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\begin{document}

\title{Hyper IgE Syndrome Related Disease Treated with Dupilumab: A Case Report}



\author[1]{Andrew Kao}%
\author[1]{Hany Deirawan}%
\author[2]{Pavadee Poowuttikul}%
\author[1]{Steven Daveluy}%
\affil[1]{Wayne State University School of Medicine}%
\affil[2]{Central Michigan University College of Medicine}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\selectlanguage{english}
\begin{abstract}
We describe a case of a 2-month-old female displaying clinical phenotype
of HIES related disease with severe eczematous dermatitis recalcitrant
to corticosteroids. Genetic panel showed a variant of unknown
significance in key immune regulator of PGM3. Patient achieved nearly
complete response from off-label use of dupilumab.%
\end{abstract}%



\sloppy


\textbf{Title:} Hyper IgE Syndrome Related Disease Treated with
Dupilumab: A Case Report

\textbf{Authors:} Andrew S. Kao\textsuperscript{1}, Hany
Deirawan\textsuperscript{2}, Pavadee Poowuttikul\textsuperscript{3},
Steven Daveluy\textsuperscript{2}

\textbf{Affiliations:}

\textsuperscript{1}Wayne State University School of Medicine

\textsuperscript{2}Wayne State University School of Medicine, Department
of Dermatology

\textsuperscript{3}Central Michigan University, Department of
Pediatrics, Division of Allergy, Immunology, and Rheumatology

\textbf{Keywords} : HIES related disease, dupilumab, pediatric
dermatology

Word Count: 1092

References: 20

Figures: 2

\textbf{Acknowledgement:} Not applicable

\textbf{Funding:} No specific funding was received to perform the work
described in this article.

\textbf{Conflict of Interest:} The authors declare no conflict of
interest. No other disclosures are reported.

\textbf{Informed Consent:} Written informed consent was obtained from
patient guardian to publish this case and images.

\textbf{Author Contributions:}

Andrew S. Kao: Writing and revision of manuscript.

Hany Deirawan: Followed up with patient's disease progression and
directed manuscript drafting.

Pavadee Poowuttikul: Supervised genetic workup and overall manuscript
development.

Steven Daveluy: Supervised dermatology clinical management and overall
manuscript drafting.

\textbf{Introduction}

Hyper IgE syndrome (HIES), a primary immunodeficiency disorder with
autosomal dominant or recessive inherence patterns characterized by
significantly elevated IgE, severe eczema, sinopulmonary infections, and
musculoskeletal deformities.\textsuperscript{1} Multiple variants are
identified to contribute to HIES-like disorders: \emph{PGM3, TYK2,
DOCK8, STAT3, IL6, IL6ST, IL6R, ZNF341, TGFBR1, TGFBR2, SPINK5, CARD11}
.\textsuperscript{2-8} Among the variants, phosphoglucomutase 3
(\emph{PGM3} ) gene encodes a glycosylation enzyme in N-glucans
biosynthesis that catalyzes the conversion of N-acetylglucosamine-6 to
N-acetylglucosamine-1, a step in the production of precursor proteins of
both the innate and adaptive immune system. One clinical phenotype
of\emph{PGM3} -HIES related diseases resulting in neutropenia,
lymphopenia, and progressive bone marrow failure lead to a clinical
presentation resembling that of severe combined immunodeficiency
(SCID).\textsuperscript{9-10} Early neurologic consequences include
developmental delay, intellectual disability, ataxia, dysarthria,
sensorineural hearing loss, myoclonus and
seizures.\textsuperscript{11}Eczematous involvement primarily of face
and scalp are common during first several weeks of life, and mildly
elevated IgE level (\textless{} 2000 IU/mL) is typical under 2 years of
age in HIES related disorders.\textsuperscript{2,12} Here we describe a
case of a 2-month-old female displaying clinical phenotype of HIES
related disease with severe eczematous dermatitis recalcitrant to
corticosteroids and achieved nearly complete response from off-label use
of dupilumab.

\textbf{Case History/Examination}

A 2-month-old female developed three episodes of severe eczematous
dermatitis with impetiginization, herpetic infection, and Staphylococcal
osteomyelitis requiring multiple hospitalizations over a six-month
period. Newborn screening for severe combined immunodeficiency was
negative, no history of abnormal bleeding, chronic diarrhea, failure to
thrive, and no known family history of atopy or immunodeficiency
syndromes. Significant cutaneous erythema and dry excoriation were seen
on the forehead, hairline, cheeks (Figure 1), chest, abdomen, bilateral
forearms, and ankles. No honey-crusting or vesicular lesions were noted.
Neurology and other exams did not reveal significant findings. She had
achieved all development milestones on time.

\textbf{Differential Diagnosis, investigations, and treatment}

Differential diagnosis included hyper-IgE syndrome, common variable
immunodeficiency, hyper IgM syndrome, and other primary immunodeficiency
diseases. Workup demonstrated hypereosinophilia of 3.9
K/mm\textsuperscript{3} (0-0.6 K/mm\textsuperscript{3}) and elevated IgE
1521 IU/mL (3-423 IU/mL) with normal levels of IgG, A, and M. Her
antibody responses to pneumococcal, diphtheria and tetanus antigens were
adequate. Lymphocyte subsets showed slightly low absolute CD3 and CD4
count, with normal absolute B cells and NK cells. Mitogen proliferation
assays to Phytohemagglutinin, Concanavalin A, and Pokeweed antigens were
normal, suggestive of adequate T-cell function.

A next generation sequencing NGS gene panel for inherited immune
dysfunction syndromes showed a variant of unknown significance in key
immune regulator of \emph{PGM3} , including a heterozygous missense
mutation c.337C\textgreater{}G (p.Pro113Ala) on exon 4. Other genes that
can lead to HIES-related diseases were negative: \emph{TYK2, DOCK8,
STAT3, IL6, IL6ST, IL6R, ZNF341, TGFBR1, TGFBR2, SPINK5, CARD11} .

She later developed recurrent wheezing responsive to asthma treatment at
4 months old and multiple blinking spells concerned of seizures at 10
months old. Between ages of 1-2, she had two bacterial pneumonia, one
required hospitalization. The recurrent eczema flares were unresponsive
to initial treatment of topical 0.1\% triamcinolone and 2.5\%
hydrocortisone, antihistamine, emollient, bleach baths, and wet wraps.
She also received topical mupirocin for impetiginization. At the fourth
months mark since first hospitalization, betamethasone 0.05\% ointment
and 1mg/kg of prednisolone daily were initiated, which only resulted
partial response. At the end of six-month period, dupilumab was
initiated with a loading dose of 120mg (12mg/kg) and maintenance dose of
60mg (6mg/kg) every four weeks.

\textbf{Outcome and Follow-up}

Over one month, her skin rash and pruritus significantly improved
(Figure 2) without adverse effects with dupilumab use, permitting a
tapered discontinuation of prednisone. Patient's eczema is adequately
managed with dupilumab maintenance dose and continual application of
emollients, and topical hydrocortisone 2.5\% on face, triamcinolone
0.1\% on torso as needed. In concern of seizure, long-term
electroencephalogram (EEG) and further neurological workup of the
patient's blinking spells did not reveal seizures or significant
findings. Six months since initiation of dupilumab, patient had an
incidence of pneumonia that resolved with antibiotics but otherwise no
other serious events.

\textbf{Discussion}

Multiple observations have shown that monoallelic mutations
of\emph{PGM3} gene can lead to idiopathic focal epilepsy, whereas
biallelic mutations are associated with glycosylation impairment and
severe immunodeficiency.\textsuperscript{13-14} In our case, we
speculated that the variant of uncertain significance in \emph{PGM3}gene
may explain the moderate severity of the clinical phenotype over a
spectrum of HIES-related disease. The heterozygous mutation
c.337C\textgreater{}G (p.Pro113Ala) in exon 4, leading to alteration of
RNA splicing site, has yet to be reported in population databases
of\emph{PGM3} -related conditions.\textsuperscript{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 \emph{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{17} Dupilumab has been reported to
successfully treat atopic dermatitis in patients with autosomal
dominant\emph{STAT3} mutation HIES, not \emph{PGM3} -HIES
specifically.\textsuperscript{2,18-19} A recent meta-analysis showed
that ocular involvement, particularly conjunctivitis followed by
blepharitis, are the most common adverse
events.\textsuperscript{20}There were also cases facial erythema,
alopecia, and arthralgia.\textsuperscript{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.

\textbf{Conclusion}

Clinical manifestation of severe eczema, recurrent sinopulmonary
infections, and initial immunologic workup revealing of HIES-like
disorders should prompt further investigation of possible contributory
genes. This case highlights the potential involvement of variant of
unknown significant in \emph{PGM3} gene. To treat the persistent eczema
refractory to topical and systemic corticosteroids, we urge clinicians
to recognize dupilumab as an efficacious alternative with high safety
profile.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
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\end{enumerate}

\textbf{Figure Legends:}

Figure 1. Initial Presentation: diffuse erythematous scaly patches with
excoriations and hemorrhagic crusting.

Figure 2. One month after initiation of dupilumab: improvement of facial
involvement with only macular erythema and fine scaling.\selectlanguage{english}
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