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Larsen Syndrome

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NORD is very grateful to John M. Graham, JR., M.D., Sc.D., Director of Clinical Genetics and Dysmorphology, Cedars-Sinai Medical Center, for assistance in the preparation of this report.

Synonyms of Larsen Syndrome

Disorder Subdivisions

General Discussion

Larsen syndrome is a rare genetic disorder that has been associated with a wide variety of different symptoms. Characteristic findings of the disorder include dislocations of the large joints, skeletal malformations, and distinctive facial and limb features. Additional findings may include abnormal curvature of the spine, clubfoot, short stature, and breathing (respiratory) difficulties. The classic form of Larsen syndrome is caused by mutations of the FLNB gene. The mutation may occur spontaneously or be inherited as an autosomal dominant trait.

FLNB-related disorders are a group of disorders (including autosomal dominant Larsen syndrome) that occur due to mutations of the Filamin B gene (FLNB) gene. This group includes atelosteogenesis types I and III, boomerang dysplasia and spondylocarpotarsal syndrome. These disorders are characterized by skeletal abnormalities affecting the bones of the hands and feet, the bones of the spine (vertebrae), joint dislocations, and distinctive facial features. The specific symptoms and severity of these disorders may vary greatly even among members of the same family.

Researchers have identified individuals with multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have different radiological findings than those with classic Larsen syndrome. Mutations in the carbohydrate sulfotransferase 3 (CHST3) gene have been identified in patients with so-called autosomal recessive Larsen syndrome that also includes humero-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. Since these disorders are known to be caused by a different gene than classic, autosomal dominant Larsen syndrome, the term autosomal recessive Larsen syndrome should probably be avoided to prevent confusion with clinical disorders resulting from mutations in FLNB.


The symptoms and severity of Larsen syndrome vary greatly, including between individuals belonging to the same family. In one large family whose members had Larsen syndrome caused by one of the recurring mutations, some affected individuals had cleft palate and multiple large joint dislocations, but others had no major anomalies and manifested only short stature and mild features, such as short distal phalanges (toe and finger tip bones) and extra bones in the wrist and ankle Mild short stature is common with height below the tenth percentile in 70% of the cases.

Skeletal and joint abnormalities with distinctive facial features are the most common findings associated with the classic, autosomal dominant Larsen syndrome. Some symptoms associated with Larsen syndrome are present at birth, such as dislocation of large joints (80% hip, 80% knee, and 65% elbow) with subluxation of the shoulders the only large joint manifestation in one mildly affected person. Clubfoot was present in 75% of affected individuals. In addition, the joints of individuals with Larsen syndrome may be extremely lax or loose (hypermobility), which may make them more prone to dislocation. The fingers, especially the thumbs, may be short and broad with squared or rounded tips. Extra bones may be present in the wrists and ankles (supernumerary carpal and tarsal bones), and some of these bones may fuse together during childhood.

Spine abnormalities occur in 84% of individuals with Larsen syndrome including abnormal sideways curvature of the spine (scoliosis) or front-to-back curvature of the spinal bones (vertebrae) in the neck (cervical kyphosis). Cervical kyphosis occurs in 50% of affected individuals, usually from subluxation or fusion of the cervical vertebral bodies, which is usually associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord damage and secondary paralysis, which occurs in at least 15% of patients.

Individuals with Larsen also have distinctive facial features, which include eyes that are wider apart than normal (hypertelorism), prominent forehead, and depressed bridge of the nose. The middle portion of the face may appear flattened. Incomplete closure of the roof of the mouth (cleft palate) or a cleft in the soft tissue that hangs down in the back of the throat (bifid uvula) may also occur in 15% of affected individuals. Deafness is common, usually preceded by ringing in the ears (tinnitus), and conductive deafness may be associated with malformations of the middle ear ossicles in 21% of individuals.

A few individuals with classic Larsen syndrome have developed abnormal softening of the cartilage of the windpipe (trachea), a condition known as tracheomalacia, but more severe conditions associated with FLNB mutations, such as atelosteogenesis, can have severe laryngotrachiomalacia.

Many individuals have been described in the medical literature with a more severe form of Larsen syndrome. Such individuals have developed additional findings to those discussed above including learning disabilities, developmental delay, life-threatening respiratory (breathing) abnormalities, and heart defects. These conditions are now known to result from different mutations in the FLNB gene and are discussed further in the Related Disorders section of this report.


The classic form of Larsen syndrome follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that classic Larsen syndrome results from mutations in the Filamin B (FLNB) gene located on the short arm of chromosome 3 (3p14). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomal locations are further specified by the dark and light bands along each arm. For example, "chromosome 3p14" refers to band 14 on the short arm of chromosome 3. These numbered bands specify the location of the genes that are located in this region of the chromosome.

The FLNB gene contains instructions for creating (encoding) a protein known as Filamin B, which plays a role in the proper development of the inner framework of a cell (cytoskeleton). Mutations in FLNB result in dysfunction of the protein encoded by this gene. The exact function of filamin B and how its dysfunction causes the various symptoms of Larsen syndrome is not yet fully understood, but it is felt to play a major role in the development of the skeletal system and its joints.

Some researchers suggest that certain cases believed to be recessively inherited cases of Larsen syndrome may represent germline mosaicism. In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the FLNB gene mutation, while other germ cells contain normal FLNB genes ("mosaicism"). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene FLNB mutation, leading to the development of Larsen syndrome, while the parent does not have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy may be available and is best discussed directly with a genetic specialist.

Researchers have determined that a few cases of Larsen syndrome may result from somatic mosaicism. In somatic mosaicism, the mutation of the FLNB gene causing Larsen syndrome occurs after fertilization and is not inherited. The mutation is found in some of the cells of the body, but not in others. The severity of the disease in these cases depends on the percentage of cells affected, and it is less severe than in individuals who have the mutation in all of their cells. In the past, such cases were thought to result from autosomal recessive inheritance when a parent’s features were too mild to be recognized as Larsen syndrome.

Spondylocarpotarsal (SCT) syndrome is caused by mutations in FLNB that result in absent filament B protein. The mutations associated with Larsen syndrome and atelosteogenesis types I and III (AOI and AOIII) encode a full-length filamin B protein that does not function properly. In some instances the same mutation has caused both AOI and AOIII. Somatic FLNB mosaicism can complicate the presentation of these conditions.

Affected Populations

Larsen syndrome affects males and females in equal numbers. It is estimated to occur in 1 in 100,000 individuals in the general population. Because of the difficulty in diagnosing Larsen syndrome, determining its true frequency in the general population is difficult. Larsen syndrome was first described in the medical literature as a distinct disease entity by Dr. Loren Larsen in 1950.

An autosomal recessive form of "Larsen syndrome" was identified in several large families on the island of La Reunion in the Indian Ocean off the east coast of Africa. Other researchers have disputed this diagnosis and suggested that these affected individuals have a similar, yet distinct, autosomal recessive genetic disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of Larsen syndrome. Comparisons may be useful for a differential diagnosis. For more information on these disorders, use the specific disorder name as a search term in the Rare Disease Database.

Atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII) were once thought to be different conditions, but now they are thought to represent a spectrum of more severe, but similar disorders resulting from FLNB mutations. AOIII is milder than AOI, commonly with survival beyond the neonatal period. Clinical findings present dislocated hips, knees, and elbows and clubfeet. Radiographic features include distal tapering of the humeri and femora, short and broad tubular bones of the hands and feet, and mild vertebral hypoplasia. Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. They have significant problems with respiratory insufficiency as a result of laryngotracheomalacia and thoracic hypoplasia. Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). Such parents have been found to have milder features due to somatic mosaicism, while their offspring have a severe phenotype due to a non-mosaic germline mutation.

AOI results in perinatal lethality with severe short-limbed dwarfism, dislocated hips, knees, and elbows, and clubfeet. Radiographic features include marked vertebral flattening; hypoplastic pelvis; incomplete or absent, shortened, or distally-tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae; and incompletely ossified metacarpals and phalanges.

Boomerang dysplasia is a perinatal lethal bone dysplasia with close similarities to AOI, distinguished primarily by characteristic bowing of the femora and, occasionally, extraskeletal manifestations including encephalocele and omphalocele. On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is seldom possible. Polyhydramnios can complicate the pregnancy, and neonates with boomerang dysplasia or AOI die shortly after birth from cardiorespiratory insufficiency.

Spondylocarpotarsal syndrome (SCT) syndrome is an autosomal recessive condition resulting from FLNB mutations. It is characterized by disproportionate short stature, with vertebral anomalies consisting of block vertebrae, scoliosis, lordosis, carpal and tarsal fusions, joint laxity, clubfeet or flat feet, and mild facial features consisting of round face, frontal bossing, short up-turned nose, cleft palate, conductive hearing loss, and dental enamel hypoplasia. SCT syndrome has also been associated with retinal anomalies and sensorineural deafness. The cataracts and retinal abnormalities described in one family with SCT syndrome were not severe enough to impair vision. Intelligence is normal.

Researchers have also identified individuals with multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have different radiological findings than those with classic Larsen syndrome. Deficiency of carbohydrate sulfotransferase 3 (CHST3 or also called chondroitin-6-sulfotransferase) has been diagnosed in patients with so-called autosomal recessive Larsen syndrome, humero-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. Key clinical features include congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfeet, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation with enhanced 4-O-sulfation, confirming functional impairment of CHST3, and distinguishing these fibroblasts from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These disorders differ from classic Larsen syndrome and the term autosomal recessive Larsen syndrome should probably be avoided to prevent confusion with clinical disorders resulting from mutations in FLNB.

FLNA-related disorders are a group of disorders that occur due to mutations of the filamin A (FLNA) gene. This group includes oto-palato-digita (OPD) syndromes types I and II, frontometaphyseal dysplasia (FMD), and Melnick-Needles syndrome. These disorders are characterized by varying degrees of skeletal malformation (dysplasia). Affected individuals may develop mild symptoms as seen with OPD type I or more severe symptoms as may be associated with FMD or OPD II.

Desbuquois syndrome is a rare genetic disorder characterized by loose or lax joints, distinctive facial features, and short stature with abnormally short arms and legs. Affected individuals may have distinctive facial features including prominent eyes, a small jaw (micrognathia), and a rounded, flattened face. Abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) may also develop. Some individuals have skeletal abnormalities affecting the hands. Desbuquois syndrome is inherited as an autosomal recessive condition.

Ehlers-Danlos syndrome is a group of hereditary connective tissue disorders. Associated features may vary greatly, depending on the specific form of the disorder present and other factors. However, primary findings may include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, "stretchy" skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes.

Additional disorders may be characterized by distinctive facial features, multiple dislocations, additional skeletal abnormalities, and/or other findings similar to those associated with Larsen syndrome.

Standard Therapies

The diagnosis of Larsen syndrome is made based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic clinical and radiological findings. Radiographic examination can detect the presence and severity of associated skeletal findings. Molecular genetic testing can confirm the presence of the FLNB gene mutation.

Prenatal diagnosis of Larsen syndrome may be possible through ultrasound imaging, where reflected sound waves are used to create an image of the developing fetus and reveal characteristic findings based on the clinical experience of the sonographer. Because most cases are sporadic, this diagnosis is seldom made, and confirmation through molecular genetic testing is necessary to confirm the diagnosis. Referral to skilled sonographers who are cognizant of genetic disorders and skeletal dysplasias may help to confirm this suspicion in prenatal cases with or without subtly affecting parents. Malformations in the skeleton like joint hyperextensions and bifid humerus (bone of the arm), clubbed feet, facial features including depressed nasal bridge, widely separated eyes, prominent forehead and abnormalities in the hands and fingers and a narrow chest with increased amniotic fluid (polyhydramnios) may be suggestive of Larsen syndrome, though other genetic skeletal disorders can also manifest these signs. When suspicion is sufficiently high, sequencing of the FLNB gene can be performed to identify a mutation and come to a definitive diagnosis. When a decision is made to continue the pregnancy with suspected Larsen syndrome, Cesarean section is recommended to prevent trauma to the limbs and the cervical spine during vaginal delivery. Breathing problems due to a small narrow chest are an important issue that should be managed by the neonatologist.

The treatment of Larsen syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, craniofacial specialists, and geneticists who assess and treat skeletal disorders, as well as other specialists who asses and treat hearing problems (audiologists) may need to systematically and comprehensively plan an affected child’s treatment.

Treatment of infants with Larsen syndrome consists of joint manipulation and corrective casts or traction. Later, orthopedic surgery may be recommended to correct skeletal dislocations or deformities. Physical therapy may be necessary to strengthen affected joints. Treatment of joint abnormalities often requires long-term therapy.

Stabilization of the cervical spine may be necessary in some cases and may include spinal surgery such as the fusion of affected spinal bones.

Because of deformities of the cervical spine, special consideration is merited during intubation (placing a breathing tube into the mouth or nose during anesthesia-induction for surgery), which may be necessary for their multiple surgeries. Cervical spine instability and postoperative respiratory complications are potential problems that need to be addressed.

For treatment of skeletal malformations and joint dislocations, physical and occupational therapy may be necessary before and after surgery. Reconstructive surgery is appropriate for nasal growth deficiency and for cleft palate, and these patients may also require speech therapy. Breathing (respiratory) problems may require supportive therapy, including ventilator assistance, special feeding techniques, and chest physical therapy.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Under a NORD Research Grant, a research team established a Larsen syndrome registry within the International Skeletal Dysplasia Registry (ISDR) at Cedars-Sinai Medical Center. The general aim of the study is to provide systematic comparison of the clinical characteristics, radiographic manifestations, and neuroimaging findings of individuals with Larsen syndrome to differentiate the dominant and recessive phenotypes, establish objective diagnostic criteria, and formulate health maintenance recommendations.

The ISDR evaluates genetic skeletal surveys and clinical features in affected individuals, as well as collecting samples for continuing research on affected individuals and members of their families. The ISDR web site provides information for affected individuals, their families, and healthcare professionals. For information, contact:

International Skeletal Dysplasia Registry
Medical Genetics Institute
Cedars-Sinai Medial Center
Los Angeles, CA 90048

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll Free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

Larsen Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:


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Report last updated: 2012/06/05 00:00:00 GMT+0