Hematopoietic Stem Cell Transplantation and Subsequent 80% Skin Exchange by Grafts from the Same Donor in a Patient with Herlitz Disease

Herlitz junctional epidermolysis bullosa (H-JEB), a rare heritable disease presenting from birth with widespread skin blistering, is characterized by an early demise of the patient, usually within the first year of life. H-JEB is caused by absence of laminin-5, an anchoring protein restricted to the basement membranes of stratifying sqamous epithelia. At present, there is no specific therapy (1). We and others have investigated the use of allogeneic skin grafts or artificial skin equivalents to treat the cutaneous manifestations of this disease (2, 3), however, these approaches were limited by immune responses. Therefore, based on our previous experience with combined allogeneic bone marrow and skin transplantation (4), we attempted to overcome the immune barrier in a H-JEB patient by hematopoietic stem cell transplantation (HSCT) and subsequent skin exchange by grafts from the same donor. HSCT from the HLA-haploidentical, blood group-incompatible father was performed at the age of 4 months. The conditioning regimen consisted of cyclophosphamide (120 mg/kg), busulfan (18 mg/kg), melphalan (140 mg/m2), and anti-T lymphocyte globulin (60 mg/kg). Significant mucositis developed after conditioning. G-CSF-stimulated peripheral blood stem cells were harvested from the father and selected for CD34. A total of 33×106 CD34-positive cells/kg recipient body weight including less than 25×103 T cells/kg were transplanted. White blood cell counts began to rise on day 10 after HSCT, reaching 1,000/μL on day 15. Approximately 4 weeks after HSCT a more rapid progression of junctional skin blistering occurred, resulting in a loss of two thirds of the total epidermis. This reflected most likely the natural course of the disease, but was possibly enhanced by the chemoconditioning. Histological examination of a skin biopsy provided no indication of graft-versus-host disease (GvHD), and there were also no clinical and laboratory signs suggestive of GvHD. Skin transplantation was started at this time point by harvesting split thickness skin grafts (0.2 mm) from a thigh of the donor. These grafts were slit and transplanted on the whole dorsal trunk and the gluteal region of the child following complete necrectomy with a dermatome adjusted to 0.2 mm. The remaining wounds were covered with glycerolized allogeneic skin to reduce the massive fluid and protein loss. One week later this material was replaced by fresh donor skin. Since the amount available was only sufficient to cover ventral trunk and legs, glycerolized skin was used again for the arms. Three weeks after initial grafting both arms were transplanted with fresh donor skin. All skin grafts healed completely with excellent biomechanical and cosmetic results (Fig. 1). However, the clinical course was complicated by bacterial (multiresistant Stenotrophomonas) and viral (HHV-6) infections. Despite antimicrobial prophylaxis with colistin, trimethoprim-sulfamethoxazole, acyclovir, amphotericin B suspension, amphotericin B inhalation, and intravenous IgG application and aggressive therapy including acyclovir, ganciclovir, foscarnet, cefepime, ceftazidime, tobramycin, metronidazol, teicoplanin, trimethoprim-sulfamethoxazole, ciprofloxacin, meropenem, amikacin, clarithromycin, liposomal amphotericin B, voriconazole, and also an infusion of granulocytes harvested from the stem cell donor after dexamethasone stimulation, the infections could not be controlled necessitating continuous ventilation with temporarily high pressures, and finally the child succumbed due to pulmonary failure and hypoxia. In skin biopsies obtained 17 and 67 days after skin grafting, the presence of donor skin was confirmed by quantitative PCR detecting one Y chromosome per cell equivalent in the epidermis of the female patient (Table 1).FIGURE 1.: Back of the patient (a) before, (b) 5 days after and (c) 4 weeks after skin transplantation; (d) abdomen 3 weeks after the transplantation and (e) histological section of a biopsy from this site 3 weeks after the transplantation.TABLE 1: Detection of the skin graft by quantitative PCRThis first case demonstrates that an 80% exchange of a patient’s skin is technically possible and supports our hypothesis that tolerance even to such extensive grafts can be achieved by a preceding HSCT from the same donor. However, it also highlights the great risks of haploidentical HSCT in H-JEB patients. Whereas serious or even fatal viral infections are typical complications of a haploidentical stem cell transplantation, chronic infections with multiresistant Pseudomonas species occur regularly in patients with Herlitz disease. Still, the encouraging result of successful large scale skin exchange in our patient suggests that this novel therapeutic approach should be evaluated prospectively in a clinical trial involving a small series of H-JEB patients. Jürgen Kopp Raimund E. Horch Department of Plastic and Hand Surgery University of Erlangen-Nuernberg Erlangen, Germany Klaus-Daniel Stachel Wolfgang Holter Michael A. Kandler Holger Hertzberg Wolfgang Rascher Department of Pediatrics University of Erlangen-Nuernberg Erlangen, Germany Valentina Campean Department of Pathology University of Erlangen-Nuernberg Erlangen, Germany Roman Carbon Department of Pediatric Surgery University of Erlangen-Nuernberg Erlangen, Germany Holm Schneider Department of Experimental Medicine I University of Erlangen-Nuernberg Erlangen, Germany