Mucopolysaccharidosis II (Hunter Syndrome)

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Mucopolysaccharidosis II (Hunter Syndrome)

In 1917, Hunter described the syndrome in two brothers.

Hunter syndrome is an X-linked recessive form of the mucopolysaccharidosis. Severe and mild forms of the syn- drome are caused by the same enzyme deficiency, iduronate sulfatase. The estimated incidence is approximately 1 in 100,000 births.

GENETICS/BASIC DEFECTS

1. Inheritance

a. X-linked recessive inheritance from pedigree data b. The gene for iduronate sulfatase mapped to Xq28 2. Primary biochemical defect and pathophysiology

a. Deficient iduronate-2-sulfatase (IDS), the enzyme required for cleavage of sulfate from iduronic acid moieties of dermatan and heparan sulfates

b. Excessive intracellular accumulation of acid mucopolysaccharides (dermatan sulfate and heparan sulfate) due to deficient iduronate sulfatase activity, leading to multiple organ system involvement, includ- ing the musculoskeletal, integumentary, cardiovascu- lar, pulmonary, and ocular systems

3. Molecular defect

a. Mutations of IDS gene

i. Missense and nonsense mutations ii. Mutations affecting splicing iii. Small insertions and deletions

iv. Partial gene deletions

v. Deletions or rearrangements of the whole IDS gene b. Major structural alterations and gross deletions of the IDS gene result in the most severe forms of Hunter syndrome

c. Single-base substitutions causing diminished but not obliterated enzyme activity is observed in mild disease

4. Hunter syndrome in females: an exceedingly rare event possibly due to the following mechanisms:

a. As the offspring of a carrier female and affected male or an unaffected male whose sperm carries a new mutation b. Uniparental disomy of the mutant X-chromosome

from a heterozygous female or an affected male c. Genetic rearrangement: e.g, translocation or deletion

resulting in nonrandom lyonization toward expression of a mutant allele

CLINICAL FEATURES

1. Clinical presentation showing a spectrum of mild to severe forms as a result of different mutations in the func- tional gene

2. Severe Hunter syndrome (MPS IIA)

a. Onset: usually between 2 and 4 years of age with pro- gressive neurologic and somatic involvement b. More common than the mild form

c. Short stature not pronounced d. Coarse facial features

i. Frontal bossing ii. Depressed nasal bridge iii. Wide nostrils

iv. Thick lips

v. Hypertrophic gums vi. A large tongue e. Skeletal deformities

i. Kyphosis

ii. Digital contractures iii. Claw hands

iv. Joint stiffness v. Absence of gibbus f. Mental retardation g. Hydrocephalus h. Retinal degeneration

i. Absence of corneal clouding j. Hearing loss

k. Respiratory difficulties

i. Upper airway obstruction due to adenoid hyper- trophy, nasal congestion, and thick rhinorrhea ii. Mouth breathing secondary to choanal stenosis iii. Sonorous breathing, frank obstructive sleep apnea,

and even death secondary to adenoid hypertrophy, tongue enlargement, and supraglottic swelling l. Cardiovascular disorders

i. Cardiac valvular involvement leading to conges- tive heart failure, the leading cause of death in affected individuals

ii. Mild thickening and shortening of the chordae tendineae contributing to the regurgitant valve dysfunction

m. Gastrointestinal problems

i. Chronic diarrhea secondary to autonomic nerv- ous system involvement and mucosal dysfunction ii. Hepatosplenomegaly

iii. Umbilical and inguinal hernias

n. Thick skin often with nodular skin lesions over the scapular area or arms

o. Carpal tunnel syndrome secondary to median nerve compression

p. Additional features of most severely affected patients, caused by large deletions that include iduronate sul- fate sulfatase and contiguous genes

i. Hurler-like symptoms ii. Early onset of seizures iii. Ptosis

q. Prognosis: typically advancing to cachexia and death before 15 years

3. Mild Hunter syndrome (MPS IIB)

a. Diagnosed slightly later than the severe form

b. Much less frequent than the severe form

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MPS II (HUNTER SYNDROME) 679

c. Preservation of normal intelligence d. No central nervous system involvement e. Somatic involvement less progressive

f. Hearing impairment g. Cardiovascular disorders h. Joint stiffness

i. Cervical myopathy due to a narrowed spinal canal and cord compression

j. Carpal tunnel syndrome more frequent and severe compared to the severe form

k. Loss of hand function resulting from joint stiffness and carpal tunnel syndrome

l. Prognosis

i. Longer survival

ii. Typically surviving to adulthood

iii. Possible death in early adulthood or even in the late teens due to airway obstruction and cardiac failure

DIAGNOSTIC INVESTIGATIONS

1. Echocardiography 2. Electrocardiography 3. Radiographic features

a. Kyphosis b. Claw hands

c. Thick cortex of the bones progressively becoming thinner as the marrow cavities expand

d. Large calvarium with shoe-shaped sella e. Broad and spatulate lower ribs

f. Hypoplasia and beaking of the lumbar vertebrae 4. Biochemical/molecular studies

a. Measurement of mucopolysaccharides in the urine.

Abnormal excretion of a large amount of dermatan sulfate and heparin sulfate in the urine

b. Deficient iduronate sulfatase in leukocytes and fibroblasts

c. Excessive intracellular accumulation of dermatan sul- fate and heparin sulfate

d. Peripheral lymphocytes, when stained with toluidine blue, exhibit metachromatic granules within vacuoles e. Mutation analysis

5. Heterozygote detection

a. Carrier detection by enzyme analysis is unreliable b. Identification of IDS gene mutations

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. Carrier mother: 50% of brothers affected, 50%

of brothers normal; 50% of sisters carriers, 50%

of sisters normal

ii. Noncarrier mother (mother of a sporadic case):

recurrence possible due to presence of gonadal mosaicism

b. Patient’s offspring

i. Severe form: not surviving to reproduction ii. Mild form: none of the sons affected; all daugh-

ters carriers 2. Prenatal diagnosis

a. Maternal serum analysis

i. Consistent increase of iduronate sulfate sulfatase in the serum of pregnant women from prepreg- nancy levels toward the end of pregnancy ii. No change in the serum enzyme levels of het-

erozygous mothers until the affected fetuses are aborted

b. Amniocentesis

i. Reduced enzyme activity in the amniotic fluid ii. Low enzyme levels in cultured amniotic cells iii. Abnormal

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incorporation into cultured

amniotic fluid cells iv. Karyotyping for fetal sex

v. Direct detection of IDS gene mutation c. CVS

i. Diminished enzyme activity in uncultured chori- onic villi of affected male fetuses. This may be seen in female carrier fetuses

ii. Karyotyping for fetal sexing

iii. Direct detection of IDS gene mutation

d. Umbilical fetal blood sampling: severe deficiency of iduronate sulfate sulfatase in the plasma of affected male fetuses

3. Management

a. Tympanostomy, adenoidectomy, and provision of hearing aids for management of otologic complica- tions

b. Symptomatic management of airway obstruction (sleep apnea)

c. Ventriculoperitoneal shunting for hydrocephalus, a relatively rare complication of Hunter syndrome d. Difficulties during anesthesia secondary to the fol-

lowing factors:

i. Rigid thoracic cage ii. Abdominal distention iii. Macroglossia

iv. Temporomandibular ankylosis v. Atlantoaxial instability vi. Short and wide neck

e. Prophylactic antibiotics for at-risk procedures in patient with mucopolysaccharidosis

f. Surgical repair of inguinal and umbilical hernias g. Surgical release to preserve apposition of the thumbs

at the earliest sign of an electrophysical evidence of progressive median nerve compression

h. Musculoskeletal complications

i. Shoe orthotics and ankle braces well tolerated and useful in maintaining mobility

ii. Achilles tendon release in some patients with advanced disease

iii. Surgical stabilization of the spine rarely indicat- ed for kyphoscoliosis which is only mildly pro- gressive and not usually resulting in spinal cord compression

i. Bone marrow transplantation

i. Possible reduction in hepatosplenomegaly, improvement in airway disease and reduction in urinary glycosaminoglycan excretion

ii. Long term prognosis for longevity, cardiac com-

plications and neurologic outcome after marrow

transplantation still remained to be determined

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Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In: Scriver CR, Beardet al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited disease Vol II, 7th ed, New York: McGraw-hill, 1995:

2465–2494.

Pannone N, Gatti R, Lombardo C, et al.: Prenatal diagnosis of Hunter syn- drome using chorionic villi. Prenat Diagn 6:207–210, 1986.

Rathmann M, Bunge S, Beck M, et al.: Mucopolysaccharidosis type II (Hunter syndrome): mutation “hot spots” in the iduronate-2-sulfatase gene. Am J Hum Genet 59:1202–1209, 1996.

Timms KM, Bondeson ML, Ansari-Lari MA, et al.: Molecular and phenotypic variation in patients with severe Hunter syndrome. Hum Mol Genet 6:479–486, 1997.

Timms KM, Edwards FJ, Belmont JW, et al.: Reassessment of biochemically determined Hunter syndrome carrier status by DNA testing. J Med Genet 35:646–649, 1998.

Upadhyaya M, Sarfarazi M, Bamforth JS, et al.: Localisation of the gene for Hunter syndrome on the long arm of X chromosome. Hum Genet 74:391–398, 1986.

Vafiadaki E, Cooper A, Heptinstall LE, et al.: Mutation analysis in 57 unrelated patients with MPS II (Hunter’s disease). Arch Dis Child 79:237–241, 1998.

Whitley CB: The mucopolysaccharidoses, in Beighton P (ed): McKusick’s Heritable Disorders of Connective Tissue, 5th ed. St. Louis, CV Mosby, 1993, pp 367.

Wilson PJ, Morris CP, Anson DS, et al.: Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. Proc Natl Acad Sci USA 87:8531–8535, 1990.

Wilson PJ, Suthers GK, Callen DF, et al.: Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome. Hum Genet 86:505–508, 1991.

Wraith JE, Cooper A, Thornley M, et al.: The clinical phenotype of two patients with a complete deletion of the iduronate-2-sulphatase gene (mucopolysac- charidosis II—Hunter syndrome). Hum Genet 87:205– 206, 1991.

Yatziv S, Erickson RP, Epstein CJ: Mild and severe Hunter syndrome (MPS II) within the same sibships. Clin Genet 11:319–326, 1977.

Yoskovitch A, Tewfik TL, Brouillette RT, et al.: Acute airway obstruction in Hunter syndrome. Int J Pediatr Otorhinolaryngol 44:273–278, 1998.

Young ID, Harper PS: Long-term complications in Hunter’s syndrome. Clin Genet 16:125–132, 1979.

Young ID, Harper PS: Psychosocial problems in Hunter’s syndrome. Child Care Health Dev 7:201–209, 1981.

Young ID, Harper PS: Mild form of Hunter’s syndrome: clinical delineation based on 31 cases. Arch Dis Child 57:828–836, 1982.

Young ID, Harper PS: The natural history of the severe form of Hunter’s syn- drome: a study based on 52 cases. Dev Med Child Neurol 25:481–489, 1983.

Young ID, Harper PS, Archer IM, et al.: A clinical and genetic study of Hunter’s syndrome. 1. Heterogeneity. J Med Genet 19:401–407, 1982.

Young ID, Harper PS, Newcombe RG, et al.: A clinical and genetic study of Hunter’s syndrome. 2. Differences between the mild and severe forms. J Med Genet 19:408–411, 1982.

Zlotogora J, Bach G: Heterozygote detection in Hunter syndrome. Am J Med Genet 17:661–665, 1984.

Zlotogora J, Bach G: Hunter syndrome: prenatal diagnosis in maternal serum.

Am J Hum Genet 38:253–260, 1986.

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REFERENCES

Archer IM, Kingston HM, Harper PS: Prenatal diagnosis of Hunter syndrome.

Prenat Diagn 4:195–200, 1984.

Archer IM, Young ID, Rees DW, et al.: Carrier detection in Hunter syndrome.

Am J Med Genet 16:61–69, 1983.

Bergstrom SK, Quinn JJ, Greenstein R, et al.: Long-term follow-up of a patient transplanted for Hunter’s disease type IIB: a case report and literature review. Bone Marrow Transplant 14:653–658, 1994.

Broadhead DM, Kirk JM, Burt AJ, et al.: Full expression of Hunter’s disease in a female with an X-chromosome deletion leading to non-random inacti- vation. Clin Genet 30:392–398, 1986.

Bunge S, Steglich C, Zuther C, et al.: Iduronate-2-sulfatase gene mutations in 16 patients with mucopolysaccharidosis type II (Hunter syndrome). Hum Mol Genet 2:1871–1875, 1993.

Bunge S, Steglich C, Lorenz P, et al.: Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,XXY male het- erozygous for a missense point mutation. Prenat Diagn 14:777–780, 1994.

Cooper A, Thornley M, Wraith JE: First-trimester diagnosis of Hunter syn- drome: very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus. Prenat Diagn 11:731–735, 1991.

Fensom AH, Benson PF: Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn 14:1–12, 1994.

Froissart R, Blond JL, Maire I, et al.: Hunter syndrome: gene deletions and rearrangements. Hum Mutat 2:138–140, 1993.

Froissart R, Maire I, Bonnet V, et al.: Germline and somatic mosaicism in a female carrier of Hunter disease. J Med Genet 34:137–140, 1997.

Froissart R, Maire I, Millat G, et al.: Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin Genet 53:362–368, 1998.

Goldenfum SL, Young E, Michelakakis H, et al.: Mutation analysis in 20 patients with Hunter disease. Hum Mutat 7:76–78, 1996.

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 22:1016–1021, 2002.

Kleijer WJ, Moody PD, Liebaers I, et al.: Prenatal monitoring for the Hunter syndrome: the heterozygous female fetus. Clin Genet 15:113–117, 1979.

Lichtenstein JR, Bilbrey GL, McKusick VA: Clinical and probable genetic het- erogeneity within mucopolysaccharidosis. II. Report of a family with a mild form. Johns Hopkins Med J 131:425–435, 1972.

Liebaers I, Di Natale P, Neufeld EF: Iduronate sulfatase in amniotic fluid: an aid in the prenatal diagnosis of the hunter syndrome. J Pediatr 90:423–425, 1977.

Liebaers I, Neufeld E: Iduronate sulfatase activity in serum, lymphocytes, and fibroblasts—simplified diagnosis of the Hunter syndrome. Pediatr Res 10:733–736, 1976.

Lissens W, Seneca S, Liebaers I: Molecular analysis in 23 Hunter disease fam- ilies. J Inherit Metab Dis 20:453–456, 1997.

Lissens W, Van Lierde M, Decaluwe J, et al.: Prenatal diagnosis of Hunter syn- drome using fetal plasma. Prenat Diagn 8:59–62, 1988.

McKinnis EJ, Sulzbacher S, Rutledge JC, et al.: Bone marrow transplantation in Hunter syndrome. J Pediatr 129:145–148, 1996.