eP018: Late-onset congenital erythropoietic porphyria associated with myeloid malignancy


      Congenital erythropoietic porphyria (CEP, OMIM #263700) is a rare disorder of heme biosynthesis characterized biochemically by elevated excretion of type I porphyrin isomers in urine and feces. The disorder is caused by decreased uroporphyrinogen III synthase (UROS) activity, leading to an overproduction of the dead-end metabolites uro- and coproporphyrinogen I, primarily in the bone marrow, and the subsequent deposition of type I porphyrin isomers in tissues.
      In most cases, the CEP results from homozygous or compound heterozygous pathogenic variants in the UROS gene. More rarely, it presents in males with specific variations of the X-linked transcription factor GATA1, which leads to decreased UROS expression in erythroid precursor cells. The clinical severity of CEP is variable and ranges from hydrops fetalis due to hemolytic anemia in utero to a mild adult-onset form with cutaneous manifestations only. Typically, however, the disorder presents soon after birth with cutaneous photosensitivity and hemolytic anemia.
      A small number of patients have been reported in the literature with clinical and biochemical features of CEP without pathogenic variants in the UROS or GATA1 genes and with normal UROS activity in erythrocytes. These patients were all males with myeloid malignancy who first presented with symptoms of cutaneous porphyria after the age of 50. The underlying cause of the CEP-like phenotype in these patients is unknown. It has been hypothesized that in those patients, UROS is defective only in a small number of myelodysplastic cells resulting from a somatic mutation in either UROS or GATA1. In that scenario, the number of clones carrying the pathogenic variant might be too low to be detected by standard molecular methods but sufficient to cause clinical and biochemical symptoms consistent with CEP.

      Case presentation

      The patient is a 52-year-old woman with a complicated past medical history who presented to a tertiary medical center with blistering lesions that started 2 years ago. Her past medical history is remarkable for type 2 diabetes, hypertension, hyperlipidemia, coronary artery disease, chronic obstructive pulmonary disease, and peripheral vascular disease.
      She was diagnosed with CEP at her local clinic but had not had any medical interventions done locally. Over the years, her clinical condition deteriorated progressively where now she had multiple areas of ulceration and blistering with hypopigmented scarring in sun-exposed areas, particularly on her face and scalp, deep routed ulcers in her hands and arm, and reddish discoloration of her urine. In the preceding months, she had also developed worsening pancytopenia needing blood transfusion. A bone marrow biopsy showed erythroid hyperplasia with dyspoietic changes confined to the erythroid lineage and hypercellularity but no morphological evidence of malignancy. Molecular DNA analysis detected pathogenic variants in the genes BCOR and TET2, both associated with myelodysplastic syndrome and acute myeloid leukemia. Based on these findings, the patient was diagnosed with low-risk myelodysplastic syndrome.
      Porphyrin analysis showed elevated levels of uro- and coproporphyrins in urine, type I porphyrin isomers in feces, and slightly increased total porphyrin in erythrocytes—a biochemical profile consistent with CEP. However, next-generation sequencing of 11 genes associated with porphyria did not detect any pathogenic variants, and the measured UROS activity in erythrocytes was within the normal range.


      The case presented here is, to our knowledge, the first female patient reported with a late-onset CEP-like phenotype associated with myelodysplastic syndrome. This demonstrates the value of biochemical investigation and clinical examination in cases where DNA analysis proves inconclusive.