Junctional epidermolysis bullosa: Diagnosis and management of a patient with the Herlitz variant

Junctional epidermolysis bullosa: Diagnosis and management of a patient with the Herlitz variant

Junctional Epidermolysis of a Patient By Allan M. Goldstein, Bullosa: Diagnosis and Management With the Herlitz Variant Thomas Boston, Davenport,...

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Junctional

Epidermolysis of a Patient By Allan

M. Goldstein,

Bullosa: Diagnosis and Management With the Herlitz Variant Thomas

Boston,

Davenport,

and

Robert

L. Sheridan

Massachusetts

A case of Herlitz-type epidermolysis bullosa (EB) is reported. The baby was born after a normal, full-term pregnancy with blisters on his extremities. Over the next several months, progressive skin sloughing involving 95% of his body surface area developed, including gastrointestinal, laryngeal,tracheobronchial, and cornea1 involvement. The diagnosis of junctional EB, Herlitz type, was made using clinical, electron microscopic, and immunohistochemical criteria. Despite meticulous wound care, aggressive nutritional support, and

continuous antimicrobial therapy, the baby died at 9 months of age. This report discusses the presentation, complications, and management of this unusual and tragic disease. J Pediatr Surg 33:756-758. Copyright o 1998 by W.B. Saunders Company.

E

(BSA) developed. Blood cultures grew Staphylococcus ureas and Candida tropicalis. Despite appropriate antibiotics, aggressive nuhitional support, and atraumatic wound care, the skin lesions progressed, and he was transferred to our hospital at 3 months of age. On arrival, the baby weighed 3.3 kg and had approximately 40% of his skin denuded on the chest, back, and extremities, with erosions of the oral mucosa. His temperature was 104”F, with a white blood cell count of 22.000/mm3, and hematocrit value of 22%. His initial care consisted of broad-spectrum antibiotics, topical polysporin powder alternating with hydrated petrolatum, and placement in a temperatureand humidity-controlled unit. He continued to have persistent skin sloughing with progression to 95% BSA. Notably, his volar hands and feet remained spared (Fig 1). At 4 months of age involvement of the respiratory tract developed, evidenced by hemoptysis containing sloughed epithelial tissue, as well as hypopharyngeal and laryngeal involvement evident on direct laryngoscopy. Progressive respiratory distress led to intubation at 6 months of age. Diarrhea soon developed with hemoccult-positive stools and enteral feeding intolerance, likely secondary to gastrointestinal involvement. Significant bilateral cornea1 defects also developed. A repeat skin biopsy was performed, which confirmed the suspicion of junctional EB using electron microscopy and monoclonal antibody studies. Throughout his hospitalization the infant remained critically ill with severe growth retardation, persistent polymicrobial sepsis, and profound anemia. At 7 months of age abdominal distension developed with markedly elevated liver function test results. An ultrasound scan showed massive hepatomegaly with an echogenic liver and gallstones, most likely secondary to persistent sepsis, long-term hyperalimentation, and probable hepatotoxicity from multiple antibiotics. One month later, sepsis worsened with disseminated intravascular coagulation, progressive hepatic failure, and increasing gastrointestinal involvement. Given the diagnosis of Herlitz and his deteriorating course, further care was felt to be futile, and supportive measures were withdrawn. An episode of acute bradycardia developed, and, consistent with the expressed wishes of the parents, resuscitation was not undertaken. The patient died at 9 months of age.

PIDERMOLYSIS BULLOSA (EB) encompasses a group of inherited blister diseases affecting approximately 1 in 40,000 live births. The disease is classified into three major categories-simplex, junctional, and dystrophic-depending on the ultrastructural cleavage plane of the blister, and further subtyped based on inheritance, prognosis, and clinical features.’ Junctional epidermolysis bullosa (JEB) is an autosomal recessive form of the disease that involves dermal-epidermal disadhesion at the level of the lamina lucida.2,3 The condition is clinically categorized into local and generalized forms depending on the anatomic extent of the blistering. The generalized form is further subtyped into Herlitz (gravis) and non-Herlitz (mitis) variants. The Herlitz variant, also called epidermolysis bullosa hereditaria lethalis, is the more frequent and malignant form of the disease, carrying a very high early mortality. This report discusses the clinical course of a patient with Herlitz-type EB and reviews the diagnosis, complications, and management of this disease. CASE

REPORT

A black male, was born to unrelated parents after an uncomplicated full-term pregnancy. Blisters were present on his extremities at birth, and a tentative diagnosis of epidermolysis bullosa simplex, based on skin biopsy, was made. At 2 weeks of age fever associated with progressive skin sloughing involving 35% of his body surface area

From the Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, and Shriners Burns Institute, Boston, MA. T&is work was supported by the Shriners Hospitals for Crippled Children. Address reprint requests to Dr R.L. Sheridan, MD, Shriners Burns Institute, 51 Blossom St, Boston, MA 02114. Copyright o 1998 by IVB. Saunders Company

0022.3468/95/3305-0026$03.00/0 756

INDEX WORDS: complications,

Junctional management.

epidermolysis

bullosa,

Herlitz,

DISCUSSION

Epidermolysis bullosa represents a heterogeneous group of inherited diseases characterized by blistering of the skin, occurring either spontaneously or after minor trauma. Journal

of Pediatric

Surgery,

Vol33,

No 5 (May),

1998: pp 756-758

JUNCTIONAL

Fig 1. junctional

EPIDERMOLYSIS

Photographs epidermolysis

757

BULLOSA

show widespread bullosa.

sloughing

of the skin,

with

the characteristic

Although all forms of the disease share this common feature of blistering, subtypes vary in their histopathology, clinical features, and prognosis. The subclassification of EB has changed over the years as novel biochemical techniques allow more precise characterization of histological and molecular markers. Originally published in 1935, the Herlitz variant, or EB hereditaria lethalis, described a type distinct from the simple and dystrophic forms of the disease already known at the time.3 As a result, the older literature refers to any form of junctional EB (JEB) as “Herlitz-type.” The terminology was largely clarified in 1991 by Fine et all in their consensus report for the National EB Registry on the subclassification of EB. The Herlitz variant now refers specifically to the most severe of the six forms of JEB, characterized by the presence from birth of widespread blistering of the skin and mucous membranes of the mouth and gastrointestinal tract, and associated with profound anemia and growth retardati0n.l The underlying molecular defect appears to be a mutation in laminin-5, a glycoprotein important in connecting hemidesmosomes to the lamina densa of the dermal-epidermal junction.4,5 Early diagnosis and accurate classification of EB are important for determining prognosis, anticipating complications, and formulating an appropriate treatment plan. Skin biopsy with electron microscopy to assesscleavage planes remains the standard diagnostic technique, with other methods added for more precise classification1 Monoclonal antibodies, for example, are used to identify the absence of specific proteins in the basement membrane in particular EB subtypes. In our patient, for instance, type VII collagen was normally expressed, with laminin-5 reduced, and uncein, an anchoring filament, undetectable. These findings are consistent with the diagnosis of JEB. In addition to the histopathologic findings, the clinical

sparing

of the hands

and feet often

seen

in patients

with

course is paramount in the accurate diagnosis of EB subtypes. The main features that distinguish JEB from other forms of EB were all seen in our patient. These are (1) severe generalized blistering present from birth, with sparing of volar hands and feet (Fig l)$ (2) multiple sites of extracutaneous involvement, including the oral cavity,3 gastrointestinal tracL7 larynx and respiratory tract,s and corneas’; (3) systemic complications of anemia and severe growth retardation’; and (4) early death caused by complications related to sepsis.9 The anemia and growth retardation, in particular, distinguish the Herlitz variant from other forms of JEB. They are thought to result primarily from significant blood and protein loss from denuded skin and mucosal surfaces, leading to anemia and hypoproteinemia that impair normal growth and development.’ Interestingly, the patient’s course was also complicated by hepatic failure and gallstones, two conditions not previously described in patients with EB. These complications may have resulted from chronic sepsis, multiple prolonged courses of antibiotics, and long-term parenteral nutrition, emphasizing that as critical care improves and we are able to treat these patients longer and more aggressively, additional complications of chronic illness will inevitably be encountered. The management of EB centers on meticulous atraumatic wound care, nutritional support, and aggressive treatment of infections. Several reports discuss a variety of alternative therapies for EB, including vitamin D, prednisone, phenothiazineiphenytoin, infrared light, and keratinocyte autografts,6~‘*~*’none of which have convincingly demonstrated a significant decrease in morbidity or mortality. Our approach to treating our patient was based on our experience with children suffering large surface area bums. Accordingly, his treatment began with placement in a temperature- and humidity-controlled environment to minimize heat and insensible water losses.

758

GOLDSTEIN,

Table

1. Organisms Grown From Blood During the Patient’s Course Staphylococcus Acinetobacter

Cultures

aureus baumanii

Enterococcus sp. Candida parasilopsis Staphylococcus Enterobacter Diphtheroids

epidermidis cloacae

Staphylococcus

Candida

hemolyticus

albicans

Candida tropicalis Xanthomonas maltophilia Staphylococcus Aspergillus

capitis flaws

Topical antibacterial dressings were applied twice daily to prevent dessication and minimize infection, both of which can potentially convert the “partial-thickness” injury of JEB into the equivalent of a full-thickness burn. Central venous access was necessary for hemodynamic monitoring, intravenous antibiotics, and parenteral nutrition once his intestinal involvement precluded enteral feeding. Ultimately, the infant also required intubation because of laryngotracheal involvement. Despite these measures, his course was continually compromised by bouts of bacterial and fungal sepsis (Table l), which ultimately led to his death. No definitive therapy is presently available for patients with junctional EB. With the recent identification of specific genetic mutations,4s5 prenatal diagnosis and carrier screening are now feasible.4 Furthermore, with the characterization of responsible genes, gene therapy for

DAVENPORT,

AND

SHERIDAN

EB, although still in early developmental stages, may become possible in the near future. Several groups are exploring keratinocyte gene therapy as a means of introducing a normal gene product into the skin. In this procedure, keratinocytes are cultured from a biopsy specimen obtained from an area of normal skin on the patient. The cells are transduced with a retrovirus containing the appropriate transgene, grown into confluent sheets in vitro, and subsequently returned to the patient as an epidermal autograft stably expressing a normal protein.‘” Until effective treatments are developed, however, patients born with this disease need aggressive supportive therapy, as outlined above. Temporary skin substitutes, like xenografts and allografts, can be used to provide an effective vapor and bacterial barrier for large open wounds. Isolated reports describe promising results with cultured epidermal allografts13 and autografts14 for the chronic cutaneous defects of JEB, but larger trials and long-term follow-up are lacking. In severe cases, the care of patients with junctional EB can be probably best delivered by facilities familiar with the treatment of severe pediatric bums, a condition that shares many pathophysiologic features with generalized EB and other severe exfoliating skin disorders. As long as the patient can be kept free of life-threatening infections and other systemic complications, the possibility remains that the disease will resolve spontaneously, as is often the case with JEB. However, with even the most meticulous care, the patient may still succumb to this tragic illness.

REFERENCES 1. Fine JD, Bauer EA, Briggaman RA, et al: Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. J Am AcadDermatol24:119-135, 1991 2. Paller AS, Fine JD, Kaplan S, et al: The generalized atrophic benign fmm of junctional epidermolysis bullosa. Arch Dermatol 122704.710,1986 3. Pearson RW, Potter B, Strauss F: Epidermolysis bullosa hereditaria letalis. Arch Dermatol 109:349-355, 1974 4. Vailly J, Pulkkinen L, Miquel C, et al: Identification of a homozygous one-basepair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence. J Invest Dermatol 104:462-465, 1995 5. Vidal F, Baudoin C, Miquel C, et al: Cloning of the laminin 013 chain gene (LAMAS) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics 30:273280,1995 6. Hashimoto I, Anton-Lamprecht I, Meyburg P: Epidermolysis bullosa hereditaria letalis: Report of a case and probable ultrastructural defects. Helv Paediat Acta 30:543-552, 1975

7. Turner TW: Two cases of junctional epidermolysis bullosa (He&z-Pearson). Br J Dermatol 102:97-107, 1980 8. Berson S, Lin AN, Ward RF, et al: Junctional epidermolysis bullosa of the larynx: Report of a case and literature review. Ann Otol Rhino1 Latyngol101:861-865, 1992 9. Holzman RS, Worthen M, Johnson KL: Anaesthesia for children with junctional epidermolysis bullosa (letalis). Can J Anaesth 34:395399,1987 10. Rogers RB, Yancey KB, Allen BS, et al: Phenytoin therapy for junctional epidermolysis bullosa. Arch Dermatol 119:925-926, 1983 11. Bergfeld WF, 011owski JP: Epidamolysis bullosa letalis and phenytoin. JAm Acad Dermatol7:275-278, 1982 12. Vogel JC: Keratinocyte gene therapy. Arch Dermatol 129:14781483,1993 13. Roseeuw D, DeRaeve L, Dangoisse C, et al: Treatment of epidermolysis bullosa with human cultured epidermal allografts. Dermatology 189:68-70, 1994 (suppl2) 14. Carter DM, Lin AN, Varghese MC, et al: Treatment of junctional epidermolysis bullosa with epidermal autografts. J Am Acad Dermatol 17:246-250, 1987