Case Report

A 11-YEARS-OLD BOY WITH MUCOPOLYSACCHARIDOSIS TYPE II

(HUNTER SYNDROME)

Presented by:

Puni Oktisari

Supervised by:

DR.dr.M.Mexitalia S, SpAK

PEDIATRIC DEPARTMENT FACULTY OF MEDICINE

DIPONEGORO UNIVERSITY / DR. KARIADI HOSPITAL

SEMARANG

2018

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 INTRODUCTION

Mucopolysaccharidosis (MPS) is a rare disease caused by impairment in lysosom

storage (lysosome storage disease, LSD). This abnormality causes many severe impairments
of organ functions because of intracellular debris accumulation in the lysosome. Until
recently, there are 40 types of LSD known aside from MPS. One of the MPS is Hunter
Syndrome. Introduced by Major Charles Hunter for the first time in 1917,
mucopolysaccharidosis type II (MPS II or Hunter Syndrome) is an X-linked recessive
chromosomal disease caused by deficiency of lysosomal enzym iduronate-2-sulfatase
(I2S).1,2
The frequency of male borns with MPS II is approximately 1:136.000. Overall
incidence of MPS (11 types known currently) is estimated about 1 of 25.000 births. Data
from Netherlands and Germany showed that incidence of MPS II is 1.3 per 100.000 male live
births. Two third of patients had CNS involvements, which showed poorer clinical phenotype
outcome.1
Because MPS II is an X-linked recessive chromosomal disease, this condition will not
affect female. Female with this condition usually has low I2S activity and weak clinical
phenotype, although somatic disorders may worsened the condition in few individuals. In
heterozygous female with this condition, there is a tendency of pre-ventilation X
chromosome inactivation to express normal allele.1 Epidemiological data about MPS in
Indonesia has not yet been obtained until now.

This case report will review a 11 years 3 month old boy diagnosed with MPS type II,
based on literature studies. Hopefully, this report may improve knowledge about clinical
manifestation, diagnosis, and management of MPS II patients.

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 CASE REPORT

The patient in this case is an 11 years 3 months old boy, lived in Pekalongan. He
is the second child in the family. He was born normally, cried directly, birth weight of
4700 grams, and unknown birth length.

At the age of 8, his parents felt that his face is rough, thickening lips, also thick
and stiff hair growth. Wide forehead, fingers and wrist was bent and difficult to be
straightened. Stiffness in fingers and wrist worsened until he could not grasp. Both knee
and feet were bent, thus he could not walk. The patient was shorter than his peer. At first,
he still can stand by himself, but later it got worsened and he could not stand. His parents
has brought him to other alternative care, but found no improvement. He also had a
bulging abdomen. His parents and both of his siblings did not have a similar phenotype.
The patient can only talk and sing a simple song with unclear pronunciations.

Patient never had blood transfusions, dyspnea, intermittent sucking, and profuse
sweating when suckling, and his body weight increased. Abnormalities in vision was not
found, the patient can watch the television in normal distance. Both of his eyes were
clear. He could play with his peers before, but tend to be shy. He could turn around when
called by name. Basic immunization was complete based on age. He did not snore and
rarely catch a cold.

No other family member with similar condition as the patient. However, there is
one cousin (child from mother’s older sibling) had mental retardation and died at the age
of 10.

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Figure 1. Patient’s Pedigree. No other family with disease similar to the patient.

Physical examinations was conducted in Kariadi Hospital Semarang, with patient

in compos mentis condition. During examinations, we found dysmorphic face, no pallor,
prominent forehead, coarse face, deep set eyes, low set ear, and bulbous tip at nose, no
signs of nasal obstruction, and patient easily breaths from nose. Wide tongue, short neck,
no neck lymph nodes enlargement. Chest examination showed no chest wall deformity,
systolic murmur at LLSB, URSB, and heart apex, lungs in normal condition. Abdominal
examination showed flat abdomen with no umbilical hernia, no hepatosplenomegaly, and
no ascites were found.

Vertebrae examination showed no abnormalities. Extremities examination showed

stubbing hands, bended fingers like claw hands. Stiff knee joint, limited movement during
extension, mild genu valgus, normal muscle tone, no clonus, normal muscle power.
Anthropometric analysis showed weight of 24 kg, height of 111 cm (WAZ NA, HAZ –
5.03 SD, BMI 0.99), and upper arm circumference of 19 cm with head circumference of
55 cm (mesocephal).

Echocardiography has been done in outpatient clinic, showing moderate stenosis in

aortic valve and moderate aortic regurgitation. The patient was treated with propanolol 5
mg/8 hours from Department of Pediatric Cardiology. Bone survey examination showed
branchicephalic features (cephalic index 93 cm), accompanied with j-shaped feature in
sella turcica and pointing appearance in proximal of digit II, V metacarpal bone in right
and left hand  suggesting mucopolysaccharidosis. Other examinations have been
completed at the outpatient clinic, since he was suspected with inherited metabolic
disorder of mucopolysaccharidosis from the first visit. Patient also managed by Pediatric

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Opthalmology Department and found no corneal clouding, cherry spot, and retinal
degeneration. ENT Department also confirmed no abnormalities in their field.

Early diagnosis for this patient was suspect of mucopolysaccharidosis with speech
disorder, acquired heart disease (moderate aortic valve stenosis and moderate aortic
regurgitation) without signs of heart failure.

In order to confirm the diagnosis, skeletal survey was conducted. Cranial X-ray
showed brachicephalic feature (size ± 93, while normal cephalic index is 72.7-91.1),
thickening of occipital bone, J-shaped sella turcica, with coronal, lambdoid, metopic and
sagittal suture not yet closed (no signs of craniosynostosis). Chest X-ray showed paddle
shape and oar-shaped ribs at posterior rib bones. Vertebrae examination showed porotic
bone with good alignment, no signs of listhesis, anterior beaking in vertebrae body L1, 2,
3, and good bilateral sacroiliac joint. Pelvic examination showed well bone structure,
epiphyseal growth plate has not closed, inferior tappering of iliac wing, flattening
acetabulum, and coxa valga. Extremities examination showed a hypoplasia of bilateral
carpal bone (according to 4 years old boy bones), bullet shape phalanxes at the proximal
digital I-V, pointed proximal of metatarsal bone digital II, V bilateral manus, bowingos of
right and left radius bone and inverted V shape at the distal of right and left radius bone,
flarring metaphysis at the distal of femur bilaterally, and lytic lession at the proximal of
bilateral radius bone. Echocardiography showed moderate aortic valve stenosis, moderate
aortic regurgitation, and left ventricle hypertrophy.

Tests used to confirm the diagnosis of mucopolysaccharidosis syndrome are blood

and urine cultures. This tests were conducted at the National Taiwan University Hospital,
Department of Medical Genetics, to assess the glycosaminoglycan level in urine and
enzyme activity in plasma. Biochemical test results was received 21 days after
examination. Blood biochemical test showed low enzyme iduronate-2-sulfatase activity in
plasma (Iduronate-2-sulphatase level is 0.47 uM/day, normal value >4.45 uM/day), while
other enzyme level appeared normal. Urine analysis showed extremely high
glycosaminoglycan activity (627.24 mg GAGs/g Creatinine, normal value for age > 5
years is 35.74 GAGs/g creatinine). This results was consistent with
mucopolysaccharidosis type II, thus confirmed the final diagnosis of this patient as
mucopolysaccharidosis type II (Hunter Syndrome).

5
 Therapy for Hunter Syndrome is enzyme replacement therapy, however this therapy
is not yet available in Kariadi Hospital Semarang and very expensive, thus it has not yet
been given to the patient.

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 DISCUSSION

Mucopolysaccharide is an important constituent in every organism. This component

abundantly found in connective tissues, parenchymal organs, cartilage, and central nervous
system. Mucopolysaccharide is a complex heterosaccharides, consists of long chain of sugar
molecules with many groups of sulfate. The polymer chains is bound with specific protein.2

Lysosome has a role in degrading metabolic wastes to simple substances, thus may be
used again by cells. This degradation process needs many specific enzyme during the event.
Lack of specific enzyme activation leads to imperfect degradation and metabolism wastes
from cell cannot be excreted by lysosome, thus they will accumulate inside the cell.
Continuous accumulation will disturb cell’s function. Impairment of degradation process and
accumulation of mucopolysaccharides are occurring in mucopolysaccharidosis.1

Mucopolysaccharidosis is divided into several types, based on enzyme impairment.

Clinical manifestation also depends on enzyme impairment (Table 1).2, 3 This disease has a
wide clinical variation, from severe abnormality, such as hydrops fetalis, until mild
manifestations, therefore patients will have nearly normal phenotype with good survival rate.1

Table 1. Several types and clinical manifestation of Mucopolysaccharidosis Syndrome

Disease Eponym Enzyme defect Clinical Manifestations

MPS I – H Hurler α – iduronidase Developmental delay in motoric
and mental aspects at the first year
of life, rough face, macrocephalus,
thick skin, corneal clouding,
hepatosplenomegaly,
developmental delay, severe
deformities in extremities and
trunk.
MPS I –S Schei α – iduronidase Similar phenotype with Hurler,
normal height, without mental
retardation. Joint paint, carpal
tunnel syndrome, and mild
impairment in skeleton.
MPS I – Varian α – iduronidase Clinical variant of Hurler and Schei

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H/S
MPS II Hunter Iduronate – 2 – X-linked inherited. Similar
sulfatase phenotype with Hurler, without
corneal clouding
MPS III Sanfilippo α – N – Normal stature, severe mental
(A,B,C) (A, B, C) acetylglucosamini deterioration, especially after 3
dase years old, hyperactivity, normal
stature, mild skeletal abnormality,
mild roughness, no corneal
clouding.
MPS IV Morquio Galactosamin-6- Very short stature after 1 year
(A, B) A, B sulphatase, B – caused by degradation of keratan
galaktosidase sulfate, severe stunting occurs after
1 years old because abnormalities
in keratan sulfate degradation,
evident
Skeletal abnormality, teeth enamel
hypoplasia, mandibular protrusion,
and face hypoplasia, corneal
clouding. Morquio B is less severe
than Morqquio A.
MPS VI Maroutex N- Clinical manifestations similar with
Lamy acetylgalactosami Hurler, without neurological
ne– 4 – sulfatase disorder, usually with normal
intelligentsia.
MPS VII Sly β - glucoronidase Similar with Hurler, usually
causing severe manifestation, such
as hydrops fetalis.
MPS IX Hyaluronidase Short stature, periarticular mass at
soft tissue, normal intelligentsia.
Multiple Austin Multiple enzyme Severe skeletal bone abnormality,
Sulfatase defect hepatosplenomegaly, loss of retinal
Deficiency pigment, optical nerve atrophy,

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 signs of neural degeneration which
causing vegetative state and death,
ichtiosis Abnormalitas tulang
skeletal yang berat,
hepatosplenomegali, hilangnya
pigmen retina, atrofi nervus
optikus, tanda – tanda
neurodegenerative yang
menyebabkan keadaan vegetative
dan kematian, ichthyosis.

In this case, patient had a chief complaint of inability to walk. At the first year of life,
there were no suspiciousness towards inherited metabolic disorder. However, along with the
course of disease, patient showed phenotypes of rough face, typical face dysmorphic and
short stature, also other clinical manifestations, such as musculoskeletal impairment and
growth & developmental problems. Additional examinations to confirm the diagnosis was
echocardiography, showing abnormalities in heart valves, suggesting for
mucopolysaccharidosis syndrome. Eye examination showed no corneal clouding.
Mucopolysaccharidosis type has not yet been defined, but it was suspected as
mucopolysaccharidosis type II (Hunter). Blood biochemical analysis indicated very high
glycosaminoglycan level, accompanied with low activity of iduronate-2-sulfate sulfatase
enzyme in plasma. This results were corresponding to mucopolysaccharidosis type II (Hunter
Syndrome).

MPS II is an inherited disorder with wide severity spectrum. In several people, brain
involvement may occur with combination of physical symptoms; others may have physical
impairments without brain involvement. Physical impairments including hearing disorder,
malformation of bone and joint, heart disorder, and respiratory disorder. Course of disease
and age onset is varied, even in siblings: in several people may progress rapidly and
diagnosed at the first year of life; while others may relatively slow-progressed and not yet to
be diagnosed until third or fourth decade in life. Generally, if clinical symptoms showed in
early life, then disease progressivity may grow rapidly and brain involvement may occur.4

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 MPS II also known as Hunter Syndrome, named from the first doctor who described
this condition. Hunter, in 1917, described the condition of two brothers with
mucopolysaccharidosis type II. Patients with Hunter disease has a similar clinical
manifestations with Hurler disease, even though they may not cause severe manifestations.
Patient is classified clinically into mild and severe type, even though both of them are
indistinguishable based on their enzyme activity. The emergence of molecular analysis and
wide heterogeneity made this classification not valid anymore. Dorfman, Matalon, and Muir
indicated that output of dermatan sulfate and heparan sulfate in this patient are the same as in
Hurler disease. Study by Fratantoni, Hall and Neufeld about Hunter and Hurler cell firstly
found correction factor for excessive accumulation of damaged sulfate; thus Hurler cell may
correct Hunter cell or otherwise. Also, Hunter correction factor may correct Hurler and other
MPS cell, but not with Hunter cell.5 Hunter factor is identified as iduronate sulfatase (Figure
1), enzyme for catalysis releasing sulfate from dermatan sulfate iduronate and heparan
sulfate. Thus, defect happened in MPS II is at early step of enzymatic breakdown from those
mucopolysaccharide. Storage amount of dermatan sulfate influenced the severity degree of
physical symptoms; storage amount of heparin sulfate influenced brain involvement.6

Figure 1. Iduronate sulfatase group, enzyme which responsible for Hunter Syndrome. There
is an accumulation of dermatan sulfate and heparan sulfate when enzyme activity in low.6

Gene for iduronate sulfatase has been identified and mapped at X-chromosome in
q28. Several changes in gene also has been found, such as point mutation especially in
Dinucleotida CpG.7

It is estimated that 1 of 136.000 male baby had MPS II. Incidence for all MPS
disorder (currently 11 types known) was estimated 1 in 25.000 birth.1-8

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 MPS disorder group is included in a bigger group, consisted of about 50 other
inherited diseases known as lysosomal storage disease, because substances which cannot be
completely degraded (mucopolysaccharide in MPS disorder) are stored in lysosome. It is
estimated that lysosomal storage disease occurred in 1 from 5.000-7.000 birth.6

MPS II is inherited in X-linked recessive pattern. “X” and “Y” chromosome

determines each people gender: male has one X chromosome and one Y chromosome (XY),
while female has two X chromosomes (XX). In MPS II, deficiency of 2-sulfatase enzyme
production coding gene is located in X chromosome. Thus, male who inherited defected X
chromosome from his mother will have MPS II; female who inherited defected X
chromosome will be the carrier, but generally has any symptoms, probably compensated by
other normal X chromosome.

If a female is MPS II carrier, every pregnancy has risk of:

 50% (1 from 2) every male baby will have MPS II; and
 50% (1 from 2) every female baby will become carrier (usually does not have MPS
II).

Female siblings and aunt from mother side of male patient has a 50% probability (1
from 2) to be a carrier and 25% (1 from 4) risk to inherited MPS II to her son.

If a male with MPS II had a child, then every female child will became a carrier and
every male child will not inherited MPS II. Although not commonly found, a few MPS II
cases may occur in generations without carrier mother or family history of this condition.9-11

In this case, from the family history, we did not know any history and phenotype
similar to the patient. However, patient’s male cousin (child from mother’s sibling) has a
history of mental retardation, which is X-linked related, thus this condition probably
associated each other. It is likely that this patient had MPS II from carrier mother. Further
search and genetic counseling are needed for this patient.

Because MPS II is an inherited disease, it is important to do genetic counseling to find

implications for other children, next pregnancy, and other family member. Genetic expert
and/or genetic counselor will explain about inheritance pattern of this disease and aid the
family to determine other family member whom need to be examined.9

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 Patient with Hunter disease has a wide spectrum of clinical activities. Every patient
has a similar decrement of enzyme activity. However, generally this disease is divided into
two groups, severe and mild phenotype.4-8

Patient with severe conditions may be identic with those who has Hurler disease
(Figure 2), except without corneal clouding, but with a very distinct behavior. Slow
progression may be found in Hurler disease and clear onset may happened later, around age 2
until 4 years old. In mild type of disease, mental development may be normal and age might
be longer as in Scheie disease.2-6

Clinical Presentation

At first, physical and mental development may be normal. If there is any brain
involvement, mental declining rate may occur and difficult to be predicted earlier. Reduction
of brain function and problems associated with behavior and communication will raise
problems in medical examination. Simple condition, such as ear infection and sore teeth as
the source of inconvenience and pain should not be ignored and immediately be treated.
Children may have increasing pain tolerance or difficult to communicate that they feel pain.3

Growth

Infant with MPS II probably bigger than average other infants and rapidly grow than
others in the first two years of life. Height ranges from 4 feet (120 cm) to 5 feet (150-165
cm). Generally, no short stature is found and the trunk is usually shorter than lower
extremities.4

Face Appearance

Severe MPS II patients (usually with brain involvement) tend to similar with one
another. Mostly, fat face with reddish cheek; short neck and wide nose with flat nasal bridge;
thick lips and enlargement of tongue; shallow eyes socket and protruded eyes; thick and
rough hair with thick eyebrows. At first, minimal changes are to be expected from slow-
progressed disease, but similar changes might happened during the disease progression.6

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Figure 2. Hunter disease patient with severe clinical manifestations, such as rough face, thick
lips, predominant hirsutism and claw hand, typical for Hunter disease. No abnormalities
found in cornea (left). An 8 years old boy with Hunter syndrome. Appearance showed rough
face, low hairline, and thick eyebrows, with thick lips. NO iduronate sulfatase activity was
found (right).6

In this case, rough phenotype was found by the parents at the age of 8. Patient’s face
became rough, thickening lips, thick and stiff hair. Wide forehead, short and stiff fingers,
difficult to be straightened.

Figure 3. Case patient’s phenotype. Face dysmorphic as in Hunter type.

Intellectual Capability

If there is brain involvement, usually intellectual development will decrease at the age
around 2-4 years old, followed by loss of skills gradually. However, this pattern is varied
among patients. Several patients can only learn to talk a few words, while others can learn to
talk and read a little. Intellectual capability will not be disrupted in patients without any brain
involvement.3

However, ability to learn in MPS II patients may be affected by other indirect

complications toward brain. For example, deafness may cause difficulties in learning oral
speech; limited hand movement may delay fine motoric development such as writing. Thus, it

13
is important to understand every problems associated with this disorder to maximize the
quality of life.4

In this case, the patient has a difficulty in talking, he can turn around if called,
understand which things are allowed and not. The patient was diagnosed with speech disorder
and received articulation and oromotor enhancement training from Department of Medical
Rehabilitation.

Eyes

Corneal clouding (the outermost clear layer of eyes) is usually not found. Vision
impairment may be disrupted caused by changes in retina, or glaucoma (increasing fluid
pressure inside the eyes). Mucopolysaccharide storage in the retina will cause loss of
peripheral vision and night blindness. Night blindness may cause unwillingness to walk at the
dark area or afraid to wake at night. The usage of night lamp may help to overcome this
condition.3

In this case, patient can see at the normal distance. Examination in Department of
Pediatric Opthalmology showed no corneal clouding, no pigmented retinitis, no retinal
degeneration, and no cherry spot.

Head

Although the patient’s head may be enlarged with protruded forehead, these are not
causing any problems. Hydrocephalus may occur. This is caused by cerebrospinal fluid
accumulation. Thickening of tissues around the brain may obstruct the blood flow and
absorption of the fluid may cause pressure to the brain. It will manifest in symptoms, such as
headache, vomitus or drowsiness; increasing head circumference. Hydrocephalus needs to be
strictly monitored and surgery may be needed, usually with VP-shunt procedure.4

In this case, patient’s head circumference anthropometrically was 55 cm. It was

described as mesocephal for children aged 11 years old. Survey skeletal of cranial X-ray also
showed brachycephalic feature (Figure 4).

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 Figure 4. Patient’s cranial X-ray

Nose

Nasal bridge may be flat and channel at the posterior of the nose may be smaller than
usual because of poor bone developmental in face and thickening connective tissue in nose
and throat, thus narrowing the respiratory tract. Chronic mucus drainage (rhinorrhea) may
occur from abnormal drainage and normal secretion and also chronic ear and sinus
infection.2,5

In this case, as seen in Figure 5, the nasal bridge is flat. No rhinorrhea or nasal
obstruction was found in this patient.

Throat

Tonsils and adenoid may be enlarged and narrowing the respiratory tract. Combined
with short neck, will contribute to difficulty in breathing. Trachea may narrowed because of
tissue thickening and weakened because abnormalities in cartilage rings.3

Chest

Chest shape usually abnormal and connection between ribs and sternum will be less
flexible. Chest became stiff and cannot be freely moved to inhale large volume of gas into the
lungs. Diaphragm will be pushed upward by enlarged liver and spleen, making less space for
lungs expansion. When lung clearance is incomplete, there is an increased risk for infection
(pneumonia). These changes may affect respiratory process and may cause breathlessness
and compromise the immune resistance.4

Breathing Problems

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 Stridor, anxiety and snoring may occur and causing problems at night. There is an
increasing risk for asthma-like episode if narrowing respiratory tract and increasing secretion
occurred: acute asthma management may relieve cough and ease breathing. Sleep apnea
usually occurs and shows low oxygen level during sleep, sooner or later may impair the
heart.6

Hunter disease is different from other mucopolysaccharidosis by nodular skin or

gravel-like skin lesion (Figure 5), specifically found at the scapular area, forearm, or lateral
thigh area. Skin lesion sometimes has ivory color. This lesion is not developed in other
mucopolysaccharidosis except Hunter disease.2, 4-6

Figure 5. Nodular skin lesion at the cutaneous tissue in patient with Hunter disease.6

Most patients progressed poorly after age 5-6 years. Decreasing physical activity;
unstable walking gait; and worsened voice and finally loss of voice. Progressive difficulty in
swallowing solid food may occur and causing weight loss. General seizures may happened at
the final months of life. Death usually occurs at the age of 15 years old caused by respiratory
or heart disease.2-4

Patient with mild disease may live until age 60 or older. Intelligentsia status may be
good with normal appearance during childhood, and rough appearance may be recognized as
time goes by. Stiffness in joint or osteoarthritis may occur. Carpal tunnel syndrome usually
occurs.9, 10

Survival rate until 87 years old has been reported before, but death may occurs at the
second decade, even for mild phenotype patients. Cause of deaths are varied, such as heart
disease, lung infection, or respiratory tract obstruction.11

Etiology of the clinical phenotypes is high accumulation of mucopolysaccharide acid

in intracellular environment. Large vacuole cells consisting metachromatic cytoplasmic

16
matters are found histologically in many tissues. In scapular nodule, there are extracellular
accumulation of metachromatic matters. Dermatan sulfate and heparan sulfate are excreted
mostly in urine with same amounts. Fibroblasts show metachromatic stain and contain many
mucopolysaccharides. Piled sulfate-labeled Hunter cells are found with
mucopolysaccharidosis typical pattern.1,2-4

In this case, it was suspected for milder phenotype, the appearance may be normal at
early life, or may be a little bit rough, then may be more recognized and clearly found at the
age of 8 years old. Prior developmental stage was normal. No recurrent respiratory or ear
tract infection was found. Fingers were short and stiff, difficult to be straightened. The
patient’s abdomen bulged and appeared very short compared to his peers. Fingers stiffness
worsen progressively, thus patient could not grasp. Both of lower extremities were bent and
causing difficulty to walk. Patient can talk and sing simple songs with unclear
pronounciation.

Patient’s phenotype development in this case.

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 1 - 3 year old patient

8 years old patient

Patient appearance when

diagnosed

Diagnosis and Work-Up

Prompt diagnosis is the main key to increase Hunter syndrome patient’s outcome and
it needs several clinical factors examinations, biochemical parameters, and molecular
characteristic.12

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Clinical Diagnosis

Clinical diagnosis for Hunter syndrome may require complete patient’s medical
history and all of the family members. Pediatrician is the first clinician to take care patient
with Hunter syndrome and there are several early signs and symptoms that should be
suspected, such as lumbar gibbous, recurrent ear infection, hernia, myocarditis, or
progressive liver and spleen enlargement that may occur before age 6 months.12

Signs and symptoms that are usually found: 12

 Face dysmorphism: rough face features, wide nose with wide nostrils, protruded
supraorbital bone, large jaw, thick lips, enlarge tongue.
 Abdominal symptoms: hernia, abdominal distention caused by enlarged liver and
spleen.
 Respiratory symptoms: recurrent upper respiratory tract infection, especially those
with ear involvement; sleep apnea.
 Musculoskeletal problems: multiplex dysostosis in radiographic examination,
including abnormal and irregular thickening bone, ossification of epiphysis in hand,
shoulder, and elbow joints; carpal tunnel syndrome.

Patients with Hunter syndrome usually underwent many surgeries since young age,
before the diagnosis is confirmed, thus Hunter syndrome should be suspected in children with
surgical intervention history, specifically for hernia or carpal tunnel syndrome. Overall
documentation of surgical procedure is important aspect to confirm the clinical diagnosis of
Hunter syndrome. Mendelsohn et al. compared surgical history of patients with Hunter
syndrome registered in Hunter Survey Results (HOS), from general population and found that
more than 80% of registered patients required surgical intervention and about 57% had
surgical intervention before diagnosed with Hunter syndrome. This percentage is higher than
what has been found in general population.13 Patients with history of hernia repair surgery,
tympanostomy, adenoidectomy, and carpal tunnel should be suspected and should remind the
pediatrician to evaluate other additional symptoms of Hunter syndrome. A checklist for signs
and symptoms of Hunter syndrome is showed in Table 1 (adapted from lists used in HOS).2,12

Table 1. Main signs and symptoms of Hunter syndrome. 3-6

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 Organ involvement Sign and Symptoms Prevalence
Head and neck Typical to Hunter disease (face dysmophism, 95
rough face, macrocephalus, hydrocephalus)
Eyes Papil edema
Retinal degeneration
Mouth Macroglossia 70
Ears Otitis media 72
Hearing loss 67
Hearing device 41
Tinnitus 2
Vertigo 3
Nose Nasal obstruction 34
Rhinorrea -
Throat Tonsil/adenoid hypertrophy 68

Chest Dyspnea -
Chronic cough/bronchitis
Sleep apnea
Difficult to intubate
Cardiovascular Murmur 62
Arrhythmia 4
Tachycardia 7
Bradycardia 2
Hypertension 6
Cardiomyopathy 8
Congestive Heart Disease 4
Heart Valve Disease 57
Myocardial Infarct 0,5
Peripheral Vascular Disease 2
Gastrointestinal Abdominal hernia 78
Hepatosplenomegali 89
Diarrhea
Skin Hunter lesion
Skeletal Joint stiffness and contracture 84
Kyphosis/scoliosis 39

Neurology Hydrocephalus 17
Seizures 18
Difficulty in swallowing 27
Carpal tunnel syndrome 25

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 Rough motoric impairment 33
Hyperactivity 31
Cognitive problems 37
Behavior problems 36

Signs and symptoms in Hunter syndrome varies based on the severity of disease, such
as age onset of signs and disease complications. Symptomatology in Hunter syndrome best
described as continuum of two extremes, severe and frail. Clinical condition may be easier to
be predicted in severe disease, while clinical phenotype and development of mild disease is
varied. Individual with mild phenotype may experience symptoms and complications
development toward severe disease and disability. Manifestation of Hunter syndrome usually
occurs at the age range of 18 months and 4 years old in severe phenotype, and may be
delayed at around 2 years old in mild phenotype. Significant delay between signs appearance
and final diagnosis in MPS patients may be caused by complex progressivity of the disease. 3
In Brazil, it is found that there is an average delay of 4.8 years for any MPS disease and that
is longer for Hunter syndrome. They also reported that most of the patients were examined by
specialists before diagnosis was confirmed.14

Biochemical diagnosis

Urine GAG analysis

In most of MPS cases, total urine GAG (uGAG) level are increased. A lot amounts of
GAG in urine showed a possibility of MPS, but it is not a definitive diagnostic test for Hunter
syndrome. Other tests should be done. Tests for analyzing uGAG including quantitative test
(uGAG total measurement, usually using dimethylene blue) and qualitative test
(electrophoresis GAG or chromatography). However, uGAG analysis method may be
affected by low sensitivity and may give a false negative results.3, 4

uGAG measurement, although relatively simple, has not yet available in every
country. Urine sample transportation to go through international border needs a complex
administration that potentially disrupt samples survival. Even with uGAG re-measurement
available, this assessment may not be covered by public or private insurance.3

Enzyme assay

21
 If uGAG analysis shows increasing dermatan and heparan sulfate, definitive
biochemical diagnosis of Hunter syndrome may be confirmed with blood enzyme test.
Enzyme test should be done to recognize enzyme I2S activity deficiency in leukocyte plasma.
Methods of assay are prepared based on testing facilities, but generally leukocytes are
preferred. Blood spot analysis upon filter paper is a useful screening instrument, especially in
area where cell or serum sample transportation is problematic.3, 17-18

Molecular diagnostic

Although rarely used to confirm the diagnosis, I2S gene molecular genetic test may
be a useful method. More than 300 gene mutations from I2S gene have been reported before.
A whole pedigree analysis should be done, if I2S gene mutation was found, and genetic
counseling should be performed in all family members. A distal pseudogene (IDS2) which
has a very similar homolog sequence was found at the end of IDS gene. This may bother
molecular analysis and thus DNA genome sequencing usually followed by cDNA analysis.15

Identification of I2S gene mutation in patients may facilitate:

 Diagnosis of precise molecular sequence

 Identify female carrier
 Initial genetic counseling
 Prompt prenatal diagnosis
 Evaluation of genotype-phenotype association

Prenatal testing may facilitate early and prompt diagnosis in fetus and available
through I2S enzyme assay taken from chorionic villi at the 11th week of gestational age, or
using amniocentesis at the 16th week of gestational age. Pre-implantation genetic diagnosis
may identify which embryo with high risks. There are two types of prenatal enzymatic
testing: (1) I2S enzyme assay for every risk pregnancy when mutation is unknown, and (2)
molecular study when mutation is known. Sex chromosome testing for female fetus should be
done using enzymatic method.16, 17, 18, 19

In this case, the patient was diagnosed using 2 type of methods:

1. Clinical diagnosis: acquired

22
 a. Face dysmorphism: rough face features, wide nose and wide nostrils, protruded
supraorbital bone, large jaw, thick lips, enlarged tongue.
b. Skeletal and joint problems: short fingers (stubbing hands), fingers like claw hand.
Stiff knee joint, limited movement especially when extension, mild genu valgus,
normal muscle tone, no clonus was found, normal muscle power.
2. Biochemical diagnosis

Blood biochemical examination showed low activity of iduronate-2-sulfate-sulfatase

enzyme in plasma (0.47 uM/hr, normal value >4.45 Um/hr), while other enzyme
activities are normal. Urine examination showed a very high glycosaminoglycan level
(627.24 mg GAGs/g creatinine, normal value for age >5 years is 35.74 GAGs/g
creatinine). The third molecular diagnostic method was not conducted because of high
cost and problem in sample transportation.

23
Prenatal Testing

Testing the fetus for inherited diseases or conditions while in utero is called prenatal
testing and can be done if there is family history of the certain condition.9,12

Prenatal testing is usually done in first trimester. If one of the parents was MPS II
carrier and they want to have prenatal testing, genetic counselling by physician as well as
geneticist or genetic counselor is essential before and after early pregnancy period.6

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of patient with MPS II as follow: 1,4

- Mucopolysaccharidosis I Hurler; I Schie; I Hurler-Scheie syndrome
- Mucopolysaccharidosis IVA (Morquio syndrome)
- Mucopolysaccharidosis VII (Sly syndrome)
- Multiple sulfatase deficiency (MSD)
- Mucolipidosis I (sialidosis), II, III, dan IV
- Mucopolysaccharidosis VI

Mucopolysaccharidosis I, IVA, VII and multiple sulfatases deficiency can be found in

early age and has clinical presentation similar to those with MPS II, although MPS II
symptoms are usually milder and without cornel clouding. Urinary GAG substrate
composition can be used to differentiate MPS type. Urinary heparan sulfate and DS excretion
are common in MPS I patients, while in MPS VI patient, almost 100% of its urine excretion
are DS. Mucopolysaccharidosis II is X-linked recessive disorders predominantly in males,
distinguished by its corneal clouding and balanced urinary heparan sulfate and DS
concentration.1,2,3 The primary test for MPS type II disease is to assess plasma sulfatase, in
which low or undetectable iduronate-2-sulfatase (I2S) activity.

Table 2. Differences between MPS enzyme deficiency and GAG accumulation9

Type Enzyme deficiency GAG accumulation Degraded

MPS IH α-L-Iduronidase DS, HS AR
MPS IS
MPS II, attenuated Iduronate-2-sulfatase DS, HS XR

24
MPS II, severe
MPS III A Heparan N-sulfatase HS AR
MPS IIIB α-N-Acetilglikosaminidase
Acetil CA: α-N-
MPS IIIC Acetilglikosaminide
asetiltransferase
MPS IIID N-asetilglikosaminine-6-
sulfatase
MPS IVA N-asetilglikosaminine-6- KS AR
sulfatase
MPS IV B Β-Galactosidase
MPS VI N-asetilglikosaminine-4- DS AR
sulfatase
MPS VII Β-Glukuronidase DS, HS, ChS AR
MPS IX Hylauronidase HA AR

In this case, patient was diagnosed with hunter syndrome due to its clinical and biochemical
examination, which are plasma I2S activity and both DS and HS accumulation in urine.

Management

General Management

Diet

Balanced diet is essential for overall health and well-being. Current clinical evidence
found no association between special diet and MPS II, while symptoms like diarrhea is
mostly on and off naturally. Changing diet can indeed alleviate some symptoms, like
excessive mucous, diarrhea or hyperactivity. Reduce milk, dairy- and sugar-based product
consumption as well as avoid additive and food coloring sometime can help ease the
symptoms. There are no diets that can reduce mucopolysaccharide accumulation, since it was
synthesized naturally by our body. Reduce sugar or other dietary components cannot change
mucopolysaccharide storage.6,9

In this case, the patient has no difficulty swallowing, and dietary managed by 3 x rice, 3 x
200 ml standard milk (%RDA; 61,78% calories, 105,5% protein and 120% liquid).

Physiotherapy

Restriction of movement and joint stiffness can significantly reduce function.

Movement exercise (passive stretch and knee bending exercise) can help conserve joint

25
functions and should be started immediately. Physiotherapy and hydrotherapy can help
patient reach certain goal and be realistic of their daily living or to help mucus secretion.
Avoid exercises that cause pain. If patient have severe motion restrictions, range of motion
improvement may not much improved, but further motion restrictions can be minimalized.
For pediatric populations, the best physiotherapy is play exercise and avoid stretch or joint
rotation.9

Living with MPS II: brain limitation

Children with MPS II and brain involvement may be overactive, strong, usually
cheerful and affectionate, but hard work is needed to provide care for them. Those children
usually have limited concentration and understanding abilities, as well as lower physical
development compared to similar age. For example, children can lock the bathroom door but
cannot understand how to unlock the door, even after being told. Children play rough and
chaotic, often make noise and prefer throwing toys rather than playing with them. Children
may not be aware of danger, stubborn, and are unresponsive to discipline because they do not
understand what they need. Some may have explosive aggressive behavior. Prolonged MPS
II abnormalities can cause children to become hyperactive, anxious and often challenging to
control their behavior. 7

Palliative care
Palliative care is a medical treatment or medication that can reduce severity of
symptoms. The aim is to prevent and alleviate suffering in order to improve patient quality of
life, especially for people who have serious and complex diseases. This include adequate
care, symptom management and end of life support that can be given over a long period of
time.15

Parental support to enjoy the presence of their MPS II children

This child may have a different life than the majority of other people, but they have a
pleasant and lovable personality. They will give true love without conditions; they will make
you laugh when you think you might never be able to laugh again. Their love spreads to
everyone around them. They are able to communicate with you even when they lose their
verbal abilities. Their eyes will trick you, their smile will attract your attention and their spirit
will increase your spirit, even when you think that no one else can.15

26
Modifying the house
Modified living spaces will enhance skills development for independent living. If
mobility was limited, wheelchairs may be needed. In addition, joint pain and stiffness, if
associated with short stature, can have significant impact on patient personal care and daily
living abilities. If this situation occurs, caregivers may be needed. If a wheelchair is needed,
the house needs to be modified to provide adequate space for wheelchair. Even though at the
present the wheelchair was not needed, it might be important to think about the possibility of
it in the future. Therefore, it needs to be planned wisely related to the future prospect.9,15
In this case, the patient is suspected to have MPS II without brain involvement.
Supportive therapy and general management regarding disease progression are given to
parents in order to provide home care. In this case, the patient was the second child, so the
psychosocial problem with siblings, his older sister, may occurs. Before patient reached 8
years old, he is still come to school like any other children in their age, he attends
kindergarten and elementary school. But after motoric limitations and speech disorder, the
patient was advised to go to Special Schools. Monitoring disease progression must be carried
out and involves multidisciplinary field.

Management
Management approach in MPS II patient is to improve quality of life, slow down
disease progression, and to prevent permanent tissues and organs damage. Early intervention
can help prevent permanent damage. Brain involvement in some MPS II patients posess a
special challenge for designing effective therapies. This is mainly because the brain is
protected by a blood-brain barrier that controls what can and cannot enter the brain. This
causes therapeutics problems since enzymes replacement that are injected into bloodstream
will face difficulty to enter the brain, hence it cannot be used to stop progressive decline of
brain function. Therefore, researchers are designing a different method that can be used to
deliver enzymes directly into the brain, and the results are still in the process.15

Several treatments that can be used for MPS II patient are: 12,15,16,17

1. Haematopoietic Stem Cell Transplant (HSCT)

Both bone marrow and cord blood transplantatation are forms of
Haematopoietic Stem Cell Transplant (HSCT). In bone marrow transplantation,
patient's bone marrow was reduction or removed and then replaced with bone marrow

27
cells from a suitable healthy donor tissue. The donor may be a family member or not
related with the bone marrow donor panel. To find a match, it can take a lot of time.12
Cord blood transplantat is based on the same principle as a bone marrow
transplantation, but using cord blood stem cells. Umbilical cord blood is collected
from the newborn placenta (with parental consent). Although it is necessary to
consider the compatibility of cord blood, the donor usually not related to the patient.
In other aspects, both procedures are similar. 15
In contrast to the cancer patients (HSCT is used regularly), removing all MPS
II patient bone marrow was unnecessary; bone marrow reduction level must be able to
provide adequate space for the growth of new bone marrow cells.15,16
Treatment that reduces patient bone marrow (known as 'conditioning') is used
to minimize the risk of a transplantation procedure. It is important to understand that
HSCT is an extensive procedure, which may require prolonged hospital stay. There
are still significant risks associated with this procedure, including infection, graft vs.
host disease and other complications that may be life threatening.1,15
There are no publications that reported HSCT can increase intellectual
outcomes in MPS II patients with brain involvement. The cause for this involvement
is unknown.16
HSCT has been shown to have positive results in MPS II disease progression
as well as increasing life expectancy of patients with MPS II without brain
involvement. Many physical aspects (face, hearing, spleen and liver enlargement, and
heart function) also improve after transplantation. However, HSCT has no effect on
skeletal structure, problems such as joint stiffness and pain, carpal tunnel syndrome
and compression of the spinal cord can still occur. Long-term supportive care with
adequate physical, medical, surgical and psychological is required in order to have
successful HSCT (level of evidence 2).1,12,17
If we look for possible risks, HSCT is usually not recommended as a first-
choice treatment for people with MPS II without brain involvement. However, it may
need to be considered if other treatments are not available or are considered medically
inappropriate or where the risk of those treatment is greater than the transplant
procedure.16

28
2. Enzyme Replacement Therapy (ERT)
After extensive clinical trials in patient with MPS II without brain
involvement, ERT is currently a treatment of choice and have similar principle as
hematopoietic stem cell transplantation. Enzyme deficiencies (2-sulphatase) is
replaced with a commercially prepared enzyme intravenous infusion into the
bloodstream. This enzyme is not produced in the body, unlike the HSCT procedures.16
Benefit of ERT compared to HSCT:16,19
(i) long-term problems and risks associated with transplantation can be
avoided
(ii) no need to find a suitable donor; and
(iii) there is no need for conditioning.

Although, there are many benefits, but both have same limitation: for example, ERT
previously have better outcome except in skeletal problems.
The commercial name for enzyme preparation used to treat MPS II patient is
called Elaprase. Prolonged used of ERT in MPS II patient for six years or more can be
safely tolerated. ERT reduce mucopolysaccharide storage, and there are continuous
improvements related to endurance, walking and climbing stairs ability, as well as
joint mobility, lung function, growth and puberty. There are also improvements of
certain characteristics such as softening hair and facial aspects, and sometimes can
increase growth. Patient will also feel the protrusion of the abdomen is greatly
reduced due to reduced liver and spleen size. However, even though ERT has
contributed to a better quality of life, patients usually still need long-term physical,
medical and surgical supportive therapy.18
ERT will not cure the disease, so that it needs to be regularly administered
throughout patient life. At present, it is usually given every week. Slow infusions are
given for several hours to minimize immune reaction to the enzyme. In Australia, this
therapy is usually done in a hospital, and ERT is currently funded by the
Commonwealth Government Lifesaving Drugs Program (LSDP) for MPS II patients
without brain involvement.15
There are no available funding for MPS II patients with brain involvement,
due to the fact that intravenous ERT cannot prevent brain function deterioration. If the
brain involvement is unknown, ERT can be approved for use until more information
available.18

29
Other Management

Other forms of treatment currently being investigated including:

Gene therapy, aims to replace damaged genes with functional genes. The principle of this
therapy is “normal” enzyme will be encoded by functional genes, and replicated throughout
all body cells (and brain cell) to produce sufficient amounts of enzymes in order to remove
mucopolysaccharide deposits and prevent further accumulation. Unlike ERT which requires
repeated administration, gene therapy is expected to require only one administration during
treatment.19

Substrate deprivation or reduction therapy, this form of treatment aims to reduce the
amount of mucopolysaccharides in the body by reduce the storage amount.

Complementary therapy, this method uses chemicals to protect and activate every enzyme
in the lysosome, so that enzymes activity and ability to break down mucopolysaccharide
increases and reduce the its storage amount.20

Generally, substrate deprivation or reduction therapy and complementary therapy will

only work for patients with mutations that still allow the production of several active
enzymes in the body. Complementary therapy is usually specific for each type of mutation.21

In this case, therapy has not been given to the MPS patient. Patient are generally
managed to overcome patient’s abnormalities, and some physiotherapy exercises to increase
motor activity, as well as articulation and oromotor exercise. Currently in Indonesia, ERT
therapy is considered expensive and not covered or funded by any insurance and government
programs. The drug itself is not available in Indonesia and cost around 3 billion-rupiah for 6
months usage. In social media, similar cases were reported in RSCM hospital, Jakarta and
this patient already received ERT therapy for 6 months. The first usage shown symptoms
improvement. But the therapy was discontinued due to the problem mentioned above.

Monitoring

Regular monitoring is important to prevent potentially serious problems and diminished MPS
II impact on quality of life. Living with progressive disorders such as MPS II can be quite
difficult and challenging, and regular monitoring can be used to reduce some of these
difficulties.4

30
Life expectancy

It is difficult to predict life expectancy because of variations in symptom severity and

age onset. Some patient with brain involvement can live to adulthood, but are usually
followed by a decrease in quality of life as their brain function decline.5

If patient have no brain involvement, a near-normal life span can be expected. But
significant physical symptoms can develop, which if without treatment, can reduce life
expectancy.4,5

Fertility

MPS II does not affect fertility. Teenagers will go through puberty, although it can be
delayed.4

Patients in this case are thought to have rapid disease progression due to the various
clinical manifestations that present in the age of 8. In addition, a very high concentration of
urinary GAG secretion as a negative prognostic was also found in these patients.
Physiotherapy therapy is currently continued by parents. When we write this paper, the
patient was still able to move normally with some limitations. Patient prognosis for his ad
functional is ad malam, and dubia ad malam for ad vitam and ad sanam.

31
 SUMMARY

The patient in this case report was diagnosed with mucopolysaccharidosis type II when
he was 11 years and 3 months old. Patients come to the referral center with complaints that
the patient unable to walk, and accompanied by short stature. The symptoms that support the
diagnosis are the presence of very short stature, typical dysmorphic features for
mucopolysaccharidosis disease (rough face, wide forehead, thick lip skin, frontal bossing)
that prominent since age 8, joint stiffness and bent legs. Radiologic finding found sella
turcica widening which looks like J-shaped form, frontal bossing accompanied by depressed
nasal bridge, dolicochephalic and hypertelorism, pointing at proximal left and right
metacarpal II, V that support MPS diagnosis. Echocardiographic examination shows
moderate valvar aortic stenosis, moderate aortic regurgitation, and left ventricular
hypertrophy. Blood biochemical analysis showed low plasma Iduronate-2-sulphate sulphatase
enzyme activity (patient Iduronate-2-sulphate sulphatase value was 0.47 uM/hr, normal value
>4.45 uM/hr), while other enzyme activity was within normal limits. Urinary examination
shows very high levels of glycosaminoglycans (627.24 mg GAGs/g creatinine, normal value
for age > 5 years is 35.74 GAGs/g creatinine). The results of this examination are in
accordance with type II mucopolysaccharidosis disease, so the patient final diagnosis was
Mucopolysaccharidosis type II (Hunter Syndrome).

Patient diagnosis was delayed due to the rarity of this condition in the community so
that dysmorphism and clinical symptoms that are actually typical for MPS are missed.
Another inhibiting factor is the limitations of blood biochemical examinations in Indonesia.
This patient is suspected to be a mild type, based on clinical symptoms, age of onset of
disease, but classified as severe due to the urinary GAG secretion amount.

Therapy for MPS II that are still being developed and investigated is enzyme
replacement therapy that considered safer than bone marrow graft, coupled with supportive
management to treat disease complications. Enzyme replacement therapy cannot be applied
in Indonesia due to its availability and prices. The patient did not get ERT therapy because of
aforementioned reason and only received supportive therapy (physiotherapy) during
hospitalization. The patient did not continue his physical therapy after discharged. The
prognosis of these patients is dubia ad malam for ad functionam and ad vitam, and ad malam
for ad sanationam.

32
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