Dystrophic epidermolysis bullosa Q81.2

Epidermolysis bullosa dystrophica, also known as dystrophic epidermolysis bullosa (DEB), is a genetic skin disease that affects the skin and nails, and less commonly, mucous membranes. It usually appears clinically at birth. The lesions heal with, in some cases, mutilating scarring. EBD is divided into two main groups depending on the pattern of inheritance:

• Recessive (autosomal-recessive) Epidermolysis bullosa dystrophica (RDEB).
• Dominant(autosomal-dominant) Epidermolysis bullosa dystrophica (DDEB).

Each type is further subdivided into several clinical subtypes. The absence of a known family history of epidermolysis bullosa dystrophica does not exclude the diagnosis (Fine JD 2016).

Clinical findings in severe generalized autosomal recessive EBD (REBD) include fragility of the skin manifested by blistering even with minimal trauma and healing with milia and scarring. EB melanocyticnevi occur in all forms of EB dystrophica.

Blistering and formation of extensive erosions may occur as early as the neonatal period. They tend to heal markedly poorly, sometimes with formation of exuberantgranulation tissue. Involvement of the oral mucosa can lead to blistering, poorly healing wounds with potential synechiae and extensive adhesions of the tongue and floor of the mouth, which can ultimately lead to progressive reduction of the size of the oral cavity. Erosions of the esophagus can lead to bar formation and strictures. The result is dysphagia of varying severity. This can lead to malnutrition and vitamin and mineral deficiencies in young children, which in turn can result in growth disorders. Corneal erosions with consecutive scarring may cause loss of vision. Scarring blisters on hands and feet, lead to contractures and pseudosyndactyly. Aggressive squamous cell carcinoma is another complication. The lifetime risk for aggressive squamous cell carcinoma is over 90%.

In contrast to severe and generalized REBD, blistering may be localized in the less severe forms of REBD. The mechanically stressed skin areas, the hands, feet, knees and elbows are preferentially affected, with or without involvement of the flexor sides and trunk, but without mutilating scarring.

In autosomal dominant inherited DEBD (dominant dystrophic epidermolysis), blistering is often mild and limited to the hands, feet, knees and elbows. Scarring also occurs in this type (as a result of dermolytic blistering). Finger and toe nails are often affected. They may be the only manifestation of DDEB ("nails only").

When phenotypic and laboratory findings suggest a diagnosis of DEB, molecular genetic testing approaches may include single-gene testing or the use of a multigene panel:

- Single gene testing. Sequence analysis of COL7A1 detects small intragenic deletions/insertions as well as missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. In this respect, it is recommended to perform a sequence analysis first. If no pathogenic variant is found or if only a single pathogenic variant is identified in an individual suspected of having recessive DEB, perform targeted gene deletion/duplication analysis to detect intragenic deletions or duplications.

- An epidermolysis bullosa multigene panel that includes COL7A1 and other genes of interest is most likely to identify the genetic cause of the disease at a reasonable cost while limiting the identification of variants of unclear significance and pathogenic variants in genes that do not explain the underlying phenotype.

Note: The genes included in the panel and the diagnostic sensitivity of the tests used for each gene vary by laboratory and are likely to change over time. Some multigene panels may include genes that are not associated with the disease discussed in this GeneReview. In some laboratories, panel options may include a laboratory-designed panel and/or phenotype-focused exome analysis that includes physician-specified genes. Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests. A multigene panel that includes deletion/duplication analysis is recommended for this condition.

Characteristic histologic findings:

- Staining for collagen VII with antibody is decreased or absent.

- In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa.

- Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4-integrin, and keratins 5 and 14) helps confirm the diagnosis of DEB.

Transmission electron microscopy (TEM):

In milder forms of EB, direct IF studies are often insufficient to make the diagnosis because near-normal antigen concentrations can be detected and no cleavage plane is observed. In such cases, TEM examination of the skin biopsy may be helpful to examine the cellular structures (Eady RA et al 2010).

Characteristic EM findings:

-All EBD: Cleavage is observed below the lamina densa of the basement membrane zone.

-Recessive EBD severely generalized: Anchoring fibrils are markedly reduced, absent, or abnormal in morphology.

-Dominant EBD, REBD-gen. and -localized: Anchoring fibrils may appear reduced in number and/or have altered morphology. Intracellular retention of collagen VII may be observed in some individuals. In some individuals with transient blistering in the neonatal period, collagen VII may be retained intracellularly in basal keratinocytes rather than being transported to the basement membrane zone.

The diagnosis is based on clinical findings, family history and various diagnostic tests. Molecular genetic analysis is the most reliable test. Direct immunofluorescence (IF) and/or transmission electron microscopy (EM) of lesional skin are particularly helpful in classifying subtypes.

The following clinical findings raise suspicion of dystrophic epidermolysis bullosa:

-Brittleness of the skin, manifested by blistering with minimal trauma, healing with milia and scarring. Blistering and erosions:

• are already present in the neonatal period
• Occur generalized all over the body including mucous membranes (most severe forms) or only localized mainly on hands, feet, knees and elbows (milder forms).
• Lead to mutilating pseudosyndactyly of the hands and feet (severe forms).
• Lead to scarring and strictures of the mouth and/or esophagus
• Lead to corneal erosions with resultant scarring leading to loss of vision
• Predispose to squamous cell carcinoma
• Lead to dystrophic or missing nails, especially toenails

-Family history suggestive of either autosomal recessive or autosomal dominant inheritance.

-Molecular genetic tests: These can be ensured, depending on the phenotype, by a combination of targeted genetic tests (single gene tests, simultaneous or serial single gene tests, multigene panel) and comprehensive genomic tests (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing). Genetic testing requires determination of which gene(s) are likely to be involved (biallelic pathogenic variant (REBD) or heterozygous pathogenic variant (DEBD) in COL7A1), whereas genomic testing does not. Because the phenotype of EBD is highly variable, individuals with the previously described findings will likely be diagnosed using targeted genetic testing. Individuals with an unclear phenotype are more likely to be diagnosed using genomic testing. The diagnosis of DEB is made in a subject who has characteristic clinical and molecular genetic findings. When molecular genetic testing is not diagnostic, examination of a skin biopsy with direct IF for specific cutaneous markers and/or EM may be required. Routine histology is not recommended.

New blisters should be lanced, drained, and in most cases dressed with a nonadherent material, covered with padding for stability and protection, and secured with an elastic bandage. In infants and children with severe generalized RDEB and poor growth, attention to fluid and electrolyte balance is needed, and nutritional support may be required, including gastrostomy.

Anemia: iron supplements; transfusions if needed.

Other nutritional supplements may include calcium, vitamin D, selenium, carnitine, and zinc.

Specific and skilled occupational therapy is useful to prevent contractures of the hand. Surgical removal of the pseudosyndactyls. Must be repeated if necessary.

Prevention of primary manifestations:

Pregnancy: in an affected fetus, delivery by sectio may reduce trauma to the skin during birth.

Age-appropriate play with activities that cause minimal trauma to the skin should be encouraged.

Dressings and padding are required to protect bony prominences from blistering impacts.

Surveillance: Beginning in the second decade of life, abnormal, poorly healing wounds should be biopsied for evidence of squamous cell carcinoma (Mellerio JE et al 2016).

Recommended regular examinations include screening for anemia and deficiencies of iron, zinc, vitamin D, selenium, and carnitine every 6-12 months.

Annual echocardiograms to detect dilated cardiomyopathy and bone mineral density examinations to detect osteoporosis are recommended.

Avoid ill-fitting or coarse-mesh clothing and footwear and activities/bandages that traumatize the skin.

Assessment of at-risk relatives: It is useful to assess an at-risk newborn for signs of blistering so that trauma to the skin is avoided as much as possible.

Genetic counseling: Dystrophic epidermolysis bullosa is inherited in either an autosomal dominant (DEBD) or autosomal recessive (REBD) manner. Molecular characterization of the pathogenic variants is the only accurate method to determine the mode of inheritance and risk of recurrence; phenotype severity and IF/EM findings alone are not sufficient.

- DEBD. Approximately 70% of individuals diagnosed with an autosomal dominant form of dystrophic epidermolysis bullosa usually have an affected parent. If one parent is affected, the risk for siblings is 50%. Each child of a person with DDEB has a 50% chance of inheriting the pathogenic variant.

- REBD. Each sibling of an affected person whose parents are both carriers has a 25% chance of being affected at conception, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the pathogenic COL7A1 variant(s) have been found, prenatal diagnostics should be performed

If the phenotype cannot be clearly assigned, comprehensive genomic testing (which does not need to determine which genes are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible (Pfendner EG 2015).

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