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

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:

• Cleavage may be within the lamina lucida or just above the hemidesmosomes in the lowest layer of the basal keratinocytes.
• Hemidesmosomes may be reduced in number or dysmorphic [Kunz et al 2000, Jonkman et al 2002, Charlesworth et al 2003, Pasmooij et al 2004].

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.

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.

Genetically Related (Allelic) Disorders

ITGB4. Mutations in ITGB4 can result in EB-PA, EBS (rare), JEB (rare) [Inoue et al 2000, Jonkman et al 2000], or pyloric atresia with desquamative enteropathy and no skin disease (rare) [Salvestrini et al 2008].

ITGA6. EB-PA is the only phenotype associated with mutations in ITGA6.

PLEC1. The other phenotypes associated with PLEC1 mutations:

• EB with muscular dystrophy (EB-MD) [OMIM 226670, Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005]. Approximately 50 cases of EB-muscular dystrophy (EB-MD) have been reported worldwide. Blistering occurs early and is generally mild. Muscular dystrophy may not appear until later childhood, adolescence, or in some cases adulthood, and can cause immobility and eventually death later in life. Mutations have been described throughout PLEC1 but seem to cluster in the two long open reading frames containing exons in the 3' end of the gene. Nonsense, missense, insertion/deletion, and splice junction mutations have been described. The mildest phenotypes are usually associated with in-frame insertions or deletions, which do not alter the reading frame of the mRNA [Pfendner et al 2005]. Inheritance is autosomal recessive.
• EB simplex-Ogna (see Epidermolysis Bullosa Simplex), observed in one Norwegian and one German family with autosomal dominant inheritance, is a result of the site-specific missense p.Arg2110Trp mutation within the rod domain of PLEC1 [Koss-Harnes et al 2002]. A single lethal case of autosomal recessive EBS resulting from PLEC1 mutations has also been described [Charlesworth et al 2003]. Kunz et al [2000] also described a case of EBS with severe mucous membrane involvement as a result of mutations in PLEC1.

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).

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.

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

• The parents of an affected child are usually obligate heterozygotes and therefore each parent carries one mutant allele.
• Because germline mosaicism and uniparental isodisomy have been reported in EB-PA [Natsuga et al 2010] and JEB [Pulkkinen et al 1997a, Takizawa et al 2000, Cserhalmi-Friedman et al 2002, Fassihi et al 2005], carrier status of parents needs to be confirmed with molecular genetic testing.
• Heterozygotes (carriers) are asymptomatic.

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.

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Author Notes

Web: www.genedx.com

Web: www.cincinnatichildrens.org/eb-center

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