome
• CLOVES syndrome
• Proteus syndrome
• hereditary hemorrhagic telangiectasia
• blue rubber bleb nevus syndrome
• COL4A1/A2-related disorders
• CADASIL
• Fabry disease
• cerebral amyloid angiopathy