A Rare Case of Congenital Atransferrinemia: International Collaboration for Genetic Diagnosis

Congenital atransferrinemia is an extremely rare hematologic disease caused by transferrin deficiency, and characterized by microcytic hypochromic anemia with iron overload, and that can be fatal if left untreated. The prevalence is unknown. To date, there have been 16 reported cases from 14 families, with few cases confirmed genetically. Here, we report a new case from the Middle East that was diagnosed on clinical ground, and then confirmed by genetic testing through international collaboration.

M.T is a 32 months old Egyptian boy, 2^nd child of a consanguineous couple, with a healthy 5.5 years older sister. He was born at full term by SVD, suffered physiological jaundice as a newborn. He also had Talipes equinovarus and hypospadias.

He was first brought to medical attention at a local hospital at the age of 8 months because of a febrile illness, when he was accidentally discovered to be very pale with Hb of 4.8 g/dl. He received packed RBC transfusion followed by oral iron therapy for 2 weeks, and then another assessment revealed Hb 6.9 g/dl, so he received another transfusion, and then referred to the University Hospital for further assessment.

Examined at the age of 20 months, he had marked pallor, tachycardia, and mild hepatosplenomegaly, otherwise the child was normal with average anthropometric measurements.

CBC revealed severe microcytic hypochromic anemia (Hb 4.8, MCV 54 fl, MCH 18 pg), MCHC 30 g/dl). Hb electrophoresis: normal Screening for Alfa and Beta thalassemia: normal wild type. Iron profile revealed hypoferremia (Serum iron: 6 ug/dl), TIBC: below assay range, and high serum ferritin: 669 ng/ml. Based on these results, atransferrinemia was suspected, so he was tested for serum transferrin, and reported as very low (8 mg/dl). Bone marrow aspirate was normocellular for age, showing normal granulopoiesis, normoblastic erythropoiesis, and normal megakaryopoiesis, no evidence of dysplasia or abnormal or malignant cells. Prussian blue stain showed depleted iron stores. Serum lead, bilirubin, liver and kidney function tests were normal

Both parents had normal blood picture and iron profile. Human apotransferrin was not available in Egypt, so, plasma transfusion was instituted every 2-4 weeks, through which regimen he is maintaining Hb level between 7-12 gm/dl.

As molecular diagnosis for that very rare disease was not feasible in Egypt, after parental consent, blood samples from patient and both parents were sent to Dr. von Haunersches Kinderspital, Munich, and a novel transferrin genemutation was detected by NGS(TF, NM_001063.3, c.1247A>G, p.Y416C) that is currently being validated by Sanger sequencing.

To the best of our knowledge, this is the first atransferrinemia report from the Middle East, where prevalence of thalassaemia and iron deficiency anemia is high. However, this rare anemia case underlines the importance of considering rare hereditary disorders like atransferrinemia as the cause for unexplained hypochromic microcytic anemia associated with iron overload, in order to initiate appropriate treatment and avoid iron overload related complications.