- Email: [email protected]
Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation
CASE
REPORTS
Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation Frederick A. Harada, MD, Tor A. Shwayder, MD, Robert J. Desnick, MD, PhD,a and Henry W. Lim, MD Detroit, Michigan, and New York, New York Congenital erythropoietic porphyria (CEP), which is the result of a deficiency of uroporphyrinogen (URO) III synthase activity, is the most disfiguring porphyria in humans. Various methods of treatment have been used to treat CEP with varying success, including erythrocyte transfusion, hydroxyurea, and splenectomy. The only treatment that corrects the enzymatic defect resulting in a cure is bone marrow/stem cell transplantation, which has been reported previously in only 5 patients worldwide. We describe the first patient with CEP who underwent successful bone marrow transplantation performed in the United States and review the therapeutic options in the management of this challenging type of porphyria. (J Am Acad Dermatol 2001;45:279-82.)
C
ongenital erythropoietic porphyria (CEP), or Günther’s disease, is a rare, autosomal recessive genodermatosis that usually presents with marked skin fragility and sunlight-induced blistering.1-3 To date, fewer than 250 cases of CEP have been reported, the majority presenting in infancy or early childhood. Recently, allogeneic stem cell transplantation (from bone marrow or umbilical cord blood) has emerged as a treatment option for CEP. We describe the first successfully transplanted patient with CEP in the United States.
CASE REPORT A white female infant first came to our attention at 2 months of age with a history of severe sunlightinduced blistering since birth. She was born prematurely at 34 weeks of gestation after a pregnancy complicated by oligohydramnios and hydrops fetalis. Her skin was normal until 2 weeks of age when she experienced intense erythema, edema, vesiculation, and crusting on the sun-exposed areas of her body after being placed in an incubator located adjacent to a window (Fig 1). Her urine demonstrated striking fluorescence with Wood’s light examination. Associated findings at 2 months of age included glau-
From the Department of Dermatology, Henry Ford Health Systems, Detroit, and the Department of Human Genetics,a Mount Sinai School of Medicine, New York. Reprint requests: Henry W. Lim, MD, Department of Dermatology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/91/114730 doi:10.1067/mjd.2001.114730
coma, retinopathy, growth retardation, osteopenia, and hemolytic anemia associated with marked splenomegaly. Congenital porphyria was suspected on the basis of these findings. Analysis of the infant’s porphyrin profile at 3 months of age revealed markedly elevated total plasma porphyrins (162.3 µg/dL; normal, 0-0.9 µg/dL), uroporphyrin I in urine (5040 nmol/L; normal, 0-90 nmol/L) and in erythrocytes (1703 µg/dL; normal, 024 µg/dL), and coproporphyrin I in urine (48,160 nmol/L; normal, 0-300 nmol/L) and in stool (3970 nmol/g; normal, 0-200 nmol/g). These results were consistent with a diagnosis of CEP, an autosomal recessive porphyria resulting from the markedly deficient activity of uroporphyrinogen (URO) III synthase.3 Delayed dentition was noted by 12 months of age. Chromosomal analysis at 15 months of age identified homozygosity for the URO-synthase C73R mutation, confirming the diagnosis. Her nonconsanguineous parents were both carriers of the C73R mutation. Initial treatments with strict sun avoidance and weekly packed erythrocyte transfusions were ineffective. At 19 months of age, splenectomy was performed, but the severe hemolytic anemia persisted. Therefore, at 23 months of age she received a bone marrow transplant from an unrelated, HLA-matched donor, which was performed at Children’s Hospital Medical Center of Cincinnati, Ohio. CD34-positive stem cells (20.5 × 106 cells) were successfully transplanted with subsequent normalization of hemoglobin. Variable tandem length repeat analysis of peripheral leukocytes at 24 months of age demonstrated complete engraftment of donor stem cells. At 11 279
280 Harada et al
J AM ACAD DERMATOL AUGUST 2001
Fig 1. Marked erythema, edema, erosions, and crusts after exposure to window glass–filtered sunlight at 2 weeks of age.
months after the transplantation, her total plasma porphyrin levels had decreased significantly (20.7 µg/dL). At 39 months of age, the patient was being weaned off oral cyclosporine. She had markedly decreased skin fragility with clearing of scars in lightexposed areas, tolerance to unlimited sunlight exposure, and normalization of her developmental milestones with increased height, weight, physical activity, and social interactions.
DISCUSSION CEP is the most mutilating type of the porphyrias in which skin fragility, vesicles, and erosions may result in alopecia, scarring atrophy, and acral deformity. Complications associated with CEP include keratoconjunctivitis, corneal scarring, cataracts, erythrodontia, hemolytic anemia with splenomegaly, and increased bone fragility.1 Our patient also had previously unreported findings of glaucoma and delayed dentition. In CEP, the deficient activity of URO III synthase results in the accumulation of porphyrin type I isomers in erythrocytes.1,2 Subsequent hemolysis releases the phototoxic porphyrins into the circulation. Exposure of porphyrins deposited in the skin to light in the Soret band spectrum (400-410 nm) results in skin fragility and blistering. Treatment of CEP has been especially challenging. The following therapeutic modalities have been reported: oral beta-carotene, intravenous hematin, plasma-
pheresis, hydroxychloroquine, and oral charcoal.1,2 The efficacy of these treatments either has not been well documented or has been inconsistent. For example, one patient was reported to benefit from oral administration of charcoal,4 another report showed a lack of efficacy,5 and yet another demonstrated an apparent exacerbation of the disorder.6 During the past few years, other therapeutic options have proven more consistently effective and are more commonly used in the management of CEP. These include strict sun avoidance, physical sunblocks or inorganic sunscreens,1,2 erythrocyte transfusion,7 hydroxyurea,8 splenectomy,9 and bone marrow transplantation.10-14 In vitro, gene transfer has been used with success.15-17 These are discussed later in the article. Sun avoidance and sunscreens The only preventive measure in the management of CEP is absolute avoidance of sunlight exposure.2 Inorganic sunscreens such as zinc oxide and titanium dioxide are effective in protecting against Soret band light, provided that they are applied as a paste, which is impractical for daily application for most patients. The micronized form of these inorganic sunscreens, and other organic ultraviolet filters such as avobenzone, afford partial protection at best. Prevention of scarring Bacterial infections of the skin require appropriate attention to minimize cutaneous scarring.
Harada et al 281
J AM ACAD DERMATOL VOLUME 45, NUMBER 2
Table I. Stem cell transplantation in congenital erythropoietic porphyria* Case No.
Author (year reported)
Age at transplantation/Sex
Follow-up period (mo)
1 2 3 4 5 6
Kauffman et al10 (1991) Thomas et al11 (1996) Zix-Kieffer et al12 (1996) Lagarde et al13 (1998) Tezcan et al14 (1998) Current report
10 y/F 2 y/F 4 y/F 2 y/F 18 mo/F 23 mo/F
11 12 10 21 36 16
Outcome
Died of cytomegalovirus infection Asymptomatic after 2 transplantations Asymptomatic Asymptomatic after 2 transplantations Asymptomatic Asymptomatic
*Bone marrow was the source of the stem cells in all except for case 3, who received stem cells derived from umbilical cord blood.
Erythrocyte transfusion Erythrocyte transfusion with induction of polycythemia has been effective in the management of hemolytic anemia.7 The rationale for this therapy is based on feedback repression of porphyrin biosynthesis in bone marrow by raising heme levels. Moderately affected patients may improve with longterm transfusion therapy and iron chelation designed to maintain their hematocrit above 32%. However, as demonstrated in our patient, many patients need a progressive increase in transfusion requirements to manage their hemolytic anemia and often require subsequent splenectomy. The benefits of erythrocyte transfusion in the management of hemolytic anemia may decrease at puberty when hormonal changes increase heme biosynthesis. Furthermore, the risks of transfusion-communicated infectious disease and iron overload must be weighed against the severity of photosensitivity and anemia before patients are committed to this course of therapy. Hydroxyurea Guarini, Piomelli, and Poh-Fitzpatrick8 described the successful treatment of a patient with CEP with the use of hydroxyurea in combination with erythrocyte transfusion. Before puberty, this patient was kept asymptomatic and the serum porphyrin levels were maintained at near normal values by transfusion alone. At the age of 14 years, this patient’s serum porphyrin levels began to rise with the appearance of vesicles. Hydroxyurea initiated in conjunction with transfusion resulted in successful reduction of serum porphyrin levels and photosensitivity. The success of hydroxyurea in suppressing erythropoiesis in conjunction with transfusion suggests a possible adjunctive use for this chemotherapeutic agent in the management of patients with transfusion-dependent CEP. Splenectomy Splenomegaly resulting from hemolytic anemia is a common finding in patients with CEP. Sequestration of leukocytes and platelets in the
enlarged spleen may result in symptomatic leukopenia and thrombocytopenia.9 In some patients, splenectomy has improved hemolytic anemia by increasing the lifespan of erythrocytes, resulting in a reduction of cutaneous photosensitivity. The results of splenectomy have been variable; as shown in our patient, splenectomy has not always been effective. Stem cell transplantation Since the early 1990s, stem cell transplantation has emerged as an effective treatment option for CEP because replacement of bone marrow erythroblasts corrects the erythroid defect. Engraftment of donor stem cells normalizes URO III synthase activity; decreases porphyrin levels, skin fragility, and photosensitivity; and re-establishes normal erythropoiesis. Allogeneic bone marrow transplantation for CEP was first reported by Kauffman et al.10 Although markedly reduced porphyrin levels and decreased photosensitivity were found 8 months after transplantation, the patient died as a result of fulminant infectious complications. Since then, 5 other patients have reportedly received stem cell transplantation, including the young girl presented in this report (Table I).11-14 One patient received umbilical cord blood as the source of stem cells,12 and the rest received stem cells derived from bone marrow. Two patients required a second transplantation. Follow-up periods ranged from 10 months to 3 years. At the end of the follow-up, all 5 patients remained well with normalization of hematologic parameters and porphyrin levels, and absence of cutaneous photosensitivity. In vitro gene transfer Since 1995, at least 2 groups of investigators have reported the successful in vitro insertion of the URO III synthase gene into cells defective in URO III synthase.15-17 Retroviral-mediated URO III synthase gene transfer has been accomplished in deficient human fibroblasts, immortalized lymphoblasts, and bone marrow cells, resulting in full metabolic correction. Enzymatic activity was completely restored,
282 Harada et al
frequently to a level 2- to 2.7-fold greater than normal. The expression of the transgene remained stable for 3 to 6 months. These in vitro studies provide the rationale for ex vivo stem cell gene therapy in severely affected patients with CEP. In summary, this patient represents the sixth successful bone marrow transplantation for CEP, and the first one in the United States. In the 16 months of follow-up after her bone marrow transplantation, this patient has shown dramatic improvement with resolution of cutaneous photosensitivity and tolerance to unlimited sunlight exposure, normalization of her hemoglobin, and attainment of appropriate developmental milestones. Because the manifestations of CEP are highly variable, only severely affected patients should be considered for transplantation because of the associated morbidity and mortality. However, the encouraging results described suggest that bone marrow transplantation is presently the treatment of choice for patients with severe CEP. As studies with gene therapy become more successful in humans, gene therapy is going to be the definitive treatment for this condition in the future. REFERENCES 1. Bickers DR, Pathak MA, Lim HW. The porphyrias. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, et al, editors. Fitzpatrick’s dermatology in general Medicine. 5th ed. New York: McGraw-Hill; 1999. p. 1766-99. 2. Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol 1997;36:594-610. 3. Desnick RJ, Glass IA, Xu W, Solis C, Astrin KH. Molecular genetics of congenital erythropoietic porphyria. Semin Liver Dis 1998; 18:77-83. 4. Pimstone NR, Gandhi SN, Mukerji SK. Therapeutic efficacy of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 1987;316:390-3. 5. Minder EI, Schneider-Yin X, Moll F. Lack of effect of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 1994;330: 1092-4.
J AM ACAD DERMATOL AUGUST 2001
6. Hift RJ, Meissner PN, Kirsch RE. The effect of oral activated charcoal on the course of congenital erythropoietic porphyria. Br J Dermatol 1993;129:14-7. 7. Piomelli S, Poh-Fitzpatrick MB, Seaman C, Skolnick LM, Berdon WE. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions. N Engl J Med 1986;314:1029-31. 8. Guarini L, Piomelli S, Poh-Fitzpatrick MB. Hydroxyurea in congenital erythropoietic porphyria. N Engl J Med 1994;330: 1091-2. 9. Murphy A, Gibson G, Elder GH, Otridge BA, Murphy GM. Adultonset congenital erythropoietic porphyria (Günther’s disease) presenting with thrombocytopenia. J R Soc Med 1995;88:357-8. 10. Kauffman L, Evans DI, Stevens RF, Weinkove C. Bone-marrow transplantation for congenital erythropoietic porphyria. Lancet 1991;337:1510-1. 11. Thomas C, Ged C, Nordmann Y, de Verneuil H, Pellier I, Fischer A, et al. Correction of congenital erythropoietic porphyria by bone marrow transplantation. J Pediatr 1996;129:453-6. 12. Zix-Kieffer I, Langer B, Eyer D, Acar G, Racadot E, Schlaeder G, et al. Successful cord blood stem cell transplantation for congenital erythropoietic porphyria (Günther’s disease). Bone Marrow Transplant 1996;18:217-20. 13. Lagarde C, Hamel-Teillac D, De Prost Y, Blanche S, Thomas C, Fischer A, et al. Allogeneic bone marrow transplantation in congenital erythropoietic porphyria: Günther’s disease. Ann Dermatol Venereol 1998;125:114-7. 14. Tezcan I, Xu W, Gurgey A, Tuncer M, Cetin M, Oner C, et al. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation. Blood 1998;92: 4053-8. 15. Moreau-Gaudry F, Ged C, Barbot C, Mazurier F, Boiron JM, Bensidhoum M, et al. Correction of the enzyme defect in cultured congenital erythropoietic porphyria disease cells by retrovirus-mediated gene transfer. Hum Gene Ther 1995;6: 13-20. 16. Mazurier F, Moreau-Gaudry F, Salesse S, Barbot C, Ged C, Reiffers J, et al. Gene transfer of the uroporphyrinogen III synthase cDNA into haematopoietic progenitor cells in view of a future gene therapy in congenital erythropoietic porphyria. J Inherit Metab Dis 1997;20:247-57. 17. Kauppinen R, Glass IA, Aizencang G, Astring KH, Atweh GF, Desnick RJ. Congenital erythropoietic porphyria: prolonged high level expression and correction of the metabolic defect by retroviral-mediated gene transfer into porphyrin and erythroid cells. Mol Genet Metab 1998;65:10-7.
REPORTS
Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation Frederick A. Harada, MD, Tor A. Shwayder, MD, Robert J. Desnick, MD, PhD,a and Henry W. Lim, MD Detroit, Michigan, and New York, New York Congenital erythropoietic porphyria (CEP), which is the result of a deficiency of uroporphyrinogen (URO) III synthase activity, is the most disfiguring porphyria in humans. Various methods of treatment have been used to treat CEP with varying success, including erythrocyte transfusion, hydroxyurea, and splenectomy. The only treatment that corrects the enzymatic defect resulting in a cure is bone marrow/stem cell transplantation, which has been reported previously in only 5 patients worldwide. We describe the first patient with CEP who underwent successful bone marrow transplantation performed in the United States and review the therapeutic options in the management of this challenging type of porphyria. (J Am Acad Dermatol 2001;45:279-82.)
C
ongenital erythropoietic porphyria (CEP), or Günther’s disease, is a rare, autosomal recessive genodermatosis that usually presents with marked skin fragility and sunlight-induced blistering.1-3 To date, fewer than 250 cases of CEP have been reported, the majority presenting in infancy or early childhood. Recently, allogeneic stem cell transplantation (from bone marrow or umbilical cord blood) has emerged as a treatment option for CEP. We describe the first successfully transplanted patient with CEP in the United States.
CASE REPORT A white female infant first came to our attention at 2 months of age with a history of severe sunlightinduced blistering since birth. She was born prematurely at 34 weeks of gestation after a pregnancy complicated by oligohydramnios and hydrops fetalis. Her skin was normal until 2 weeks of age when she experienced intense erythema, edema, vesiculation, and crusting on the sun-exposed areas of her body after being placed in an incubator located adjacent to a window (Fig 1). Her urine demonstrated striking fluorescence with Wood’s light examination. Associated findings at 2 months of age included glau-
From the Department of Dermatology, Henry Ford Health Systems, Detroit, and the Department of Human Genetics,a Mount Sinai School of Medicine, New York. Reprint requests: Henry W. Lim, MD, Department of Dermatology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/91/114730 doi:10.1067/mjd.2001.114730
coma, retinopathy, growth retardation, osteopenia, and hemolytic anemia associated with marked splenomegaly. Congenital porphyria was suspected on the basis of these findings. Analysis of the infant’s porphyrin profile at 3 months of age revealed markedly elevated total plasma porphyrins (162.3 µg/dL; normal, 0-0.9 µg/dL), uroporphyrin I in urine (5040 nmol/L; normal, 0-90 nmol/L) and in erythrocytes (1703 µg/dL; normal, 024 µg/dL), and coproporphyrin I in urine (48,160 nmol/L; normal, 0-300 nmol/L) and in stool (3970 nmol/g; normal, 0-200 nmol/g). These results were consistent with a diagnosis of CEP, an autosomal recessive porphyria resulting from the markedly deficient activity of uroporphyrinogen (URO) III synthase.3 Delayed dentition was noted by 12 months of age. Chromosomal analysis at 15 months of age identified homozygosity for the URO-synthase C73R mutation, confirming the diagnosis. Her nonconsanguineous parents were both carriers of the C73R mutation. Initial treatments with strict sun avoidance and weekly packed erythrocyte transfusions were ineffective. At 19 months of age, splenectomy was performed, but the severe hemolytic anemia persisted. Therefore, at 23 months of age she received a bone marrow transplant from an unrelated, HLA-matched donor, which was performed at Children’s Hospital Medical Center of Cincinnati, Ohio. CD34-positive stem cells (20.5 × 106 cells) were successfully transplanted with subsequent normalization of hemoglobin. Variable tandem length repeat analysis of peripheral leukocytes at 24 months of age demonstrated complete engraftment of donor stem cells. At 11 279
280 Harada et al
J AM ACAD DERMATOL AUGUST 2001
Fig 1. Marked erythema, edema, erosions, and crusts after exposure to window glass–filtered sunlight at 2 weeks of age.
months after the transplantation, her total plasma porphyrin levels had decreased significantly (20.7 µg/dL). At 39 months of age, the patient was being weaned off oral cyclosporine. She had markedly decreased skin fragility with clearing of scars in lightexposed areas, tolerance to unlimited sunlight exposure, and normalization of her developmental milestones with increased height, weight, physical activity, and social interactions.
DISCUSSION CEP is the most mutilating type of the porphyrias in which skin fragility, vesicles, and erosions may result in alopecia, scarring atrophy, and acral deformity. Complications associated with CEP include keratoconjunctivitis, corneal scarring, cataracts, erythrodontia, hemolytic anemia with splenomegaly, and increased bone fragility.1 Our patient also had previously unreported findings of glaucoma and delayed dentition. In CEP, the deficient activity of URO III synthase results in the accumulation of porphyrin type I isomers in erythrocytes.1,2 Subsequent hemolysis releases the phototoxic porphyrins into the circulation. Exposure of porphyrins deposited in the skin to light in the Soret band spectrum (400-410 nm) results in skin fragility and blistering. Treatment of CEP has been especially challenging. The following therapeutic modalities have been reported: oral beta-carotene, intravenous hematin, plasma-
pheresis, hydroxychloroquine, and oral charcoal.1,2 The efficacy of these treatments either has not been well documented or has been inconsistent. For example, one patient was reported to benefit from oral administration of charcoal,4 another report showed a lack of efficacy,5 and yet another demonstrated an apparent exacerbation of the disorder.6 During the past few years, other therapeutic options have proven more consistently effective and are more commonly used in the management of CEP. These include strict sun avoidance, physical sunblocks or inorganic sunscreens,1,2 erythrocyte transfusion,7 hydroxyurea,8 splenectomy,9 and bone marrow transplantation.10-14 In vitro, gene transfer has been used with success.15-17 These are discussed later in the article. Sun avoidance and sunscreens The only preventive measure in the management of CEP is absolute avoidance of sunlight exposure.2 Inorganic sunscreens such as zinc oxide and titanium dioxide are effective in protecting against Soret band light, provided that they are applied as a paste, which is impractical for daily application for most patients. The micronized form of these inorganic sunscreens, and other organic ultraviolet filters such as avobenzone, afford partial protection at best. Prevention of scarring Bacterial infections of the skin require appropriate attention to minimize cutaneous scarring.
Harada et al 281
J AM ACAD DERMATOL VOLUME 45, NUMBER 2
Table I. Stem cell transplantation in congenital erythropoietic porphyria* Case No.
Author (year reported)
Age at transplantation/Sex
Follow-up period (mo)
1 2 3 4 5 6
Kauffman et al10 (1991) Thomas et al11 (1996) Zix-Kieffer et al12 (1996) Lagarde et al13 (1998) Tezcan et al14 (1998) Current report
10 y/F 2 y/F 4 y/F 2 y/F 18 mo/F 23 mo/F
11 12 10 21 36 16
Outcome
Died of cytomegalovirus infection Asymptomatic after 2 transplantations Asymptomatic Asymptomatic after 2 transplantations Asymptomatic Asymptomatic
*Bone marrow was the source of the stem cells in all except for case 3, who received stem cells derived from umbilical cord blood.
Erythrocyte transfusion Erythrocyte transfusion with induction of polycythemia has been effective in the management of hemolytic anemia.7 The rationale for this therapy is based on feedback repression of porphyrin biosynthesis in bone marrow by raising heme levels. Moderately affected patients may improve with longterm transfusion therapy and iron chelation designed to maintain their hematocrit above 32%. However, as demonstrated in our patient, many patients need a progressive increase in transfusion requirements to manage their hemolytic anemia and often require subsequent splenectomy. The benefits of erythrocyte transfusion in the management of hemolytic anemia may decrease at puberty when hormonal changes increase heme biosynthesis. Furthermore, the risks of transfusion-communicated infectious disease and iron overload must be weighed against the severity of photosensitivity and anemia before patients are committed to this course of therapy. Hydroxyurea Guarini, Piomelli, and Poh-Fitzpatrick8 described the successful treatment of a patient with CEP with the use of hydroxyurea in combination with erythrocyte transfusion. Before puberty, this patient was kept asymptomatic and the serum porphyrin levels were maintained at near normal values by transfusion alone. At the age of 14 years, this patient’s serum porphyrin levels began to rise with the appearance of vesicles. Hydroxyurea initiated in conjunction with transfusion resulted in successful reduction of serum porphyrin levels and photosensitivity. The success of hydroxyurea in suppressing erythropoiesis in conjunction with transfusion suggests a possible adjunctive use for this chemotherapeutic agent in the management of patients with transfusion-dependent CEP. Splenectomy Splenomegaly resulting from hemolytic anemia is a common finding in patients with CEP. Sequestration of leukocytes and platelets in the
enlarged spleen may result in symptomatic leukopenia and thrombocytopenia.9 In some patients, splenectomy has improved hemolytic anemia by increasing the lifespan of erythrocytes, resulting in a reduction of cutaneous photosensitivity. The results of splenectomy have been variable; as shown in our patient, splenectomy has not always been effective. Stem cell transplantation Since the early 1990s, stem cell transplantation has emerged as an effective treatment option for CEP because replacement of bone marrow erythroblasts corrects the erythroid defect. Engraftment of donor stem cells normalizes URO III synthase activity; decreases porphyrin levels, skin fragility, and photosensitivity; and re-establishes normal erythropoiesis. Allogeneic bone marrow transplantation for CEP was first reported by Kauffman et al.10 Although markedly reduced porphyrin levels and decreased photosensitivity were found 8 months after transplantation, the patient died as a result of fulminant infectious complications. Since then, 5 other patients have reportedly received stem cell transplantation, including the young girl presented in this report (Table I).11-14 One patient received umbilical cord blood as the source of stem cells,12 and the rest received stem cells derived from bone marrow. Two patients required a second transplantation. Follow-up periods ranged from 10 months to 3 years. At the end of the follow-up, all 5 patients remained well with normalization of hematologic parameters and porphyrin levels, and absence of cutaneous photosensitivity. In vitro gene transfer Since 1995, at least 2 groups of investigators have reported the successful in vitro insertion of the URO III synthase gene into cells defective in URO III synthase.15-17 Retroviral-mediated URO III synthase gene transfer has been accomplished in deficient human fibroblasts, immortalized lymphoblasts, and bone marrow cells, resulting in full metabolic correction. Enzymatic activity was completely restored,
282 Harada et al
frequently to a level 2- to 2.7-fold greater than normal. The expression of the transgene remained stable for 3 to 6 months. These in vitro studies provide the rationale for ex vivo stem cell gene therapy in severely affected patients with CEP. In summary, this patient represents the sixth successful bone marrow transplantation for CEP, and the first one in the United States. In the 16 months of follow-up after her bone marrow transplantation, this patient has shown dramatic improvement with resolution of cutaneous photosensitivity and tolerance to unlimited sunlight exposure, normalization of her hemoglobin, and attainment of appropriate developmental milestones. Because the manifestations of CEP are highly variable, only severely affected patients should be considered for transplantation because of the associated morbidity and mortality. However, the encouraging results described suggest that bone marrow transplantation is presently the treatment of choice for patients with severe CEP. As studies with gene therapy become more successful in humans, gene therapy is going to be the definitive treatment for this condition in the future. REFERENCES 1. Bickers DR, Pathak MA, Lim HW. The porphyrias. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, et al, editors. Fitzpatrick’s dermatology in general Medicine. 5th ed. New York: McGraw-Hill; 1999. p. 1766-99. 2. Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol 1997;36:594-610. 3. Desnick RJ, Glass IA, Xu W, Solis C, Astrin KH. Molecular genetics of congenital erythropoietic porphyria. Semin Liver Dis 1998; 18:77-83. 4. Pimstone NR, Gandhi SN, Mukerji SK. Therapeutic efficacy of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 1987;316:390-3. 5. Minder EI, Schneider-Yin X, Moll F. Lack of effect of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 1994;330: 1092-4.
J AM ACAD DERMATOL AUGUST 2001
6. Hift RJ, Meissner PN, Kirsch RE. The effect of oral activated charcoal on the course of congenital erythropoietic porphyria. Br J Dermatol 1993;129:14-7. 7. Piomelli S, Poh-Fitzpatrick MB, Seaman C, Skolnick LM, Berdon WE. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions. N Engl J Med 1986;314:1029-31. 8. Guarini L, Piomelli S, Poh-Fitzpatrick MB. Hydroxyurea in congenital erythropoietic porphyria. N Engl J Med 1994;330: 1091-2. 9. Murphy A, Gibson G, Elder GH, Otridge BA, Murphy GM. Adultonset congenital erythropoietic porphyria (Günther’s disease) presenting with thrombocytopenia. J R Soc Med 1995;88:357-8. 10. Kauffman L, Evans DI, Stevens RF, Weinkove C. Bone-marrow transplantation for congenital erythropoietic porphyria. Lancet 1991;337:1510-1. 11. Thomas C, Ged C, Nordmann Y, de Verneuil H, Pellier I, Fischer A, et al. Correction of congenital erythropoietic porphyria by bone marrow transplantation. J Pediatr 1996;129:453-6. 12. Zix-Kieffer I, Langer B, Eyer D, Acar G, Racadot E, Schlaeder G, et al. Successful cord blood stem cell transplantation for congenital erythropoietic porphyria (Günther’s disease). Bone Marrow Transplant 1996;18:217-20. 13. Lagarde C, Hamel-Teillac D, De Prost Y, Blanche S, Thomas C, Fischer A, et al. Allogeneic bone marrow transplantation in congenital erythropoietic porphyria: Günther’s disease. Ann Dermatol Venereol 1998;125:114-7. 14. Tezcan I, Xu W, Gurgey A, Tuncer M, Cetin M, Oner C, et al. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation. Blood 1998;92: 4053-8. 15. Moreau-Gaudry F, Ged C, Barbot C, Mazurier F, Boiron JM, Bensidhoum M, et al. Correction of the enzyme defect in cultured congenital erythropoietic porphyria disease cells by retrovirus-mediated gene transfer. Hum Gene Ther 1995;6: 13-20. 16. Mazurier F, Moreau-Gaudry F, Salesse S, Barbot C, Ged C, Reiffers J, et al. Gene transfer of the uroporphyrinogen III synthase cDNA into haematopoietic progenitor cells in view of a future gene therapy in congenital erythropoietic porphyria. J Inherit Metab Dis 1997;20:247-57. 17. Kauppinen R, Glass IA, Aizencang G, Astring KH, Atweh GF, Desnick RJ. Congenital erythropoietic porphyria: prolonged high level expression and correction of the metabolic defect by retroviral-mediated gene transfer into porphyrin and erythroid cells. Mol Genet Metab 1998;65:10-7.