A Novel Phosphoglucomutase-3 Gene Variant Causing Milder Phenotype in Two Families.

backgroundPhosphoglucomutase 3 deficiency (PGM3 deficiency) is a rare congenital disorder of glycosylation classically associated with severe immunodeficiency, skeletal abnormalities, and neurodevelopmental impairment. However, emerging evidence suggests that PGM3 deficiency may also present with attenuated or milder clinical phenotypes. In this study, we describe patients with a novel PGM3 variant exhibiting a less severe immunological and clinical presentation, thereby expanding the known phenotypic spectrum of PGM3 deficiency.

methodsDemographic-data and Wechsler Intelligence Scale for Children profiles were evaluated alongside laboratory data, including complete blood cell counts, lymphocyte subsets, serum immunoglobulin levels, vaccine antibody titers, and lymphocyte cytokine profiles. Whole exome sequencing was conducted, and phospho-flow assays were utilized for the analysis of p-STATs.

resultsFive patients with a mild form of PGM3 deficiency were described, exhibiting a Hyper-IgE Syndrome phenotype without severe skeletal dysplasia or dysmorphism, with the exception of one patient displaying very mild skeletal dysplasia and three patients exhibiting mild to moderate intellectual disability. All patients demonstrated an increase in Natural Killer T cells and a decrease in B cells, alongside an increase in activated CD4 + T cells (CD45RO+), a decrease in naïve CD4 + and CD8 + T cells (CD45RA+ CCR7+), and an increase in TEMRA CD8 + T cells (CD45RA+CCR7–). Functional analysis of all patients revealed impaired PGM3 function, as evidenced by decreased surface expression of gp130 and p-STAT3.

conclusionDefective glycosylation in PGM3 deficiency leads to reduced gp130 expression and attenuated gp130-dependent STAT3 phosphorylation. The resulting cellular features partially overlap with those observed in STAT3 loss-of-function and gp130 deficiency, supporting a shared signaling mechanism while remaining clinically distinct.