[Clinical, therapeutic and pathophysiological aspects of Darier's disease]. / Aspects physiopathologiques cliniques et thérapeutiques de la maladie de Darier.

Darier Disease is a rare autosomal dominant inherited skin disorder classified as an acantholytic dermatosis. It manifests around puberty as brownish keratotic papules of skin folds and seborrheic areas, associated with onychopathy and mucosal involvementand have a chronic relapsing-remitting course with frequent exacerbations triggered by sun exposure, heat, friction, or infections. Darier patients have an increased risk of neuropsychiatric disorders, type 1 diabetes and heart failure. Short-term management relies on antibiotics/antiviral, topical corticosteroids and/or retinoids. Moisturizers, sun protection and avoiding triggers are essential for long-term management. Conventional long-term treatment is not standardized and many topical treatments, physical and surgical measures and systemic treatments are described in the literature.

La maladie de Darier est une génodermatose rare à transmission autosomique dominante. Elle se manifeste autour de la puberté par des papules kératosiques brunâtres des plis et des zones séborrhéiques, associées à une onychopathie et une atteinte muqueuse, et évolue par poussées déclenchées par les UV, la chaleur, les frottements ou les infections. Les patients atteints présentent un risque accru de diabète de type 1, d'insuffisance cardiaque et de troubles neuropsychiatriques. La prise en charge à court terme consiste en des antibiotiques/antiviraux, des corticostéroïdes topiques et/ou des rétinoïdes. Celle à long terme repose sur les émollients et l'éviction des facteurs déclenchants. Le traitement à long terme n'étant pas codifié, de nombreux traitements locaux et sytémiques, mesures physiques et chirurgicales sont décrits dans la littérature.

Paediatric onset lymphomatoid papulosis: results of a multicentre retrospective cohort study, on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid Papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population is scarce. OBJECTIVES: To characterize epidemiological, clinical, histopathological, and prognostic features of paediatric LyP. METHODS: This was a retrospective, multicentre international cohort study including 87 cases of children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years old at disease onset were included. Diagnosis was made in each centre based on clinical-pathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. The mean age at onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2:1. The mean time between onset of first cutaneous lesions and diagnosis was 1.3 years (range 0-14 years). Initial misdiagnosis concerned 26.4% of patients. Initially, LyP was most often misdiagnosed as Pityriasis lichenoides et varioliformis acuta (PLEVA), insect bites, or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned for 20.7% of patients. The main histological subtype was type A in 55.1% of the cases. If analysed, monoclonal TCR rearrangement was found in 76.5% of the skin biopsies. The overall survival rate was 100% with follow up at 5 years available for 33 patients and at 15 years for 8 patients. A development of associated haematological malignancy (HM) occurred in 9.6% of the cases (7/73), including four mycosis fungoides (MF) cases, one primary cutaneous anaplastic large cell lymphoma (pc-ALCL), one systemic ALCL and one case of acute myeloid leukaemia. If we compare incidence rates of cancer with the world 0-19 years old population from 2001-2010, we estimate a significantly higher risk of associated malignancy in general, occurring before the age of 19 years old with incidence rate ratio of 87.49 (CI 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall the prognosis of the disease is good, with excellent survival rates for all patients. Due to increased risk of associated HM, a long-term follow-up should be recommended for LyP patients.

Mosaic RASopathies concept: different skin lesions, same systemic manifestations?

BACKGROUND: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS, KRAS, and less frequently, NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders. METHODS: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF. RESULTS: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica. CONCLUSION: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up.

Case Report: Pansclerotic Morphea-Clinical Features, Differential Diagnoses and Modern Treatment Concepts.

Pansclerotic morphea (PSM) is a rare skin disease characterized by progressive stiffening of the skin with or without the typical superficial skin changes usually seen in morphea (localized scleroderma). Standard therapy, consisting of a combination of systemic glucocorticoids and methotrexate or mycophenolate mofetil, does rarely stop disease progression, which may lead to severe cutaneous sclerosis and secondary contractures. Little is known about the efficacy of newer biologicals such as abatacept, a fusion protein antibody against CTLA-4, or tocilizumab, a fully humanized IL-6R antibody, in the treatment of this pathology. We present the case of an 8 years old girl with an unusual, progressive stiffening of the skin, which was eventually diagnosed as pansclerotic morphea. A treatment with systemic glucocorticoids and methotrexate combined with tocilizumab led to a good clinical response within 2 months after initiation. In this paper, we discuss differential diagnoses to be considered and this new promising treatment option based on a case review of the literature.

Distal-type epitheloid sarcoma mimicking a wart in a child: A diagnosis not to be missed.

Epithelioid sarcoma is a rare soft-tissue tumor that occurs mainly in children and young adults. It typically presents as a subcutaneous or deep dermal mass in distal extremities. Due to its benign-appearing clinical presentation, infrequent occurrence, and histologic similarities with other pathologies, the diagnosis of epithelioid sarcoma in its early stages can be extremely difficult and can be easily confused with benign lesions such as warts or foreign body granuloma. In this paper, we report the case of a 12-year-old boy with a distal-type epithelioid sarcoma of the hand and wish to emphasize the difficulties of diagnosing this potentially lethal tumor both clinically and histologically.

Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is a rare inherited autosomal dominant disorder caused by germline mutations in the tumour suppressor gene FLCN, encoding the protein folliculin. Its clinical expression typically includes multiple pulmonary cysts, recurrent spontaneous pneumothoraces, cutaneous fibrofolliculomas and renal tumours of various histological types. BHD has no sex predilection and tends to manifest in the third or fourth decade of life. Multiple bilateral pulmonary cysts are found on chest computed tomography in >80% of patients and more than half experience one or more episodes of pneumothorax. A family history of pneumothorax is an important clue, which suggests the diagnosis of BHD. Unlike other cystic lung diseases such as lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis, BHD does not lead to progressive loss of lung function and chronic respiratory insufficiency. Renal tumours affect about 30% of patients during their lifetime, and can be multiple and recurrent. The diagnosis of BHD is based on a combination of genetic, clinical and/or skin histopathological criteria. Management mainly consists of early pleurodesis in the case of pneumothorax, periodic renal imaging for tumour detection, and diagnostic work-up in search of BHD in relatives of the index patient.

Keratinocytic epidermal nevi associated with localized fibro-osseous lesions without hypophosphatemia.

Keratinocytic epidermal nevi (KEN) are characterized clinically by permanent hyperkeratosis in the distribution of Blaschko's lines and histologically by hyperplasia of epidermal keratinocytes. KEN with underlying RAS mutations have been associated with hypophosphatemic rickets and dysplastic bone lesions described as congenital cutaneous skeletal hypophosphatemia syndrome. Here, we describe two patients with keratinocytic epidermal nevi, in one associated with a papular nevus spilus, who presented with distinct localized congenital fibro-osseous lesions in the lower leg, diagnosed on both radiology and histology as osteofibrous dysplasia, in the absence of hypophosphatemia or rickets, or significantly raised FGF23 levels but with distinct mosaic HRAS mutations. This expands the spectrum of cutaneous/skeletal mosaic RASopathies and alerts clinicians to the importance of evaluating for bony disease even in the absence of bone profile abnormalities.

Feline maculopapular cutaneous mastocytosis: a retrospective study of 13 cases and proposal for a new classification.

CASE SERIES SUMMARY: Cutaneous mastocytosis is a disorder rarely reported in veterinary dermatology and usually described as 'urticaria pigmentosa'. This study aimed to evaluate the diagnosis, treatment and outcome of 13 affected cats, selected from the files of a private referral dermatology practice within a period of 14 years. Breeds of the affected individuals included Sphynx (n = 9), Devon Rex (n = 2) and Sphynx/Devon Rex crossbreeds (n = 2). Females (n = 9) were over-represented and the median duration of clinical signs prior to diagnosis was 8 months. The clinical presentation of these 13 cats was compared with cases reported in the veterinary literature and classified according to the current human consensus on cutaneous mastocytosis. Three clinical forms could be distinguished in cats: (1) large papular lesions and wheals, typically localised to the head, shoulders, ventral neck and axillae, and which may spontaneously resolve (termed polymorphic maculopapular cutaneous mastocytosis); (2) erythematous dermatitis, characterised by small maculopapular lesions often associated with crusts and with a poorer prognosis (termed monomorphic maculopapular cutaneous mastocytosis); and (3) more chronic dermatitis characterised by lichenification and hyperpigmentation, similar to the human condition 'urticaria pigmentosa' (termed pigmented maculopapular cutaneous mastocytosis). Histopathology was performed in eight cases and revealed a superficial-to-deep dermatitis characterised by infiltrates of mast cells and eosinophils. The response to various treatments, including antihistamines, steroids and ciclosporin, was variable. RELEVANCE AND NOVEL INFORMATION: This article reports 13 new cases of feline cutaneous mastocytosis, confirming the clinical presentation and apparent breed predisposition. The feline maculopapular cutaneous mastocytosis seems to be clinically very close to the human form. This study proposes a new classification system for the feline disease based on the current human consensus, clinical presentation and prognosis, with three different subforms: polymorphic maculopapular cutaneous mastocytosis with eventual spontaneous regression; monomorphic maculopapular cutaneous mastocytosis with chronic evolution; and pigmented maculopapular cutaneous mastocytosis.

The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives.

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.

Scleroderma-like cutaneous lesions during treatment with paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. Review of literature.

BACKGROUND: Chemotherapy-induced skin sclerosis is generally not associated with other manifestations of systemic sclerosis. It is featured by skin sclerosis without visceral involvement (i.e., Raynaud's phenomenon, esophageal dysmotility, and pulmonary fibrosis), temporal association with chemotherapy administration, and the absence of detectable autoantibodies. The clinical course of scleroderma-like changes induced by paclitaxel or gemcitabine are refractory to treatment and commonly progressive, even after discontinuation of the triggering drugs. OBJECTIVE: Report a case of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma and determine other published cases of scleroderma-like skin changes following treatment with nab-paclitaxel, paclitaxel, or gemcitabine through the period from 2002 to 2018. METHODS: Literature search from the year 2002 onwards using combinations of "Scleroderma" AND "paclitaxel," AND/OR "gemcitabine." RESULTS: Additional to our case report we reviewed 14 other cases in the literature. Most of these cases share three prominent features: skin sclerosis without systemic involvement, temporal association with chemotherapy administration, and absence of detectable scleroderma-specific autoantibodies. CONCLUSION: To our knowledge, this is the first case report of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. However, given the current literature, these scleroderma-like lesions are most likely induced by nab-paclitaxel or paclitaxel, rather than by gemcitabine.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum: A brief report.

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.

Successful forearm prosthesis fitting in a patient with epidermolysis bullosa dystrophica: Case report.

BACKGROUND: Epidermolysis bullosa dystrophica is a rare dermatological disease characterized by extreme skin fragility and elevated risk of developing a squamous cell carcinoma. In some cases, amputation of a limb is necessary. Case description and methods: A 37-year-old man with recessive, severe generalized epidermolysis bullosa dystrophica developed a squamous cell carcinoma on the right forearm requiring a below-elbow amputation. Preoperative advice concerning indication and level of amputation was given. Due to potential skin problems, a conventional prosthesis was not feasible. Findings and outcomes: A custom-designed adaptive prosthesis with an upper arm cuff was trialed and was well tolerated. Multiple working tools, attached with a rotation and inclination system, allowed independence and return to work. CONCLUSION: Despite multiple potential skin problems of the stump, the patient was successfully fitted with a custom-designed adaptive prosthesis. Preparation for this fitting was done by a comprehensive multidisciplinary patient-centered approach. Clinical relevance Despite severe skin fragility, a patient with epidermolysis bullosa dystrophica was successfully fitted with a custom-designed adaptive upper limb prosthesis allowing good functional outcome. This required a multidisciplinary and patient-centered approach.

Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the POLH gene.

We describe the characterization of Xeroderma Pigmentosum variant (XPV) in a young Caucasian patient with phototype I, who exhibited a high sensitivity to sunburn and multiple cutaneous tumors at the age of 15 years. Two novel mutations in the POLH gene, which encodes the translesion DNA polymerase η, with loss of function due to two independent exon skippings, are reported to be associated as a compound heterozygous state in the patient. Western blot analysis performed on proteins from dermal fibroblasts derived from the patient and analysis of the mutation spectrum on immunoglobulin genes produced during the somatic hypermutation process in his memory B cells, show the total absence of translesion polymerase η activity in the patient. The total lack of Polη activity, necessary to bypass in an error-free manner UVR-induced pyrimidine dimers following sun exposure, explains the early unusual clinical appearance of this patient.

PIGO deficiency: palmoplantar keratoderma and novel mutations.

BACKGROUND: Several genetic defects have been identified in the glycosylphosphatidylinositol (GPI) anchor synthesis, including mutations in PIGO encoding phosphatidylinositol glycan anchor biosynthesis class O protein. These defects constitute a subgroup of the congenital disorders of glycosylation (CDG). Seven patients from five families have been reported carrying variants in PIGO that cause an autosomal recessive syndrome characterised by dysmorphism, psychomotor disability, epilepsy and hyperphosphatasemia. METHODS: Whole exome sequencing was performed in a boy with dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia and platelet dysfunction without a clinical bleeding phenotype. RESULTS: Two novel variants in PIGO were detected. The missense variant encoding p. His871Pro was inherited from the boy's father while the frameshift variant encoding p. Arg604ProfsTer40 was maternally inherited. CONCLUSION: A boy with two novel PIGO variants is reported. The skin phenotype and platelet dysfunction in this patient have not been described in previously reported patients with PIGO deficiency but it is of course uncertain whether these are caused by this disorder. The literature on PIGO deficiency is reviewed.

Inverse Association Between Atopy and Melanoma: A Case-control Study.

Heightened cutaneous immune surveillance in atopic patients may inhibit development of melanoma. The aim of this study was to analyse the association between atopy and melanoma (development and outcome). A total of 188 cases of melanoma and 596 healthy controls were interviewed by telephone with a standardized questionnaire on atopic, demographic and melanoma characteristics. Cases were matched with controls on important confounders (age, sex, sunburn sensitivity, hair colour, number of moles, sunburn as juvenile, ever solarium, familial melanoma). Melanoma outcome data (disease relapse and death) within cases were retrieved. Analysis showed a general inverse association between atopy and melanoma development, but this was statistically significant only for a history of personal atopy (odds ratio 0.53, 95% confidence interval: 0.30-0.96, p-value = 0.04). Among melanoma patients, atopy did not affect survival or progression. In conclusion, this study suggests an inverse association between a history of atopy and melanoma development, but not with disease progression.

Transarterial embolization of peripheral arteriovenous malformations with ethylenevinyl alcohol copolymer - feasibility, technical outcomes, and clinical outcomes.

BACKGROUND: The technical and clinical outcomes of catheter-directed embolization for peripheral arteriovenous malformations (AVM) using Onyx® (ethylene-vinyl alcohol copolymer) are not well documented. The purpose of this study was to retrospectively assess the safety, technical outcomes and clinical outcomes of catheter-directed Onyx® embolisation for the treatment of symptomatic peripheral AVMs. PATIENTS AND METHODS: Demographics, (pre-)interventional clinical and radiological data were assessed. Follow-up was based on hospital medical records and telephone calls to the patients' general practitioners. Radiological success was defined as complete angiographic eradication of the peripheral AVM nidus. Clinical success was defined as major clinical improvement or complete disappearance of the initial symptoms. RESULTS: 25 procedures were performed in 22 patients. The principal indications for treatment were pain (n = 10), limb swelling (n = 6), recurrent bleeding (n = 2), tinnitus (n = 3), and exertional dyspnoea (n = 1). Complete radiological success was obtained in eight patients (36 %); near-complete eradication of the nidus was achieved in the remaining 14 patients. Adjunctive embolic agents were used in nine patients (41 %). Clinical success was observed in 18 patients (82%). Major complications were reported in two patients (9 %). During follow-up, seven patients (32 %) presented with symptom recurrence, which required additional therapy in three patients. CONCLUSIONS: Catheter-directed embolisation of peripheral AVMs with Onyx® resulted in major clinical improvement or complete disappearance of symptoms in the vast majority of patients, although complete angiographic exclusion of the AVMs occurred in only a minority of patients.

Diverse Cutaneous Presentations of Langerhans Cell Histiocytosis in Children: A Retrospective Cohort Study.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease, frequently affecting young children. PROCEDURE: We performed a retrospective study in patients younger than 16 years old manifesting with skin symptoms, and documented their different cutaneous lesions and systemic symptoms. We compared subgroups of children with single-system, skin-only, and multisystem disease and sought signs predictive for multisystem disease. In a small sample of patients, BRAF mutations were analyzed in archived biopsies. RESULTS: A wide spectrum of cutaneous presentations varying from crusted nodules and papules, blisters, vascular tumor-like lesions, scaling orange to red macules (frequently in seborrheic regions) to purpuric macules, and papules was documented in our cohort of 32 children. Otitis externa was a common manifestation and mucosal lesions were seen in three patients. A novel manifestation was a red-blue nodule that appeared in a patient after a vaccination. None of the cutaneous lesions was predictive for the classification or final outcome as a single-system or multisystem disease. However, later onset and a more protracted course of skin lesions were more frequent findings in multisystem LCH. Mucosal lesions and otitis externa were almost exclusively seen in patients with multisystem disease, a finding that warrants further investigation. Both wild-type (WT) and mutated BRAF were found not only in multisystem LCH, but also in skin-only LCH. Two cases with rapidly resolving congenital lesions had WT BRAF. CONCLUSIONS: Late onset and a protracted course of skin lesions are associated with MS-LCH, whereas WT BRAF is found in rapidly resolving skin lesions.