Clinical Manifestations of Phosphoglucomutase 3 (PGM3) Deficiency

Background and Aims Phosphoglucomutase 3 (PGM3) deficiency is a congenital disorder of glycosylation characterized by elevated IgE, atopy, recurrent infections, autoimmunity, cognitive impairment, and cytopenias. As more patients have been described, the variability in clinical presentation has become apparent. We aimed to further characterize the phenotype of PGM3 deficiency at our center. Methods Medical records were retrospectively reviewed for 10 patients from 4 families with PGM3 deficiency seen at the NIH Clinical Center. Results Ten patients (7 males and 3 females), aged 5 to 38 years, were evaluated at our center. Atopy was the most common manifestation, with eczema seen in all 10 patients and food and drug allergies in 9 and 8 patients, retrospectively. Sinopulmonary infections were noted in 8 patients, complicated by bronchiectasis in 5, and 5 had viral mucocutaneous infections. Seven patients had varying levels of neurocognitive impairment. Five patients had autoimmunity, including vasculitis in 4, glomerulonephritis in two, and psoriasis in one. Three affected siblings had malignancy: two with EBV-positive Hodgkin’s lymphoma, two with EBV-positive diffuse large B cell lymphoma (including one with prior Hodgkin’s), and one with squamous cell CA (SCC). Additional findings included bony abnormalities in 8 (6 with scoliosis, 2 with endplate abnormalities), single kidney (1), and heart failure (1). Nine patients had lymphopenia, 7 had severe chronic neutropenia (ANC < 500), and one had hemolytic anemia. Bone marrow biopsies were evaluated for 7 patients; three were normocellular despite neutropenia, one was hypocellular with no dysplastic features, and one had erythroid hypercellularity due to chronic hemolysis. One patient is alive and well after hematopoietic cell transplantation (HCT), with resolution of recurrent infections, severe neutropenia, and atopic dermatitis, and one patient had a lung transplant for severe bronchiectasis. There were 3 fatalities between ages 36 and 42 from malignancy (2 with lymphoma and one SCC) and one COVID-related fatality at age 18. Conclusions Although this is a multi-systemic disorder, the 30% mortality in early adulthood due to virally driven malignancies along with severe infection and chronic neutropenia suggests that HCT should be strongly considered.