History
Type A mucopolysaccharidosis type II (MPS IIA) - severe form
Disease presentation usually occurs between age 2-4 years and is characterized by progressive neurological involvement and concurrent somatic effects. [13, 15] Initial clinical features may include coarse facies, short stature, skeletal deformities, joint stiffness, developmental delay, and intellectual disability. Additional features at presentation or upon reevaluation may include hyperactivity, retinal degeneration, progressive hearing loss, recurrent ear infections, hepatomegaly, and carpal tunnel syndrome.
Communicating hydrocephalus can develop and can further contribute to neurological deterioration. The neurologic involvement is progressive and profound in the late stages of life (typically the second and third decades of life). Other features occasionally seen, especially in patients who are severely affected, are seizures and an overall phenotypic severity approaching that of Hurler syndrome (MPS I).
Valvular heart leaflets become dysfunctional owing to glycosaminoglycan (GAG) accumulation. A thickened myocardium eventually leads to coronary artery compromise, myocardial disease, and, in conjunction with airway disease, pulmonary hypertension.
The gastrointestinal system also is affected via autonomic dysregulation and, possibly, mucosal dysfunction, which causes chronic diarrhea in younger patients; marked constipation may be a problem in older patients.
Death is usually due to complications of obstructive airway disease, cardiac failure, or a combination of both.
Type B mucopolysaccharidosis type II (MPS IIB) – milder attenuated form
The presentation of MPS IIB typically occurs in adolescence or adulthood. [16, 17, 18, 19, 20, 21, 22]
Somatic involvement is distinguishable from that seen in patients with MPS IIA by the decreased rate of progression and the lesser degree of eventual handicap. Intelligence is usually preserved. Hearing impairment, joint stiffness, coarse facial features, upper airway disease, and carpal tunnel syndrome as seen in MPS IIA remain hallmarks in MPS IIB, but become evident over a more protracted time period.
Communicating hydrocephalus does not occur as often, although papilledema has been seen in the absence of increased intracranial pressure, suggesting a localized process involving the optic nerves.
Absence of corneal clouding is a feature that differentiates MPS IIA and MPS IIB from MPS I; however, there have been reports of patient with MPS II who have discrete corneal opacities viewed on slit-lamp examination. These opacities appear not to impair visual acuity. Retinal degeneration is seen to a lesser degree in MPS IIB.
Patients diagnosed with MPS IIB can live beyond the fifth decade of life. Death often is secondary to obstructive airway disease and cardiac failure, as is seen in patients with MPS IIA.
Physical
Both MPS IIA and MPS IIB have deficient IDS activity. Distinguishing between these types is useful to clinically describe the extremes of MPS II disease spectrum.
MPS IIA
Common presenting signs and symptoms in children with classic MPS IIA include progressive coarsening of facial features, short stature, joint stiffness, hepatosplenomegaly, and hernias. Children with MPS IIA are macrocephalic and tend to have severe intellectual disability. In MPS II, corneal opacities are absent; however other ocular findings occur and include an atypical retinal degeneration and a chronic form of papilledema that leads to visual impairment. [19, 20, 21] Hearing impairment progresses to profound deafness. This hearing loss may be either conductive or sensorineural but often is of a mixed type. Inspection of the oropharynx can reveal widely spaced teeth and an enlarged tongue. The enlarged tongue is more pronounced in children older than 5 years.
Phenotypically, persons with MPS IIA have a short neck, broad chest, a protuberant abdomen, hepatosplenomegaly, and an umbilical hernia. Musculoskeletal findings include dysostosis multiplex and thoracolumbar kyphosis, and the trunk appears short in length when compared to the length of the extremities. Joint mobility is decreased, and the fingers may have clawlike deformities. Patients tend to walk with a stiff gait. Short stature usually is not noted until after age 3 years. Data from the Hunter Outcome Survey indicated that patients follow an average height curve until age 9-10 years and then cease growing, subsequently falling in the height curve to less than the third percentile as they age. [12]
Children with MPS IIA and MPS IIB may have ivory-colored papular skin lesions that are symmetrically distributed on the upper back between the angles of the scapulae and posterior axillary lines, in the pectoral region, and on the lateral upper arms and thighs. These skin lesions, which develop in a reticular pattern and appear pebbly, are pathognomonic for the disease. The skin lesions typically develop before age 10 years. When biopsied, the pathology describes a dermal mucinosis. Additional dermatologic findings include hypertrichosis, thickened skin, and multiple Mongolian spots. Hypertrichosis may result in synophrys. Mongolian spots in MPS II tend to be found in the lumbosacral region, are large, and can extend to both buttocks and onto the back.
MSP IIB
Children with MPS IIB typically do not have intellectual disability but do have physical features that are similar to those of patients with MPS IIA. Skeletal manifestations in adults with MPS IIB may be only small carpal bones or mild dysplasia of the pelvis and femoral heads with premature osteoarthritis.
Growth patterns in 28 males with MPS IIB were cataloged from birth to 27 years, encompassing a 20-year period. [23] At birth, patients were typically larger than the general population and for the first 3 years of life. After age 3 years, there was a distinct, persistent decline in growth rates. In another study, 18 males with MSP II were studied before and after the start of enzyme replacement therapy (ERT). ERT seemed to improve growth rates in children, especially among those beginning ERT prior to age 10 years. [24]
Causes
MPS II (Hunter syndrome) differs from the other MPSs in that it is inherited in an X-linked recessive fashion. The remaining known MPSs are inherited in an autosomal recessive fashion. MPS II is due to deficiency or absence of the lysosomal enzyme, iduronate 2-sulfatase deficiency (IDS). The cytogenetic location for the IDS gene is Xq28.
Defects in the gene encoding iduronate sulfatase (IDS) are causative. [25] Molecular analysis shows a wide variety of defects in IDS that cause Hunter syndrome. No single mutation has a high frequency of occurrence. Identical mutations have been found in patients diagnosed with either MPS IIA or MPS IIB, implicating the contribution of other genetic or environmental modifiers on the phenotype. [26, 27]
Although no strong point mutation correlations between genotype and phenotype are recognized, patients with large genomic deletions or genomic rearrangements plus involvement of contiguous genes to the IDS gene phenotypically have severe disease. Patients with contiguous deletions have additional findings attributed to the other genes involved. [5, 28] Such contiguous gene deletions are identified in around 20% of patients with MPS II. [29, 30]
Skewed X-inactivation of the non-altered X chromosome in a heterozygous female can lead to clinical disease. Severity is related to the type of mutation on the active X chromosome, as is seen in male patients, and is also related to the ratio of altered to non-altered X chromosome activity in the female patient. [31]
