Integrin α(3) is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin ...α(3) gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis.
Summary
Background
Impaired growth and anaemia are major extracutaneous complications of epidermolysis bullosa (EB), but data on their development are lacking.
Objectives
To determine the clinical ...course of growth and anaemia in children with EB and clarify the impact of nutritional compromise, inflammation and genetic factors.
Methods
A retrospective study was conducted of 200 children, 157 with recessive dystrophic EB (RDEB) and 43 with junctional EB (JEB)‐generalized intermediate, followed at the main referral centre in Germany. Growth charts were calculated using the modified LMS method and were correlated with parameters of anaemia, nutrition, inflammation and the molecular defect in a linear model.
Results
In our cohort of patients with RDEB, weight impairment started at 12–18 months old; by the age of 10 years, 50% showed wasting. The predicted median weight at age 20 years was 35·2 kg for men and 40·1 kg for women. In JEB, growth resembled that of healthy children. Anaemia was present from the second year of life onwards in RDEB and JEB. Low levels of haemoglobin, iron, vitamin D, zinc and albumin, high levels of C‐reactive protein, and absence of collagen VII correlated significantly with low weight in RDEB. No correlation was observed in JEB.
Conclusions
The results highlight that nutritional compromise occurs early in children with RDEB and therefore may require interventions as of the first year or two of life.
What's already known about this topic?
Children with epidermolysis bullosa (EB) suffer from failure to thrive and anaemia as major extracutaneous complications.
The course of growth and the development of anaemia in EB are poorly characterized.
What does this study add?
A molecularly well characterized cohort of 200 children with EB was followed with regard to anthropometrics, anaemia and inflammation.
We demonstrate early onset of growth failure and anaemia, most pronounced in the subset of recessive dystrophic EB.
Awareness of early growth delay and nutritional deficiencies will improve EB care in daily practice.
Linked Comment: Laimer. Br J Dermatol 2020; 182: 1327–1328.
Plain language summary available online
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Junctional epidermolysis bullosa (JEB), a group of hereditary skin fragility disorders, is associated with a wide variety of phenotypes, although all forms are characterised by trauma induced skin ...blistering and tissue separation at the dermal-epidermal junction zone. A subgroup, coined JEB-other, is associated with mutations in the COL17A1 gene encoding collagen XVII or, more rarely, with mutations in the laminin 332 genes LAMA3, LAMB3, or LAMC2. The objective of this study is comprehensive genotype-phenotype analysis in JEB-other patients with COL17A1 mutations and elucidation of disease mechanisms underlying different skin phenotypes.
COL17A1 mutations and their clinical and cellular consequences were systematically analysed in 43 patients with JEB-other. Cell culture, RT-PCR, and protein biochemistry were applied to assess the effects of splice site mutations-that is, the nature and amounts of transcripts and polypeptides synthesised and their association with the phenotypic outcome. 34 distinct COL17A1 mutations were disclosed, 12 of them novel. mRNA and protein analyses demonstrated that patients with only about 12-14% of the physiological collagen XVII levels had mild cutaneous involvement and a long life span.
In contrast to complete null phenotypes, presence of minor amounts of collagen XVII protein in JEB skin is associated with mild phenotypic manifestations. The data have significant implications for design of molecular therapies for JEB, since they suggest that already a low extent of collagen XVII restoration will improve skin stability and alleviate symptoms.
大疱性表皮松解症患儿生长发育及贫血的研究 Reimer, A.; Hess, M.; Schwieger‐Brie, A. ...
British journal of dermatology (1951),
June 2020, 20200601, Volume:
182, Issue:
6
Journal Article
Summary
Severe subtypes of epidermolysis bullosa (EB) are devastating conditions that cause extremely fragile skin and mucosal membranes and lots of wounds. So far, no cure for EB exists. About 5,000 ...people in the U.K. and 500,000 people worldwide suffer from different EB types.
Apart from skin problems, children with EB often have trouble gaining weight, and they develop anaemia (deficiency of iron). As wound healing works best when the body is strong, researchers needed to see how exactly children with EB grow and what factors may stop them from growing properly.
To address this, a research group from the German EB reference centre, has looked back at weight, height and blood measurements of 200 children with EB. 157 had a type of EB called recessive dystrophic EB (RDEB) and 43 had junctional EB (JEB).
The researchers calculated growth charts that allowed better comparison with growth of healthy children and can help to find EB‐specific growth patterns.
The researchers found that the growth of children with RDEB was impaired from the second year of life (age 18 months+). In JEB, growth resembled that of healthy children. Anaemia was present from the second year of life onwards in RDEB and JEB. Children with RDEB who suffered from anaemia and deficiency of proteins, vitamins and certain minerals in the blood had impaired growth compared to those who did not.
A lot of inflammation in the body also compromised the growth of children with EB.
The EB growth charts from this study will help doctors and families in making decisions on feeding, like giving extra vitamins or tube feeding. The results are also important now that therapies for EB are being developed, so that we can compare how growth will improve in line with such therapies. The direct results of this study are printable growth charts that can be used throughout the world immediately, to assess and counsel children with EB.
This is a summary of the study: Natural history of growth and anaemia in children with epidermolysis bullosa: a retrospective cohort study
Linked Article: Reimer et al. Br J Dermatol 2020; 182:1437–1448
Spontaneous read-through of a premature termination codon (PTC) has so far not been observed in patients carrying nonsense mutations. This report describes a patient with junctional epidermolysis ...bullosa who was expected to die because of compound heterozygous nonsense mutations in the gene LAMA3 (R943X/R1159X), but was rescued by spontaneous read-through of the R943X allele.
FACS analysis of cells carrying various PTCs surrounded by their natural neighbouring codons revealed significant reporter gene expression despite the PTC only for this patient's genetic context. Gene expression could be abolished by replacing the first or third nucleotide before, or one of the two nucleotides following the PTC. Site-directed mutagenesis was used to identify genotypes allowing PTC read-through. The genetic context of the LAMA3 mutation R943X is close to a hypothetical consensus sequence for maximum PTC read-through. Bioinformatic analysis showed that this consensus sequence is present in four sequences from the NCBI reference database, each of which contains another in-frame termination codon three or four codons apart. This indicates strong selective pressure against leaky termination codons in the human genome. This patient's mutated full length mRNA escaped nonsense-mediated decay, leading to LAMA3 mRNA levels similar to those of a healthy control, and full length laminin α3 could be detected in culture supernatant of the patient's keratinocytes. Immunofluorescence analyses of skin biopsies and continuous clinical improvement of the patient's condition suggested accumulation of intact laminin-332 in the epidermal basement membrane. These findings provide important clues for the prediction of PTC read-through in human genetic disease.
Plectin, a highly versatile and multifunctional cytolinker, has been implicated in several multisystemic disorders. Most sequence variations in the human plectin gene (PLEC) cause epidermolysis ...bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin-blistering disorder associated with progressive muscle weakness. In this study, we performed a comprehensive cell biological analysis of dermal fibroblasts from three different patients with EBS-MD, where PLEC expression analyses revealed preserved mRNA levels in all cases, whereas full-length plectin protein content was significantly reduced or completely absent. Downstream effects of pathogenic PLEC sequence alterations included massive bundling of vimentin intermediate filament networks, including the occurrence of ring-like nuclei-encasing filament bundles, elongated mitochondrial networks, and abnormal nuclear morphologies. We found that essential fibroblast functions such as wound healing, migration, or orientation upon cyclic stretch were significantly impaired in the cells of patients with EBS-MD. Finally, EBS-MD fibroblasts displayed reduced adhesion capacities, which could be attributed to smaller focal adhesion contacts. Our study not only emphasizes plectin’s functional role in human skin fibroblasts, it also provides further insights into the understanding of EBS-MD–associated disease mechanisms.
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