MANAGEMENT OF URINARY TRACT IN CHILDREN WITH EPIDERMOLYSIS BULLOSA CRAIG F. DONATUCCI, M.D. TIMOTHY G. BERGER, M.D. GEORGE E. DESHON, JR., M.D.

From the Urology Service, Department of Surgery, and Dermatology Service, Department of Medicine, Letterman Army Medical Center, Presidio, San Francisco, California ABSTRACT-Epidermolysis bullosa is a group of rare genetic disorders characterized by noninflammatory blistering lesions of the skin occurring after minor mechanical trauma. In association with junctional epidermolysis bullosa, a syndrome of pyloric atresia has occasionally been noted in the literature. Several infants who had this combined disorder have been reported to have severe genitourinary tract involvement. Most of these patients have died at an early age because of severe urinary tract involvement. We describe a rare survivor who was initially treated with urinary diversion. Subsequent attempts at undiversion of this patient were unsuccessful. He is presently stable following rediversion. The entities of e. bullosa and e. bullosa/pyloric atresia are reviewed with emphasis on urologic associations.

Epidermolysis bullosa is a group of rare, genetic disorders characterized by noninflammatory blistering lesions of the skin caused by minor mechanical trauma. Although originally considered to be solely dermatologic conditions, the systemic nature of these diseases has subsequently been recognized. Involvement of the respiratory, gastrointestinal, and genitourinary tracts have all been reported. When the skin condition is mild or moderate, underlying organ system involvement may be of greater consequence to survival and may become the predominant problem. Major morbidity resulting from urologic disease has not, until recently, been recognized, and lack of precedent in the urologic literature makes formulation of a rational plan of management difficult. The incidence of e. bullosa has been estimated at 20 cases per million births. l Four basic subtypes have been described based on the level of the blister as shown by electron microscopy The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

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and by the inheritance pattern (Table I). However, the subtypes are usually clinically divided into two groups: those that heal with scarring (dystrophic) and those that heal without scarring. Recessive e. bullosa dystrophica, the prototype of the scarring group, is a severe, recessively inherited disorder in which the digits of the hands and feet slowly become encased in a covering of epidermis, caused by repeated blistering. The junctional disorders were originally thought to be progressively fatal. The discovery that some patients survive into adulthood caused the change from the original term, epidermolysis bullosa hereditaria letalis, to junctional epidermolysis bullosa. TABLE

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Subtype

Classification of evidermolusis bullosa Inheritance

Level of Blister

Simplex Junctional

Autosomal dominant Autosomal recessive

Intraepidermal Basement membrane zone

Dystrophic Dominant Recessive

Autosomal dominant Autosomal recessive

Upper dermis Upper dermis

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Epidermolysis

Bullosa Dystrophica

In recessive dystrophic forms of e. bullosa, electron microscopy shows a split in the upper dermis below the basement membrane. Lesions heal and subsequent scarring causes progressive disfigurement. Genitourinary disease is caused by this scarring. Kretkowski2 reported on a three-year-old boy who had e. bullosa dystrophica and urinary retention Extensive scarring was noted over the trunk and extremities. The urethral meatus was pinpoint. Intravenous pyelogram revealed bilateral pyelocaliectasis and ureterectasis. Meatotomy was performed; the child’s voiding pattern returned to normal, and renal function remained stable. Another child who had e. bullosa dystrophica, a pinpoint urethral meatus, and scarring of the glans penis was reported by Cohen.3 Uroradiographic studies revealed a dilated urethra compatible with distal obstruction. Again, treatment was simple meatotomy. Shackelford and associates4 reported on a ten-year-old girl who had e. bullosa dystrophica and a history of recurrent infections. The child’s genitalia were severely involved, with partial fusion of the labia and narrowing of the vestibule of the vagina. A voiding cystourethrogram revealed a markedly dilated urethra and reflux of contrast material into a dilated vagina with subsequent filling of the uterine cavity. The hymen and fused labia were cut, which released a large amount of retained urine from the vagina. The patient subsequently voided normally, and findings on follow-up cystograms remained stable over five years. Meatal stenosis secondarv, to healing of the lesions of e. bullosa dystrophica was the major problem in all of these children. The meatal scarring caused predictable obstructive changes and infection. Surgical relief of obstruction was sufficient therapy and resulted in stabilization or improvement of the urinary tract. Systemic control of the disease-through use of steroids or phenytoin (Dilantin)-may also be effective.

FIGURE1. Large bullae on buttocks several days postoperative (reprinted with permission from Pediatric Dermatologylo).

FIGURE 2. Electron micrographs of spontaneously formed blister show cleavage through lamina lucida (reduced from x 5,000 magnification); inset: Lamina den.sa at base of blister (reduced from x 16,000 magnification). Reprinted with permission from Pediatric Dermatology.‘O

Junctional e. bullosa is inherited as an autosomal recessive trait. Blisters are usually present at birth and heal without scarring (Fig. 1). Histologically, the epidermis is sharply separated from the dermis; the plane of cleavage lies between the plasma membrane of the basal cells

and the lamina densa (Fig. 2). The involvement of large areas of the integument leads to high neonatal mortality. Rapid loss of third-space fluid makes management of these children difficult. Breakdown of the bullae combined with immaturity of the immune system often leads to overwhelming sepsis and death. However, the extent of the disorder is variable, and those children who have mild or moderate degrees of involvement of the integument may survive. Genitourinarv dysfunction in these children is a primary pro&s and may not correlate with extent of cutaneous disease. Schachner, Lazarus, and Dembitze? reported the first instance of junctional e. bullosa in association with urologic pathology. In an infant born with skin defects over large areas of

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Junctional Epidermolysis Bullosa/Pyloric Atresia

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the body, an overwhelming sepsis developed shortly after birth and the infant died. Electron microscopic examination of the skin revealed characteristic dermal-epidermal separation within the basement membrane zone. Similar lesions were found in the gastrointestinal tract, trachea, and the urinary bladder; however, despite this microscopic involvement, no gross disease of the bladder was evident. Although most children who have junctional e. bullosa are not at risk for genitourinary disease, specific high-risk groups can be identified. Korber and Glasson, although not recognizing the significance of urinary tract involvement, were the first to report an association between junctional e. bullosa and pyloric atresia. Since that time, 20 cases of e. bullosa in associaton with pyloric atresia have been reported, and 10 of these cases have featured involvement of the urinary tract to varying degrees. Chang, Perrin, and Bove’ were the first to report a case of e. bullosa/pyloric atresia complex with significant genitourinary involvement in a male neonate, who was born eight weeks prematurely, with hypospadias, pyloric atresia, and junctional e. bullosa. Sepsis and hematuria developed, and he died on the eighth day after birth. Postmortem electron microscopic examination confirmed the presence of junctional e. bullosa. Light micoscopy revealed subepithelial separations between the basal cell layer and underlying basement membrane throughout the renal pelvis, ureter, and bladder. Whether or not urologic disease contributed to this child’s death is unknown. El Shafie and associates8 reported on a male newborn who had e. bullosalpyloric atresia complex and died of sepsis at age fifteen days. Postmortem examination revealed marked bilateral stenosis of the ureterovesical junction with bilateral pyonephrosis. Extensive gastrointestinal and tracheobronchial ulcerations were also present. The clinical manifestation of significant genitourinary disease in a child was first reported by Bull and associates.g A female neonate had e. bullosa/pyloric atresia complex and underwent pyloroplasty at two days; she recovered from the procedure and was discharged. At two months of age, gross hematuria developed, and an intravenous pyelogram revealed right hydronephrosis secondary to distal ureteral obstruction. During cystoscopy, the right ureteral orifice could not be identified. Hydronephrosis progressed, and a right cutaneous loop ureteros-

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tomy was performed on the girl at age six months. The patient failed to thrive, suffered from continued skin involvement, and died of bronchopneumonia at age eleven months. Postmortem examination revealed enlarged hydronephrotic kidneys and dilatation of both ureters. Bladder mucosa was extensively involved as were the gastrointestinal and respiratory systems. A second patient reported by Bull and associates! had e. bullosa/pyloric atresia complex and underwent successful operative repair of the pyloric atresia. At age two months, gross hematuria developed, and intravenous pyelography demonstrated bilateral hydroureteronephrosis with minimal left renal function. Bilateral ureteral reimplantation was performed, and at time of surgery the bladder showed extensive bullae formation and edema. Severe skin involvement with e. bullosa continued, and the child died at age four months. Autopsy was denied, and the fate of the reimplants is unknown. Rosenberg et aZ.Q”reported on a two and onehalf-year-old male with mild skin involvement secondary to junctional e. bullosa, corrected pyloric atresia, and ureteral obstruction, The bladder wall was markedly thickened, and there was extensive ureteral fibrosis, These authors managed the ureteral obstruction by creating bilateral ureterostomies. Our patient, previously reported,‘O is a rare known survivor of junctional e. bullosa and pyloric atresia after pyloroplasty. His skin involvement, which appeared in the first few days of life, was of moderate severity. At age five months the child presented with gross hematuria, hypertension, and renal insufficiency. Intravenous pyelogram revealed mild right and massive left hydroureteronephrosis (Fig. 3). Voiding cystourethrography demonstrated no evidence of ureteral reflux or posterior urethral valves. An edematous bladder with massive bullae, an appearance described as “cobblestoning” of the bladder, was noted at cystoscopy. He underwent left cutaneous loop ureterostomy and vesicostomy, Follow-up intravenous pyelogram revealed decreased hydroureteronephrosis on the left but increased right obstruction. Therefore, at age ten months, he underwent right cutaneous loop ureterostomy and closure of the vesicostomy. Evaluation at age two years revealed functioning bilateral loop ureterostomies and stable e. bullosa, which did not require medication. 139

FIGURE 4. Intraoperative photograph shows thickened bladder wall with bullae formation over entire mucosal surface.

There was no stenosis of the ostomy sites, and no appliance was required because the child was maintained in diapers. Intravenous pyelogram demonstrated mild bilateral hydronephrosis. At cystoscopy, a small-capacity bladder with bullae was noted. Antegrade pyelography revealed free flow of contrast medium into the bladder on the right but occlusion at the level of the left ureterovesical junction. Although the etiology of the original ureterovesical junction obstruction was unknown, and this obstruction was not perceived to result from the intrinsic bladder pathology of e. bullosa, initial therapy was aimed at restoring functional integrity to the urinary tract. Sequential operations were performed to take down the right cutaneous ureterostomy, reimplant the left ureter, and take down the left ureterostomy. One month later, when the left ureter was being reimplanted, the bladder wall was found to be severely thickened and extensive bullae formation was noted over the entire mucosal surface (Fig. 4). Follow-up intravenous pyelography revealed recurrence of mild right hydroureteronephrosis to the level of the bladder and delayed left renal

function with severe hydronephrosis. A trial of indwelling catheter drainage failed to alleviate the hydronephrosis and led to breakdown of the skin where the catheter was anchored to the body. The child had an irregular voiding pattern and frequent bladder spasms. Urodynamic studies confirmed markedly decreased detrusor compliance with hyperreflexia. Antispasmotics were tried but found to be of limited value. Indwelling, soft, ureteral catheters used to bypass ureterovesical junction obstruction did not help, and renal deterioration continued. Remaining therapeutic options were limited. We carefully considered the use of an ileal loop or Kock continent ileal bladder, but feared such a diversion might fail if latent e. bullosa were provoked in the previously uninvolved bowel. Therefore, bilateral end-cutaneous ureterostomies were repeated. The ureters were hypoperistaltic postoperatively and required chronic intubation to function. The hypoperistalsis resulted from chronic obstruction as well as ureteral vascular damage, both secondary to multiple operations. The patient has been followed for five years since his rediversion and remains stable with evidence of mild chronic renal insufficiency. Our fear of provoking latent gastrointestinal problems may have been unfounded since a subsequent case reported by Eklof and Parkkulainen” was diverted. The patient presented at birth with pyloric atresia and underwent pyloroplasty. Epidermolysis bullosa was diagnosed in the postoperative period. At eight weeks of age, he experienced gross hematuria and cystitis. Intravenous pyelogram revealed only slight dilatation of the upper tracts. The

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FIGURE

3. Intravenous pyelogram at age five months shows marked left and mild right hydroureteronephrosis (reprinted with permission from Pediatric Dermatology’*).

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patient had recurrent infections until age eleven months when a repeat intravenous pyelogram revealed moderate bilateral upper urinary tract dilatation, reduced bladder capacity, and irregular bladder mucosa. A voiding cystourethrogram was interpreted as consistent with posterior urethral valve. Electroresection of the bladder neck and valve failed to relieve the patient’s symptoms and instead led to desquamative balanitis with meatitis and pan urethral strictures. Urethral reconstruction failed, and the patient was treated by vesicostomy until age nine years when ureterosigmoidostomy was performed. Eklof (personal communication, 1985) reported that this patient’s urinary tract deterioration continued with frequent episodes of pyelonephritis and the development of renal insufficiency. Kock (personal communication, 1986) reported that this patient had an enormous dilatation of the colon, and daily catheterizations were necessary to empty the colon and rectum. In 1984, Kock performed a continent cutaneous urinary diversion (Kock pouch). After the diversion, the patient did well and his renal function stabilized. Four to five daily catheterizations of the pouch did not lead to significant scarring. Comment The major pitfall in the care of children who have e. bullosa is the failure to recognize the urologic pathology as a unique disease entity that is associated with the e. bullosalpyloric atresia complex. If an infant has a history of pyloric atresia and e. bullosa, pyelography and cystoscopy should be performed in order to evaluate genitourinary disease. The disease may be present throughout the urothelium; however, obstruction apparently occurs only at the ureterovesical junction. The cause of this obstruction is unknown. Minor trauma to the bladder epithelium may result from mechanical storage and emptying of the urine. Such trauma may lead to breakdown of the urothelium much the way that slight mechanical pressure leads to skin breakdown in e. bullosa. Secondary fibrosis may occur as urine comes in contact with detrusor muscle. This mechanical-inflammatory hypothesis was advanced by Honig, Yoder, and Ziegler12 who reported acquired pyloric atresia in an infant who had e. bullosa. Unfavorable therapeutic interventions reported in the literature suggest that management of these patients should be conservative

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and aimed at maximal preservation of renal function until permanent diversion can be performed. The extensive involvement of the bladder in our patient leads us to disagree with the conclusions of Reitelman and associatesI that widely refluxing ureteroneocystotomies should be performed. Primary bladder dysfunction with decreased compliance and high intravesical pressures will rapidly lead to further deterioration of renal function. The cause of the obstruction is unknown, and the sole successful reimplantation reported is of unknown duration. Consequently, we believe excision of the obstructed ureterovesical junction and ureteral reimplantation should be avoided. In addition, the upper urinary tract diversion through cutaneous ureterostomy is the initial procedure of choice in these patients. In the infant, urine collection is not problematic because diapers will suffice. Stoma1 devices are difficult to maintain. All mechanisms that keep storage devices water-tight also exert mechanical pressure on the skin. In the patient who has junctional e. bullosa, the use of these devices will rapidly lead to formation of bullae, breakdown, and local infection, but stenosis does not occur. The experience of Kock indicates that the presence of e. bullosa does not necessarily preclude the successful use of bowel diversion; rather, it may be the procedure of choice. Early diversion may save renal function in the child who survives long enough for significant genitourinary disease to develop. Subsequent formation of a continent ileal bladder may allow the patient to reach adulthood with stable disease and socially acceptable urinary function. Epidermolysis bullosa is a rare genetic disorder that was once thought to be a dermatologic condition; however, the systemic nature of the disease is now well recognized. Urologic involvement is determined by the subtype of disease present. Epidermal scarring secondarily involves the genitourinary tract in e. bullosa dystrophica. Simple surgical correction of the obstruction results in resolution of symptoms and improvement in renal function. In junctional e. bullosa, genitourinary involvement appears limited to patients born with pyloric atresia. The majority of these infants will succumb to the primary disease. In those who do survive, the underlying genitourinary dysfunction may become life-threatening. A patient who has junctional e. bullosa, a history of pyloric atresia, and hematuria should

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be thoroughly investigated. Attempts at definitive correction of ureteral obstruction should be undertaken, Any surgery that might lead to ureteral devitalization should be avoided so as not to preclude satisfactory permanent diversion. Conservative management by using diversion of the upper urinary tract will allow stabilization of renal function until an age when satisfactory permanent diversion can be performed. A continent ileal bladder may be the procedure of choice in these patients, despite concern that the ileum may be involved in the disease.

1. Gedde-Dahl T Jr: Epidermolysis Bullosa: A Clinical Genetic and Epidemiological Study, Baltimore, The Johns Hopkins Press, 1971, pp 129-134. 2. Kretkowski RC: Urinary tract involvement in epidermolysis bullosa, Pediatrics 51: 938 (1973).

3. Cohen EL: Genital complication of epidermolysis bullosa, Clin Pediatr 22: 443 (1983). 4. Shackelford GD, Bauer EA, Graviss ER, and McAlister WH: Upper airway and external genital involvement in epidermolysis bullosa dystrophica, Radiology 143: 429 (1982). 5. Schachner L, Lazarus GS, and Dembitzer H: Epidermolysis bullosa hereditaria letalis. Pathology, natural history and therapy, Br J Dermatol 96: 51 (1977). 6. Korber JS, and Glasson MJ: Pyloric atresia associated with epidermolysis bullosa, J Pediatr 96: 600 (1977). 7. Chang CH, Perrin EV, and Bove KE: Pyloric atresia associated with epidermolysis bullosa: special reference to pathogenesis, Pediatr Path01 1: 449 (1983). 8. El Shafie M, et al: Pyloric atresia and epidermolysis bullosa letalis: a lethal combination in two premature newborn siblings, J Pediatr Surg 14: 446 (1979). 9. Bull MJ, et al: Epidermolysis bullosa-pyloric atresia. Autosomal recessive syndrome, Am J Dis Child 137: 449 (1983). 9a. Rosenberg D, et al: Involvement of the urinary tract in a syndrome of congenital epidermolysis bullosa and atresia of the pylorus, Arch Fr Pediatr 44: 867 (1987). 10. Berger TG, Detlefs RL, and Donatucci CF: Junctional epidermolysis bullosa, pyloric atresia, and genitourinary disease, Pediatr Dermatol 3: 130 (1986). 11. Eklof 0, and Parkkulainen K: Epidermolysis bullosa dystrophica with urinary tract involvement, J Pediatr Surg 19: 215 (1984). 12. Honig PJ, Yoder M, and Ziegler M: Acquired pyloric obstruction in a patient with epidermolysis bullosa letalis, J Pediatr 102: 598 (1983). 13. Reitelman C, Burbige KA, Mitchell ME, and Hensle TW: The urological manifestations of epidermolysis bullosa, J Urol 136: 1320 (1986).

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Urology Service Department of Surgery Fitzsimons Army Medical Center Aurora, Colorado 800452 (DR. DONATUCCI) References

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Management of urinary tract in children with epidermolysis bullosa.

Epidermolysis bullosa is a group of rare genetic disorders characterized by noninflammatory blistering lesions of the skin occurring after minor mecha...
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