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Epidermolysis Bullosa with Pyloric Atresia

Synonyms: Carmi Syndrome, EB-PA, Junctional Epidermolysis Bullosa with Pyloric Atresia, PA-JEB. Includes: ITGA6-Related Epidermolysis Bullosa with Pyloric Atresia, ITGB4-Related Epidermolysis Bullosa with Pyloric Atresia, PLEC1-Related Epidermolysis Bullosa with Pyloric Atresia

, PhD and , MD.

Author Information
, PhD
Director, EBDx Program
GeneDx, Inc
Gaithersburg, Maryland
, MD
Director, Cincinnati Children's Epidermolysis Bullosa Center
Cincinnati Children's Hospital
Cincinnati, Ohio

Initial Posting: ; Last Update: February 14, 2013.

Summary

Disease characteristics. Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). The course of EB-PA is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of EB include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, contractures, and dilated cardiomyopathy.

Diagnosis/testing. Because the clinical features of all types of epidermolysis bullosa (EB) overlap significantly, examination of a skin biopsy by transmission electron microscopy (TEM) and/ or immunofluorescent antibody/antigen mapping is usually required to establish the diagnosis. The three genes in which mutations are known to cause EB-PA are ITGB4 (~80% of EB-PA), ITGA6 (~5%), and PLEC1 (~15%).

Management. Treatment of manifestations: Surgical intervention to correct pyloric atresia; standard treatment for gastroesophageal reflux disease; tracheostomy when indicated for respiratory failure; lance and drain new blisters and dress with three layers (primary: nonadherent; secondary: for stability and protection; tertiary: elastic properties to insure integrity); protect skin from shearing forces; teach caretakers proper handling of infants and children; psychosocial support, including social services and psychological counseling.

Prevention of secondary complications: Antibiotics and antiseptics to prevent wound infections; attention to fluid and electrolyte balance; additional nutritional support including a feeding gastrostomy when necessary; calcium, vitamin D, zinc, selenium, carnitine, and iron supplements as indicated.

Surveillance: Annual screening for anemia and zinc, vitamin D, and other nutritional deficiencies; periodic echocardiographic screening for dilated cardiomyopathy; bone mineral density scanning for detection of osteopenia and/or osteoporosis; surveillance in the second decade of life for squamous cell carcinoma.

Agents/circumstances to avoid: Shearing forces on the skin; ordinary medical tape or Band-Aids®; poorly fitting or coarse-textured clothing and footwear.

Pregnancy management: Consider cesarean section to reduce trauma to the skin of an affected fetus during delivery.

Genetic counseling. EB-PA is inherited in an autosomal recessive manner. The parents of an affected child are usually obligate heterozygotes (i.e., carriers). Because germline mosaicism and uniparental isodisomy are possible, carrier status of parents needs to be confirmed with molecular genetic testing. At conception, each sib of an affected individual whose parents are both carriers 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. Carrier testing for family members at increased risk and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of epidermolysis bullosa with pyloric atresia (EB-PA) is suspected in newborns with the following:

  • Congenital pyloric atresia with vomiting and abdominal distension resulting from complete obstruction of the gastric outlet. Radiographs reveal that the stomach is distended and filled with air (see Figure 1).
  • Fragility of the skin with:
    • Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring.
    • Significant oral and mucous membrane involvement
    • Large areas of absent skin (aplasia cutis congenital), often with a thin membranous covering, affecting the extremities or head
  • Ureteral and renal anomalies, including hydronephrosis, ureterocele, absent bladder, dysplastic kidneys, urinary collecting system/kidney duplication, obstructive uropathy, glomerulosclerosis
Figure 1

Figure

Figure 1. Radiograph of a 36-week gestational-age, one-day-old neonate with EB-PA. Note the single gastric bubble (white arrow).

Because the clinical features of all subtypes of epidermolysis bullosa (EB) overlap significantly (see Differential Diagnosis), clinical diagnosis of the specific subtype is unreliable and examination of a skin biopsy is usually required to establish the diagnosis of EB-PA, especially in infants (see Testing, Skin biopsy). Siblings of a previously affected child with the same biologic parents who have symptoms of gastric obstruction and skin fragility are likely to also have EB-PA.

Testing

Skin biopsy. Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping are the best ways to reliably establish the diagnosis of EB-PA.

A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). (Older blisters undergo change that may obscure the diagnostic morphology).

Note:

  • For TEM
    • Specimens must be placed in special fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test.
    • Formaldehyde-fixed samples cannot be used for electron microscopy.
  • For immunofluorescent antibody/antigen mapping
    • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus’) as specified by the laboratory performing the test.
    • Some laboratories prefer flash-frozen tissue.
    • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed.
  • Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB.

Transmission electron microscopy (TEM) is used to examine the number and morphology of the basement membrane zone structures — in particular, the number and morphology of anchoring fibrils, the presence of and morphology of hemidesmosomes, anchoring filaments, and keratin intermediate filaments as well as the presence of micro-vesicles showing the tissue cleavage plane.

Findings on TEM in EB-PA include the following:

Immunofluorescent antibody/antigen mapping. Findings include the following:

  • Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of mutations in either ITGA6 or ITGB4
  • Abnormal or absent staining with antibodies to plectin in EB-PA as a result of PLEC1 mutations

Normal staining for other antigens (e.g., collagen VII, laminin 332, keratins 5 and 14) confirms the diagnosis of EB-PA.

Note: Especially in milder forms of EB, indirect immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In addition, absence of one hemidesmosomal component (e.g., ITGA6 or ITGB4) may reduce the staining of other hemidesmosomal components as well (e.g., PLEC1, COL17). In these cases electron microscopic examination of a skin biopsy must be performed.

Molecular Genetic Testing

Genes. Mutations in three genes are known to cause EB-PA [Nakamura et al 2005, Pfendner & Uitto 2005, Pfendner et al 2005, Varki et al 2006, Pfendner et al 2007]:

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Epidermolysis Bullosa with Pyloric Atresia

Gene SymbolProportion of EB-PA Attributed to Mutations in This Gene 1 Test MethodMutations Detected
ITGB4 80% Sequence analysis Sequence variants 2, 3, 4
Deletion / duplication analysis 5 Exonic or whole-gene deletion 6
ITGA6 5% Sequence analysis Sequence variants 2
Deletion / duplication analysis 5 Unknown; none reported
PLEC1 15% Sequence analysis Sequence variants 2
Deletion / duplication analysis 5Unknown; none reported 7

1. Varki et al [2006]

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. 50% of persons of Hispanic heritage in the US have the ITGB4 mutation p.Cys61Tyr [Varki et al 2006].

4. Sequencing detects more than 98% of mutations present.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Birnbaum et al [2008]

7. No deletions or duplications of PLEC1 have been reported to cause epidermolysis bullosa with pyloric atresia.

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

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish of the diagnosis in a proband. The skin biopsy should be used to guide the molecular genetic testing strategy:

  • If the α6β4 integrin protein is reduced or absent on immunofluorescent antibody/antigen mapping and the cleavage plane on TEM is within the lamina lucida, most often mutations in ITGB4 are responsible and molecular genetic testing of ITGB4 should be pursued.
  • If no ITGB4 mutations are identified and biopsy results by immunofluorescent antibody/antigen mapping suggest that the α6β4 integrin protein is affected, molecular genetic testing of ITGA6 may be pursued.
  • In some cases the cleavage plane on TEM may be just above the hemidesmosomes in the lowest keratinocyte layer and plectin staining is reduced or absent on immunofluorescent antibody/antigen mapping [Charlesworth et al 2003, Nakamura et al 2004, Pfendner & Uitto 2005]. In these cases PLEC1 sequencing should be undertaken before ITGA6.

Carrier testing for at-risk relatives (in families with autosomal recessive inheritance) requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The course of epidermolysis bullosa with pyloric atresia (EB-PA) is usually severe and often lethal in the neonatal period. Infants with extensive aplasia cutis congenita and blistering or erosions may have fatal infections with sepsis and severe electrolyte imbalance in the first weeks to months of life.

Most affected children succumb as neonates; those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life.

Although mutations in ITGB4, ITGA6, and plectin usually result in EB-PA, there are also rare reports of ITGB4 resulting in milder forms of EB described as epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB) [Inoue et al 2000, Jonkman et al 2000] and pyloric atresia with enteropathy [Salvestrini et al 2008]. Although plectin mutations causing EB-PA usually result in severe blistering associated with PA, other mutations result in milder blistering and the disorders EBS Ogna and EB-MD.

Pyloric atresia may be detected in utero as oligohydramnios. Pyloric atresia is evident at birth and is characterized by vomiting, failure to tolerate any feeding or to pass stool, and a distended abdomen with a large stomach bubble (see Figure 1). Surgical repair of the pyloric atresia is necessary for survival.

Renal and ureteral anomalies can include dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder [Puvabanditsin et al 1997, Kambham et al 2000, Nakano et al 2000, Wallerstein et al 2000, Varki et al 2006, Pfendner et al 2007].

The long-term prognosis of EB-PA depends on the severity of the cutaneous manifestations.

Manifestations that can occur in EB-PA as well as JEB Herlitz (H-JEB) and non-Herlitz (NH-JEB) types, dystrophic epidermolysis bullosa (DEB), and EBS. The following manifestations are now recognized to be found in the major EB types as described in the findings of the National EB Registry [Fine et al 1999]:

  • Congenital localized absence of skin (aplasia cutis congenita) can be seen in any of the major types of EB and is not a discriminating diagnostic feature of any of these types of EB in general or any subtype of JEB. Congenital absence of skin on the extremities had been classified as Bart syndrome [OMIM 132000] but currently is considered a manifestation of all types of EB.
  • Milia are small white-topped papules; they are often confused with epidermal cysts and are not confined to any type of EB, although they are most common in individuals with DEB.
  • Nail dystrophy is defined as changes in size, color, shape, or texture of nails and is not confined to any one form of EB.
  • Scarring alopecia is defined as complete loss of scalp hair follicles as a result of scarring and loss of hair follicles. Scarring alopecia is more prevalent in JEB and DEB but is not confined solely to any one form of EB.
  • Hypotrichosis is defined as reduction in the number of hair follicles in a given area compared to the number of hair follicles in the same area of a normal individual of the same gender. Hypotrichosis is not confined to any one form of EB.
  • Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet. "Other contractures" refers to loss of mobility of any other joints as a result of fibrous tissue scars. Although these changes are more prevalent in DEB, they have also been observed occasionally in the other forms of EB.
  • Scarring is not confined to any form of EB and has been observed in 30% of those with EBS, 76% of those with JEB, and up to 98% of those with DEB.
  • Exuberant granulation tissue. Although exuberant granulation tissue was previously thought to be confined to those with JEB (23%), it has also been observed in a small percentage of those with DEB (≤12%) and EBS (0.7%). This finding is misleading because it does not usually appear until the affected child is a few years old and most children with H-JEB do not survive that long.
  • Dilated cardiomyopathy. Dilated cardiomyopathy can occur in individuals with different forms of epidermolysis bullosa who survive the neonatal period. The development of dilated cardiomyopathy was associated with nutritional deficiency of carnitine in one study, and it has been postulated that nutritional deficiency of selenium may also contribute. However, these associations have not been proven to be causative [Sidwell et al 2000].

Genotype-Phenotype Correlations

The forms of EB-PA with the severest cutaneous manifestations are caused by a mutation on each allele that results in a premature termination codon, although a number of amino acid substitutions also result in a severe phenotype, such as the recurrent ITGB4 mutation p.Cys61Tyr in Hispanic individuals with EB-PA [Varki et al 2006].

Individuals with EB-PA mutations in the genes encoding α6 or β4 integrin may also show renal and ureteral anomalies.

Penetrance

Mutations in ITGB4, ITGA6, and PLEC1 are 100% penetrant in individuals who have two mutations on different alleles in the same gene.

Prevalence

According to the National EB Registry, prevalence of all types of junctional epidermolysis bullosa (JEB) is 0.44 per million in the US population [Fine et al 1999]. Historically, EB-PA was considered a subclass of JEB; however, EB-PA is rare and its prevalence and incidence have not been determined.

Since EB-PA is extremely rare, carrier frequency in the general population is not known; however, it can be conservatively estimated to be less than one in 5000 (~10x rarer than Herlitz junctional epidermolysis bullosa [HJEB], the carrier frequency of which is ~1:700).

Differential Diagnosis

Pyloric atresia. In contrast to pyloric stenosis, which presents insidiously with vomiting, pyloric atresia is present at birth and causes complete obstruction of the gastric outlet. The diagnosis of epidermolysis bullosa with pyloric atresia (EB-PA) should be considered in every neonate with pyloric atresia regardless of the degree of skin blistering.

Epidermolysis bullosa. The four major types of EB, caused by mutations in ten different genes, are EB simplex (EBS), hemidesmosomal EB, junctional EB (JEB), and dystrophic EB (DEB) (see Figure 2).

Figure 2

Figure

Figure 2. Diagram showing locations affected by mutations causing the four major subtypes of EB syndromes

Although agreement exists as to diagnostic criteria for some types of EB, the validity of rarer subtypes and their diagnostic criteria are disputed. Excellent clinical reviews include the chapter on EB in Emery and Rimoin’s Principles and Practice of Medical Genetics [Anton-Lamprecht & Gedde-Dahl 2002] and Fine's revised classification system [Fine et al 1999, Fine et al 2000].

The four major types of EB share fragility of the skin, manifested by blistering with little or no trauma. A positive Nikolsky sign (blistering of uninvolved skin after rubbing) is common to all types of EB. No clinical findings are specific to a given type; thus, establishing the type of EB requires a fresh skin biopsy from a newly induced blister that is stained by indirect immunofluorescence for critical basement membrane protein components. The diagnosis is established by determining the cleavage plane on TEM and the presence/absence of these protein components by immunofluorescent antibody/antigen mapping and their distribution. Electron microscopy is also diagnostic and often more useful in milder forms of EB.

Clinical examination is useful in determining the extent of blistering, the presence of oral and other mucous membrane lesions, and the presence and extent of scarring.

Limitations of the clinical findings in establishing the type of EB include the following:

  • In young children and neonates the extent and severity of blistering and scarring may not be established or significant enough to allow identification of EB type.
  • Mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators (see Clinical Description).
  • Post-inflammatory changes such as those seen in EBS, Dowling-Meara type (EBS-DM) are often mistaken for scarring or mottled pigmentation.
  • Scarring can occur in EBS and JEB 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 (i.e., EBS, JEB, DEB) and is not a discriminating diagnostic feature (see Clinical Description).

Clinical findings that tend to be characteristic for a specific type of EB include the following:

  • Corneal erosions, esophageal strictures, and nail involvement may indicate either DEB or JEB.
  • Scarring limited to the hands and feet in milder cases suggests autosomal dominant DEB (DDEB).
  • Pseudosyndactyly (mitten deformities) and contractures in older children and adults usually suggests autosomal recessive DEB (RDEB).
  • Granulation tissue suggests JEB.
  • Hyperkeratosis of the palms and soles suggests EBS, especially the Dowling-Meara type.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin that results in nonscarring blisters caused by little or no trauma. Four clinical subtypes of EBS range from relatively mild blistering of the hands and feet to more generalized blistering, 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 approximately age 18 months; 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-DM.
  • In EBS with mottled pigmentation type (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, Dowling-Meara type (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.

Hemidesmosomal EB. Pulkkinen & Uitto [1999] proposed that EB with muscular dystrophy (EB-MD) and EB with pyloric atresia (EB-PA) be considered "hemidesmosomal JEB" because the involved proteins are located in the hemidesmosomes. 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.

Note: "Hemidesmosomal epidermolysis bullosa" is not a universally accepted designation; the following three types typically have been included either with EBS or JEB.

Junctional EB (JEB). Separation occurs above the basement membrane of the dermis, within the lamina lucida of the dermal-epidermal junction, resulting in nonscarring blistering.

Because atrophy may develop over time, in Europe the term "atrophicans" has been applied to individuals with some form of JEB.

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

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

Dystrophic EB (DEB). 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 all forms of DEB, both dominant and recessive [Varki et al 2007].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa with pyloric atresia (EB-PA), the following evaluations are recommended:

  • Evaluation of the sites of blister formation including skin and oral mucosa
  • Tests of renal function and renal ultrasound if indicated
  • Delineation of involvement of the whole esophagus (with concentration on the upper cervical portion) by barium swallow as needed; endoscopy can be traumatic and should be avoided, if possible.
  • Medical genetics consultation; consideration of molecular genetic testing as directed by the results of skin biopsy with transmission electron microscopy and immunofluorescent antibody/antigen mapping

Treatment of Manifestations

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

In most cases, dressings for blisters involve three layers:

  • A primary nonadherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers include the following:
    • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® gauze, Adaptic®, Xeroform®)
    • Nonstick products (e.g., Telfa®, N-terface®)
    • Silicone-based products without adhesive (e.g., Mepitel®, Mepilex®)
    • Addition of a topical antibiotic or antiseptic such as bacitracin, mupirocin, silver or honey
  • A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Kerlix® or Conform) are commonly used.
  • A tertiary layer that 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® or Tubifast®).

GI tract. Surgical intervention is required to correct pyloric atresia. Many children need medical treatment for gastroesophageal reflux disease.

Esophageal strictures and webs can be dilated repeatedly to improve swallowing [Azizkhan et al 2007].

Other. A hoarse cry in an infant should alert the clinician to the possibility of airway obstruction with granulation tissue [Ida et al 2012]. Decisions about tracheostomy should involve the family and take into consideration the medical condition of the infant. Because of the poor prognosis and severe pain and discomfort experienced by these infants, a discussion with the family and hospital ethics committee often helps to determine the type of intervention and comfort care to provide [Yan et al 2007].

Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation.

Psychosocial support, including social services and psychological counseling, is essential [Lucky et al 2007].

Dental care is necessary because of inherent enamel abnormalities [Kirkham et al 2000].

Prevention of Primary Manifestations

New blister formation can be minimized by wrapping and padding of extremities, use of soft and properly fitted clothing and footwear, avoidance of contact with adhesives, and a life style that avoids contact sports and other activities that create friction.

Prevention of Secondary Complications

The most common secondary complication is infection. In addition to wound care, treatment of chronic infection of wounds is a challenge. Many affected individuals become infected with resistant bacteria, most often methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Pseudomonas aeruginosa. Both antibiotics and antiseptics need to be employed.

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.

In children who survive the newborn period, nutritional deficiencies must also be addressed when they are identified:

  • Calcium and vitamin D replacement for osteopenia and osteoporosis
  • Zinc supplementation for wound healing [Mellerio et al 2007]
  • Selenium and carnitine replacement for possible prevention of dilated cardiomyopathy.

Iron deficiency anemia, a chronic problem, can be treated with oral or intravenous iron infusions and red blood cell transfusions.

Surveillance

Perform annual screening for iron deficiency anemia with complete blood counts and possibly measurement of serum iron concentration to provide iron supplementation when necessary.

Screen annually for zinc deficiency by measuring serum zinc concentration to provide zinc supplementation when necessary for enhanced wound healing.

Periodic echocardiographic screening to evaluate for the development of dilated cardiomyopathy is appropriate.

Screening with bone mineral density scanning may detect early osteopenia and/ or osteoporosis. No guidelines have been established regarding the age at which this should begin.

Because of the risk for squamous cell carcinoma, surveillance in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal is essential. Frequent biopsies of suspicious lesions, followed by local excision, may be necessary.

Agents/Circumstances to Avoid

Most persons with EB-PA cannot use ordinary medical tape or Band-Aids®.

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

In general, activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) should be avoided; affected individuals who are determined to participate in such activities should be encouraged to find creative ways to protect their skin.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Cesarean section is often recommended to reduce trauma to the skin of an affected fetus during delivery.

Therapies Under Investigation

See Junctional Epidermolysis Bullosa, Management, Therapies Under Investigation.

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

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. —ED.

Mode of Inheritance

Epidermolysis bullosa with pyloric atresia (EB-PA) is inherited in an autosomal recessive manner.

To date, there is no evidence to indicate that a heterozygous mutation in ITGB4, ITGA6, or PLEC1 results in EB-PA.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual whose parents are both carriers 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 risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with EB-PA are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the family. Sequencing of the entire gene in the unaffected reproductive partner of a known carrier is possible and is expected to identify over 99% of mutations in that gene, as large deletions or insertions are extremely rare (a single report in the literature).

Related Genetic Counseling Issues

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.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

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 diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal testing for pregnancies at increased risk for EB-PA is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing alleles 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.

Ultrasound examination. Occasionally pyloric atresia may be suspected because of oligohydramnios, with or without elevated concentration of alpha-fetoprotein and acetylcholinesterase, and echogenic material in the amniotic fluid [Dolan et al 1993, Azarian et al 2006].

Fetoscopy. Electron microscopic evaluation of fetal skin biopsies obtained by fetoscopy is also diagnostic in EB-PA. Fetoscopy carries a greater risk to pregnancy than CVS or amniocentesis and is performed relatively late (18-20 weeks) in gestation. Prenatal diagnosis for EB-PA using fetoscopy is not currently available in the US but may be available in Europe.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • DEBRA International
    Am Heumarkt 27/3
    Vienna 1030
    Austria
    Phone: +43 1 876 40 30-0
    Fax: +43 1 876 40 30-30
    Email: office@debra-international.org
  • DebRA of America, Inc. (Dystrophic Epidermolysis Bullosa Research Association)
    16 East 41st Street
    3rd Floor
    New York NY 10017
    Phone: 866-332-7276 (toll-free); 212-868-1573
    Email: staff@debra.org
  • DebRA UK
    DebRA House
    13 Wellington Business Park
    Crowthorne Berkshire RG45 6LS
    United Kingdom
    Phone: +44 01344 771961
    Fax: +44 01344 762661
    Email: debra@debra.org.uk
  • Medline Plus
  • EBCare Registry
    The EBCare Registry is a resource for individuals and families affected by all forms of epidermolysis bullosa (EB) and qualified researchers working on approved EB research projects.
    Phone: 866-332-7276
    Fax: 888-363-0790
    Email: coordinator@EBCare.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Epidermolysis Bullosa with Pyloric Atresia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Epidermolysis Bullosa with Pyloric Atresia (View All in OMIM)

147556INTEGRIN, ALPHA-6; ITGA6
147557INTEGRIN, BETA-4; ITGB4
226730EPIDERMOLYSIS BULLOSA JUNCTIONALIS WITH PYLORIC ATRESIA
601282PLECTIN 1; PLEC1

ITGB4

Normal allelic variants. The normal full-length cDNA is encoded in 41 exons spanning 36 kb of the genomic DNA. The cDNA comprises 5921 bp with an open reading frame of 5258 nucleotides encoding 1822 amino acids. Two splicing variants express different isoforms of the protein [Pulkkinen et al 1997c]. The most common epidermal variant does not express exon 33.

Pathologic allelic variants. More than 100 mutations spanning all of ITGB4 have been described in EB-PA [Pulkkinen et al 1997b, Pulkkinen et al 1997c, Pulkkinen et al 1998a, Pulkkinen et al 1998b, Ashton et al 2001, Nakano et al 2001, Iacovacci et al 2003, Varki et al 2006]. Mutations that cause premature termination codons on both alleles result in the most severe phenotypes, which are frequently lethal in the neonatal period. Other types of mutations including amino acid substitutions and splicing mutations may result in a less severe phenotype [Mellerio et al 1998, Pulkkinen et al 1998b, Chavanas et al 1999, Varki et al 2006]. In one case severe blistering without pyloric atresia was described from a homozygous missense mutation in ITGB4 [Inoue et al 2000] and in another a homozygote with missense and PTC ITGB4 mutations [Inoue et al 2000, Jonkman et al 2000]. Few recurrent mutations have been described; however the mutation p.Cys61Tyr is common in Hispanic persons with JEB-PA in the US [Varki et al 2006]. See Table 2.

Table 2. Selected ITGB4 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.182G>Ap.Cys61TyrNM_000213​.3
NP_000204​.3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Integrins associate in pairs containing one alpha and one beta chain. α6β4 integrin comprises one α6 and one β4 integrin protein from the integrin family of proteins and is a component of the hemidesmosomes of the epidermis. Within the hemidesmosome, α6β4 integrin forms attachments with collagen XVII to fulfill its role in the network of protein giving the epidermal strength and integrity and anchor the epidermal cells to the underlying dermis through attachments of the hemidesmosomes with the basement membrane. α6β4 integrin has also been shown to be involved in cell signaling and may play a role in carcinogenesis [Chung et al 2004, Guo et al 2006, Yoon et al 2006, Folgiero et al 2007].

Abnormal gene product. Null alleles may result in little or no protein seen with staining with anti-α6β4 integrin antibodies. Reduced staining was seen in some milder cases resulting from amino acid substitutions or splice junction mutations.

ITGA6

Normal allelic variants. Two transcript variants encoding two different isoforms have been found for this gene. The normal cDNA of variant 1 comprises 5680 bp with an open reading frame of 3273 nucleotides encoding 1091 amino acids in 26 exons. Transcript variant 2 contains an alternate coding exon from variant 1 that results in a frameshift and is encoded in a 5810-bp cDNA. The resulting protein isoform b is shorter (1073 amino acids) than isoform a and has a distinct C terminus.

Pathologic allelic variants. Only five individuals with EB-PA as a result of α6 integrin mutations have been described in the literature. Insertion/deletion, splice junction, and amino acid substitution mutations have been described [Ruzzi et al 1997, Gache et al 1998, Lepinard et al 2000, Varki et al 2006].

Normal gene product. Integrins associate in pairs containing one alpha and one beta chain. α6β4 integrin comprises one α6 and one β4 integrin from the integrin family of proteins and is a component of the hemidesmosomes of the epidermis. Integrins are known to participate in cell adhesion as well as cell surface-mediated signaling.

Abnormal gene product. Null alleles may result in little or no protein seen with staining with anti-α6β4 integrin antibodies.

PLEC1

Normal allelic variants. The normal cDNA of variant 1 is 14755 bp with an open reading frame of 13722 nucleotides encoding 4575 amino acids in 32 exons [McLean et al 1996]. Expression of the different isoforms result from alternative splicing of exon 1 as well as use of different 5' untranslated regions. At least ten other variant transcripts have been described. The expression of different 5' regions affects the subcellular localization of the protein and the resulting attachments to organelles and intermediate filaments [Rezniczek et al 2003]. There is also a rodless form lacking exon 31.

Pathologic allelic variants. The three phenotypes associated with plectin mutations are EB-PA, EB-MD, and EBS-Ogna:

Table 3. Selected PLEC1 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.6328C>Tp.Arg2110Trp 1 NM_201380​.2
NP_958782​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Koss-Harnes et al [2002]

Normal gene product. Plectin is a large cytolinker protein expressed in the epidermis, muscle, and other tissues. Plectin acts in the epidermis to link the intermediate filament network to the hemidesmosome and desmosomes thereby allowing stable attachments between cells and of cells to the underlying basal lamina. In the epidermis, plectin is found as a component of the hemidesmosome and forms attachments to α6β4 integrin. At least 11 different isoforms are produced by alternative splicing and use of different 5' untranslated regions [Rezniczek et al 2003].

Abnormal gene product. Null alleles may result in little or no protein seen with staining with anti-plectin antibodies. In-frame deletions or insertions, splicing mutations, and certain missense mutations may result in some partially functional protein and reduced or patchy staining with anti-plectin antibodies and a milder phenotype.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

Revision History

  • 14 February 2013 (me) Comprehensive update posted live
  • 28 April 2009 (cd) Revision: PLEC1 testing clinically available; prenatal testing available
  • 22 February 2008 (me) Review posted to live Web site
  • 10 May 2007 (egp) Original submission
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