Case Report Treatment of Congenital Erythropoietic Porphyria in Children by Allogeneic Stem Cell Transplantation: a Case Report and Review of the Literature

Bone Marrow Transplantation (2001) 27, 101–105  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Case report Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature

PH Shaw1, AJ Mancini1, JP McConnell2, D Brown1 and M Kletzel1

Departments of 1Pediatrics and Dermatology, Northwestern University Medical School and Children’s Memorial Hospital, Chicago, IL; and 2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Summary: ocular complications, hemolytic anemia and extreme photosensitivity which results in mutilating scarring. The anemia Congenital erythropoietic porphyria (CEP) is a rare may be severe enough to require chronic transfusion. As a autosomal recessive disorder of porphyrin metabolism result of the ravages of this disease, people who have it in which the genetic defect is the deficiency of uropor- historically have a shorter life expectancy. phyrinogen III cosynthase (UIIIC). Deficiency of this Many modalities have been used to treat this disease1–24 enzyme results in an accumulation of high amounts of with temporary, if any, effect because they are supportive uroporphyrin I in all tissues leading to hemolytic ane- and do not address the primary cause of the disease, the mia, splenomegaly, erythrodontia, bone fragility, deficiency of uroporphyrinogen III cosynthase. Thus far, exquisite photosensitivity and mutilating skin lesions. stem cell transplantation (SCT) is the only curative therapy We describe the case of a 23-month-old boy who was for CEP. It is effective because the transplanted stem cells cured of his CEP by a matched-sibling allogeneic bone produce normal levels of UIIIC and reverse the disease marrow transplant, and review the published clinical manifestations. Five reports of children with CEP treated experience regarding transplantation in this disease. He with SCT have been published worldwide, four of them is alive and disease-free 15 months post transplant. All being long-term survivors with abatement of disease mani- of his disease manifestations except for the erythrodon- festations.25–29 We report the successful treatment of CEP tia have resolved. His UIIIC level and stool and erythro- in a 23-month-old boy by allogeneic bone marrow trans- cyte porphyrin metabolites have almost completely cor- plantation (BMT) from a matched-sibling donor. rected. He is the sixth child reported to be cured of this disease by stem cell transplantation, five cases being long-term survivors. If patients with this disease have Case report an HLA-matched sibling, then stem cell transplantation should be strongly considered because this is currently Clinical history the only known curative therapy. Bone Marrow Trans- plantation (2001) 27, 101–105. A boy of Palestinian descent who was full-term was born Keywords: congenital erythropoietic porphyria; porphy- vaginally without complications. During his first month of ria; stem cell transplantation; bone marrow transplantation life, he was found to have pink urine. He was evaluated by a pediatric nephrologist who found no abnormalities. When his teeth began to erupt, they were noted to be dark blue. As the patient became more active, his parents noticed that Congenital erythropietic porphyria (CEP), or Gunther’s dis- cuts and bruises on his face and limbs required several ease, is one of the rarest of the porphyrias, a group of meta- weeks to heal. bolic disorders in which excessive quantities of porphyrins At the age of 15 months, during a visit to Israel, he was or their precursors are produced. This autosomal recessive exposed to the sun and exposed areas of his skin began to disorder is caused by a defect of the enzyme uroporphyrin- erupt into large vesicles. These lesions healed poorly, ogen III cosynthase (UIIIC) that leads to an accumulation became easily infected and formed large scars. He was sus- of uroporphyrinogen I and coproporphyrinogen I in all pected of having erythropoietic porphyria and sent to the tissues. The primary clinical manifestations of this accumu- United States for confirmation of the diagnosis. lation include erythrodontia, bone fragility, hypertrichosis, The family medical history was significant for two first- degree cousins with beta-thalassemia. There was no family history of porphyria and no consanguinity. His parents were Correspondence: Dr M Kletzel, Box #30, Division of Hematology/ Oncology, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, unrelated Lebanese Muslims from different regions of IL 60614, USA Israel and he had two healthy sisters aged 4 and 6 years. Received 21 June 2000; accepted 4 October 2000 On examination he was noted to have areas of hypo- Stem cell transplantation for congenital porphyria PH Shaw et al 102 Transplantation procedure His older sister was an HLA-identical match, so at the age of 23 months he received a bone marrow transplant with this sister serving as the donor. The conditioning regimen consisted of busulfan 4 mg/kg i.v. in four divided doses daily from day −9 to day −6 (total dose 16 mg/kg) and cyclophosphamide 50 mg/kg once daily from day −5 to day −2 (total dose 200 mg/kg). He also received mesna 360 mg/m2 i.v. on each day he received cyclophosphamide (total dose 1440 mg/m2). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine 3 mg/kg i.v. in two divided doses daily beginning on day −1 and metho- trexate 15 mg/m2 i.v. once on day +1 and 10 mg/m2 once daily on days +3 and +6. Granulocyte colony-stimulating ␮ Figure 1 Patient with congenital erythropoietic porphyria prior to bone factor (GCSF) 10 g/kg i.v. was given daily starting on marrow transplantation. Note hypo- and hyperpigmentation, scarring, ero- day +7. Cytogam 100 mg/kg i.v. was administered weekly sions, crusting and mild hypertrichosis. starting on day −1 and continued for 3 months and then monthly for 3 months. Pentamidine 4 mg/kg i.v. was given monthly starting day −1asPneumocystis carinii prophy- and hyperpigmentation over his face and extremities with laxis and continued until day +180. multiple poorly healed crusted lesions over these areas and a few intact tiny vesicles (Figure 1). His skin was also sig- Clinical course nificant for hypertrichosis over his forehead and temples. His teeth were well developed but dark blue (Figure 2). The patient reached an absolute neutrophil count of 500/␮l Wood’s lamp examination of his teeth, urine and sclerae on day +13, received his last platelet transfusion on day revealed red–orange fluorescence. His splenic tip was pal- +11 and his last packed red blood cell transfusion on day pable 3 cm below the left costal margin but he had no hepa- +26 post transplant. He never manifested signs of GVHD. tomegaly. His urine was pink in appearance and urinalysis Variable-number tandem repeats (VNTR) at days +12 and demonstrated hemoglobinuria and trace protein. His labora- +100 demonstrated 100% donor origin DNA consistent tory investigations were remarkable for a hemoglobin (Hb) with full chimeric engraftment. The patient is currently 15 of 9.4 g/dl, a reticulocyte count of 4%, a zinc protoporphy- months post transplant and his skin lesions have completely rin (ZPP) level of 670 ␮mol/mol Hb (normal 30–70) and healed. He no longer develops blisters or scars when a lactic dehydrogenase (LDH) of 644 IU/l (normal 221– exposed to direct sunlight. His hypertrichosis has also 473). His erythrocyte, urine and fecal porphyrin levels were resolved. His urine is normal in color and unremarkable on all significantly elevated while his erythrocyte uroporphyri- urinalysis and on Wood’s lamp examination. His hemoglo- nogen III cosynthase level was low (Table 1). These labora- bin is normal at 12 g/dl. His primary teeth remain dark tory findings, in conjunction with his history and physical blue in color and continue to fluoresce red-orange under examination were diagnostic of CEP. the Wood’s lamp. As prior to transplant, he remains devel- The patient and his family were HLA-typed. While opmentally appropriate and is a very verbal, engaging boy. awaiting these results, he was prescribed a zinc oxide-based Stool and erythrocyte porphyrin levels and uroporphoryi- sun protectant and was instructed to stay out of direct sun- nogen III cosynthase levels were assessed prior to trans- light. plant, 7 months post transplant and 12 months post transplant. His fecal coproporphyrin I, fecal coproporphyrin III, erythrocyte protoporphyrin, erythrocyte coproporphyrin, erythrocyte uroporphyrin and erythrocyte uroporphyrinogen III cosynthase levels were almost completely cor- rected by 7 months post transplant and continued to be near normal at 12 months (Table 1). The only value to never completely normalize was fecal coproporphyrin I which reduced from 57792 ␮g/24 h to 888 ␮g/24 h at 12 months. Urine porphyrin levels, which were assayed at diagnosis and found to be elevated (Quest Diagnostics, Teterboro, NJ, USA) were not examined after the transplant.

Discussion

Congenital erythropoietic porphyria was ﬁrst described in 1874 when Schultz30 wrote of a 33-year-old weaver who Figure 2 Red–blue discoloration of the teeth (erythrodontia). had had cutaneous photosensitivity since 3 months of age,

Bone Marrow Transplantation Stem cell transplantation for congenital porphyria PH Shaw et al 103 Table 1 Hemoglobin, enzyme levels and porphyrin metabolites before and after bone marrow transplantation

Examination Pre-BMT 7 months post BMT 12 months post BMT Normal range

Hemoglobin 9.4 g/dl 11.3 g/dl 12.0 g/dl 11.5–13.5 g/dl Erythrocyte uroporphyrinogen III cosynthase 67 RU — 83 RU 85–100 RUa Erythrocyte protoporphyrin 870 ␮g/dl — 66 ␮g/dl 16–60 ␮g/dl Erythrocyte coproporphyrin 75 ␮g/dl — Ͻ1 ␮g/dl Ͻ2 ␮g/dl Erythrocyte uroporphyrin 132 ␮g/dl — Ͻ1 ␮g/dl Ͻ2 ␮g/dl Fecal coproporphyrin I 57792 ␮g 711 ␮g 888 ␮g Ͻ500 ␮g Fecal coproporphyrin III 7070 ␮g 146 ␮g 153 ␮g Ͻ400 ␮g Fecal isocoproporphyrin 374 ␮g 107 ␮g37␮g Ͻ200 ␮g Fecal isopentacarboxyl 137 ␮g3␮g6␮g Ͻ80 ␮g Fecal pentacarboxyl I 762 ␮g8␮g11␮g Ͻ20 ␮g Fecal pentacarboxyl III 99 ␮g Ͻ1 ␮g2␮g Ͻ20 ␮g Urine coproporphyrin 386 ␮g— — Ͻ155 ␮g Urine pentaporphyrin 129.9 ␮g— — Ͻ4.7 ␮g Urine hexaporphyrin 18.8 ␮g— — Ͻ0.9 ␮g Urine heptaporphyrin 56.4 ␮g— — Ͻ6.8 ␮g Urine uroporphyrin 2318.3 ␮g — — 3.3–29.5 ␮g Urine total porphyrins 2909.1 ␮g — — 12–190 ␮g

All fecal and urine samples were 24 h collections. All erythrocyte studies were performed on a single sample. aThe normal range was established using erythrocytes from 45 healthy adult volunteers. Analysis of this enzyme in more patients with biochemically and clinically established cases of CEP is necessary to firmly establish a pathologic range for this enzyme assay. The method cannot reliably distinguish between heterozygotes and normal individuals. — = not performed; BMT = bone marrow transplant; RU = relative units. splenomegaly, anemia and wine-colored urine. In 1911, it hyperpigmentation are also evident in exposed areas and was described in greater detail by Gunther31 and came to hypertrichosis is usually seen. Skeletal deposition leads to be known as Gunther’s disease. It is one of the rarest of bone fragility. By adulthood, patients can develop severe the porphyrias (less than 150 cases reported). Seen in all osteolysis, resorption of the terminal phalanges, contrac- ethnic groups, Fritsch et al1 catalogued all documented tures and other bony deformities. Vitamin D deficiency patients to 1994. This disease usually manifests in infancy from avoidance of sunlight may contribute to these abnor- or early childhood, although it can be diagnosed later in malities of bone structure. Ocular manifestations include life. conjunctivitis, blepharitis, photophobia, cataracts, corneal The disease is the result of decreased activity of uropor- scarring and the loss of eyelashes and eyebrows. Porphyrin phyrinogen III cosynthase, the fourth of eight enzymes deposition in the sclerae leads to fluorescence with Wood’s along the pathway that produces heme from glycine and lamp exposure. Identical fluorescence occurs in the succinyl CoA. The substrate upon which this enzyme acts, patients’ teeth caused by deposition of porphyrins in den- hydroxymethylbilane (HMB) accumulates and condenses tine and enamel during tooth formation. When not under spontaneously to uroporphyrinogen I which in turn can be the Wood’s lamp, the teeth appear blue or red–brown in decarboxylated to coproporphyrinogen I. Both uroporphyri- color (erythrodontia). nogen I and coproporphyrinogen I accumulate in the bone Hematologic manifestations are also part of CEP’s clini- marrow, erythrocytes, plasma, bones and teeth where they cal presentation. Excessive porphyrins in erythrocytes are metabolized to uroporphyrin I (a.k.a. urogen I) and results in fragility and osmotic hemolysis, which in turn coproporphyrin I (a.k.a. coprogen I) and are excreted in leads to chronic hemolytic anemia and consequent spleno- feces and urine. These porphyrins become excited by vis- megaly. Hepatomegaly is also occasionally seen as a result ible light (especially 400–410nm in wavelength) and emit of this. Because the heme synthesis pathway is disrupted, a red fluorescence, as evidenced when our patient’s teeth, erythropoiesis is obviously less effective. As a result of this, sclerae and urine were exposed to a Wood’s lamp. The ZPP is elevated and many nucleated red blood cells (which energy released reacts with oxygen to produce free radicals themselves are fluorescent) are prominent on a peripheral that damage involved tissue. blood smear. Patients with CEP can have the worst skin manifestations In addition to the pathognomonic clinical features of of all the porphyrias due to the massive elevation of lipid CEP, there are also characteristic laboratory findings. Uro- soluble porphyrins, which deposit in the skin. This photo- porphyrinogen III cosynthase activity in erythrocytes is sensitivity leads to phototoxic reactions and increased col- markedly decreased or absent. Elevated protoporphyrin lev- lagenase production resulting in second- or third-degree els are seen in erythrocytes and uroporphyrin I and copro- burns with vesicle and bullae formation. These become porphyrin I levels are detectable in erythrocytes, plasma, ulcerated, infected, require a prolonged period to heal and urine and feces. Anemia, as mentioned above, is partially over time can lead to mutilations of the extremities and compensated by an elevated reticulocyte count. LDH is also face. Nails and fingers may be lost. Hypopigmentation and elevated as an indicator of hemolysis. The splenomegaly of

Bone Marrow Transplantation Stem cell transplantation for congenital porphyria PH Shaw et al 104 Table 2 Pediatric patients with CEP treated with stem cell transplantation

Author/Ref. Age at Sex Transplant Stem cell Pre-transplant Post-transplant Clinical Length of transplant regimen source UIIC UIIIC outcome follow-up (normal range) (normal range)

Kauffman et al25 10 years F BU/CY Sibling NA 364 nmol/ml Died 11 months BM (159–352) CMVa Zix-Kieffer et al26 4 years F BU/CY/ATG Sibling 2.2 nmol/h 9.6 nmol/h Alive 10 months UCB (8–12) (8–12) RD Thomas et al27 22 months F Bu/CY × 2 Sibling 0.7 nmol/h 4.4 nmol/h Alive 13 BM × 2 (control = 9.3) (control = 9.3) RD monthsb Lagarde et al28 2 years F NA Sibling 0.7 nmol/h/mg 5.2 nmol/h/mg Alive 21 BM × 2 (6–10) (6–10) RD monthsb Tezcan et al29 18 months F BU/CY Sibling ND ND Alive 35 months BM RD Shaw et al this study 23 months M BU/CY Sibling 67 RU 83 RU Alive 15 months BM (85–100) (85–100) RD

F = female; M = male; UIIIC = uroporphyrinogen III cosynthase level; BU = busulfan; CY = cyclophosphamide; ATG = anti-thymocyte globulin; BM = HLA-identical bone marrow; UCB = HLA-identical umbilical cord blood; CMV = cytomegalovirus; a = patient had improvement of disease manifestations prior to death; b = after second BMT; NA = not available; ND = not done; RD = resolution of disease manifestations.

hemolytic anemia can lead to sequestration of platelets and her first transplant when she had evidence of graft failure. thus a secondary thrombocytopenia. She was completely asymptomatic 1 year after her second All aspects of CEP make it a potentially devastating and BMT. Her donor was a heterozygote with 50% enzyme deforming disease requiring some form of treatment. Thera- activity, a level the patient attained after transplant. The peutic interventions in the past have included protection fourth successful treatment of CEP was reported by from sunlight (which is essential until definitive treatment Lagarde et al28 when they described the treatment and is implemented), beta-carotene to reduce oxidative dam- course of a 2-year-old girl who was clinically well 21 age,1,2 splenectomy to decrease anemia and thrombocyto- months after her second BMT from the same BM source penia,1–12 transfusion regimens13 and i.v. hematin (oxidized (a heterozygote sibling). As with Thomas’ patient, she free heme) therapy8,14–16 to suppress hemoglobin pro- required a second infusion of bone marrow cells, in this duction, adsorbents to bind to porphyrins and increase their case 8 months after the first. Both patients transplanted with excretion,17,20–22 hydroxyurea,13,23,24 and steroids.13,17–20 marrow from HLA-identical heterozygotes produced The most effective therapy would be one that increases approximately 50% of normal levels of UIIIC and had com- uroporphyrinogen III cosynthase activity into the normal plete resolution of disease manifestations, demonstrating range, as it is reduced to 0 to 40% of normal in erythrocytes that using a matched sibling carrier as the stem cell source and fibroblasts of patients with CEP (approximately 50% is still a good option. The fifth and most recent published of normal in carriers). Romeo and Levin32 first identified case by Tezcan et al29 described an 18-month-old trans- this enzymatic deficiency in 1969, and as of 1998, 18 differ- fusion-dependent girl who was cured of her CEP by allo- ent mutations of chromosome 10 causing CEP had been geneic BMT and is alive and disease-free 3 years later. described.33 Knowing the location of a mutation makes Adding our patient to the collective experience brings gene therapy an attractive method of treatment, but the total number of published cases of CEP successfully although promising, this work is only in the pre-clinical treated with SCT to six (Table 2). Although this number is stages.33–35 small, all children were effectively cured of their disease Stem cell transplantation is another logical therapy and had no clinically significant sequelae from their por- because the UIIIC enzyme defect is present in red blood phyria. As this treatment modality continues to be the only cells and fibroblast derivatives, all of which have a common method of curing CEP, we suggest early transplantation in stem cell ancestor. It is now known to be the only curative future cases if the patient has an HLA-identical sibling who therapy for CEP. The first documented use of SCT for CEP is a carrier or is unaffected. If there are no adequate bone was published by Kauffman et al in 1991.25 Their patient, marrow donors available, unrelated umbilical cord blood a 10-year-old girl fully engrafted and had improvement of may be a viable stem cell option for these patients, but this her skin lesions but died of CMV pneumonitis 11 months remains to be investigated. post BMT. Zix-Kieffer et al26 in 1995 reported a 4-year- old girl transplanted with her brother’s HLA-identical cord blood. She was alive and disease-free 10 months later, with References resolution of all disease manifestations including improve- 27 ment in dental color. Soon after, Thomas et al reported 1 Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythro- a 22-month-old girl transplanted for CEP who required a poietic porphyria. J Amer Ac Derm 1997; 36: 594–610. second infusion of donor bone marrow at 8 months after 2 Pierini AM. Rare metabolic disorders: porphyrias. In:

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