Sneddon syndrome

Sneddon syndrome is primarily characterized by livedo reticularis (net-like patterns of discoloration on the skin) and neurological abnormalities.^[1][2] The average age of onset of neurological symptoms is 39 years, though the livedo generally occurs up to 10 years earlier (sometimes since childhood).^[3]

The type of livedo reticularis that occurs is called livedo racemosa, a generalized and persistent form of livedo. It may affect the arms and legs, buttocks, trunk, face, hands, and feet.^[3] Some affected individuals also have signs of Raynaud’s phenomenon and/or widespread, mottled-purple discoloration on the body.^[3]

Neurological symptoms may include transient ischemic attacks (mini-strokes) and strokes; headache; and dizziness.^[1][2] Reduced blood flow to the brain may cause reduced intellectual ability, memory loss, psychiatric disturbances, personality changes, and/or other neurological symptoms.^[1][3] Concentration, attention, memory, visual perception and visuospatial construction are the most commonly described cognitive impairments. Dementia ultimately occurs in many affected people. Rarer neurological symptoms include seizures, chorea, and myelopathies (disorders of the spinal cord).^[3]

Other signs and symptoms may include high blood pressure, heart disease, ophthalmologic (eye) complications, and impaired renal (kidney) function.^[3]

The underlying cause of Sneddon syndrome is not well-understood. About 50% of cases are idiopathic (of unknown cause). In some cases, it is associated with autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, Behçet disease, or mixed connective tissue disease.^[2]

Genetic factors are thought to play a role in the development of Sneddon syndrome, as familial cases have been reported.^[2] In one family, a mutation in the CECR1 gene was identified as the cause of the condition.^[4] Mutations in this gene have been found to cause adenosine deaminase 2 deficiency, a condition that also causes livedo racemosa (and other symptoms) and has earlier onset than Sneddon syndrome.

The signs and symptoms of the condition are caused by excessive growth of the inner surface of blood vessels (endothelium), leading to occlusion of the arteries with impaired blood flow and clotting.^[2]

Most cases of Sneddon syndrome are sporadic (not inherited), occurring in people with no family history of the disorder. However, some familial cases with an autosomal dominant inheritance pattern have been reported. In these cases, a genetic susceptibility is likely.^[2] A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances.^[1]

The main criteria for a diagnosis of Sneddon syndrome are general livedo racemosa with characteristic findings on skin biopsy, and focal neurological deficits. Supportive criteria include a history of transient ischemic attacks or stroke and evidence of small bright foci on T2-weighted MRI.^[3]

Anyone suspected to have Sneddon syndrome may undergo:^[3][2]

• blood tests (see below)
• a thorough cardiovascular (heart) evaluation;
• brain MRI which may reveal white matter changes, infarcts, microbleeds or atrophy;
• cerebral angiography (abnormal in up to 75% of patients); and
• skin biopsy, which may reveal occlusion of arterioles by proliferation of the inner lining (characteristic of Sneddon syndrome)

Blood tests may screen for:^[3][2]

• lupus anticoagulant
• immunoglobulin IgG and possibly IgM anti-cardiolipinantibodies (types of antiphospholipid antibodies, which may be positive in about 60% of cases)
• anti-nuclear (ANA) and anti-double-stranded DNA autoantibodies
• thrombocytopenia and leukopenia (low white cell count)
• VDRL
• cryoglobulins
• circulating immune complexes
• antithrombin-III
• protein C or protein S

The optimal management of Sneddon syndrome has not been established, and controlled trials have not yet been performed.^[3] Currently, the most widely accepted treatment is anticoagulation with warfarin. Some suggest that aPL-negative patients should follow a less aggressive approach consisting of antiplatelet therapy with aspirin, while others recommend warfarin with a higher international normalized ratio target.^[2]

Angiotensin-converting enzyme (ACE) inhibitors have been suggested to reduce endothelial proliferation (growth of the inside lining of the vessels), and prostaglandin to improve blood flow and gas exchange in small vessels (microvascular perfusion).^[2] Abstaining from smoking and abstaining from using estrogen oral contraceptives may prevent or decrease the severity of neurological symptoms.^[3]

While the use of immunosuppressive therapy appears generally ineffective, there are data indicating that rituximab may be effective in aPL-positive patients.^[2]

Additional research exploring the underlying causes of Sneddon syndrome may identify treatment options based on the cause in each affected person.^[3]

Sneddon syndrome is a chronic, progressive disease that leads to major morbidity.^[2] The exact neurological symptoms vary, depending upon the location of arterial blockages.^[1] However, the condition often causes progressive reduction of mental and cognitive function. Dementia ultimately occurs in many patients, resulting in early retirement.^[2] Aphasia, the loss of ability to express or understand speech, is also common.^[1] While we are not aware of statistics regarding the life expectancy of people with Sneddon syndrome, studies have estimated the six year mortality rate to be 9.5%.^[5]

Sneddon syndrome has an estimated annual incidence of approximately 1/250,000.^[2] It has been reported much more often in females than in males, especially young women under the age of 45.^[1] It does occur occasionally in girls as young as 10 years old.^[3]