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Epidermolysis Bullosa with Pyloric Atresia

Synonyms: Carmi Syndrome, EB-PA, Junctional Epidermolysis Bullosa with Pyloric Atresia, PA-JEB

, PhD and , MD.

Author Information

Initial Posting: ; Last Update: September 7, 2017.

Estimated reading time: 28 minutes

Summary

Clinical 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.

The diagnosis of EB-PA is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with EB-PA: ITGA6 (~5% of EB-PA), ITGB4 (~80%), or PLEC (~15%). Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping can be performed but is no longer the preferred method of diagnosis.

Management.

Treatment of manifestations: 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; surgical intervention to correct pyloric atresia; standard treatment for gastroesophageal reflux disease; nutrition consultation to address oral intake and nutritional needs; referral to urology and/or nephrology for renal anomalies and abnormal renal function; tracheostomy when indicated for respiratory failure; psychosocial support, including social services and psychological counseling.

Prevention of primary manifestations: Minimization of new blister formation by wrapping and padding of extremities, use of soft and properly fitted clothing and footwear, avoidance of contact with adhesives and of contact sports and other activities that create friction.

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.

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 or preimplantation genetic diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in the family.

Diagnosis

Suggestive Findings

Epidermolysis bullosa with pyloric atresia (EB-PA) should be suspected in newborns with the following clinical features:

  • 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, and glomerulosclerosis
Figure 1. . Radiograph of a 36-week gestational-age, one-day-old neonate with EB-PA.

Figure 1.

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

Establishing the Diagnosis

The diagnosis of EB-PA is established in a proband by one or both of the following:

Note: Genetic testing is the preferred diagnostic method. Skin biopsy for diagnostic purposes is no longer routinely performed

Molecular Genetic Testing

Molecular testing approaches can include use of a multigene panel, more comprehensive genomic testing, and serial single-gene testing.

A multigene panel (including phenotype-focused exome analysis) that includes ITGA6, ITGB4, PLEC, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing including exome sequencing and genome sequencing may also be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Serial single-gene testing

Table 1.

Molecular Genetic Testing Used in Epidermolysis Bullosa with Pyloric Atresia

Gene 1Proportion of EP-BA Attributed to Pathogenic Variants in This Gene 2Proportion of Pathogenic Variants 3 Detectable by Test Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ITGA65%5%None reported
ITGB460%~98% 6Rare 7
PLEC15%15%None reported
1.
2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

50% of persons of Hispanic heritage in the United States have the ITGB4 pathogenic variant p.Cys61Tyr [Varki et al 2006].

7.

Skin Biopsy

Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping is sometimes performed to 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; and 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 pathogenic variants in either ITGA6 or ITGB4
  • Abnormal or absent staining with antibodies to plectin in EB-PA as a result of PLEC pathogenic variants

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., PLEC, COL17). In these cases electron microscopic examination of a skin biopsy must be performed.

Clinical Characteristics

Clinical Description

The course of epidermolysis bullosa with pyloric atresia (EB-PA) is usually severe and often lethal in the neonatal period. Most affected children succumb as neonates.

Cutaneous manifestations. Those who survive the neonatal period 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. Many of the findings listed below are present in multiple forms of EB and are not diagnostic of EB-PA.

  • 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. 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.
  • Milia are small white-topped papules; they are often confused with epidermal cysts.
  • Nail dystrophy is defined as changes in size, color, shape, or texture of nails.
  • Scarring alopecia is defined as complete loss of scalp hair follicles as a result of scarring and loss of hair follicles.
  • 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.
  • Exuberant granulation tissue does not usually appear until the affected child is a few years old and most children with EB-PA do not survive that long.
  • Contractures may result from loss of mobility of joints as a result of fibrous tissue scars.

Pyloric atresia may be detected in utero using ultrasound or MRI (see Genetic Counseling, Prenatal Testing and Preimplantation Genetic Diagnosis). Pyloric atresia is evident at birth. It 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, Walker et al 2017].

Genotype-Phenotype Correlations

The forms of EB-PA with the severest cutaneous manifestations are caused by a pathogenic variant 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 variant p.Cys61Tyr, which is common in Hispanic individuals with EB-PA [Varki et al 2006, Masunaga et al 2015, Mutlu et al 2015, Mencía et al 2016, Masunaga et al 2017].

Penetrance

Pathogenic variants in ITGA6, ITGB4, and PLEC are 100% penetrant in individuals who have biallelic pathogenic variants 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 junctional EB (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 at 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 (EB). According to the 2014 classification system, the four major types of EB, caused by pathogenic variants in 18 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome (KS) [Fine et al 2014]. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis.

The four major types of EB share easy fragility of the skin (and mucosa in many cases), 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, defining characteristics such as 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, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge 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 generalized severe EBS (EBS-gen sev), are often mistaken for scarring or mottled pigmentation. Scarring can 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 four major types of EB and is not a discriminating diagnostic feature.

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

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin that results in nonscarring blisters caused by little or no trauma. The four most common clinical subtypes of EBS range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. Although EB-PA caused by biallelic pathogenic changes in PLEC is classified as a form of EBS, affected individuals are very rare compared to the overwhelming majority of individuals with EB caused by heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14, which encode keratin 5 or 14, respectively. Therefore, the 2014 nomenclature refers to the specific pathogenic variants found in KRT5 or KRT14 (see EBS: Nomenclature).

  • In EBS, localized (EBS-loc; previously known as Weber-Cockayne type), 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, generalized intermediate (EBS-gen intermed; previously known as Koebner type), blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-gen sev.
  • In EBS with mottled pigmentation type (EBS-MP), skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; 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, generalized severe (EBS-gen sev; previously known as Dowling-Meara type), 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. 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-gen sev may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.

EB caused by pathogenic variants in PLEC. Biallelic and heterozygous pathogenic variants in PLEC, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause cleavage in the basal keratinocyte layer. Hence, these disorders are classified as EBS in the 2014 classification system. In most cases, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia) are more complex:

Junctional EB (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers, and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. The broad classification of JEB is divided into generalized and localized major subtypes with subordinate phenotypic subtypes. JEB, generalized includes: JEB, generalized severe (JEB-gen sev, formerly Herlitz JEB); JEB, generalized intermediate (JEB-gen intermed); JEB with pyloric atresia (JEB-PA); JEB-late onset (JEB-LO); and JEB with respiratory and renal involvement (JEB-RR).

  • In JEB-gen sev, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur.
  • In JEB-gen intermed, the phenotype may be milder with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period.

Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, and joint contractures. Biallelic pathogenic variants in one of the following four genes are known to cause JEB: LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%).

JEB with pyloric atresia has been associated with biallelic pathogenic variants in either α6β4 integrin or plectin; inheritance is autosomal recessive.

Dystrophic EB (DEB). The blister forms below the basement membrane, in the superficial dermis. The basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Pathogenic variants in COL7A1, the gene encoding type VII collagen, have been demonstrated in all forms of DEB, both dominant and recessive [Varki et al 2007].

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, if they were not performed as part of the evaluation that led to the diagnosis:

  • Evaluation of the sites of blister formation including skin and oral mucosa
  • Tests of renal function including BUN, creatinine, and urinalysis
  • Renal ultrasound
  • 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.
  • Consultation with a clinical geneticist and/or genetic counselor

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®).

Gastrointestinal

  • 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].
  • Consultation with a dietitian or nutritionist can be helpful, especially if there is significant mucosal blistering in the mouth preventing adequate oral intake.

Renal. The following are appropriate:

  • Referral to an urologist if there are symptoms of difficulty or discomfort with voiding
  • Referral to a nephrologist if renal function studies and/or urinalysis are abnormal

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].

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; and avoidance of: contact with adhesives, 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), multidrug resistant Pseudomonas aeruginosa, and Group A beta-hemolytic Streptococci. 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.

Dilated cardiomyopathy can occur in individuals 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 [Sidwell et al 2000].

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.

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 recommended by some obstetricians 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 in the US and www.ClinicalTrialsRegister.eu in Europe 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 pathogenic variant in ITGA6, ITGB4, or PLEC 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.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with EB-PA are obligate heterozygotes (carriers) for an ITGA6, ITGB4, or PLEC pathogenic variant.

Other family members. Each sib of the proband's carrier parents is at a 50% risk of being a carrier of an ITGA6, ITGB4, or PLEC pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the EB-PA-related pathogenic variants in the family.

Sequencing of the entire gene in the unaffected reproductive partner of a known carrier is possible and is expected to identify more than 99% of pathogenic variants in that gene, as large deletions or insertions are extremely rare.

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the ITGA6, ITGB4, or PLEC pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for EB-PA are possible.

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 [Azarian et al 2006]. Gastric blockage may also be observed on fetal MRI [Maurice et al 2013, Merrow et al 2013]. Complete chorioamniotic membrane separation detected through ultrasound can also be suggestive of the diagnosis of EB-PA [Dural et al 2014].

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 Chile
    Francisco de Villagra 392
    Ñuñoa Region Metropolitana
    Chile
    Phone: +56 2 22286725
  • 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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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; PLEC

Molecular Genetic Pathogenesis

Integrins associate in pairs containing one alpha and one beta chain. The α6β4 integrin comprises one α6 (encoded by ITGA6) and one β4 integrin (encoded by ITGB4) from the integrin family of proteins, and is a component of the hemidesmosomes of the epidermis. Plectin is a large cytolinker protein expressed in the epidermis, muscle, and other tissues. Together, along with collagen XVII and CD151 (which are transmembrane proteins) and BP230, plectin and α6β4 integrin are critical structural components of the hemidesmosomes in the epidermis. The α6β4 integrin and plectin associate, causing a conformational change to a stable complex. This stabilization is thought to cause the recruitment of the other proteins into the hemidesmosomes. The α6β4 integrin also binds laminin 332 located in the basement membrane lamina lucida, and plectin binds the cytokeratins (as well as BP230), forming a continuous network of proteins that anchor the basement membrane complex to the cytokeratin layers of the epidermis. The result is a structurally resilient network of proteins binding the layers of the epidermis together [Chung et al 2004, Guo et al 2006, Yoon et al 2006, Folgiero et al 2007, de Pereda et al 2009].

ITGA6

Gene structure. Two transcript variants encoding two different isoforms have been reported. The 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Only six individuals with EB-PA caused by α6 integrin pathogenic variants have been described in the literature. Insertion/deletion, splice junction, and amino acid substitution variants have been described [Ruzzi et al 1997, Gache et al 1998, Lépinard et al 2000, Varki et al 2006, Masunaga et al 2017].

Normal gene product. ITGA6 encodes integrin-α6, the alpha chain of α6β4 integrin.

Abnormal gene product. Loss or reduction of integrin-α6 results in disease.

ITGB4

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 100 pathogenic variants 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]. Pathogenic variants 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 variants including amino acid substitutions and splicing variants may result in a less severe phenotype [Mellerio et al 1998, Pulkkinen et al 1998b, Chavanas et al 1999, Varki et al 2006]. Rarely, homozygous variants associated with severe blistering without pyloric atresia have been described [Inoue et al 2000, Jonkman et al 2000]. Few recurrent pathogenic variants have been reported; however the variant p.Cys61Tyr is common in Hispanic persons with JEB-PA in the United States [Varki et al 2006]. Large deletions have also been described [Mencía et al 2016].

Table 2.

Selected ITGB4 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein 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 authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. ITGB4 encodes integrin-β4, the alpha chain of α6β4 integrin.

Abnormal gene product. Loss or reduction of integrin-β4 results in disease.

PLEC

Gene structure. 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 results 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. All types of plectin variants causing EB-PA have been described: nonsense, missense, and splicing variants, insertions, and deletions [Schara et al 2004, Nakamura et al 2005, Pfendner et al 2005, Uitto et al 2007]. These variants have an autosomal recessive inheritance pattern and have been found throughout the gene, although clustering in the last two large exons has been observed. The mildest phenotypes are usually associated with amino acid substitutions or in-frame insertions or deletions [Pfendner et al 2005].

Normal gene product. Plectin links the intermediate filament network to the hemidesmosome and desmosomes (see Molecular Genetic Pathogenesis). At least 11 different isoforms are produced by alternative splicing and use of different 5' untranslated regions [Rezniczek et al 2003].

Abnormal gene product. Loss or reduction of plectin results in disease.

References

Literature Cited

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Chapter Notes

Revision History

  • 7 September 2017 (ma) Comprehensive update posted live
  • 14 February 2013 (me) Comprehensive update posted live
  • 28 April 2009 (cd) Revision: PLEC testing clinically available; prenatal testing available
  • 22 February 2008 (me) Review posted live
  • 10 May 2007 (egp) Original submission
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