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\begin{document}

\title{Limited diagnostic facilities impending the therapeutic approach of
Mucopolysaccharidosis in Bangladesh: A case report}



\author[1]{Orindom Shing Pulock}%
\author[1]{Susmita Dey Pinky}%
\author[1]{Syeda Humaida  Hasan}%
\affil[1]{Chattogram Medical College and Hospital}%


\vspace{-1em}



  
  \date{May 05, 2024}


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\selectlanguage{english}
\begin{abstract}
In resource-constrained settings, mucopolysaccharidosis (MPS) is a rare
hereditary metabolic illness that frequently remains undiagnosed. We
present a scenario that illustrates the challenges in diagnosing and
managing MPS due to test inaccessibility, as well as potential
approaches to minimize the hurdles.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The mucopolysaccharidoses (MPS) are a set of rare genetic disorders
characterized by a lack of or malfunctioning of enzymes that metabolize
glycosaminoglycans (GAGs) at the lysosomal level. They account for fewer
than 0.1 percent of all genetic disorders. \textsuperscript{1,2} MPS can
be found in various forms worldwide. Coarse facial characteristics,
cognitive retardation, hepatosplenomegaly, hernias, kyphoscoliosis,
corneal clouding, and other clinical symptoms vary depending on the
individual enzyme deficit. Different MPS exhibit comparable symptoms,
especially MPS I and II; however, there are some differences, such as
severe neurological issues in MPS III and hydrops fetalis in MPS
VII.\textsuperscript{3} These clinical signs help diagnose, but early
and precise diagnosis in the asymptomatic stage is critical for better
outcomes. The diagnosis is confirmed by identifying the malfunctioning
enzyme and searching for a mutation. For patient management and family
screening, it is essential to recognize mucopolysaccharidosis. Novel
approaches such as urinary and blood GAG tests, enzyme assays, and gene
tests aid in diagnosing and subtyping MPS. \textsuperscript{3,4} Based
on experimental and clinical investigations, hematopoietic stem cell
transplantation and enzyme replacement treatment have been established
in the previous three decades. \textsuperscript{5}

MPS is divided into seven types, and eleven subtypes differentiated
biochemically by the related enzyme deficit. The incidence of MPS varies
depending on the geographic location. For instance, MPS II is the most
prevalent in the study site (Asia), whereas in Europe, MPS I \& MPS III
are more prevalent. \textsuperscript{3} MPS II or Hunter syndrome is the
only X-linked-inherited mucopolysaccharidosis primarily affecting males
with an incidence rate ranging from 0.38 to 1.09 per 100,000 live male
births. However, no documented study in Bangladesh shows the prevalence
of Hunter's disease. \textsuperscript{6} Besides, both MPS I and II
present with hepatosplenomegaly, cognitive retardation, Dystosis
multiplex (large dolichocephalic skull, thickened calvarium with
hyperostosis of the cranium, boot-shaped Sella tursica, thickened
clavicles, ovoid vertebral bodies with a peak like projection, tapering
of the terminal phalanges, flared ribs, etc.), dysmorphic appearance,
corneal clouding, and cardiac abnormalities. Additionally, MPS II has
features of dermatological signs. MPS III has limited CNS involvement
features and probable Dystosis multiplex and dysmorphic
appearances\textsuperscript{7,8}.

Confirmatory diagnosis of MPS can be made by urinary and blood GAGs
test, enzyme assay, and gene test; moreover, this can be diagnosed
antenatally by fibroblast enzymatic activity in amniotic fluid and marke
d GAGs storage in fetal organs \textsuperscript{9,10}. A newborn
screening program by enzymatic assay is recommended in the USA, Taiwan,
and Italy.~In the rest of the world, the newborn screening program
doesn't exist. The physicians are confronted with the issue of
identifying MPS patients in the early stages of the disease before
irreversible damage has occurred. \textsuperscript{11} Moreover, most of
these enzymatic studies are unavailable in resource-limited centers such
us in Bangladesh. Hence a careful and critical approach with supportive
imaging features of the skeletal survey following patient's clinical
features is essential for diagnosing MPS types \textsuperscript{12,13}.
Attempts had been to diagnose the MPS types without the biochemical
test. A mnemonic screening tool for MPS II (Hernia/Hearing, Unusual
faces, Nasal obstruction, Tongue and Tonsils, enlarged liver and spleen,
Respiration/Range of Motion) (Mnemonic -- HUNTER) was developed by the
Hunter Outcome Survey (HOS) group. This tool is 95\% accurate for
diagnosing MPS II or Hunter syndrome. \textsuperscript{14} Additionally,
few researchers from a neighboring country (Nepal) diagnosed MPS II from
history, clinical features, and skeletal survey as they lack biochemical
testing facilities in their limited-resource
settings.\textsuperscript{12,15}

Managing MPS entails halting the disease's severity and enhancing one's
quality of life. Patients with MPS have several therapy choices,
including palliative care, surgery, and disease-specific treatments such
as Enzyme Replacement Therapy (ERT) and Hematopoietic Stem Cell
Transplantation (HSCT). \textsuperscript{3} However, to accept the
treatment, detailed clinical evaluation and disease history must be
considered \textsuperscript{5}. Although novel treatments such as
substrate reduction therapy, pharmacological chaperone therapy, and gene
therapy are becoming clinically available, early diagnosis is crucial to
avail these treatment facilities. Many of these therapies, especially
enzyme replacement therapy, have demonstrated the potential of
alleviating the outcome and significantly raising the quality of life if
started early in the disease \textsuperscript{5}. Overall, clinical
evaluation, early identification, and rapid diagnosis of the cases are
the key to a better outcome since the treatment in these cases is
time-sensitive.

\textbf{Case presentation:}

An 11-year-old South Asian boy was born to healthy, non-consanguineous
parents as their middle child who presented to the pediatric in-patient
department with lethargy, poor feeding of two months duration, and
respiratory distress of two days. On inquiry, the patient had a history
of difficulty swallowing both liquid and solid foods developed over two
months, leading to severe dehydration. According to the parent's
statement, they noticed a delay in his developmental milestones for the
first time when he could not sit properly even at the age of 9 months.
Afterward, a history of repeated respiratory infections was mentioned,
although he never required any admission into hospitals for this. The
parents also complained of the child's disturbed sleep pattern and
agitated behavior. He was unable to communicate verbally, and so never
attended any school. However, the patients' attendants mentioned that
before this episode of his hospitalization, he used to have a good
appetite and could sit and walk some distance independently.

Nevertheless, he did not develop any bowel or bladder control to date.
There was no significant family history, and his siblings were affected.
The patient had no history of convulsion, loss of consciousness,
bleeding manifestation, jaundice, vomiting, constipation, or diarrhea.

There was a manifestation of growth retardation and coarse facial
features \textbf{{[}Figure 1(a){]}} . The patient had an occipitofrontal
circumference (OFC) of 58 centimeters, frontal bossing, thick eyebrows,
depressed nasal bridge, broad lip, malocclusion of
teeth\textbf{{[}Figure 1(a){]}} , oral ulcer, short neck, and tiny
stubby fingers \textbf{{[}Figure 1(c,d){]}} . No clouding of the cornea
was observed.~Expert opinion from the ophthalmology department was
taken, and no abnormality was detected in the cornea, fundus, or lens.

The patient had hepatomegaly, 6 cm measuring from the subcostal margin
in the right midclavicular line with a palpable spleen and an umbilical
hernia \textbf{{[}Figure 1(b){]}} . Palpatory and auscultatory findings
of bronchopneumonia were also present.

A chest X-ray revealed spatulated ribs (tapering of the posterior end of
the rib) regarding the imaging factors. The right dome of the diaphragm
was 4cm higher than the left \textbf{{[}Figure 2(a){]}} . Hand wrist
radiograph showed proximal tapering of metacarpal bones (bullet shape)
and fusion of interphalangeal joints \textbf{{[}Figure 2(b){]}.~} The
clinical aspects of this presenting case are summarized in \textbf{Table
1.}

Investigations after his admission to the hospital manifested severe
hypernatremia (168 mEq/L) with hyperchloremia (132 mEq/L). Complete
blood count, Thyroid-stimulating hormone, and Ft4 were within normal
range. Ultrasonography of the whole abdomen reported no abnormality, and
kidney and liver function were normal. Due to the financial constraints
and lack of testing facility, no urinalysis and echocardiography were
done. The clinical evaluation and radiological findings made a probable
diagnosis of Mucopolysaccharidosis II (Hunter Syndrome).

\textbf{Discussion:}

This case report describes a case of an 11 years old boy diagnosed with
probable MPS II from the clinical correlations and radiological findings
in a resource-limited setting where the confirmatory biochemical tests
were not available. Since Infants with attenuated MPS appear pretty
normal at birth, and early developmental milestones may also be typical.
At the same time, some signs and symptoms overlap with common childhood
complaints; often, MPS can stay undiagnosed until a later part of their
childhood. \textsuperscript{16} In our case, the patient showed a delay
in reaching his early developmental milestones and developed
characteristic coarse facial features with repeated visits at the
primary care center with recurrent respiratory tract infection. The
possibility of a rare and genetic disease could not be investigated even
after the presence of multiple red flag signs\textsuperscript{16} that a
single illness could explain otherwise.

The presentation of this case is consistent with the expression of MPS I
\& II in Table 1. However, he did not have any corneal change consistent
with his MPS II diagnosis \textsuperscript{16}. Previous cases reported
with tonsillitis, adenoids, polyp presence on the laryngeal inlet,
polypoid lesions, supraglottic narrowing, thickening of tongue,
oropharyngeal mucosa due to deposition of glycosaminoglycans (GAG)
explained the rationality of the dysphagia and sleep apnea in our
patient. \textsuperscript{17} Structural involvement of his heart and
brain couldn't be detected as no echocardiography, computed tomography,
and magnetic resonance imaging tests were done. A screening test to
diagnose mucopolysaccharidosis biochemically (urine for GAG test) and
enzyme assay was initially planned to do. Still, it couldn't be
implemented due to the unavailability and financial constraint of the
family. After nine days of his hospital stay, the family was discharged
against medical advice.

Even though this patient did not have the financial capability to afford
the definite~treatment of the disease and thus only received supportive
care, still the rationality of treating this patient with ERT or HSCT
remained open to debate since the efficacy of ERT and HSCT is presumably
better in the early inception of the disease.
\textsuperscript{18}However, studies denoted that MPS II patients,
irrespective of the age of presentation and CNS involvement, should
receive ERT that may attenuate the disease's severity.
\textsuperscript{19}

This case depicts a dilemma for the patient, his family members and the
physicians. His family and the physician have faced that lack of testing
facility led to delayed diagnosis at an older age, which hampers the
capability of available treatment to work as the irreversible changes
have already occurred. Therefore, improve disease recognition and early
diagnosis through precise clinical evaluation, especially in
resource-limited settings is at utmost necessity. The stakeholders at
resource-limited stages can follow the guideline to categorize possible
MPS patients into high-risk and low-risk groups so that screening tests
at an early age can be implemented \textsuperscript{11}. In turn, this
will help patients avail the novel therapeutics, hematopoietic stem cell
transplantation, or enzyme replacement therapy that are likely to
increase survival rates while significantly improving their quality of
life. Moreover, initiatives should be taken to invest more in research
to discover novel, cost-effective, and sustainable treatment approaches,
which may act even in elder age.

\textbf{List of abbreviations}

MPS : Mucopolysaccharidosis

GAGs : Glycosaminoglycans

IDS : Iduronate-2-sulfatase

ERT : Enzyme replacement therapy

HSCT : Hematopoietic stem cell transplantation

CNS : Central nervous system

OFC : Occipito-frontal Circumference

\textbf{Availability of data and materials}

The data used to support the findings of this study are included within
the article.

\textbf{Conflict of interest}

Submitting authors are responsible for coauthors declaring their
interests.

\textbf{Funding}

The authors declare that they have received no funding.

\textbf{Acknowledgments}

We thank our patient's parents for their cooperation and for providing
consent for the publication and appreciate the continuous support from
the Department of Pediatrics, Chattogram Medical College Hospital.

\textbf{Author Contributions:}

Orindom Shing Pulock: collected data, contributed to analysis and
interpretation of data, and drafted the article and was involved in the
care of the patient.

Susmita Dey Pinky: collected data, contributed to analysis and
interpretation of data, and drafted the article and was involved in the
care of the patient.

Syeda Humaida Hasan: contributed to analysis and interpretation, and
drafted and critically revised the article.

\textbf{References}

1. Suarez-Guerrero JL, G\selectlanguage{ngerman}ómez Higuera PJI, Arias Flórez JS,
Contreras-García GA. {[}Mucopolysaccharidosis: clinical features,
diagnosis and management{]}. \emph{Rev Chil Pediatr} .
2016;87(4):295-304. doi:10.1016/j.rchipe.2015.10.004

2. Gaffke L, Pierzynowska K, Podlacha M, Brokowska J, W\selectlanguage{polish}ę\selectlanguage{english}grzyn G. Changes
in cellular processes occurring in mucopolysaccharidoses as
underestimated pathomechanisms of these diseases. \emph{Cell Biol Int} .
2021;45(3):498-506. doi:10.1002/cbin.11275

3. Zhou J, Lin J, Leung WT, Wang L. A basic understanding of
mucopolysaccharidosis: Incidence, clinical features, diagnosis, and
management. \emph{Intractable Rare Dis Res} . 2020;9(1):1-9.
doi:10.5582/irdr.2020.01011

4. Michaud M, Belmatoug N, Catros F, et al. Mucopolysaccharidoses~:
quand y penser~? \selectlanguage{ngerman}\emph{La Revue de Médecine Interne} .
2020;41(3):180-188. doi:10.1016/j.revmed.2019.11.010

5. Stapleton M, Hoshina H, Sawamoto K, et al. Critical review of current
MPS guidelines and management. \emph{Mol Genet Metab} .
2019;126(3):238-245. doi:10.1016/j.ymgme.2018.07.001

6. D'Avanzo F, Rigon L, Zanetti A, Tomanin R. Mucopolysaccharidosis Type
II: One Hundred Years of Research, Diagnosis, and
Treatment.\emph{International Journal of Molecular Sciences} .
2020;21(4):1258. doi:10.3390/ijms21041258

7. Wraith JEd. Chapter 102 - Mucopolysaccharidoses. In: Rimoin D,
Pyeritz R, Korf B, eds. \emph{Emery and Rimoin's Principles and Practice
of Medical Genetics} . Academic Press; 2013:1-40.
doi:10.1016/B978-0-12-383834-6.00107-5

8. Matalon R, Matalon KM. Mucopolysaccharidoses. In: Aminoff MJ, Daroff
RB, eds. \emph{Encyclopedia of the Neurological Sciences} . Academic
Press; 2003:237-241. doi:10.1016/B0-12-226870-9/01991-2

9. Torres R de O, Pintor AVB, Guedes FR, et al. Oral and craniofacial
manifestations in a Hunter syndrome patient with hematopoietic stem cell
transplantation: A case report. \emph{Spec Care Dentist} .
2018;38(1):51-54. doi:10.1111/scd.12260

10. Chen CP, Lin SP, Tzen CY, et al. Prenatal diagnosis and genetic
counseling of mucopolysaccharidosis type II (Hunter
syndrome).\emph{Genet Couns} . 2007;18(1):49-56.

11. Kubaski F, de Oliveira Poswar F, Michelin-Tirelli K, et al.
Diagnosis of Mucopolysaccharidoses. \emph{Diagnostics} . 2020;10(3):172.
doi:10.3390/diagnostics10030172

12. Shah GS, Mahal T, Sharma S. Atypical clinical presentation of
mucopolysaccharidosis type II (Hunter syndrome): a case report. \emph{J
Med Case Rep} . 2010;4:154. doi:10.1186/1752-1947-4-154

13. Rasheeedah I, Patrick O, Abdullateef A, Mohammed A, Sherifat K,
Gbadebo I. Challenges in the Management of Mucopolysaccharidosis Type II
(Hunter's Syndrome) in a Developing Country: a Case Report. \emph{Ethiop
J Health Sci} . 2015;25(3):279-282. doi:10.4314/ejhs.v25i3.12

14. Cohn GM, Morin I, Whiteman DAH, on behalf of the Hunter Outcome
Survey Investigators. Development of a mnemonic screening tool for
identifying subjects with Hunter syndrome. \emph{Eur J Pediatr} .
2013;172(7):965-970. doi:10.1007/s00431-013-1967-x

15. Rayamajhi A, Pokharel PJ, Chapagain R, Rayamajhi AK.
Mucopolysaccharidosis type II with inguinal hernia. \emph{J Nepal Health
Res Counc} . 2013;11(25):293-295.

16. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric
practice: practical considerations and common pitfalls. \emph{Eur J
Pediatr} . 2012;171(4):631-639. doi:10.1007/s00431-012-1703-y

17. Suzuki K, Sakai H, Takahashi K. Perioperative airway management for
aortic valve replacement in an adult with mucopolysaccharidosis type II
(Hunter syndrome). \emph{JA Clin Rep} . 2018;4(1):24.
doi:10.1186/s40981-018-0162-5

18. Orchel-Szastak K, Ptak K, Hrnciar K, Pilch B, Kania U,
Bik-Multanowski M. {[}Early enzyme replacement therapy - hope for
patients with mucopolysaccharidosis Type II{]}. \emph{Pediatr Endocrinol
Diabetes Metab} . 2017;23(2):111-116. doi:10.18544/PEDM-23.02.0082

19. Christianto A, Watanabe H, Nakajima T, Inazu T. Idursulfase enzyme
replacement therapy in an adult patient with severe Hunter syndrome
having a novel mutation of iduronate-2-sulfatase gene. \emph{Clin Chim
Acta} . 2013;423:66-68. doi:10.1016/j.cca.2013.04.022

\par\null

Table 1: Presenting features of the case in compare to the features of
MPS I, II and III.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Signs} & \textbf{Case Status} & \textbf{MPS II} & \textbf{MPS I}
& \textbf{MPS III}\tabularnewline
Coarse Facial features & Present/ frontal bossing, thick eyebrows,
depressed nasal bridge, broad lip, malocclusion of teeth, oral ulcer,
short neck and small stubby fingers~\textbf{{[}Figure 1(a,c,d){]}} & ++
& ++ & +\tabularnewline
Macrocephaly & Present/ OFC 58 cm & ++ & ++ & +\tabularnewline
Communicating hydrocephalus & Not assessed & + & + & -\tabularnewline
Dental abnormalities & Present & ++ & + & -\tabularnewline
Cognitive/ developmental delay & Present & + (Severe patients only) & +
(Severe patients only) & ++\tabularnewline
Spinal cord compression & Not assessed & + & + & -\tabularnewline
Carpal tunnel syndrome & Absent & ++ & ++ & -\tabularnewline
Hyperactivity, aggression, impulsivity & Present & + & - &
++\tabularnewline
Seizures & Absent & + & - & +\tabularnewline
Hearing loss & Mild & ++ & ++ & +\tabularnewline
Recurrent ear infection & Present & ++ & ++ & +\tabularnewline
Persistent rhinorrhea & Present & ++ & ++ & +\tabularnewline
Frequent respiratory infections & Present & ++ & ++ & +\tabularnewline
Respiratory obstruction & Present & ++ & ++ & -\tabularnewline
Sleep apnea & Present & ++ & ++ & +\tabularnewline
Hepatosplenomegaly & Present/ hepatomegaly 6 cm from subcostal margin in
right sub clavicular line. & ++ & ++ & +\tabularnewline
Umbilical hernia & Present \textbf{{[}Figure 1(b){]}} & ++ & ++ &
+\tabularnewline
Chronic diarrhea & Absent & ++ & + & +\tabularnewline
Dystosis multiplex & Present (bullet shaped meta-phalanges, spatulated
ribs)~\textbf{{[}Figure 2(a,b){]}} & ++ & ++ & +\tabularnewline
Growth retardation & Present & ++ & ++ & -\tabularnewline
Claw hands & Absent & ++ & ++ & -\tabularnewline
Joint stiffness & Present & ++ & ++ & +\tabularnewline
Cardiac valve disease & Not assessed & ++ & ++ & +\tabularnewline
Corneal clouding & \textbf{Absent} & \textbf{-} & \textbf{++} &
-\tabularnewline
``+'' = Present, ``-'' = Absent & ``+'' = Present, ``-'' = Absent &
``+'' = Present, ``-'' = Absent & ``+'' = Present, ``-'' = Absent &
``+'' = Present, ``-'' = Absent\tabularnewline
Structure of this table is modified upon the work of Burton, B.K.,
Giugliani, R. Diagnosing Hunter syndrome in pediatric practice:
practical considerations and common pitfalls. Eur J Pediatr 171,
631--639 (2012). \emph{https://doi.org/10.1007/s00431-012-1703-y} &
Structure of this table is modified upon the work of Burton, B.K.,
Giugliani, R. Diagnosing Hunter syndrome in pediatric practice:
practical considerations and common pitfalls. Eur J Pediatr 171,
631--639 (2012). \emph{https://doi.org/10.1007/s00431-012-1703-y} &
Structure of this table is modified upon the work of Burton, B.K.,
Giugliani, R. Diagnosing Hunter syndrome in pediatric practice:
practical considerations and common pitfalls. Eur J Pediatr 171,
631--639 (2012). \emph{https://doi.org/10.1007/s00431-012-1703-y} &
Structure of this table is modified upon the work of Burton, B.K.,
Giugliani, R. Diagnosing Hunter syndrome in pediatric practice:
practical considerations and common pitfalls. Eur J Pediatr 171,
631--639 (2012). \emph{https://doi.org/10.1007/s00431-012-1703-y} &
Structure of this table is modified upon the work of Burton, B.K.,
Giugliani, R. Diagnosing Hunter syndrome in pediatric practice:
practical considerations and common pitfalls. Eur J Pediatr 171,
631--639 (2012).
\emph{https://doi.org/10.1007/s00431-012-1703-y}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

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