The association of Greig syndrome and mastocytosis reveals the involvement of the hedgehog pathway in advanced mastocytosis.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.

Multidisciplinary consensus recommendations from a European network for the diagnosis and practical management of patients with incontinentia pigmenti.

BACKGROUND: Incontinentia pigmenti (IP) is a rare multisystemic X-linked dominant genetic disorder characterized by highly diagnostic skin lesions. The disease can be misdiagnosed in infants, and complications affecting the eyes and/or the brain can be severe. Our objective was to highlight the urgency of an appropriate diagnosis and management strategy, as soon as the first symptoms appear, and the need for a well-codified monitoring strategy for each child. METHODS: An in-depth literature review using a large number of databases was conducted. The selection criteria for articles were literature review articles on the disease, case series and retrospective studies based on the disease, clinical studies (randomized or not) on treatment, articles discussing patient care and management (treatment, diagnosis, care pathways), and recommendations. The research period was from 2000 until 2018. A group of multidisciplinary experts in IP management was involved, issued from different healthcare providers of the European Network for Rare Skin Diseases (ERN-Skin). The final recommendations have been submitted to two patient representative associations and to a general practitioner and a neonatal specialist prior to their finalization. RESULTS AND CONCLUSION: The diagnosis of IP must be promptly performed to detect potential extracutaneous manifestations, thus allowing the timely implementation of specific therapeutic and monitoring strategies. Eye involvement can be a therapeutic urgency, and central nervous system (CNS) involvement requires a very rigorous long-term follow-up. Assessments and patient support should take into account the possible co-occurrence of various symptoms (including motor, visual and cognitive symptoms).

[Early-onset melanoma (congenital, neonatal, infantile): A systematic review of literature cases]. / Les mélanomes d'apparition précoce (congénitaux, néonataux, du nourrisson) : revue systématique des cas de la littérature.

INTRODUCTION: Neonatal and infantile malignant melanoma is rare. It may be difficult to diagnose and often carries a poor prognosis. MATERIAL AND METHODS: We decided to review the data on congenital, neonatal and infantile malignant melanomas in order to understand their presentation (clinical, histological, molecular), diagnosis, management and outcomes. We performed a literature search of all cases of early-onset melanoma published in PubMed from its inception to March 2019 using the following keywords: "malignant melanoma" OR "melanoma" OR "pigmented nevus" OR "malignant pigmented" AND "infantile" OR "congenital" OR "children" OR "childhood" OR "infancy" OR "neonatal". Congenital melanoma associated with maternal-foetal transmission was not included in the study. RESULTS: Sixty-five articles were selected and 85 cases were included in the study. Most patients were male (sex ratio: 1.6). The average age at diagnosis was 5.5 months (minimum-maximum: 0-24 months). The main site reported for congenital melanoma was the head-and-neck area and for neonatal and infantile melanoma the trunk. Half of all patients had a metastatic disease at the time of diagnosis. In metastatic cases, the prognosis was poor with the exception of patients undergoing complete excision of the tumour and metastases. The main treatment for cutaneous melanomas and operable metastasis was surgery, and secondarily, chemotherapy/immunotherapy. CONCLUSION: Neonatal and infantile malignant melanoma are rarely reported and not well-documented. It is necessary to collect additional cases to improve our knowledge of this rare disease.

[The role of new molecular tests in the diagnosis of melanoma in a setting of congenital nævus in an infant]. / Apport des nouveaux tests moléculaires dans le diagnostic d'un mélanome sur nævus congénital chez un nourrisson.

INTRODUCTION: Congenital and infantile melanomas are extremely rare. We report a case of a child presenting at birth with a giant congenital nevus complicated by melanoma and on long-term follow-up with exploration using new immunohistochemistry and molecular biology tools. OBSERVATION: A new-born girl presented at birth with a large congenital cervico-mandibular tumour with para-pharyngeal extension and underlying osteolysis. At 7 months, histology and immunohistochemistry of the operative specimen revealed nodules with atypical features (mitotic figures, necrosis and positive expression of KI67 and P53 in approximatively 50 % of the melanocytic nuclei). A diagnosis was made of infantile melanoma associated with congenital nevi. Repeated surgery and monitoring (clinical and imaging) were performed. At the age of 7 years, as there was no evidence of metastatic lesions, further analyses were performed on the initial operative specimen. Investigation of transcription factor expression using immunohistochemistry, comparative genomic hybridization and histology-guided mass spectrometry, although suspect, did not in itself support a diagnosis of melanoma. Finally, at the age of 7 years, hepatic and pulmonary metastases were reported. Despite combined immunotherapy with ipilimumab and nivolumab, the child died 5 months later. CONCLUSION: This case illustrates the complexity of diagnosis of infantile melanoma and the risk of metastatic involvement long after the initial diagnosis. Diagnosis may be difficult and necessitates expert advice and the application of several recent methods to reach a conclusion and initiate appropriate treatment.

[A case of "juvenile" self-healing cutaneous mucinosis in an adult]. / Mucinose cutanée « juvénile ¼ auto-involutive chez l'adulte.

INTRODUCTION: Self-healing juvenile cutaneous mucinosis (SHJCM) is a stereotypical disease in children characterized by the acute onset of subcutaneous papules and nodules on the face, dorsum of the hands and peri-articular regions that disappear spontaneously within a few months or years. A few cases have been reported in adults, but these display more heterogeneous clinical and histopathological features. Herein we report a case with a juvenile clinical presentation in an adult woman. OBSERVATION: A 36-year-old patient with a history of Von Willebrand disease was referred to our dermatology department following the rapid development of subcutaneous nodules on her face, hands and large joints, together with periorbital edema. Three nodules were surgically removed and histology demonstrated mucin deposition in the dermis with dissociation of collagen fibers. Autoimmune disease, neoplasia, infection and dysthyroidism were ruled out. Bilateral carpal tunnel syndrome was confirmed by electromyogram in this patient carrying out manual work. Treatment with hydroxychloroquine proved unfruitful. After 1.5 years of follow-up, her lesions showed partial regression. CONCLUSION: The form of SHJCM described in pediatric populations may occur in rare cases in adults. Should the name of juvenile mucinosis still be used in this event?

Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases.

BACKGROUND: Cutaneous mosaicism is an area of dermatology in which there has been an explosion of knowledge within the current decade. This has led to fundamental changes in the understanding of the conditions in this field, and to an ongoing paradigm shift in the approach to management of mosaic skin disorders. OBJECTIVES: To lay out the general principles of mosaicism as they are currently understood, summarize the known cutaneous mosaic abnormalities of the skin with associated phenotypic and genotypic information, review the latest trials on targeted therapies and propose guidelines for the general approach to a patient with suspected mosaicism. METHODS: This was a consensus expert review as part of the European Reference Network project (ERN-Skin). CONCLUSIONS: This study provides clinicians with a practical approach to the patient with suspected mosaicism, redefines mosaicism for the modern genetic era, and proposes a new classification system based on genetic mechanism. What's already known about this topic? Cutaneous mosaicism is a complex field of dermatology that encompasses most birthmarks, and many rare syndromes. Some cutaneous patterns are known to be seen in mosaicism. Very few treatment options are available for most mosaic abnormalities of the skin. Recent high-sensitivity genetic techniques have led to an explosion of knowledge about genotype and phenotype in the literature. What does this study add? Expert consensus from the European Reference Network project. Review of knowledge of confirmed mosaic abnormalities of the skin, including cutaneous phenotype, extracutaneous associated features and genotype. Proposed new classification of mosaic abnormalities of the skin by genetic mechanism and therefore inheritance potential. Practical tips on correct sample collection and genetic investigation. Review of trials of targeted therapies. Guidelines for a practical clinical approach to the patient with suspected mosaicism.

[Erythroderma revealing IPEX syndrome]. / Érythrodermie révélatrice d'un syndrome IPEX.

BACKGROUND: Primary immunodeficiencies are rare and frequently life-threatening conditions in the first year of life. They may present with isolated skin manifestations and the absence of other clinical signs may delay diagnosis and management of the disease. Herein we describe a case of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) that illustrates this situation. PATIENTS AND METHODS: A 2.5-month-old boy was seen with a psoriasiform eruption. Despite applications of topical steroids, skin lesions progressed to severe exfoliative ichtyosiform erythroderma. A skin biopsy showed keratinocyte necrosis with a dense, epidermotropic, lymphocytic CD8+ infiltrate. The infant presented increased serum IgE and eosinophilia. He developed an enteropathy with severe and profuse diarrhea, septicemia and hypovolemic shock that led to sudden cardiac arrest. DNA analysis revealed a mutation in the FOXP3 gene, confirming IPEX syndrome. A favorable outcome was achieved following allogeneic bone marrow transplant. DISCUSSION: IPEX syndrome is characterized by early secretory enteropathy with profuse diarrhea, dermatitis and diabetes mellitus. Onset usually occurs within the first weeks or months of life, and the natural course of the disease is often lethal. Cutaneous manifestations appear to be mostly eczematiform, psoriasiform or ichthyosiform. These may be the first sign of the disease and a common inflammatory skin disorder may be wrongly diagnosed. The severity of the lesions and their limited response to topical steroids should alert the clinician. CONCLUSION: The early onset of severe cutaneous manifestations with persistent lesions and poor response to topical steroids should lead to an early skin biopsy. If histopathological changes show a cytotoxic lymphocytic infiltrate with keratinocyte necrosis, a diagnosis of primary immunodeficiency must be considered enabling rapid intitation of specific management.

Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

Laryngeal lesion associated with epidermolysis bullosa secondary to congenital plectin deficiency.

INTRODUCTION: Epidermolysis bullosa (EB) is a congenital disease characterized by fragility of epithelial structures. The skin is the organ primarily affected, resulting in the formation of skin blisters. Some forms of EB may also present mucosal lesions. CASE REPORT: We report the case of a girl with epidermolysis bullosa simplex (EBS) associated with muscular dystrophy secondary to congenital plectin deficiency. She presented severe respiratory tract lesions extending from the oral cavity to the larynx. In particular, we describe our medical and surgical management of the laryngeal lesions, responsible for several episodes of respiratory distress and feeding difficulties. DISCUSSION: Epidermolysis bullosa simplex associated with muscular dystrophy is a rare hereditary form of EB, as fewer than 50 cases have been reported in the literature. This form is characterized by mucosal lesions involving the upper aerodigestive tract, with consequences for feeding, phonation and breathing. Special care must be taken when performing diagnostic and therapeutic procedures to avoid worsening the lesions of this very fragile mucosa. Tracheotomy is a harmful procedure in these patients and should only be considered as a last resort.

Long-term evolving profile of childhood autoimmune blistering diseases: Retrospective study on 38 children.

BACKGROUND: Autoimmune bullous dermatoses (AIBDs) in children are uncommon, and their long-term evolution remains unknown. OBJECTIVE: The aim of this retrospective study was to characterize the long-term prognosis of AIBDs that started during childhood. METHODS: We conducted a monocentric retrospective study, in the French dermatology centre, by including all children affected by AIBDs. The long-term outcome was obtained through a phone call questionnaire. RESULTS: Sixty-three patients were included from January 1993 to December 2015, 34 female and 29 males: 27 Linear immunoglobulin A disease (LAD), 12 bullous pemphigoid (BP), 12 pemphigus, 8 herpetiform dermatitis (DH) and 4 epidermolysis bullosa aquisita (EBA). The mean age was 4.7 years old. Twenty-five patients were lost during the follow-up. For the 38 remaining patients, the mean follow-up duration for all pathologies was 6.6 years. Twenty-nine of them had at least one relapse. Late relapses were observed in two cases of DH and six cases of pemphigus (7-34 months). The mean treatment duration was 30.6 months with variability according to the AIBDs. Topical corticosteroids were used alone, effectively, for seven patients and in association with other treatment in 19 patients in complete remission. Complete remission was noted in 34/38 children with a follow-up of 4.4 years (0.08-19.5). The mean duration to complete remission was 30.5 months (6-114 months). Late nasal synechiae were reported in one EBA only. There was no significant associated comorbidity, but an association with a primary immune deficiency (PID) was observed in two cases. CONCLUSION: Childhood AIBDs appear to be of good overall prognosis but a long-term follow-up is mandatory, as relapses can be late, except for BP. The use of topical corticosteroids is frequently effective alone or in association. The association with PID leads to think about the possibility of a possible underlying dysimmunity in the child.

Multiple capillary malformations of progressive onset: Capillary malformation-arteriovenous malformation syndrome (CM-AVM).

BACKGROUND: Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder first described in 2003. PATIENTS AND METHODS: An 8-year-old girl was referred for the progressive appearance of multiple capillary malformations in childhood, evocative of CM-AVM syndrome. Molecular analysis of the RASA1 gene revealed a mutation but further examinations did not show arteriovenous malformation. DISCUSSION: CM-AVM syndrome is an autosomal dominant disease caused by RASA1 gene mutations. More than 100 mutations have been identified to date. The EPHB4 gene may also be involved. Capillary malformations with particular characteristics are described. High-flow vascular malformations are associated in 18.5% of cases, with 7.1% being intracerebral. CONCLUSION: CM-AVM syndrome is a recent diagnostic entity. Diagnosis should be considered in the presence of multifocal capillary malformations. This diagnosis may lead to the detection of high-flow arteriovenous malformation and raises the question of specific management for these patients.

Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of KIT. A prospective study.

BACKGROUND: Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes. OBJECTIVES: To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course. METHODS: This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and > 4 years of disease course were enrolled. The mean ± SD age at the final evaluation was 13·2 ± 4·8 years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics. RESULTS: Patients presented with maculopapular cutaneous mastocytosis (n = 44), diffuse cutaneous mastocytosis (n = 6) or mastocytoma (n = 3). The mean duration of disease was 12·1 years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2 years) is associated with worse evolution. CONCLUSIONS: PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.

[Recurrent nevus: Case-report about a pagetoid form occurring from a congenital nevus in infancy]. / Une forme pagétoïde de pseudomélanome d'Ackerman secondaire à un naevus congénital dans l'enfance : à propos d'un cas.

INTRODUCTION: Recurrent nevus (RN) is a cutaneous benign tumour with similarities with malignant lesions. Typically, it occurs after a partial resection of commun-acquired nevus. Its incidence varies from 0.3 to 27% according to the studies. We present here a pediatric case of a pagetoid form of a recurrent nevus occurring from a congenital nevus. CASE REPORT: A congenital nevus was removed from a 9-month-old girl. Pathologists concluded to a commun-acquired nevus of complete exeresis. Two other cutaneous lesions appeared and we decided to realise a total removal. Analysis showed a recurrent nevus with some atypical histological features. No recurrence has occurred during the three post-operative of follow-up. DISCUSSION: It is an interesting case because of the occurrence of a RN after the removal of a congenital nevus in a child. Furthermore, it displayed some atypical histological features. Practicians, such as surgeons, dermatologists or pathologists, have to be aware of the risk of misdiagnosis with this lesion, which presents some similarities with SSM melanoma. It would be interesting to determinate some markers to statuate about its benign feature. There is no management recommendation about this lesion but it seems to be necessary to remove it to eliminate a malignant tumour.