Congenital Erythropoietic Porphyria Due to Co-Inheritance of GATA1 and UROS Gene Mutations

Abstract 3208 The Congenital Erythropoietic Porphyria (CEP) is a rare form of Chronic Porphyria characterized by severe photosensivity. Secondary infections of cutaneous lesions may lead to scarring, deformities and disfigurement of the light-exposed parts of the body such as hands, ears, nose, and eyelids. Erythrodontia, osteodystrophia, combining osteolysis and osteoporosis, hypercellular bone marrow, hemolytic anemia, hypersplenism, splenomegaly and red-coloured urine are present in almost all patients. Generally, CEP is an autosomic recessive disease caused by mutations in homozygosis or compound heterozygosis in UROS gene coding for the fourth enzyme of the heme biosynthesis pathway. At present a new form of CEP with an X-linked inheritance associated with R216W mutation in the GATA 1 gene has been described only in one French-English family by Philips JD et al. GATA1 is a key zinc finger transcription factor that coordinates hematopoietic cell differentiation. We described a Turkish family where a severe CEP phenotype segregates with thalassemia and thrombocytopenia. The propositus is an 4 year old boy who presented photosensitive bullous dermatosis, splenomegaly, short stature and pallor. His mother was chronically anemic (Hb 10.9 g/dL) and thrombocytopenic (96×109/L) known as chronic immune thrombocytopenic purpura, whereas the father and the brother were asymptomatic. At birth, the boy had hypochromic, microcytic anemia, thrombocytopenia and thrombasthenia. Reticulocyte counts slightly increased. At 2 months he was transfused, splenomegaly and heart murmur were detected on physical examination. At this point his Hb level was 6,9 g/dl, WBC 7,400×109/L, platelets 64–106×109/L, MCV 70 flL, RDW 28%. The patient's peripheral-blood smear revealed microcytic, hypochromic red cells, target cells, basophilic stippling, and rare nucleated red cells, findings compatible with thalassemia but DNA analysis for beta and alpha thalassemia was normal. A bone marrow aspirate revealed a hypercellular marrow and erythroid hyperplasia. Dyserythropoiesis was noted with nuclear budding, nuclear bridging, and occasional multinucleation. Megakaryocytes were decreased in number, Hb electrophoresis revealed increased levels of fetal hemoglobin (HbA2 2%; Hb F 68%). At 3 years liver MRI detected iron overload. Ferritin level was 329ng/dL. Because of some skin lesions on his body he was then tested with urine and plasma analysis and the results were consistent with the diagnosis of congenital erythropoietic porphyria. Urine total porphyrins were 5414 nmol/mmol creatinin (N<35) with an excess of isomer I of both Uroporphyrins and Coproporhyrins. Total plasma porhyrins were 312 nmol/L (N<10). We analyzed the UROS gene and we identified a new mutation c.338A>T (D113V) in heterozygosis in the propositus, in his father and in his brother. On the basis of hematological status we decided to analyze also GATA1 gene and the mutation c.646C>T (R216W) has been detected in the child and on one allele of his mother who presents a balanced pattern of X-inactivation. The patient is similar to the case of association of CEP with an hematologic phenotype of beta-thalassemia intermedia. Markedly elevated Hb F levels, and thrombocytopenia result from mutations in the transacting factor GATA-1 presented by Philips JD et al. This patient additionally has a severe liver iron overload. A newborn sibling died at birth because of sepsis and neonatal hepatitis. Liver iron overload was also detected in the sibling's autopsy. All components of family were heterozygous for the H63D mutation in HFE gene but no other HAMP, HJV and SLC40A1 mutations were found. The patient started a regular transfusion program and Deferasirox was given for hemosiderosis after Desferroxamine uncompliance. This is the first report of the association of GATA1 and UROS gene mutations that could explain the very severe hematological phenotype. Disclosures: No relevant conflicts of interest to declare.