Search

Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

H syndrome is a rare autosomal recessive disorder with clinical features comprising: hyperpigmentation, hypertrichosis, hearing loss, heart anomalies, low height, hypogonadism and hepatosplenomegaly. H syndrome results from loss-of-function mutations in SLC29A3 which leads to abnormal proliferation and function of histiocytes. Herein, we discuss the considerable phenotypic heterogeneity detected in a consanguineous Egyptian family comprising of four affected siblings, two of which are monozygotic twin and the possible therapeutics. The phenotypic variability may be attributed to the role of histiocytes in the tissue response to injury. Such variable expressivity of H syndrome renders the diagnosis challenging and delays the management. The different treatment approaches used for this rare entity are reviewed.

Background Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder due to a lack of type VII collagen. At present, treatment is mainly supportive. Objectives To determine whether intravenous allogeneic bone marrow–derived mesenchymal stromal/stem cells (BM-MSCs) are safe in RDEB adults and if the cells improve wound healing and quality of life. Methods We conducted a prospective, phase I/II, open-label study recruiting 10 RDEB adults to receive 2 intravenous infusions of BM-MSCs (on day 0 and day 14; each dose 2-4 × 106 cells/kg). Results BM-MSCs were well tolerated with no serious adverse events to 12 months. Regarding efficacy, there was a transient reduction in disease activity scores (8/10 subjects) and a significant reduction in itch. One individual showed a transient increase in type VII collagen. Limitations Open-label trial with no placebo. Conclusions MSC infusion is safe in RDEB adults and can have clinical benefits for at least 2 months.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS: In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 10(6) cells/cm(2) of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS: Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION: To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION: ClincalTrials.gov NCT02493816. FUNDING: Cure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and Fondation René Touraine Short-Exchange Award.

Oral homeostasis depends largely on proteins and mucins present in saliva that coat all oral surfaces. The present study compared the protein composition of residual fluid on mucosal surfaces in subjects with normal salivary flow with that of patients with dry mouth caused by salivary hypofunction. Samples of residual mucosal fluid were collected using paper strips and then analysed by protein electrophoresis and immunoblotting. In both patients and controls, residual fluids on mucosal surfaces (except the anterior tongue in control subjects) had higher protein concentrations than unstimulated whole-mouth saliva. High-molecular-weight mucin (MUC5B) was present in greater amounts on the anterior tongue than on other surfaces in control subjects. In dry mouth patients who were unable to provide a measurable saliva sample, MUC5B was often still present on all mucosal surfaces but in reduced amounts on the anterior tongue. The membrane-bound mucin, MUC1, was prominent on buccal and labial surfaces in patients and controls. Statherin was still present on surfaces that were dried to remove salivary fluid, suggesting that it may be adsorbed as a protein pellicle. It is concluded that oral mucosal surfaces in dry mouth patients can retain MUC5B and other salivary proteins, although the functional integrity of these proteins is uncertain.

In the inherited blistering skin disease, recessive dystrophic epidermolysis bullosa (RDEB), there is clinical heterogeneity with variable scarring and susceptibility to malignancy. Currently, however, there are few biochemical markers of tissue inflammation or disease progression. We assessed whether the non-histone nuclear protein, high mobility group box 1 (HMGB1), which is released from necrotic cells (including keratinocytes in blister roofs), might be elevated in RDEB and whether this correlates with disease severity. We measured serum HMGB1 by ELISA in 26 RDEB individuals (median 21.0 ng/ml, range 3.6-54.9 ng/ml) and 23 healthy controls (median 3.6, range 3.4-5.9 ng/ml) and scored RDEB severity using the Birmingham Epidermolysis Bullosa Severity Score (BEBSS; mean 34/100, range 8-82). There was a positive relationship between the BEBSS and HMGB1 levels (r = 0.54, P = 0.004). This study indicates that serum HMGB1 levels may represent a new biomarker reflecting disease severity in RDEB.

Summary Olmsted syndrome (OS) is a rare congenital skin disorder characterized by palmoplantar keratoderma, periorificial hyperkeratotic lesions and alopecia. Constriction of digits, onychodystrophy and pruritus may also occur. Recently, pathogenic heterozygous mutations in TRPV3 were identified, with most cases showing de novo dominant inheritance. We present the clinical and molecular features of OS in a 10-year-old Iranian boy. He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits. TRPV3 was sequenced and a new de novo heterozygous missense mutation, c.2076G>C (p.Trp692Cys), was identified. This case illustrates the characteristic clinical features and complications that can present in OS, and further expands the molecular basis of this genodermatosis.