Stéphane Barete

Pediatric Mastocytosis Is a Clonal Disease Associated with D816V and Other Activating c-KIT Mutations

Adult mastocytosis is an incurable clonal disease associated with c-KIT mutations, mostly in exon 17 (D816V). In contrast, pediatric mastocytosis often spontaneously regresses and is considered a reactive disease. Previous studies on childhood mastocytosis assessed only a few patients and focused primarily on codon 816 mutations, with various results. In this study, we analyzed the entire c-KIT sequence from cutaneous biopsies of 50 children with mastocytosis (ages 0-16 years). A mutation of codon 816 (exon 17) was found in 42% of cases, and mutations outside exon 17 were observed in 44%. Unexpectedly, half of the mutations were located in the fifth Ig loop of c-KITs extracellular domain, which is encoded by exons 8 and 9. All mutations identified in this study were somatic and caused a constitutive activation of c-KIT. There was no clear phenotype-genotype correlation, no clear relationship between the mutations and familial versus spontaneous disease, and no significant change in the relative expression of the c-KIT GNNK+ and GNNK isoforms. These findings strongly support the idea that, although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with activating mutations in c-KIT.

Blood CD34−c-Kit+ cell rate correlates with aggressive forms of systemic mastocytosis and behaves like a mast cell precursor

Mastocytosis is a heterogeneous disease characterized by the accumulation of mast cells in one or more organs. Our objective was to identify a peripheral mast cell precursor and assess its variation rate in mastocytosis. A peripheral blood phenotypic analysis was performed among 50 patients with mastocytosis who were enrolled in a prospective multicentric French study, and the phenotypic analysis results of the patients were compared with those of healthy donors. The rate of peripheral blood CD34(-)c-Kit(+) cells correlated with the severity of mastocytosis. This cellular population was isolated from healthy donors as well as from patients with systemic mastocytosis. After 30 days of culture, the CD34(-)c-Kit(+) cells gave birth to mature mast cells, indicating that this cellular population constitutes a mast cell circulating precursor. Monitoring peripheral CD34(-)c-Kit(+) cells by flow cytometry could be a useful and low-invasive tool to determine the disease severity and the relapses and to assess treatment efficiency.

Actualités sur la compréhension et le traitement des mastocytoses systémiques

PURPOSE Mast cell disorders are defined by an abnormal accumulation of tissue mast cells in one or more organ systems. Clinical symptoms in mastocytosis result from mast cells derived mediators and, less frequently, from destructive infiltration of mast cells. Systemic mastocytosis is regressive among children, whereas the disease is persistent among adults. A clonal haematological non-mast cell lineage disease can be associated. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. Until recently, the only treatment of this incurable disease was symptomatic. CURRENT KNOWLEDGE AND KEY POINTS Recent advances were done in understanding the physiopathology of this myeloproliferative syndrome which results from an activating mutation of the stem cell factor receptor: C-Kit. A somatic C-Kit mutation is usually detectable in mast cells and their progenitors. Different mutations were found and the mutation D816V is the most frequent. Their specific transduction paths were also studied. Diagnosis of systemic mastocytosis does not only rest upon pathological examination but also on molecular as well as immunological and immunochemical tools. FUTURE PROSPECTS AND PROJECTS Physiopathological advancements led to suggest new treatments in order to directly inhibit proliferative paths of masts cells such as tyrosine kinase inhibitors and rapamycin.

Manifestations dermatologiques du syndrome des antiphospholipides

A wide variety of dermatologic manifestations has been described in the antiphospholipid syndrome (APS). The most frequent skin lesion is livedo reticularis, present not only on the limbs but also on the trunk, with a fine irregular pattern. It belongs to the arterial subset of APS. Circumscribed ulcerations, resembling livedoid vasculitis, may be the first manifestation of APS. Ulcerations may also occur as a late complication of recurrent venous thrombosis. Extensive skin necrosis is a classic manifestation of catastrophic APS. Pseudo-vasculitis lesions are misdiagnosed if a skin biopsy is not performed, especially in the context of systemic lupus erythematosus. In systemic lupus erythematosus, primary anetoderma is always associated with antiphospholipid antibodies.

Traitement des mastocytoses systémiques

Resume Propos. – Les mastocytoses systemiques sont des maladies rares, caracterisees par une proliferation mastocytaire au sein de differents organes. Les manifestations cliniques sont de deux types : celles liees au relargage des mediateurs mastocytaires et celles liees a l’envahissement des differents organes par les mastocytes pathologiques, ces dernieres definissant les formes agressives de la maladie. Jusque recemment, le traitement n’etait que symptomatique et sans effet sur le syndrome tumoral. Actualites et points forts. – Des progres ont ete faits ces dernieres annees dans la comprehension de la maladie avec la mise en evidence d’une mutation du proto-oncogene c-kit et l’assimilation des mastocytoses systemiques a un syndrome myeloproliferatif. Perspectives et projets. – De nouvelles approches therapeutiques fondees sur l’experience acquise dans le traitement de certains syndromes myeloproliferatifs sont en cours de developpement. Dans cette optique, l’association interferon–cytarabine d’une part et la cladribine d’autre part, constituent des voies prometteuses. Enfin, une nouvelle famille de molecules actives sur la proteine c-kit, les inhibiteurs de tyrosine kinase, a recemment demontre avec l’imatinib mesylate une grande efficacite dans le traitement des tumeurs stromales gastro-intestinales (GIST) comportant une mutation de c-kit. Par analogie, il est possible d’esperer une reponse chez les malades porteurs d’une mutation de c-kit sensible a ces inhibiteurs.

Contact dermatitis due to ultrasound gel: A case report and published work review.

Adverse skin reactions with ultrasound gel are rare and related mostly to allergic contact dermatitis or contact urticaria. We report an allergic contact dermatitis with Doppler ultrasound gel applied in a 67‐year‐old man. The patient developed atypical purpuric cutaneous presentation located on vascular axes. Semi‐open test with ultrasound gel and patch test with phenoxyethanol were followed by the same clinical purpuric eruption which strongly suggested the accountability of this later component as allergen. Based on this observation, we present a review of published work with a focus on clinical features and allergens involved in ultrasound gel cutaneous reaction.

Invasive cutaneous Neoscytalidium infections in renal transplant recipients: a series of five cases

BackgroundNeoscytalidium species (formerly Scytalidium species) are black fungi that usually cause cutaneous infections mimicking dermatophytes lesions. Very few publications have reported invasive or disseminated infections.Case presentationIn this paper, we report the clinical presentations, treatments and outcomes of five cases of invasive Neoscytalidium infections with cutaneous involvement, including two cases with disseminated infection, in five renal transplant recipients. To our knowledge, this is the first report of a series—albeit small—of renal transplant patients in whom this infection was identified. All cases occurred in a single hospital in Paris, France, between 2001 and 2011. Patients all originate from tropical area.ConclusionTreatments of Neoscytalidium infection varied greatly, underlining the lack of a recommendation for a standardized treatment. All patients were cured after long-term antifungal therapy and/or surgical excision. Interestingly, one patient with disseminated infection involving the left elbow, the right leg, the lungs and the nasal septum was cured by medical therapy only without surgery. This may suggest that in contrast to others mycoses (such as mucormycosis), an adequate medical treatment could be sufficient for treating Neoscytalidium. We also point out the difficulties we had in diagnosing two patients with Kaposi’s sarcoma because of the similarity of the lesions. Furthermore, our report underlines the need to check for this rare infection in immunocompromised kidney transplant recipients originating from tropical areas.

Expanding the spectrum of livedoid vasculopathy: peculiar neuromuscular manifestations.

Livedoid vasculopathy (LV) is a rare and recurrent chronic disorder mainly restricted to the skin. LV is characterized by recurrent purpura, livedo reticularis of the legs associated with painful ulcerations, resulting in atrophic, porcelain scars [1]. This disease is considered a thrombo-occlusive vasculopathy of superficial dermal micro-vessels due to either idiopathic cause or secondary to a defined state of thrombophilia [2]. Diagnosis is based on the characteristic skin lesions and presence of intraluminal thrombosis, endothelial cell hyperplasia and sub-intimal hyaline degeneration in dermal vessels [3]. LV is not a vasculitis sensu-stricto, as generally no inflammation occurs within the wall of the vessels, but perivascular inflammation may be present secondarily [4]. Neurological involvement in LV is rare and may expand its nosological spectrum. Symptoms comprise mononeuritis multiplex, and the underlying pathophysiology has been postulated to be the result of ischaemia [5,6]. However, vasculitis has been observed, in an association between LV and periarteritis nodosa (PAN) [7]. From a physiopathological point of view, this entity is surprising, as a general state of hypercoagulability leads to damage confined to the skin and much less frequently to the peripheral nervous system, but not to other tissues. Here, we describe LV patients with a peripheral neuropathy attributed to thrombotic vasculopathy without signs of vasculitis. Furthermore, we illustrate the involvement of the skeletal muscle, characterized by an extreme loss of capillaries, associated with peculiar perifascicular pathology. In a retrospective observational study, primary LV patients (n = 18, 10 females and mean age of 50.1 years) diagnosed by international criteria [8] were enrolled. We identified three patients, who had undergone combined nerve–muscle biopsy to explore peripheral neurological symptoms. Patients were 58, 44 and 22 years at time of the first skin manifestation (patient A, B and C, respectively). Neurological signs appeared respectively 10 (patients A), 20 (patient B) and 23 years after (patient C) the first skin manifestation. One patient (patient A) suffered from mononeuritis multiplex. Electroneurography confirmed popliteal sciatic nerve damage and showed injuries of median and ulnar nerves. Patient B suffered from sensory polyneuropathy of lower limbs. Patient C had bilateral dysesthaesia and hypaesthesia of the back of the right foot, and his EMG showed a motor and sensory axonal neuropathy. No proximal weakness was observed in any of the three patients, and all of them had normal CK levels. Other causes of peripheral neuropathy were excluded by extensive laboratory tests, and there was no history of drugs, neurotoxin exposure or association with cancer. All patients showed remarkably similar morphological alterations. A severe loss of myelinated axons, with only few thinly myelinated axons (with minimal signs of axonal regeneration) and endoneurial replacement by fibrous tissue, was the most prominent finding (Figure 1A,B). Furthermore, a relevant formation of collagen pockets on ultra-structural examination illustrated loss of un-myelinated axons (Figure 1C). All fascicles were equally affected. The second observation consisted of enlarged vessels with conspicuous engorgement mainly in the epineurium (Figure 1D). Importantly, in all cases, inflammatory infiltrates basically consisting of CD3 lymphocytes were detected around enlarged vessels in the epineurium (Figure 1D), however without signs of vasculitis. In addition, we found a remarkable vascular pathology mainly involving capillaries of the endoneurium. Alterations consisted of enlarged endothelial cells, which appeared thickened, occasional basal membrane duplication, apposition of endothelial cells layers, as well as necrosis of capillaries (Figure 1A,E,F). Indirect signs of neuropathy were also observed in all muscle biopsies with neurogenic features consisting of nuclear clumps, grouped atrophic fibres and fibre-type grouping (Figure 1G). Additional myopathic changes included split fibres, and round and hypertrophic fibres with internalized nuclei (Figure 1H). Although neurogenic changes are frequently associated with myopathic features especially during a chronic course of disease, we also detected myopathic changes not attributable to neu-

Brief Report: De Novo Human Herpesvirus 8 Tumors Induced by Rituximab in Autoimmune or Inflammatory Systemic Diseases

Human herpesvirus 8 (HHV‐8), also known as Kaposis sarcoma (KS)–associated herpesvirus, is involved in KS and other tumors, including multicentric Castlemans disease and primary effusion lymphoma. Rituximab (RTX) is currently used for the treatment of several autoimmune or inflammatory diseases and humoral organ transplant rejection. De novo HHV‐8 tumors induced by RTX used for these indications have not been reported previously. This study was undertaken to evaluate de novo HHV‐8 tumors induced by RTX.