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.

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.).

Diagnostic challenge in a series of eleven patients with hyper IgE syndromes.

Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 (STAT3) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.

Pyogenic Granuloma-Like Kaposi Sarcoma: A Diagnostic Challenge.

An 81-year-old woman presented with a 2-month history of a painless nodule on the left foot that bled easily after minor trauma. She had no medical history and did not report any preexisting lesion. Physical examination revealed a 2 cm × 3 cm, exophytic and reddish-colored nodule, with an ulcerated and soft surface (Figure 1). There were no other skin lesions or abnormal physical findings. The diagnosis of a pyogenic granuloma (PG) was suggested. A biopsy specimen was obtained from the center of the lesion and stained with hematoxylin and eosin. Histopathologic examination revealed a marked proliferation of both capillary cells and spindle-shaped cells separated by slit-like vessels containing multiple erythrocytes (Figure 2A). Immunochemical analysis showed positivity for CD34 and human herpes virus (HHV)-8 in both endothelial and spindle cells (Figure 2B). Perls' staining showed abundant hemosiderin deposits in the tumor stroma (Figure 2C). These findings were consistent with the diagnosis of Kaposi sarcoma (KS). Laboratory tests eliminated a human immunodeficiency virus (HIV) infection, and no metastatic lesions were found on radiologic examinations. The lesion was treated with laser excision, with no recurrence at the 2-year follow-up.

Alopecia areata in Tunisia: epidemio-clinical aspects and comorbid conditions. A prospective study of 204 cases.

BACKGROUND: Alopecia areata (AA) is an autoimmune condition that usually presents as patchy, nonscarring hair loss. Autoimmune disorders and atopy are reported as comorbid conditions. We aimed to investigate the demographics, clinical characteristics, and associations of AA in Tunisian patients. METHODS: Demographic data, pattern of alopecia, age of onset, and associations were evaluated in 204 patients from January 2012 to June 2016. RESULTS: Two hundred and four cases of AA were seen. The male to female ratio was 0.68. The mean age at presentation was 23 years old. Positive family history was noticed in 22.1% of patients. Personal history of atopy was associated with AA in 18.1%. Associated autoimmune diseases were thyroid disorders (12.7%), vitiligo (1.5%), psoriasis (three cases), type 1 diabetes (two cases), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome (two cases), lichen sclerosus atrophicus (one case), and pemphigus vulgaris (one case). Patchy AA was the most common manifestation (49.5%) followed by alopecia universalis (27.5%), alopecia ophiasis (12.7%), and alopecia totalis (10.3%). Nail changes consisting of pitting, trachyonychia, and longitudinal ridging were reported in 24.8%. AA patterns were more severe in females (P = 0.049). Severe forms showed more persistent disease duration (P = 0.005), earlier onset (P = 0.001), and more recurring episodes (P = 0.002) and were significantly associated with nail involvement (P < 0.001). CONCLUSIONS: Our study aimed to review epidemio-clinical characteristics and comorbid conditions of AA in Tunisian patients. More severe cases with a pejorative value of early-onset AA, long disease duration, and nail involvement were seen in our study.

Post traumatic amelanotic subungual melanoma.

Subungual melanomas are rare; a delay in the diagnosis is common and is associated with advanced stage. Part of the reason for a delay in presentation to the physician is that patients often attribute the lesion to trauma. Trauma may play a role in the pathogenesis or just draw attention to a skin tumor that may be more susceptible to injury. We report a case of subungual melanoma that was observed in an 86 year old man. The preceding trauma history and misleading clinical appearance delayed the diagnosis slightly. Biopsy of every nodular acral tumor is very important. A direct role of the trauma in the pathogenesis of melanoma remains unclear.

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis.

Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and whole-exome sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease.

Undifferentiated sebaceous carcinoma: an unusual childhood cancer.

Sebaceous carcinoma is an aggressive, adnexal, rare malignant tumor that may arise in ocular or extra-ocular sites. Extraorbital sebaceous carcinoma is exceptional in childhood. We report a 12-year-old boy with an ocular sebaceous carcinoma who was first seen with an asymptomatic firm, cutaneous nodule on the right eyebrow. The tumor developed slowly within 1 year. Histologically, it was an undifferentiated sebaceous carcinoma. The patient had surgery with wide surgical margins. He was alive and free from disease at a follow-up of 34 months. Close follow-up of this tumor is recommended because of the risk of aggressive behavior.

Netherton's syndrome: the importance of eyebrow hair.

Netherton's syndrome (NS) is a rare autosomal recessive disease associated with variable expressions: congenital ichthyosiform erythroderma, ichthyosis linearis circumflexa, specific hair shaft defects (trichorrhexis invaginata) and atopic diathesis. We report the case of 14-year-old non-identical twins whose diagnosis of NS was established on light microscopy of eyebrow hairs. The sisters consulted for a severe episode of atopic dermatitis. Skin examination revealed an ichthyosiform eruption with generalized, polycyclic erythematous plaques with fine double-edged scaling. The flexural creases were lichenified and multiple eczematoid patches were noted. Blood investigation revealed eosinophilia and high IgE level. Microscopy of scalp hair of the twins was repeatedly normal, but the one of the eyebrows revealed typical trichorrhexis invaginata. The presence of trichorrhexis invaginata is necessary to make the diagnosis of NS, but its identification can be difficult because this defect is variable in time and localization. The examination of eyebrow hairs is especially beneficial for patients first seen in late childhood and adults.

[Lyell's syndrome: a report of 16 cases]. / Le syndrome de Lyell: a propos de 16 observations.

BACKGROUND: Lyell's syndrome (SL) or toxic epidermal necrolysis is a rare mucocutaneous eruption, which is characterised by an acute necrosis of the totality of the epidermis +/- the mucosal epithelium. This is a serious affection considering the severity of systemic manifestations, the unpredictable evolution, and the absence of specific therapy. AIM: To assess epidemiological and clinical features of this condition in our departments. METHODS: This was a retrospective study concerning the cases of Lyell's syndrome carried in the dermatology and the intensive care department of Farhat Hached hospital over a 26 year period. RESULTS: We listed 12 women and 4 with a mean age of 48.9 years. Epidermal detachment varied between 26 and 80% of the body surface and mucus were involved in 87.5% of cases. Systemic manifestations were noted in 11 patients. A drug etiology was found in 87,5% of cases, half of which was due to antibiotics. CONCLUSION: Our results are similar to those in the literature. Our study illustrates the severity of this toxiderma with a high mortality rate (43.75% of cases), conformable with what was predicted by the severity-of-illness score "SCORTEN". Infectious complications were the principal cause of death.

[A particular type of cicatricial Pemphigoid with unique IgA deposit]. / Forme particulière de Pemphigoide cicatricielle à dépôt unique d'IgA.

Cicatricial Pemphigoid is a subepithelial bullous dermatosis which essentially involves the mucous membranes with cicatricial evolution We report the case of a 66-year old patient hospitalized with erosive gingivitis associated with dysphagia, dyspnea and blurred vision. Dermatologic examination showed erosive lesions involving the palate and the pharynx. Ophthalmologic examination showed symblepharons, ectropion and bilateral cataract. Gingival biopsy revealed a necrotic detachment of the buccal epithelium. Direct immunofluorescence showed linear IgA deposit at the dermo-epidermal junction. Indirect immunofluorescence test was negative. The diagnosis of cicatricial pemphigoid was confirmed. Esophagogastroduodenoscopy objectified double stenosis of the esophagus. Nasopharyngeal and bronchial endoscopy showed ulceration of the epiglottis, hypopharynx, pharynx and bronchial tree. The patient was treated with Solumedrol bolus corresponding to 0.5mg/kg/day prednisone associated with 100mg/day disulone. The patient showed a favorable early clinical outcome complicated because of the aggravation of dysphagia and esophageal stenosis after 2 months. Our case study is singular due to the occurrence of a cicatricial pemphigoid in a male patient with a serious clinical picture due to lesions extending to conjunctival, oral, nasal, esophageal and bronchial mucous membranes associated with direct immunofluorescence only showing IgA deposit.

Hemophagocytic lymphohistiocytosis: an unusual complication of leprosy.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition of chaotic uncontrolled immune system stimulation and not fully understood pathophysiology. Most reported cases of hemophagocytic syndrome in patients with mycobacterial infections have been associated with Mycobacterium tuberculosis. As far as we could ascertain, to date, no established HLH case complicating leprosy has been published in the medical literature. CASE REPORT: We describe here a new case of Hansen's disease in a 58-year-old Tunisian man with an unusual complicated clinical course documented as hemophagocytic syndrome. Cutaneous and neurological involvements were the main clinical signs of Hansen's disease. Histological findings suggested the diagnosis of leprosy and were somewhat more characteristic of the lepromatous leprosy type. While on antileprosy treatment, he developed unexplained persistent fever, organomegaly, bicytopenia, and elevated rate of inflammatory markers with bone marrow aspirate showing large macrophages with increased phagocytosis of mature and immature blood elements, typical features of hemophagocytic syndrome. CONCLUSION: A high index of suspicion is essential for prompt diagnosis of hemophagocytic syndrome in the setting of disseminated infection such as leprosy.