History
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.
Tonsillar hypertrophy is a typical symptom in patients with mucopolysaccharidoses. Early disease-specific treatment before the development of irreversible damage (ie, fibrosis of heart valves) should result in an improved outcome no matter what type of treatment. An early diagnosis is critical for the success of this therapy and can be realized by qualified histological examination. [8] The accumulation of glycosaminoglycans in the vocal source leading to unbalanced enlargement can exhibit pathological jitter and shimmer. This reduced rate of syllable vocalization may be explained by the enlarged lips and tongues, which may impede their rapid repetition of consonant-vowel syllables. Mixed hearing loss (conductive and sensorineural) can be also present. [9]
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.
Children with mucopolysaccharidosis are usually characterized by short stature, mainly a short trunk; lower values referring to head and neck height, shoulder, and hip breadth; and a higher degree of adiposity. [10]
Results of a study of Bradley et al revealed worsening linear growth over time in individuals with mucopolysaccharidosis type II and type VI and significantly elevated body mass index standard deviation score. The elevated body mass index in individuals with mucopolysaccharidosis is a risk factor for long-term cardiovascular disease. [11]
Physical Examination
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. [12, 13]
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. [14]
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). [15]
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. [16, 17]
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. [18]
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. [19]
Neonatal respiratory distress is more frequent in patients with mucopolysaccharidosis type II than in the general population. This may reflect airway disease already present in this disorder at the time of birth. The literature suggests that respiratory distress from any cause may occur in as many of 4-5% of term infants, whereas in the study of Dodsworth et al, it was observed in 32% of 34 infants with mucopolysaccharidosis type II. [20]
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. More developmental delay can be misdiagnosed as autism spectrum disorder or idiopathic developmental delay. [21]
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 and symptoms include thickened facial features, coarse hair, genu valgum, short neck, frequent ear and upper respiratory tract infections, and hearing loss. Hirsutism is common.
Children become inattentive and deteriorate rapidly, losing the power of speech.
Mild hepatosplenomegaly is common.
Osteoporosis and osteomalacia are possible skeletal defects. 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. Orthopedic manifestations (scoliosis, lumbar lordosis, kyphosis, hip dysplasia and pain, trigger digits, carpal tunnel syndrome, joint contractures) appear only in a minority of patients. [21]
The course of the disease is progressive; most patients die before age 20 years.
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. [22]
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. See the images below.
An 8-year-old boy with Morquio syndrome and severe kyphoscoliosis. Courtesy of Dennis P. Grogan, MD.
A 7-year-old girl with Morquio syndrome and typical severe genu valgum. Courtesy of Dennis P. Grogan, MD.
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. [23]
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. [23]
Dental complications include unerupted dentition, dentigerous cystlike follicles, malocclusions, condylar defects, and gingival hyperplasia. [24]
Altered metabolism of GAGs in the extracellular matrix can contribute to the development of the left ventricular aneurysm. [25]
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. [23]
Okamura et all reported a case of a 7-year-old Mongolian boy with a novel homozygous missense mutation, c.278 C>T, p.P93L, who had extensive large Mongolian spots on his back. [26] . Diffuse dermal melanocytosis, which is not common in mucopolysaccharidosis type VI, was also reported in a case of a 4-year-old girl. The faint gray lesion were presented on her back, shoulders, and buttocks from birth. [27]
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. [28]
A very rare finding is fetal hydrops. [29] 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. [30]
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. [31]
Cardiac abnormalities of mucopolysaccharidoses
In the study by Lin et al, 27 (96%) of 28 Taiwanese patients with mucopolysaccharidosis types I, II, IV-A, or VI had abnormal cardiac geometric features, including 57% with asymmetric septal hypertrophy, 46% with mitral valve prolapse, and 46% with diastolic dysfunction. They reported the effects of enzyme replacement therapy on cardiac structure and function. Enzyme replacement therapy appears to be effective in reducing intraventricular septal hypertrophy, and it may have better results when started at a younger age; however, it seemed to have little or no effect on valvular heart disease. [32]
Gniadek et al found changes that are consistent with, but expand on, the original description of Sly syndrome (mucopolysaccharidosis type VII) and appear to be typical of other mucopolysaccharidoses. The involvement of the coronary arteries and coronary arterioles suggests a combination of the features seen in mucopolysaccharidosis types I and II (large artery thickening with intimal proliferation), as well as mucopolysaccharidosis type VI (coronary arteriole intimal proliferation). [33]
Spinal involvement in mucopolysaccharidoses
Spinal involvement is common in patients with mucopolysaccharidosis type IV-A (Morquio A syndrome), type VI (Maroteaux-Lamy syndrome), type I (Hurler syndrome), type II (Hunter syndrome), type III (Sanfilippo syndrome), and VII (Sly syndrome). This includes musculoskeletal abnormalities such as dysostosis multiplex, flattening and elongation (platyspondyly) of the vertebral bodies, and wedge-shaped vertebral bodies with anterior beaking, resulting thoracolumbar kyphosis or even gibbus deformity and odontoid dysplasia. Spinal stenosis, which mainly results from focal or multilevel thickening of the connective tissues within the central spinal canal, particularly of the meninges, posterior longitudinal ligament, and flaval ligaments, is due to GAG deposition. Spinal cord compression may involve multiple spinal cord levels, but usually the craniocervical junction and thoracolumbar spine. It can be related to central spinal canal stenosis due to GAG deposits in the periodontoid tissue, supporting ligaments, and meninges, or to vertebral abnormalities, dysplasia of the odontoid process, ligamentous laxity, and invagination of the posterior arch of Atlas, leading to atlantoaxial subluxation and instability. [34]
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An 8-year-old boy with Morquio syndrome and severe kyphoscoliosis. Courtesy of Dennis P. Grogan, MD.
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A 7-year-old girl with Morquio syndrome and typical severe genu valgum. Courtesy of Dennis P. Grogan, MD.
Tables
Mucopolysaccharidosis Type |
Syndrome Name |
Deficiency |
EC Number |
MPS type I-H |
Hurler syndrome |
Alpha-L-iduronidase |
3.2.1.76 |
MPS type I-S (formerly MPS type V) |
Scheie syndrome |
Alpha-L-iduronidase |
N/A |
MPS type I-H/S |
Hurler-Scheie syndrome |
Alpha-L-iduronidase |
N/A |
MPS type II, mild |
Hunter syndrome, mild form |
L-sulfoiduronate sulfatase |
N/A |
MPS type II, severe |
Hunter syndrome, severe form |
L-sulfoiduronate sulfatase |
3.1.6.13 |
MPS type III-A |
Sanfilippo syndrome type A |
Heparan sulfate sulfamidase |
3.1.6.14 |
MPS type III-B |
Sanfilippo syndrome type B |
N -acetyl-alpha-D-glucosaminidase |
3.2.1.50 |
MPS type III-C |
Sanfilippo syndrome type C |
Acetyl-coenzyme A (CoA): alpha-glucosamide N -acetyltransferase |
2.3.1.3 |
MPS type III-D |
Sanfilippo syndrome type D |
N -acetyl-alpha-D-glucosamine-6-sulfatase |
3.1.6.14 |
MPS type IV-A |
Morquio syndrome, classic form |
N -acetylgalactosamine-6-sulfatase (gal-6-sulfatase) |
3.1.6.4 |
MPS type IV-B |
Morquiolike syndrome |
Beta-galactosidase |
3.2.1.23 |
MPS type VI |
Maroteaux-Lamy syndrome, mild form |
N -acetylgalactosamine-4-sulfatase (arylsulfatase B) |
N/A |
MPS type VI |
Maroteaux-Lamy syndrome, severe form |
N -acetylgalactosamine-4-sulfatase (arylsulfatase B) |
3.1.6.1 |
MPS type VII |
Sly syndrome |
Beta-glucuronidase |
3.2.1.31 |
