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.

Trusted Insights from Nemours' KidsHealth

Dwarfism

There's been a lot of discussion over the years about the proper way to refer to someone with dwarfism. Many people who have the condition prefer the term "little person" or "person of short stature." For some, "dwarf" is acceptable. For most, "midget" definitely is not.

But here's an idea everyone can agree on: Why not simply call a person with dwarfism by his or her name?

Being of short stature is only one of the characteristics that make a little person who he or she is. If you're the parent or loved one of a little person, you know this to be true.

But here are some facts that other people may not realize about dwarfism and those who have it.

Dwarfism:

  • is characterized by short stature. Technically, that means an adult height of 4 feet 10 inches or under, according to the advocacy group Little People of America (LPA).
  • can be caused by any one of more than 300 conditions, most of which are genetic. The most common type, accounting for 70% of all cases of short stature, is called achondroplasia.
  • can and most often does occur in families where both parents are of average height. In fact, 4 out of 5 of children with achondroplasia are born to average-size parents.

Dwarfism isn't:

  • an intellectual disability. A person who has dwarfism is typically of normal intelligence.
  • a disease that requires a "cure." Most people with one of these conditions live long, fulfilling lives.
  • a reason to assume someone is incapable. Little people go to school, go to work, marry, and raise children, just like their average-size peers.

What Causes Short Stature?

More than 300 well-described conditions are known to cause short stature in a child. Most are caused by a spontaneous genetic change (mutation) in the egg or sperm cells prior to conception. Others are caused by genetic changes inherited from one or both parents.

Similarly, depending on the type of condition causing the short stature, it is possible for two average-size parents to have a child with short stature, and is also possible for parents who are little people to have an average-size child.

What prompts a gene to mutate is not yet clearly understood. The change is seemingly random and unpreventable, and can occur in any pregnancy. If parents have some form of dwarfism themselves, the odds are much greater that their children will also be little people. A genetic counselor can help determine the likelihood of passing on the condition in these cases.

Dwarfism has other causes, including metabolic or hormonal disorders in infancy or childhood. Chromosomal abnormalities, pituitary gland disorders (which influence growth and metabolism), absorptive problems (when the body can't absorb nutrients adequately), and kidney disease can all lead to short stature if a child fails to grow at a normal rate.

Types of Short Stature

Most types of dwarfism are known as skeletal dysplasias, which are conditions of abnormal bone growth. They're divided into two types: short-trunk and short-limb dysplasias. People with short-trunk dysplasia have a shortened trunk with more average-sized limbs, whereas those with short-limb dysplasia have an average-sized trunk but shortened arms and legs.

By far, the most common skeletal dysplasia is achondroplasia, a short-limb dysplasia that occurs in about 1 of every 15,000 to 40,000 babies born of all races and ethnicities. It can be caused by a spontaneous mutation in a gene called FGFR3, or a child can inherit a change in this gene from a parent who also has achondroplasia.

People with achondroplasia have a relatively long trunk and shortened upper parts of their arms and legs. They may share other features as well, such as a larger head with a prominent forehead, a flattened bridge of the nose, shortened hands and fingers, and reduced muscle tone. The average adult height for someone with achondroplasia is a little over 4 feet.

Diastrophic dysplasia is a different form of short-limb dwarfism. It occurs in about 1 in 100,000 births, and is also sometimes associated with cleft palate, clubfeet, and ears with a cauliflower-like appearance. People who have this diagnosis tend to have shortened forearms and calves (this is known as mesomelic shortening).

Spondyloepiphyseal dysplasias (SED) refers to a group of various short-trunk skeletal conditions that occurs in about 1 in 95,000 babies. Along with achondroplasia and diastrophic dysplasia, it is one of the most common forms of dwarfism. In some forms, a lack of growth in the trunk area may not become apparent until the child is between 5 and 10 years old; other forms are apparent at birth. Kids with this disorder also might have clubfeet, cleft palate, and a barrel-chested appearance.

In general, dwarfism caused by skeletal dysplasias results in what is known as disproportionate short stature — meaning the limbs and the trunk are not the same proportionally as those of typically-statured people.

Metabolic or hormonal disorders typically cause proportionate dwarfism, meaning a person's arms, legs, and trunk are all shortened but remain in proportion to overall body size.

Diagnosis

Some types of dwarfism can be identified through prenatal testing if a doctor suspects a particular condition and tests for it.

But most cases are not identified until after the child is born. In those instances, the doctor makes a diagnosis based on the child's appearance, failure to grow, and X-rays of the bones. Depending on the type of dwarfism the child has, diagnosis often can be made almost immediately after birth.

Once a diagnosis is made, there is no "treatment" for most of the conditions that lead to short stature. Hormonal or metabolic problems may be treated with hormone injections or special diets to spark a child's growth, but skeletal dysplasias cannot be "cured."

People with these types of dwarfism can, however, get medical care for some of the health complications associated with their short stature.

Some forms of dwarfism also involve issues in other body systems — such as vision or hearing — and require careful monitoring.

Possible Complications and Treatments

Short stature is the one quality all people with dwarfism have in common. After that, each of the many conditions that cause dwarfism has its own set of characteristics and possible complications.

Fortunately, many of these complications are treatable, so that people of short stature can lead healthy, active lives.

For example, a small percentage of babies with achondroplasia may experience hydrocephalus (excess fluid around the brain). They may also have a greater risk of developing apnea — a temporary stop in breathing during sleep — because of abnormally small or misshapen anatomy or, more likely, because of airway obstruction by the adenoids or the tonsils. Occasionally, a part of the brain or spinal cord is compressed. With close monitoring by doctors, however, these potentially serious problems can be detected early and surgically corrected.

As a child with dwarfism grows, other issues may also become apparent, including:

  • delayed development of some motor skills, such as sitting up and walking
  • a greater susceptibility to ear infections and hearing loss
  • breathing problems caused by small chests
  • weight problems
  • curvature of the spine (scoliosis, kyphosis, and/or lordosis)
  • bowed legs
  • trouble with joint flexibility and early arthritis
  • lower back pain or leg numbness
  • crowding of teeth in the jaw

Proper medical care can alleviate many of these problems. For example, surgery often can bring relief from the pain of joints that wear out under the stress of bearing weight differently with limited flexibility.

Surgery also can be used to improve some of the leg, hip, and spine problems people with short stature sometimes face.

Nonsurgical options may help, too — for instance, excessive weight can worsen many orthopedic problems, so a nutritionist might help develop a healthy plan for shedding extra pounds. And doctors or physical therapists can recommend ways to increase physical activity without putting extra stress on the bones and joints.

Helping Your Child

Although types of dwarfism, and their severity and complications, vary from person to person, in general a child's life span is not affected by dwarfism. Although the Americans with Disabilities Act protects the rights of people with dwarfism, many members of the short-statured community don't feel that they have a disability.

You can help your child with dwarfism lead the best life possible by building his or her sense of independence and self-esteem right from the start.

Here are some tips to keep in mind:

  • Treat your child according to his or her age, not size. If you expect a 6-year-old to clean up his or her room, don't make an exception simply because your child is small.
  • Adapt to your child's limitations. Something as simple as a light switch extender can give a short-statured child a sense of independence around the house.
  • Present your child's condition — both to your child and to others — as a difference rather than a hindrance. Your attitude and expectations can have a significant influence on your child's self-esteem.
  • Learn to deal with people's reactions, whether it's simple curiosity or outright ignorance, without anger. Address questions or comments as directly as possible, then take a moment to point out something special about your child. If your child is with you, this approach shows that you notice all the other qualities that make him or her unique. It will also help prepare your child for dealing with these situations when you're not there.
  • If your child is teased at school, don't overlook it. Talk to teachers and administrators to make sure your child is getting the support he or she needs.
  • Encourage your child to find a hobby or activity to enjoy. If sports aren't going to be your child's forte, then maybe music, art, computers, writing, or photography will be.
  • Finally, get involved with support associations like the Little People of America. Getting to know other people with dwarfism — both as peers and mentors — can show your child just how much he or she can achieve.

Reviewed by: Angela L. Duker, MS, CGC
Date reviewed: March 2011