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DOI: 10.1542/peds.2008-0999; originally published online November 9, 2009;2009;124;e1228Pediatrics
Schwartz, R. E. Wood and E. WraithMolter, M. V. Muoz Rojas, J. W. Ogilvie, R. Parini, U. Ramaswami, M. Scarpa, I. V.
Harmatz, W. Kamin, C. Kampmann, S. T. Koseoglu, B. Link, R. A. Martin, D. W.
Joseph Muenzer, M. Beck, C. M. Eng, M. L. Escolar, R. Giugliani, N. H. Guffon, P.Multidisciplinary Management of Hunter Syndrome
http://pediatrics.aappublications.org/content/124/6/e1228.full.htmllocated on the World Wide Web at:
The online version of this article, along with updated information and services, is
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2009 by the American Academypublished, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
publication, it has been published continuously since 1948. PEDIATRICS is owned,PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
at Universiteit van Amsterdam on December 11, 2013pediatrics.aappublications.orgDownloaded from at Universiteit van Amsterdam on December 11, 2013pediatrics.aappublications.orgDownloaded from
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Multidisciplinary Management of Hunter Syndrome
abstractHunter syndrome is a rare, X-linked disorder caused by a deficiency of
the lysosomal enzyme iduronate-2-sulfatase. In the absence of suffi-
cient enzyme activity, glycosaminoglycans accumulate in the lyso-
somes of many tissues and organs and contribute to the multisystem,
progressive pathologies seen in Hunter syndrome. The nervous, car-
diovascular, respiratory, and musculoskeletal systems can be involved
in individuals with Hunter syndrome. Although the management of
some clinical problems associated with the disease may seem routine,
the management is typically complex and requires the physician to be
aware of the special issues surrounding the patient with Hunter syn-
drome, and a multidisciplinary approach should be taken. Subspecial-
ties such as otorhinolaryngology, neurosurgery, orthopedics, cardiol-ogy, anesthesiology, pulmonology, and neurodevelopment will all have
a role in management, as will specialty areas such as physiotherapy,
audiology, and others. The important management topics are dis-
cussed in this review, and the use of enzyme-replacement therapy with
recombinant human iduronate-2-sulfatase as a specific treatment for
Hunter syndrome is presented. Pediatrics2009;124:e1228e1239
Hunter syndrome, or mucopolysaccharidosis II, is an X-linked, progres-
sive lysosomal storage disease in which patients are deficient in the lyso-
somal enzyme iduronate-2-sulfatase(I2S),1,2 which resultsin cellular accu-
mulation of the glycoaminoglycans dermatan and heparan sulfate. Huntersyndrome occurs almostexclusively in males, with a reported incidence of
1 in 170 000 male births.3 The accumulationof glycoaminoglycans within
tissues and organs contributes to the Hunter phenotype, which was re-
cently reviewed in detail by Martin et al.3 Hunter syndrome is a heteroge-
neous disorder, both in age at onset of symptoms and severity. Patients
typically have a normal appearance at birth, with the initial signs and
symptoms emerging between 18 months and 4 years of age in the severe
form and2 years later for those with an attenuated phenotype form.1,3,4
All patients experience somatic involvement, which can include facial dys-
morphism, enlarged liver and spleen, stiff joints andcontractures, cardiac
valve disease, and upper-airway obstruction. The most severely affectedpatients, who are estimated to include 75% of all patients with Hunter
syndrome,4 haveprofound neurologic involvement leading to cognitive im-
pairment and developmental regression; death usually occurs in the sec-
ond decade of life.1,3 Patients with an attenuated phenotype may have nor-
mal intelligence and typically survive into adulthood.
In 2006, Shire Human Genetic Therapies, Inc (Cambridge, MA) invited an
international panel of physicians experienced in the management of
patients with Hunter syndrome to discuss aspects of this metabolic
disorder. The initial work of that group of experts resulted in a article
that discussed the recognition and diagnosis of Hunter syndrome.3 The
AUTHORS:Joseph Muenzer, MD, PhD,a M. Beck, MD,b C. M.
Eng, MD,c M. L. Escolar, MD,a R. Giugliani, MD, PhD,d N. H.
Guffon, MD,e P. Harmatz, MD,f W. Kamin, MD,b C.
Kampmann, MD,b S. T. Koseoglu, MD,f B. Link, MD,g R. A.Martin, MD,h D. W. Molter, MD,i M. V. Munoz Rojas, MD,d
J. W. Ogilvie, MD,j R. Parini, MD,k U. Ramaswami, MD,l M.
Scarpa, MD, PhD,m I. V. Schwartz, MD, PhD,d R. E. Wood,
MD, PhD,n and E. Wraith, MDo
aDepartment of Pediatrics, University of North Carolina, Chapel
Hill, North Carolina;bVilla Metabolica, Childrens Hospital,
University of Mainz, Mainz, Germany;cDepartment of Molecular
and Human Genetics, Baylor College of Medicine, Houston, Texas;dMedical Genetics Service, Hospital de Clinicas de Porto Alegre,
and Department of Genetics, Universidade Federal do Rio
Grande do Sul, Porto Alegre, Brazil;eHopital Edo uard Herriot
Pavilion S, Maladies Metaboliques, Lyon, France;fDivision of
Ophthalmology, Childrens Hospital and Research Center
Oakland, Oakland, California;g
Orthopedic Department,University Hospital Johannes Gutenberg-University, Mainz,
Germany;hDivision of Medical Genetics, St Louis University, St
Louis, Missouri;iDepartment of Otolaryngology, Washington
University in St Louis, St Louis, Missouri;jDepartment of
Orthopaedic Surgery, University of Utah School of Medicine, St
Lake City, Utah;kPediatric Department, Ospedale San Gerardo,
Monza, Italy;lPaediatric Metabolic Unit, Addenbrookes Hospital,
Cambridge, United Kingdom;mDepartment of Pediatrics,
University of Padova, Padova, Italy;nDivision of Pulmonary
Medicine, Cincinnati Childrens Hospital Medical Center,
Cincinnati, Ohio;oInherited Metabolic Medicine, Genetic
Medicine, St. Marys Hospital, Manchester, United Kingdom
KEY WORDS
Hunter syndrome, mucopolysaccharidosis II, lysosomal storagediseases, enzyme-replacement therapy
ABBREVIATIONS
I2Siduronate-2-sulfatase
CNScentral nervous system
OSA obstructive sleep apnea
CSF cerebrospinal fluid
HSCT hematopoietic stem cell transplantation
ERT enzyme-replacement therapy
Dr Martins current affiliation is Shire Human Genetic Therapies,
Inc, Cambridge, MA.
www.pediatrics.org/cgi/doi/10.1542/peds.2008-0999
doi:10.1542/peds.2008-0999
Accepted for publication Dec 11, 2008
Address correspondence to Joseph Muenzer, MD, PhD,
Department of Pediatrics, CB 7487, Medical School Wing E Room
117, University of North Carolina at Chapel Hill, Chapel Hill, NC
27599-7487. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2009 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE:Drs Muenzer, Beck, Eng, Escolar,
Giugliani, Guffon, Harmatz, Kamin, Kampmann, Koseoglu, Link,
Martin, Molter, Munoz Rojas, Ogilvie, Parini, Ramaswami,
Scarpa, Schwartz, Wood, and Wraith have received honoraria,
travel grants, or research grants from Shire Human Genetic
Therapies, Inc.
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In 1 case, motor function was reported
to improve after ventriculoperitoneal
shunting.11 Little other experience has
been reported in the medical litera-
ture; thus, the issue about when to
shunt remains unresolved. It is our
opinion that shunting might be consid-
ered for patients with MRI evidence of
progressive ventricular enlargement
and/or a confirmed CSF pressure of
25 to 30 cm H2O (1822 mm Hg).
Spinal cord compression caused by
dural thickening or by instability of
the atlantoaxial joint has been re-
ported1315 (Fig 1). Symptoms may in-
clude abnormal gait, muscle weakness,
clumsiness with fine motor skills, and
bladder dysfunction.1316 Patients with
Hunter syndrome should be screened
for clinical and radiologic evidence of
spinal cord compression. Atlantoaxial
instability can be identified by flexion-
extension radiography, but MRI is re-
quired to confirm cord compression
secondary to dural thickening.13,14 Care
should be taken during general anes-
thesia to prevent cord compression re-
sulting from atlantoaxial instability.
Because cord compression is often as-
sociated with irreversible neurologic
dysfunction, decompression surgery
should be considered at the onset of
symptoms before significant impair-
ment has occurred.13
Seizures are common in patients with
a severe phenotype,17 and their inci-
dence parallels the cognitive deterio-
ration. In contrast, seizures are much
less common in patients with an atten-
uated phenotype. In 1 recent study, sei-
zures were reported in 27.7% of pa-
tients with a severe phenotype and in
only 5.9% of those with an attenuated
phenotype.17 The initial onset of sei-
zures may not be readily recognized by
parents, because they may take the
form of absence seizures that are
characterized by staring episodes
and may not require treatment. The in-
cidence of these subtle seizures
should be considered as a trigger for
further neurologic assessment. No
FIGURE 1Cervical cord compression secondary to dural
glycoaminoglycan deposition in a patient with
Hunter syndrome.
TABLE 1 Suggested Evaluations for Patients With Hunter Syndrome
Organ System/Involvement Assessment Recommendation
Neurologic
Hydroce phalus MRI or compute d tom ography im aging of the he ad Upon diagnos is, the n every 1 3 ySpinal cord compression MRI of the cervical spine Upon diagnosis, then every 13 y
Atlantoaxial instability Cervical spine flexion/extension Upon diagnosis, every 23 y, and before general
anesthesia
Progressive cognitive involvement Neurobehavioral Upon diagnosis, then yearly
Carpal tunnel syndrome Nerve conduction 4 to 5 y old, then at 1- to 2-y intervals
Hand function tests Upon diagnosis, then yearly
Heart
Valvular dysfunction Cardiac echocardiography, 12-lead electrocardiogram,
and possibly Holter monitoring if indicated
Upon diagnosis, then at 1- to 3-y intervals
Hearing Otologic and audiologic Upon diagnosis, then every 612 mo depending on
symptoms
Respiratory involvement Pulmonary function Upon diagnosis or when patient is old enough to
cooperate, then yearly
Sleep study Upon diagnosis, every 35 y, and then upon suspicion of
OSA
Bronchoscopy As necessary to evaluate pulmonary involvement or in
preparation for general anesthesia
Skeletal involvement Joint range of motion Upon diagnosis, then yearly
Radiograph of s pi ne and hi p Upon diagnos is and thereafte r in res ponse to signs and
symptoms
General
Inguinal hernia Clinical evaluation At every examination
Hepatosplenomegaly Clinical evaluation At every examination
Dental Standard dental care 6-mo intervals
Eye Standard ophthalmologic examination Yearly intervals
Shown is a schedule of assessments that should be performed for the evaluation of organ or system involvement in patients with Hunter syndrome. The term, upon diagnosis refers to the
initial diagnosis of Hunter syndrome. Once a clinical problem is identified, the management and/or treatment and follow-up schedule will depend on the usual practice of the specialists
involved.
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studies have been reported that evalu-
ated the association of behavioral
problems and seizures, and it is
our opinion that these problems are
not related. Generalized tonic-clonic
seizures are common as disease
progresses and usually can be con-
trolled by anticonvulsant monotherapy.
Carpal tunnel syndrome is the most
common entrapment neuropathy in
adults, but it is rarely seen in children.
However, carpal tunnel syndrome is
commonlyseen in patientsaged5 to 10
years with Hunter syndrome and, if un-
treated, may result in irreversible con-
tracture of distal interphalangeal
joints as well as dysesthesia, sensibil-
ity loss of the first 3 fingers, and pare-
sis of the thenar muscles.18 Impor-
tantly, patients rarely report pain until
loss of function occurs. Standard elec-
trophysiologic testing will identify me-
dian nerve compression even before
symptoms appear, and it should be ini-
tiated by the ages of 4 to 5 years and
repeated at 1- or 2-year intervals. For
some patients, sedation or general an-
esthesia might be necessary to obtainhigh-quality results. (Please note that
both sedation and general anesthesia
are high-risk procedures for patients
with Hunter syndrome, as described in
the General Anesthesia section be-
low.) Electromyography testing is not
typically tolerated by the unsedated
child. Decompression surgery is rec-
ommended for patients with demon-
strated loss of hand function or abnor-
mal nerve-conduction studies andresults in rapid and sustained im-
provement of function.1822 The rate of
reoccurrence of carpal tunnel syn-
drome after surgery in patients with
Huntersyndromeis not known, and pa-
tients have remained symptom-free
for up to 11 years.18 However, because
reoccurrence of median nerve com-
pression caused by scarring or con-
tinued glycoaminoglycan deposition
is a possibility, ongoing monitoring
is necessary.
HEARING
Hearing loss is nearly universal in
Hunter syndrome,23,24 and it is charac-
terized by both conductive and senso-
rineural involvement.25 Chronic otitis
media is common and contributes to
the conductive hearing loss.25,26 The
mucosa of the middle ear has been de-
scribed as thick and edematous, with
large, foamy cells that stain positive
with periodic acid Schiff, indicative of
glycoaminoglycan storage.27 Otoscle-
rosis has been described and also
contributes to conductive hearing
loss.2730 The etiology of neurosensoryloss of hearing is less well established.
In 1 case, compression of the cochlear
nerve caused by arachnoid hyperpla-
sia was described.25 Reduction in spi-
ral ganglion cells and degeneration of
hair cells also may contribute to neu-
rosensory loss.31 Because hearing loss
can contribute to behavioral problems
and learning difficulties, it is important
to perform routine otologic and audio-
logic evaluations for patients withHunter syndrome at least every 6 to 12
months. Myringotomy with placement
of ventilating tubes may improve hear-
ing.26 The use of hearing aids should be
encouraged.
EYE
Obvious corneal clouding is not prom-
inent in Hunter syndrome.1 In the larg-
est study of the eye in Hunter syn-
drome (N 33 patients), optic nervehead swelling was seen in 20%, and
optic atrophy was found in 11% of
the patients.32 Retinopathy has been
reported also.3237 Retinal dysfunction
has been revealed by electroretinogra-
phy and may result in night blindness
and loss of peripheral vision.38
Routine ophthalmologic eye care is
suggested for patients with Hunter
syndrome. If disk swelling is discov-
ered, the cause must be determined. If
elevated CSF pressure is found, then
shunting maybe indicated (see above).
It is important to note that papilledema
may indicate elevated CSF pressure or
hydrocephalus, but the absence of
papilledema does not confirm normalCSF pressure. Papilledema is not a typ-
ical feature of increased intracranial
pressure in Hunter syndrome.
SWALLOWING DISORDERS
The skeletal changes of Hunter syn-
drome lead to poor jaw mobility, which
limits the ability to open the mouth and
negatively affects the ability to chew.
Enlarged tonsils, adenoids, and/or
tongue may interfere with the coordi-nation of swallowing activity. Neural in-
volvement and cognitive impairment
may also influence the coordination
required for efficient chewing and
swallowing.25
DENTAL
Most patients exhibit some dental ab-
normality. Teeth are reported to be
widely spaced, peg-shaped, and hypo-
plastic in some cases.3941 Delayed
eruption is associated with areas of
bone involvement resembling denti-
gerous cysts, particularly with first
permanent molars.39 Routine dental
procedures may be difficult in patients
with Hunter syndrome because of the
limited maximum opening of the jaw.
General anesthesia may be required
for some procedures in patients with
severe disease (eg, for extractions or
restorations), but anesthesia itself
presents special risks in Hunter syn-
drome (see below). Even surgical ap-
proaches are difficult because of the
short neck, bone density, and reported
toughness and inelasticity of soft
tissues.40
RESPIRATORY INVOLVEMENT
Upper-airway obstruction is a major
contributor to the morbidity and mortal-
ity of patients with Hunter syndrome.1
SPECIAL ARTICLES
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Changes to soft tissues are responsible
for most respiratory problems associ-
ated with Hunter syndrome. These
changesincludeenlarged tonsilsand ad-
enoids,4244 tongue,45 and lingual tonsils.
Bony changes leading to complete naso-
pharyngeal obstruction have been re-
ported in 1 patient.42 The mucosa overly-
ing thearytenoid cartilages is often quite
redundant, and it swells impressively
when mechanically stimulated, such as
during blind intubation attempts. As the
disease progresses, pharyngomalacia
maydevelop andbecome severe,leading
to significant airway obstruction (pri-
marily on inspiration) caused by col-
lapse of the airways above the larynx
duringinspiration. Similarly, tracheoma-
lacia, in which the normal shape of the
trachea cannot be maintained, may lead
to dynamic airway collapse during inspi-
ration.45,46 In addition, a small chest cav-
ity coupled with abnormally shaped and
stiff ribs and restriction resulting from
abdominal organ enlargement contrib-
ute to restrictive lung disease. OSA is
commonly observed in Hunter syn-drome47,48 and causes episodic reduc-
tion in oxygen saturation,47 which often
prevents patients from reaching sleep
states 3 and 4 (Fig 2). The lack of restful
sleep may result in daytime behavioral
disturbances.9
In some patients,the lower respiratory
tract also may be involved, with depo-
sition of glycoaminoglycan in the tra-
cheobronchial mucosa. This may be
generalized, giving the tracheal mu-
cosa the appearance of edema, or it
may be nodular. Mucosal thickening
may contribute to increased airway re-
sistance; it rarely extends beyond the
segmental bronchi.
Diagnosis of airway obstruction in-
volves a comprehensive evaluation of
medical history, physical examination,
and imaging studies. Pulmonary func-
tion testing using spirometry may be
useful for monitoring progressive
changes in respiratory function. How-
ever, spirometry requires the cooper-
ation of the patient and, thus, cannot
be performed on very young patients
or on patients with a severe pheno-
type. Although OSA may be obvious by
observing the patient, an overnight
sleep study conducted in the hospital
during normal, unsedated sleep
should be used to evaluate its severity
and to document the effect of treat-
ment strategies. Common measure-
ments include thoracic and abdominal
motion, pulse oximetry to measure ar-
terial oxygen saturation and pulse
rate, electrocardiography, end-tidal
PCO2 measurement, electroencepha-
lography (selected leads), and video
and sound recording.48 However, be-
cause many children find sleeping in
the hospital environment to be diffi-
cult, a screening study can be con-
ducted at home by using a recording
portable pulse oximeter, with the re-
sults reviewed by a pulmonologist.
Bronchoscopy may be performed for a
more thorough evaluation of respira-
tory involvement. A rigid broncho-
scope will provide a high-quality image
but also may distort the anatomy and
thus obscure dynamic airway obstruc-
tion. A flexible bronchoscope may beneeded for patients with limited mobil-
ity of the jaw; in any case, this will allow
more accurate observation of the dy-
namic obstruction that occurs during
breathing. It is important to under-
stand that these 2 types of broncho-
scopes should be considered comple-
mentary, because one method may
visualize things that the other one
cannot. Regular pulmonary follow-up
is required for any patient with
Hunter syndrome who has respira-
tory invol vement.49
Management of airway involvement be-
gins with the surgical removal of ob-
structions, including tonsillectomy and
adenoidectomy, but because of the pro-
gressive nature of the airway changes,
this approach may yield only temporary
relief. Continuous positive airway pres-
sure (CPAP) during sleep is often added
to the management plan. CPAP provides
inspired air at an elevated pressure
through a specially fitted mask that
helps to maintain airway patency during
inspiration.50,51 An extension of this ap-
proach is bi-level positive airway pres-
sure (BiPAP). BiPAP varies the level of
positive pressure so that a lower posi-
tive pressure is maintained during exha-
lation. CPAP and BiPAP require training
for both the child and his or her caregiv-ers and can be noisy, limiting compli-
ance. The requirement for special equip-
ment also may make traveling difficult.
Tracheotomy may be an effective way
of maintaining an airway in patients
with severe obstruction, but complica-
tions are common. Granulation tissue
formation around the tip of the trache-
ostomytube is often seen,52 necessitat-
ing additional bronchoscopy for me-
FIGURE 2Comparison of sleep-stage studies in an otherwise healthy child (left) and a child with mucopolysac-
charidosis II (right). REM indicates rapid eye movement.
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chanical debridement45 or replacement
of the tube with one of a different length.
Tracheal stenting has been reported in
patients with Hunter syndrome,53 but it
can have significant complications. Sil-
icone stents tend to migrate, espe-
cially with growth, and inhibit the
clearance of tracheal secretions.53 Me-
tallic stents become embedded in tis-
sue and do not expand with the normal
growth of the child. These stents also
may cause mucosal impaction. Both
types of stents arecommonly associated
with granulation tissue formation, which
may be lethal and, atbest, requiresbron-
choscopic debridement.53
GENERAL ANESTHESIA
The anatomic changes discussed
above, including short neck, immo-
bility of the jaw, and obstruction of
the airways by tissues of the throat
and trachea, may complicate general
anesthesia in patients with Hunter
syndrome. Because of the distorted
anatomy, difficult intubation is com-
mon with Hunter syndrome. Two sum-
maries of anesthesia in Hunter syn-
drome reported failed or difficult
intubation in 5 (42%) of 12 patients.54,55
In some experienced centers, it is com-
mon practice to perform and video-
record a bronchoscopy by using a flex-
ible fiber-optic bronchoscope before
surgery so that the anesthesiologist
can be prepared for the individual
anatomy that is about to be encoun-
tered. Bronchoscopic intubation (over
a flexible bronchoscope) is often the
most appropriate (and sometimes theonly feasible) technique for intubation.
It is important to have a back-up plan
for establishment of an airway in the
event of acute airway obstruction, in-
cluding consulting with the parents
about the possibility of urgent trache-
otomy or cricothyrotomy. There is
some evidence that early extubation
directly after the procedure may re-
duce the risk of urgent tracheotomy.
For difficult intubations or in patients
scheduled for brief procedures, a la-
ryngeal mask airway may provide ade-
quate control of the airway.56,57
The risk of airway complications does
not end at the successful completion of
surgery. Edema of the larynx and other
tissue can make extubation difficult, if
not impossible. Patients maybe unable
to maintain an airway after extubation,
requiring urgent reintubation or tra-
cheostomy. Postprocedure edema
may exacerbate upper-airway obstruc-
tion and has been reported to occur as
late as 27 hours after surgery.40 In that
case, acute respiratory obstruction re-
sulted in an unsuccessful emergency
tracheostomy and, ultimately, thedeath of the patient. Postobstructive
pulmonary edema also has been re-
ported.58 The precise pathophysiologic
mechanism of postobstructive pulmo-
nary edema is not known, but the pri-
mary mechanism is forced inspiratory
effort against an obstruction, resulting
in large negative transpulmonary
pressure gradient that results in
translocation of fluid from pulmonary
capillaries to the interstitial space.58
The use of a helium-oxygen breathing
mixture59 at the time of extubation may
relieve the obstruction and improve
outcome, because the reduced density
of this air mixture compared with am-
bient airdecreases the work of breath-
ing and increases linear flow rates.59,60
General anesthesia represents a high-
risk procedure and, therefore, should
be administered only by anesthesiolo-
gists who have experience in treatingpatients with mucopolysaccharidoses
and only in major medical centers. In
addition to an experienced anesthesi-
ologist, in some centers it is common
practice for an otolaryngologist or pe-
diatric pulmonologist to be available
during the induction of anesthesia and
intubation of the patient. One effective
approach is to intubate over a flexible
bronchoscope in virtually all cases,
because this procedure also allows
documentation of airway anatomy and
dynamics and contributes to the long-
term management of the patient. Be-
cause of the risks associated with gen-
eral anesthesia, it is good practice to
try to perform multiple planned surgi-cal procedures during a single anes-
thesia session. It is our experience that
the risks associated with general an-
esthesia are lower for a patient who
has undergone previous general anes-
thesia without sequelae, provided that
the interval between the 2 procedures
is sufficiently short. However, such a
patient should be considered at high
risk if a longer interval has passed be-
cause of the progressive nature ofHunter syndrome.
Many pediatric patients require seda-
tion or anesthesia for the conduct of
diagnostic studies. Although it can be
tempting to use sedation by adminis-
tration of an oral or intravenous drug
rather than formal anesthesia, this
procedure can be quite risky for pa-
tients with Hunter syndrome because
of the high incidence of upper-airway
problems. On the other hand, manipu-lation of the airway (ie, intubation) has
its own risks. In our opinion, sedation
in patients with Hunter syndrome
should be performed only in a setting
appropriate for general anesthesia,
with careful and continuous monitor-
ing and provision for immediate and
appropriate intervention by an experi-
enced anesthesiologist.
SKELETAL INVOLVEMENTSkeletal involvement is nearly univer-
sal in Hunter syndrome and is charac-
terized by stiff joints and decreased
joint range of motion.1,3 These skeletal
problems limit mobility and adversely
affect quality of life. Radiographic ex-
amination reveals abnormal thickness
of all bones and irregular epiphyseal
ossification of many joints.43 Coxa
valga deformity of the hip joints has
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been described and is associated with
degenerative changes in the femoral
heads.40,61 Joint contractures often
prevent patients with Hunter syn-
drome from standing erect and may
limit mobility.
Physical therapy is designed to pre-
serve and improve physical function
and offers an initial conservative (ie,
nonsurgical) approach to the manage-
ment of joint involvement of Hunter
syndrome. The first steps should be to
rule out neurologic influences (eg, spi-
nal cord compression causing spastic
gait or weakness13) and design a pro-
gram directed at the appropriate
problem areas. This program may in-
volve mobilization, strength and en-
durance training, enhancement of fine
motor skills for the hands, and gait
training for lower-limb joints. It is im-
portant that the patient be able to per-
form the training on his or her own,
because regular, short training ses-
sions (eg, 10 minutes/day) may be
more successful than a single weekly
session with a physical therapist. Al-
though no studies providing evidence
of benefit of physical therapy in Hunter
syndrome have been published, it is
important to document progress by
performing baseline and periodic eval-
uations. The evaluation should be ap-
propriate for the joints that are tar-
geted. For example, joint range of
motion testing is often used, but joint
range of motion measures individual
joints in single directions, whereas ac-
tivities of daily living require the coor-
dinated activities of several joints. The
patient also must be able to cooperate
in the testing. Photograph or video
documentation may be sufficient for
documenting improvement during
therapy.
Orthopedic surgery has a role in the
management of Hunter syndrome. In
the case of the hip joint, the acetabu-
lum is very shallow, and flattening of
the femoral head has been report-
ed40,61 (Fig 3). These deformities are
predictive of osteoarthritis and poor
mobility. In an otherwise healthy pa-
tient, surgery would be indicated to
preserve long-term mobility. Similarly,
for a patient with Hunter syndrome
with expected longevity, corrective
surgery should be considered. Trig-
gering of the fingers is often second-
ary to carpal tunnel syndrome (see
above), but it also may occur indepen-
dently. However, glycoaminoglycan
deposition in flexural tendons may
limit theirexcursion, causing contrac-
tures of their distal interphalangeal
joints.20 Early recognition and surgery
to release the tendons is essential for
preventing permanent contracture of
the joints.20
CARDIAC INVOLVEMENTCardiac involvement is common in
Hunter syndrome. Recent studies have
suggested that nearly all patients re-
gardless of phenotype exhibit cardiac
abnormalities on echocardiographic
examination.17,62 For example, Schwartz
etal17 studied 38 patients and reported
that the 7 patients with a severe phe-
notype and the 11 patients with an at-
tenuated phenotype had abnormal
echocardiogram results. Of the 20 pa-tients who were too young to be clas-
sified as having the severe or attenu-
ated phenotype, only 5 patients had
normal echocardiogram results.
Valvular dysfunction is common, with
mitral, aortic, tricuspid, and pulmonary
valves affected in decreasing order.17,62
Autopsy examinations have shown nodu-
lar thickening of the valves,6264 and
histologic and electron-micrographic
examination has revealed storage mate-rial in the valves and in interstitial
fibroblast-like cells in the myocardium.65
Conduction abnormalities (eg, atrio-
ventricular block) also contributeto car-
diac mortality in patients with Hunter
syndrome.66
Management of the cardiac involve-
ment of Hunter syndrome should in-
clude regular echocardiography, 12-
lead electrocardiography, and/or Holter
monitoring, if indicated. The frequency
of these examinations should be deter-
mined by the cardiologist, but every
1 to 3 years is typically recommended.
Valve replacement has been reported,
but this procedure remains uncom-
mon.62,63,67 Because of the valvular dys-
function, prophylactic antibiotic ther-
apy is required before any surgery or
major dental procedure. Hypertension
in this population has been underap-
FIGURE 3Pelvic radiographs showing common skeletal deformities of the hip joint observed in a 1-year-old
(left) and an 8-year-old (right) with Hunter syndrome.
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preciated and should be treated as
medically indicated.68
ENDOCRINE FUNCTION
Boys with Hunter syndrome, both se-
vere and attenuated, can have normal
height up to8 years ofagebutlagfar
behind nonaffected boys thereafter.17
This short stature leads to psychoso-
cial issues in some children,69 and
many parents have sought human
growth hormone therapy to stimulate
growth. However, the risks and bene-
fits of human growth hormone for
Hunter syndrome are not yet known,
and no published evidence currently
exists to support its use in patients
with Hunter syndrome. The cause of
short stature in Hunter syndrome is
not known, but it is thought to be at
least partially the result of osseous
growth-plate disturbances.61 Although
necropsy examinations have sug-
gested pituitary dysfunction,61 ante-
rior pituitary function in a 13-year-old
patient was found to be normal in the
only case reported in the literature.69
END-OF-LIFE MANAGEMENT
In the patient with severe disease, the
progression of neurologic involvement
eventually results in a general decline
in activity and function.24 The patient
will become increasingly disabled,
gradually losing the ability to commu-
nicate, chew, and swallow. The ability
to control bowel and bladder function
will be lost completely, and the patient
will become bedridden. Historically,the cause of death listed on the death
certificate is often pneumonia, but se-
vere neurologic impairment and a ca-
chexic state, as a result of an inability
to eat, are contributing factors.4
During the end-of-life period, a gas-
trostomy tube should be considered
when poor oral intake results in weight
loss. All other care should be palliative
and directed at maintaining the comfort
of the patient, including the use of pain
medications, if indicated.
SPECIFIC TREATMENT
Treatments aimed at providing re-
placement of I2S in Hunter syndrome
have been reported, including fibro-
blast transplantation,70 serum or
plasma infusion,71 white blood cell in-
fusions,72 and human amnion mem-
brane implantation.73 These treat-
ments have been tested in single
patients or in small series of patients,
and no evidence of clinical benefit has
been reported. Other methods include
hematopoietic stem cell transplanta-
tion (HSCT)7480 and enzyme-replacement
therapy (ERT) with recombinant humanI2S. Only recombinant human I2S has
been tested in randomized clinical
trials.81,82
Hematopoietic Stem Cell
Transplantation
HSCT has become the treatment of
choice for the severe form of mucopo-
lysaccharidosis I (Hurler syndrome),
in which it is reported to reduce so-
matic involvement and prevent neuro-
cognitive decline, provided it is per-
formed before 24 months of age.83,84 No
controlled clinical studies have been
conducted regarding the efficacy of
HSCT in Hunter syndrome, and the ex-
tent of the medical literature includes
only single cases or small case se-
ries.7480,85 Although some evidence of
improvement in the somatic signs and
symptoms of Hunter syndrome has
been reported with bone marrowtransplantation,75,76 the results of
these studies have provided no consis-
tent evidence of benefit. Umbilical cord
blood has been proposed as a readily
available source of hematopoietic
stem cells for transplant. A single re-
port of the use of cord blood in Hunter
syndrome has been published. Mullen
et al85 treated a 10-month-old boy with
unrelated umbilical cord blood andre-
ported that his hepatomegaly resolved
and his growth was normal.
The use of HSCT for treatment of
Hunter syndrome remains controver-
sial because of the significant morbid-
ity and mortality that may be associ-
ated with this therapy.86 For patients
experiencing chronic graft-versus-
host disease, the chronic use of ste-
roids maylead to orthopedic complica-
tions (eg, osteonecrosis of the hip),
and the presence of moderate-to-
severe graft-versus-host disease pre-
cludes most orthopedic interventions.
It remains unknown whether success-
ful HSCT, even when completed very
early in life or with umbilical cord
blood as the source of stem cells, willalter the course of cognitive involve-
ment in patients with the severe phe-
notype.76 Patients and their parents
must consider these risks and weigh
them against the potential improve-
ments in the quality of life that trans-
plantation may confer.
Enzyme-Replacement Therapy
Recombinant human I2S (Elaprase
[Shire Human Genetic Therapies, Inc,
Cambridge,MA]) is now available forERT
for patients with Hunter syndrome. Its
approval in the United States, Europe,
and elsewhere was based primarily on
the results of a phase 2/3 clinical trial.
This randomized, double-blind, placebo-
controlled study demonstrated that
weekly doses of idursulfase adminis-
tered as an intravenous infusion at a
dose of 0.5 mg/kg significantly improved
the primary outcome, a composite ofchange in distance walked in 6 minutes,
and change in percent predicted forced
vital capacity (FVC) compared with those
who were taking a placebo.81 Reductions
in liver andspleen volume and in urinary
glycoaminoglycan excretion also were
experienced by patients treated with
idursulfase. Thispivotal clinical trial con-
tinued as an open-label extension study
in which all patients were treated with
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weekly doses of idursulfase at 0.5 mg/kg
for at least 2 years. Results of this exten-
sion study have not yet been published.
In clinical trials, idursulfase was well tol-
erated, and most of the adverse events
reported were consistent with those ex-
pected in an untreated population with
Hunter syndrome. The most common
treatment-related adverse events were
related to the infusions (ie, headache,
erythema, pyrexia, flushing, urticaria,
and/or rash). These infusion reactions
were managed by slowing or interrupt-
ing the infusion and by premedication
with antihistamine and/or corticoste-
roids. Life-threatening anaphylactic re-
actions have been observed in some
patients during infusion of idursulfase,
as have biphasic anaphylactic reactions
in which a secondary reaction occurred
24 hours after treatment and reso-
lution of the initial anaphylactic re-
sponse.87 Patients who haveexperienced
these reactions may require prolonged
observation after receiving an idursul-
fase infusion. Treatment of anaphylactic
reactions have included epinephrine, in-
haled -adrenergic agents, and cortico-
steroids.87
The issue regarding when to initiate
ERT remains undetermined for many
patients with Hunter syndrome. The
ERT clinical trials demonstrated clini-
cal benefit of idursulfase treatment for
patients with Hunter syndrome 5
years of age were able to cooperate
with investigators and complete the
testing as required. Clinical experi-
ence suggests that ERT should be initi-
ated before the onset of irreversible
changes and, ideally, before significant
disease progression. Although pa-
tients with the severe form of Hunter
syndrome were not studied in the clin-
ical trials, there is no reason to believe
that the somatic manifestations of
their disease would not be benefited by
idursulfase treatment. Early clinical
observations support this statement.In contrast, idursulfase is not expected
to cross the blood-brain barrier, and
patients with a severe phenotype are
not anticipated to have cognitive im-
provement or stabilization with ERT.
Idursulfase treatment of a patient with
a severe phenotype may significantly
improve his or her quality of life, but
the long-term benefits of ERT in older
patients with severe neurologic im-
pairment remain to be determined.
GENOTYPE-PHENOTYPE
CORRELATION
Determining the relationship between
genotype and phenotype in Hunter syn-
drome could help identify patients
with the severe phenotype and, thus,
direct the course of management and
treatment of individual patients. Unfor-
tunately, this approach has been of lim-
ited utility for several reasons. First,
most mutations are private and occur in
a single family. Second, no standardized
method exists for grading the severity of
the phenotype. Finally, it must be under-
stood that other factors may modify the
phenotypic expression of even simple
mendelian disorders.88
Complete deletions of the I2S gene (IDS)
always result in a severe phenotype,
as do complex rearrangements of
IDS. Several missense mutations have
been associated with a severe pheno-
type (p.R468Q,8994 p.R468W,9599 and
p.S333L96,100), although each one has
been reported in patients with an in-
termediate or attenuated phenotypes.
Similarly, the mutation c.1122C3T
(which creates an alternate splice site
with the loss of 20 amino acids) is pri-
marily associated with the attenuated
phenotype.92,93,96,98
CONCLUSIONS
Hunter syndrome is a rare, X-linked dis-
order that affects multiple organs and
systems; therefore, its management re-
quires a multidisciplinary approach.
Pediatric subspecialties (ie, otorhino-
laryngology, neurosurgery, orthopedics,
cardiology, anesthesiology, pulmonol-
ogy, neurodevelopment) will all play a
role, as will specialty areas suchas phys-
iotherapy, audiology, and others. Any
surgical procedures that require gen-
eral anesthesia should be performed in
a medicalcenter thathas extensive expe-
rience in handling children with Hunter
syndrome. Although ERT offers the po-
tential to treat patients with mucopo-
lysaccharidosis II, CNS disease is not ex-
pected to be affected by intravenously
administered ERT. The impact of ERT ini-
tiated early in life on growth and skeletalabnormalities is not known. Regular
monitoring of the clinical status of pa-
tients with mucopolysaccharidosis II re-
ceiving ERT is needed to determine long-
term benefits.
ACKNOWLEDGMENTS
Shire Human Genetic Therapies, Inc
paid for the editorial assistance pro-
vided by Edward Weselcouch, PhD, and
reviewed the manuscript to ensure the
accuracy of all statements regarding
ERT with idursulfase.
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DOI: 10.1542/peds.2008-0999; originally published online November 9, 2009;2009;124;e1228Pediatrics
Schwartz, R. E. Wood and E. Wraith
Molter, M. V. Muoz Rojas, J. W. Ogilvie, R. Parini, U. Ramaswami, M. Scarpa, I. V.Harmatz, W. Kamin, C. Kampmann, S. T. Koseoglu, B. Link, R. A. Martin, D. W.
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