Published online February 1, 2008
PEDIATRICS Vol. 121 No. 2 February 2008, pp. e377-e386 (doi:10.1542/peds.2007-1350)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Martin, R.
Right arrow Articles by Muenzer, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Martin, R.
Right arrow Articles by Muenzer, J.
Related Collections
Right arrow Genetics & Dysmorphology
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

REVIEW ARTICLE

Recognition and Diagnosis of Mucopolysaccharidosis II (Hunter Syndrome)

Rick Martin, MDa, Michael Beck, MDb, Christine Eng, MDc, Roberto Giugliani, MD, PhDd, Paul Harmatz, MDe, Verónica Muñoz, MDd and Joseph Muenzer, MD, PhDf

a Department of Pediatrics, St Louis University, St Louis, Missouri
b Children's Hospital, University of Mainz, Mainz, Germany
c Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
d Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
e Research Center, Children's Hospital of Oakland, Oakland, California
f Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina


   ABSTRACT
TOP
 ABSTRACT
HUNTER SYNDROME
 HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 
Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyzes a step in the catabolism of glycosaminoglycans. In patients with mucopolysaccharidosis II, glycosaminoglycans accumulate within tissues and organs, contributing to the signs and symptoms of the disease. Mucopolysaccharidosis II affects multiple organs and physiologic systems and has a variable age of onset and variable rate of progression. Common presenting features include excess urinary glycosaminoglycan excretion, facial dysmorphism, organomegaly, joint stiffness and contractures, pulmonary dysfunction, myocardial enlargement and valvular dysfunction, and neurologic involvement. In patients with neurologic involvement, intelligence is impaired, and death usually occurs in the second decade of life, whereas those patients with minimal or no neurologic involvement may survive into adulthood with normal intellectual development. Enzyme replacement therapy has emerged as a new treatment for mucopolysaccharidosis disorders, including Hunter syndrome. The purpose of this report is to provide a concise review of mucopolysaccharidosis II for practitioners with the hope that such information will help identify affected boys earlier in the course of their disease.

Key Words: lysosomal storage disease

Abbreviations: MPS—mucopolysaccharidosis • GAG—glycosaminoglycan • I2S—iduronate-2-sulfatase • EOW—every other week

Hunter syndrome is a mucopolysaccharidosis (MPS) that is 1 of a family of inherited disorders of glycosaminoglycan (GAG) catabolism.1 Each MPS is caused by a deficiency in the activity of 1 of the distinct lysosomal enzymes required for the stepwise degradation of the GAGs dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate.1 In affected patients, undegraded or partially degraded GAG accumulates within lysosomes and is excreted in excess in the urine.2 It is the accumulation, or storage, of GAG within lysosomes that contributes to the signs and symptoms of these disorders. MPS is chronic and progressive. A newborn infant may appear normal, and yet, within a few years progress into a physically abnormal and mentally impaired individual. MPS is rare and occurs in people of all ethnicities, with an estimated prevalence of between 3.4 and 4.5 per 100000 births (Table 1). 3–9


View this table:
[in this window]
[in a new window]

  		TABLE 1 Incidence of MPSs Per 100 000 Births

 

   HUNTER SYNDROME
TOP
 ABSTRACT
 HUNTER SYNDROME
HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 
The biochemical cause of Hunter syndrome is a deficiency in the activity of the lysosomal enzyme, iduronate-2-sulfatase (I2S),10 which catalyzes the removal of the sulfate group at the 2 position of L-iduronic acid in dermatan sulfate and heparan sulfate.1 Hunter syndrome, or MPS II, is 1 of the most common MPSs, with an estimated prevalence of ~1 in 170000 male live births (Table 1).3,4,6,11 Its prevalence among Ashkenazi and Oriental or Sephardic Jews living in Israel is reported to be approximately twice that reported in other populations.12–14


   HISTORY
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 
The first description of an MPS disease was made by Charles Hunter,15 a Canadian physician who, in 1917, described a rare disease in 2 brothers. His original description of the physical features of this disease, which would eventually bear his name, was nearly complete, even by modern standards. The 2 brothers, 8 and 10 years of age, respectively, were undersized with large heads and dysmorphic facial features. Their abdomens were distended, which was the result of gross enlargement of the spleen and liver. The range of motion in all joints of the extremities was limited,and their arms and legs remained slightly flexed; neither boy could raise his hands above his head. Their gait was described as clumsy and stiff. Respiration was noisy, and during sleep, it became labored, uneasy, and was characterized by heavy snoring. The older boy had an enlarged heart with distinct diastolic and systolic murmurs. Both boys were described as being of normal intelligence, although hearing was impaired in both of them. Several years later, Gertrud Hurler16 reported on 2 unrelated girls with features similar to those described by Hunter, with the addition of mental impairment, corneal clouding, and gibbus formation. These 2 similar diseases were considered 1 and were often referred to as Hurler-Hunter syndrome until the elucidation of the biochemical basis of each ~50 years later.17

In 1952, Brante18 was the first to use the term "mucopolysaccharidosis" after identifying a chondroitin sulfate-like material from the liver of patients with Hurler syndrome, and 5 years later, Dorfman and Lorincz2 first demonstrated the excess urinary excretion of dermatan sulfate and heparan sulfate in an individual with Hurler syndrome. The excess tissue storage of these GAGs was originally thought to be caused by a metabolic defect that resulted in overproduction; however, in 1968, Fatantoni et al19 showed that the accumulation of GAG in skin fibroblasts cultured from patients with Hunter and Hurler syndrome was a result of reduced degradation and not caused by excessive synthesis or decreased cellular secretion. Additional experimental work by this group showed that the metabolic defect in fibroblasts cultured for patients with Hunter syndrome could be corrected by a factor secreted by fibroblasts cultured from patients with Hurler syndrome. Similarly, the metabolic defect in fibroblasts from patients with Hurler syndrome would be corrected by a factor secreted from cells cultured from patients with Hunter syndrome. Within a year, the Hunter-corrective factor was isolated from normal human urine and shown to be a protein20 and, shortly thereafter, identified as sulfoiduronate sulfatase, now known as I2S.10 The amino acid sequence of I2S was deduced from its complementary DNA clone by Wilson et al.21 The protein consists of 550 amino acids, including a 25-amino acid amino-terminal signal sequence, and has 7 potential N-glycosylation sites.


   GENETICS
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
 GENETICS
CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 
Hunter syndrome is an X-linked, recessive inherited disease that affects males nearly exclusively.1 The I2S gene (IDS) is located at Xq28, and >300 mutations have been described. These mutations include whole and partial deletions and large gene rearrangements, which may be responsible for up to 25% of cases of Hunter syndrome,22 and point mutations and other changes (eg, deletions, insertions, small duplications).22–28 Of interest is the presence of an IDS pseudogene (I2S2, IDSP1) located on the telomeric side of the I2S gene within 80 kb.29 I2S2 contains sequences that are homologous to exons 2 and 3, although in reverse sequence, and to introns 2, 3, and 7 of the I2S gene. Homologous chromosomal recombination events that involve the IDS and I2S2 loci are reported to be found in 13% of patients with Hunter syndrome.30 No surveys of the frequency of de novo IDS mutational events have been published, although such mutations have been documented (eg, Lin et al31). Reproducing males are rare; therefore, the de novo mutation rate likely approaches 0.33, as calculated by standard Bayesian methods for all male reproductive X-linked lethal conditions.

Genotype-Phenotype
The rarity of Hunter syndrome and the fact that most mutations are private makes evaluation of the genotype-phenotype relationship difficult; however, the complete absence of functional enzyme caused by total or partial gene deletion or by gene/pseudogene rearrangement seems to result in the severe phenotype.32,33 Point mutations that result in the change of single amino acids in the enzyme have been reported to be associated with a wide range of phenotypes, spanning the entire spectrum from severe to attenuated.22,26,33,34 Deletions extending beyond the IDS locus may result in symptoms atypical of Hunter syndrome because of the deletion of additional genes. Such mutations have been associated with a severe phenotype in combination with ptosis and seizures.25 It is important to realize that the same IDS mutation may be associated with different phenotypes. For example, at least 2 sets of brothers have been described in which 1 brother exhibits a severe phenotype and 2 other brothers exhibit a relatively attenuated phenotype.35 Although complete absence of I2S activity is invariably associated with a severe phenotype, the converse is not true. Neither the amount of I2S nor its activity, as determined by routine diagnostic assays, correlates with phenotype severity in patients with Hunter syndrome.36

Carriers
Females carrying a mutation in 1 IDS allele are usually asymptomatic. Enzyme activity cannot be used to identify female carriers because, although on average I2S activity in female carriers is ~50% of that seen in nonaffected individuals, considerable overlap exists.31 The finding of the IDS mutation, usually previously identified in an affected male relative, is needed to confirm carrier status, although sometimes the pedigree analysis alone could give this information (Fig 1). Identification of the mutation in a potential carrier is very important for genetic counseling and prenatal diagnosis, because many centers do not perform prenatal diagnosis by measurement of enzyme activity in fetal samples.


Figure 1
View larger version (75K):
[in this window]
[in a new window]

  		FIGURE 1 A, Pedigree of the families shown in B. Open squares represent unaffected males. Males with Hunter syndrome are shown as filled squares. Carrier females are presented as open circles containing a black dot. A circle with a question mark indicates that the carrier status of the female is unknown. The numbers refer to the subjects in B. B, A South American family with Hunter syndrome. The white rectangles show the affected males in the sibship, and the white ovals show the confirmed female carriers. The carrier status of all other females is unknown at this time. The numbers correspond to the symbols on the pedigree in A.

 
Hunter Syndrome Recognized in Females
Although it is X linked, Hunter syndrome has been well documented in a small number of females.37–39 In 1 case, an 11-year-old girl with growth retardation and hepatomegaly, but no other signs or symptoms of Hunter syndrome, was found to be homozygous for a mutation that resulted in a mild form of the disease in previously undiagnosed male family members.39 The most common mechanism of expression in females is skewed X-chromosome inactivation of the paternal gene.37,39,40 X-chromosome inactivation occurs during development of the female embryo and is usually a random event that results in the inactivation of the paternal or maternal X chromosome in a somatic cell. Because it is a random event, most females have a mosaic expression of approximately equal proportions of maternal and paternal X-chromosome alleles. However, in some female individuals, the inactivation is nonrandom and is skewed toward expression of the paternal X-chromosome alleles. At least 1 instance of Hunter syndrome in a female was the result of a de novo mutation on the paternal X-chromosome coupled with skewed X-chromosome inactivation.39 The severity of the phenotype seems to depend on the individual mutation and the degree of skewing of X-chromosome inactivation.


   CLINICAL ASPECTS OF HUNTER SYNDROME
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 
Hunter syndrome is a disease with multiorgan and multisystem involvement that has a variable age of onset and a variable rate of progression.1 The phenotypic expression spans a wide spectrum of clinical severity. In its severe form, clinical features appear between 2 and 4 years of age.1 In these cases, progressive neurologic involvement is prominent and progresses to severe mental impairment. Death usually occurs in the first or second decade of life, usually because of obstructive airway disease and/or cardiac failure associated with loss of neurologic function.1,41 At the opposite end of the spectrum, clinical signs and symptoms have a slightly later onset, but neurologic dysfunction is minimal. These patients have normal intelligence and survive into adulthood.1,42,43 The severe phenotype may be up to 3 times more prevalent than the attenuated phenotype,44 but no comprehensive studies have been reported. The signs and symptoms of Hunter syndrome are thought to be mainly results of accumulation of GAG within tissues and organs.

General Appearance and Skeletal Abnormalities
The appearance and skeletal abnormalities are similar regardless of the severity of the phenotype. Patients typically appear normal at birth. The most common presenting feature is a coarsening of facial features, which becomes apparent between 2 and 4 years of age (Fig 2). 41,42 The patients tend to have broad noses with flared nostrils, prominent supraorbital ridges, and large jowls. The lips may be thick, and they may have an enlarged protruding tongue. The head is of large circumference throughout life.41,42 Patients tend to be tall for their age until ~4 or 5 years of age, when they begin to lag behind unaffected boys.41,42 Mobility is restricted because of joint stiffness and contractures.


Figure 2
View larger version (54K):
[in this window]
[in a new window]

  		FIGURE 2 A series of photographs showing the progression of the characteristic facial features of Hunter syndrome. The ages of the boy from left to right are 6 months and 5, 9, and 30 years.

 
The skeletal findings of Hunter syndrome, along with other MPS diseases, are collectively known as dysostosis multiplex, and most were described by Hunter in his original report.15 Radiographic examination reveals abnormal thickness of all bones, and irregular epiphyseal ossification in the joints of the hand, shoulder, and elbow.15 The hands are reported to take on a claw-like appearance,42 and, in combination with carpal tunnel syndrome,45 loss of hand function can result.46 The ribs are thickened and have an unusual shape (Fig 3), and clavicles can be increased in bulk.15 The lateral surfaces of the vertebral bodies are irregularly notched in appearance. These skeletal changes result in profound loss of joint range of motion and restricted mobility. Patients with Hunter syndrome often walk on their toes because of joint stiffness and tight heel cords. Many of these abnormalities are evident in the patient shown in Fig 4.


Figure 3
View larger version (98K):
[in this window]
[in a new window]

  		FIGURE 3 Chest radiograph of a patient with Hunter syndrome. Note the unusual shape of the ribs. (Photo courtesy of Wolfgang Kamin.)

 

Figure 4
View larger version (48K):
[in this window]
[in a new window]

  		FIGURE 4 Fourteen-year-old boy with Hunter syndrome. Note the coarse facial features (A), "clubbing" of the fingers (B), and the stiffness in shoulder joint (C), which restricts his ability to raise his arms.

 
Eyes
Corneal clouding is not a feature of Hunter syndrome, but slit-lamp examination may reveal discrete corneal lesions that do not affect vision.1,47 Retinal dysfunction is evident by using electroretinography. Ophthalmoscopy has revealed bilateral pigmentary changes and the loss of field of vision in some patients.48 This loss of vision is underrecognized in Hunter syndrome, for which screening should be performed on a regular basis. Other findings include disk swelling and scleral thickening, which may cause optic nerve compression.1,47,49 Glaucoma is not a common finding in Hunter syndrome.

Ear, Nose, and Throat
Frequent upper respiratory infections occur in most patients with Hunter syndrome. The enlarged tongue, hypertrophic adenoids and tonsils, and skeletal changes in the jaw and neck that limit the opening of the mouth50,51 all contribute to respiratory problems, as noted in "Respiratory System" Most patients have recurrent ear infections, and nearly all of them experience progressive hearing loss.41,42,52 The hearing loss is caused by both conductive and sensorineural deficits.41,52 Middle-ear effusion is recognized as an important contributor to hearing loss in patients with Hunter syndrome, and evidence exists that suggests that tympanomastoid abnormalities may also contribute to conductive hearing loss.52 Sensorineural hearing deficit has been commonly reported. The teeth have been described as peg shaped, and are irregularly shaped, and gingival tissue is hyperplastic and hypertrophic.50,51

Gastrointestinal Involvement
Because of GAG storage, the liver and spleen of patients with Hunter syndrome are often enlarged, resulting in abdominal distention. In a recent study of 96 patients with attenuated Hunter syndrome between 5 and 31 years of age, hepatomegaly (as determined by abdominal MRI) was present in 76% of study participants, whereas the majority of patients had normal spleen volume.53 Other studies have reported a prevalence between of 57% and 90% of an enlarged liver or spleen.42,54 Umbilical hernia is commonly observed, and inguinal hernias are reported in ~60% of male patients.41,42 Chronic diarrhea is commonly seen in patients with neurologic involvement, but is not common in the more mildly affected patients.44

Respiratory System
Progressive airway obstruction is a common finding in Hunter syndrome,55,56 and complications are a common cause of death. Contributing factors include narrowed and abnormally shaped trachea and bronchi,56,57 enlarged tongue, hypertrophic adenoids and tonsils, large epiglottis,42 frequent upper respiratory infections, recurrent pneumonia, and thick nasal and tracheal secretions.58 Restricted movement of the temporomandibular joints, stiffness of the chest wall, and abdominal distention also inhibit normal breathing.42,59 A common complication of the airway obstruction seen in Hunter syndrome is sleep apnea.57,60,61 Airway involvement is progressive, first becoming apparent in the upper airways, and gradually involving the lower airways. Tracheobronchomalacia, a weakness of the tracheal or bronchial walls, is commonly observed and can lead to acute airway obstruction or collapse.58 Permanent tracheostomy, continuous positive airway pressure, and/or ventilation are often used to maintain airway patency.62

Cardiovascular System
Cardiac disease is present in almost all patients with Hunter syndrome and is a major cause of death in this population.41,42 Signs and symptoms of heart disease present as early as 5 years of age.42 Valvular disease, which leads to right and left ventricular hypertrophy and heart failure, are commonly reported.42,62 In a study of 27 boys with Hunter syndrome between the ages of 2 and 11 years, only 5 had normal echocardiographic and/or autopsy results; 19 had morphologic changes in the mitral valve, 5 had morphologic changes in the aortic valve, and 10 had clinical signs of heart disease.63 In a similar study, abnormal mitral valves were found in 11 of 18 patients.64

Skin
The skin of patients with Hunter syndrome may be thickened and inelastic.65 Patients with Hunter syndrome may have a distinctive skin lesion, which is described as ivory-white papules that are 2 to 10 mm in diameter, often coalescing to form ridges.65–68 The pebbling of skin is not seen in all cases, and although it is thought to be characteristic of Hunter syndrome,65 grouped papules have been reported in at least 1 patient with MPS I.69 In 1 reported case, these papules were the only outward sign of Hunter syndrome.67

Neurologic Involvement
Neurologic involvement is initially suspected by globally delayed developmental milestones; for example, the ability to sit unsupported, ability to walk, and ability to speak all occur later in patients with severe MPS II than in unaffected children.41,42 The mental impairment is profound and progressive, with development regression reported to begin at mean and model ages of 8 and 6.5 years, respectively.41 The common finding of moderate-to-severe communicating hydrocephalus may exacerbate the deterioration of the central nervous system.35,46,70 The elevated intracranial pressure may occasionally cause optic disk swelling and optic nerve atrophy.47 In severely affected patients with Hunter syndrome, seizures are reported in more than half who reach the age of 10 years.41 Death usually occurs in these severely affected patients in the first or second decade of life, usually because of obstructive pulmonary disease, cardiovascular disease, neurologic problems, or a combination of these and other factors.1

At the opposite end of the phenotype spectrum are patients with minimal-to-no neurologic involvement. Although the patients experience all the somatic complications of Hunter syndrome, they retain normal or nearly normal intelligence.42 Seizures are uncommonly reported in patients with this attenuated phenotype.42 These patients typically survive into adulthood, although death may occur in the late-teenage years or early adulthood, with airway obstruction and cardiac failure cited as contributing factors to death.1

Carpal tunnel syndrome, which is the most common entrapment neuropathy in adults, is rare in unaffected children. However, in children with MPS disorders, it is common and underrecognized.45 In 1 study of 7 consecutive patients with Hunter syndrome, all patients >2 years of age had signs of carpal tunnel compression with rapid progression of clinical signs and symptoms.71 Tunnel decompression surgery results in clinical improvement in most patients.45,71

Spinal cord compression may occur because of narrowing of the spinal canal1 and instability of the atlantoaxial joint, and special care must be taken to prevent dislocation of the atlantoaxial joint during general anesthesia and surgery.62

Miscellaneous
Bladder obstruction72 and neurogenic urinary retention73 have been reported. Severe behavioral disturbances, such as overactivity, obstinacy, and aggression, are commonly seen in severely affected patients with Hunter syndrome, but are not typically observed in those with the attenuated phenotype.74 It is estimated that approximately half of the severely affected patients become toilet trained, but most, if not all, will lose the ability as the disease progresses.


   DIAGNOSIS OF HUNTER SYNDROME
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 
The signs and symptoms described are not specific to Hunter syndrome, and not all of them will be present in each patient. Thus, in the absence of a family history of Hunter syndrome, the delay between presentation of signs and symptoms and the ultimate diagnosis may be substantial. Few if any signs and symptoms of Hunter syndrome will be present at birth and will only begin to emerge after several years. The initial suspicion of Hunter syndrome is often based on facial features and is made by the physician/health care provider during an examination for other issues.

Urine GAG Excretion
Analysis of urine GAG levels can be used to confirm the suspicion of MPS. As in almost all cases of MPS, the total urinary GAG level is increased. The presence of excess dermatan sulfate and heparan sulfate in urine is evidence that MPS I, MPS II, or MPS VII is present.1 It is not diagnostic of Hunter syndrome, so additional tests must be performed. A negative urine GAG test does not necessarily rule out a diagnosis of Hunter syndrome, because false-negative results can occur as a result of a lack of sensitivity of the testing method.

Enzyme Activity
I2S is present in all cells (except mature red blood cells); therefore, enzyme activity can be measured in a variety of cells and body fluids. Assays based on cultured fibroblasts, leukocytes, plasma, or serum are commonly used; the choice depends on the preference of the testing facility. Methods that are based on the analysis of dried blood spots have been described recently75,76 and may be used primarily for screening purposes, especially in areas where the transport of cells or serum samples is unreliable. Absent or low I2S activity in males is diagnostic of Hunter syndrome, provided that another sulfatase is measured and it has normal activity, which would rule out multiple sulfatase deficiency. Absolute enzyme activity cannot be used to predict the severity of the phenotype. Enzyme activity cannot be used to identify female carriers because, although on average I2S activity in female carriers is ~50% of that seen in nonaffected individuals, considerable overlap exists.31 Mutation analysis is necessary to confirm carrier status in females.

Gene Analysis
Mutation analysis may be used to confirm Hunter syndrome in males. Gene analysis is the only secure way to identify female carriers and could be used for prenatal diagnosis, increasing the importance of being able to identify the mutation in every family. Mutations that result in complete absence of the enzyme or its activity are commonly associated with Hunter syndrome with neurologic involvement.

Prenatal Diagnosis
Enzyme activity assays may be conducted on cells that are cultured from amniotic fluid or in chorionic villus biopsy tissue,77–80 and even in fetal blood, but this test is available in only a few laboratories worldwide. In addition, prenatal diagnosis can be performed by using molecular analysis if the family specific mutation is known.81,82 It is important to realize that these tests may not be widely available.

Differential Diagnosis
Analysis of urinary GAG composition may be used to discriminate among the different MPS disorders (Table 2). 1 However, it cannot distinguish between MPS I and MPS II, and it cannot be used to discriminate between subtypes of individual MPSs. Although the constellation of signs and symptoms associated with each MPS may be diagnostic, with the advent of specific enzyme replacement therapies for several of these diseases,53,83,84 early and accurate diagnosis is essential to ensure appropriate treatment. Thus, enzyme analysis and genetic testing are needed to confirm the diagnosis.


View this table:
[in this window]
[in a new window]

  		TABLE 2 Urinary GAG Composition in the MPSs

 
Other storage disorders present a phenotype similar to MPS, including mucolipidosis I, II, and III, mannosidosis, fucosidosis, and multiple sulfatase deficiency.17,85,86 Other conditions characterized by macrocephaly and/or organomegaly that are coupled with developmental delay may also be confused with MPS.87,88


   MANAGEMENT AND TREATMENT
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
FUTURE PROSPECTS
 REFERENCES
 
Until recently, the management of Hunter syndrome has been palliative and focused on the treatment of signs and symptoms. Historically, methods of replacing the enzyme missing in Hunter syndrome have included bone marrow transplantation,89 human amnion membrane implantation,90 fibroblast transplantation,91 serum or plasma infusion,92 white blood cell infusions,93 gene therapy,94–96 intraperitoneal implantation of myoblasts overexpressing I2S,97 and enzyme replacement therapy.53,98 Of these strategies, only intravenous enzyme replacement therapy with recombinant human I2S has been tested in randomized clinical trials. The results of these trials are discussed briefly below in "Bone Marrow Transplant."53,98

Bone Marrow Transplant
Hematopoietic stem cell transplantation via umbilical cord blood transplantation or bone marrow transplantation has been proposed as a way of providing sufficient enzyme activity to slow or stop the progression of the disease.99–101 However, only case reports, rather than systematic clinical trials, have been presented, and the results have been disappointing.102

Enzyme Replacement Therapy
Idursulfase (Elaprase, Shire Human Genetic Therapies, Inc, Cambridge, MA) is a recombinant human I2S produced in a human cell line that was recently approved in the United States and the European Union for the treatment of Hunter syndrome. This approval was based on the results of a randomized, placebo-controlled, double-blind clinical trial that showed a clinical benefit in patients treated with idursulfase compared with patients treated with placebo.53 In this study, 96 patients were randomly assigned to placebo or a 0.5 mg/kg idursulfase dosage that was infused either weekly or every other week (EOW). After 1 year of treatment, patients in the weekly idursulfase group demonstrated a statistically significant improvement rate compared with placebo of the primary end point, which is a composite consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity on the basis of the sum of ranks of change from baseline. The EOW group also showed a statistically significant improvement compared with placebo, but the magnitude of the difference was approximately half of that seen in the weekly group. In addition, urine GAG excretion and liver and spleen volumes were significantly reduced from baseline by both idursulfase dosing regimens. Idursulfase was generally well tolerated, and the majority of treatment-emergent adverse events were consistent with the natural history of untreated Hunter syndrome. The most common treatment-related adverse events were infusion related. On the basis of the larger clinical response in the weekly group compared with the EOW group, idursulfase was approved for the treatment of MPS II in both the United States and European Union at a dose of 0.5 mg/kg weekly.


   FUTURE PROSPECTS
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
REFERENCES
 
Gene Therapy
In vivo gene transfer has been tested as a therapeutic approach for the treatment of Hunter syndrome, but only in preclinical animal experiments,94–96 and the results have been encouraging. For example, Cardone et al94 reported that I2S gene transfer in knockout mice lacking the I2S gene completely cleared GAG from all tissues and organs that were evaluated. A single patient has been treated with autologous peripheral blood lymphocytes transduced with a retroviral vector containing the I2S gene, but no evidence of clinical benefit was observed (Chester Whitley, MD, personal verbal communication, 2007).

Newborn Screening
Therapies are now available for several lysosomal storage diseases and, because of the progressive nature of each of these diseases, early initiation of therapy is likely to provide greater benefit than therapy that was started only after signs and symptoms have emerged. Although the incidence of these genetic diseases is quite low, their combined incidence is ~1 in 7000 births, which is in the range considered to be feasible for a newborn screening program.103 A 2-tiered approach, with an initial screen identifying the lysosomal protein markers LAMP-1 and saposin C (or other protein markers) followed by evaluation of lysosomal substrate in affected individuals, has been described,104 and a recent study suggested that such a strategy may be successful in identifying Hunter syndrome in newborns.105 A recently described tandem mass spectrometry method for assaying I2S activity in dried blood spots can be multiplexed with tandem mass spectrometry assays for other lysosomal storage diseases, offering the advantage of using a single instrument run to simultaneously screen for several enzyme deficiencies from a single dried blood spot.106 The measurement of I2S activity is now possible by using the same dried blood spot sample collected for screening for phenylketonuria, congenital hypothyroidism, and other diseases.75,76


   ACKNOWLEDGMENTS
 
Shire HGT paid for the editorial assistance provided by Edward Weselcouch, PhD, and reviewed the manuscript to ensure the accuracy of all statements regarding company-sponsored clinical studies.


   FOOTNOTES
 
Accepted Jul 5, 2007.

Address correspondence to Rick Martin, MD, St Louis University, 1465 S Grand Blvd, St Louis, MO 63104. E-mail: rmarti41{at}slu.edu

Financial Disclosure: Drs Martin, Beck, Harmatz, Eng, Giugliani, Muñoz, Muenzer have received honoraria, travel grants, or research grants from Shire Human Genetic Therapies.


   REFERENCES
TOP
 ABSTRACT
 HUNTER SYNDROME
 HISTORY
 GENETICS
 CLINICAL ASPECTS OF HUNTER...
 DIAGNOSIS OF HUNTER SYNDROME
 MANAGEMENT AND TREATMENT
 FUTURE PROSPECTS
 REFERENCES
 

  1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, ed. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3421–3452
  2. Dorfman A, Lorincz AE. Occurence of urinary acid mucoploysaccharides in the Hurler syndrome. Proc Natl Acad Sci USA 1957;43 (6):443 –446[Free Full Text]
  3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28 (6):1011 –1017[CrossRef][Web of Science][Medline]
  4. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in the Netherlands. Hum Genet. 1999;105(1–2) :151 –156
  5. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281 (3):249 –254[Abstract/Free Full Text]
  6. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997;101 (3):355 –358[CrossRef][Web of Science][Medline]
  7. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet. 2003;123 :310 –313
  8. Lowry RB, Renwick DH. Relative frequency of the Hurler and Hunter syndromes. N Engl J Med. 1971;284 :221 –222[Web of Science][Medline]
  9. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics. 2000;105 (1). Available at: www.pediatrics.org/cgi/content/full/105/1/e10
  10. Bach G, Eisenberg F Jr, Cantz M, Neufeld EF. The defect in the Hunter syndrome: deficiency of sulfoiduronate sulfatase. Proc Natl Acad Sci USA. 1973;70 (7):2134 –2138[Abstract/Free Full Text]
  11. Young ID, Harper PS. Incidence of Hunter's syndrome. Hum Genet. 1982;60 (4):391 –392[CrossRef][Web of Science][Medline]
  12. Zlotogora J, Schaap T, Zeigler M, Bach G. Hunter syndrome in Jews in Israel: further evidence for prenatal selection favoring the Hunter allele. Hum Genet. 1991;86 (5):531 –533[Web of Science][Medline]
  13. Schaap T, Bach G. Incidence of mucopolysaccharidoses in Israel: is Hunter disease a "Jewish disease"? Hum Genet. 1980;56 :221 –223[Medline]
  14. Ben-Simon-Schiff E, Zlotogora J, Abeliovich D, Zeigler M, Bach G. Hunter syndrome among Jews in Israel. Biomed Pharmacother. 1994;48(8–9) :381 –384
  15. Hunter C. A rare disease in two brothers. Proc R Soc Med. 1917;10 :104 –116
  16. Hurler G. A type of multiple degeneration that mainly affects the skeletal system [in German]. Z Kinderheilkd. 1919;24(5-6) :220 –234
  17. Lorincz AE. The mucopolysaccharidoses: advances in understanding and treatment. Pediatr Ann. 1978;7 (2):104 –122[Web of Science][Medline]
  18. Brante G. Gargoylism: a mucopolysaccharidosis. Scand J Clin Lab Invest. 1952;4 (1):43 –46[Web of Science][Medline]
  19. Fratantoni JC, Hall CW, Neufeld EF. The defect in Hurler's and Hunter's syndromes: faulty degradation of mucopolysaccharide. Proc Natl Acad Sci USA. 1968;60 (2):699 –706[Free Full Text]
  20. Cantz M, Chrambach A, Bach G, Neufeld EF. The Hunter corrective factor: purification and preliminary characterization. J Biol Chem. 1972;247(17) :5456 –5462
  21. Wilson PJ, Morris CP, Anson DS, et al. Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient. Proc Natl Acad Sci USA. 1990;87(21) :8531 –8535
  22. Li P, Bellows AB, Thompson JN. Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome). J Med Genet. 1999;36 (1):21 –27[Abstract/Free Full Text]
  23. Lissens W, Seneca S, Liebaers I. Molecular analysis in 23 Hunter disease families. J Inherit Metab Dis. 1997;20 (3):453 –456[CrossRef][Web of Science][Medline]
  24. Kim CH, Hwang HZ, Song SM, et al. Mutational spectrum of the iduronate 2 sulfatase gene in 25 unrelated Korean Hunter syndrome patients: identification of 13 novel mutations. Hum Mutat. 2003;21 (4):449 –450[Medline]
  25. Timms KM, Bondeson ML, Ansari-Lari MA, et al. Molecular and phenotypic variation in patients with severe Hunter syndrome. Hum Mol Genet. 1997;6 (3):479 –486[Abstract/Free Full Text]
  26. Vafiadaki E, Cooper A, Heptinstall LE, Hatton CE, Thornley M, Wraith JE. Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease). Arch Dis Child. 1998;79 (3):237 –241[Abstract/Free Full Text]
  27. Wilson PJ, Suthers GK, Callen DF, et al. Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome. Hum Genet. 1991;86 (5):505 –508[Web of Science][Medline]
  28. Froissart R, Maire I, Millat G, et al. Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin Genet. 1998;53 (5):362 –368[CrossRef][Web of Science][Medline]
  29. Bondeson ML, Malmgren H, Dahl N, Carlberg BM, Pettersson U. Presence of an IDS-related locus (IDS2) in Xq28 complicates the mutational analysis of Hunter syndrome. Eur J Hum Genet. 1995;3 (4):219 –227[Web of Science][Medline]
  30. Bondeson ML, Dahl N, Malmgren H, et al. Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. Hum Mol Genet. 1995;4 (4):615 –621[Abstract/Free Full Text]
  31. Lin SP, Chang JH, Lee-Chen GJ, Lin DS, Lin HY, Chuang CK. Detection of Hunter syndrome (mucopolysaccharidosis type II) in Taiwanese: biochemical and linkage studies of the iduronate-2-sulfatase gene defects in MPS II patients and carriers. Clin Chim Acta. 2006;369 (1):29 –34[CrossRef][Web of Science][Medline]
  32. Froissart R, Moreira da Silva I, Guffon N, Bozon D, Maire I. Mucopolysaccharidosis type II: genotype/phenotype aspects. Acta Paediatr Suppl. 2002;91(439) :82 –87
  33. Gort L, Chabas A, Coll MJ. Hunter disease in the Spanish population: molecular analysis in 31 families. J Inherit Metab Dis. 1998;21 (6):655 –661[CrossRef][Web of Science][Medline]
  34. Moreira da Silva I, Froissart R, Marques dos Santos H, Caseiro C, Maire I, Bozon D. Molecular basis of mucopolysaccharidosis type II in Portugal: identification of four novel mutations. Clin Genet. 2001;60 (4):316 –318[CrossRef][Web of Science][Medline]
  35. Yatziv S, Erickson RP, Epstein CJ. Mild and severe Hunter syndrome (MPS II) within the same sibships. Clin Genet. 1977;11 (5):319 –326[Web of Science][Medline]
  36. Parkinson EJ, Muller V, Hopwood JJ, Brooks DA. Iduronate-2-sulphatase protein detection in plasma from mucopolysaccharidosis type II patients. Mol Genet Metab. 2004;81 (1):58 –64[Web of Science][Medline]
  37. Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA. Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr Neurol. 2005;32 (4):270 –272[CrossRef][Web of Science][Medline]
  38. Sukegawa K, Matsuzaki T, Fukuda S, et al. Brother/sister siblings affected with Hunter disease: evidence for skewed X chromosome inactivation. Clin Genet. 1998;53 (2):96 –101[Web of Science][Medline]
  39. Cudry S, Tigaud I, Froissart R, Bonnet V, Maire I, Bozon D. MPS II in females: molecular basis of two different cases. J Med Genet. 2000;37(10) :E29
  40. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961;190 :372 –373[CrossRef][Medline]
  41. Young ID, Harper PS. The natural history of the severe form of Hunter's syndrome: a study based on 52 cases. Dev Med Child Neurol. 1983;25 (4):481 –489[Web of Science][Medline]
  42. Young ID, Harper PS. Mild form of Hunter's syndrome: clinical delineation based on 31 cases. Arch Dis Child. 1982;57(11) :828 –836
  43. Lichtenstein JR, Bilbrey GL, McKusick VA. Clinical and probable genetic heterogeneity within mucopolysaccharidosis I: report of a family with a mild form. Johns Hopkins Med J. 1972;131 (6):425 –435[Web of Science][Medline]
  44. Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of Hunter's syndrome 2: differences between the mild and severe forms. J Med Genet. 1982;19 (6):408 –411[Abstract/Free Full Text]
  45. Norman-Taylor F, Fixsen JA, Sharrard WJ. Hunter's syndrome as a cause of childhood carpal tunnel syndrome: a report of three cases. J Pediatr Orthop B. 1995;4 (1):106 –109[Web of Science][Medline]
  46. Muenzer J. Mucopolysaccharidoses. Adv Pediatr. 1986;33 :269 –302[Medline]
  47. Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006;51 (1):1 –17[CrossRef][Web of Science][Medline]
  48. Topping TM, Kenyon KR, Goldberg MF, Maumenee AE. Ultrastructural ocular pathology of Hunter's syndrome: systemic mucopolysaccharidosis type II. Arch Ophthalmol. 1971;86 (2):164 –177[Abstract/Free Full Text]
  49. Anawis MA. Hunter syndrome (MPS II-B): a report of bilateral vitreous floaters and maculopathy. Ophthalmic Genet. 2006;27 (2):71 –72[CrossRef][Web of Science][Medline]
  50. Hopkins R, Watson JA, Jones JH, Walker M. Two cases of Hunter's syndrome: the anaesthetic and operative difficulties in oral surgery. Br J Oral Surg. 1973;10 (3):286 –299[CrossRef][Medline]
  51. Downs AT, Crisp T, Ferretti G. Hunter's syndrome and oral manifestations: a review. Pediatr Dent. 1995;17 (2):98 –100[Medline]
  52. Peck JE. Hearing loss in Hunter's syndrome: mucopolysaccharidosis II. Ear Hear. 1984;5 (4):243 –246[Web of Science][Medline]
  53. Muenzer J, Wraith JE, Beck M, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome) [published correction appears in Genet Med. 2006;8(9):599]. Genet Med. 2006;8 (8):465 –473[Web of Science][Medline]
  54. Pinto LL, Schwartz IV, Puga AC, Vieira TA, Munoz MV, Giugliani R. Prospective study of 11 Brazilian patients with mucopolysaccharidosis II. J Pediatr (Rio J). 2006;82 (4):273 –278[Medline]
  55. Brama I, Gay I, Feinmesser R, Springer C. Upper airway obstruction in Hunter syndrome. Int J Pediatr Otorhinolaryngol. 1986;11 (3):229 –235[CrossRef][Web of Science][Medline]
  56. Shih SL, Lee YJ, Lin SP, Sheu CY, Blickman JG. Airway changes in children with mucopolysaccharidoses. Acta Radiol. 2002;43 (1):40 –43[Web of Science][Medline]
  57. Shapiro J, Strome M, Crocker AC. Airway obstruction and sleep apnea in Hurler and Hunter syndromes. Ann Otol Rhinol Laryngol. 1985;94(5 pt 1) :458 –461
  58. Morehead JM, Parsons DS. Tracheobronchomalacia in Hunter's syndrome. Int J Pediatr Otorhinolaryngol. 1993;26 (3):255 –261[CrossRef][Web of Science][Medline]
  59. Yoskovitch A, Tewfik TL, Brouillette RT, Schloss MD, Der KV. Acute airway obstruction in Hunter syndrome. Int J Pediatr Otorhinolaryngol. 1998;44 (3):273 –278[CrossRef][Web of Science][Medline]
  60. Orliaguet O, Pepin JL, Veale D, Kelkel E, Pinel N, Levy P. Hunter's syndrome and associated sleep apnoea cured by CPAP and surgery. Eur Respir J. 1999;13 (5):1195 –1197[Abstract]
  61. Leighton SE, Papsin B, Vellodi A, Dinwiddie R, Lane R. Disordered breathing during sleep in patients with mucopolysaccharidoses. Int J Pediatr Otorhinolaryngol. 2001;58 (2):127 –138[CrossRef][Web of Science][Medline]
  62. Sasaki CT, Ruiz R, Gaito R Jr, Kirchner JA, Seshi B. Hunter's syndrome: a study in airway obstruction. Laryngoscope. 1987;97(3 pt 1) :280 –285
  63. Dangel JH. Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders: clinical and echocardiographic findings in 64 patients. Eur J Pediatr. 1998;157 (7):534 –538[CrossRef][Web of Science][Medline]
  64. Chen MR, Lin SP, Hwang HK, Yu CH. Cardiovascular changes in mucopolysaccharidoses in Taiwan. Acta Cardiol. 2005;60 (1):51 –53[CrossRef][Web of Science][Medline]
  65. Thappa DM, Singh A, Jaisankar TJ, Rao R, Ratnakar C. Pebbling of the skin: a marker of Hunter's syndrome. Pediatr Dermatol. 1998;15 (5):370 –373[CrossRef][Web of Science][Medline]
  66. Lonergan CL, Payne AR, Wilson WG, Patterson JW, English JC III. What syndrome is this? Hunter syndrome. Pediatr Dermatol. 2004;21 (6):679 –681[CrossRef][Web of Science][Medline]
  67. Demitsu T, Kakurai M, Okubo Y, et al. Skin eruption as the presenting sign of Hunter syndrome IIB. Clin Exp Dermatol. 1999;24 (3):179 –182[CrossRef][Web of Science][Medline]
  68. Panine VV, Hashimoto K. What syndrome is this? Hunter syndrome (mucopolysaccharidosis II). Pediatr Dermatol. 1995;12 (4):370 –372[Web of Science][Medline]
  69. Schiro JA, Mallory SB, Demmer L, Dowton SB, Luke MC. Grouped papules in Hurler-Scheie syndrome. J Am Acad Dermatol. 1996;35(5 pt 2) :868 –870
  70. van Aerde J, Plets C, Van der Hauwaert L. Hydrocephalus in Hunter syndrome. Acta Paediatr Belg. 1981;34 (2):93 –96[Web of Science][Medline]
  71. Haddad FS, Jones DH, Vellodi A, Kane N, Pitt MC. Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses. J Bone Joint Surg Br. 1997;79 (4):576 –582[CrossRef][Medline]
  72. Rigante D, Ferrara P, Ricci R, Antuzzi D, Segni G. Bladder obstruction in Hunter's syndrome. Scand J Urol Nephrol. 1999;33 (3):200 –201[CrossRef][Web of Science][Medline]
  73. Koyama K, Moda Y, Sone A, Tanaka H, Hino Y. Neurogenic bladder in Hunter's syndrome. J Med Genet. 1994;31 (3):257 –258[Abstract/Free Full Text]
  74. Young ID, Harper PS. Psychosocial problems in Hunter's syndrome. Child Care Health Dev. 1981;7 (4):201 –209[CrossRef][Web of Science][Medline]
  75. Dean CJ, Bockmann MR, Hopwood JJ, Brooks DA, Meikle PJ. Detection of mucopolysaccharidosis type II by measurement of iduronate-2-sulfatase in dried blood spots and plasma samples. Clin Chem. 2006;52 (4):643 –649[Abstract/Free Full Text]
  76. Civallero G, Michelin K, de Mari J, et al. Twelve different enzyme assays on dried-blood filter paper samples for detection of patients with selected inherited lysosomal storage diseases. Clin Chim Acta. 2006;372(1–2) :98 –102
  77. Keulemans JL, Sinigerska I, Garritsen VH, et al. Prenatal diagnosis of the Hunter syndrome and the introduction of a new fluorimetric enzyme assay. Prenat Diagn. 2002;22(11) :1016 –1021
  78. Archer IM, Kingston HM, Harper PS. Prenatal diagnosis of Hunter syndrome. Prenat Diagn. 1984;4 (3):195 –200[CrossRef][Web of Science][Medline]
  79. Pannone N, Gatti R, Lombardo C, Di Natale P. Prenatal diagnosis of Hunter syndrome using chorionic villi. Prenat Diagn. 1986;6 (3):207 –210[CrossRef][Web of Science][Medline]
  80. Cooper A, Thornley M, Wraith JE. First-trimester diagnosis of Hunter syndrome: very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus. Prenat Diagn. 1991;11 (9):731 –735[CrossRef][Web of Science][Medline]
  81. Bunge S, Steglich C, Lorenz P, et al. Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis: a 47,XXY male heterozygous for a missense point mutation. Prenat Diagn. 1994;14 (9):777 –780[CrossRef][Web of Science][Medline]
  82. Grosso M, Balzano N, Rippa E, et al. Molecular genetic characterization and prenatal diagnosis in a family with Hunter disease. Biochem Mol Biol Int. 1995;35 (6):1261 –1267[Web of Science][Medline]
  83. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediatr. 2006;148 (4):533 –539[CrossRef][Web of Science][Medline]
  84. Wraith JE, Clarke LA, Beck M, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr. 2004;144 (5):581 –588[CrossRef][Web of Science][Medline]
  85. Wraith JE. The mucopolysaccharidoses: a clinical review and guide to management. Arch Dis Child. 1995;72 (3):263 –267[Free Full Text]
  86. Sardiello M, Annunziata I, Roma G, Ballabio A. Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship. Hum Mol Genet. 2005;14(21) :3203 –3217
  87. Orstavik KH, Stromme P, Ek J, Torvik A, Skjeldal OH. Macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters: a new autosomal recessive syndrome? J Med Genet. 1997;34 :849 –851[Abstract/Free Full Text]
  88. Türkmen S, Gillessen-Kaesbach G, Meinecke P, et al. Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Eur J Hum Genet. 2003;11(11) :858 –865
  89. Bergstrom SK, Quinn JJ, Greenstein R, Ascensao J. Long-term follow-up of a patient transplanted for Hunter's disease type IIB: a case report and literature review. Bone Marrow Transplant. 1994;14 (4):653 –658[Web of Science][Medline]
  90. Muenzer J, Neufeld EF, Constantopoulos G, et al. Attempted enzyme replacement using human amnion membrane implantations in mucopolysaccharidoses. J Inherit Metab Dis. 1992;15 (1):25 –37[CrossRef][Web of Science][Medline]
  91. Dean MF, Stevens RL, Muir H, et al. Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome. J Clin Invest. 1979;63 (1):138 –146[Web of Science][Medline]
  92. Yatziv S, Statter M, Abeliuk P, Meshulam M, Russel A. A therapeutic trial of fresh plasma infusions over a period of 22 months in two siblings with Hunter's syndrome. Isr J Med Sci. 1975;11 (8):802 –808[Web of Science][Medline]
  93. Knudson AG Jr, Di Ferrante N, Curtis JE. Effect of leukocyte transfusion in a child with type II mucopolysaccharidosis. Proc Natl Acad Sci USA. 1971;68 (8):1738 –1741[Abstract/Free Full Text]
  94. Cardone M, Polito VA, Pepe S, et al. Correction of Hunter syndrome in the MPS II mouse model by AAV2/8-mediated gene delivery. Hum Mol Genet. 2006;15 (7):1225 –1236[Abstract/Free Full Text]
  95. Tomanin R, Friso A, Alba S, et al. Nonviral transfer approaches for the gene therapy of mucopolysaccharidosis type II (Hunter syndrome). Acta Paediatr Suppl. 2002;91(439) :100 –104
  96. Stroncek DF, Hubel A, Shankar RA, et al. Retroviral transduction and expansion of peripheral blood lymphocytes for the treatment of mucopolysaccharidosis type II, Hunter's syndrome. Transfusion. 1999;39 (4):343 –350[CrossRef][Web of Science][Medline]
  97. Friso A, Tomanin R, Alba S, et al. Reduction of GAG storage in MPS II mouse model following implantation of encapsulated recombinant myoblasts. J Gen Med. 2005;7 :1482 –1491[CrossRef]
  98. Muenzer J, Gucsavas-Calikoglu M, McCandless S, Schuetz T, Kimura A. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. 2007;90 :325 –355
  99. Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis. 1999;22 (5):638 –648[CrossRef][Web of Science][Medline]
  100. Coppa GV, Gabrielli O, Zampini L, et al. Bone marrow transplantation in Hunter syndrome. J Inherit Metab Dis. 1995;18 (1):91 –92[CrossRef][Web of Science][Medline]
  101. Mullen CA, Thompson JN, Richard LA, Chan KW. Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia. Bone Marrow Transplant. 2000;25(10) :1093 –1097
  102. Peters C, Krivit W. Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome). Bone Marrow Transplant. 2000;25(10) :1097 –1099
  103. Fletcher JM. Screening for lysosomal storage disorders: a clinical perspective. J Inherit Metab Dis. 2006;29(2–3) :405 –408
  104. Meikle PJ, Ranieri E, Simionsen H, et al. Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy. Pediatrics. 2004;114 (4):909 –916[Abstract/Free Full Text]
  105. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88 (4):307 –314[CrossRef][Web of Science][Medline]
  106. Wang D, Wood T, Sadilek M, Scott CR, Turecek F, Gelb MH. Tandem mass spectrometry for the direct assay of enzymes in dried blood spots: application to newborn screening for mucopolysaccharidosis II (Hunter disease). Clin Chem. 2007;53 (1):137 –140[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Martin, R.
Right arrow Articles by Muenzer, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Martin, R.
Right arrow Articles by Muenzer, J.
Related Collections
Right arrow Genetics & Dysmorphology
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?