Outcome After Surgical Repair of Junctional Epidermolysis Bullosa–Pyloric Atresia Syndrome: Title and subTitle BreakA Report of 3 Cases and Review of the Literature FREE

JUNCTIONAL epidermolysis bullosa–pyloric atresia syndrome (JEB-PA) is a rare, autosomal recessive disorder characterized by the association of congenital atresia of the gastric antrum or pylorus with bullous disease of the skin and oral mucosa.¹ This condition was considered part of the category of JEB gravis, but it has recently been recognized as a distinct genetic subset with molecular defects distinct from those found in JEB gravis.^{2 - 6}

In JEB-PA, the PA and resultant gastrointestinal tract obstruction demand a decision regarding surgical correction. Most infants who undergo surgical correction die within the first months of infancy from a variety of other causes, among which gastrointestinal and nutrition-related problems are particularly important.^{1 ,7 - 13} We report our experience with 3 patients with JEB-PA. Despite successful surgical intervention in 2 of the cases, failure to thrive and death ensued. In the third case, an infant with both JEB-PA and aplasia cutis congenita, surgical correction was not attempted after consultation with the parents.

A male infant was born at 37 weeks' gestation to a gravida 8, para 3-4 mother with 2 previous therapeutic and 2 spontaneous abortions. Three older maternal half siblings were healthy without history of bullous skin disease or bowel obstruction. The infant in this case was the product of the first pregnancy for this couple. Prenatal history was notable for polyhydramnios. After birth, excessive spitting and desaturation were noted during feeding. Radiographs revealed a large stomach with a "single bubble" sign and no gas visible in the small bowel, consistent with the presence of PA. Coincidentally, there was progressive blister formation at sites of minor trauma on the extremities, back, and face and in the oropharynx.

Light microscopy findings of skin biopsy specimens showed pauci-inflammatory subbasal vesicle formation. Transmission electron microscopy (EM) demonstrated a split above the level of the basal lamina with hemidesmosomes reduced in number and many without subbasal dense plates or substantial attachment plaques, confirming a diagnosis of JEB. Immunoperoxidase staining showed normal linear staining along the dermoepidermal junction with antibodies to laminin 5, type VII collagen, type IV collagen, and bullous pemphigoid antigen (α₆: GoH3, BQ16; β₄: 3E1, 3D5, UM-A9, 450-11a, 439-9b).¹⁴ (3D5 is an antibody recognizing an intracellular epitope of integrin β₄ subunit.) Staining for integrin α₆β₄ was greatly reduced, and the β4 subunit exhibited an enhanced detergent sensitivity indicative of a faulty structural organization.¹⁵

At age 12 days, the patient underwent successful surgical repair of the PA. Operative findings included an annular pancreas. A thick fibrotic band of muscularis and submucosal tissue without any visible lumen connected the stomach and the small intestine at the site where the pylorus would have been expected. The surgical wound healed normally without any blistering. Feeding problems persisted, and the patient had trouble with secretions. Videofluoroscopic examination results showed swallowing dysmotility that necessitated continuation of nasoduodenal feeding. Despite maintenance on hyperalimentation and regular supplementation with breast milk, he failed to gain weight adequately. Admission weight was 2.34 kg; weight at discharge at age 55 days was 2.57 kg. A fecal α₁-antitrypsin level was lower than 0.3 mg/g (normal, 0.1-3.0 mg/g). Blisters continued to form at sites of minor trauma, but these rapidly healed, and the extent of skin involvement was relatively minor and manageable. He had one urinary tract infection with Escherichia coli. He was discharged to home with nasogastric hyperalimentation supplemented with breast milk; he was scheduled for weekly physician office visits and close home nursing follow-up. He died at home at age 12 weeks of presumed sepsis and severe failure to thrive. No postmortem examination was performed.

A premature male infant was born at 29 5/7 weeks' gestation to a gravida 1 mother. The pregnancy was uncomplicated until premature labor and early cesarean delivery owing to breech presentation. After Apgar scores of 4 at 1 minute and 7 at 5 minutes, he developed severe respiratory distress requiring intubation. Shortly after birth, he had several areas of skin disruption and sloughing, particularly of the hands, feet, face, and areas suffering minor local trauma. Electron microscopy findings of a skin biopsy specimen confirmed a diagnosis of JEB showing the split to be at the lamina lucida level. Immunoperoxidase analysis findings demonstrated decreased staining for integrin α₆β₄ and a greater reduction in the β₄ subunit level (α₆: GoH3; β4: 3E1, 3D5, 439-9b). Radiologic contrast study results of the gastrointestinal tract revealed obstruction at the level of the pylorus.

At age 9 days, successful surgical repair of the PA was performed. Eight days later, tube feeds were begun but not tolerated at full strength or rate owing to large gastric residuals and emesis. Despite additional efforts, he was unable to tolerate gastrointestinal feeding, and parenteral nutrition was required. Extubation was achieved at age 24 days, but declining respiratory status required reintubation at age 28 days. After extensive family conferences, a decision was made to withdraw support. At age 31 days, the patient died within a few hours of extubation. Postmortem examination was refused.

A female infant was born at 30 5/7 weeks' gestation to a 27-year-old gravida 3, para 0-1 mother. She had had 2 previous intrauterine fetal demises in Mexico. The father of all 3 pregnancies was from the same small town in southern Mexico, but there was no known consanguinity or any family members with blistering skin disease or perinatal deaths. The prenatal history included "small femurs" per results of a second-trimester ultrasound performed in the United States. As a result of fetal distress and premature labor, cesarean delivery was done; the infant weighed 1.42 kg and had several areas of absent skin on her scalp and extremities, including the right lower extremity from the inguinal region to the foot, with concomitant symmetric undergrowth of that leg relative to the left. Radiographs revealed a prominent single stomach bubble and absence of bowel gas distal to the stomach. Enteral feeding was not attempted, and an orogastric tube was placed for decompression. Surgical consultation was obtained for the probable PA. Transmission EM examination of skin biopsy specimens showed a split at the lamina lucida, and immunohistochemical staining showed absence of staining for integrin β₄ (UM-A9; 3D5) and reduced integrin α₆ expression (GoH3; BQ16).

After discussion with the mother, hyperalimentation and aggressive fluid administration were discontinued. With continued medical treatment directed at her comfort, the infant died on the fifth day of life.

Epidermolysis bullosa (EB) encompasses a group of disorders that manifest as fragility of the skin leading to blister formation after minor mechanical trauma. The disorders are heterogeneous, with distinct clinical courses and patterns of inheritance.¹⁶ The primary distinction among the different conditions that make up EB is the level within the skin at which blister formation occurs. In JEB, the separation is within the lamina lucida of the basement membrane.

Junctional EB has at least 3 distinct subtypes: JEB generalized atrophic benign, JEB gravis, and JEB-PA, all of which show autosomal recessive inheritance and usually present at or shortly after birth. Junctional EB generalized atrophic benign, also called JEB-mitis or generalized atrophic benign EB, has a more benign clinical course than the other subtypes and is characterized by fragile skin and blistering in a generalized distribution. Affected individuals have dystrophic nails, oral lesions, esophageal and urinary tract involvement, and scarring alopecia. Obstructive urinary tract abnormalities and their complications, in addition to the fragile skin, pose the primary problems of long-term management, but early lethality is rare. Defects in either laminin 5 or the 180-kd bullous pemphigoid antigen, both components of the hemidesmosome complex, have been described in JEB generalized atrophic benign.¹⁷ Junctional EB gravis (also known as letalis or Herlitz variant) is a more severe disease that is most often lethal in infancy. There is widespread generalized blistering, mucosal involvement, and often problems with fluid and electrolytes, as well as sepsis. Exuberant granulation tissue that can form vegetating lesions and severe growth retardation are common in longer-term survivors. Involvement of the respiratory and urinary tracts is also clinically significant. In patients with JEB gravis who survive infancy, life expectancy is substantially shortened. In JEB gravis, mutations have also been identified in components of laminin 5.¹⁸

A subset of patients with JEB also have PA. These infants were initially classified with infants having JEB gravis because of the severity of the disease and the outcome. Based on concordance among affected siblings for both PA and JEB, it was hypothesized that JEB-PA was a distinct syndrome and not the result of a chance association.¹ Uncertainty still existed as to whether the PA was an independent manifestation of the same gene or if it occurred as a secondary phenomenon of repeated blistering of the pyloric mucosa. One infant in whom pyloric obstruction seemed to develop at age 1 month provided support for the latter idea.¹⁹ That PA had never been reported in EM-confirmed simplex or dystrophic forms of EB that also have gastrointestinal tract involvement argued against it.^{4 ,20} Recently mutations in integrin α₆β₄, and not the laminin 5 mutations found in JEB gravis, have been identified in cases where JEB is associated with PA, confirming that JEB-PA is a genetically distinct entity.^{2 - 3 ,6 ,15 ,21 - 26} Further, integrin α₆β₄ is responsible for the skin and pyloric abnormalities in integrin β4 null mice.^{27 - 28}

Integrin α6β4 is a heterodimer transmembrane component of the hemidesmosome complex. It is a receptor for the extracellular ligand laminin 5. Together, these hemidesmosomal components allow basal keratinocytes to form stable cell adhesions to the epidermal basement membrane. This explains the shared ultrastructural features of JEB gravis and JEB-PA and the distinct immunofluorescent findings.^{29 - 32}

We found 70 cases of newborn infants with PA and EB in the literature, plus the 3 cases reported here.^{1 - 13 ,15 ,19 - 26 ,33 - 55} The standard for the diagnosis of JEB-PA is transmission EM evidence of blister formation in the skin at the level of the lamina lucida and alterations in hemidesmosome structure, in conjunction with PA. Nonetheless, we included those cases of EB in which PA was seen, even if no EM confirmation was available. In 22 cases, EM studies were not performed (n=18), were uninterpretable (n=2), or were suggestive of other types of EB (n=2). These last 2 cases deserve mention regarding the diagnosis of dystrophic vs junctional disease. In one, while PA was present, EM findings were interpreted as consistent with dystrophic, not junctional, EB.⁴⁵ The authors classified EB into dystrophic and simplex without recognition of a junctional variant. No electron micrographs were provided. The description of findings was "discontinuity of the basement membrane."⁴⁵ This is consistent with the EM features of JEB-PA. In the second report (case B), there were no details given of the EM findings.⁵¹ The authors stated that the EM diagnosis of dystrophic disease was at odds with the lack of clinically evident scarring. Thus the evidence supporting an association of PA with forms of EB other than junctional is not convincing.

Two infants with JEB did not have gastrointestinal atresia.^{3 ,42} Their siblings (n=2 and n=1, respectively) did.

In addition to PA, other commonly reported complications in these patients included premature birth (n=37), polyhydramnios (n=37), aplasia cutis congenita or congenital localized absence of skin (n=17) (confirming that this feature is not limited to dystrophic EB); and urinary tract involvement (6 of the survivors, 13 of those who died).

In 51 cases, surgical repair of the PA was attempted (Table 1).^{1 - 5 ,7 - 13 ,15 ,19 - 21 ,23 - 25 ,33 - 37 ,45 ,47 ,50 - 52 ,54 - 55} Despite successful repair, the outcome was nevertheless fatal in 35 of the 51. The mean age of death in this group was 70 days. In the 16 survivors, ages ranged from 30 days to 16 years (mean age, 4.0 years; median age, 2.75 years). One of the long-term survivors reported at age 22 months had acquired rather than congenital PA.¹⁹ Three other survivors did not develop blisters until after age 1 week, 3 months, and 2 years, respectively.¹⁵

Many infants die of this disorder owing to the extensive denudation of skin, resultant loss of barrier function, fluid and electrolyte problems, and sepsis. A minority tolerate the surgical correction of the gastrointestinal tract obstruction and seem to have a limited and manageable extent of skin and mucous membrane blistering. Our 3 patients are in many ways typical. The first 2, despite surgical correction of the anatomical defect and manageable, limited blistering, had fatal outcomes. Difficulty with oral feedings and the development of diarrhea with a protein-losing enteropathy seem to be common features in many of these infants, including survivors, and are major contributing factors to death in early infancy. The urinary and respiratory tract difficulties experienced by infants with JEB-PA can in part be explained by the fact that the epithelium of the upper airway and the transitional epithelium of the bladder and urinary tract, in common with the skin, have basement membranes in which hemidesmosomes are found. The cause of the PA and malabsorption is not intuitively obvious, as hemidesmosomes per se are not found in gut epithelium. However, some of the proteins that make up hemidesmosomes, including integrin α₆β₄, are found in the basement membrane zone of normal human gut epithelium.⁵⁶ The occurrence of gastrointestinal tract involvement in mice with JEB-PA in which the cytoplasmic domain of integrin β₄ subunit has been deleted²⁷ suggests that integrin α₆β₄ serves both structural and signal transduction roles in the human intestine.

Survivability in JEB-PA may be limited to specific mutations (ie, certain alleles may confer lesser likelihood of lethality), as suggested by the concordance of survival among affected siblings and cousins and by preliminary work suggesting that infants homozygous for mutations that result in premature codon termination may have more severe disease.^{2 - 3 ,7 ,15 ,21 - 26 ,39} The number of patients evaluated by molecular studies thus far is small, and no definitive conclusions can be drawn. There may prove to be reliable genotype-phenotype correlations that can allow for more accurate predictions of outcome based on molecular diagnosis, but these are not available now. Similarly, results of immunofluorescence staining for antibodies against α6 and β4 are not predictive of clinical outcome, at least in the few infants studied to date.

When the family and medical team begin to weigh the issues involved in attempting to repair the gastrointestinal tract obstructions found in infants born with JEB-PA, the overall poor prognosis even in the face of successful repair must be considered. Some will view a 25% to 30% chance of survival, even in compromised health, as a chance worth taking. For these families, aggressive support may be the correct choice. Others may believe that such a choice serves only to prolong pain and suffering. For these, a decision to not intervene, but instead to provide palliative care and support, may be appropriate. Uncertainty in individual situations will always make these decisions complicated and difficult.

Accepted for publication May 14, 1999.

This work was supported in part by training grants 5T32 AR07019 (Drs Dank and Kim) and 5T326M07454 (Dr Parisi) and grant NIH PO1 AR21557-20 (Drs Sybert, Smith, and Brown) from the National Institutes of Health, Bethesda, Md.

Corresponding author: Virginia P. Sybert, MD, Division of Dermatology, Box 356524, University of Washington Medical Center, Seattle, WA 98195-6524 (e-mail: flk01@u.washington.edu).