Mucopolysaccharidosis Type II

CLINICAL CHARACTERISTICS

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with the neuronopathic phenotype, central nervous system (CNS) involvement (manifesting primarily as progressive cognitive deterioration), progressive airway disease, and cardiac disease usually results in death in the first or second decade of life. In those with the non-neuronopathic phenotype, the CNS is minimally or not affected. However, the effect of GAG accumulation on other organ systems can be severe. Survival into the early adult years with normal intelligence is common in the non-neuronopathic phenotype. Additional findings in neuronopathic and non-neuronopathic MPS II include: short stature, macrocephaly with or without communicating hydrocephalus, macroglossia, hoarse voice, conductive and sensorineural hearing loss, dysostosis multiplex, spinal stenosis, carpal tunnel syndrome, and hepatosplenomegaly.

DIAGNOSIS/TESTING: The diagnosis of MPS II is established in a male proband by identification of absent or reduced iduronate 2-sulfatase (I2S) enzyme activity in leukocytes, fibroblasts, or plasma in the presence of normal activity of at least one other sulfatase; or of a hemizygous pathogenic variant in by molecular genetic testing. The diagnosis of MPS II is usually established in a female proband with suggestive clinical features by identification of a heterozygous pathogenic variant by molecular genetic testing.

MANAGEMENT

Weekly enzyme replacement therapy (ERT) with infusions of idursulfase (Elaprase), a recombinant form of human I2S, is approved to treat somatic manifestations and prolong survival. Pretreatment with anti-inflammatory drugs or antihistamines may be needed for mild or moderate infusion reactions. Hematopoietic stem cell transplantation (HSCT) could provide sufficient enzyme activity to slow or stop the progression of the disease; however, no controlled clinical studies have been conducted in individuals with MPS II. Treatment of ocular manifestations by ophthalmologist with experience in MPS; tonsillectomy and adenoidectomy as needed; early and aggressive treatment of ear infections including pressure-equalizing tubes; hearing aids may be helpful; hip replacement as needed; physiotherapy; positive pressure ventilation (CPAP) as needed; CT examination of the trachea to assess airway issues; tracheostomy only as needed; anesthesia is best administered in centers familiar with the potential complications in persons with MPS II; umbilical and inguinal hernia repair as needed; treatment of cardiovascular manifestations per cardiologist with medications and/or cardiac valve replacement; developmental and educational support; occupational and physical therapy; shunting for hydrocephalus as needed; carpal tunnel release as needed; treatment of spinal stenosis per neurosurgeon/orthopedist; standard management of behavioral problems and seizures; melatonin may be beneficial for sleep problems; transitional care plan; family and social work support. Assess growth every six to 12 months throughout childhood; ophthalmology examination annually or as needed; assess feeding and swallowing at each visit or at least every six to 12 months in those with neuronopathic MPS II; assess for adenoid and tonsil hypertrophy at least annually; dental evaluation every six months; audiogram at least annually; annual orthopedic evaluation; annual pulmonology evaluation including pulmonary function testing; sleep study as needed and prior to surgery; assess for umbilical and inguinal hernia, chronic diarrhea, and liver and spleen size annually or as needed; cardiology assessment with echocardiogram annually or per cardiologist; EKG annually in adults or more frequently as needed; annual developmental, cognitive, behavioral, and neurologic assessment including assessment for seizures and manifestations of spinal stenosis; head and neck MRI to assess ventricular size and for cervical medullary narrowing as needed; assess opening pressure on lumbar puncture as needed; nerve conduction study for carpal tunnel syndrome annually; assess family needs at each visit. I2S biochemical testing and/or molecular genetic testing of at-risk male family members allows early diagnosis and prompt initiation of treatment; the importance of prompt initiation of treatment has been demonstrated in studies involving affected sibs who were diagnosed and treated at different ages.

GENETIC COUNSELING

MPS II is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has an pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will typically be asymptomatic. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Once the pathogenic variant has been identified in an affected family member, molecular genetic carrier testing for at-risk female relatives and prenatal/preimplantation genetic testing for pregnancies at increased risk are possible.