Discussion
Multiple observations have shown that monoallelic mutations ofPGM3 gene can lead to idiopathic focal epilepsy, whereas biallelic mutations are associated with glycosylation impairment and severe immunodeficiency.13-14 In our case, we speculated that the variant of uncertain significance in PGM3gene may explain the moderate severity of the clinical phenotype over a spectrum of HIES-related disease. The heterozygous mutation c.337C>G (p.Pro113Ala) in exon 4, leading to alteration of RNA splicing site, has yet to be reported in population databases ofPGM3 -related conditions.1,13-14 Available evidence is insufficient to determine the pathogenicity of this variant. However, atopy, recurrent infections, seizure episodes are features of HIES-like disorder, along with the immunologic profile of increased IgE, low T-cell counts and hypereosinophilia.
Management of PGM3 deficiency is challenging, with a lack of evidence to guide decisions. Prognosis is poor in cases of elevated IgE, as recurrent pulmonary infections create pneumatoceles for colonization of bacteria and fungi, leading to pulmonary hemorrhage and systemic infections.15 Our patient’s disease remained uncontrolled with oral corticosteroids. In addition to antibiotic prophylaxis, high dose intravenous immunoglobulins (IVIG) has been shown to be effective in patients with autosomal dominant HIES. However, its use is limited to those with poor vaccine response and low serum immunoglobulins, which were not observed in our patient. Hematopoietic stem cell transplant is another therapeutic option for AD-HIES, but case reports have shown failure to resolve immunologic impairment in disease with elevated IgE level.16
Hallmarks of severe TH2 immune dysregulation with exuberant eczematous and allergic phenotype were evident in this case. Dupilumab is a humanized IgG4 monoclonal antibody that blocks the IL-4R alpha subunit of receptor complex, thereby inhibiting the IL-4 and IL-13 signaling pathways that promote the release of pro-inflammatory cytokines and immunoglobulin E. It is indicated for the treatment of atopic diseases including moderate-to-severe atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis.17 Dupilumab has been reported to successfully treat atopic dermatitis in patients with autosomal dominantSTAT3 mutation HIES, not PGM3 -HIES specifically.2,18-19 A recent meta-analysis showed that ocular involvement, particularly conjunctivitis followed by blepharitis, are the most common adverse events.20There were also cases facial erythema, alopecia, and arthralgia.20 However, these are yet to be seen as the patient’s clinical course continued to improve significantly with dupilumab therapy. Further studies are still warranted to assess the long-term adverse events.