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Larsen Syndrome


Last updated: September 05, 2018
Years published: 1988, 1990, 1992, 1999, 2001, 2003, 2008, 2012, 2015, 2018


NORD gratefully acknowledges John M. Graham, JR., MD, ScD, Pediatric Consultant in Clinical Genetics and Dysmorphology, Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center for assistance in the preparation of this report.

Disease Overview


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 with a frequency of 1 in 100,000. The mutation may occur spontaneously or be inherited as an autosomal dominant trait. Introduction 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. A variant of Larsen syndrome was reported in patients from Reunion Island in the southern Indian Ocean and characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It is inherited in an autosomal recessive fashion and results from a founder homozygous missense mutation in B4GALT7. Mutations in the linkeropathy genes (XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3) can be associated with ocular findings, including blue sclerae, refractive errors, corneal clouding, strabismus, nystagmus, cataracts, glaucoma, and retinal abnormalities, including retinal detachment. A consanguineous Saudi family with severe and recurrent large joint dislocation and severe myopia, was identified with a homozygous truncating variant in GZF1. These ocular findings are not seen in FLNB-related disorders. Since these disorders are known to be caused by different genes 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.

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Signs & Symptoms

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 have cleft palate and multiple large joint dislocations, but others have no major anomalies and manifested only short stature and mild features, such as short distal phalanges (toe and fingertip 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 is present in about 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. Retrognathia, patellar dislocation, kyphoscoliosis and dural ectasia also occurs.

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.

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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. Filamin B (FLNB) is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. 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 appear to 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.

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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 Reunion Island in the Indian Ocean off the east coast of Africa. This disorder results in multiple joint dislocations, but it has different clinical and radiologic features, and it is caused by a founder homozygous missense mutation in B4GALT7. Mutations in the carbohydrate sulfotransferase 3 (CHST3) gene have been identified in patients with so-called autosomal recessive Larsen syndrome. Homozygous truncating GZF1 variants have also been reported in consanguineous Saudi families affected by severe myopia, retinal detachment, and recurrent large joint dislocations.

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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 knowledgeable regarding 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.

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Standard Therapies

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 is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

The International Skeletal Dysplasia Registry (ISDR) at UCLA 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
David Geffen School of Medicine at UCLA
Los Angeles, CA

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

Some current clinical trials also are posted on the following page on the NORD website:

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

For information about clinical trials conducted in Europe, contact:

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