Liliane Laroche

Treatment of adult systemic mastocytosis with interferon‐α: results of a multicentre phase II trial on 20 patients

Summary. Systemic mastocytosis (SM) is characterized by proliferation of mast cells in various organs, which may release a wide variety of mediators, thereby explaining the broad clinical spectrum of disease manifestations. The potentially life‐threatening systemic symptoms and tumoral proliferation are poorly controlled despite the use of several cytotoxic chemotherapies and/or symptomatic treatments. Twenty consecutive adult SM patients with histologically confirmed bone marrow (BM) involvement received interferon‐α subcutaneously (1–5 million units/m2/d, with progressive dose intensification over the first month of treatment) and were evaluated after 6 months of therapy. Seven of them had previously received symptomatic treatments, including steroids, which were ineffective. Among the 13 patients treated for at least 6 months, seven partial and six minor responses, mainly concerning vascular congestion and skin lesions, were obtained, while BM infiltration remained unchanged in 12 patients. The significant reduction of mast‐cell mediator levels after 6 months of treatment was not predictive of clinical remission. The rate of depression was unexpectedly high (seven patients; 35%). Two patients died soon after starting therapy (one myocardial infarction, one septic shock). Six months of interferon‐α may relieve vascular congestion in adults with SM, probably by inhibiting mast‐cell degranulation.

Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity

We describe two patients from distinct Cowden disease families with specific germline PTEN mutations whose disease differs from the usual appearance of Cowden disease. Their phenotype associates classical manifestations of Cowden disease and congenital dysmorphisms including segmental overgrowth, arteriovenous and lymphatic vascular malformations, lipomatosis and linear epidermal nevus reminiscent of the diagnosis of Proteus syndrome. We provide evidence in one of the two patients of a secondary molecular event: a loss of the PTEN wild-type allele, restricted to the atypical lesions that may explain an overgrowth of the affected tissues and the atypical phenotype. These data provide a new demonstration of the Happle hypothesis to explain some segmental exacerbation of autosomal-dominant disorders. They also show that a bi-allelic inactivation of PTEN can lead to developmental anomalies instead of malignant transformation, thus raising the question of the limitations of the tumor suppressive function in this gene. Finally, we suggest using the term ‘SOLAMEN syndrome’ (Segmental Overgrowth, Lipomatosis, Arteriovenous Malformation and Epidermal Nevus) in these peculiar situations to help the difficult distinction between the phenotype of our patients and Proteus syndrome.

Rituximab for Patients With Refractory Mucous Membrane Pemphigoid

BACKGROUND Mucous membrane pemphigoid (MMP) still represents a potentially life- and sight-threatening disease. In a subset of patients with severe MMP, conventional immunosuppressants are ineffective or contraindicated. OBSERVATIONS Twenty-five patients with severe refractory MMP, including 5 with mucous membrane-dominant epidermolysis bullosa acquisita, received 1 or 2 cycles of rituximab (375 mg/m(2) weekly for 4 weeks). Twenty-one of the patients were receiving concomitant therapy with dapsone and/or sulfasalazine therapy, which was maintained during rituximab cycles. Complete responses in all affected sites (ocular and/or extraocular) were obtained in 17 patients (68%) by a median time of 12 weeks after the first cycle, and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. In all but 1 of the 10 patients with ocular lesions, their eyes became noninflammatory within a mean of 10 weeks. Among the 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids and were hypogammaglobulinemic. Treatment with immunosuppressants was discontinued for all other patients, and no other infection was observed. Ten patients experienced relapse after a mean of 4 (range, 1-16) months after achieving complete responses. CONCLUSIONS Rituximab appears to have rapid and dramatic efficacy in patients with severe, refractory MMP. The occurrence of severe infections in patients receiving concomitant conventional immunosuppressants supports using rituximab without other immunosuppressants. Controlled prospective studies are warranted to define an optimal treatment protocol.

Brain magnetic resonance imaging in patients with Cowden syndrome.

Abstract: Cowden syndrome (CS) is a rare autosomal dominant genodermatosis, characterized by multiple hamartomas, particularly of the skin, associated with high frequencies of breast, thyroid, and genitourinary malignancies. Although Lhermitte-Duclos disease (LDD) or dysplastic gangliocytoma of the cerebellum, a slowly progressive unilateral tumor, is a major criterion of CS, its frequency in patients with CS is unknown. Other cerebral abnormalities, especially meningioma and vascular malformations, have also been described, albeit rarely, in these patients. The aim of the current study was to use cerebral magnetic resonance imaging (MRI) to evaluate LDD frequency and to investigate other brain abnormalities in CS patients recruited by dermatologists. A multicenter study was conducted in 8 hospital dermatology departments between January 2000 and December 2003. Twenty patients with CS were included; specific cerebral MRI abnormalities were found in 35% (7/20) of them. Cerebral MRI revealed LDD in 3 patients, a meningioma in 1, and numerous vascular malformations in 6 patients. Five patients had venous angiomas (3 associated with LDD) and 2 patients had cavernous angiomas (1 associated with LDD and a venous angioma). The discovery of asymptomatic LDD in 3 patients and a cavernous angioma in another prompted us to perform neurologic examinations regularly and MRI to estimate the size and the extension of the tumor, and to assess the need for surgery. CS similarities with Bannayan-Riley-Ruvalcaba (BRR) are discussed because some patients could also have the BRR phenotype (for example, genital lentigines, macrocephaly, multiple lipomas) and because BRR seems to have more central nervous system vascular anomalies. Because CS signs can involve numerous systems, all physicians who might encounter this disease should be aware of its neurologic manifestations. Our findings confirm the contribution of brain MRI to detecting asymptomatic LDD, vascular malformations, and meningiomas in patients with CS. Abbreviations: BRR = Bannayan-Riley-Ruvalcaba, CNS = central nervous system, CS = Cowden syndrome, CT = computed tomography, LDD = Lhermitte-Duclos disease, MRI = magnetic resonance imaging, PTEN = phosphatase and tensin homolog deleted on chromosome 10.

Black Patients of African Descent and HLA-DRB1*15:03 Frequency Overrepresented in Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune bullous disease (AIBD). However, higher EBA incidence and predisposing genetic factor(s) involving an HLA haplotype have been suspected in some populations. This retrospective study assessed the overrepresentation of black patients with EBA, its link with HLA-DRB1*15:03, and their clinical and immunological characteristics. Between 2005 and 2009, 7/13 (54%) EBA and 6/183 (3%) other-AIBD patients seen consecutively in our department were black (P=10(-6)); moreover 7/13 (54%) black patients and 6/183 (3%) white patients had EBA (P=10(-6)). In addition, between 1983 and 2005, 12 black patients had EBA. Finally, among the 19 black EBA patients, most of them had very atypical clinical presentations, 9 were natives of sub-Saharan Africa, 1 from Reunion Island, 7 from the West Indies, and 2 were of mixed ancestry. HLA-DRB1*15:03 allelic frequencies were 50% for African patients, significantly higher than the control population (P<10(-3)), and 21% for the West Indians (nonsignificant). High EBA frequencies have already been reported in American blacks significantly associated with the HLA-DR2. In conclusion, black-skinned patients developing EBA seem to have a genetic predisposition, and EBA should be suspected systematically for every AIBD seen in this population.

Histologic and Immunohistologic Characterization of Skin Localization of Myeloid Disorders

A retrospective analysis of 173 skin biopsy specimens of myeloid leukemia cutis (MLC) was performed to determine histologic and immunophenotypic criteria that could distinguish the varied myeloid disorders from one another. For the study, 11 relevant histologic items were scored and 12 antigens were studied (CD68 [KP1], CD163, CD14, CD4, myeloperoxidase [MPO], CD33, CD117, CD34, CD56, MIB-1, CD303, and CD123). Underlying myeloid disorders were essentially acute myeloid leukemias (65.3%), chronic myelomonocytic leukemias (11.0%), and refractory anemia (10.4%). Skin lesions were de novo in 7.5%, concurrent in 26.6%, and subsequent in 60.7%. Several morphologic characteristics (density, size of tumor cells, inflammatory background) were statistically useful in distinguishing between varied myeloid disorders. De novo MLCs displayed a specific morphologic profile. Association of CD68, CD33, and MPO could diagnose 100% of the cases of MLC. However, the immunohistochemical panel could not distinguish between the varied underlying myeloid disorders, with the exception that CD123 was particularly powerful in recognizing chronic myelomonocytic leukemia and also permitted reclassification of 4 cases as blastic plasmacytoid dendritic cell neoplasm.

A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid.

Abstract: We conducted a prospective study between 1995 and 2002 to investigate nose and throat (NT) manifestations of mucous membrane pemphigoid (MMP). One hundred ten consecutive patients with clinical, histologic, and immunologic criteria of MMP were seen in 2 referral centers for bullous diseases. They were systematically asked about the existence of persistent NT symptoms. Patients who had any were examined with a flexible nasopharyngolaryngoscope by the same otorhinolaryngologist. When possible, NT mucous membrane (MM) biopsies were taken for direct immunofluorescence (IF) assays to determine lesion specificity. Thirty-eight (35%) patients (23 F/15 M; mean age, 58.5 yr) had the following NT symptoms: 35 (92%) nasal, 19 (50%) pharyngeal, and 10 (26%) laryngeal. Five (13%) had acute dyspnea. Thirty-three (87%) of the 38 symptomatic patients had lesions at physical examination: 30 (79%) nasal, 6 (16%) pharyngeal, and 19 (50%) laryngeal. Laryngeal involvement was asymptomatic in 11 patients. Lesions were mainly atrophic rhinitis and oropharyngeal and epiglottal erosions. Nasal valves, choanae, pharynx, and/or larynx were severely scarred in 7 (18%) patients, causing the death of 3. Direct IF showed malpighian epithelium associated with linear immune deposits (IgG, IgA, or C3) along the chorioepithelial junction in all 18 biopsies performed, including those of 4 symptomatic patients without lesions at physical examination. The presence of severe ophthalmologic lesions (p = 0.02) and ≥3 sites involved other than NT (p = 0.02) were predictive of laryngeal involvement. In contrast, laryngeal symptoms, disease duration, HLA DQB1*0301, and smoking were not significantly associated with laryngeal lesions. In conclusion, at least 35% of MMP patients had NT involvement. Atrophic rhinitis was the most frequent lesion. The most severe were the laryngeal lesions that were significantly associated with severe ocular involvement and disseminated disease, and could be fatal. Our results highlight the necessity of a multidisciplinary approach to MMP management to assure early diagnosis of NT involvement, to guide therapeutic choices, and to improve patient survival and functional outcomes. Abbreviations: BMZ = basement membrane zone, BP = bullous pemphigoid, EBA = epidermolysis bullosa acquisita, HLA = human leukocyte antigen, IEM = immunoelectron microscopy, IF = immunofluorescence, MM = mucous membrane, MMP = mucous membrane pemphigoid, NT = nose and throat, SSS = salt-split skin.

Specific skin lesions in chronic myelomonocytic leukemia: a spectrum of myelomonocytic and dendritic cell proliferations: a study of 42 cases.

Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic disorder that can also involve the skin. The histopathology of these skin lesions is not clearly defined, and few data are available in the literature. To better understand tumoral skin involvements in CMML we carried out an extensive, retrospective clinicopathologic study of 42 cases selected from the database of the French Study Group of Cutaneous Lymphomas. On the basis of clinical data, morphology, and phenotype we identified 4 clinicopathologic profiles representing 4 distinct groups. The first group comprised myelomonocytic cell tumors (n=18), exhibiting a proliferation of granulocytic or monocytic blast cells, which were CD68 and/or MPO positive but negative for dendritic cell markers. The second group comprised mature plasmacytoid dendritic cell tumors (n=16), denoted by a proliferation of mature plasmacytoid dendritic cells, which were CD123, TCL1, and CD303 positive but CD56, CD1a, and S100 negative. The third group comprised blastic plasmacytoid dendritic cell tumors (n=4), characterized by a proliferation of monomorphous medium-sized blast cells, which were CD4, CD56, CD123, TCL1 positive but CD1a and S100 negative. The fourth group consisted of a putatively novel category of tumor that we named blastic indeterminate dendritic cell tumors (n=4), distinguished by a proliferation of large blast cells that not only exhibited monocytic markers but also the dendritic markers CD1a and S100. These 4 groups showed distinctive outcomes. Finally, we showed, by fluorescence in situ hybridization analysis, a clonal link between bone marrow disease and skin lesions in 4 patients. Herein, we have described a novel scheme for pathologists and physicians to handle specific lesions in CMML, which correspond to a spectrum of myelomonocytic and dendritic cell proliferations with different outcomes. A minimal panel of immunohistochemical markers including CD68, CD1a, S100, Langerin, and CD123 is necessary to make the correct classification in this spectrum of cutaneous CMML tumors, in which dendritic cell lineage plays an important role.

Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid

Background  Mucous membrane pemphigoid (MMP) still represents a potentially life‐ and sight‐threatening disease. Immunosuppressants, such as cyclophosphamide (CYC), are indicated for patients with severe and/or refractory MMP.

CGI-58/ABHD5 gene is mutated in Dorfman–Chanarin syndrome

I read with interest the report by El-Kabbany et al. [2003] on an Egyptian child with typical Dorfman–Chanarin syndrome (DCS). In fact, the causative gene in this disorder is already known. The authors claim that this autosomal recessive disease may have an Arabic origin since the majority of cases are from Middle Eastern countries. Nevertheless patients from French [Kaassis et al., 1998], Spanish [Banuls et al., 1994; Pena-Penabad et al., 2001], Indian [Rajeevan et al., 1999; Tullu et al., 2000], Asian [Chanarin et al., 1975], and American [Igal et al., 1997] origin have been reported, favoring a worldwide distribution. The higher frequency of this syndrome observed in Arabic countries may be related to the great degree of consanguinity encountered in these areas but not by a founder effect as we observed in our genetic studies [Lefèvre et al., 2001]. Secondly, the comments on the pathophysiology of DCS are incomplete. Metabolic studies on cultured cells from DCS patients have shown that the lipid storage was identified as triacylglycerols accumulated as cytoplasmic droplets. No abnormality in uptake, transport or b-oxydation of fatty acids has been found. In the same way, the biosynthetic rate of triacylglycerols was normal in DCS cells. In contrast, pulsechase experiments have demonstrated a block in the degradation pathway [Hilaire et al., 1995] and an abnormal recycling of triglyceride-derived monoor diacylglycerol to specific phospholipids [Igal et al., 1997]. The activities of various enzymes involved in the metabolism of lipids (lipases, cholesteryl esterases, and carboxylesterases) were always found to be in the normal range [Hilaire et al., 1995; Igal and Coleman, 1998]. Because this classical biochemical approach was unsuccessful in explaining the mechanisms of DCS, we recently used a reverse genetic approach [Lefèvre et al., 2001]. We collected 9 families originating from 5 different countries (France, Morocco, Turkey, Tunisia, Algeria) with DCS including 13 affected patients and 35 nonaffected individuals. Linkage with a locus on 3p21 (CNG012, LOD score of 11 at y1⁄4 0) was found and linkage-disequilibrium analysis reduced the locus to a 1.3 Mb region. Two candidate genes involved in the fatty acid metabolism were excluded, but eight distinct mutations (1 insertion, 1 deletion, 2 splice-site, 4 point mutations) in a new gene, CGI-58, were found in the 13 patients. CGI-58 has seven exons, and its mRNA is expressed in skin, lymphocytes, liver, and skeletal muscle. It encodes a 349-amino-acid protein of 39 kDa predicted molecular weight. Analysis of its sequence did not reveal a signal peptide, predicted a cytoplasmic localization, and strong homology with the a/b hydrolase family and the esterase/lipase/thioesterase subfamily. Finally, our identification of CGI-58, recently renamed ABHD5 and mutated in DCS, will permit development of a molecular approach for detection of heterozygotes, prenatal diagnosis, and genetic counseling. It will allow phenotype– genotype correlations and will detect possible heterogeneity in this syndrome.