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.

"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.

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.

[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.

Optically enhanced production of metastable xenon.

Metastable states of noble gas atoms are typically produced by electrical discharge techniques or "all-optical" excitation methods. Here we combine electrical discharges with optical pumping to demonstrate "optically enhanced" production of metastable xenon (Xe*). We experimentally measure large increases in Xe* density with relatively small optical control field powers. This technique may have applications in systems where large metastable state densities are desirable.

Nanofiber-segment ring resonator.

We describe a fiber ring resonator comprised of a relatively long loop of standard single-mode fiber with a short nanofiber segment. The evanescent mode of the nanofiber segment allows the cavity-enhanced field to interact with atoms in close proximity to the nanofiber surface. We report on an experiment using a warm atomic vapor and low-finesse cavity, and briefly discuss the potential for reaching the strong coupling regime of cavity QED by using trapped atoms and a high-finesse cavity of this kind.

[Treatment of angiolymphoid hyperplasia with eosinophilia (ALHE) using topical tacrolimus: Two cases]. / Traitement de l'hyperplasie angiolymphoïde avec éosinophilie (HALE) par le tacrolimus topique : deux observations.

BACKGROUND: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare disease, currently considered a benign vascular proliferation of unknown etiology, and whose treatment is still unclear and challenging. PATIENTS AND METHODS: Two women in their thirties consulted for itchy lesions of the right ear. Both presented with a reddish bleeding papulonodular infiltration of the auricle, with a nodule at the entrance to the external auditory canal in the first patient. Laboratory tests showed no abnormalities and in particular no hypereosinophilia or elevated serum immunoglobulin E. In both cases, histology of lesional skin showed vascular proliferation with thick-walled vessels lined by plump endothelial cells, protruding into the lumen, together with a mixed dermal inflammatory infiltrate consisting primarily of eosinophils and lymphocytes. A diagnosis of ALHE was made in both patients based on clinical and histological features. MRA revealed no underlying vascular malformation in both cases. Patients started treatment with 0.1% tacrolimus ointment twice daily. The pruritic sensation and bleeding had completely subsided within two weeks and the reddish infiltration and nodules had practically disappeared after two months of topical tacrolimus. Continuous application resulted in no recurrence at 6 months of follow-up. DISCUSSION: Treatment of ALHE is still poorly standardized due to doubts concerning the pathophysiology of this rare condition and the small number of available studies. Topical tacrolimus was originally developed for the treatment of moderate to severe atopic dermatitis because of its anti-inflammatory and immunomodulatory properties. Recent studies suggest that this drug may be effective in treating other forms of inflammatory dermatosis. Our two observations suggest that tacrolimus ointment also represents potentially valuable treatment in AHLE.

Plantar keloids: diagnostic and therapeutic issues in six patients.

BACKGROUND: Keloids are benign fibro-proliferative skin lesions that very rarely occur on the soles. Because of their rarity, the diagnosis of plantar keloids can be difficult. We describe the clinical and histopathological characteristics of eight plantar keloids. METHODS: All patients presenting with plantar keloids between 2005 and 2012 in our Dermatology unit were retrospectively included. Diagnosis was definitely established by re-reading of pathological slides in all cases. Clinical characteristics, histopathological features, treatments given and their results were collected. RESULTS: Six patients were included. Five patients had a single plantar keloid and one had three lesions. They all were of African descent. Only one patient remembered of a previous injury at the site of the keloid. Three patients presented with associated extra-plantar keloids. In four patients, the diagnosis of keloid was not initially suspected clinically or histologically. Re-reading of the clinical photographs showed that the eight plantar keloids shared common morphological features, leading to a distinctive clinical picture, defined by a hardened lesion of rounded or polycyclic shape, with a pink surface crossed by keratotic furrows and the presence of a hyperkeratotic rim. Concerning pathological features, typical hyalinized collagen can be missing and deep fibrosis should not rule out the diagnosis of keloid. Intralesional injection of triamcinolone acetonide and orthopaedic shoes were useful. All patients who had surgical excision presented recurrence. CONCLUSION: The knowledge of the clinical features of plantar keloids is helpful to the diagnosis. There is no well-established treatment, but supportive measures are important.

Saturated absorption at nanowatt power levels using metastable xenon in a high-finesse optical cavity.

Strong saturated absorption at nanowatt power levels has been demonstrated using metastable xenon in a high finesse optical cavity. The use of metastable xenon allows a high quality factor of Q = 2 × 10(8) to be achieved at relatively high atomic densities without any contamination or damage to the optical surfaces, which is often a problem when using high-density rubidium or other alkali atoms. This technique provides a relatively straightforward way to produce nonlinearities at the single-photon level with possible applications in quantum communications and computing.

Enhancing in vitro biocompatibility and corrosion protection of organic-inorganic hybrid sol-gel films with nanocrystalline hydroxyapatite.

Application of novel organic-inorganic hybrid sol-gel coatings containing dispersed hydroxyapatite (HAp) particles improves the biocompatibility, normal human osteoblast (NHOst) response in terms of osteoblast viability and adhesion of a Ti6Al4V alloy routinely used in medical implants. The incorporation of HAp particles additionally results in more effective barrier proprieties and improved corrosion protection of the Ti6Al4V alloy through higher degree of cross-linking in the organopolysiloxane matrix and enhanced film thickness.

Triethylphosphite as a network forming agent enhances in vitro biocompatibility and corrosion protection of hybrid organic-inorganic sol-gel coatings for Ti6Al4V alloys.

The biocompatibility and life of metallic implants can be enhanced through improving the biocompatibility and corrosion protection characteristics of the coatings used with these materials. In this study, triethylphosphite (TEP) was used to introduce phosphorus into organic-inorganic hybrid silica based sol-gel coatings prepared using γ-methacryloxypropyltrimethoxysilane and tetramethylorthosilicate. Addition of TEP dramatically increased the rate of intermolecular condensation and resulted in materials showing greater cross-linking. Protein (fibrinogen) uptake, osteoblast in vitro biocompatibility and corrosion resistance was enhanced in coatings containing TEP. Although higher concentrations of phosphorus supported the greatest improvement in biocompatibility, a compromise in the phosphorus concentration used would be required if corrosion resistance was most desirable parameter for optimisation. Films prepared by dip coating on Ti6Al4V alloys from these sols offer a promising alternative to wholly metallic prostheses.

[Myeloproliferative hypereosinophilic syndrome revealed by bipolar mucosal ulcerations]. / Syndrome hyperéosinophilique d'origine myéloproliférative révélé par des ulcérations muqueuses bipolaires.

BACKGROUND: Hypereosinophilic syndrome (HES) is defined as an eosinophil count equal to or greater than 1.5 G/L for more than 6 months with organ damage (heart, nervous system, lung, etc) after the exclusion of other common causes of eosinophilia. A myeloproliferative variant of HES with FIP1L1-PDGFRα fusion gene inducing constitutive activation of a tyrosine kinase receptor has been characterized. We report a case in which the diagnosis was revealed by mucosal erosions and ulcerations. PATIENTS AND METHODS: A 50-year-old man reported bipolar erosions. He presented with an erosion on the glans, an ulceration on the lower lip and mild dermographism. He had an eosinophil count of 7.5 G/L (n<0.7) and raised LDH at 520 IU/L (n<480). Screening for the usual causes of eosinophilia was negative. Histology of the labial ulceration showed a polymorphous inflammatory infiltrate containing eosinophils. A chest scan demonstrated a ground glass-like pulmonary infiltrate and broncho-alveolar lavage revealed eosinophilic alveolitis. The myelogram showed rich bone marrow with eosinophils. FIP1L1-PDGFRα fusion transcript was detected in the blood. Imatinib (Glivec(®)) was initiated and a favourable outcome was achieved within a few months and maintained after one year of treatment. DISCUSSION: Cutaneous signs are frequent features of HES. They are polymorphous and include pruritis, erythematous rash and urticaria. Mucosal ulcerations are uncommon and appear more frequently with the myeloproliferative FIP1L1-PDGFRα-associated variant of HES. Early diagnosis allows the onset of a targeted treatment with imatinib that may prevent the apparition of organ damage.

[Porphyria cutanea tarda revealed by voriconazole]. / Porphyrie cutanée tardive révélée par le voriconazole.

BACKGROUND: Voriconazole is a systemic antifungal drug that can induce phototoxic reactions suggestive of porphyria cutanea tarda (PCT); however, porphyrin levels in urine, blood and stool remain within the normal range. Superficial cheilitis is frequently associated with this clinical picture; it is believed to be related to drug-induced impairment of endogenous retinoid metabolism. We report a case of true PCT associated with cheilitis, both occurring soon after the introduction of voriconazole and partially disappearing after withdrawal of this drug. CASE REPORT: A 65-year-old man with a past history of excessive alcohol consumption presented with typical features of PCT associated with a mild superficial desquamating cheilitis. Both symptoms had appeared 12 days after initiation of oral voriconazole for a cavitary aspergillosis. Laboratory tests confirmed a sporadic case of PCT. Withdrawal of voriconazole (replaced by itraconazole) resulted in complete disappearance of the cheilitis but incomplete remission of the PCT. Ultimately, the patient was successfully treated by venous puncture. DISCUSSION: This patient had both voriconazole-induced superficial cheilitis and a true PCT which seemed related to the same drug. The mechanism by which voriconazole may have revealed PCT remains elusive and could possibly have involved decreased uroporphyrinogen decarboxylase activity in the liver or potentiation of the phototoxic effects of porphyrins by the cutaneous toxicity of voriconazole. CONCLUSION: On presentation of a clinical picture of PCT-like photosensitivity in a patient on voriconazole, laboratory investigations should be performed routinely to rule out true PCT, even in cases of associated cheilitis.