A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia

IMPORTANCE: Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis. OBSERVATIONS: Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging. CONCLUSIONS AND RELEVANCE: This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome. Copyright 2014 American Medical Association. All rights reserved

Pityriasis lichenoides et varioliformis acuta with numerous CD30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases

Pityriasis lichenoides comprises a clinicopathologic spectrum of cutaneous inflammatory disorders, with the 2 most common variants being pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica. The aim of the study was to describe 13 cases of a unique PLEVA variant characterized in the conspicuous CD30 component and thus mimicking lymphomatoid papulosis (LyP), a condition currently classified in the spectrum of CD30 lymphoproliferative disorders. The cohort included 10 female and 3 male patients whose ages at diagnosis ranged from 7 to 89 years (mean 41 y; median 39 y). The clinical manifestation was that of PLEVA, with small erythematous macules quickly evolving into necrotic papules. No waxing and waning was seen on follow-up in any of the cases. Histopathologically, typical features of PLEVA were present, but an unusual finding was occurrence of a considerable number of CD30 small lymphocytes as detected immunohistochemically. Over half of the cases also displayed a large number of CD8 cells and showed coexpression of CD8 and CD30 in the intraepidermal and dermal component of the infiltrate. Of the 11 cases of PLEVA studied for T-cell receptor gene rearrangement, 6 evidenced a monoclonal T-cell population, and 5 were polyclonal. Parvovirus B19 (PVB19) DNA was identified in 4 of 10 cases investigated, and positive serology was observed for PVB19 in 2 patients, altogether suggesting that PVB19 is pathogenetically linked to PLEVA at least in a subset of cases. The presence of CD30 lymphocytes and CD8 lymphocytes would be consistent with an inflammatory antiviral response, as CD30, even atypically appearing lymphoid cells have been identified in some viral skin diseases. The main significance of the PLEVA variant is, however, its potential confusion with LyP or some cytotoxic lymphomas. Admittedly, the CD30 PLEVA variant described herein and LyP show considerable overlap if one takes into account all known variations of the 2 conditions recognized in recent years, thus suggesting that LyP and PLEVA may be much more biologically closely related entities than currently thought or can even occur on a clinicopathologic spectrum

Congenital and Disseminated Pyogenic Granuloma-like Vascular Lesions

International audienceWe report an exceptional case of multiple cutaneous and visceral neonatal pyogenic granuloma (PG) initially suggestive of a diffuse neonatal haemangiomatosis. CASE REPORT A full-term female newborn, with no significant past medical history, was referred to our department for treatment of an acute respiratory distress syndrome of neurological origin at day 8 of life. At birth, she presented with 3 small angiomatous papules and 4 subcutaneous nodules suggestive of neonatal hae-mangiomatosis (NH) (Fig. 1). A brain MRI revealed a highly vascularised brain stem tumour suggestive of glioma (Fig. 2), associated with 2 abnormal hepatic lesions consistent with infantile haemangiomas (IH) on ultrasound and CT scan. Methylprednisolone was started for the suspected glioma-associated oedema, and vincristine and propranolol were introduced for NH. After initial improvement, an acute intracranial hypertension related to cystic evolution of the disease necessitated surgical resection at the age of 2 months. Pathological examinations of the brain, cutaneous and subcutaneous lesions were similar, showing a vascular lobular proliferation of capillaries highly suggestive of PG. The misdiagnosis of glioma was eliminated. The GLUT-1 antigen marker was negative, ruling out the diagnosis of NH-like infantile haemangioma (Fig. 3). Lymphatic marker (D2-40) was also negative and eliminated a multifocal lymphangioendotheliomato-sis with thrombocytopaenia (MLT). Cutaneous and hepatic lesions gradually regressed. She is currently in complete remission after completing a treatment over 18 months with propranolol but a spontaneous improvement can not be excluded. DISCUSSIO

Corneodesmosomal Cadherins Are Preferential Targets of Stratum Corneum Trypsin- and Chymotrypsin-like Hyperactivity in Netherton Syndrome

SPINK5 (serine protease inhibitor Kazal-type 5), encoding the protease inhibitor LEKTI (lympho-epithelial Kazal-type related inhibitor), is the defective gene in Netherton syndrome (NS), a severe inherited keratinizing disorder. We have recently demonstrated epidermal protease hyperactivity in Spink5−/− mice resulting in desmosomal protein degradation. Herein, we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS. We demonstrated that, in a majority of patients, desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) were dramatically reduced in the upper most living layers of the epidermis. These defects were associated with premature degradation of corneodesmosomes. Stratum corneum tryptic enzyme (SCTE)-like and stratum corneum chymotryptic enzyme (SCCE)-like activities were increased, suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins. SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced. In contrast, a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations. This suggests a degree of correlation between cadherin degradation and clinical severity. This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression

Molecular characterization of subcutaneous panniculitis-like T-cell lymphoma reveals upregulation of immunosuppression- and autoimmunity-associated genes

Peer reviewe

Phenotypic and genotypic characteristics of mastocytosis according to the age of onset.

International audienceAdult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

New Insights in Paediatric Dermatopathology

Paediatric dermatology is an expanding subspeciality [...

Update on Superficial Spindle Cell Mesenchymal Tumors in Children

The diagnosis of cutaneous and subcutaneous spindle cell neoplasms in children is often challenging and has potential therapeutic and prognostic implications. Although correctly diagnosing dermatofibrosarcoma protuberans and infantile fibrosarcoma is paramount, pathologists should not ignore a number of diagnostic pitfalls linked to mostly rare tumors with completely different clinical outcomes. In the last decade, a spectrum of novel entities has been described; information from molecular biology has helped to shape this new landscape for spindle cell tumors. Here, we review the most noteworthy neoplasms in this spectrum, with a focus on their histological similarities: fibroblastic connective tissue nevus, medallion-like dermal dendrocyte hamartoma, or plaque-like CD34-positive dermal fibroma, which share features with fibrous hamartoma of infancy; lipofibromatosis and lipofibromatosis-like neural tumor; and plexiform myofibroblastoma, a recently described neoplasm that should be distinguished from plexiform fibrohistiocytic tumor. These tumors also have genetic similarities, particularly gene rearrangements involving NTRK3 or NTRK1. These genetic features are not only essential for the differential diagnosis of infantile fibrosarcoma but are also of diagnostic value for lipofibromatosis-like neural tumors. The more recently described RET, RAF1, and BRAF gene fusions are also discussed