Bullous pemphigoid in infants: characteristics, diagnosis and treatment

BACKGROUND: Bullous pemphigoid (BP) in infants is a rare but increasingly reported autoimmune blistering skin disease. Autoantibody reactivity is usually poorly characterized. Current guidelines do not address specific aspects of the infantile form of BP. The objectives of this study are to define clinical and diagnostic characteristics of infantile BP and develop a treatment algorithm. METHODS: Detailed characterization of a current case series of five infants with BP from our departments. Comprehensive analysis of all reported cases (1-12 months) with respect to clinical and laboratory characteristics, treatment and outcome. RESULTS: In total 81 cases were identified (including our own). The mean age was 4.5 months. Moderately severe and severe disease was seen in 84% of cases. Involvement of hands and feet was present in all cases. Immunofluorescence microscopy was comparable with BP in adults. Where analyzed, the NC16A domain of bullous pemphigoid 180 kDa antigen/collagen XVII (BP180) was identified as the major target antigen. BP180 NC16A ELISA values in our cohort were significantly higher than in a control cohort of 28 newly diagnosed adult patients. 50% of patients were treated with systemic corticosteroids, 20% with a combination of systemic corticosteroids and dapsone or sulfapyridine and 10% with topical corticosteroids alone. 14% of patients needed a combination of multiple immunosuppressants. All but one patient reached remission. Relapses were rare. CONCLUSIONS: Presentation of infantile BP is often severe with blistering of hands and feet present in all cases. Pathogenesis and diagnostic criteria are comparable to adult BP, yet BP180 NC16A ELISA levels seem to be significantly higher in infants. The overall disease outcome is favorable. Based on the results of this study we propose a treatment algorithm for infantile BP

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstreamtranslation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.Peer reviewe

Life-Threatening Primary Varicella Zoster Virus Infection With Hemophagocytic Lymphohistiocytosis-Like Disease in GATA2 Haploinsufficiency Accompanied by Expansion of Double Negative T-Lymphocytes

Two unrelated patients with GATA2-haploinsufficiency developed a hemophagocytic lymphohistiocytosis (HLH)-like disease during a varicella zoster virus (VZV) infection. High copy numbers of VZV were detected in the blood, and the patients were successfully treated with acyclovir and intravenous immunoglobulins. After treatment with corticosteroids for the HLH, both patients made a full recovery. Although the mechanisms leading to this disease constellation have yet to be characterized, we hypothesize that impairment of the immunoregulatory role of NK cells in GATA2-haploinsufficiency may have accentuated the patients' susceptibility to HLH. Expansion of a double negative T-lymphocytic population identified with CyTOF could be a further factor contributing to HLH in these patients. This is the first report of VZV-triggered HLH-like disease in a primary immunodeficiency and the third report of HLH in GATA2-haploinsufficiency. Since HLH was part of the presentation in one of our patients, GATA2-haploinsufficiency represents a potential differential diagnosis in patients presenting with the clinical features of HLH—especially in cases of persisting cytopenia after recovery from HLH

Erblich bedingte Hauterkrankungen: Update Genodermatosen

Die Zahl der bekannten Genodermatosen ist groß und steigt stetig durch wachsendes Wissen. Jedoch treten die einzelnen Erkrankungen selten auf. Um dennoch den Überblick nicht zu verlieren und Patienten eine gezielte Diagnostik zu ermöglichen, ist es hilfreich, die spezifischen Leitsymptome der wichtigsten Genodermatosen zu kennen und die Kompetenz von Zentren seltener Erkrankungen zu nutzen

Subcutaneous fat necrosis associated with hypercalcemia in neonates with neonatal encephalopathy treated with therapeutic hypothermia

Subcutaneous fat necrosis of the newborn (SFNN) is a rare, self-resolving panniculitis. The onset of skins lesions occurs within the first week of life, with a median age of onset around day 6 of life (range 1-70). About 50% of neonates with SFNN will develop hypercalcemia in the first month though some present later. Typically, SFNN develops prior to hypercalcemia. Only half of the neonates have classic symptoms of hypercalcemia; routine screening for hypercalcemia is recommended for neonates with SFNN or at-risk. The mechanism for hypercalcemia is usually aberrant 1,25-dihydroxyvitamin D synthesis in the necrotic tissue increasing intestinal absorption of calcium. Prompt recognition and treatment is required, often in hospital. Treatment options are low calcium-vitamin D formula or sometimes intravenous bisphosphonates. Regular monitoring post-intervention is required when normalizing the diet. Outcomes are good with routine surveillance and interventions. A multidisciplinary team approach (neonatologists, pediatric endocrinologists and nephrologists, dieticians) is optimal

Betulin-based oleogel to improve wound healing in dystrophic epidermolysis bullosa: a prospective controlled proof-of-concept study

INTRODUCTION: Skin fragility and recurrent wounds are hallmarks of hereditary epidermolysis bullosa (EB). Treatment options to accelerate wound healing are urgently needed. Oleogel-S10 contains a betulin-rich triterpene extract from birch bark. In this study, we tested the wound healing properties of topical Oleogel-S10 in patients with dystrophic EB. METHODS: We conducted an open, blindly evaluated, controlled, prospective phase II pilot trial in patients with dystrophic EB (EudraCT number 2010-019945-24). Healing of wounds treated with and without topical Oleogel-S10 was compared. Primary efficacy variable was faster reepithelialization as determined by 2 blinded experts. The main secondary outcome variable of the study was percentage of wound epithelialization. RESULTS: Twelve wound pairs of 10 patients with dystrophic EB were evaluated. In 5 of 12 cases, both blinded reviewers considered epithelialization of the intervention wounds as superior. In 3 cases, only one reviewer considered Oleogel-S10 as superior and the other one as equal to control. Measurements of wound size showed a trend towards accelerated wound healing with the intervention but without reaching statistical significance. CONCLUSION: Our results indicate a potential for faster reepithelialization of wounds in patients with dystrophic EB when treated with Oleogel-S10 but larger studies are needed to confirm significance

Mechanism of Oleogel-S10: A triterpene preparation for the treatment of epidermolysis bullosa

Epidermolysis bullosa (EB) is a group of rare heterogeneous, genetic disorders. Currently, there is no effective pharmacological or genetic therapy for all EB subtypes. Dry extract from birch bark and betulin upregulate some pro-inflammatory mediators and downregulate others. The increase in pro-inflammatory cytokines is temporary and attenuated over long-term treatment. This inflammatory stimulus is thought to be prerequisite for a secondary anti-inflammatory response. Dry extract from birch bark and its active marker substances have also been shown to increase the migration of primary human keratinocytes, accelerate wound closure, and promote differentiation of keratinocytes in vitro and in vivo-processes that are essential for reepithelialization and maintenance of the skin barrier. Comprehensive clinical data are available to support the use of Oleogel-S10 in the treatment of partial thickness wounds of different etiologies, and a proof-of-concept Phase 2 study in patients with dystrophic EB has suggested the potential for faster reepithelialization of wounds treated with Oleogel-S10

Oleogel-S10 Phase 3 study "EASE" for epidermolysis bullosa: study design and rationale

BACKGROUND Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016-002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. METHODS EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm$^{2}$) present for > 21 days and < 9 months, are randomized in a 1:1 ratio to receive wound dressings according to local standard of care with or without Oleogel-S10. Placebo is based on the Oleogel-S10 vehicle, which is sunflower oil formulated to have a consistency indistinguishable from that of the active product. The primary endpoint of the trial, directed by the US health authority according to the required study endpoints for chronic cutaneous ulcer and burn wounds, is to compare the efficacy of Oleogel-S10 versus placebo according to the proportion of patients with complete closure of the target wound within 45 ± 7 days of treatment. Additional EB-focused endpoints include wound burden, patient-reported outcomes, and safety. RESULTS Results of the primary endpoint are anticipated to be available by H2 2019. TRIAL REGISTRATION ClinicalTrials.gov, NCT03068780 . EudraCT, 2016-002066-32. Registered on 3 March 2017