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. [1, 2, 3, 4]
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. [1, 2, 3, 4]
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. [1, 2, 3, 4, 5, 6, 7, 8] 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). [1] The same year, Brailsford also reported a patient with MPS IV. [2] 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. [1]
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]). [3] In 1965, McKusick et al classified Morquio syndrome, as well as Hurler and Hunter syndromes, as hereditary acid mucopolysaccharidoses (MPS I to MPS VI). [9]
In 1971, Orii et al reported an attenuated (intermediate) form of MPS IVA. [4] 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. [8] 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. [10] 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. [11] 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. [12] 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. [13]
Morquio A syndrome varies from severe systemic bone dysplasia to a lesser form of the disease, including only mild bone involvement. [4, 5, 6, 7, 12, 13, 14, 15, 16, 17] See the image below.
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.
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. [7] 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. [10, 11] 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.
Pathophysiology
Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases caused by a deficiency of lysosomal enzyme(s). Excessive accumulation of GAGs such as dermatan sulfate (DS), heparan sulfate (HS), chondroitin sulfate (CS), and KS in multiple tissues leads to coarse facial features, CNS damage, organomegaly, connective tissue disorders, and skeletal dysplasia. GAGs accumulate in lysosomes, intracellular matrix, and extracellular matrix. MPS is categorized into 7 groups, with 11 different deficient lysosomal enzymes.
In Morquio syndrome, the degradation of KS is defective because of deficiency of either GALNS in Morquio A syndrome or β-galactosidase in Morquio B syndrome. Deficiency of GALNS also influences the catabolism of C6S. KS and C6S have various physiological and biological functions. Both Morquio A syndrome and Morquio B syndrome are inherited through an autosomal-recessive trait. KS is closely involved in cellular motility, embryo implantation, wound healing, corneal transparency, and nerve regeneration. [18] C6S is also involved in embryo development, maintaining mechanical skin strength and cell proliferation.
Epidemiology
Morquio A Syndrome
The incidence of Morquio A syndrome is 1 per 216,000 births in the British Columbia, [19] 1 per 76,000 births in Northern Ireland, [20] 1 per 201,000 births in Australia, [21] 1 per 450,000 births in Portugal, [22] 1 per 640,000 births in Western Australia, [23] and 1 per 625,000 births in Japan. [7] Data on Morquio A syndrome incidence in the United States are not available.
Morquio B Syndrome
To date, no epidemiological studies on the incidence of Morquio B syndrome have been conducted. However, the incidence of Morquio B syndrome is much lower than that of Morquio A syndrome.
Prognosis
Patients with the severe form of Morquio syndrome can develop cervical myelopathy early. [24, 25] Those with the severe form do not survive past their second or third decade of life if untreated. [25] Two-thirds of patients die of respiratory distress followed by cardiac issues. [26] A shorter-than-usual lifespan might also be attributed to paralysis caused by myelopathy, restrictive chest movement, and valvular heart disease. [24, 26] Owing to advancements made in comprehensive care, the lifespan among patients with Morquio syndrome is improving.
Patients with mild manifestations of Morquio syndrome (mucopolysaccharidosis type IV), regardless of type, have been reported to survive into the seventh decade of life.
Patients with severe manifestations, primarily related to cervical instability and pulmonary compromise, often do not survive beyond the second or third decade of life.
The length of survival may improve with the improved comprehensive care available to these patients today.
Patient Education
Many resources are available to patients with Morquio syndrome and their families to increase their understanding of the disorder, including the following:
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International Morquio Organization ( The Carol Ann Foundation)
It is also important to educate the patient’s primary physicians, teachers, counselors, school administrators, and classmates to help them understand the unique needs of an individual with Morquio syndrome.
Morquio syndrome does not affect fertility, and a child born to a parent with Morquio syndrome will be a carrier but will not have Morquio syndrome unless he or she partners with another Morquio syndrome carrier. Then, the risk is 25% that their offspring will have Morquio syndrome. As in all autosomal-recessive conditions, if both parents have the same subtype of Morquio syndrome, they will have a 100% chance of having offspring with Morquio syndrome.
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Lateral view of spine in a child aged 8 years and 7 months. This radiograph shows advanced platyspondyly, irregularity, and anterior beaking of vertebral bodies characteristic of dysostosis multiplex. Note also the gibbus deformity and lordosis, which are characteristic of Morquio syndrome.
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Cervical spine, flexion and extension views, in a child aged 5 years and 11 months. These flexion and extension images depict anterior and posterior subluxation, respectively, of the atlas secondary to odontoid hypoplasia.
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Bilateral lower extremity views in a patient aged 22 years and 6 months. Metaphyseal irregularities and the characteristic genu valgus deformity are easily observed in this image.
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Bilateral hand radiographs in a patient aged 22 years and 6 months. Note the tapering of the proximal portion of metacarpals 2 through 5 and small irregular carpal bones. The epiphyseal involvement characteristic of Morquio syndrome is exemplified by the tapered irregular distal radius and ulna. Overall, the bones are osteopenic with cortical thinning.
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Upper extremities in a child aged 6 years and 11 months. Note the irregular epiphyses and widened metaphyses. Cortical thinning and mild widening of the diaphysis of the humerus are visible.
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Multiple abnormalities are present in the pelvis, including dysplastic femoral heads and oblique acetabular roof with coxa valgus deformity. Flared iliac wings usually observed in Morquio syndrome are not well represented in this radiograph.
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Anteroposterior view of the chest in a child aged 8 years and 4 months with Morquio syndrome. To reference the relatively small size of this chest, this patient's vital capacity was 500 cc, but the expected value based on height and weight was 1400 cc. Widened metaphyses and irregular epiphyses of the humeri and generalized platyspondyly are present. Oar-shaped ribs (widening ribs anteriorly and narrowing at the vertebrae) are easily observed and are another key characteristic of dysostosis multiplex.
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Defects in keratan sulfate (KS) degradation resulting in Morquio syndrome.
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The individual on the front of the scooter is 19 years old and has Morquio syndrome. Her friend on the back is an average-stature 10 year old without Morquio syndrome. On the driver, note the enlargement at the knees and the wrist deformity. Also, note the successful adaptation of the scooter to ambulate.
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Note the short trunk and protuberant rib structure in this child with Morquio syndrome. More importantly, notice that Morquio syndrome is not preventing this child from being active and fishing.
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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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Clinical features of a patient with Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]). This patient had a severe form of MPS IVA at age 3 years and had bone abnormalities of pectus carinatum, kyphoscoliosis, genu valgum, short stature, prominent forehead, and abnormal gait (height, 90 cm; 50th percentile of male MPS IVA growth chart; body weight, 14 kg). Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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MRI of the cervical spine in a patient aged 4 years. A baseline study of the upper cervical anatomy is recommended no later than age 2 years or at diagnosis using flexion/extension radiography. If severe pain or pain associated with weakness or strength or tremors (or clonus) in the arms or legs occurs, the patient should undergo studies of the neck to evaluate for the slippage (subluxation) of the neck vertebrae and compression of the spinal cord. Radiography and MRI are performed with the head bent forward (flexion) and with the neck back (extension) and is performed annually for monitoring. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Clinical picture of hip deformity in an 8-year-old patient with Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]). Multiple abnormalities are shown in the hip, including spondyloepiphyseal dysplastic femoral heads, oblique acetabular roof with coxa valgus deformity, and flared iliac wings. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Skeletal/joint disease - hands. Bilateral hand radiographs in a patient aged 6 years. Note the tapering of the proximal portion of metacarpals 2 through 5 and small irregular carpal bones. The joints may become hyperlaxity by age 2 years. Eventually, the hands take on a characteristic tilting of the radial epiphysis toward the ulna due to a combination of metaphyseal deformities, hypoplasia of the bones, and degradation of connective tissues near the joint secondary to GAG accumulation. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Skeletal/joint disease - hands. The epiphyseal involvement characteristic of Morquio syndrome is exemplified by the tapered irregular distal radius and ulna. Overall, the bones are osteopenic with cortical thinning. Upper extremities in a child aged 2 years, 3 months (left panel). Note the irregular epiphyses and widened metaphyses. Cortical thinning and mild widening of the diaphysis of the humerus are visible. With aging, the bone deformity progresses, eg, with the tilting of the radial epiphysis toward the ulna. The humerus usually appears shortened later. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Skeletal/joint disease - hands. Unlike other mucopolysaccharidoses, Morquio syndrome is associated with ligamentous laxity. The cause of abnormal joint function remains unknown, presumably derived from a combination of metaphyseal deformities, hypoplasia of the bones, and degradation of connective tissues near the joint secondary to GAG accumulation. The wrist and fingers (small joints) are usually extremely weak, resulting in a very weak grip. Difficulties with dressing, personal hygiene, and writing can result from this hypermobile ligament. Range-of-motion exercises, swimming, and computer typing appear to offer some benefits in preserving joint function and fine motor skills and should be started early in the clinical course. Wrist splints and plastic braces may benefit fine motor functioning. The indication of physical therapy and its benefits in Morquio syndrome should be studied further. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Skeletal/joint problem – hands and legs. This 10-year-old patient with Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]) showed skeletal habitus with a disproportionate short stature of short trunk type with relatively long extremities. The upper extremities show lateral bowing and prominence of the radius. In the lower extremities, there is genu valgum (knocked knee). A skew foot posture is seen in both feet, as well as increased sandal gap between toes 1 and 2. Extreme ligamentous laxity permits very hypermobile knees, fingers, and wrists. The feet show pronated pes planus. Muscle bulk is reduced, particularly in the extremities. Generalized mild to moderate hypotonia is present. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Spinal cord pathophysiology. Odontoid hypoplasia is the most critical skeletal feature to be recognized in any patient with Morquio syndrome (mucopolysaccharidosis type IV [MPS IV]). This, in combination with ligamentous laxity and extradural mucopolysaccharide deposition, results in atlantoaxial subluxation, with consequential quadriparesis or even death. Another potential complication is cervical myelopathy. A history of exercise intolerance in patients with MPS IV often predicts occult cervical myelopathy, which can also cause bowel and bladder dysfunction and compression of the spinal cord, leading to weakness or paralysis. Mortality and morbidity are primarily related to the atlantoaxial instability and subsequent cervical myelopathy, and patients with a severe form, primarily related to cervical instability, often do not survive beyond the second or third decade of life. A minor fall or extension of the neck can result in spinal cord injury and subsequent quadriparesis or sudden death. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Pathophysiology of difficult airway in Morquio A syndrome. Both restrictive and obstructive respiratory pathology are common in patients with Morquio A syndrome. The restrictive defect results from thoracic cage deformity, and the obstructive defect is caused by tracheobronchial abnormalities, large tongue and mandible, adenoidal, tonsillar, and vocal cord hypertrophy by the accumulation of storage materials. An imbalance of growth between trachea, cervical spine, and brachiocephalic artery causes tracheal obstruction. Moreover, individuals with Morquio A syndrome have small nasal passages caused by thickened mucous membranes and thick and copious secretions. Chronic upper respiratory tract infection further decreases the already diminished airway lumen. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
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Tracheal obstruction. CT angiography in a 29-year-old patient shows severe tracheal obstruction. Tracheal narrowing (T; trachea), often due to compression from the crossing brachiocephalic (innominate) artery, increases with age. Note the position of the brachiocephalic artery (A) anterior to the trachea. Cervicothoracic spine moves forward while a severe pectus carinatum (M: manubrium) compresses backward. Courtesy of the Carol Ann Foundation; image adapted from Educational CD for International Morquio Organization.
