Muenzer 2009 Multidisciplinary Management of Hunter Syndrome

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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

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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

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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

SPECIAL ARTICLES



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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

SPECIAL ARTICLES



10/14

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.

Joseph Muenzer, M. Beck, C. M. Eng, M. L. Escolar, R. Giugliani, N. H. Guffon, P.Multidisciplinary Management of Hunter Syndrome

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Muenzer 2009 Multidisciplinary Management of Hunter Syndrome