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HomePediatrics: Genetics and Metabolic DiseaseMorquio Syndrome (Mucopolysaccharidosis Type IV)

Morquio Syndrome (Mucopolysaccharidosis Type IV)

Background

Morquio syndrome (mucopolysaccharidosis type IV [MPS IV]) is a rare lysosomal storage disease (LSD) that is inherited in an autosomal-recessive fashion. Morquio syndrome is classified into two types, Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]; OMIM 253000) and Morquio B syndrome (mucopolysaccharidosis type IVB [MPS IVB]; OMIM 253010), based on a deficiency of different lysosomal enzymes—N-acetylgalactosamine-6-sulfate sulfatase (GALNS) and β-galactosidase, respectively. GALNS deficiency induces the accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS), and chondroitin-6-sulfate (C6S) in multiple tissues, particularly bone, cartilage, heart valves, and cornea, while β-galactosidase deficiency induces the accumulation of only KS in those tissues.

Morquio syndrome is characterized by a unique skeletal dysplasia with excessive accumulation of KS and/or C6S. Although most individuals with Morquio syndrome appear normal at birth, skeletal abnormalities often develop within the first year of life. At birth, some affected newborns may have a minor skeletal phenotype, such as hump back, chest protrusion, and prominent forehead, as confirmed with radiography.

Skeletal dysplasia is characterized by incomplete ossification and successive imbalance of growth, which results in a prominent forehead, abnormal face with a large mandible, short neck, cervical spinal cord compression, tracheal obstruction, disproportionate short-trunk dwarfism, pectus carinatum, flaring of the rib cage, coxa valga, genu valgum, hypermobile joints, and pes planus.
The severity of bone and cartilage damage differs by the type of bone affected. Affected bone with growth plate is affected more severely.

In 1929, Morquio first reported four Swedish patients with MPS IV (now classified as MPS IVA).
The same year, Brailsford also reported a patient with MPS IV.
Clinical features of MPS IV described at the time included prominent forehead, abnormal face with a large mandible, short neck, pectus carinatum, flaring of the rib cage, hypermobile joints, genu valgum, disproportionate short-trunk dwarfism, and pes planus; however, aortic valve disease and corneal clouding were not described in the original publication.

In 1962, Pedrini et al isolated and identified KS in the urine of three patients with Morquio syndrome and reported that this metabolic disorder differs from that observed in Hurler syndrome (mucopolysaccharidosis type I [MPS I]).
In 1965, McKusick et al classified Morquio syndrome, as well as Hurler and Hunter syndromes, as hereditary acid mucopolysaccharidoses (MPS I to MPS VI).

In 1971, Orii et al reported an attenuated (intermediate) form of MPS IVA.
At age 5 months, adduction of both thumbs was recognized, and, at age 18 months, a chest abnormality was noticed. At age 3 years, the patient had kyphosis, and an abnormal gait was present by age 5 years. The patient had keratosulfaturia and was diagnosed enzymatically with Morquio A syndrome at age 15 years. At age 18 years, he was 135 cm tall and showed milder skeletal deformities, such a pectus carinatum, hypermobile joints, and genu valgum, in addition to corneal clouding.

In 1974, GALNS enzyme and its deficiency were discovered and identified using oligosaccharide substrate prepared from C6S containing N-acetylgalactosamine-6-sulfate.
In 1976, O’Brien et al reported a patient with a mild clinical status similar to that of Morquio A syndrome. However, this patient was deficient in β-galactosidase.
In 1977, Arbisser et al reported a similar case with mild Morquio A syndrome–like symptoms resulting from a deficiency of β-galactosidase, described as MPS IVB.
Since then, Morquio syndrome has been differentiated into two forms, Morquio A syndrome and Morquio B syndrome.

In 1981, Orii et al reported a very mild form of Morquio A syndrome in two siblings.
Their initial symptom was hip joint pain at age 8 years; thus, both patients underwent femoral osteotomy at age 13 years. Both patients had keratosulfaturia, mild thorax changes, and corneal clouding, although they did not show unique pectus carinatum, genu valgum, excessive joint laxity, or facial changes. Initial radiographic studies in both cases revealed mild platyspondyly, slight anterior wedging of the lumbar vertebra, and minimal odontoid hypoplasia, as well as subtle capital femoral epiphyses. However, when they were aged 18 and 22 years, respectively, the ossified femoral heads had disappeared with erosion and widening of the femoral necks. These signs were more significant in the older brother. The two brothers were not diagnosed with Morquio A syndrome until age 29 and 25 years, respectively, and their heights were 147 and 157 cm, respectively. In 2015, they were age 52 and 57 years, respectively, and their clinical conditions were stable at the time. GALNS enzyme activity in fibroblasts of these patients was about 10% of that seen in cells from healthy controls.

Morquio A syndrome varies from severe systemic bone dysplasia to a lesser form of the disease, including only mild bone involvement.
See the image below.

Clinical pictures of patients with Morquio A syndr

Clinical pictures of patients with Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]). Left panel: a 31-year-old female patient with a severe form. Middle panel: an 18-year-old male patient with an intermediate form. Right panel: a 25-year-old male patient with a mild form. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.

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Individuals with untreated severe Morquio A syndrome die of respiratory obstruction, cervical spinal cord complications, or heart valve disease in their second or third decade of life. The lifespan of individuals with the attenuated form of Morquio A syndrome has been noted to be as long as 70 years.
The height prognosis is poor among individuals with severe bone dysplasia. Intellectual impairment does not occur in Morquio A syndrome.

Historically, Morquio B syndrome was considered to have milder manifestations than Morquio A syndrome. The clinical manifestations of Morquio B syndrome include platyspondyly, femoral epiphyses, atlanto-occipital instability, genu valgum, gait abnormalities, and cornel clouding. Morquio B syndrome is associated with normal or near-normal stature with normal neck development and absence of hearing loss and hepatomegaly.
The skeletal involvement in Morquio B syndrome is not as pronounced as in Morquio A syndrome. However, radiographic and other phenotypical analysis cannot be used to differentiate between Morquio A and Morquio B syndrome because of the extensive overlap, which depends on the skeletal symptoms, the enzyme activity, recognition of complications, and response to surgery, among other factors.

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