Review ArticleSneddon Syndrome: A Comprehensive Overview
Introduction
Sneddon syndrome (SS) is a rare, episodic or chronic, slowly progressive neurocutaneous syndrome and characterized by generalized livedo racemosa (LR; patchy, violaceous, skin discoloration) and recurrent cerebrovascular events. Ehrmann first reported the findings of LR in 1907 in a patient with syphilis. He described this as a blue slender tree-branching and “forked lighting” pattern that worsens in cool temperature.1 Isolated cases of livedo and strokes have been described since 1959.2, 3 However, Dr. Ian Bruce Sneddon, a British dermatologist, first described a detailed analysis of 6 patients with generalized LR and recurrent strokes in 1965.4 These patients did not have any evidence of systemic disorder such as systemic lupus erythematosus (SLE), polyarteritis nodosa, or syphilis. But, the term, Sneddon or SS, was not commonly used until the late 1970s.5
SS is a rare syndrome, and most publications involved a single case report or a small case series, with an only a rare report of a cohort consisting of >50 patients from a single institute.6 Zelger et al estimated the incidence of SS as 4 new cases/year/1 million people, based on the diagnosis of 21 SS patients over 10 years in Innsbruck, Austria (Approximate population of 500,000 at the time of the study).7 Rebello reported an SS prevalence of 0.26% in a hospital-based cohort of strokes from all causes.8, 9 Approximately 80% of the SS patients are women with a median age of diagnosis at 40 years. However, the onset of the disease during childhood have been reported. Furthermore, some patients with the presumed adult-onset disease have subtle symptoms and signs since early childhood period. Kume et al reported 1 Japanese SS patient, who started to have facial erythema and frostbite of the extremities from age 1 year and was ultimately diagnosed with SS at age 24 years.10 Charles et al reported a girl child with SS who had excessive sleepiness, mood swings, and memory disturbance secondary to bilateral thalamic infarction.11 Presentation of this rare disorder during the pediatric age group is discussed in details in a separate section.
Section snippets
Classification
SS is primarily classified as antiphospholipid (aPL) positive or negative depending on the presence or absence of any of these 3 antibodies: anticardiolipin, lupus anticoagulant, and anti-beta 2-glycoprotein I.12, 13 Less than half of the patients with SS have positive aPL antibody.14 Levine et al reported a 44-year-old SS patient with aPL positivity in 1988 and supported an idea of antibody-mediated pathogenesis.15
The aPL positive SS patients may behave like primary aPL antibody syndrome,
Clinical Features
SS is characterized by the association of typical skin lesion with recurrent strokes.
Etiology/Pathogenesis
Etiology of the SS is unknown, and pathogenesis is unresolved with 2 primary mechanisms proposed – autoimmune/inflammatory versus thrombotic disease. A subset of familial cases had early onset inflammatory features akin to vasculitis – recurrent fevers and elevated inflammatory markers.41, 42, 43 However, histopathological evidence of inflammation is rare, and in some cases may represent reactive inflammation secondary to vascular lumen obstruction. Controversy exists if SS is a homogeneous
Evaluation
There is no specific biologic marker for the diagnosis of SS. The patients who initially present with only LR should undergo testing to rule out other etiologies of livedo (detailed in the Differential Diagnosis Section). The patients who present after an episode of stroke should undergo an extensive investigation including neuroimaging to rule out other causes of strokes in young adults, summarized in Table 1.
aPL antibodies are absent in aPL negative cases. However, inconsistently other
Differential Diagnosis
Diseases that can cause generalized LR or similar skin lesions are summarized in Table 4.
Several diseases can cause strokes in young adults and summarized in Table 1. However, strokes due to hypertension, cardioembolic strokes, due to migraine and use of oral contraceptives, and strokes due to isolated cerebral angiitis and systemic vasculitis are the closest differentials.
Combination of LR and recurrent strokes can also be seen in Divry van Bogaert Syndrome (DBS).68 In contrast to DBS, true
Treatment
Treatment of SS is primarily based on anecdotal reports. There have been no prospective controlled studies to guide therapy.69 Estrogen-containing contraceptives have been associated with SS, but their effect on the onset or progression of the disease is unclear. Anecdotal reports suggest possible improvement of neurological symptoms after discontinuation of contraceptives. Several other factors such as pregnancy, smoking, diabetes mellitus, atherosclerosis, and hyperlipidemia have been
Prognosis
Neuropsychiatric prognosis of SS is relatively poor. Though motor deficit generally improves with time and does not cause severe handicap, after a variable period, dementia and cognitive impairment set in to produce moderate to severe disability. Cognitive deficit correlates with MRI features of cortical atrophy, which may have a parietal-occipital region predominance.24 A broad range of neuropsychiatric deficits is detected with predominant involvement of concentration, attention, visual
Sneddon Syndrome in Children
The presentation in pediatric patients is similar to adults, and dermatologic manifestations are usually apparent for many years before the onset of recurrent strokes. Though most patients with SS are diagnosed after 20 years of age, a substantial number of them may have LR in the pediatric age group, particularly during or after puberty. However, a relative unawareness of this condition among pediatricians and pediatric subspecialists lead to significantly delayed diagnosis. Most of the data
Conclusions
SS is a rare disease of unknown etiology with striking dermatological manifestation and recurrent strokes. Recent research suggests that the prognosis of stroke recurrence might be better compared to the historical data due to the increasing use of antiplatelet/antithrombotic agents for secondary stroke prophylaxis. However, long-term data are needed to see an improvement in the cognitive profile with decreasing stroke recurrence. As several manifestations can precede strokes by several years
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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2023, Revue de Medecine InterneLocalized livedo racemosa as an indicator for giant cell arteritis
2022, JAAD Case ReportsCitation Excerpt :The skin lesions, which were reminiscent of SS, were the first indicator prompting specific investigation into neurological symptoms. SS is characterized by the appearance of livedo racemosa associated with cerebrovascular manifestations (eg, transient ischemic attacks).3 However, the neurologic examination found no evidence for a stroke attack or paresis but identified the headache as the leading symptom.
Antiphospholipid-negative Sneddon's syndrome: A comprehensive overview of a rare entity
2022, Annales de Dermatologie et de VenereologieCitation Excerpt :Recent findings in APS have shown that endothelial cell dysfunction mediated by aPL binding to beta-2-GP1 receptors results in increased risk for thrombosis and accelerated atherosclerosis mediated by nitric oxide synthase inhibition, platelet activation, complement system activation, neutrophil activation, adhesions and increased NETosis, as well as intimal hyperplasia vasculopathy mediated by the mTOR activation pathway [39]. Two primary mechanisms have been proposed: autoimmune/inflammatory vs. thrombotic disease [40]. Inflammatory mechanisms play a role in certain monogenic diseases, including ADA2 deficiency, which may present as aPL− SS (see section on differential diagnosis) [11].
28-Year-Old Man With Recurrent Vertigo, Syncope, and Progressive Memory Impairment
2021, Mayo Clinic ProceedingsCoexistence of scleromyxedema and Sneddon syndrome
2021, JAAD Case ReportsCitation Excerpt :Scleromyxedema is a cutaneous mucinosis characterized by generalized or localized papular eruptions with sclerodermoid induration of the skin. Histopathology of the classic form is characterized by a triad of microscopic features, including mucin deposition, proliferation of fibroblasts, and increased collagen deposition in the dermis.1-3 Histologically, our cases exhibited an interstitial granuloma annulare-like pattern with many CD163+ and/or factor XIIIa+ macrophages resembling an unusual histological variant of scleromyxedema, with interstitial histiocyte components in addition to classic signs.4
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.