Morquio Syndrome

Morquio Syndrome is another name for mucopolysaccharidosis IV (MPS IV); it was first described by Luis Morquio in 1919 (4). The frequency of Morquio syndrome is 1 in 640,000 births (7).

 
How Morquio Syndrome Is Inherited

Morquio syndrome follows an autosomal recessive inheritance pattern (9).

 
Causes of Morquio Syndrome

A mutation is the GALNS gene, which encodes for N-acetyl galactosamine-6-sulfatase, causes Morquio, type A (4). Type B is caused by mutations of the GLB1 gene, which encodes for β-galactosidase (4). Both enzymes, however, are responsible for keratan sulfate degradation. In type A, the activity of the sulfatase was found to be less than 1% (6). Due to the enzymes’ ineffectiveness, mucopolysaccharides aggregate within intracellular lysosomes. Mucopolysaccharides are long, unbranched chains of repeating saccharide, or sugar, units. They are important components of the body’s connective tissues and are often times covalently linked to proteins. In Morquio Syndrome, the lysosomal enzymes that are responsible for breaking down mucopolysaccharides are ineffective. As a result, the long sugar molecules begin to collect in the body’s cells and connective tissues. The accumulation ultimately causes cellular damage that manifests as skeletal malformations.

 
Physical Characteristics
Face & Skull
  • Mildly coarse facial features
  • Accentuated lower portion of the face
  • Broad mouth
  • Short anteverted nose
  • Corneas of the eyes become cloudy
  • Widely spaced teeth
  • Hypoplasia of tooth enamel
Trunk, Chest, & Spine:
  • Barrel shaped chest
  • Flaring lower rib cage
  • Prominent sternum
  • Stunted neck and trunk
  • Considerably short spine marked platyspondyly
  • Abnormal posture
Arms & Legs:
  • Severe flexion deformities of the limbs
  • Ligamentous laxity, especially at the wrists and small joints
  • Joint restriction prominent at the larger joints, most notably at the hips
  • Awkward gait
  • Knock-knees
  • Flat feet
  • Prominent buttocks
  • Short and stubby hands
What are the X-ray characteristics?

The major radiographic features of Morquio syndrome include marked platyspondyly in the thoracic and lumbar spine. The shape of the vertebrae change from ovoid, to ovoid with anterior projection, to flat. 

Odontoid hypoplasia with atlanto-axial instability is typical. With progression of the disease, acute thoracolumbar kyphosis is possible; the first indication of spinal cord compression is at the level of C1/C2.The skull is mildly dolichocephalic with underdevelopment of mastoid cells and flat or concave mandibular condyles. A flaring lower rib cage with pectus carinatum is typical of the thorax. 

A premature fusion of the ossification centers of the sternum usually occurs. The long bones are short and curved, with irregular tabulation. Metaphyses are irreguarly wide. Ossification centers tend to develop slowly. Coxa valga is characteristic, along with an abnormal femoral neck and flattening of the femoral head. 

Genu Valgus and a medial spur of tibial metaphysis are often times seen. The bases of the second through fifth metacarpals are conically shaped. The feet have irregular contour with delayed ossification of the tarsal bones. There is central constriction and general shortness of the metacarpals and phalanges.

 
Making the Diagnosis

Morquio Syndrome is typically not recognized at birth. Onset does not occur until the second to fourth year of life. The most frequently recognized symptoms include gait disturbance and growth deficiency.

Diagnostic procedures include flexion-hyperextension radiographs of the cervical spine and/or MRI of the cervical or thoracolumbar spine.

To confirm the diagnosis, two-dimension electrophoresis or thin-layer chromatography of isolated urinary glycosaminoglycans is employed.

Heterozygote detection is possible.

Prenatal recognition can be done using amniotic fluid cells and chorionic villi.

 
Musculoskeletal Problems
Lower Limbs

Pectus carinatum and knock-knee deformity (genu valgus) begin at approximately 3 years of age, and progressively worsen as growth continues. Ligamentous laxity plays a part in the development of knock-knee. In severe cases, the knock-knee may interfere with ambulation. Around age 7 or 8, a patient typically has a lower limb osteotomy to correct the deformity. Typically, the outcome is good, and the results are permanent because growth typically stops around this age. However, due to the habitual atlantoaxial instability, neurological integrity may be compromised, and patients have considerable difficulty in learning to walk again.

Hips

Dislocation of the hips is typically observed, especially as weight-bearing increases. The dislocation, however, is asymptomatic and usually does not impair function. Therefore, most patients abstain from surgical intervention. Yet if patients are considerably physically active, especially as adults, symptomatic osteoarthritis of the hip may develop.

Upper Limbs

Ligamentous laxity is severe, especially of the wrists and ankles. The force able to be delivered by the long flexors of the fingers and thumbs becomes considerably weak. The wrists need to be stabilized, which will help to increase the effectiveness of the muscles and to improve function. Wrist fusions have been attempted, however most attempts have failed.

Spine

Atlanto-axial instability along with myelopathy of the upper cervical spinal cord is a severe problem. Upper motor neurons begin to lose function, there is vague pain in the lower limbs, superficial paresthesias of the feet, vibratory sensation progressively worsens, mobility becomes impaired, and the ability to control the sphincters and to breathe is compromised. If left untreated, most males lose their ability to walk and may possibly die of chronic respiratory failure. The course is typically not as severe in female patients. The rate of progression of cervical myelopathy is variable, however surgical intervention is needed to halt the downward trend. Fusion of the upper cervical spine is frequently recommended. However, care must be taken when administering the anesthesia, due to the risks associated with atlanto-axial instability. Spinal fusion may be supplemented by instrumentation (metal implants) to support the bones until the fusion mass consolidates. In cases of diagnostic doubt, further information can be obtained by means of an MRI scan (with flexion-extension views and CSF flow studies). It allows accurate determination of the degree of spinal cord compression and space available for the cord.

 
Problems Elsewhere in the Body
Respiratory

By late teens and adulthood, the ribs are nearly horizontal and the sagittal diameter of the chest is greater than average. As a result, respiratory expansion becomes considerably impaired. Moreover, frequent upper respiratory tract infections, including otitis media, may occur due to the malformation of the rib cage. The trachea is narrow and may collapse during head flexion. Lung function tests and sleep studies are frequently used to diagnose breathing problems in skeletal dysplasias. Regular review by a pulmonologist is recommended. Prolonged breathing difficulties may warrant a tracheostomy and long-term ventilatory support.

Cardiac

Cardiac complications may occur, including cardiomyopathy, valvular disease, or a late onset of aortic regurgitation. Cardiac anomalies are predominately left sided. Severe cases have resulted in death before the age of 20.

Ear

Hearing loss, inguinal hernia, and hepatomegaly are all problems associated with the ear. Hearing aids and tubes are often times required.

Eye

Corneal opacity is typical once patients reach age 5; glaucoma of the eyes and pigmentary retinal degeneration may occur in older patients. Ophthalmologic examination is needed at frequent intervals.

Skin

Cutaneous abnormalities may also be present, including loose, thickened, tough, and inelastic skin, particularly of the extremities. Generalized telangiectasia of the face and limbs has also been reported.

Teeth

Appropriate dental care is required due to the hypoplasia of tooth enamel. Teeth often brown and discolor easily. The permanent posterior teeth have pointed cusps; there is often times pitting of the bucal surfaces. The teeth are also widely spaced.

Mental Capacity

Intelligence and mentality is typically not impaired in Morquio type A. However, progressive mental deficiency does occur in Morquio Type B.

 
What to Look For

Although the first 18 months are characterized by relatively normal development, beyond this age, Morquio patients tend to decline, especially in proportionate growth and mobility.

Any change in walking ability, endurance, or breathing merits further assessment by a physician to rule out spinal cord compression. Specific neurological symptoms such as tingling or numbness in the arms or legs, weakness, shooting leg or arm pain, or problems controlling bladder/ bowel function should be investigated further.

Considering that eye and teeth problems are especially associated with Morquio Syndrome, ophthalmologic consultation and dental examinations are recommended for early detection and treatment.

Generally all skeletal dysplasias warrant multidisciplinary attention. Regular assessment by an orthopedist, geneticist, pediatrician, dentist, neurologist, and physical therapist will provide the most comprehensive treatment.

 
References
  1. Cole, D.E.C. Fukuda, S. Gordon, B.A. Rip, J.W. LeCouteur, A.N. Rupar, C.A. Tomatsu, S. Ogawa, T. Sukegawa, K. Orii, T. Heteroallelic Missense Mutations of the Galactosamine-6-Sulfate Sulfatase (GALNS) Gene is a Mild Form of Morquio Disease (MPS IVA) American Journal of Medical Genetics. 63: 558-565. 1996.
  2. Giugliani, R. Jackson M. Skinner S.J. Vimal C. M. Fensom A. H. Fahmy A. Sjövall. Beson, P. F. Progressive mental regression in siblings with Morquio disease Type B (mucopolysaccharidosis IV B). Clinical Genetics. 32: 313-325. 1987.
  3. Greaves, M.W. Inman, P. M. Cutaneous Changes in the Morquio Syndrome. Br. J. Derm. 81: 29-36. 1969.
  4. Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006
  5. Kopits, Steven E. Orthropedic Complications of Dwarfism. Clinical Orthopedics and Related Research. 144: 153-179. 1976.
  6. Matalon, R.; Arbogast, B.; Dorfman, A. Morquios syndrome: a deficiency of chondroitin sulfate N-acetylhexosamine sulfate sulfatase. (Abstract) Pediat. Res. 8: 436, 1974.
  7. Nelson, J.; Crowhurst, J.; Carey, B.; Greed, L. Incidence of the mucopolysaccharidoses in western Australia. Am. J. Med. Genet. 123A: 310-313, 2003.
  8. Scott, Charles I. Dwarfism. Clinical Symposium, 1988; 40(1):9-10.
  9. Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.
  10. Taybi, Hooshang. Lachman, Ralph S. Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias. St. Louis, MO: Mosby-Year Book, Inc. 1996.

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