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Epidermolysis Bullosa Simplex

[Includes: Epidermolysis Bullosa Simplex with Mottled Pigmentation; Epidermolysis Bullosa Simplex, Dowling-Meara Type; Epidermolysis Bullosa Simplex, Koebner Type; Epidermolysis Bullosa Simplex, Weber-Cockayne Type]

Summary

Disease characteristics. Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin that results in non-scarring blisters caused by little or no trauma. Four clinical subtypes of EBS range from relatively mild blistering of the hands and feet (EBS, Weber-Cockayne type) to more generalized blistering (EBS, Koebner type; EBS with mottled pigmentation; EBS, Dowling-Meara type), which can be fatal. In EBS, Weber-Cockayne type (EBS-WC), blisters are rarely present at birth and may occur on the knees and shins with crawling or on the feet at about 18 months of age; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant. In EBS, Koebner type (EBS-K), blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-WC, but generally milder than in EBS, Dowling-Meara type (EBS-DM). In EBS with mottled pigmentation (EBS-MP), skin fragility is evident at birth and clinically indistinguishable from EBS-DM; over time, progressive brown pigmentation interspersed with depigmented spots develops on the trunk and extremities, the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur. In EBS-DM, onset is usually at birth; severity varies greatly, both within and among families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid to late childhood. EBS-DM appears to improve with warmth in some individuals. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyperpigmentation and hypopigmentation can occur. Mucosal involvement in EBS-DM may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.

Diagnosis/testing. EBS, Weber-Cockayne type (EBS-WC) can almost always be diagnosed clinically. Diagnosis of generalized forms of EBS requires a skin biopsy obtained from the leading edge of a fresh blister; diagnosis is based on transmission electron microscopic examination that reveals splitting within or just above the basal cell layer of the skin or on immunohistochemistry using appropriate fluorescent antibodies. All four forms of EBS are caused by mutation in either the KRT5 gene or the KRT14 gene. Molecular genetic testing of the KRT5 and KRT14 genes detects mutations in 75%-90% of individuals with biopsy-diagnosed EBS-K, EBS-DM, and EBS-WC, and 90%-95% of mutations in those with EBS-MP. Such testing is clinically available but rarely used in diagnosis; it is primarily used in genetic counseling.

Management. Management of EBS includes supportive care to protect the skin from blistering, dressings that will not further damage the skin and will promote healing, and prevention and treatment of secondary infection. Children's activities should minimize skin trauma and new blisters should quickly be lanced and drained. Dressings involve three layers: a primary non-adherent dressing, a secondary layer providing stability and adding padding, and a tertiary layer with elastic properties. Aluminum chloride (20%) applied to palms and soles can reduce blister formation in some individuals. Cyproheptadine (Periactin) can reduce blistering in some individuals with EBS-DM. Keratolytics and softening agents for palmar plantar hyperkeratosis may prevent tissue thickening and cracking. Surveillance for infection and proper wound healing is indicated. Excessive heat may exacerbate blistering and infection. Individuals should avoid poorly fitting or coarse-textured clothing and footwear.

Genetic counseling. EBS is usually inherited in an autosomal dominant manner, but in rare families, especially those with consanguinity, it can be inherited in an autosomal recessive manner. For autosomal dominant EBS, affected individuals may have inherited the mutated gene from an affected parent or have the mutated gene as the result of a de novo gene mutation. For autosomal dominant EBS, the chance that an affected person will pass the disease-causing mutation to each child is 50%. Prenatal testing is available by molecular genetic testing for autosomal dominant EBS if the disease-causing mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

The diagnosis of EBS is suspected in individuals with fragility of the skin manifested by blistering with little or no trauma. The blisters are non-scarring. While examination of a skin biopsy is often required to establish the diagnosis, it may not be necessary in some individuals, especially those with a positive family history who have blisters on the palms and soles only.

Testing

Skin biopsy.  Transmission electron microscopic examination of a skin biopsy or immunofluorescent antibody/antigen mapping is the sine qua non for the diagnosis of EBS. The leading edge of a fresh (less than 12 hours old) or mechanically induced blister with some normal adjacent skin should be biopsied as older blisters undergo change that may obscure the diagnostic morphology.

Note: Although it is possible that a punch biopsy (versus an elliptical or shave excision) can introduce confusing artifact, careful use of the punch to avoid loss of the epidermis is usually successful.

• In all cases of EBS, splitting is observed within or just above the basal cell layer of the skin.
• In EBS, Dowling-Meara type (EBS-DM), the tonofilaments (also called keratin filaments) are clumped, a finding that serves as a distinguishing feature.
• In the rare cases of autosomal recessive EBS, tonofilaments are absent from basal keratinocytes.
• Abnormal or absent staining with antibodies to keratin 5 or keratin 14, coupled with normal staining for other antigens (e.g., laminin and type VII collagen), confirm the diagnosis of EBS.

Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of EBS.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.  The only two genes currently known to be associated with EBS are KRT5 and KRT14.

Other loci.  Because only 75%-90% of individuals with biopsy-proven EBS have identifiable mutations in KRT5 or KRT14, it is possible that mutations in another as-yet-unidentified gene are also causative [personal communication, E Pfendner].

Clinical uses

• Confirmatory diagnostic testing
• Carrier testing (in rare families with autosomal recessive inheritance)
• Prenatal diagnosis

Clinical testing

• Sequence analysis.  Sequence analysis is performed first in the KRT5 and KRT14 gene regions in which a high percentage of mutations are known to occur and may be targeted on the basis of the individual's clinical presentation. Sequence analysis of remaining KRT5 and KRT14 exons may be performed if a mutation is not identified in the initially tested gene regions. Mutation detection frequency in individuals with biopsy-diagnosed EBS is 75%-90% [personal communication, E Pfendner].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex EBS Subtype  1 Test Method Mutations Detected Mutation Detection Frequency in Individuals with Biopsy- Diagnosed EBS Test Availability EBS-WC KRT5 and KRT14 sequence analysis KRT5 and KRT14 sequence variants 75%-90%  2 Clinical EBS-K EBS-DM EBS-MP KRT5 P25L 90%-95%  3

1. EBS-WC = EBS, Weber-Cockayne type EBS-K = EBS, Koebner type EBS-DM = EBS, Dowling-Meara type EBS-MP = EBS with mottled pigmentation 2. Personal communication, E Pfendner 3. Horiguchi et al (2005) describe a second mutation associated with EBS-MP.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

A skin biopsy is required (especially in newborns) to determine the type of EB and thus should be performed as soon as possible after initial evaluation in order to facilitate genetic testing and to determine recurrence risk.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in KRT5 and KRT14.

Clinical Description

Natural History

Before the molecular basis of epidermolysis bullosa simplex was understood, EBS was subdivided into clinical phenotypes — EBS, Weber-Cockayne type (EBS-WC); EBS, Koebner type (EBS-K); EBS, Dowling-Meara type (EBS-DM); and EBS with mottled pigmentation (EBS-MP) — based primarily on dermatologic and histopathologic findings. Although it is now recognized that these phenotypes are part of a continuum and have overlapping features, it is reasonable to continue to think of EBS in terms of the phenotypes in order to provide affected individuals with information about the expected clinical course. The clinical features of these disorders are summarized in Table 2 .

EBS, Weber-Cockayne type (EBS-WC).   Blisters are rarely present at birth. The first episodes may occur on the knees and shins with crawling or on the feet at about 18 months, after walking is firmly established. Some affected individuals do not manifest the disease until adolescence or early adult life; the classic story is that of the army recruit with EBS-WC who blisters severely after the first enforced march. Although blisters are usually confined to the hands and feet, they can occur anywhere given adequate trauma; affected individuals have developed blisters on the buttocks after horseback riding and around the waist after wearing a tight belt. The palms and soles are usually more involved than the backs of the hands and the tops of the feet. Symptoms are worse in warm weather (as is true for all forms of EBS except EBS-DM) and worsen with sweating. Hyperkeratosis of the palms and soles can develop in later childhood and adult life. Occasionally, a large blister in a nail bed may result in shedding of the nail.

EBS, Koebner type (EBS-K).   Blisters may be present at birth or develop within the first few months of life. EBS-K is distinguished from EBS-WC by its more widespread involvement and from EBS-DM by absence of clumped tonofilaments in basal keratinocytes on electron microscopy. In general, EBS-K is milder than EBS-DM, but clinical overlap is high. Similarly, mild EBS-K can be misdiagnosed as EBS-WC. Branches of one large pedigree were reported separately as EBS-K and EBS-WC, reflecting the heterogeneity in severity even within families. As all the EBS disorders are allelic, this overlap should not be surprising.

EBS with mottled pigmentation (EBS-MP).   Skin fragility in EBS-MP is evident at birth and case descriptions suggest that it is clinically indistinguishable from EBS-DM. Over time, progressive brown pigmentation interspersed with depigmented spots, different from post-inflammatory hyperpigmentation and hypopigmentation, develops on the trunk and then on the extremities. The pigmentation disappears in adult life. Focal palmar and plantar hyperkeratoses may occur.

EBS, Dowling-Meara type (EBS-DM).   Onset is usually at birth and severity varies greatly, both within and between families. Widespread and severe blistering and/or multiple grouped clumps of small blisters (whose resemblance to the blisters of juvenile dermatitis herpetiformis gave the disorder one of its names) are typical. Hemorrhagic blisters are common. The mucosa can be involved; this usually resolves with age. Improvement occurs during mid to late childhood and blistering may be a minimal component of the disorder in adult life. Unlike other forms of epidermolysis bullosa, the Dowling-Meara variant appears to improve with heat or warmth in some individuals. Spontaneous prolonged clearing with fevers has been reported. Progressive hyperkeratosis (punctate or diffuse) of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia, typically thought to be limited to dystrophic disease, are common. Both hyperpigmentation and hypopigmentation can occur. Mucosal involvement in EBS-DM may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.

Cancer risk.  Squamous cell carcinoma is not usually associated with EBS.

Genotype-Phenotype Correlations

A moderate correlation exists between the EBS phenotypes and the functional domain of either KRT5 or KRT14 in which the mutation occurs [reviewed in Irvine & McLean 2003].

• Mutations in the non-helical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-WC.
• Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-K.
• Mutations in the beginning of the 1A or the end of the 2B segments of the rod domain of KRT5 and beginning of the 1A or 2B segments of the rod domain of KRT5 and KRT14 are typical in EBS-DM.
• The Pro24Leu and 1649delG mutations in KRT5 are associated with EBS-MP.

Autosomal dominant mutations are those that cause signs in heterozygotes by acting in a dominant negative manner, i.e., the abnormal protein produced by the mutated allele interferes with the normal protein produced by the normal allele in the process of keratin filament assembly. In two different highly consanguineous families with autosomal dominant EBS, offspring homozygous for a missense mutation have been reported. In one case, a KRT5 allele was fully dominant and in the second a KRT14 allele was partially dominant [Stephens et al 1995 , Hu et al 1997].

Conversely, autosomal recessive mutations are those that cause symptoms only in homozygotes. In the few reported cases of autosomal recessive EBS, these are usually null alleles that produce no gene product. Heterozygotes are unaffected because 50% of the normal keratin product is adequate to stabilize the skin.

The proportion of KRT5 and KRT14 mutations producing each phenotype are outlined in the following table. Clinical overlap between EBS-K and EBS-DM is substantial; thus, much of the molecular genetic data have been lumped in the literature and the proportions presented in Table 3 are necessarily imprecise.

Penetrance

Penetrance is 100% for known autosomal dominant and autosomal recessive KRT5 and KRT14 mutations. Disease severity may be influenced by other factors and may show intrafamilial variation [Indelman et al 2005].

Anticipation

Anticipation is not observed in EBS.

Nomenclature

In 1886, Koebner coined the term epidermolysis bullosa hereditaria. In the late nineteenth and early twentieth centuries, Broq and Hallopeau coined the terms traumatic pemphigus, congenital traumatic blistering, and acantholysis bullosa; these terms are no longer in use [Fine et al 1999].

Prevalence

The prevalence of EBS is uncertain; estimates range from 1:30,000 to 1:50,000. EBS-WC is most prevalent as it does not result in neonatal death and interferes least with fitness. EBS-DM and EBS-K are rare, and EBS-MP is even rarer.

The experience of the National Epidermolysis Bullosa Registry (NEBR) suggests that ascertainment is highly biased and incomplete. A review of the Health Surveillance Registry Cards for British Columbia (1952-1989) showed 27 individuals with EB in a population of approximately 3,000,000 for a prevalence approaching 1:100,000 and an incidence, based on the birth rates during 1952-1989, of 1:56,000 for all types of EB [Sybert, unpublished].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

The three major types of epidermolysis bullosa syndrome, caused by mutations in ten different genes, are EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB). While agreement exists as to diagnostic criteria for some types of epidermolysis bullosa, the validity of rarer subtypes and their diagnositic criteria are disputed. For excellent clinical reviews, see Gedde-Dahl 1971 and Fine's Revised Classification System [Fine et al 2000].

The three major types of EB share easy fragility of the skin, manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, the presence and extent of scarring — especially in young children and neonates — may not be established or significant enough to allow identification of EB type; thus, skin biopsy is usually required to establish the diagnosis. A positive Nikolsky sign (blistering of uninvolved skin after rubbing) is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators. Post-inflammatory changes such as those seen in EBS, Dowling-Meara type (EBS-DM) are often mistaken for scarring or mottled pigmentation. Scarring can also occur in simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface. Congenital absence of the skin can be seen in any of the three major types of EB and is not a discriminating diagnostic feature.

Corneal erosions, esophageal strictures, and nail and tooth enamel involvement may indicate either DEB or JEB. Scarring especially of the hands and feet in milder cases suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB.

In almost all cases, a fresh biopsy from a newly induced blister stained by indirect immunofluorescence for the critical basement membrane protein components is necessary to establish the type of EB by determining the cleavage plane and the presence/absence of these protein components and their distribution.

Junctional EB .  Separation occurs above the basement membrane of the dermis within the lamina lucida of the dermal-epidermal junction, resulting in non-scarring blistering. Because atrophy may develop over time, the term "atrophicans" has been used in Europe to describe individuals with some form of junctional EB.

Broad classification of JEB includes lethal (or Herlitz) JEB and non-lethal (non-Herlitz) JEB, based on severity and survival past the first years of life. GABEB (generalized atrophic benign epidermolysis bullosa) historically has been ascribed to COL17A1 mutations, but the phenotype overlaps significantly with non-Herlitz JEB.

Mutations in the genes that encode the subunits of laminin 5 (LAMA3, LAMC2, LAMB3) and type 17 collagen (COL17A1) are causative. JEB with pyloric atresia has been associated with α6β4 integrin and plectin mutations (see below).

Dystrophic EB .  The blister forms below the basement membrane, and the basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Mutations in COL7A1, the gene encoding type VII collagen, have been demonstrated in some forms of dystrophic epidermolysis bullosa, both dominant and recessive.

• Bart syndrome [OMIM 132000], characterized by congenital absence of the skin on the lower legs and feet, non-scarring blistering of the skin and oral mucosa, and nail abnormalities, was originally reported as a subtype of EBS; however, demonstration of decreased anchoring fibrils and mutations in COL7A1 in one family led to recategorization as DEB. Some consider Bart syndrome to be most often, but not exclusively, a manifestation of dominant dystrophic EB, but the absence of skin on the legs can be seen in all forms in EB and may not be a distinguishing feature of any particular form.

EB caused by mutations in PLEC1.  Mutations in PLEC1, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause a cleavage in the lowest keratinocyte layer; hence, they could be considered to cause EBS. However, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia, and the rare and controversial EBS Ogna) are more complex.

• EB with muscular dystrophy [OMIM 226670].   Some individuals with EB resulting from PLEC1 mutations develop muscular dystrophy either in childhood or later in life [Smith et al 1996 ; Shimizu et al 1999 ; Charlesworth et al 2003 ; Koss-Harnes et al 2004 ; Schara et al 2004 ; Pfendner, Rouan et al 2005]. Within basal keratinocytes, plectin is localized to the inner plaques of the hemidesmosomes, which are hypoplastic and show poor association with keratin filaments. Electron microscopy of skin biopsies reveals a plane of cleavage (level of separation) within the bottom layer of the basal keratinocytes, just above the hemidesmosomes. Inheritance is autosomal recessive.

• EB with pyloric atresia [OMIM 226730].   In several US and Japanese families, EB with pyloric atresia is associated with premature termination mutations in PLEC1 and the genes encoding alpha 6 integrin (ITGA6) and beta 4 integrin (ITGB4) [Nakamura et al 2005 , Pfendner & Uitto 2005]. Disease course is severe and usually lethal in the neonatal period. Inheritance is autosomal recessive.

  Note: Pulkkinen & Uitto (1999) proposed that EB with muscular dystrophy and EB with pyloric atresia be considered "hemidesmosomal JEB" because the involved proteins are located in the hemidesmosomes.

• EB-Ogna [OMIM 131950], observed in one Norwegian and one German family, is caused by a site-specific missense mutation within the rod domain of PLEC1 [Koss-Harnes et al 2002]. Inheritance is autosomal dominant.

Management

Evaluations Following Initial Diagnosis

Evaluation of the sites of blister formation, including oral and esophageal blisters and erosions, may indicate the severity of the disease.

Treatment of Manifestations

Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing, and prevention and treatment of secondary infection are the mainstays of EB treatment.

Children are encouraged to tailor their activities to minimize trauma to the skin while participating as much as possible in age-appropriate play.

New blisters should be lanced and drained to prevent further spread from fluid pressure.

In most cases, dressings involve three layers:

• A primary non-adherent dressing that will not strip the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers: Some individuals with EBS can use ordinary bandaids. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline Gauze, Adaptic, Xeroform). Nonstick products (e.g., Telfa or N-Terface) or silicone-based products without adhesive (e.g., Mepitel or Mepilex) are also popular.
• A secondary layer provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g, Kerlix) are commonly used.
• A tertiary layer usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban or elasticized tube-gauze of varying diameters, such as Band Net).

Prevention of Primary Manifestations

Twenty percent aluminum chloride applied to palms and soles can reduce blister formation in some individuals, presumably by decreasing sweating.

Cyproheptadine (Periactin) can substantially reduce blistering in some individuals with EBS, Dowling-Meara type (EBS-DM) [Neufeld-Kaiser & Sybert 1997].

Use of keratolytics and softening agents for palmar plantar hyperkeratosis has some limited benefit in preventing tissue thickening and cracking.

Prevention of Secondary Complications

In infants and children with EBS-DM or EBS-K with more severe involvement, failure to thrive may be a problem, requiring additional nutritional support.

Fluid and electrolyte problems, which can be significant and even life-threatening in the neonatal period and in infants with widespread disease, require careful management.

The most common secondary complication is infection. Surveillance for wound infection is important and treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful.

Some children have delays or difficulty walking because of blistering and hyperkeratosis, especially in EBS-DM. Appropriate footwear and physical therapy are essential to preserve ambulation.

Surveillance

Surveillance for infection and proper wound healing is indicated.

Agents/Circumstances to Avoid

Excessive heat may exacerbate blistering and infection in EBS.

Poorly-fitting or coarse-textured clothing and footwear can cause trauma and should be avoided.

Avoiding activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) can reduce skin damage, but affected individuals who are determined to find ways to participate in these endeavors should be encouraged.

Most persons with EBS cannot use ordinary medical tape or bandaids.

Therapies Under Investigation

Proposed approaches to gene therapy for EBS include use of ribozymes, addition of other functional proteins [D'Alessandro et al 2004], and induction of a compensating mutation [Smith, Morley et al 2004]; no clinical trials have been carried out. The inducible mouse model for EBS should facilitate the development of these therapeutic approaches [Arin & Roop 2004].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

If a fetus is known to be affected with any form of EB, caesarean delivery may reduce the trauma to the skin during delivery.

No rigorous studies of treatment with Dilantin have been performed in EBS [Fine et al 1999].

Although the use of corticosteroids and vitamin E in treating EBS has been reported anecdotally, no rigorous clinical trials have been undertaken.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

Epidermolysis bullosa simplex (EBS) is usually inherited in an autosomal dominant manner, but in rare families it can be inherited in an autosomal recessive manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Many individuals diagnosed with EBS have an affected parent.
• However, a proband with EBS may have the disorder as the result of a de novo gene mutation. The more severe forms of autosomal dominant EBS are usually caused by a de novo mutation for an autosomal dominant allele.
• Recommendations for the evaluation of parents of a child with EBS and no known family history of EBS include a careful family and personal history and a physical examination if history is suggestive. Many families include individuals with a history of "blistering" but are unaware that they have EBS.

Sibs of a proband

• The risk to the sibs of the proband depends upon the genetic status of the parents.
• If a parent is affected, the risk is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the disease-causing mutation cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been reported in the mother of a proband with EBS [Nagao-Watanabe et al 2004].

Offspring of a proband

• Each child of an individual with EBS has a 50% chance of inheriting the mutation.
• In the rare situation in which both parents have an autosomal dominant mutation (e.g., in consanguineous unions), each child has a 75% chance of having at least one mutation.

Other family members of a proband.   The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and thus carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband.   The offspring of an individual with EBS are obligate heterozygotes (carriers) for a mutant allele causing EBS.

Other family members of a proband.   Each sib of a proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is available on a clinical basis once the mutations have been identified in the proband.

Related Genetic Counseling Issues

Establishing the mode of inheritance.  The mode of inheritance in a given family is usually established by pedigree analysis. Inheritance of EBS in families in which only one child is affected could be either autosomal dominant (as the result of a de novo gene mutation) or autosomal recessive; a de novo dominant mutation is the more likely mode of inheritance. Furthermore, EBS inherited in an autosomal recessive manner can generally be distinguished by immunohistochemistry.

Autosomal recessive inheritance of null alleles needs to be considered, especially if the parents are consanguineous. Autosomal recessive inheritance is suspected in (1) pedigrees showing consanguinity and affected sibs born to unaffected parents; and (2) individuals whose skin biopsy reveals absent tonofilaments in the basal cells or lack of staining with antibodies to either keratin 5 or keratin 14 (see Clinical Diagnosis).

Considerations in families with an apparent de novo mutation.  When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking.   DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and disease will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only or the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Molecular genetic testing.   Prenatal testing for pregnancies at increased risk for EBS is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Fetoscopy.   Electron microscopic evaluation of fetal skin biopsies is also diagnostic in EBS, Dowling-Meara type (EBS-DM), but the biopsy must be obtained by the procedure of fetoscopy. Fetoscopy carries a greater risk to pregnancy than CVS or amniocentesis and is performed relatively late (18-20 weeks) in gestation. It is not currently available in the US.

Preimplantation genetic diagnosis (PGD).  Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified in an affected family member in a research laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.