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Erythropoietic Uroporphyria Associated with Myeloid Malignancy Is Likely Distinct from Autosomal Recessive Congenital Erythropoietic Porphyria

2011; Elsevier BV; Volume: 131; Issue: 5 Linguagem: Inglês

10.1038/jid.2011.5

1523-1747

Robert Sarkany, Sally H. Ibbotson, Sharon D. Whatley, C.M. Lawrence, Pamela Gover, Ghulam J. Mufti, Gillian Murphy, Gillian S. Masters, Michael N. Badminton, George H. Elder,

Methemoglobinemia and Tumor Lysis Syndrome

burst-forming unit congenital erythropoietic porphyria myelodysplastic syndrome uroporphyrinogen III synthase TO THE EDITOR Congenital erythropoietic porphyria (CEP; MIM 263700) is a rare autosomal recessive disease caused by mutations in uroporphyrinogen III synthase (UROS) or, rarely, in GATA1 genes, leading to UROS deficiency (Fritsch et al., 1997Fritsch C. Bolsen K. Ruzicka T. et al.Congenital erythropoietic porphyria.J Am Acad Dermatol. 1997; 36: 594-610Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar; De Verneuil et al., 2003De Verneuil H. Ged C. Moreau-Gaudry F. Congenital erythropoietic porphyria.in: Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook, Vol. 14, Medical Aspects of Porphyries. Academic Press, Amsterdam2003: 43-66Crossref Scopus (19) Google Scholar; Phillips et al., 2007Phillips J.D. Steensma D.P. Pulsipher M.A. et al.Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.Blood. 2007; 109: 2618-2621Crossref PubMed Scopus (125) Google Scholar). The resulting overproduction of type I porphyrin isomers by erythroid cells causes severe photosensitivity and hemolytic anemia. It usually presents in infancy; however, 13 patients have been reported who did not present with the disease until adulthood (Fritsch et al., 1997Fritsch C. Bolsen K. Ruzicka T. et al.Congenital erythropoietic porphyria.J Am Acad Dermatol. 1997; 36: 594-610Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar; Kontos et al., 2003Kontos A.P. Ozog D. Bichakjian C. et al.Congenital erythropoietic porphyria associated with myelodysplasia presenting in a 72-year-old man: report of a case and review of the literature.Br J Dermatol. 2003; 148: 160-164Crossref PubMed Scopus (34) Google Scholar; De Verneuil et al., 2003De Verneuil H. Ged C. Moreau-Gaudry F. Congenital erythropoietic porphyria.in: Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook, Vol. 14, Medical Aspects of Porphyries. Academic Press, Amsterdam2003: 43-66Crossref Scopus (19) Google Scholar). Some of them had mild late-onset autosomal recessive CEP (De Verneuil et al., 2003De Verneuil H. Ged C. Moreau-Gaudry F. Congenital erythropoietic porphyria.in: Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook, Vol. 14, Medical Aspects of Porphyries. Academic Press, Amsterdam2003: 43-66Crossref Scopus (19) Google Scholar); however, five of the seven presenting with the disease after the age of 50 years had an associated myeloid malignancy, usually myelodysplastic syndrome (MDS; Kontos et al., 2003Kontos A.P. Ozog D. Bichakjian C. et al.Congenital erythropoietic porphyria associated with myelodysplasia presenting in a 72-year-old man: report of a case and review of the literature.Br J Dermatol. 2003; 148: 160-164Crossref PubMed Scopus (34) Google Scholar). We describe three new patients (patients 1–3) aged 64–75 years with a preexisting myeloid malignancy (Supplementary Table S1 online), who subsequently developed CEP (Table 1). Archived blood samples were also available from a previously reported patient (patient 4; Murphy et al., 1995Murphy A. Gibson G. Elder G.H. et al.Adult-onset congenital erythropoietic porphyria (Gunther's disease) presenting with thrombocytopenia.J R Soc Med. 1995; 88: 357P-358PPubMed Google Scholar). We show that these patients have a disorder that, although similar to CEP, is likely distinct, with biochemical and molecular features that define it as a separate condition, which we term “erythropoietic uroporphyria secondary to myeloid malignancy”. All patients gave informed consent to participate in the investigation. Institutional approval for the study was obtained as required. The study was conducted in accordance with the Declaration of Helsinki principles. Download .pdf (.02 MB) Help with pdf files Supplementary InformationTable 1Metabolite and enzyme measurements in patients with uroporphyriaPatientAge at onset of myeloid disorder (years)Age at onset of bullous skin lesions (years)Total urine porphyrin (nmoll−1)Total fecal porphyrin (nmolg−1)Plasma porphyrin (nmoll−1)Erythrocyte porphyrin (μmoll−1)Erythrocyte UROS activity (% mean control)171723,278 (79%)718 (86%)1501Median of 12 measurements over 64 months; range 89–1,818nmoll−1.2.42Median of 8 measurements over 64 months; range 1.3–14.3μmoll−1. (58%)982747519,332 (82%)1,413 (79%)Increased5.3 (52%)1123576412,330 (69%)2,628 (76%)5434.73Mainly zinc protoporphyrin.—44Data from the study by Murphy et al, 1995.606512,280 (97%)1,655—1.9—Childhood-onset CEPNo myeloid disorder<544,000 (7)6,111 (7)1,121 (15)22.1 (15)16–26 (3)11,986–123,2491,797–11,687232–5,1257.2–125.1(NS)5Significance of difference between patient (patients 1–4) and CEP groups: NS, not significant. For methods, see Supplementary Materials and Methods online.(P=0.02)5Significance of difference between patient (patients 1–4) and CEP groups: NS, not significant. For methods, see Supplementary Materials and Methods online.(P=0.003)5Significance of difference between patient (patients 1–4) and CEP groups: NS, not significant. For methods, see Supplementary Materials and Methods online.Reference range20–32010–200<11.20.4–1.7Abbreviations: CEP, congenital erythropoietic porphyria; UROS, uroporphyrinogen III synthase.Urinary and fecal porphyrin concentrations for childhood-onset CEP are for adults. Figures in parentheses are percent isomer I for uroporphyrin (urine) or coproporphyrin (feces), percent zinc-protoporphyrin for erythrocyte porphyrin or, for CEP, number of patients. For CEP, figures are medians and ranges. Fluorescence emission maxima for total plasma porphyrins were 617–618nm in all cases.1 Median of 12 measurements over 64 months; range 89–1,818nmoll−1.2 Median of 8 measurements over 64 months; range 1.3–14.3μmoll−1.3 Mainly zinc protoporphyrin.4 Data from the study by Murphy et al., 1995Murphy A. Gibson G. Elder G.H. et al.Adult-onset congenital erythropoietic porphyria (Gunther's disease) presenting with thrombocytopenia.J R Soc Med. 1995; 88: 357P-358PPubMed Google Scholar.5 Significance of difference between patient (patients 1–4) and CEP groups: NS, not significant. For methods, see Supplementary Materials and Methods online. Open table in a new tab Abbreviations: CEP, congenital erythropoietic porphyria; UROS, uroporphyrinogen III synthase. Urinary and fecal porphyrin concentrations for childhood-onset CEP are for adults. Figures in parentheses are percent isomer I for uroporphyrin (urine) or coproporphyrin (feces), percent zinc-protoporphyrin for erythrocyte porphyrin or, for CEP, number of patients. For CEP, figures are medians and ranges. Fluorescence emission maxima for total plasma porphyrins were 617–618nm in all cases. All four patients had bullae on the back of their hands and produced excess porphyrins in the characteristic CEP pattern, but porphyrin concentrations were lower than that in childhood-onset CEP (Table 1). Unlike hereditary CEP, erythrocyte UROS activity was normal (Table 1). We sequenced UROS genomic DNA from peripheral blood obtained from these patients and from 24 patients with childhood-onset CEP (Supplementary Materials and Methods online). UROS mutations were identified in 19 of the 24 childhood-onset cases but in none of our four MDS patients (P≤0.01), implying that MDS-associated uroporphyria is not caused by a germline UROS mutation. Deletion of one UROS allele was also excluded by demonstrating heterozygosity for a single-nucleotide polymorphism in intron 8 (rs2281955; patients 1–3) and for single-nucleotide polymorphisms in exon 1, intron 5, and intron 8 (rs4256900, rs10901444, rs2281954, and rs3740179; patients 2 and 3). Fluorescence microscopic studies of bone marrow aspirates from patients 1 and 2 showed that only ∼25% of normoblasts had the characteristic red nuclear fluorescence of uroporphyrin (Figure 1a and b). We cultured burst-forming unit–erythroid colonies from the peripheral blood of patient 2; of seven colonies picked at random, only one showed red porphyrin fluorescence (Figure 1c and d). We conclude that the porphyric defect is present in only a minority of hemopoietic cells. Genomic instability of myeloid progenitors in MDS causes gross chromosomal abnormalities and point mutations. Bone marrow karyotyping showed that patient 2 had a partial deletion of chromosome 11q (breakpoint in band q1.4), whereas patient 1 had no abnormalities. No deletions of chromosome 10, which carries UROS (q25.2–q26.3), were observed. No UROS mutations were identified by sequencing UROS genomic DNA (patients 1 and 2) or complementary DNA (patient 1) from unfractionated bone marrow cells. Both patients showed the same single-nucleotide polymorphism heterozygosity pattern in genomic DNA from bone marrow as in peripheral blood cells, excluding deletion of one allele in the majority of marrow cell nuclei. Mutations in GATA-1 on the X chromosome may also cause CEP. Karyotyping showed no X chromosome abnormalities, and no GATA-1 mutations were identified in genomic DNA from peripheral blood (all four patients) or from bone marrow (patient 1) by sequencing or by denaturing high-performance liquid chromatography (Supplementary Methods online). Similar to the fluorescence microscopic results, these data suggest that any acquired UROS or GATA1 mutation causing the porphyria is unlikely to be present in a high proportion of hemopoietic cells. Our three patients bring the total number of reported cases of erythropoietic uroporphyria associated with myeloid malignancy to eight. All were male patients, had a preexisting myeloid disorder, and presented with fragility and blistering in exposed skin after the age of 50 years. Hemorrhagic bullae in our four patients and in others presumably reflect thrombocytopenia (Kontos et al., 2003Kontos A.P. Ozog D. Bichakjian C. et al.Congenital erythropoietic porphyria associated with myelodysplasia presenting in a 72-year-old man: report of a case and review of the literature.Br J Dermatol. 2003; 148: 160-164Crossref PubMed Scopus (34) Google Scholar). None had erythrodontia, a feature of childhood CEP also absent from the adult-onset hereditary cases (Deybach et al., 1981Deybach J.C. de Verneuil H. Phung N. et al.Congenital erythropoietic porphyria (Gunther's disease): enzymatic studies on two cases of late onset.J Lab Clin Med. 1981; 97: 551-558PubMed Google Scholar). None had a family history of CEP. We have shown that these patients have lower erythrocyte porphyrin concentrations compared with childhood (Table 1) or adult-onset CEP (Deybach et al., 1981Deybach J.C. de Verneuil H. Phung N. et al.Congenital erythropoietic porphyria (Gunther's disease): enzymatic studies on two cases of late onset.J Lab Clin Med. 1981; 97: 551-558PubMed Google Scholar) and that erythrocyte UROS activity is normal (Table 1) in contrast to the reduced activity in the hereditary disease (Deybach et al., 1981Deybach J.C. de Verneuil H. Phung N. et al.Congenital erythropoietic porphyria (Gunther's disease): enzymatic studies on two cases of late onset.J Lab Clin Med. 1981; 97: 551-558PubMed Google Scholar; Desnick and Astrin, 2002Desnick R.J. Astrin K.H. Congenital erythropoietic porphyria: advances in pathogenesis and treatment.Br J Haematol. 2002; 117: 779-795Crossref PubMed Scopus (105) Google Scholar; De Verneuil et al., 2003De Verneuil H. Ged C. Moreau-Gaudry F. Congenital erythropoietic porphyria.in: Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook, Vol. 14, Medical Aspects of Porphyries. Academic Press, Amsterdam2003: 43-66Crossref Scopus (19) Google Scholar). We did not find germline mutations in UROS or GATA1, in contrast to hereditary CEP (Desnick and Astrin, 2002Desnick R.J. Astrin K.H. Congenital erythropoietic porphyria: advances in pathogenesis and treatment.Br J Haematol. 2002; 117: 779-795Crossref PubMed Scopus (105) Google Scholar; De Verneuil et al., 2003De Verneuil H. Ged C. Moreau-Gaudry F. Congenital erythropoietic porphyria.in: Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook, Vol. 14, Medical Aspects of Porphyries. Academic Press, Amsterdam2003: 43-66Crossref Scopus (19) Google Scholar; Phillips et al., 2007Phillips J.D. Steensma D.P. Pulsipher M.A. et al.Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.Blood. 2007; 109: 2618-2621Crossref PubMed Scopus (125) Google Scholar). These clinical and pathological findings identify “uroporphyria associated with myeloid malignancy” as a syndrome distinct from hereditary CEP. The low erythrocyte porphyrin and normal UROS activity in our patients suggest that only a small proportion of circulating red cells are uroporphyric and are consistent with the evidence from bone marrow microscopy and cell culture (Figure 1) that erythroid cells in uroporphyria associated with MDS are a mosaic of normal and uroporphyric cells, with the former predominating. Acquired forms of α-thalassemia (Steensma et al., 2005Steensma D.P. Gibbons R.J. Higgs D.R. Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies.Blood. 2005; 105: 443-452Crossref PubMed Scopus (99) Google Scholar) and erythropoietic protoporphyria (Goodwin et al., 2006Goodwin R.J. Kell W.J. Laidler P. et al.Photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in haematopoietic cells.Blood. 2006; 107: 60-62Crossref PubMed Scopus (48) Google Scholar) occurring in association with MDS result from somatic mutations in clones of myelodysplastic cells. It seems probable that the minor clone of uroporphyric erythropoietic cells in our patients similarly contains an acquired somatic mutation but one that leads to UROS deficiency. The cause of UROS deficiency in uroporphyric cells remains to be identified. Our inability to find UROS or GATA1 mutations may be explained by the difficulty experienced in detecting mosaicism when the proportion of abnormal cells is low; the techniques we used were unlikely to detect less than ∼15% of mutant DNA. Alternatively, the abnormality may be in another gene that determines UROS activity. We thank Dr John Phillips, University of Utah School of Medicine, for providing GATA1 mutant DNA; Professor Peter Shoolingin-Jordan, University of Southampton, for providing recombinant PBG deaminase; Ms Jacqueline Woolf, Ms Nicola Mason, and Ms Cindy Derby for skilled technical assistance; Dr Hazel Tinegate and Dr Christopher Tiplady (Department of Haematology and Blood Transfusion, North Tyneside General Hospital, Tyne and Wear), and Dr Margaret Semple (Department of Haematology, Epsom General Hospital) for their roles in the clinical management of patients 1 and 2. The Biomedical Research Centre of Kings College London and Guys and St Thomas’ NHS Foundation Trust funded Dr Sarkany for this work. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid