Larsen Syndrome

views updated

Larsen syndrome

Definition

Larsen syndrome is an inherited condition characterized by congenital dislocation of multiple body joints along with other unusual features of the face, hands, and bones.

Description

This condition was first described in 1950 by Larsen, Schottstaedt, and Bost, who compiled information on six people with sporadic cases of Larsen syndrome.

Larsen syndrome has been called both a skeletal dysplasia (a condition caused by abnormalities of bone structure), and a hypermobility syndrome (a condition involving abnormally loose joints). It is most likely caused by inherited abnormalities of connective tissue that affect both bone and joint structure.

Present at birth are multiple dislocations of the elbows, hips, and most commonly the knees. Persons with Larsen syndrome have other distinctive physical features that can include a prominent forehead, widely spaced eyes, long cylindrical fingers, and short bones of the hand. Sometimes present are other birth defects such as structural heart defects, cleft palate, cataracts, extra bones of the wrist, and abnormalities of the vertebrae.

Most people have moderate symptoms that can be treated, allowing for a relatively normal life span. However, a small number of babies have a severe form of the condition and die at birth.

Genetic profile

There are likely to be multiple different causes for Larsen syndrome. Both recessive and dominant patterns of inheritance have been described thus far.

Some cases are sporadic, meaning the affected person is the first in the family to have the condition. Many sporadic cases are thought to be caused by new dominant mutations (spontaneous changes in the genetic material). A person with sporadic Larsen syndrome has a change in the genetic material that is not present in either parent but can be passed on, with 50/50 odds in each child, to his or her offspring.

Patients have been reported who have affected brothers or sisters but unaffected parents. Most of these cases probably represent a recessive form of Larsen syndrome in which a person must have two copies of a genetic change in order to be affected. The parents of a person with a recessive condition must each have one copy of the genetic change in order to have an affected child.

There are rare instances in which a person with Larsen appears to have the recessive form but then gives birth to an affected child. These cases are most likely dominant rather than recessive. It can be difficult to be certain of the inheritance pattern in some families and genetic counselors must be careful to address both forms of inheritance when discussing chances of recurrence.

The autosomal dominant form of Larsen syndrome is thought to be due to mutations in a gene called LAR1, on the short arm of chromosome 3. The exact structure and function of this gene is not yet known. There may be other genes responsible for a proportion of cases of dominant Larsen syndrome; however, no other candidate genes have been located.

Another dominantly inherited condition called Atelosteogenesis Type III (AOIII) has features which overlap with Larsen syndrome, and may, in fact, be a variant of Larsen caused by mutations in the same gene.

Demographics

Larsen syndrome is an extremely rare genetic condition that occurs in about one in every 100,000 births.

A variant of Larsen syndrome is found in high frequency on La Reunion island near East Africa. Over 40 affected children have been reported, with an incidence of one in 1,500 births. This variant is thought to be recessive but the responsible gene has not yet been located.

Signs and symptoms

The symptoms of Larsen syndrome are widely variable from person to person and can range from lethal to very mild, even among members of the same family.

Typical characteristics at birth are multiple joint dislocations that can include hips, elbows, wrists, and knees. Babies can be born with their knees in hyperextension with their ankles and feet up by their ears, a deformation called genu recurvatum. Clubfoot is common and persistent flexion, or contractures, of other joints, such as the wrist and fingers, can also occur.

Persons with Larsen syndrome often have distinctive facial features. Common findings, in addition to a large forehead and wide spaced eyes, are flat cheekbones and a flat bridge of the nose, which is sometimes indented and called "saddle nose." The hands are often short but the fingers are long and lack the normal tapered ends.

Other birth defects can occur but are not present in all people. Cleft palate, cataracts, and heart defects of the valves or between the upper or lower chambers occur occasionally.

Often, babies have floppy muscle tone giving them a "rag doll" appearance. Respiratory problems are frequently seen at birth because of laxity of the trachea. Feeding and swallowing difficulties are common.

Abnormalities of the bones are frequent. Underdevelopment and abnormal shape of some of the vertebral bones can lead to problems such as scoliosis or kyphosis. Abnormalities of the epiphyses (centers of bone growth) can develop in childhood. Height is often reduced, and an adult height of four to five feet is not uncommon. The joints between the bones of the ear may be abnormal and may cause conductive hearing loss.

Hypermobility of joints lasts throughout life and may lead to early-onset arthritis, recurrent dislocations, and may necessitate joint replacement at an early age. Cervical spine instability is a very serious complication of Larsen syndrome as it can cause compression of the spinal cord and lead to paralysis or death.

The condition does not affect intelligence and children can expect to have normal school experiences, with the exception of physical education, which will need to be adapted to each child's needs.

Diagnosis

Larsen syndrome should be suspected in any baby having multiple joint dislocations at birth. As of 2001, there is no genetic test to confirm the diagnosis and, thus, diagnosis must be based on clinical and x ray findings. Babies suspected to have the condition warrant a complete evaluation by a medical geneticist (a physician specializing in genetic syndromes).

Larsen syndrome is sometimes misdiagnosed as another condition called arthrogryposis, which involves multiple joint contractions. Larsen syndrome can be distinguished from this and other syndromes involving joint dislocations or contractions because of the unusual constellation of features found in the face and hands. Extra bones of the wrist, often seen in Larsen syndrome, are extremely rare in other syndromes.

Some people have very mild symptoms and may not have joint dislocations or other problems at birth. The diagnosis can be missed in these people unless they are carefully evaluated.

A person with dominantly inherited Larsen syndrome has a 50% chance with each pregnancy of having a child with the same disorder. Genetic counseling can help couples sort out their options for parenthood. Some couples would choose to adopt rather than take the chance of an affected child, others would go ahead with a pregnancy, and others would choose to have prenatal diagnosis. The only form of prenatal diagnosis available to date is ultrasound.

Fetal ultrasound performed by a specialist at 18-20 weeks of pregnancy can sometimes reveal signs of Larsen syndrome. Knee dislocations and hyperextension, club feet, fixed flexion of elbows, wrists, and fingers, and some of the characteristic facial features can sometimes be noted by ultrasound in affected fetuses. Physical findings from ultrasound can suggest but do not confirm the diagnosis of Larsen syndrome in a fetus.

Treatment and management

Treatment will vary according to the symptoms of a particular child. Joint problems require long-term orthopedic care. Dislocations, clubfeet, and joint contractures are treated with intensive physical therapy, splints, casting, and/or surgery. Physical therapy is also important after joint surgery to build up muscles around the joint and preserve joint stability. Occupational therapy may be helpful for children with wrist and finger contractures.

Respiratory problems at birth may necessitate oxygen or assistive breathing devices. If not alleviated by medication or special feeding techniques, eating and swallowing problems may require tube feeding. Heart problems, cleft palate, and cataracts often warrant surgical correction. Special care is needed if laxity of the trachea is present because of an increased risk for respiratory problems during and after surgery.

People with chronic pain associated with hypermobile joints often can be helped by techniques taught in a pain management clinic.

Magnetic resonance imaging (MRI) of the neck is recommended in childhood to screen for cervical vertebral problems. Early diagnosis and surgical stabilization of the spine can help patients avoid paralysis and death from spinal cord compression. Scoliosis is usually treated by bracing, or by a surgically placed metal rod. Artificial hip and knee replacements may be needed in early-to-mid adulthood because of degeneration of unstable joints.

Regular medical examinations are crucial to assess the condition of the bones, joints, spine, heart, and eyes. Hearing should be evaluated on a periodic basis, especially in children, because of the potential for conductive hearing loss. Ophthalmologic examinations are recommended periodically to screen for cataracts.

Prognosis

The effects of the syndrome vary markedly from person to person. Therefore, prognosis is based on the findings in a given individual. The usual causes of early death are either severe respiratory problems or compression of the cervical spine from vertebral instability.

If careful and consistent orthopedic treatment is initiated early, prognosis can be good, with a normal life span. Weak and unstable joints and limited range of motion from contractures may cause walking difficulties and restrict other physical activities. Contact sports and heavy lifting should be avoided as anything that puts extra strain or pressure on the joints can cause harm. Swimming is a good activity because it helps strengthen muscles without joint strain.

Resources

PERIODICALS

Becker, R., et al. "Clinical Variability of Larsen Syndrome: Diagnosis in a Father after Sonographic Detection of a Severely Affected Fetus." Clinical Genetics 57 (2000): 148-150.

Tongsong, T., et al. "Prenatal Sonographic Diagnosis of Larsen Syndrome." Journal of Ultrasound Medicine 19 (2000): 419-421.

ORGANIZATIONS

Arthritis Foundation. 1330 West Peachtree St., Atlanta, GA 30309. (800) 283-7800 or (404)965-7537. <http://www.arthritis.org>.

Scoliosis Research Society. 6300 N. River Rd., Ste 727, Rosemont, IL 60018-4226. (847)698-1627. Fax: (847) 823-0536. [email protected]. <http://www.srs.org/>.