Clinical characterization of the rare G6PD pawnee variant: A five-patient case series Free

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common genetic condition, affecting an estimated 500 million people worldwide. Of these, the G6PD Pawnee variant (c.1406G>C; p. Arg439Pro) is extremely rare for which limited data are known about its clinical and biochemical characteristics. In this case series we describe five patients diagnosed with G6PD Pawnee variant who were managed at the hematology clinic at St Jude Children's Research Hospital. All five patients presented with chronic non spherocytic hemolytic anemia (CNSHA) which was categorized as WHO Class A (revised WHO classification).

Patient 1 presented with symptomatic anemia (Hgb 8.9 g/dL, percent reticulocyte counts of 3.03%) at the age of 1. He had stable but persistently low hemoglobin (8.5–10.5 g/dL). At age 6, workup at our hematology clinic revealed macrocytic anemia (Hgb 10.9 g/dL, MCV 96 fL, reference range = 77-95 fL, retic 4%), normal B12/folate, negative DAT, and a low G6PD level (1.8 units/g Hgb, reference range= 9.9-16.6 units/g Hgb) with genetic testing confirming a hemizygous G6PD Pawnee variant.

Patient 2 is a 6-year-old male who presented with fever and abdominal pain. He was found to have normocytic anemia (initial Hgb 7.0 g/dL, later 8.0 g/dL) with an elevated reticulocyte count (5.9%, rising to 9.9%), and MCV 94.6 fL. Other labs showed an elevated LDH, low haptoglobin, total bilirubin of 1.7 mg/dL (range = <1.1 mg/dl), and a negative DAT. He received two doses of intravenous corticosteroids with minimal effect on hemoglobin, although his percent reticulocyte count increased to 9.9%. In our clinic, his G6PD enzyme activity was 1.8 units/g Hgb. Genetic testing revealed the G6PD Pawnee variant. He has not required any transfusion support, and his hemoglobin has remained stable between 11.0 g/dL - 12.2 g/dL.

Patient 3 is a previously healthy 5-year-old male who presented with fatigue, rash, and was found to have macrocytic anemia (initial Hgb 7.7 g/dL, dropping to 7.1 g/dL) in the setting of RSV, positive mononucleosis screen, and confirmed parvovirus infection (IgM and IgG positive). His initial reticulocyte count was low at 0.3%, consistent with acute parvovirus infection. Post-transfusion, his hemoglobin rose to 11.6 g/dL and reticulocyte count increased to 14.3% with MCV rising from 96.3 to 99 fL. G6PD enzyme activity was low at 4.4 units/g Hb, and genetic testing confirmed the G6PD Pawnee variant.

Patient 4 (hemoglobin range: 7.4 g/dL to 11.5 g/dL) and patient 5 (hemoglobin range: 10.4 g/dL to 12.5 g/dL) are the brothers of patient 3 and have a similar clinical history of episodic anemia but have not required any transfusions to date. Genetic testing via a hereditary hemolytic anemia panel confirmed they are hemizygous for the Pawnee variant. Despite the shared genotype, their clinical course has been milder, with no need for transfusion support.

According to the previous WHO classification of G6PD variants (ranging from Class I [severe deficiency with chronic hemolysis] to Class V [increased activity]), there has been a discrepancy in the classification of G6PD Pawnee. Although initially classified as a WHO Class II variant, G6PD Pawnee is increasingly recognized as causing a phenotype consistent with CNSHA. Based on the revised WHO classification, our patients, the previous WHO Class I variants, are now classified as Class A variants. Our patients all would be classified as revised WHO Class A variants based on their enzyme levels and CNSHA clinical phenotype.

To our knowledge, this is the largest reported case series of G6PD Pawnee. Given the paucity of data, this series of 5 patients is a valuable source of clinical data on the presentation of G6PD Pawnee and its natural history, which appears to align with CNSHA. Our findings highlight how important it is to identify rare G6PD variants and show that more research is needed to better understand how to care for and support individuals with these conditions.