Subject(s)
Agammaglobulinemia/diagnosis , Livedo Reticularis/diagnosis , Severe Combined Immunodeficiency/diagnosis , Agammaglobulinemia/genetics , Biopsy , Child, Preschool , Diagnosis, Differential , Humans , Livedo Reticularis/genetics , Lower Extremity , Male , Severe Combined Immunodeficiency/geneticsABSTRACT
OBJECTIVES: To analyse the prevalence of CECR1 mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study. METHODS: Direct sequencing of CECR1 was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor. RESULTS: Biallelic homozygous or compound heterozygous CECR1 mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without CECR1 mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect. CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.
Subject(s)
Adenosine Deaminase/deficiency , Adenosine Deaminase/genetics , Intercellular Signaling Peptides and Proteins/deficiency , Intercellular Signaling Peptides and Proteins/genetics , Livedo Reticularis/genetics , Polyarteritis Nodosa/genetics , Stroke/genetics , Adolescent , Age of Onset , Case-Control Studies , Child , Child, Preschool , DNA Mutational Analysis , Female , Heterozygote , Homozygote , Humans , Immunoglobulins/blood , Immunosuppressive Agents/therapeutic use , Infant , Italy , Livedo Reticularis/drug therapy , Livedo Reticularis/enzymology , Male , Pedigree , Polyarteritis Nodosa/drug therapy , Polyarteritis Nodosa/enzymology , Stroke/enzymology , Thalidomide/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Young AdultABSTRACT
AIM: Thrombosis and inflammation play an important role in pathophysiology of livedoid vasculopathy (LV). Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of fibrinolysis and is a pivotal modulator in a broad range of biological processes. METHOD: The study specimens were retrospectively selected from archives of pathology department. We investigated PAI-1 mRNA expression in the paraffin blocks of patients with biopsy-proven LV and controls. We analyzed the presence of thrombus, fibrinoid necrosis, ulcer, and epidermal atrophy in study samples. The correlation between histologic findings and PAI-1 expression was investigated. RESULTS: Analyses were performed in 14 LV patients (mean age 31±20, 79% female) and 4 controls (mean age 64±19, 50% female). PAI-1 gene expression was significantly higher in LV compared to the control group (median 7.74 (Iqr:13.94) vs 1.0 (0.31)), P=.011. Histological analysis displayed that fibrinoid necrosis was present on all patients with LV, 61.5% displayed thrombus, 46.2% displayed ulcer, and 15.4% displayed epidermal atrophy. Overall, we did not observe any discerning difference in PAI-1 expression between the LV blocks with or without thrombus, fibrinoid necrosis, or epidermal atrophy, yet the LV specimens that displayed ulcer histologically had higher PAI-1 mRNA expression compared to those without ulcer (median 13.98 (Iqr:19.21) vs 2.86 (5.59)), (P=.046). CONCLUSION: PAI-1 mRNA expression is significantly increased in cutaneous lesions of patients with LV. Histological finding of ulcer is associated with increased PAI-1 expression in LV specimen. In the current era of PAI-1 inhibitors, enhanced local PAI-1 expression can form a novel and local therapeutic target in LV.
Subject(s)
Livedo Reticularis/genetics , Plasminogen Activator Inhibitor 1/genetics , RNA, Messenger/genetics , Skin Ulcer/genetics , Skin/chemistry , Adolescent , Adult , Biopsy , Female , Genetic Markers , Humans , Livedo Reticularis/pathology , Male , Middle Aged , Paraffin Embedding , Real-Time Polymerase Chain Reaction , Retrospective Studies , Skin/pathology , Skin Ulcer/pathology , Up-Regulation , Young AdultSubject(s)
Actins/deficiency , Aortic Aneurysm, Thoracic/surgery , Aortic Rupture/etiology , Endovascular Procedures/adverse effects , Iris/abnormalities , Livedo Reticularis/surgery , Actins/genetics , Angiography , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/genetics , Aortic Rupture/diagnosis , Aortic Rupture/genetics , Echocardiography, Transesophageal , Fatal Outcome , Humans , Iris/surgery , Livedo Reticularis/diagnosis , Livedo Reticularis/genetics , Male , Middle Aged , Septal Occluder DeviceSubject(s)
Cold Temperature/adverse effects , Endothelial Cells/metabolism , Interleukin-8/blood , Livedo Reticularis/blood , Microvessels/metabolism , Neutrophil Infiltration , Receptors, Interleukin-8B/metabolism , Seasons , Skin Ulcer/blood , Skin/blood supply , Cells, Cultured , Chemokine CXCL1/metabolism , Endothelial Cells/immunology , Endothelial Cells/pathology , Humans , Interleukin-8/genetics , Livedo Reticularis/genetics , Livedo Reticularis/immunology , Livedo Reticularis/pathology , Microvessels/immunology , Microvessels/pathology , Receptors, Interleukin-8B/immunology , Skin/immunology , Skin/pathology , Skin Ulcer/immunology , Skin Ulcer/pathology , Up-RegulationABSTRACT
We report a new case of Warsaw Breakage syndrome (WABS) with 2 confirmed mutations in DDX11. Like the previous reported cases [Capo-Chichi et al., 2012; Van der Lelij et al., 2010], there was evidence of pre- and postnatal growth retardation, severe microcephaly, intellectual disability and facial dysmorphism. The patient had sensorineural hearing loss with evidence of bilateral hypoplastic cochleas on imaging, another feature which has been reported in the previous cases of WABS. In our case the patient exhibited a chronic rash of livedo reticularis with telangiectasia on her legs. Abnormally pigmented lesions and cutis mamorata were reported in the original WABS case.
Subject(s)
Abnormalities, Multiple/genetics , DEAD-box RNA Helicases/genetics , DNA Helicases/genetics , Adolescent , Facies , Female , Fetal Growth Retardation/genetics , Hearing Loss, Sensorineural/genetics , Humans , Intellectual Disability/genetics , Livedo Reticularis/genetics , Microcephaly/genetics , Premature Birth , Telangiectasis/genetics , United KingdomABSTRACT
Sneddon syndrome is defined by the association of livedo racemosa and recurrent cerebrovascular ischemic lesions. The annual incidence is 4/1,000,000. This syndrome particularly affects young women, some reports suggesting a family predisposition. It is a chronic, progressive, arterio-occlusive disease of unknown etiology that involves small and medium-sized arteries. It is usually associated with antiphospholipid antibodies. We report the case of a female patient with Sneddon syndrome with significant family history, personal history of stroke, epilepsy, migraine, cardiovascular involvement, three miscarriages, cognitive decline, noncompliant to therapy, in the absence of antiphospholipid antibodies. This paper aims to analyze the main characteristic features and management of Sneddon syndrome by conducting a literature review related to a clinical case.
Subject(s)
Livedo Reticularis/diagnosis , Skin/pathology , Sneddon Syndrome/diagnosis , Adult , Angina Pectoris/diagnosis , Biopsy , Diagnosis, Differential , Epilepsy/diagnosis , Female , Humans , Hypertension/diagnosis , Livedo Reticularis/drug therapy , Livedo Reticularis/genetics , Magnetic Resonance Imaging , Migraine Disorders/diagnosis , Pedigree , Prognosis , Rare Diseases , Risk Factors , Sneddon Syndrome/drug therapy , Sneddon Syndrome/genetics , Stroke/diagnosis , Treatment OutcomeABSTRACT
Aortic root and ascending aortic dilatation are indicators associated with risk of aortic dissection, which varies according to underlying etiologic associations, indexed aortic root size, and rate of progression. Typical aortic involvement is most commonly seen in syndromic cases for which there is increasing evidence that aortic aneurysm represents a spectrum of familial inheritance associated with variable genetic penetrance and phenotypic expression. Aortic root and ascending aortic dimensions should be measured routinely with echocardiography. Pharmacologic therapy may reduce the rate of progression. Timing of surgical intervention is guided by indexed aortic size and rate of change of aortic root and ascending aorta dimensions. Lifelong surveillance is recommended.
Subject(s)
Aortic Aneurysm/therapy , Actins/deficiency , Actins/genetics , Aortic Aneurysm/diagnosis , Aortic Aneurysm/genetics , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/genetics , Aortic Aneurysm, Thoracic/therapy , Aortic Valve/abnormalities , Arachnodactyly/diagnosis , Arachnodactyly/genetics , Arachnodactyly/therapy , Bicuspid Aortic Valve Disease , Contracture/diagnosis , Contracture/genetics , Contracture/therapy , Diagnosis, Differential , Ductus Arteriosus, Patent/diagnosis , Ductus Arteriosus, Patent/genetics , Ductus Arteriosus, Patent/therapy , Echocardiography , Ehlers-Danlos Syndrome/diagnosis , Ehlers-Danlos Syndrome/genetics , Ehlers-Danlos Syndrome/therapy , Heart Valve Diseases/diagnosis , Heart Valve Diseases/genetics , Heart Valve Diseases/therapy , Humans , Iris/abnormalities , Livedo Reticularis/diagnosis , Livedo Reticularis/genetics , Livedo Reticularis/therapy , Loeys-Dietz Syndrome/diagnosis , Loeys-Dietz Syndrome/genetics , Loeys-Dietz Syndrome/therapy , Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Marfan Syndrome/therapy , Mitral Valve Prolapse/diagnosis , Mitral Valve Prolapse/genetics , Mitral Valve Prolapse/therapy , Myopia/diagnosis , Myopia/genetics , Myopia/therapy , Prognosis , Skin Diseases/diagnosis , Skin Diseases/genetics , Skin Diseases/therapyABSTRACT
Livedoid vasculopathy is a rare chronic relapsing disorder characterised by recurrent painful thrombotic and vasculitic ulcers on the legs. We present the cases of two Indian women with livedoid vasculopathy that were found to be associated with an underlying factor V Leiden heterozygous mutation. There were no other thrombotic manifestations, and livedoid vasculopathy was the sole presenting feature of the factor V Leiden mutation, although this could also be coincidental. Initial treatment with high-dose immunosuppressive therapy was suboptimal, and the addition of pentoxifylline and antiplatelet therapy was crucial in achieving disease control and remission. These cases highlight the possible association with an underlying prothrombotic disorder, such as factor V Leiden mutation, in patients with livedoid vasculopathy. Although this association is relatively uncommon, it is more relevant to Indian patients, as the presence of factor V Leiden mutation is highest in this ethnicity as compared to the local Malay and Chinese populations.
Subject(s)
DNA/genetics , Factor V/genetics , Livedo Reticularis/genetics , Point Mutation , Skin Diseases, Vascular/genetics , Skin/blood supply , Adult , Blood Vessels/pathology , Factor V/metabolism , Female , Humans , Leg Ulcer/blood , Leg Ulcer/genetics , Leg Ulcer/pathology , Livedo Reticularis/blood , Livedo Reticularis/diagnosis , Polymerase Chain Reaction , Skin Diseases, Vascular/blood , Skin Diseases, Vascular/pathologyABSTRACT
DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome") in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.
Subject(s)
DNA Polymerase II/genetics , Facial Bones/abnormalities , Growth Disorders/enzymology , Growth Disorders/genetics , Immunologic Deficiency Syndromes/enzymology , Immunologic Deficiency Syndromes/genetics , Livedo Reticularis/enzymology , Livedo Reticularis/genetics , Adolescent , Adult , Alternative Splicing , Base Sequence , Body Height/genetics , Cell Proliferation , Child , Child, Preschool , Chromosomes, Human, Pair 12/genetics , Consanguinity , DNA Mutational Analysis , DNA Polymerase II/deficiency , Female , France , G1 Phase Cell Cycle Checkpoints/genetics , Gene Expression , Genes, Recessive , Humans , Immunologic Deficiency Syndromes/immunology , Introns , Livedo Reticularis/pathology , Male , Pedigree , Point Mutation , Poly-ADP-Ribose Binding Proteins , Syndrome , Young AdultABSTRACT
Livedoid vasculopathy is characterized by painful purpuric lesions on the extremities which frequently ulcerate and heal with atrophic scarring. For many years, livedoid vasculopathy has been considered to be a primary vasculitic process. However, there has been evidence considering livedoid vasculopathy as an occlusive vasculopathy due to a hypercoagulable state. We present the case of livedoid vasculopathy in a 21-year-old female who had been suffering of painful lower extremity lesions of 3 years duration. The patient was found to be lupus anticoagulant positive and homozygous for methylenetetrahydrofolate reductase C677T mutation. The patient was successfully treated with low-molecular-weight heparin.
Subject(s)
Anticoagulants/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Livedo Reticularis , Lupus Coagulation Inhibitor , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Point Mutation , Adult , Female , Humans , Livedo Reticularis/drug therapy , Livedo Reticularis/genetics , Livedo Reticularis/pathologySubject(s)
Anticoagulants/administration & dosage , Leg Ulcer/drug therapy , Livedo Reticularis/drug therapy , Warfarin/administration & dosage , Adult , Female , Humans , Leg Ulcer/pathology , Livedo Reticularis/genetics , Livedo Reticularis/physiopathology , Male , Methylenetetrahydrofolate Reductase (NADPH2)/geneticsSubject(s)
Fibrinolytic Agents/therapeutic use , Livedo Reticularis/drug therapy , Livedo Reticularis/genetics , Plasminogen Activator Inhibitor 1/genetics , Promoter Regions, Genetic , Prothrombin/genetics , Tissue Plasminogen Activator/therapeutic use , Adult , DNA Mutational Analysis , Drug Therapy, Combination , Female , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Hyperbaric Oxygenation , Livedo Reticularis/blood , Livedo Reticularis/pathology , Mutation , Skin/pathology , Treatment OutcomeABSTRACT
The pathogenesis of livedoid vasculopathy (LV) is still unclear. However, with increasing knowledge of disorders of coagulation over the past few years, the cause of some cases of LV has been elucidated. LV has now been described in association with hyperhomocysteinaemia, activated protein C resistance, and prothombin gene mutations in the absence of significant underlying inflammatory disease. When LV is seen in association with systemic lupus erythematosus or polyarteritis nodosa, it is probably due to the pro-coagulable state induced by these diseases rather than being true vasculitis. We review recent insights into LV provided by published clinical cases and discuss its pathogenesis.
Subject(s)
Livedo Reticularis/etiology , Skin/blood supply , Thrombosis/complications , Vasculitis/complications , Blood Coagulation Disorders/complications , Humans , Livedo Reticularis/diagnosis , Livedo Reticularis/genetics , MutationABSTRACT
Livedoid vasculopathy (LV) is an occlusive thrombotic disease of lower extremities. A 34-year-old woman presented with 4-year history of recurrent necrotic and painful lesions with violaceous and purpuric border on both legs. Initial treatment with hydroxychloroquine, dapsone and prednisone were unsuccessful. Skin biopsy showed inflammatory infiltrate with epidermal necrosis. Prothrombin G20210A and factor V-Leiden heterozygosity, and MTHFR C677T homozygosity with hyperhomocysteinemia were confirmed. LV diagnosis was made; acetylsalicylic acid, folic acid, vitamin B12, and prednisone treatement resulted in complete healing. This is the first report on coexistence of prothrombin G20210A, factor V-Leiden, and homozygous MTHFR C677T with hyperhomocysteinemia in LV.