Sneddon Syndrome

A number sign (#) is used with this entry because of evidence that Sneddon syndrome (SNDNS) is caused by compound heterozygous mutation in the CECR1 gene (ADA2; 607575) on chromosome 22q11. One such family has been reported.

Mutation in the ADA2 gene can also cause vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), which shows earlier onset.

Description

Sneddon syndrome is a noninflammatory arteriopathy characterized by onset of livedo reticularis in the second decade and onset of cerebrovascular disease in early adulthood (summary by Bras et al., 2014).

Livedo reticularis occurs also with polyarteritis nodosa, systemic lupus erythematosus, and central thrombocythemia, any one of which may be accompanied by cerebrovascular accidents (Bruyn et al., 1987).

Clinical Features

Sneddon (1965) described 6 patients (5 females, 1 male), varying in age from 20 to 48 years, who had association of livedo reticularis with cerebrovascular accident. Rebollo et al. (1983) reported 8 patients and concluded that the disorder was inherited as an autosomal dominant in 3 of them. Multiple occlusions and medium-sized arteries were demonstrated by cerebral and hand arteriograms. Digital artery biopsies showed intimal hyperplasia in 7 cases and recanalized thrombosis in 1. Rebollo et al. (1983) concluded that the Sneddon syndrome is a genetic progressive arteriopathy, occlusive and noninflammatory, involving medium-sized vessels.

Scott and Boyle (1986) reported 2 sibs with the disorder. The 24-year-old proposita had generalized livedo reticularis and progressive intellectual decline. Brain imaging showed multifocal areas of cerebral infarction, occlusive disease of major vessels, and arteriovenous malformation, and moya-moya type anastomoses. Berciano (1988) pointed out that the phenotype may be restricted to an unperceived livedo reticularis and that detailed investigation of relatives had rarely been done or commented on in published reports; hence, the role of genetic factors in this disorder may have escaped attention.

Zelger et al. (1993) provided long-term follow-up of 21 patients. They specifically commented that family history was negative in all of them; in the case of 9 of the 21 patients, first- and second-degree relatives had risk factors such as precocious vascular disorders (peripheral occlusive vascular disease, myocardial infarction, or ischemic strokes before age 60 years), but in these patients disease course and intensity were no different from those in the remaining patients. Zelger et al. (1993) considered the disorder to be vasculitic in nature.

Kalashnikova et al. (1991) investigated the relationship of Sneddon syndrome to the antiphospholipid syndrome (107320), which in turn is related to systemic lupus erythematosus and other autoimmune disorders that tend to aggregate in families, but provided no genetic information. Pettee et al. (1994) presented the clinical, hematologic, and radiographic findings in 2 brothers with Sneddon syndrome associated with antiphospholipid antibodies. One brother had anticardiolipin antibody and the other had lupus anticoagulant, which was detected only upon repeated blood testing. Pettee et al. (1994) suggested that in familial cases of antiphospholipid antibody syndrome, inherited predisposition is involved in disease pathogenesis.

Hilton and Footitt (2003) described the neuropathologic findings in an isolated case of Sneddon syndrome in a 64-year-old man who died of myocardial infarction. Several months before death, the man had suffered several strokes, and physical exam showed 'florid' livedo reticularis affecting his trunk, arms, and legs. He was also found to have a lupus anticoagulant. Histologic examination showed multiple small, predominantly cortical, infarcts, with focal hyperplasia and fibrotic occlusion of arterial vessels in the superficial white matter, cortex, and leptomeninges. Occasional arterial thrombi were seen. The authors concluded that Sneddon syndrome is caused by a noninflammatory arteriopathy affecting superficial cerebral vessels.

Mascarenhas et al. (2003) reported 3 Portuguese brothers with Sneddon syndrome. Two presented with ischemic strokes at 28 and 42 years of age, and the third with hemorrhagic strokes at ages 23 and 34 years. A 32-year-old sister was examined, but had no evidence of cerebrovascular events. All patients had normal cerebral angiography. All patients also had persistent violaceous livedo reticularis, primarily on the lower limbs and trunk, that began in the teenage years. Skin biopsy of the reticular pattern showed partial endothelial detachment in dermohypodermic blood vessels in only 1 patient. The 3 brothers had atrophic scars on the lower limbs from seasonal ulceration. A maternal aunt and uncle reportedly had livedo reticularis or livedoid vasculitis. This family had previously been reported by Santo et al. (2002).

Legierse et al. (2008) reported 3 unrelated patients with a clinical diagnosis of Sneddon syndrome. All presented in their twenties with focal neurologic signs resulting from intracerebral ischemic attacks. Neurologic symptoms included hemianopsia, headache, hemiplegia, facial paralysis, and dysarthria. All developed livedo racemosa within a few years after onset of neurologic signs and symptoms. Two patients developed hypertension associated with renal dysfunction thought to result from thickened renal vessels. Skin biopsy of 2 patients showed the classic findings of Sneddon syndrome, with small arteries showing intimal proliferation, thickened walls, and occasional occlusion. Immunostaining was positive for smooth muscle cells in the vessels. Skin biopsy in the third patient showed only a few slightly dilated small vessels, but otherwise was normal. Legierse et al. (2008) noted the difficulty of defining the diagnostic criteria of Sneddon syndrome and stated that although there is no gold standard for the diagnosis of this disorder, skin biopsy should be performed.

Molecular Genetics

In 3 Portuguese sibs with Sneddon syndrome, previously reported by Mascarenhas et al. (2003), Bras et al. (2014) identified compound heterozygous missense mutations in the CECR1 gene (T119A, 607575.0010 and G142S, 607575.0011). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed.

Population Genetics

Sneddon syndrome has an incidence of about 4 per million per year. It is more common in women and usually presents in young adulthood (Legierse et al., 2008).

Nomenclature

Bruyn et al. (1987) stated that in the European literature the term 'livedo reticularis' is used for the cutaneous vascular phenomenon that disappears after the skin is warmed, whereas 'livedo racemosa' is used for the findings that persist after warming. On the other hand, in the American literature, reticulated skin coloration that disappears after warming in infants and young adults is referred to as 'cutis marmorata,' reserving the term 'livedo reticularis' for the permanent change. It should be noted, however, that Sneddon, a British dermatologist, used the term 'livedo reticularis.'