Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

Phenotypic intrafamilial variability including H syndrome and Rosai-Dorfman disease associated with the same c.1088G > A mutation in the SLC29A3 gene.

BACKGROUND: Mutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, have been implicated in syndromic forms of histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai-Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai-Dorfman disease. METHODS: We investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family members' diagnosed with Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis using direct Sanger sequencing. RESULTS: Genetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G > A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with the classical H syndrome phenotype. While their cousin's features were in keeping with Familial Rosai-Dorfman disease diagnosis with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family. CONCLUSION: We report a rare event of 5 Tunisian family members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype-phenotype correlation for the disease.

Paclitaxel extravasation treated with systemic corticosteroids.

Chemotherapy extravasation is a rare but severe cutaneous complication associated with administration of intravenous chemotherapy. Extravasation causes serious disability and diminishes the quality of life in patients with cancer undergoing antineoplastic therapy. Treatment of chemotherapy extravasation is not standardized. We report a patient with paclitaxel extravasation who was successfully treated with corticosteroids.

Deep dermatophytosis and inherited CARD9 deficiency.

BACKGROUND: Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. METHODS: We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. RESULTS: Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. CONCLUSIONS: All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.).

EPIMAG: International Cross-Sectional Epidemiological Psoriasis Study in the Maghreb.

BACKGROUND: Psoriasis is a common skin disorder that is characterized by red plaques covered with silvery scales and is associated with considerable psychosocial impact. It has been described in several studies worldwide, but specific data from the Maghreb (Algeria, Morocco and Tunisia) are unavailable. OBJECTIVES: To characterize the frequency of new psoriasis cases and to describe the epidemiological and clinical profile of psoriasis in the Maghreb. METHODS: A psoriasis working group for the Maghreb initiated the EPIMAG international multicentre cross-sectional observational epidemiological study coupled with a 2-week psoriasis screening study via medical consultation. Data were collected via questionnaires. RESULTS: The total analysis population included 373 pre-existing and 326 new psoriasis cases, described by 261 participating investigators. The frequency of new psoriasis cases was 10.26/1,000 in Algeria, 15.04/1,000 in Morocco and 13.26/1,000 in Tunisia, and thus 12.08/1,000 in the Maghreb. In all 699 psoriasis subjects, the mean age was 46 years, the mean BMI was 26.6, and 55.7% of subjects were men. Two thirds of the subjects had never smoked, and 85.0% had never consumed alcohol. Half had brown skin, and 28.6% had a family history of psoriasis. Three quarters had localized psoriasis, 85.8% had plaque psoriasis, coupled with pruritus in over 70.0% of cases. Flares or outbreaks were most often triggered by stress (79.4%) and change of season (43.1%). The majority of subjects used topical therapy, and the investigators considered overall treatment efficacy to be partial in over half of the cases. Among patients with pre-existing psoriasis, secondary analyses showed that 73.2% had severe psoriasis, and that quality of life was severely affected in 40.1% of cases. The mean number of missing school or work days over 6 months was 3.2 (±12.1) days. CONCLUSIONS: Our study provides novel information relative to psoriasis epidemiology and characterization in the Maghreb and highlights the need to improve psoriasis screening and management in the region. The data will help optimize psoriasis management, to ensure appropriate national health care policies.