Hematopoietic Stem Cell Transplant as a Cure for Glucose‐6Phosphate Isomerase Deficiency in Siblings—Case Report From a Tertiary Care Center in India

To the Editor: A 15-year-old girl from Karnataka, second born to a third-degree consanguineously married couple, was normal until 1 year of age when she presented with increasing pallor requiring packed cell transfusion and mild jaundice. She continued to require packed cell transfusion once every 3–4 months (pre-transfusion hemoglobin being 5–6 g%) until 11 years of age, when she was evaluated extensively, along with her younger brother who also required frequent blood transfusions. On examination, she was pale and mildly icteric with splenohepatomegaly (liver 3 cm below costal margin; spleen 5 cm along its long axis). Complete blood count (CBC) and peripheral smear revealed severe hemolytic anemia; red cell indices were suggestive of macrocytosis with high reticulocyte count. There was mild indirect hyperbilirubinemia, and the direct Coombs test was negative (Table 1). Hemoglobin high-performance liquid chromatography was normal; the father had beta thalassemia trait; however, the patient's alpha and beta globin gene panels were normal; red cell osmotic fragility test and flow cytometry using eosin-5-maleimide to rule out hereditary spherocytosis were also normal; enzyme levels for the most common enzymopathies, G6PD and pyruvate kinase, were also non-contributory. Bone marrow was suggestive of erythroid hyperplasia with megaloblastic features. Ultimately, upon a strong clinical suspicion, glucose-6-phosphate isomerase (G6PI) enzyme level was low (12.2 IU/g Hb), which confirmed the diagnosis, and bone marrow transplant was planned. Coincidentally, her elder sister, a healthy girl who was never anemic or required a blood transfusion, was a full HLA match and was selected as the donor after her G6PI enzyme level was done and reported to be normal (46 IU/g Hb). Post two cycles of pre-transplant immunosuppressive therapy with cyclophosphamide and fludarabine, she underwent matched sibling donor hematopoietic stem cell transplantation (HSCT). Myeloablative conditioning with cyclophosphamide, antithymocyte globulin, busulfan, and fludarabine was used. A combination of calcineurin inhibitor (cyclosporine) starting from Day-3 and anti-metabolite (methotrexate) on days +1, 3, 6, and 11 was given for graft versus host disease (GVHD) prophylaxis. EBMT criteria were used to define and grade veno-occlusive disease (VOD) and GVHD [1]. Bone marrow from donor was used as the source, with CD34 cell dose of 3.94 million cells/kg. The post-transplant period was complicated by febrile neutropenia, moderate VOD, acute kidney injury, and drug-induced hypertension, which was managed conservatively. Neutrophils and platelets were engrafted on days +17 and +18, respectively, and she was discharged from the hospital on Day +19. Follow-up chimerism studies done at 1, 3, and 6 months post-transplant showed >95% donor chimerism. She is currently 48 months post-HSCT; organomegaly has regressed, icterus has resolved, and she has not required any more packed cell transfusions. Her younger brother who had also presented with similar complaints requiring frequent packed cell transfusions (once in 3–4 months) from 18 months of age was evaluated on similar lines (Table 1). G6PI enzyme level done was −21.1 IU/g Hb that revealed the diagnosis. He also underwent MSD HSCT, 2 years after his sister was transplanted, with the same donor as his sister (Table 1). Donor bone marrow was used, with CD34 cell dose of 7.36 million cells/kg. The post-transplant period was uneventful, and post BMT chimerism was persistently >95%. He is currently 1 year and 6 months post-transplant and is growing well. G6PI deficiency is the second most common enzymopathy (after pyruvate kinase) in the anaerobic glycolysis pathway [2, 3] with autosomal recessive inheritance [4-6]. There are only about 100 cases of G6PI enzyme deficiency reported in the literature worldwide [4, 7]. Children present with varying degrees of hemolytic anemia ranging from mild to moderate to severe anemia with hydrops fetalis [8, 9], and varying degrees of jaundice and splenomegaly. Onset is often in the neonatal period/infancy, although diagnosis is delayed due to misdiagnosis, lack of awareness, or nonavailability of the G6PI enzyme assay. There has been no correlation observed between the extent of enzyme deficiency and the severity of symptoms [5]. There are no treatment guidelines established for the management of G6PI deficiency. Symptomatic treatment includes packed cell transfusion and iron chelators, which has, however, not been effective in alleviating the complications of long-term blood transfusion, like iron overload, infection, and cholecystitis. Splenectomy has been effective in decreasing the need for blood transfusion; however, it comes with serious complications, mainly OPSI, pulmonary hypertension, and venous thromboembolism. Hence, the decision of splenectomy should be cautiously taken [10]. HSCT for G6PI deficiency has not been reported in literature except for one case report of two children who underwent a matched unrelated donor transplant and are doing well 2 years post-transplant [11]. HSCT is associated with immediate and long-term complications; however, it provides a reasonable therapeutic option for children with G6PI deficiency and chronic hemolytic anemias [12], also offering them a better quality of life. Currently, HSCT is an experimental treatment option for G6PI deficiency, and long-term follow-up is essential before it can be recommended as a treatment strategy. Written informed consent was obtained from the patient's parents for publication of this report. The authors declare no conflicts of interest.