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1.
J Invest Dermatol ; 139(9): 2004-2015.e13, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31059696

RESUMO

The management of large congenital melanocytic nevi (lCMN) is based exclusively on iterative surgical procedures in the absence of validated medical therapy. The aim of our study was to develop an intra-lesional medical treatment for lCMN. Seventeen patients harboring NRAS-mutated lCMN were included. Nevocytes obtained from lCMN displayed an overactivation of mitogen-activated protein kinase and phosphoinositide 3-kinase (Akt) pathways. Mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Akt inhibitors reduced the nevosphere diameter in sphere-forming assays, as well as cell viability and proliferation in in vitro assays. Standardized lCMN explants were then cultured ex vivo with the same inhibitors, which induced a decrease in MelanA+ and Sox10+ cells in both epidermis and dermis. Finally, intradermal injections of these inhibitors were administered within standardized lCMN xenografts in Rag2-/- mice. They induced a dramatic decrease in nevocytes in treated xenografts, which persisted 30 days after the end of treatment. Using original nevus explant and xenograft preclinical models, we demonstrated that intradermal MEK/Akt inhibition might serve as neoadjuvant therapy for the treatment of NRAS-mutated congenital melanocytic nevi to avoid iterative surgeries.

2.
Pigment Cell Melanoma Res ; 32(5): 708-713, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30945443

RESUMO

A girl, born with a posterior  lumbosacral giant congenital nevus, developed a central nodule that expanded over a period of 14 months into a 10-cm pedunculated mass. Histological analysis of the mass revealed melanoma of myxoid, small round-cell type with areas of  rhabdomyosarcomatous  transformation confirmed by immunohistochemistry. RNA sequencing identified an in-frame SASS6(e14)-RAF1(e8) fusion in both components and the nevus. A RAF1 FISH break-apart test found a balanced rearrangement pattern in the nevus and an unbalanced pattern in the malignant areas. Wild-type status of NRAS and BRAF was confirmed by NGS techniques. The array-CGH profile displayed copy number alterations commonly found in rhabdomyosarcomas. Despite intensive treatment, widespread metastatic evolution of the melanomatous component was observed.

3.
JAMA Dermatol ; 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31017643

RESUMO

Importance: Myofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease. Objective: To determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis. Design, Setting, and Participants: In this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib. Main Outcomes and Measures: Frequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally. Results: Of the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations. Conclusions and Relevance: Gain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.

4.
Nat Genet ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429576

RESUMO

In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.

5.
Nat Genet ; 50(12): 1650-1657, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374066

RESUMO

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

6.
Am J Dermatopathol ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30252693

RESUMO

Langerhans cell (LC) histiocytoma is a neonatal tumor that often consists of a single, ulcerated nodule. Systemic involvement is rare, and LC histiocytoma is considered to be a variant of congenital, self-healing LC histiocytosis (also referred to as Hashimoto-Pritzker disease). In view of its low prevalence, LC histiocytoma is not always diagnosed in a clinical examination and requires histological confirmation. Furthermore, the histological and molecular features of LC histiocytoma have not been well characterized. Here, we report on 6 cases of this rare disease and review the corresponding literature. LC histiocytoma differs from classical self-healing LC histiocytosis with regard to the pathological features; we found that LC histiocytoma was associated with massive infiltration by histiocytes of various sizes and shapes (although often large) throughout the dermis and the superficial subcutis. Epidermotropism was rare, mitotic figures were not inconspicuous, and necrotic or calcified areas were often present. Immunohistochemical assessment revealed a mixture of different types of histiocytes (with CD1a CD207, CD1a CD207, and CD1a CD207 CD163 cells). Genetic testing was performed in 5 cases; it revealed a BRAF mutation (p.V600E and p.485_490delinsF) in 2 cases, a HRAS mutation (p.T58I) in 1 case, a combination of 2 PTEN mutations in another case (p.I224M and p. R234W), and no mutations in the fifth case. All the lesions regressed spontaneously, and none recurred during follow-up.

7.
Virchows Arch ; 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30187166

RESUMO

Cutaneous spindle-cell neoplasms in adults as well as children represent a frequent dilemma for pathologists. Along this neoplasm spectrum, the differential diagnosis with CD34-positive proliferations can be challenging, particularly concerning neoplasms of fibrohistiocytic and fibroblastic lineages. In children, cutaneous and superficial soft-tissue neoplasms with CD34-positive spindle cells are associated with benign to intermediate malignancy potential and include lipofibromatosis, plaque-like CD34-positive dermal fibroma, fibroblastic connective tissue nevus, and congenital dermatofibrosarcoma protuberans. Molecular biology has been valuable in showing dermatofibrosarcoma protuberans and infantile fibrosarcoma that are characterized by COL1A1-PDGFB and ETV6-NTRK3 rearrangements respectively. We report a case of congenital CD34-positive dermohypodermal spindle-cell neoplasm occurring in a female infant and harboring a novel KHDRBS1-NTRK3 fusion. This tumor could belong to a new subgroup of pediatric cutaneous spindle-cell neoplasms, be an atypical presentation of a plaque-like CD34-positive dermal fibroma, of a fibroblastic connective tissue nevus, or represent a dermatofibrosarcoma protuberans with an alternative gene rearrangement.

8.
Pediatr Dermatol ; 35(6): e378-e381, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30216519

RESUMO

Verrucous hemangioma or verrucous venous malformation is a superficial venous malformation frequently misdiagnosed as a lymphatic malformation because of its classical hyperkeratotic appearance. Clinical characteristics of VVM were studied in patients with a histologically confirmed VVM, and validated in a prospective study of 18 patients. VVM was made of separated vascular elements with irregular shape, in a linear disposition, with variable thickness and keratosis. Its specific vascular pattern consisting of an erythematous patch with scattered small red to violet dots was easily identified using dermoscopy. In many cases, the typical clinical presentation of verrucous hemangioma is sufficient to establish the diagnosis and a biopsy may not be required.


Assuntos
Hemangioma/patologia , Dermatopatias Vasculares/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Dermoscopia/métodos , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Lactente , Anormalidades Linfáticas/patologia , Masculino , Pele/patologia , Adulto Jovem
11.
12.
Pediatr Dermatol ; 35(5): 644-650, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30024070

RESUMO

BACKGROUND: Fibroblastic connective tissue nevi (FCTN) are benign skin conditions characterized by bland spindle cells infiltrating the reticular dermis and the upper subcutis with preservation of adnexal structures. A subset of FCTN expresses CD34, which may cause difficulties in the differential diagnosis, in particular with dermatofibrosarcoma (DFSP). We aim to study clinical and histological main features of congenital FCTN to better understand their heterogeneity. METHODS: We present 3 cases of congenital FCTN with misleading pseudo-tumoral presentations and compare them with published cases in literature. We provide a diagnostic algorithm for congenital neonatal connective tissue tumors. RESULTS: Clinically, FCTN mostly present as well-limited and nontender plaques or nodules mainly located in the neck and face areas or in the trunk. Histologically, FCTN are composed of irregularly distributed fascicles of bland spindled cells and are defined by a list of fundamental features: (i) no atypia, pleomorphism, or mitotic activity; (ii) skin appendages entrapped but unaffected; (iii) no evidence for malignancy. In most cases CD34 is positive, but in some cases, cells can express SMA or are even CD34- and SMA-. CONCLUSION: The initial presentation and natural history of FCTN fit better with a neoplasm than with a hamartoma. Thus, we suggest replacing the term "nevus" with tumor and considering fibroblastic connective tissue tumor (FCTT) as the right denomination of this clinico-pathological entity. FCTTs are difficult to diagnose due to their clinical heterogeneity. Clinical and histological malignant and benign differential diagnoses are discussed.


Assuntos
Nevo/patologia , Neoplasias Cutâneas/patologia , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Nevo/cirurgia , Pele/patologia , Neoplasias Cutâneas/cirurgia
13.
15.
Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

16.
Pediatrics ; 141(Suppl 5): S496-S500, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29610179

RESUMO

We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-κb2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies. Febrile nodules relapsed in 2 patients, and recurrent attacks of unexplained fever (without relapse of panniculitis) occurred in the third. Skin biopsy revealed predominantly lympho-histiocytic or septal neutrophilic panniculitis in 1 and 3 patients, respectively. Panniculitis was associated with dermal involvement in the 4 patients. Patients with B-cell deficiency received monthly intravenous immunoglobulin replacement. Two patients who underwent bone marrow transplant died of bone marrow transplant-related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In these cases, the need for careful immunologic evaluation of patients who present with unexplained panniculitis, especially early-onset panniculitis before the age of 2 years, is highlighted.

18.
Am J Dermatopathol ; 40(1): e9-e11, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28816737

RESUMO

Necrotizing infundibular crystalline folliculitis (NICF) is a rare disorder, which was described for the first time by Lucke et al in 1999. NICF is characterized by multiple folliculocentric papules with a predilection for occurring in seborrheic areas in adults and corresponding dilated follicular ostia containing crystalline material. The precise pathogenesis and nature of this crystalline material are currently unknown. Here, we report an unusual case of NICF presented as an uncommon generalized skin rash in an adolescent. In addition, we present analysis using infrared microscopy for improved characterization of this crystalline material. Similar to previous cases, a biopsy revealed a dilated follicular ostium with the appearance of containing crystalline material associated with parakeratosis. Infrared microscopy analysis produced specific spectral features of calcium palmitate.


Assuntos
Foliculite/patologia , Ácido Palmítico , Adolescente , Humanos , Masculino
19.
Transpl Infect Dis ; 20(1)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29094463

RESUMO

OBJECTIVE: Severe dermatophytosis is described in immunocompromised patients with defective cellular immunity. We report here a large series and a literature review of severe dermatophytosis in solid-organ transplant (SOT) recipients. METHOD: The data main source was a national French retrospective study of severe dermatophytosis in SOT recipients between 2010 and 2016. Inclusion criteria were the presence of dermatophytes in skin culture and 1 severity criteria: dermal invasion by dermatophytes (invasive dermatophytosis) or involvement of at least two body sites or >10% of body surface area (extensive dermatophytosis). RESULTS: A total of 12 patients were included (8 men, median age of 56 years [range: 33-71]). Of the 12 patients, 10 underwent kidney transplantation. The median time from transplantation to severe dermatophytosis diagnosis was 16 months [range: 2-94]. Clinical signs of superficial dermatophytosis were present in 8/12 patients before the emergence of severe dermatophytosis. Nine patients had invasive forms and three extensive ones, and nodules of the lower extremities were found in eight. Trichophyton rubrum was isolated in 11 cases. First-line treatment was terbinafine (7/12), posaconazole (3/12), or topical treatment alone (2/12). Immunosuppressive therapy was reduced in 3 patients because of associated infections. Complete response was obtained for 3/3 and 5/9 patients with extensive or invasive forms, respectively, after a median treatment's duration of 2.5 [range: 1.5-5] months and 7.5 months [range: 4-12]. Unrelated deaths (n = 2) and graft function impairment (n = 3) occurred. CONCLUSION: Severe dermatophytosis is a late complication in SOT recipients presenting with lower limb nodules, which might be prevented by prompt treatment of superficial dermatophytosis.


Assuntos
Transplante de Órgãos/efeitos adversos , Tinha/epidemiologia , Tinha/microbiologia , Transplantados , Trichophyton/isolamento & purificação , Adulto , Idoso , Feminino , França/epidemiologia , Humanos , Hospedeiro Imunocomprometido , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Tinha/etiologia
20.
J Am Acad Dermatol ; 78(6): 1164-1170, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29066274

RESUMO

BACKGROUND: Self-healing juvenile cutaneous mucinosis (SHJCM) is a rare disorder, and its pathogenesis and long-term prognosis are unknown. OBJECTIVE: To elucidate the clinical and histopathologic characteristics, pathogenesis, and outcome in patients with SHJCM. METHODS: Retrospective study of 9 patients with SHCJM. To complement initial findings, data collection forms were sent to the referring physicians. RESULTS: All patients had an acute onset of firm nodules. Of the 9 patients, 6 presented initially with waxy papules on the dorsum of the hands; 5 suffered from periorbital edema, and 6 had a febrile prodrome. Histopathologic assessment of the papules revealed dermal mucin deposition, whereas the nodules showed proliferative fasciitis-like features or nonspecific chronic lobular panniculitis. Laboratory studies elicited evidence of active viral infection in 2 patients (human herpes virus 6 and rotavirus). Seven cases had spontaneous resolution within 6 months, and 2 patients with incomplete resolution showed subsequent transition to fibroblastic rheumatism and an autoinflammatory rheumatologic disease, respectively. LIMITATIONS: This was a retrospective study with incomplete data from referring physicians. CONCLUSIONS: Although spontaneous complete regression is expected, patients with SHJCM need long-term follow-up because of the possible development of dematorheumatolgic conditions. The pathogenetic role of microbial agents deserves further investigation.

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