Mucopolysaccharidoses Types I-VII Clinical Presentation

Mucopolysaccharidosis usually manifests during infancy or early childhood.

• The organs most involved include bone, the viscera, connective tissue, and the brain.
• Dysostosis multiplex denotes the characteristic bony abnormalities.
• Hepatosplenomegaly is a frequent finding.
• Coarse facies, retinal disease, deafness, cardiovascular anomalies, and neurologic abnormalities can be present.
• Common cutaneous findings are lichenified, dry, thick skin with diminished elasticity; increased pigmentation on the dorsum of the hands; sclerodermalike changes; hypertrichosis of the extremities; pale-colored hair; and alopecia areata.
• Obstructive sleep apnea reportedly is a finding in children with mucopolysaccharidoses. Obstructive respiratory problems are common in patients with mucopolysaccharidosis. The severity of obstructive sleep apnea varies with each type of mucopolysaccharidosis.
• Severe neurologic deficits and mental retardation are frequently associated with disrupted ganglioside metabolism in a variety of gangliosidoses and lysosomal storage disorders.
• All types of mucopolysaccharidoses are linked with thickened and inelastic-appearing skin. Mucopolysaccharidosis type II (Hunter syndrome) reportedly is the only type with distinctive cutaneous findings; ivory-white papules or nodules 3-4 mm in diameter are present on the trunk, sometimes in a reticulate pattern. However, grouped skin-colored papules were described in a 5-year-old boy with Hurler-Scheie syndrome.

Mucopolysaccharidosis type I-H (Hurler syndrome)

The onset of mucopolysaccharidosis type I-H (Hurler syndrome) occurs in early childhood (ie, 6-12 mo).

The skin is thickened and inelastic, as in other mucopolysaccharidoses. Hypertrichosis is common. Grouped skin-colored papules were described in 1 child with Hurler-Scheie syndrome.

Findings of generalized mongolian spots have been reported in newborns, which can lead to early detection and early treatment.^{[6, 7]}

Neurologic symptoms include hypertensive hydrocephalus syndrome, changes in the tonus of the musculature and the tendon reflex, and damage of the cranial nerves.

Myxedema may occur in patients with associated hypothyroidism.

Skeletal findings include dwarfism, with rather characteristic radiologic changes of the hands and the lumbar vertebral column; lumbar gibbus; stiff articulations; coarse facies; hip dysplasia; genu valgum; spine abnormalities; and hand abnormalities.

Other findings include hepatosplenomegaly and cardiovascular involvement. The cardiovascular findings include cardiac murmurs at the end of the second year and valvular heart disease; coronary artery insufficiency and peripheral vascular insufficiency are late findings. Fatal cardiomyopathy with autopsy-confirmed endocardial fibroelastosis has been reported.

CNS signs include progressive deterioration of intellect after a period of apparently normal development, debility, and speech disturbances. CNS lesions include lissencephaly, excessive ventricular enlargement and Dandy-Walker malformation with vermis atrophy, and cerebellar cysts. The association with lissencephaly is rare. The combination of mongolian spots and severe CNS lesions in Hurler syndrome is considered a rare clinical occurrence.

Ocular symptoms include progressive clouding of the cornea, megalocornea, hereditary glaucoma, and congestion and atrophy of the optic disc.

Mucopolysaccharidosis type I-S (Scheie syndrome)

Mucopolysaccharidosis type I-S (Scheie syndrome) usually occurs in persons aged 5-15 years.

Skeletal findings include mild skeletal deformation and deformity of the hands. Growth may be normal.

Aortic stenosis or regurgitation may be present. Mucopolysaccharidosis IS patients have an impairment of ascending aortic elasticity. Measured with transthoracic echocardiography in mucopolysaccharidosis IS patients, aortic stiffness index was significantly increased, while aortic distensibility was significantly decreased compared with age- and sex-matched controls. Further follow-up studies are needed to examine arterial elasticity using other methods in this patient population and to detect possible effects of enzyme replacement therapy.^[8]

Hepatosplenomegaly may be present.

Intelligence is usually normal.

The clinical signs of mucopolysaccharidosis type I-H/S (Hurler-Scheie syndrome) begin in persons aged 2-4 years; the signs are the same as those of mucopolysaccharidosis type I-H, but they are milder with a slower progression.

Mucopolysaccharidosis type II (Hunter syndrome)

Mucopolysaccharidosis type II (Hunter syndrome) manifests in persons aged 1-3 years.

Clouding of the cornea does not occur, although patients have a pigmentary change in the ocular fundus with diminution of visual acuity and deposits of mucopolysaccharides.

Lumbar gibbus is rare in persons with Hunter syndrome.

Progressive deafness is a major problem. This also occurs in persons with Hurler syndrome, but severe mental retardation and early death make it a relatively inconspicuous feature.

Hepatosplenomegaly, stiff articulations, coarse facial features, and cardiovascular involvement occur as in Hurler syndrome.

Cutaneous manifestations include hirsutism; thickening of the skin, particularly over the fingers; and multiple, ivory-white, pebbly papules or nodules overlying the scapula and in the area of the posterior axillary fold. These nodules are most often localized symmetrically between the scapula angle and the linea axillaris posterior or on the thorax and the neck.

Papules with a pebbly appearance are a specific marker for the disease. These papules fade away through the digestion of a large amount of hyaluronic acid in cutaneous tissues by normal tissue histiocytes or enzymes of donor origin at an early stage after hematopoietic stem cell transplantation (SCT).^[9]

Mongolian spots are observed at birth in 100% of Japanese, 96% of African American, 46% of the Hispanic, 9.5% of the white, 6.65% of Jewish, and 11.8% of Arab infants. They usually resolve and disappear by age 5-6 years. The most frequently involved region is the sacrococcygeal area, followed by gluteal and lumbar areas.^{[10, 11]}

The brain MRI abnormalities in patients with mucopolysaccharidosis types I and II who have only mild clinical manifestations are abnormal signal intensity in the white matter, widening of the cortical sulci, the size of the supratentorial ventricles, dilatation of the perivascular spaces, and enlargement of the subarachnoid spaces.^[12]

Cerebral involvement is common. The increased myo-inositol-to-creatine (mI/Cr) ratio in patients with the neuronopathic form suggests the triggering of a glial response, and may be a surrogate marker of cerebral dysfunction in mucopolysaccharidosis II.

Carpal tunnel syndrome (CTS) is very common (85-96%) in patients with Hunter syndrome, and it starts in very early childhood, as early as age 26 months.^[13]

Mucopolysaccharidosis type III (Sanfilippo syndrome)

The main findings of mucopolysaccharidosis type III (Sanfilippo syndrome) are regression of psychomotor development and neurologic signs (eg, hyperactivity, autistic features, behavioral disorder), which occur in children aged 2-6 years.

The sleep disruption in Sanfilippo syndrome consists of an irregular sleep/wake pattern, which at its onset might appear as a disorder of initiating or maintaining sleep. This could explain why some patients do not respond to conventional hypnotics.

Dysmorphic features are relatively rare.

Other signs include thickened facial features, coarse hair, genu valgum, and a short neck. Hirsutism is common.

Children become inattentive and deteriorate rapidly, losing the power of speech.

Mild hepatosplenomegaly is common.

The course of the disease is progressive; most patients die before age 20 years.

Osteoporosis and osteomalacia are possible skeletal effects. They probably result from nutritional deficiencies and the inability to walk, rather than from the genetic defect itself. Secondary skeletal involvement in patients with mucopolysaccharidosis type III may represent a considerable cause of morbidity and requires intervention to reduce the risk of pathological fractures.

The 4-point scoring system was arranged to classify patients into groups with a rapid or slower course of mucopolysaccharidosis type IIIA. Meyer et al performed the first systematic and comprehensive study on the natural course of the disease.^[14]

In the cohort of patients with mucopolysaccharidosis type IIIA, the first symptoms of disease were observed, on average, at age 7 months. Speech and motor development were delayed in 66.2% and 33.9% of patients, respectively. The median age at diagnosis was 4.5 years. The onset of regression in speech, motor, and cognitive function was observed at an average of age 3.3 years. The loss of all 3 of the assessed abilities was observed at an average of age 12.5 years. Speech was lost before motor and cognitive functions. In a small group of patients who were older than 12.5 years (9.9%), speech, motor, and cognitive skills were partially preserved up to a maximum of age 23.8 years.

The 4-point scoring system may have an important impact on parental counseling, as well as therapeutic interventions.

Mucopolysaccharidosis type IV (Morquio syndrome)

Mucopolysaccharidosis type IV (Morquio syndrome) is characterized by abnormalities of the skeletal system (eg, kyphoscoliosis, pectus carinatum, luxation of the hips), aortic valvular disease, and dental abnormalities.

The clinical and radiographic appearances of the teeth resemble hypoplastic amelogenesis imperfecta with thin enamel of normal radiodensity.

Odontoid hypoplasia is common and can lead to deadly atlantoaxial instability if not treated.

Ophthalmologically, diffuse corneal opacification and alterations of the trabecular meshwork occasionally lead to glaucoma.

In Morquiolike syndrome, hearing deficits, dental abnormalities, cardiac murmurs, hepatomegaly, and joint laxity are absent.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)

In mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), the first clinical signs usually appear in the first 2 years of life and manifest as psychomotor retardation.

This syndrome resembles Hurler syndrome with typical facial changes including frontal bossing, a depressed nasal bridge, open mouth associated with enlarged tongue, gingival hypertrophy, delayed dental eruption, and hypertrichosis.^[15]

A large head, short neck, corneal opacity, an enlarged tongue, enlargement of skull, and a long anteroposterior dimension are the main characteristic features.

Slowly, the thoracic deformity appears. Lumbar kyphosis, limited joint mobility, and a claw position of the hands are also present.

Usually, hepatosplenomegaly is present; less often, only splenomegaly is present.

Intelligence is usually normal, but visual and hearing impairments are present.

Compression of the spinal cord with successive neurologic complications can appear because of hypoplasia of the cervical vertebrae.

Growth often slows after the first year of life, with complete cessation at age 3-4 years. Adult height is generally less than 120 cm.^[15]

Dental complications include unerupted dentition, dentigerous cystlike follicles, malocclusions, condylar defects, and gingival hyperplasia.^[16]

Altered metabolism of GAGs in the extracellular matrix can contribute to the development of the left ventricular aneurysm.^[17]

Patients older than 10 years may progress to severe pulmonary obstruction and respiratory failure requiring tracheostomy, cardiac valve regurgitation or stenosis requiring valve replacement, severe joint disease (especially of the hips), claw-hand deformities secondary to flexion contractures and carpal tunnel disease, severe spinal kyphosis, scoliosis, and cervical stenosis with spinal cord compression.^[15]

Mucopolysaccharidosis type VII

Early after birth, children with mucopolysaccharidosis type VII have hepatosplenomegaly and facial deformities, such as hypertelorism, a prominent maxilla, and a depressed bridge of the nose.

Dwarfism with pectus carinatum and kyphosis is present.

Children have frequent upper respiratory tract infections.

Many develop corneal clouding.

Mental retardation is mild.

Craniovertebral instability and spinal cord compression can occur in persons with mucopolysaccharidosis type VII (Sly syndrome), with deposition of GAGs at the craniovertebral junction.^[18]

A very rare finding is fetal hydrops.^[19] It is the most severe form of mucopolysaccharidosis type VII and is always fatal. Ultrasound findings include generalized edema, ascites, hydrothorax, pericardial effusion, and increased nuchal translucency. Milder forms may present with symptoms at birth or within the first years of life, with coarse facies, hepatosplenomegaly, umbilical or inguinal herniae, recurrent respiratory infections, developmental delay, and multiple skeletal abnormalities known as dysostosis multiplex.^[20]

Ocular manifestations of mucopolysaccharidoses

Corneal clouding is a very common feature of mucopolysaccharidosis types IH,IH/S, VI, and VII (Sly syndrome), but it can also occur in the other mucopolysaccharidosis types.

Moderate-to-severe retinopathy has been reported for patients with mucopolysaccharidosis type I (all subtypes), mucopolysaccharidosis type II, mucopolysaccharidosis type III, and mucopolysaccharidosis type IV (Morquio syndrome).

Open-angle and acute and chronic closed-angle glaucoma have been observed in almost all mucopolysaccharidosis type but are most severe in mucopolysaccharidosis type IH, mucopolysaccharidosis type IH/S and mucopolysaccharidosis type VI.

Optic disc swelling and optic nerve atrophy may occur in all mucopolysaccharidosis types but most commonly affect patients with mucopolysaccharidosis type I and mucopolysaccharidosis type VI. About half of the patients with mucopolysaccharidosis type IH, mucopolysaccharidosis type IH/S and mucopolysaccharidosis type VI have swollen optic discs.^[21]

See Pathophysiology.