Genetics of Mucopolysaccharidosis Type II Clinical Presentation

• Type A mucopolysaccharidosis type II (MPS II) disease (severe form)

  • Disease presentation is usually between age 2-4 years and is characterized by progressive involvement of the nervous system and somatic effects.^[10]
  • Upon initial presentation, suggestive features may include coarse facies, short stature, skeletal deformities, joint stiffness, and mental retardation.
  • Given the age of presentation, the physical characteristics tend to prompt an evaluation earlier than developmental concerns might.
  • Additional features at presentation or thereafter may include hyperactivity, progressive hearing loss, hepatomegaly, carpal tunnel syndrome, progressive retinal degeneration, and recurrent ear infections.
  • Involvement of the GI system both via autonomic dysregulation and, possibly, mucosal dysfunction causes chronic diarrhea in younger patients; significant constipation may be a problem later on.
  • 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).
  • Cause of death is commonly complications of obstructive airway disease, cardiac failure, or both.
  • Glycosaminoglycan (GAG) accumulation involves the cardiac valvular leaflets, leading to dysfunction. The myocardium causes thickening and eventually leads to coronary artery compromise, myocardial disease, and, in conjunction with the airway disease, pulmonary hypertension.
  • Other features occasionally seen, especially in those patients considered most severely affected, include seizures and an overall severity approaching that of Hurler syndrome.
  • Some of these severely affected patients have extensive genomic deletions involving iduronate sulfatase (IDS) and contiguous genes.^[3]
• Type B disease (milder form)^{[12, 13, 14, 15, 16, 17, 18]}

  • Presentation is typically later in adolescence or adulthood.
  • Somatic involvement is distinguished from that seen in severe Hunter syndrome by the rate of progression and the degree of eventual handicap.
  • Intelligence is usually preserved.
  • Hearing impairment, joint stiffness, coarse facial features, upper airway disease, and carpal tunnel syndrome remain hallmarks, even in the milder form of disease, only with a more protracted time frame.
  • Communicating hydrocephalus is not as often encountered, although papilledema has been seen in the absence of intracranial pressure elevation, suggesting a localized process involving the optic nerve within the eye.
  • Also, although corneal clouding is a feature that, by its absence, differentiates MPS II from MPS I (Hurler), reports of discrete corneal opacities seen on slit-lamp examination and of no significant effect on visual acuity have been reported. Clouding of the cornea.
  • Retinal degeneration is also seen to a lesser degree in type B disease.
  • Death is often secondary to airway disease (obstructive) and cardiac failure, as is seen in type A disease, although usually beyond the fifth decade of life.

Both types A and B MPS II have deficient IDS activity and are retained as terms useful in clinically describing the extremes of a disease spectrum.

• Children with classic type A MPS II have progressive coarsening of facial features, short stature, joint stiffness, hepatosplenomegaly, and hernias as common presenting signs and symptoms. Children with type A MPS II tend to have severe mental retardation and deafness. Other presentations include cerebral ventricular dilation and dysostosis multiplex. Skin findings include hypertrichosis, thickened skin, and multiple Mongolian spots. Children with type A and B MPS II may have papular skin lesions that are ivory in color and are located on the upper back and on the lateral upper arms and thighs.

  • The skin lesions, which develop in a reticular pattern and appear pebbly, are considered a marker for the disease. The papules and nodules are ivory-white and are symmetrically distributed between the angles of the scapulae and posterior axillary lines. They also develop in the pectoral region and on the lateral aspects of the upper arms and legs. The skin lesions typically develop before age 10 years. When biopsied, the description is of a dermal mucinosis. The Mongolian spots in Hunter syndrome tend to develop in the lumbosacral region and are large, extending to both buttocks and onto the back. The hypertrichosis may result in synophrys.
  • Respiratory obstruction is secondary to the accumulation of glycosaminoglycans in the cells of the trachea.
  • Patients frequently have macrocephaly. The facial features of Hunter syndrome are coarse, but the children still have faces that resemble other family members.
  • Patients with Hunter syndrome tend to have short necks, broad chests, and a protuberant abdomen, with an umbilical hernia accompanied by hepatosplenomegaly. These patients tend to have a thoracolumbar kyphosis, and their trunk is relatively short when compared with their extremities. Joint mobility is decreased, and the fingers may have clawlike deformities. Patients tend to walk with a stiff gait.
  • Short stature is not usually detected until after the child is aged 3 years. Data from the Hunter Outcome Survey indicates that patients display normal, average height until age 9-10 years and then height below the third percentile thereafter.^[9]
  • The hearing loss observed with MPS II is often of mixed type but may be either conductive or sensorineural and is progressive in nature.
  • These patients may exhibit some oral manifestations of the disease with widely spaced teeth and an enlarged tongue. The enlarged tongue is more pronounced in children older than 5 years.
  • Despite the absence of corneal opacities that are observed in other mucopolysaccharidoses, MPS II has ocular findings. These findings include an atypical retinal degeneration and a chronic form of papilledema that leads to visual impairment.^{[15, 16, 17]}
• Children with type B disease do not usually have mentally retardation but have physical features that are similar to those with type A. Skeletal manifestations in adults with type B may be restricted to small carpal bones or mild dysplasia of the pelvis and femoral heads with premature osteoarthritis.
• Growth patterns in 28 males with Hunter syndrome from birth to 27 years, and followed longitudinally over 20 years, were reported.^[19] Patients were typically larger than the general population at birth 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 Hunter syndrome were studied before and after the start of ERT therapy. ERT seemed to improve growth rates in children, especially those beginning ERT before age 10 years.^[20]

• Hunter syndrome differs from the other MPSs in that it is transmitted in an X-linked recessive fashion.
• Defects in the gene encoding IDS are causative. 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 with both mild and severe disease, implicating the contribution of other genetic or environmental modifiers on the phenotype.^{[21, 22]}
• Although no strong point mutation correlations between genotype and phenotype are recognized, all patients with large deletions or rearrangements of the IDS gene have severe disease. Patients with contiguous deletions have additional findings attributed to the other genes involved.^{[3, 23]} Such contiguous gene deletions are identified in around 20% of patients.^{[24, 25]}
• Finally, skewed inactivation of the nonmutant allele 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 active mutant and nonmutant alleles in the female patient.^[26]