French national protocol for the management of congenital ichthyosis.

Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases.

Perception of Oral Health-Related Quality of Life in Children with Epidermolysis Bullosa: A Quantitative and Qualitative Study.

KNOWLEDGE TRANSFER STATEMENT: The results of this study confirm the difficulties experienced by patients in the oral sphere. They also show that patients are able to adapt and that their demands go beyond functional rehabilitation. This work should encourage dental practitioners to be part of the overall management of the disease, involving regular checkups, preventive dental measures, and oral hygiene education. Therefore, more effective communication is required, not only between the dental and dermatological teams but also with the parents and caregivers.

Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice.

BACKGROUND: Dupilumab is the first biotherapy available for the treatment of moderate-to-severe childhood atopic dermatitis (AD). OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of dupilumab in daily practice. METHODS: Patients aged 6-11, who had received a first dose of dupilumab, were included in this multicentre retrospective cohort study. The primary endpoint was change in SCORAD after 3 months of treatment. Secondary endpoints were change in IGA score at 3 months, proportion of patients with SCORAD50 and SCORAD75, description of adverse events and proportion of children in our cohort who would be excluded from pivotal phase 3 clinical trial. RESULTS: Eighty patients were included. After 3 months of treatment, there was a significant decrease in SCORAD (mean: 21.8 ± 13.8 vs 53.9 ± 18.5; P < 0.0001) and IGA (1.3 ± 0.8 vs 3.5 ± 0.7; P < 0.0001). Conjunctivitis was observed in 11.3% (n = 9/80); three patients experienced dupilumab facial redness (DFR); 17.5% (n = 14/80) reported injection site reactions; 6.3% (n = 5/80) discontinued treatment. 61.2% (n = 49/80) children were ineligible in the phase 3 trial. LIMITATIONS: There is no control group. Because it was a real life study based on information from patient medical records in a French multicentre cohort, we cannot rule out the presence of reporting bias generated by the use of patient reported characteristics and missing information. CONCLUSION: These real-life data confirm the efficacy and safety of dupilumab in children with moderate to severe AD extended to dyshidrosis and atopic prurigo, but it also revealed a lower frequency of DFR and conjunctivitis. However, administration in injectable form may be a barrier in this age group.

New developments in the molecular treatment of ichthyosis: review of the literature.

Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. Several ongoing trials are investigating the potency of these new approaches and various studies have already been published. Furthermore, a lot of case series report that biological therapeutics are effective treatment options, mainly for Netherton syndrome and autosomal recessive congenital ichthyosis. It is expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis.

Proposal for a 6-step approach for differential diagnosis of neonatal erythroderma.

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients.

BACKGROUND: Neurofibromatosis 1 (NF1) is one of the most common inherited disorders characterized by mutations in the tumour suppressor gene NF1. Its clinical manifestations are highly variable and unpredictable. A specific NF1 mutation does not predict the severity or complications of the disease. OBJECTIVE: The objective of this study was to build an empirical classification scheme without any a priori hypotheses to identify the underlying NF1 subtypes that best explain the observed heterogeneity. METHODS: We performed latent class analysis (LCA) of 1351 consecutive NF1 patients aged >17 years seen between 2002 and 2014. Data and phenotypic features were collected prospectively on a standardized form. RESULTS: The median age was 36.8 (17-81) years. A three-class model showed the best fit: 706 (52%) belonged to the LC1 'Cutaneous neurofibromas' class having preferentially cutaneous neurofibromas (99%), plexiform neurofibromas (63%) and blue-red macules (29%); 593 (44%) belonged to the LC2 'Subcutaneous neurofibromas' class characterized by the presence of at least 10 subcutaneous neurofibromas (21%) and a familial form (77%) and 52 (4%) belonged to the LC3 'Dysmorphic phenotype' class characterized by dysmorphic features (78%) and learning difficulties (87%). Patients in LC1 had a higher likelihood of developing scoliosis (RR = 1.7, 95% confidence interval (CI) [1.2-2.4]). Patients in LC2 were more likely to be men (RR = 1.4, 95% CI [1.1-1.7]). Patients in LC3 were at higher risk of having an optic pathway glioma (RR = 4.8, 95% CI [1.9-11.8]) and epilepsy (RR = 4.5, 95% CI [1.8-11.6]). CONCLUSION: Our findings invite the performance of a larger cohort study to test whether the various latent classes reflect different underlying genetic modifiers of these phenotypic traits.

Leg ulcers in childhood: A multicenter study in France.

BACKGROUND: Leg ulcers in adults are a major public health concern. Their incidence increases with age and many causes have been identified, predominantly associated with vascular diseases. Leg ulcers in children and teenagers are less frequent. The aim of our study was to identify the causes of leg ulcers in children and teenagers, and to evaluate their management. METHODS: This retrospective multicenter study was conducted by members of the Angio-dermatology Group of the French Society of Dermatology and of the French Society of Pediatric Dermatology. Data from children and teenagers (< 18 years), seen between 2008 and 2020 in 12 French hospitals for chronic leg ulcer (disease course>4 weeks), were included. RESULTS: We included 27 patients, aged from 2.3 to 17.0 years. The most frequent causes of leg ulcer were: general diseases (n=9: pyoderma gangrenosum, dermatomyositis, interferonopathy, sickle cell disease, prolidase deficiency, scleroderma, Ehlers-Danlos syndrome), vasculopathies (n=8: hemangioma, capillary malformation, arteriovenous malformation), trauma (n=4: bedsores, pressure ulcers under plaster cast), infectious diseases (n=4: pyoderma, tuberculosis, Buruli ulcer) and neuropathies (n=2). Comorbidities (59.3%) and chronic treatments (18.5%) identified as risk factors for delayed healing were frequent. The average time to healing was 9.1 months. DISCUSSION: Leg ulcers are less frequent in children and teenagers than in adults and their causes differ from those in adults. Comorbidities associated with delayed healing must be identified and managed. Children and teenagers tend to heal faster than adults, but a multidisciplinary management approach is necessary.

Value of Doppler ultrasound scans in deciding whether to treat infantile haemangioma with oral propranolol.

BACKGROUND: Oral propranolol (Pr) must be administered until the end of the proliferation phase of infantile haemangioma (IH). This phase may be difficult to assess, particularly where a deep component is involved. Doppler ultrasound scans (DUS), which identify vascular activity (VA), could assist the clinician in making the correct therapeutic decision (CTD). PATIENTS AND METHODS: All children with IH treated with Pr for at least 3 months and up to the age of 9 months, and who also underwent DUS, were enrolled in this retrospective, single-centre, observational study. The quality of DUS as a binary diagnostic test for IH proliferation was assessed, together with its value in deciding whether to discontinue Pr (at the end of the presumed proliferation phase) or resume this drug (in the case of suspected recurrence). RESULTS: A total of 29 children were enrolled and 45 DUS were performed. Thirty-nine (87%) DUS were of high quality (80% sensitivity, 95% specificity) and made a major, moderate, or minimal contribution to the CTD in respectively 20%, 60% and 7% of cases. DISCUSSION: DUS proved to be a high-value tool. They were essential in some cases of IH, mainly periocular and localised forms, and those involving deep components, in which the question of discontinuing Pr arose (age>1 year) and where clinical examination had not been sufficient to make the CTD. Furthermore, in the vast majority of cases, they provide a helpful examination and complement clinical findings in terms of patient follow-up and reaching a CTD. CONCLUSION: DUS is an effective and complementary tool to clinical investigation.

Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature.

BACKGROUND: No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments. OBJECTIVES: To review the different treatments tried in patients with hPPK since 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treat hPPK. METHODS: We undertook a comprehensive review of the literature data published since 2008. RESULTS: Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance. New targeted treatments, according to the specific mechanisms of hPPK, appear promising for the future. CONCLUSIONS: More studies using robust methodology and involving larger cohorts of well-characterized patients (phenotype-genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN-Skin), with the aim of better management of patients with rare skin diseases.

Factors influencing quality of life in children with low-flow vascular malformations: a qualitative study using focus groups.

BACKGROUND: Very few studies have evaluated the quality of life (QoL) of children suffering from low-flow vascular malformations. This is the first study investigating the influencing factors. OBJECTIVES: To identify the factors influencing QoL in children with low-flow vascular malformations. METHODS: We conducted a qualitative study employing focus group interviews (Clinical Trials Number: NCT03440827). The study was a prospective, interventional, non-comparative, multicentre study performed in four expert centres for vascular anomalies. Qualitative data about personal experiences, feelings, difficulties, needs and various factors influencing behaviours were collected. Theme-based content analysis (manual and specialist textural software guided) were used to analyse the verbatim transcripts of all focus group sessions. Manual qualitative discourse analysis was performed to identify the different themes and categories. Informatics' analyses were subsequently performed for each individual category. RESULTS: Ten focus groups (26 individuals including 10 children aged 11 to 15 years) were conducted until saturation. Influencing factors were related to 4 categories: medical care, self-image, social impact on daily activities and challenging social relationships. These factors were responsible for intrafamily upheavals and may lead to future identity-building problems. CONCLUSIONS: This study provides an essential framework from which physicians can develop strategies to improve patient care and quality of life. These data may also be useful to develop specific age-sensitive QoL questionnaires.

[Linear lesions: A key dermatological feature of X-linked ectodermal dysplasia in a young girl]. / Lésions linéaires : un signe dermatologique clé de la dysplasie ectodermique liée à l'X chez la fille.

INTRODUCTION: X-linked hypo/anhidrotic ectodermal dysplasia (AED) is the most common form of AED. It is manifested in boys by involvement of the adnexa, teeth and sweat glands. In girls, signs are usually minor and may include linear lesions that are poorly known since they are reported infrequently or overlooked. Herein we report 3 cases. PATIENTS AND METHODS: There were two female patients who had been followed for several years, as well as the mother of one of the patients. Both of the younger patients had early diagnosis of DEA in childhood based on severe dental abnormalities, i.e. hypodontia and conical teeth, a typical facies, and cutaneous xerosis. The mother had milder signs and the diagnosis was made at the time of her daughter's diagnosis. All 3 had hypopigmented linear skin lesions (arms, buttocks or back), associated with a decrease in hair in one of them. Genetic analysis showed the R156H missense mutation at exon 3 of the EDA gene in all 3 patients. CONCLUSION: These hypopigmentation linear lesions, sometimes with hair loss, are well known to pediatric clinicians and dermatologists concerning early diagnosis of AED in girls, especially where the other signs are mild. Early diagnosis enables appropriate therapeutic management and genetic counseling regarding future pregnancy.

[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.

[Voriconazole-induced lentigines on photo-exposed skin: A little-known complication]. / Lentigines des zones photo-exposées induites par le voriconazole : une complication mal connue.

BACKGROUND: The appearance of diffuse lentigines in children is rare and a genetic syndrome should initially be envisaged. Another little-known cause of photo-distributed lentigines is use of voriconazole. We present a new case in which the original feature is the very short time of onset. PATIENTS AND METHODS: A 9-year-old immunosuppressed girl treated with voriconazole for 3 months presented lentigines in exposed areas after only 4 weeks of exposure. DISCUSSION: The literature contains only around ten cases of photo-distributed lentigines under voriconazole in children. The condition can appear very early, as in our case. Voriconazole also appears to induce cutaneous squamous cell carcinomas and even melanoma. The benefit-risk ratio of prescribing this drug must therefore be carefully evaluated, and close clinical monitoring and photoprotection must be instituted.