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.