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      Very Early Diagnosis and Management of Congenital Erythropoietic Porphyria

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          Abstract

          Congenital erythropoietic porphyria (CEP), a rare form of porphyria, is caused by a defect in the heme biosynthesis pathway of the enzyme uroporphyrinogen III synthase (UROS). Uroporphyrinogen III synthase deficiency leads to an accumulation of nonphysiological porphyrins in bone marrow, red blood cells, skin, bones, teeth, and spleen. Consequently, the exposure to sunlight causes severe photosensitivity, long-term intravascular hemolysis, and eventually, irreversible mutilating deformities. Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusions, hydroxyurea, and splenectomy are commonly used in the management of CEP. Currently, the only available curative treatment of CEP is hematopoietic stem cell transplantation (HSCT). In this article, we present a young girl in which precocious genetic testing enabled early diagnosis and allowed curative treatment with HSCT for CEP at the age of 3 months of age, that is, the youngest reported case thus far.

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          New Insights Into Multicenter PICU Mortality Among Pediatric Hematopoietic Stem Cell Transplant Patients.

          Matt Zinter, Christopher C. Dvorak, Aaron Spicer … (2015)
          Over 2,500 children undergo hematopoietic stem cell transplantation in the United States each year, and up to 35% require PICU support for life-threatening complications. PICU mortality has dropped from 85% to 44%, but interpretation is confounded by significant cohort heterogeneity. Reports conflict regarding outcomes for patients with different underlying hematopoietic stem cell transplantation indications, and the burden of infectious complications for these patients has not been evaluated. We aim to describe infections, critical care interventions, and mortality for pediatric hematopoietic stem cell transplantation patients requiring PICU admission.
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            Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.

            John Phillips, David P Steensma, Michael A. Pulsipher … (2007)
            Congenital erythropoietic porphyria (CEP), an autosomal recessive disorder, is due to mutations of uroporphyrinogen III synthase (UROS). Deficiency of UROS results in excess uroporphyrin I, which causes photosensitization. We evaluated a 3-year-old boy with CEP. A hypochromic, microcytic anemia was present from birth, and platelet counts averaged 70 x 10(9)/L (70,000/microL). Erythrocyte UROS activity was 21% of controls. Red cell morphology and globin chain labeling studies were compatible with beta-thalassemia. Hb electrophoresis revealed 36.3% A, 2.4% A(2), 59.5% F, and 1.8% of an unidentified peak. No UROS or alpha- and beta-globin mutations were found in the child or the parents. The molecular basis of the phenotype proved to be a mutation of GATA1, an X-linked transcription factor common to globin genes and heme biosynthetic enzymes in erythrocytes. A mutation at codon 216 in the child and on one allele of his mother changed arginine to tryptophan (R216W). This is the first report of a human porphyria due to a mutation in a trans-acting factor and the first association of CEP with thalassemia and thrombocytopenia. The Hb F level of 59.5% suggests a role for GATA-1 in globin switching. A bone marrow allograft corrected both the porphyria and the thalassemia.
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              Congenital erythropoietic porphyria: Recent advances

              Angelika Erwin, Robert J Desnick (2018)
              Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Disease-causing mutations in either gene result in absent or markedly reduced UROS enzymatic activity. This in turn leads to the accumulation of the non-physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I, which damage erythrocytes and elicit a phototoxic reaction upon light exposure. The clinical spectrum of CEP depends on the level of residual UROS activity, which is determined by the underlying pathogenic loss-of-function UROS mutations. Disease severity ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous involvement. The clinical characteristics of CEP include exquisite photosensitivity to visible light resulting in bullous vesicular lesions which, when infected lead to progressive photomutilation of sun-exposed areas such as the face and hands. In addition, patients have erythrodontia (brownish discoloration of teeth) and can develop corneal scarring. Chronic transfusion-dependent hemolytic anemia is common and leads to bone marrow hyperplasia, which further increases porphyrin production. Management of CEP consists of strict avoidance of exposure to visible light with sun-protective clothing, sunglasses, and car and home window filters. Adequate care of ruptured vesicles and use of topical antibiotics is indicated to prevent superinfections and osteolysis. In patients with symptomatic hemolytic anemia, frequent erythrocyte cell transfusions may be necessary to suppress hematopoiesis and decrease marrow production of the phototoxic porphyrins. In severe transfection-dependent cases, bone marrow or hematopoietic stem cell transplantation has been performed, which is curative. Therapeutic approaches including gene therapy, proteasome inhibition, and pharmacologic chaperones are under investigation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Clin Pediatr (Phila)
                Journal ID (iso-abbrev): Clin Pediatr (Phila)
                Journal ID (publisher-id): CPJ
                Journal ID (hwp): spcpj
                Title: Clinical Pediatrics
                Publisher: SAGE Publications (Sage CA: Los Angeles, CA )
                ISSN (Print): 0009-9228
                ISSN (Electronic): 1938-2707
                Publication date (Electronic): 11 October 2022
                Publication date (Print): June 2023
                Volume: 62
                Issue: 5
                Pages: 399-403
                Affiliations
                [1 ]CHU de Québec, Centre Hospitalier de l’Université Laval, Department of Pediatrics, Université Laval, Québec City, QC, Canada
                [2 ]CHU de Québec, Centre Hospitalier de l’Université Laval, Division of Dermatology, Department of Medicine, Université Laval, Québec City, QC, Canada
                [3 ]CHU Sainte-Justine, Division of Hematology/Oncology, Department of Pediatrics, University of Montréal, Montréal, QC, Canada
                Author notes
                [*]Marie-Pier Desjardins, CHU de Québec, Centre Hospitalier de l’Université Laval, Department of Pediatrics, Université Laval, 2705 Boulevard Laurier, Quebec City, QC G1V 4G2, Canada. Email: marie-pier.desjardins.5@ 123456ulaval.ca
                Author information
                https://orcid.org/0000-0001-9584-2320
                Article
                Publisher ID: 10.1177_00099228221128661
                DOI: 10.1177/00099228221128661
                PMC ID: 10170564
                PubMed ID: 36217751
                SO-VID: 96494bba-ae78-4e6d-95df-ab07cfb0e0a4
                Copyright © © The Author(s) 2022
                License:

                This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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                Subject: Brief Reports
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                Keywords: congenital erythropoietic porphyria,hematopoietic stem cell transplantation,hematology
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                Keywords: congenital erythropoietic porphyria, hematopoietic stem cell transplantation, hematology

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