Disease definition. Dystrophic epidermolysis bullosa (DEB) is a form of inherited epidermolysis bullosa (EB) characterized by cutaneous and mucosal fragility. Epidermolysis bullosa (EB) is a group of inherited bullous disorders characterized by blister formation in response to mechanical trauma. EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL RECESSIVE, LOCALISATA VARIANT, INCLUDED. EPIDERMOLYSIS BULLOSA DYSTROPHICA.
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CC HPO: Autosomal recessive dystrophic epidermolysis bullosa is a severe skin disorder beginning at birth and characterized by recurrent blistering at the level of the sublamina densa beneath the cutaneous basement membrane. This results in mutilating scarring and contractures of the hands, feet, and joints. Patients also developed strictures of the gastrointestinal tract from mucosal involvement, which can lead to poor nutrition.
Epivermolysis individuals have an increased risk of developing aggressive byllosa cell carcinoma Christiano et al. Allelic disorders include autosomal dominant DEB DDEB;in which the phenotype is less severe, and nonsyndromic congenital nail disorder-8 NDNC8;which has been found epivermolysis segregate as an autosomal dominant trait in heterozygous carriers in some families with recessive DEB. All had extreme fragility of the skin since birth.
The skin involvement led to extensive mutilating scarring, loss of nails, fusion of the digits, and joint contractures. The patients also had blistering of the mucous membranes in the oral cavity and esophageal strictures that caused severe malnutrition and anemia, which led to death in the oldest brother at age 21 years.
Skin biopsies showed subbasal lamina dermal-epidermal separation with no anchoring fibrils. Two of the families were consanguineous. All presented at birth or soon after dystrophia skin blistering on the fingers, lips, oral mucosa, and ears, which later became widespread.
Older patients had multiple erosions, scarring, mitten deformities of dystgophica hands from fusion, and joint contractures. Other features included loss of nails and esophageal strictures. Electron microscopy showed hypoplastic anchoring fibrils and cleavage at the level of the sublamina bjllosa, consistent with dystrophic EB.
One patient had skin missing from the left thumb and both feet at birth, showing phenotypic overlap with Bart syndrome Obligate heterozygous parents were clinically unaffected.
The inversa subtype of autosomal recessive dystrophic epidermolysis bullosa is a rare variant characterized by lesions involving primarily the flexural areas of the body epidermolysid sparing of the fingers and toes Wright et al. Gedde-Dahl first described EBD inversa in 13 patients from 6 Norwegian families and noted the difference in distribution of skin involvement and in the course of the disease, including corneal, perianal and perivulvar involvement, compared to the Bulllosa type of DEB.
Pearson and Paller described 4 American patients with DEB inversa and emphasized the occurrence of severe oral and esophageal mucosal involvement. Fingernails were normal or minimally involved, whereas toenails were mildly to moderately dystrophic or atrophic.
The microscopic changes were said to be similar to those of the Hallopeau-Siemens form of eepidermolysis bullosa. Although there was clinical variability in the severity and distribution of skin involvement, none of the patients showed dystrophida digital webbing, severe bulosa blistering, or growth retardation characteristic of Hallopeau-Siemens DEB.
All patients had oral involvement, including ankyloglossia, loss of tongue papillae, and obliteration of the oral epicermolysis between the lips and gingiva. The oral opening was significantly reduced in older patients compared to controls. The teeth were not clinically abnormal or malformed and showed no evidence of generalized enamel hypoplasia. An year-old girl had neck, axilla, groin, and oral blistering with sparing of the hands and feet as well as sparing of the rest of the body. She dysrtophica had severe and recurrent esophageal stenosis.
The other patient had a similar clinical course. Skin biopsies of both patients showed cleavage beneath the lamina densa, absence of normal anchoring fibrils, and small numbers of rudimentary fibrils on electron microscopy. One patient had finger web scarring that required surgical correction and also had mild syndactyly of toes. The parents of one of the patients were cousins. She presented with lid ulcerations, chronic conjunctivitis, diffuse subepithelial corneal scarring, corneal ulceration, and cataracts.
Management with intensive lubricant therapy, soft-bandage contact lenses, and cataract extraction successfully restored her sight. Histologic examination via light and electron microscopy revealed blister formation and scarring beneath the epithelial basement membrane of both the skin and cornea, confirming the diagnosis of RDEB.
Other features included fusion of all fingers and toes dystriphica mittenlike deformities and severe contractures of all 4 limbs. She had survived a spontaneous esophageal perforation and had had 15 squamous cell carcinomas removed from the limbs.
A similarly affected sister died at the age of 26 years from metastatic squamous cell carcinoma. On the basis of an analysis of patients with epidermolysis bullosa of various types, Travis et al. Lingual adhesions or microstomia occurred in dystrophic epidermolysis bullosa only, and were 8 dystropuica more common in the recessive form than in the dominant form.
These lesions were provoked by the trauma of eating and reduced food intake, which exacerbated constipation caused by anal blisters and resulted in malnutrition. Stricture of the esophagus was frequent, with single or multiple esophageal webs.
One was 22 years old when the diagnosis of amyloidosis was made. Despite rapidly deteriorating renal function, dialysis was deemed impossible because of her extensive cutaneous infection.
The older sister had negative findings of a search for amyloidosis at the age of 26 years. Although her skin disease was equally as severe as her sister’s, she did not develop amyloid nephropathy until the age of 35 years.
On the basis of an analysis of patients with epidermolysis bullosa, Melville et al.
Both were malnourished and showed severely retarded growth. The authors suggested that the likely cause for the cardiomyopathy was a micronutrient deficiency, most probably selenium deficiency, because the serum selenium level was reduced in the case in which they measured it, and also in 14 of 25 other children with dystrophic epidermolysis bullosa.
Echocardiographic screening of 18 other patients with recessive dystrophic epidermolysis bullosa showed bjllosa evidence of cardiomyopathy. The disorder was of the severe Hallopeau-Siemens form in 5 families and the generalized nonmutilating form in 1. In an African American family in which 4 individuals related as first cousins once removed had autosomal recessive epidermolysis bullosa dystrophica, Christiano et al.
The unaffected mother and half-brother were heterozygous for the mutation.
OMIM Entry – # – EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL RECESSIVE; RDEB
The unaffected parents were each heterozygous epideromlysis 1 of the mutations. Two families were compound heterozygous for a glycine substitution and a premature termination mutation see, e.
In all 4 recessive families, the glycine substitution mutation was silent in heterozygous carriers who had bulloss disease manifestations. Inspection of the location of the glycine substitutions did not show a positional effect in terms of phenotype or pattern of inheritance. Heterozygous carriers of the GR allele had normal skin but isolated toenail dystrophy, also called nonsyndromic congenital nail dystrophy-8 NDNC8; In family members with dystrophic changes limited to the toenails but without skin fragility, they identified heterozygosity for the glycine substitutions GR The patients with RDEB in each family were compound heterozygous for 1 of these mutations, respectively, in combination with a nonsense These results supported the idea that certain glycine substitutions in the collagenous domain of COL7A1 cause a limited nail deformity, and bulllsa these alleles can also contribute to variable degrees of skin fragility when present in combination with nonsense or frameshift mutations in COL7A1.
Mutations were found in 1 or both alleles in The authors reviewed the spectrum of COL7A1 mutation and genotype-phenotype correlations, noting that patients with severe recessive DEB tended to have truncating mutations, whereas those with milder dominant DEB tended to have glycine substitutions. Seven patients had features of both dominant and recessive forms of disease and were found to carry both dominant and recessive mutations.
Although a second pathogenic mutation was not identified, the authors presenting convincing evidence that the disorder was recessive in bulloaa cases. In 2 brothers with recessive DEB dystrophjca, Kahofer et al. A defect in collagenase MMP1; was implicated early on in the pathogenesis of dystrophic epidermolysis bullosa. Type VII collagen is susceptible to degradation by collagenase Seltzer et al. Bauer found that procollagenase purified from fibroblasts of 2 patients with DEB was more thermolabile, showed decreased calcium affinity, and had decreased activity in vitro compared to control values.
Bauer and Eisen observed enhanced collagenase production by cultured skin fibroblasts in 8 of 10 patients with autosomal recessive dystrophic epidermolysis bullosa. Increased levels of immunoreactive collagenase were found in unaffected and eoidermolysis areas of the skin. However, Winberg et al. Phenytoin, which was found to inhibit synthesis or secretion of collagenase, had been thought to be effective in the systemic treatment of RDEB Bauer et al.
Van den Akker et al. Of the 19 known missense mutations, all involved substitutions of arginine or glycine. Three of the 5 arginine substitutions e. Unlike parent cells from these patients, the gene-corrected cells had normal morphology, proliferative potential, matrix attachment, and motility.
Human skin regenerated by gene-corrected cells had restored expression of type VII collagen and formation of anchoring fibrils at the dermal-epidermal junction in vivo. Skin regenerated using these cells displayed stable correction of hallmark RDEB disease features, including type VII collagen protein expression, anchoring fibril formation, and dermal-epidermal cohesion. This expression was stable for the week duration of the experiment.
They showed variable reductions in blister formation between 30 and days after transplantation. Two patients had rapid and substantial clinical improvement, 1 had slow improvement with only a modest overall benefit, 1 had rapid improvement on short-term follow-up, and 1 had a recurrence of blistering after an early period of almost no blistering.
One recipient died at days after transplant from graft rejection and infection. Skin biopsies showed a substantial proportion of donor cells in the skin and mucosa.
The cells appeared to ba hematopoietic in origin, but their identity could not be fully determined. The authors suggested that the donor bullowa secreted type VII collagen that was subsequently incorporated into the lamina densa. Type VII collagen deposition could be detected in skin biopsies after treatment, but anchoring fibrils never appeared normal. In the family with 3 affected sibs in which linkage studies excluded the involvement of the collagenase locus on 11q22, Hovnanian et al.
By linkage studies, Colombi et al. The same family had other members affected with a form of cerebellar ataxia of postpubertal onset.
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The 3 genes, as well as fibronectin FN1; on chromosome 2, were excluded as being involved in both phenotypes. The expression and posttranslational modification profile of the recombinant collagen type VII was comparable to that of the wildtype counterpart. Homozygous mice appeared normal at birth, but developed blisters on the paws by 24 to 48 hours after birth.
Hypomorphic mice showed poor general condition resulting from poor nutrition and blisters of the tongue. A liquid diet resulted in increased survival. Mitten deformities of the paws were found to result from soft tissue accumulation and contraction due to aberrant fibrosis that accompanied wound healing.
The phenotype resembled the human recessive disorder, including skin fragility, nail dystrophy, pseudosyndactyly, and growth retardation. Intradermal injection with wildtype fibroblasts restored Col7a1 deposition and function and resulted in phenotypic improvement. Prenatal diagnosis of epidermolysis bullosa dystrophica Hallopeau-Siemens with electron microscopy of fetal skin.