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Pancytopenia and megaloblastic erythropoiesis reveal a novel GIF mutation

A 16-month-old male, born to consanguineous Algerian parents, presented with pallor, asthenia, anorexia, mild diarrhoea and vomiting. He had shown moderate growth failure since he was 13 months of age. Blood tests revealed pancytopenia with a non-regenerative macrocytic anaemia (haemoglobin concentration 69 g/l; mean corpuscular volume 95 fl; reticulocytes 53 9 10/l), neutropenia (0 6 9 10/l) and mild thrombocytopenia (137 9 10/l). His peripheral blood film showed macro-ovalocytes and hypersegmented neutrophils (top left, May–Gr€ unwald–Giemsa (MGG) stain). A bone marrow aspirate showed hyperplastic megaloblastic erythropoiesis and giant metamyelocytes (top middle and right, MGG), consistent with vitamin B12 or folic acid deficiency. The serum vitamin B12 level was <60 ng/l (normal range 145–569 ng/l). Targeted sequencing of the gastric intrinsic factor (GIF) gene revealed a novel bi-allelic variant c.544T>C (yielding a p.Lys182Arg substitution) in the propositus and his 6-yearold sister (bottom). The patient’s sister had been diagnosed with chronic vitamin B12 deficiency and treated in Algeria with vitamin B12 replacement. The family had then moved to France, where their general practitioner discontinued the treatment. She remained asymptomatic with a normal full blood count, as the treatment had been stopped only a few months before her brother’s diagnosis. However, her serum vitamin B12 concentration was 67 ng/l. The parents were heterozygous carriers, which highlighted the recessive pattern of inheritance of the condition (bottom). Intrinsic factor deficiency (Mendelian Inheritance in Man Entry 261000) is a rare autosomal recessive disorder of vitamin B12 absorption caused by bi-allelic GIF mutation. Fewer than 50 cases have been described. The disease usually manifests before five years of age. When there is delayed diagnosis, irreversible neurological complications can occur, such as peripheral neuropathy, subacute combined degeneration of the spinal cord and ataxia. However, lifelong vitamin B12 replacement therapy fully prevents these complications. Clinical and laboratory signs of vitamin B12 deficiency and genetic testing are key to the correct diagnosis of this condition.