Congenital Erythropoietic Porphyria, β-Thalassemia Intermedia and Thrombocytopenia Due to a GATA1 Mutation.
Authors: Phillips John D. , Steensma David P. , Spangrude Gerald J. , Kushner James P. 
Published: April 2020

Abstract
Congenital erythropoietic porphyria (CEP), a rare photomutilating disorder, is due to homozygosity or compound heterozygosity for mutant alleles encoding uroporphyrinogen III synthase (U3S), a cytosolic enzyme that converts hydroxymethyl bilane to uroporphyrinogen III. Deficiency of U3S results in an excess of biologically useless uroporphyrin I (URO I), which causes the photomutilation. Clinical expression of CEP is usually associated with co-existence of congenital dyserythropoietic anemia type I, also an autosomal recessive trait. We evaluated a 3-year-old boy of English-French extraction with a photosensitive bullous dermatosis; CEP was suspected. The boy had a hypochromic, microcytic anemia and thrombocytopenia from birth with hemoglobin values averaging 7.0 g/dL, MCV’s averaging 67 fL and platelet counts averaging 70,000/μL. A physical exam revealed scars on the face, hands and forearms, generalized hirsutism and splenomegaly. The diaper fluoresced under a Wood’s lamp. Fifty mL of urine contained 2,003 μg of URO (normal=trace), 92% of which was URO I. Erythrocyte U3S activity was 21% of controls, confirming the diagnosis of CEP. Red cell morphology was compatible with thalassemia and fluorescent red cells were apparent. Hb electrophoresis revealed 36.3% Hb A, 2.4% Hb A2, 59.5% Hb F and 1.8% of a fast moving peak, likely Hb Bart’s. Both parents were hematologically normal, had no evidence of porphyria, and had normal Hb electrophoreses. Genomic U3S was characterized (including the promoter), no mutations or deletions were found in the child or the parents. Characterization of the α and β-globin loci also revealed no mutations or deletions. Lack of a molecular explanation for either the low U3S activity or the β-thalassemia/thrombocytopenia phenotype led us to sequence GATA1, an X-linked transcription factor common to globin genes and the first 4 steps of the heme biosynthetic pathway in erythrocytes. A mutation was found at codon 216 in the child and on one allele of his mother, changing arginine to tryptophan (R216W). A more conservative arginine to glutamine mutation (R216Q) previously described by Yu et al. (Blood2002; 100:2040–5) is the only known human mutation of the DNA-binding domain of the N-finger of GATA1, and did not result in porphyria. Here, in contrast to the reduced activity of U3S, erythrocyte activities of the proximal heme biosynthetic enzymes were normal. To explore the mechanism responsible for the extremely high Hb F levels we sequenced the proximal promoter regions of the γ globin loci. The Xmn I polymorphism (−158 C to T), associated with increased production of G-γ chains, was identified in the promoter region of one G-γ allele in the child and in one allele of his father. The G-γ to A-γ ratio in the child’s Hb F was 2:1, a moderate increase in the expected ratio. Xmn I, when present with the Hb S mutation, results in variable Hb F elevations but almost always &lt;20% (Miller et al Blood1987; 70:716–20), far below the 59.5% level observed. 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% is not fully explained but a role for GATA1 R216W in altering globin switching is possible. The selective effect of the R216W mutation on U3S suggests that cis-elements vary in their affinity for GATA1. A bone marrow allograft corrected both the porphyria and the thalassemia.