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The term Sneddon's syndrome (SS) has been used since 1965 to describe a vasculopathy characterized by a combination of cerebrovascular disease with livedo racemosa. SS may be classified as antiphospholipid+ (aPL+) or antiphospholipid- (aPL-). Little is known about aPL- SS; in this review we describe the epidemiology and pathogenesis of aPL- SS, as well as the clinical and histologic features. We discuss recent findings in terms of neurologic and cardiac involvement. Moreover, differential diagnoses of conditions that may present with both livedo racemosa and stroke are discussed. Finally, we discuss real-life practical issues such as the initial investigations to be performed, long-term follow-up, and therapeutic management of aPL- SS patients.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.

The skin often provides initial clues of hypercoagulability with features such as livedo reticularis, livedo racemosa, retiform purpura, necrosis, and ulcerations. Because these cutaneous manifestations are nonspecific, laboratory testing is often needed to evaluate for underlying causes of hypercoagulability. Importantly, these disorders are reported to be the most common mimicker, resulting in an erroneous diagnosis of pyoderma gangrenosum. Understanding inherent properties of, and indications for, available tests is necessary for appropriate ordering and interpretation of results. Additionally, ordering of these tests in an indiscriminate manner may lead to inaccurate results, complicating the interpretation and approach to management. This second article in this continuing medical education series summarizes information on methodology, test characteristics, and limitations of several in vitro laboratory tests used for the work up of hypercoagulability and vasculopathic disease as it pertains to dermatologic disease.

Macular arteritis (MA) has a striking discordance between the clinical presentation of hyperpigmented macules and the histopathologic findings of a lymphocytic arteritis with intraluminal hyalinized fibrin ring and thrombosis. It has been proposed that MA represents the chronic, indolent, lymphocytic form of the neutrophil-predominant cutaneous polyarteritis nodosa. MA usually affects middle-aged women asymptomatically on the legs. There is also a slightly more severe variant with more infiltrated plaques and livedo racemosa, termed lymphocytic thrombophilic arteritis. MA and lymphocytic thrombophilic arteritis have similar histologic features, both with a largely intact vascular elastic lamina, despite the abundant fibrin and endarteritis obliterans. There is no evidence for progression from MA to lymphocytic thrombophilic arteritis to cutaneous polyarteritis nodosa, and aggressive therapy should be avoided in MA, given the indolent, benign disease course.

Background Lymphocytic thrombophilic arteritis (LTA), or macular lymphocytic arteritis, is defined by a primary lymphocytic vasculitis. However, the nosology of LTA has been controversial, with speculation that it may represent an indolent non–nodule-forming variant of cutaneous polyarteritis nodosa (cPAN). Objective This study compares the clinicopathologic features of patients with LTA or cPAN to assess if these conditions should be considered distinct entities. Methods This is a cross-sectional study of all LTA and cPAN cases at a single tertiary center using prospectively collected clinical data and blinded histologic assessment. Results The study included 17 patients with LTA and 13 patients with cPAN. Clinically, cases of LTA were distinguished by a more widespread pattern of livedo racemosa, which was noninfiltrated and asymptomatic. In contrast, cPAN was associated with localized starburst livedo, purpura, and episodic features including nodules, pain, and large inflammatory ulcers. When patients were separated according to the presence (>5%) or paucity (≤5%) of neutrophils on blinded histology review, they had distinct clinical features and differences in disease course. Limitations This was a single-center study. Conclusion Our data support the classification of LTA and cPAN as separate entities rather than a spectrum of the same disorder and highlight the importance of clinicopathologic correlation in distinguishing these conditions.

Livedo is a net-like violaceous skin pattern. It can be classified as physiological or pathological. The physiological livedo reticularis usually appears in cold conditions, whereas the pathological and irregular livedo, which persists in warm temperatures, is often labeled as 'livedo racemosa'. Some neurological pathologies are associated with livedo, most commonly those with an inflammatory component or those derived from systemic disorders. The present review summarizes the most important central and peripheral neurological diseases in pediatric and adult age groups associated with livedo, providing physicians with an overview of the clinical presentation, etiology, diagnosis and management of these conditions.

Herein, we report a case-based review of the Sneddon Syndrome (SS), a rare chronic condition which affects small to medium blood vessels. It is known by its skin presentation, livedo racemosa (LRC), and the relapsing cerebrovascular events. However, neither LRC nor cerebrovascular events are exclusive to SS. A 36-year-old female with history of mitral valve prolapse, hypothyroidism, Raynaud phenomenon, hypertension, migraines, and four episodes of transient ischemic attacks (TIA), presented to our clinic with new skin findings, suggestive of LRC. Based on her previous history, current presentation and skin biopsy results, she was diagnosed with SS secondary to antiphospholipid syndrome. The present report illustrates the difficulty in recognizing SS and how the heterogeneity of the disease may be contributing to the difficulty making a distinct diagnosis.

Acute viral pneumonia, hypoxemic respiratory failure and severe inflammatory response are hallmarks of severe coronavirus disease 2019 (COVID-19). The COVID-19-associated inflammatory state may further lead to symptomatic thromboembolic complications despite prophylaxis. We report a 66-year-old female patient with post-mortem diagnosis of COVID-19 who presented progressive livedo racemosa, acute renal failure and myocardial injury, as well as an absence of respiratory symptoms. Transthoracic echocardiography showed severe spontaneous echo contrast in the right cardiac chambers and right-sided cardiac overload presumed to result from pulmonary microvascular thrombosis or embolism. d-dimer levels were increased. The patient developed an acute ischemic stroke and died 2 days following presentation despite therapeutic anticoagulation. Her predominantly thromboembolic presentation supports the concept of coronavirus infection of endothelial cells and hypercoagulability, or COVID-19 endotheliitis. The case we report highlights that COVID-19-associated hyperacute multi-organ thromboembolic storm may precede or present disproportionately to respiratory involvement. Electronic supplementary material The online version of this article (10.1007/s11239-020-02173-w) contains supplementary material, which is available to authorized users.

Sneddon syndrome (SS) is a rare medium-vessel vasculopathy which characteristically presents with livedo racemosa (LR) and complications such as strokes. This case report describes a female presenting acutely with a stroke and, initially, no evidence of LR. Her antiphospholipid antibodies were negative, and her neuroimaging revealed multiple territory strokes with extensive vasculopathy and fragile neo-formed vessel collateralisation. She had progressive memory loss and multiple transient ischaemic attacks on a background of established infarctions. SS should be considered in any idiopathic medium-vessel vasculopathy despite the absence of LR. Medical therapy can be challenging and the importance of antiphospholipid status in risk stratifying anticoagulation against antiplatelet therapy is discussed with a proposed rheumatology management strategy. The medical option of hydroxychloroquine should be considered in all patients in view of its anti-thrombotic properties and efficacy in diseases such as systemic lupus erythematosus and antiphospholipid syndrome with the suggestion that SS may be a forme fruste of these diseases. Neurosurgical options should be considered for recurrent transient neurological symptoms. For our patient, this included an extracranial to intracranial bypass via a radial artery graft for haemodynamic stroke management confirmed on SPECT imaging. The traditional hallmark of SS has previously been LR. This case highlights an atypical presentation stressing the importance of diagnostic vigilance in a patient with an idiopathic medium-vessel vasculopathy, together with balancing the medical risk of antiplatelet therapy, anticoagulation and thrombolysis whilst revealing possible neurosurgical options in select SS patients.

Calciphylaxis is a potencially disorder in patients with hyperphosphatemic familial tumoral calcinosis (HFTC). Patients commonly present livedo racemosa and retiform purpura, which may progress to necrosis and very painful ulcers. Treatment with sodium thiosulfate provides good results; however, intralesional and intravenous treatment can be limited by its adverse effects. Topical sodium thiosulfate has been successfully reported for cutaneous calcification associated with connective tissue diseases and calciphylaxis in patients with chronic kidney disease. We provide a case report of a patient with HFTC and calciphylaxis who was treated with topical sodium thiosulfate with a rapid and complete response with no side effects.

Background Sneddon syndrome is a rare, progressive small and medium-vessel vasculopathy characterized by the clinical occurrence of livedo racemosa and ischaemic cerebrovascular events. Objectives We present the clinical course and management of this rare condition. Methods An 18-year-old female of East Indian descent presented with the following: CNS involvement: Recurrent Cerebral Venous Sinus Thromboses + Cognitive impairment - Skin: Livedo reticularis rash - Eyes: Bilateral optic nerves atrophy - CVS: Mild to moderate LAD dilation (16/12/2020) - MS: Polyarticular arthritis She first presented at 8-years-old with new-onset squint, ataxia and fever and was treated as culture-negative meningitis (CSF white cells 1238 neutrophils, CSF protein 110mg/ dL). At 16-years-old, she presented with expressive aphasia, headache, fever, left earache and was treated as acute mastoiditis. Regarding the recurrent presentations of CVST's there was involvement of left transverse sinus (untreated 2 years ago), then over a 1-month period despite anticoagulation, right transverse sinus with extension into the right sigmoid sinus and left straight and posterior superior sagittal sinus. She presented with headache, vomiting and new-onset seizures (GTCS) prior to these presentations. An extension of this clot after being non-compliant with low-molecular weight heparin for 1 week resulted in a venous infarct with surrounding oedema. She presented with progressive right-sided weakness and expressive aphasia and within 24 hours, encephalopathic with decerebrate posturing in subclinical status epilepticus. She was managed in PICU for refractory status epilepticus and raised intracranial pressure. There is also a family history of early stroke (maternal cousin with CVST at 8yo on long-term anticoagulation). Results Her inflammatory markers continued to increase despite antibiotic coverage at meningitic doses and she was treated for a CNS vasculitis/Catastrophic Antiphospholipid syndrome with IV anticoagulation (UFH), high-dose steroids then IVIG. Her neurological state gradually improved (coma -> vegetative state -> minimally conscious -> conscious). This was followed by Rituximab therapy 375 mg/m2 weekly x4. Her neurological function gradually improved as she was able to verbally communicate and developed anti-gravity movement of the right side. Hypertension and fever also settled, and inflammatory markers steadily decreased post treatment. Investigations: ANA, dsDNA, ENA negative pANCA borderline positive but MPO, PR3 Antibodies negative Anticardiolipin antibodies negative (on warfarin) Infectious screen (HIV, Hepatitis, COVID-19 serology, Mantoux test, CSF Acid-fast bacilli) - negative CSF cell count - 33 white cells (neutrophils), protein 183mg/dL Skin biopsy report (26/11/2020) - Neutrophils, lymphocytes of leucocytoclasis seen in vessels of dermis. Thrombosis of fibrinoid necrosis of vessel walls and extravasated red blood cells also seen - Obstructive vasculopathy for clinical correlation;Possible Sneddon syndrome/Antiphospholipid syndrome Conclusions There are few case reports describing the clinical course and treatment of this rare syndrome. In our case, treatment for Catastrophic Antiphospholipid syndrome (steroids, IVIG, rituximab and anticoagulation) was beneficial in improving the clinical outcome.

BACKGROUND: The abundance of publications of COVID-19-induced chilblains has resulted in a confusing situation. METHODS: This is a prospective single-institution study from March 15 to May 13, 2020. Thirty-two patients received PCR nasopharyngeal swabs. Of these, 28 had a thoracic CT-Scan, 31 had blood and urine examinations, 24 had skin biopsies including immunohistochemical and direct immunofluorescence studies, and 4 patients had electron microscopy. RESULTS: COVID-19-induced chilblains are clinically and histopathologically identical to chilblains from other causes. Though intravascular thrombi are sometimes observed, no patient had a systemic coagulopathy or severe clinical course. The exhaustive clinical, radiological and laboratory work-up in this study ruled-out other primary and secondary causes. Electron microscopy revealed rare, probable viral particles whose core and spikes measured from 120-133 nm within endothelium and eccrine glands in 2 cases. CONCLUSION: This study provides further clinicopathologic evidence of COVID-19 related chilblains. Negative PCR and antibody tests do not rule-out infection. Chilblains represents a good prognosis, occurring later in the disease course. No systemic coagulopathy was identified in any patient. Patients presenting with acral lesions should be isolated, and chilblains should be distinguished from thrombotic lesions (livedo racemosa, retiform purpura or ischemic acral necrosis). This article is protected by copyright. All rights reserved.

Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.

Sneddon syndrome (SS) is an episodic or chronic, slowly progressive disorder and characterized by generalized livedo racemosa (patchy, violaceous, skin discoloration) and recurrent cerebrovascular events. The histopathology of skin and brain is remarkable for a noninflammatory thrombotic vasculopathy involving medium- and small-sized dermal and cerebral arteries, respectively. 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. Etiopathogenesis of SS is unknown with 2 primary mechanisms proposed - autoimmune/inflammatory versus thrombophilia. SS is primarily classified as antiphospholipid positive or negative type. Neurological manifestations usually occur in 3 phases: (1) prodromal symptoms such as headaches, dizziness, and vertigo, (2) recurrent strokes, and (3) early onset dementia. Livedo racemosa precedes the onset of recurrent strokes by more than 10 years, but in many instances, the significance of the skin lesion is recognized only after the appearance of the stroke. The involvement of the heart valves, systolic labile hypertension, and retinal changes are also commonly associated with this syndrome. Treatment of SS is primarily based on anecdotal reports. Antiplatelet and antithrombotic agents are used for secondary stroke prophylaxis, and a recent study showed a relatively lower stroke recurrence rate with the universal use of antiplatelet/antithrombotic agents. Routine use of anti-inflammatory or immunosuppressive therapies is controversial. Neuropsychiatric prognosis of SS is relatively poor with predominant deficits in the concentration, attention, visual perception, and visuospatial skills.

Background Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive autoinflammatory condition. Recognised features include vasculitis predominantly affecting medium sized vessels, livedoid skin rash, central and peripheral nervous system involvement, variable degrees of immunodeficiency, and marrow failure, amongst other clinical presentations. We present the case of a six year old male with DADA2 who presented with acute testicular ischaemia secondary to vasculitis, the first such description in DADA2. Case presentation A six year old male presented acute right-sided testicular pain. His history included transient infantile neutropenia, resolved hepatosplenomegaly, and longstanding livedo racemosa, leading to screening and confirmation of DADA2 caused by homozygous c.139G > C (p.G47R) mutation of ADA2. As his only clinical feature was that of mild livedo racemosa with normal laboratory parameters at diagnosis, he was being actively monitored prior to starting any treatment. At a routine clinic follow-up a 24 h history of testicular pain was noted on systems review. He was afebrile, and his only physical signs were that of moderate livedo racemosa, and tenderness of the right testicle. Laboratory parameters revealed C-reactive protein (CRP) 8 mg/L (reference range [RR]

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.

Adults and children hospitalized with COVID-19 display a range of mucocutaneous eruptions, the diversity of which is likely due to the varying immune response generated in response to SARS-CoV-2 infection. In the hospitalized patient, livedo racemosa and retiform purpura were associated with more severe disease course, poorer prognosis, prolonged hospitalization, and higher mortality. In contrast, most viral exanthem and inflammatory lesions, such as urticarial and vesicular eruptions, were associated with a less severe COVID-19 disease course, although were nevertheless reported more frequently in the inpatient setting. One exception, however, is the presence of an inflammatory rash associated with MIS-C in the inpatient pediatric population, which has been associated with more severe COVID-19 disease and disease sequelae. Prompt recognition of the mucocutaneous manifestations presented in this article is paramount to facilitate timely diagnosis, proper treatment, and accurate prognostication of clinical course.

Background Livedoid vasculopathy (LV) is a rare disease characterized by livedo racemosa, atrophie blanche, ulcerations, and severe pain. Low molecular weight heparins and rivaroxaban can be used in LV-patients. In addition, intravenous immunoglobulins (IVIG) have been described as treatment-option. Objectives Objective was to investigate the therapeutic effect of IVIG on ulcer, pain and restrictions in daily life. Methods Thirty-two LV-patients who received IVIG at the Department of Dermatology Tübingen between 01/2014 and 06/2019 were identified. Twenty-five of these patients were available for further follow up and were included in the study. Patients were interviewed using a questionnaire focusing on the course of the disease, symptoms, and subjective response to IVIG-treatment. Results Twenty-five patients were included in the study (mean follow up: 28.9 months). Patients received an average of 6.8 cycles (range 1-45) of IVIG during the observed period. Significant improvements were seen regarding skin findings, pain, and limitation of daily activities. Complete remission of symptoms was observed in 68% of patients. Good tolerability of IVIG was shown in 92%. Conclusions A good therapy response regarding ulceration, pain, and daily life restrictions with good tolerability was demonstrated for IVIG (2 g/kg bodyweight over 5 days).

Moyamoya angiopathy (MA) is a progressive cerebrovascular disease with a poorly understood pathophysiology. It is mainly characterized by progressive bilateral stenosis of the terminal intracranial part of the supraclinoid internal carotid arteries and the proximal parts of the middle and anterior cerebral arteries, as well as the development of a fragile collateral network at the base of the brain. This results in early-onset ischemic or hemorrhagic strokes. The disease may be idiopathic (known as Moyamoya disease) or associated with other heritable or acquired conditions, including type 1 neurofibromatosis or other RASopathies, sickle cell disease, Down syndrome, or autoimmune disorders (known as Moyamoya syndrome). Although the disease is thought to selectively involve the brain vessels, systemic manifestations such as cardiac and ocular ones have been reported in MA, mostly in the syndromic form. Various cutaneous manifestations have also been described in MA patients. These include changes in the epidermis, dermis, or skin appendages for example cafe-au-lait spots, hypomelanosis of Ito, livedo racemosa, hemangiomas, premature graying of hair, etc. The present review summarizes the cutaneous associations as well as the coincidental dermatological findings seen in MA patients.

This study presents a single center experience with livedoid vasculopathy (LV). A rare disease that can lead to severe quality of life impairment. Characterize clinical data of LV patients at the Dermatology Division at the University of Sao Paulo. A retrospective and transversal study was conducted, from 1 January 2005 to 31 December 2019. About 75 patients diagnosed as LV and confirmed by skin biopsy were included. Epidemiology, clinical appearance, histopathology data, and treatment history were observed. There were 78.66% Caucasian women, with a mean age of 39.9 years. Frequent cutaneous manifestations were ulcers, atrophic blanche-like scars, hyperpigmentation, purpuras, telangiectasias, and livedo racemosa. Pain, pruritus, and hypoesthesia were the main symptoms. After treatment, almost 40% of cases relapsed during spring and summer months. About 66% of cases had thrombophilia factors associated, such as high levels of lipoprotein(a). Frequent treatments included acetylsalicylic acid, pentoxifylline, and diosmin with hesperidin. Not being a prospective study. This research provides useful data on Latin American LV patients, indicating multifactorial conditions involved in LV pathogenesis. An extensive work-up including autoimmune laboratory tests, thrombophilia factors, and other conditions associated with venous stasis should be part of LV investigation and controlled to improve treatment response.

The increasingly frequent cutaneous manifestations of coronavirus disease (COVID-19) remain to pose a problem to clinicians. Herein, we aimed to describe the clinical and pathological findings of skin lesions in patients with COVID-19. The case series, which was based on the International Dermatological Registry circulated to dermatologists worldwide, was conducted across organizations and societies belonging to five different countries. We documented 31 patients with dermatologic manifestations associated with COVID-19, including maculopapular rashes (16.10%), urticarial lesions (26.80%), pseudochilblains (22.60%), petechiae/purpura (6.50%), distal ischaemia and necrosis (6.50%), livedo racemosa (12.90%), and others (9.70%). Twenty-six cases (83.90%) were qRT-PCR-confirmed COVID-19 cases, two (6.50%) were serologically confirmed, while two others (9.7%) were suspected cases owing to previous contact with COVID-19-positive patients. Therefore, our findings indicate that a febrile rash or even a rash in an afebrile state in the early stages of the disease may be the only clinical manifestation of COVID-19. In the future, we recommend close monitoring of all patients with skin lesions not attributable to other causal factors, in the diagnostic perspective, clinicians should aim to confirm if the skin lesions are associated with COVID-19.

BACKGROUND: The infection by coronavirus disease 2019 (COVID-19) has been associated with multiple cutaneous manifestations, although characterization of them in Hispanic patients with darker skin phototypes is lacking. The objective of this study is to characterize the clinical dermatological manifestations associated with COVID-19 infection in cases with few or without general symptoms in patients from Latin America. METHODS: Cross-sectional study using a questionnaire that was made for health professionals (physicians with a specialty in dermatology) to investigate dermatological lesions associated with COVID-19 infection in patients from 25 countries of Latin America. The survey was active from June 9 to July 30, 2020. RESULTS: In this study, information was collected from a total of 347 patients. We found a female gender predominance: 179/347 (51.6%). The mean age at presentation was 40.87 years. The most frequent dermatological manifestations were maculopapular rash and urticarial lesions, followed by papulovesicular lesions, vesicular lesions, chilblain-like lesions, papular lesions, ecchymosis, petechial purpura, pityriasis rosea-like lesions, pruritus, palmoplantar dysesthesias, transient livedo, acral necrosis, palpable purpura, livedo racemosa, and retiform purpura. As far as we know, there are no previous reports of pruritus and palmoplantar dysesthesias. CONCLUSIONS: This registry emphasizes skin manifestations as an important criterion for establishing the diagnosis of COVID-19 infection in Latin American countries. This information will be useful for the early identification of suspected cases by health professionals (dermatologists and nondermatologists) and will allow contact tracing to mitigate the impact on health systems at different levels

Simple Summary Patients diagnosed with COVID-19 and concomitant skin rashes have been frequently reported. We summarized the cases described to date, including only patients with positive RT-PCR testing from nasopharyngeal swabs. Six hundred and fifty-five patients were found who presented different types of skin rashes, from maculopapular, vascular, vesicular, urticarial, to atypical forms and ocular involvement. Chilblains which are lesions resembling frostbite have been more frequent in the younger population and seemed to predict a milder disease course. Vascular-purpuric lesions appeared in older patients and were linked to a more severe evolution. In the case of vesicular rashes, the possibility of herpesvirus co-infections was raised. Moreover, cutaneous hydroxychloroquine drug reactions have been described. For patients with conjunctivitis, eye discharge might be contagious. These skin manifestations may help identify asymptomatic COVID-19 carriers in some cases or predict a more severe evolution in others. Abstract There have been increasing reports of skin manifestations in COVID-19 patients. We conducted a systematic review and included manuscripts describing patients with positive RT-PCR coronavirus testing from nasopharyngeal swabs who also developed cutaneous manifestations. A total of 655 patients were selected, with different types of skin rashes: Erythematous maculopapular (n = 250), vascular (n = 146), vesicular (n = 99), urticarial (n = 98), erythema multiforme/generalized pustular figurate erythema/Stevens-Johnson syndrome (n = 22), ocular/periocular (n = 14), polymorphic pattern (n = 9), generalized pruritus (n = 8), Kawasaki disease (n = 5), atypical erythema nodosum (n = 3), and atypical Sweet syndrome (n = 1). Chilblain-like lesions were more frequent in the younger population and were linked to a milder disease course, while fixed livedo racemosa and retiform purpura appeared in older patients and seemed to predict a more severe prognosis. For vesicular rashes, PCR determined the presence of herpesviruses in the vesicle fluid, which raised the possibility of herpesvirus co-infections. The erythema-multiforme-like pattern, generalized pustular figurate erythema and Stevens-Johnson syndrome were most frequently linked to hydroxychloroquine intake. A positive PCR determination of SARS-COV-2 from conjunctival swabs suggest that eye discharge can also be contagious. These cutaneous manifestations may aid in identifying otherwise asymptomatic COVID-19 carriers in some cases or predict a more severe evolution in others.

Iatrogenic vascular occlusion secondary to filler injection, such as with hyaluronic acid, is a known but rare, entity. It typically occurs in the setting of facial cosmetic procedures but has also been described in the setting of osteoarthritis. We present a patient with ankle osteoarthritis who developed an asymmetric, reticular, livedoid eruption after intraarticular injection with hyaluronic acid. She was diagnosed with livedo racemosa secondary to vascular occlusion and placed on low molecular weight heparin. Later, a transition to low-dose daily aspirin maintained the improvement.

Lymphocytic thrombophilic arteritis and Sneddon syndrome can have very similar clinical presentations with chronic persistent widespread blanchable livedo racemosa. Lymphocytic thrombophilic arteritis has only recently been described and generally is associated with a benign prognosis. Sneddon syndrome is associated with the development of multiple cerebrovascular accidents and progressive neurological impairment. We present three cases of Sneddon syndrome and compare them with lymphocytic thrombophilic arteritis to identify patients at risk of neurological events.

Summary The SARS‐Cov‐2 is a single‐stranded RNA virus composed of 16 non‐structural proteins (NSP 1‐16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid‐19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid‐19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a ‘cytokine storm’. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D‐dimer, lactic dehydrogenase, reactive‐C‐protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug‐related intertriginous and flexural exanthema. This review describes the complexity of Covid‐19, its pathophysiological and clinical aspects.

Background SARS-Cov-2 is a single-stranded RNA virus, a Betacoronavirus, composed of 16 non-structural proteins, with specific roles in replication of coronaviruses. The pathogenesis of COVID-19 is not yet fully understood. The virus and host factors interplay among distinct outcomes of infected patients. Methods Using MeSH (Medical Subject Headings) in PubMed, authors searched for articles cotaining information on COVID-19 and the skin. Results The pathophysiology of the disease is multifactorial: association with innate immune response, hypercoagulability state, lung tissue damage, neurological and/or gastrointestinal tract involvement, monocytic/macrophage activation syndrome, culminating in exaggerated cytokine secretion, called “cytokine storm”, which leads to worsening and death. These systemic conditions may be associated with cutaneous lesions, that have polymorphic aspects, where at histopathological level show involvement in different skin changes. These lesions may be associated with multisystemic manifestations that could occur due to angiotensin-converting enzyme 2 receptor and transmembrane serine protease action, allowing the pulmonary infection and possibly skin manifestation. Several reports in literature show cutaneous lesions similar to chilblain, urticarial eruptions, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicle trunk, purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and others. Conclusions This review describes the complexity of Covid-19, pathophysiological and clinical aspects, dermatological finding and other dermatological conditions associated with SARS-CoV-2 infection or COVID-19.

Objective Sneddon’s syndrome is a cerebrocutaneous non-inflammatory progressive distal arteriopathy, characterized by livedo racemosa, stroke, and neuropsychiatric symptoms. Our aim was to highlight the characteristic neuroimaging features of Sneddon’s syndrome that might be helpful to clinicians in timely diagnosis of this entity. Methods Twelve patients (median age 49 years, 11 female) with primary Sneddon’s syndrome, diagnosed in last 10 years, were analyzed from the perspective of magnetic resonance imaging (MRI) features. In addition, a novel pseudoangiomatosis score was defined for grading angiographic abnormalities (range: 0 to 6). Results Median interval from the onset of neurological symptoms to diagnosis was 6 years. Presentation was with acute stroke in 5, seizures in 3, dementia/speech problems in 2, seizures plus cognitive dysfunction in 1, and chronic progressive hemiparesis in 1. All patients had a typical lesion pattern on MRI. This included multiple (median 3) cortical-subcortical supratentorial and cerebellar non-territorial infarcts, accompanied by multifocal cerebral atrophy. Of note, large territorial infarcts due to cerebral parent artery occlusion, an embolic pattern with multi-territorial involvement on diffusion-weighted imaging, small vessel disease features like severe white matter involvement or lacunar infarcts, and cerebral hemorrhage in the absence of anticoagulation were not observed. MRI lesion severity was not correlated with angiographic arteriopathy severity, clinical stage, or presentation symptoms. Conclusion Sneddon’s syndrome is characterized by highly typical clinico-radiological features. Brain MRI has diagnostic value. By knowing the characteristics of the syndrome, misdiagnosis and potentially harmful treatment can be prevented in this entity that might pose a diagnostic challenge.

Decompression sickness and arterial gas embolism, collectively known as decompression illness (DCI), are serious medical conditions that can result from compressed gas diving. DCI can present with a wide range of physiologic and neurologic symptoms. In diving medicine, skin manifestations are usually described in general as cutis marmorata (CM). Mainly in the Anglo-American literature the terms cutis marmorata, livedo reticularis (LR), and livedo racemosa (LRC) are used interchangeably but actually describe pathophysiologically different phenomena. CM is a synonym for LR, which is a physiological and benign, livid circular discoloration with a net-like, symmetric, reversible, and uniform pattern. The decompression-associated skin discolorations, however, correspond to the pathological, irregular, broken netlike pattern of LRC. Unlike in diving medicine, in clinical medicine/dermatology the pathology of livedo racemosa is well described as a thrombotic/embolic occlusion of arteries. This concept of arterial occlusion suggests that the decompression-associated livedo racemosa may be also caused by arterial gas embolism. Recent studies have shown a high correlation of cardiac right/left (R/L) shunts with arterial gas embolism and skin bends in divers with unexplained DCI. To further investigate this hypothesis, a retrospective analysis was undertaken in a population of Austrian, Swiss, and German divers. The R/L shunt screening results of 18 divers who suffered from an unexplained decompression illness (DCI) and presented with livedo racemosa were retrospectively analyzed. All of the divers were diagnosed with a R/L shunt, 83% with a cardiac shunt [patent foramen ovale (PFO)/atrium septum defect (ASD)], and 17% with a non-cardiac shunt. We therefore not only confirm this hypothesis but when using appropriate echocardiographic techniques even found a 100% match between skin lesions and R/L shunt. In conclusion, in diving medicine the term cutis marmorata/livedo reticularis is used incorrectly for describing the actual pathology of livedo racemosa. Moreover, this pathology could be a good explanation for the high correlation of livedo racemosa with cardiac and non-cardiac right/left shunts in divers without omission of decompression procedures.

Sneddon's syndrome is a rare, noninflammatory thrombotic vasculopathy characterized by the combination of livedo racemosa, recurrent stroke, and histopathological skin lesions of endarteritis obliterans. Although multiorgan involvement suggests its systemic nature, detailed pathological description of affected organs - including the kidney - is exceptional. We report a case of Sneddon's syndrome with chronic kidney disease, associated with features of endarteritis obliterans in the skin and the kidney. The clinical presentation of our patient is compared to previously reported cases of Sneddon's syndrome with biopsy-proven kidney disease. We also discuss the differential diagnosis, pathophysiological mechanisms, relationship with antiphospholipid syndrome, and management of patients with Sneddon's syndrome and kidney disease. This clinical observation supports the systemic nature of Sneddon's syndrome and provides insights into the mechanisms by which this rare but probably underdiagnosed disease alters kidney function. .

Livedo racemosa is a cutaneous finding characterized by a persistent, erythematous, or violaceous discoloration of the skin, in a broken, branched, discontinuous, and irregular pattern. A retrospective review of 33 cases with clinical diagnosis of livedo racemosa over the past 6 years was evaluated in the dermatology department of a tertiary care hospital. We found predominance in Caucasian women (78.8%); age ranged from 8 to 81 years, with a mean age of 36 years. Livedo racemosa was described as generalized in 12 patients (36.4%), although the main localization was on lower limbs (42%). After laboratory testing and histopathological examinations, 12 patients (36.4%) were classified with idiopathic livedo racemosa; secondary diseases were diagnosis in 21 patients (63.6%), including Sneddon’s syndrome, cutaneous polyarteritis nodosa, systemic lupus erythematosus, and others. Medical history of thrombotic events was described in 8 (24.2%) patients, and also 8 (24.2%) patients had abnormal results for 2 or more thrombophilia laboratory tests. Skin biopsy showed no histological abnormalities in 11 cases (33.3%), thrombosis of dermal blood vessels in 10 (30.3%), intimal/subintimal thickening in 7 (21.2%), and vasculitis in 5 (15.2%). In conclusion, livedo racemosa is a clinical feature that might be correlated to vascular disorders, such as thrombotic and/or hypercoagulable states, autoimmune diseases, and neoplastic diseases, or it can be secondary to specific medications. It is essential to establish a correct approach in cases of livedo racemosa, which includes anamnesis, physical examination, laboratory test, histological examination, and complementary examination according to clinical findings, in order to diagnosis underlying causes.

IMPORTANCE: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described. OBJECTIVE: To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies. RESULTS: All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients. CONCLUSIONS AND RELEVANCE: This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

We describe three patients who presented with a striking erythematous non-blanching annular eruption and features of lymphocytic thrombophilic arteritis (LTA), with a prominent lymphocytic vasculitis involving deep dermal vessels. Lymphocytic inflammation was also evident in the superficial vessels and one patient had small superficial ulcers over the ankle area resembling livedoid vasculopathy (LV). Multiple biopsies demonstrated a persistent absence of neutrophils in the infiltrate consistent with a lymphocytic process. In addition to highlighting the annular morphology as a novel presentation of LTA, these cases suggest a possible relationship between LV and LTA and support the notion that they are distinct from neutrophilic vasculitides such as cutaneous polyarteritis nodosa.

Sneddon syndrome is a rare non-inflammatory obliterative vasculopathy, characterized by the association of cardiovascular (arterial hypertension, intermittent claudication, and coronary artery disease) and neurological events (ischemic stroke, headache, dizziness and convulsions), and livedo reticularis/livedo racemosa. The case is presented of a woman admitted with an ischemic neurological disease, hypertension, vascular problems, and skin lesions. The skin biopsy was classified as surface perivascular lymphocytic dermatitis, suggestive of occlusive lesion.

Dermatologic manifestations are observed in almost all systemic vasculitides, even in large-and medium-vessel vasculitides, although such vessels are not found in the skin. Cutaneous manifestations may be related to a direct skin localization of the systemic vasculitis or a non-specific process associated with the vasculitis. According to the 2012 International Chapel Hill consensus, the two major variants of large-vessel vasculitides are Takayasu arteritis and giant-cell arteritis. In Europe and North America, acute inflammatory nodules or erythema nodosum-like lesions are the most commonly observed skin lesions with Takayasu arteritis. Medium-sized arteriole vasculitis of the dermis or subcutis but also septal or lobular panniculitis may be found during pathological examination. In Japan, widespread pyoderma gangrenosum-like lesions are more frequent. Cutaneous manifestations of giant-cell arteritis are rare; they are ischemic, linked to arterial occlusions, or non-ischemic, with various mechanisms. The two major medium-vessel vasculitides are Kawasaki disease and polyarteritis nodosa. Kawasaki disease is characterized by a mucocutaneous lymph node syndrome without skin vasculitis. Two subsets of polyarteritis nodosa with different skin manifestations are described, without transition from one to the other. In the systemic subset, the most frequent skin lesions are in the order of frequency purpura, livedo, and nodules. Cutaneous polyarteritis nodosa mainly features nodules, livedo racemosa, and ulcerations. Genetic screening and measurement of plasma levels of adenosine deaminase 2 should be considered for patients with uncommon systemic polyarteritis nodosa or early-onset cutaneous polyarteritis nodosa.

For the past decades, hydrophilic polymer gel coating have been widely used on endovascular devices to decrease friction and to aid with binding and delivering of medications in drug eluting stents. In the recent years, hydrophilic polymer emboli disease has been recognized as an iatrogenic adverse effect which has led to considerable morbidity and mortality of patients. This under-recognized embolic phenomenon now has reproducible pathognomonic histologic findings. Small to medium sized blood vessels are occluded with basophilic, amorphous, non-refractile, non-polarizable, whirled aggregates of foreign body material. Depending on the affected organ, the patients have variable symptomatology, from livedo racemosa, gangrene of extremities to cardiac arrhythmias, hemiparesis, stroke and death. Here, we present a unique case of hydrophilic polymer vasculopathy six years post endovascular procedure with coinciding pseudoxanthoma elasticum-like changes. As the literature has seen increased reporting of individual cases and case series documenting the patients’ diverse symptomatology; hydrophilic polymer vasculopathy should be entertained sooner in the patient's differential diagnosis.

We report a 40-year-old female. The high blood pressure was found in Family history, hospitalized in neurology for recurrent ischemic stroke so the etiological assessment was negative, opinion was sought for lesions of livedo at the level of the members back to 2 years without the concept of miscarriage or Raynaud’s phenomenon, neither photosensitivity nor a dry syndrome. Dermatologic examination showed dusky erythematous to violaceous, irregular, broken circular segments, resulting in a seemingly larger pattern, located on limbs, trunk, and buttocks, exaggerated by the cold and persistent on warming. A report looking for the antiphospholipid antibodies syndrome was positive and the skin biopsy was in favor of a Sneddon syndrome. The patient was treated by anticoagulants and antiplatelet agents with good evolution.

Sneddon syndrome is a rare vasculopathy of small and medium-sized arteries, characterized by the clinical occurrence of livedo racemosa together with ischemic cerebrovascular events.1 First cases of patients with livedo racemosa and neurologic symptoms were reported in the 1950s and 1960s.1, 2, 3 This syndrome is rare with an estimated incidence of 4 of 1 million per year and mainly affects young women with a mean onset in the third decade of life.4, 5 We present an early-onset idiopathic form of Sneddon syndrome with a long-term follow-up of 19 years in a young male.

Lymphocytic thrombophilic arteritis (LTA) is a recently described entity defined by primary lymphocytic vasculitis; it typically has a chronic indolent course. We describe a patient who presented with clinical and histological findings consistent with LTA and later developed bilateral focal testicular infarcts as well as an acute median nerve neuropathy.

Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) that has conventional cutaneous manifestations of DM, but paradoxically, little or no muscle involvement. In 2005, a novel antibody was described in association with CADM - anti-melanoma differentiation-associated gene 5 (anti-MDA5). Patients with this serologic marker have a characteristic mucocutaneous phenotype consisting of skin ulceration among other signs. We describe the case of a 46-year-old woman with CADM, elevated anti-MDA5 autoantibodies, and unusual clinical features (livedo racemosa, florid acral edema) among the classical phenotype of MDA5 DM (arthralgias, ulcerations, panniculitis) and classical DM lesions (Gottron papules, heliotrope rash). The patients did not develop interstitial lung disease or internal malignancies and experienced a rapid response to prednisolone and intravenous immunoglobulins. After 2 years, she has no relapse of her cutaneous disease and continues 5 mg prednisolone and 2 g/kg kilogram of intravenous immunoglobulin every 3 months for maintenance. Our case highlights the clinical heterogeneity of CADM and underscores the importance of a comprehensive approach to DM patients. It was previously postulated that anti-MDA5 antibody could target vascular cells and compromise vascular function, the presence of livedo racemosa lesions, and MDA5 antibodies in a patient with negative thrombophilia workup, reinforce this idea. This is the first case, to our knowledge, of CADM with acral panniculitis and livedo racemosa.

Objective In Europe, MMA is a very rare non-inflammatory vasculopathy. MMA is an important differential diagnosis of cerebral vasculitis. Systemic manifestations, such as livedo racemosa or renal artery stenosis, associated with Moyamoya variants suggest the involvement also of non-cerebral vessels. Hypothetically, capillary microscopy could be a promising non-invasive screening method to visualize microcirculation, for example prior to cerebral angiography. Methods Standardized capillary microscopic images were taken in European patients with MMA and subsequently evaluated in a blinded analysis, using data obtained from a large NP cohort and a large SLE cohort by the same blinded Investigator as controls. Results Twenty-four European MMD patients and 14 healthy accompanying controls were included in this study. The results were compared to 116 SLE patients and 754 NP subjects. In MMD patients, no capillary morphological differences were found in comparison with NP, in particular no density reduction or increased neoangiogenesis. The pattern observed in the SLE cohort was clearly distinct from NP and MMD with regard to vascular density, vascular damage, and neoangiogenesis. Conclusions MMD is not associated with microvascular changes of the nailfold capillaries. In this respect, it is clearly distinct from SLE.

A 34-year-old woman presented with acute onset left facial weakness and dysarthria. Examination showed diffuse livedo racemosa (figure, A). Brain MRI demonstrated right frontal acute stroke (figure, B), with numerous chronic ischemic lesions in the deep white matter (figure, C). CT angiogram revealed multiple irregularities along the cortical branches of intracranial vessels (figure, D and E). Skin biopsy was nonspecific.1 Extensive immunologic, hematologic, and infectious workup was unremarkable.2 The patient was diagnosed with Sneddon syndrome and discharged on aspirin.