ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

French national diagnostic and care protocol for Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis with a particular tropism for the coronary arteries. KD mainly affects male children between 6 months and 5 years of age. The diagnosis is clinical, based on the international American Heart Association criteria. It should be systematically considered in children with a fever, either of 5 days or more, or of 3 days if all other criteria are present. It is important to note that most children present with marked irritability and may have digestive signs. Although the biological inflammatory response is not specific, it is of great value for the diagnosis. Because of the difficulty of recognising incomplete or atypical forms of KD, and the need for urgent treatment, the child should be referred to a paediatric hospital as soon as the diagnosis is suspected. In the event of signs of heart failure (pallor, tachycardia, polypnea, sweating, hepatomegaly, unstable blood pressure), medical transfer to an intensive care unit (ICU) is essential. The standard treatment is an infusion of IVIG combined with aspirin (before 10 days of fever, and for a minimum of 6 weeks), which reduces the risk of coronary aneurysms. In case of coronary involvement, antiplatelet therapy can be maintained for life. In case of a giant aneurysm, anticoagulant treatment is added to the antiplatelet agent. The prognosis of KD is generally good and most children recover without sequelae. The prognosis in children with initial coronary involvement depends on the progression of the cardiac anomalies, which are monitored during careful specialised cardiological follow-up.

"African" acral keratoderma: Further evidence for a single entity. A retrospective study of 42 patients.

BACKGROUND: Several phenotypes of non-inflammatory palmar and plantar keratoderma (PPK) have been described in patients of Sub-Saharan African descent. They include keratosis punctata of the palmar creases, marginal keratoderma, also known as acrokeratoelastoidosis or focal acral hyperkeratosis, knuckle pads, other forms of diffuse hyperkeratosis, the very rare "mosaic acral keratosis", and ainhum. A previous survey has shown that these various forms of PPK are particularly frequent in patients of Sub-Saharan African descent and that they commonly occur concurrently, suggesting that they could form part of a single entity called "African" Acral Keratoderma (AAK). AIM: To assess the validity of the concept of AAK and clarify its main characteristics. METHODS: A retrospective, descriptive, monocenter study was carried out on patients with AAK seen at our institution between 2009 and 2020. RESULTS: There were 42 patients (median age 38 years, range: 12-69 years), all of Sub-Saharan African descent. The male-female sex ratio was 0.3. Thirty-three (78%) had diffuse keratoderma, 25 (59%) had marginal keratoderma on their hands and/or feet, 20 (48%) had knuckle pads, 20 (48%) had keratosis punctata of the palmar creases, 3 had ainhum, and 2 had mosaic acral keratoderma. Mixed forms were seen in 76% of the patients (n = 32). Familial histories were reported by 17 patients (40%). Treatment was topical in over 90% of patients and systemic in 9 patients (21%). Ainhum was managed surgically. CONCLUSION: This retrospective study provides additional evidence for the concept of AAK. A genetic origin is suggested by the familial aggregation of cases.

Children with psoriasis and COVID-19: factors associated with an unfavourable COVID-19 course, and the impact of infection on disease progression (Chi-PsoCov registry).

BACKGROUND: The COVID-19 pandemic has raised questions regarding the management of chronic skin diseases, especially in patients on systemic treatments. Data concerning the use of biologics in adults with psoriasis are reassuring, but data specific to children are missing. Moreover, COVID-19 could impact the course of psoriasis in children. OBJECTIVES: The aim of this study was therefore to assess the impact of COVID-19 on the psoriasis of children, and the severity of the infection in relation to systemic treatments. METHODS: We set up an international registry of paediatric psoriasis patients. Children were included if they were under 18 years of age, had a history of psoriasis, or developed it within 1 month of COVID-19 and had COVID-19 with or without symptoms. RESULTS: One hundred and twenty episodes of COVID-19 in 117 children (mean age: 12.4 years) were reported. The main clinical form of psoriasis was plaque type (69.4%). Most children were without systemic treatment (54.2%); 33 (28.3%) were on biologic therapies, and 24 (20%) on non-biologic systemic drugs. COVID-19 was confirmed in 106 children (88.3%) and 3 children had two COVID-19 infections each. COVID-19 was symptomatic for 75 children (62.5%) with a mean duration of 6.5 days, significantly longer for children on non-biologic systemic treatments (P = 0.02) and without systemic treatment (P = 0.006) when compared with children on biologics. The six children who required hospitalization were more frequently under non-biologic systemic treatment when compared with the other children (P = 0.01), and particularly under methotrexate (P = 0.03). After COVID-19, the psoriasis worsened in 17 cases (15.2%). Nine children (8%) developed a psoriasis in the month following COVID-19, mainly a guttate form (P = 0.01). DISCUSSION: Biologics appear to be safe with no increased risk of severe form of COVID-19 in children with psoriasis. COVID-19 was responsible for the development of psoriasis or the worsening of a known psoriasis for some children.

[Pediatric exposure to endocrine disruptors and carcinogenic, mutagenic or reprotoxic substances by pharmaceutical forms intended for the cutaneous route: Regulatory provisions in France, in Europe, and state of the art of scientific knowledge]. / Exposition pédiatrique aux perturbateurs endocriniens et substances cancérogènes, mutagènes ou reprotoxiques par des formes pharmaceutiques destinées à la voie cutanée : dispositions réglementaires en France, en Europe, et état de l'art des connaissances scientifiques.

OBJECTIVES: The objective is to conduct a review of pediatric exposure to substances whose endocrine disrupting (ED), carcinogenic, mutagenic, or reprotoxic (CMR) character has been confirmed or remains controversial, through their use in pharmaceutical forms intended for the cutaneous route, as well as regulatory measures diligent at the national and European levels. METHODS: A bibliographical search was carried out on the databases PubMed, Web of Science, Cochrane Library, supplemented by a search for recommendations from French and European authorities. References were selected following an assessment of their relevance to our topic. RESULTS: Seventy-one references were selected. Pediatric exposure to endocrine disruptors and CMR substances remains through products formulated for their use, but also through indirect exposure to products commonly used by adults. Exposure arises both from the choice of excipients (parabens, phenoxyethanol), packaging materials (bisphenols, phthalates) and the qualitative or quantitative nature of the active ingredients (iodine, boron, pyrethroids, organic sunscreens). CONCLUSION: The health professional must be able to develop a critical mind on such substances in order to inform and promote therapeutic adherence, guaranteeing the safety of the child's care.

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.

Dystrophic epidermolysis bullosa pruriginosa: a new case series of a rare phenotype unveils skewed Th2 immunity.

BACKGROUND: Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of hereditary epidermolysis bullosa, with a poorly understood pathogenesis and no satisfactory treatment. OBJECTIVES: To assess the clinical and biological features, genetic basis and therapeutic management, to better characterize this rare genodermatosis. METHODS: We have conducted a retrospective study, reviewing the clinical presentation, genetic diagnosis, immunohistopathological findings and biological characteristics and management of patients with dystrophic epidermolysis bullosa pruriginosa. This study was conducted in the Department of Dermatology at Saint-Louis Hospital and the Department of Genetics at Necker Hospital (Paris, France). All patients with a diagnosis of DEB-Pr seen between 2010 and 2020 were included. RESULTS: Seven patients were included, the average age of 50.1 years [range 36-76]. Pruriginous-lichenified papules, plaques or nodules appeared at 27.6 years on average [range 7-66] on pretibial areas and forearms, associated with milia and toenails dystrophy. All patients received multiple treatments, but none could sustainably reduce pruritus. Immunohistopathological analysis of lesion skin revealed subepidermal blister with fibrosis, milia and mast cell infiltration. Serum TNFα, IL1ß and IL6 levels were elevated in 2/6 patients. Total serum IgE levels were increased in 7/7 patients, with no history of atopy. Immunophenotyping of circulating T-cells revealed an increased Th2 subset in 4/4 patients, with reduced Th1 and Th17 subpopulations. Genetic analysis of COL7A1 identified 7 distinct causative mutations, six of which were new. Intra-familial clinical variability was documented in 5/7 patients and was associated with the co-inheritance of a recessive COL7A1 mutation or an FLG2 mutation in 2 families. CONCLUSION: Our study confirms the stereotyped presentation of DEB-Pr with large intra-familial variability in disease expression. Mast cell infiltration, elevated IgE and increased Th2 subset without atopy strongly support a role of Th2-mediated immunity in DEB-Pr, and further argue for new targeted therapeutic options such as dupilumab.

[Dermocorticoides and sun exposure: A misunderstanding?] / Dermocorticoïdes et exposition solaire : un malentendu ?

INTRODUCTION: Fear of dermocorticoids (DCs) or corticophobia is based on an overestimation of the risks of actual side effects and on unfounded beliefs such as DCs-induced photosensitivity among community pharmacists. The objective of this study was to assess the community pharmacy teams' fear of dermocorticoids in atopic dermatitis (DA) in sunny weather and its impact on drug use advice. MATERIAL ET METHODS: A questionnaire as a real case (a summer prescription for atopic dermatitis for an 18-month-old child) was posted on Facebook via groups of pharmacists, technicians and students. Data collected concerned the health professional, his or her reluctance to DCs, advice associated with dispensation, detailed concerns about the DC and sun association, and sources of information. RESULTS: In total, 126 participants responded (48.4% pharmacists, 40.5% technicians, 10.3% students): 12% were reluctant to DCs, 36% were reluctant to DCs and considered them photosensitizing, and 51% were not reluctant but considered them photosensitizing. The impact on the patient advice was: a suggestion to stop DC during sun exposure (28%), to stop or limit DC (dose, duration) (43%). Concerns about the association DC/sun were mainly due to UV rays (46%). Sources cited were: monographs (54%), Internet (6%), training courses (13%). CONCLUSION: The false belief of DC/sun incompatibility in DA is strong among pharmacists and impacts on patients' advice. The role of the official team in dispensing dermocorticoids is essential: training and information for professionals helps to fight false information.

Genotypic and Phenotypic Analysis of 34 Cases of Inherited Junctional Epidermolysis Bullosa caused by COL17A1 Mutations.

Inherited epidermolysis bullosa defines a heterogeneous group of genodermatoses characterized by skin and/or mucosa fragility resulting in blistering. The junctional variant (JEB) is associated with mutations affecting the genes expressing the components of the dermo-epidermal junction (DEJ) [1-2]. We report 34 JEB patients with COL17A1 genetic mutations diagnosed in our Center between 1993 and 2019. Medical and biological records were collected with a standardized questionnaire.

[Polymorphism and differential diagnosis of neonatal lupus erythematosus]. / Polymorphisme et diagnostics différentiels du lupus érythémateux néonatal.

INTRODUCTION: Neonatal lupus erythematosus (NEL) is a rare condition secondary to transplacental transfer of maternal anti-nuclear antibodies, generally anti-Ro/SSA. The most common signs are dermatological and cardiac. The most frequently reported clinical association is periorbital erythema, known as "owl eye", and bipolar erythematous maculopapular plaques with fine scales. However, many semiological variants can result in diagnostic errors or delays. PATIENTS AND METHODS: This was a single-centre retrospective observational study collating all cases of NEL seen at paediatric dermatology consultations between 2010 and 2018. The diagnosis of NEL was confirmed by the presence of specific antinuclear antibodies (ANA) in the mother. The aim was to describe the different clinical forms of NEL and to discuss differential diagnosis. RESULTS AND DISCUSSION: We identified ten cases of NEL, all addressed without diagnosis or with misdiagnosis. They were divided into 3 groups based on the semiology of skin lesions: 5 presented inflammatory macular papules on the cephalic extremity and head; 3 presented acquired periorbital depigmentation; 2 presented atrophic and diffuse livedoid lesions. None had heart disease and associated haematological and hepatic damage was mild. Spontaneous remission was seen in all cases before the age of 6 months. The mothers, who were generally symptom-free or paucisymptomatic, presented anti-Ro/SSA NAAs. CONCLUSION: Recognition of the different clinical forms of NEL enables early institution of suitable therapy and monitoring of subsequent pregnancies.

Incontinentia pigmenti in boys: Causes and consequences.

INTRODUCTION: Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by mutation of the NEMO/IKBKG gene. While lethal in male foetuses, heterozygous females survive because of X-inactivation mosaicism. Herein we discuss 9 male patients with IP. MATERIALS AND METHODS: This is an observational, descriptive, retrospective, multicentre, French study carried out with the help of the SFDP research group. Statistical analysis was performed both on our own patients and on those reported in the literature. RESULTS: Nine boys with no family history of IP but with typical neonatal skin reactions were included. Genetic analysis of blood (n=8) and skin biopsy (n=3) confirmed the diagnosis of IP by identification of common deletion of the IKBKG/NEMO gene (exons 4 to 10) in the state of somatic mosaic in 6 and 2 cases respectively. Where analysed, the karyotype was normal (n=6). Over a median follow-up period of 48 months (3 months to 10 years), 3 patients had neurological abnormalities, 2 had severe ophthalmologic abnormalities, and 1 had dental abnormalities. Extensive skin involvement is a systemic risk factor, unlike cutaneous scarring. CONCLUSION: IP in boys is often due to a mosaic mutation that should be sought in blood and skin. Long-term neurological and ophthalmological monitoring is essential, especially in cases of extensive skin involvement.

Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare monogenic autoinflammatory disease caused by NOD2 mutations. BS classically presents in early childhood as a triad of granulomatous polyarthritis, uveitis and skin involvement. Joint and ocular involvement have been characterized by several cohort studies but only very little data are available on skin lesions. OBJECTIVES: We aimed to provide a detailed clinical and microscopic analysis of skin manifestations and to study whether they may contribute to an early diagnosis. METHODS: We conducted a retrospective multicentre study in a French cohort of 21 patients diagnosed with genetically confirmed BS. RESULTS: Skin involvement was the first clinical manifestation of BS in 15/16 patients with dermatological manifestations. The presence of skin lesions was associated with significant shorter age at diagnosis (P = 0.03) and diagnostic delay (P = 0.04). Dermatological assessment allowed an earlier diagnosis (P = 0.001) and reduces the diagnostic delay (P = 0.007). Early skin lesions had a homogeneous, stereotypical clinical presentation, namely non-confluent erythematous or pigmented millimetric papules in 13/14(93%) patients. In contrast, skin lesions occurring during later disease stages had a more heterogeneous clinical presentation, including ichthyosiform dermatosis, panniculitis, livedoid lesions and vasculitis. Whatever their time of occurrence and the clinical aspect, all biopsied showed histologically presence of granuloma. CONCLUSION: Skin involvement in BS is the earliest clinical manifestation of the BS in the large majority of patients. The recognition of dermatological manifestations as granulomatous skin lesions and early dermatological expertise are the key to an early diagnosis of BS. In view of our results, it seems reasonable to propose a simplified view of skin lesions of BS in which the granuloma is the key structure.

Severe early-onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB: transient improvement in ectopic calcification with sodium thiosulfate.

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by fragmentation and progressive calcification of elastic fibres in connective tissues. Overlap has been reported between the inherited PXE phenotype associated with ENPP1, ABCC6 or NT5E mutations and acquired PXE clinical manifestations associated with haemoglobinopathies induced by HBB mutations. No treatment is currently available for PXE. A young boy presented with severe early-onset systemic calcifications occurring in the skin as elastosis perforans serpiginosa (EPS) and in the arteries, causing mesenteric and limb ischaemia. Analyses revealed deleterious ABCC6, ENPP1 and HBB mutations. The diagnosis of severe PXE was retained and we have coined the term 'PXE+ syndrome' to describe the cumulative effects of the various mutations in this uncommon phenotype. Given the severity, rapid progression and a potentially fatal prognosis, intravenous sodium thiosulfate (STS) was initiated at 25 g three times weekly for 6 months. Numerous side-effects prompted dosage adjustment to 10 g intravenously daily. Treatment efficacy was evaluated at 6 months. Asthaenia, anorexia and pre-/postprandial pain had subsided, entailing weight gain. Abdominal EPS had diminished. Calcific stenosis of the coeliac and mesenteric arteries was no longer detectable on arterial ultrasonography. Follow-up revealed only transient efficacy of STS. Discontinuation of treatment to evaluate the persistence of effects resulted in relapse of the initial symptomatology after 4 months. STS efficacy is conceivably due to strong antioxidant properties and chelation of calcium to form soluble calcium thiosulfate complexes. This case is suggestive of PXE+ syndrome for which STS may represent potential treatment in severe cases. What's already known about this topic? Generalized arterial calcification of infancy may occur in association with ABCC6 mutations and pseudoxanthoma elasticum (PXE) can be linked to ENPP1 mutations. A PXE-like phenotype has also been reported in a subset of patients with inherited haemoglobinopathies, namely sickle cell disease or ß-thalassaemia, related to HBB mutations. To date, there is still no cure for PXE. What does this study add? We report a severe case of PXE resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB. We suggest the term 'PXE+ syndrome' to describe such patients. Sodium thiosulfate therapy could represent a potential option in severe cases of PXE+ syndrome.

[Acral melanoma in a patient with hereditary keratoderma of the palms and soles (mal de Meleda): A chance association?] / Mélanome acral chez un patient atteint de kératodermie palmoplantaire de type mal de Méléda : une association fortuite ?

INTRODUCTION: Development of acral malignant melanoma in Mal de Meleda is highly unusual. As far as we could ascertain, to date, only 10 previous cases have been published. Herein, we report a new case. OBSERVATION: A 64-year-old Algerian man was followed for familial Mal de Meleda. The diagnosis was based on clinical presentation as he had a non-syndromic hereditary foul-smelling and yellowish palmoplantar keratoderma transgrediens. After the failure of acitretin, which had not prevented retractile and mutilating progression of the palmoplantar keratoderma, he had undergone surgery with graft excision of both palms. At the age of 59 years, he presented a tumor on the dorsal aspect of the 1st phalanx of the 3rd finger of the right hand in a non-grafted area. The diagnosis of acral melanoma was confirmed histologically. The radiological findings showed a specific homolateral axillary adenopathy. He underwent digital amputation of the 3rd finger, with lymph node dissection and chemotherapy involving dacarbazine. Follow-up at 5 years showed complete remission of the melanoma. DISCUSSION: Mal de Meleda is a hereditary palmoplantar keratoderma due to mutation of the SLURP1 gene. Clinical diagnosis is based on the typical phenotype in adulthood. The occurrence of acral melanoma, which is a rare form of melanoma (1 to 7%), especially in the fingers, together with an unusual palmoplantar keratoderma in a subject of type IV phototype does not appear to be a chance event. This association seems to be the outcome of immune dysregulation rather than of chronic inflammation.

Age-specific characteristics of neutrophilic dermatoses and neutrophilic diseases in children.

BACKGROUND: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. OBJECTIVES: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. METHODS: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). RESULTS: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease. CONCLUSIONS: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.