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 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.
Some researchers have identified individuals with apparent multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have more severe symptoms than those with classic Larsen syndrome. It is not clear whether these individuals have an autosomal recessive form of Larsen syndrome or a similar, yet distinct, disorder.
The symptoms and severity of Larsen syndrome vary greatly from one individual to another, even among members of the same family. Because of the wide, clinical variety of potential symptoms and the difficulty in obtaining an accurate diagnosis, the true spectrum of abnormalities associated with Larsen syndrome is unknown and controversial. Skeletal and joint abnormalities and distinctive facial features are the most common findings associated with the classic (autosomal dominant) Larsen syndrome.
Some symptoms associated with Larsen syndrome may be present at birth (congenital) including dislocation of certain large joints, especially the hip, knees, elbows, and wrists. Dislocations occur at the joints where long bones meet other bones causing these bones to assume unusual positions. In addition, the joints of individuals with Larsen syndrome may be extremely lax or loose (hypermobility) with may make them more prone to dislocation.
The feet of some affected individuals may have a heel that is bent upward while the foot is turned inward (clubfoot or equinovarus) or outward (equinovalgus). The fingers, especially the thumbs, may be short and broad with squared or rounded tips. Extra bones may develop in the wrists and ankles (supernumerary carpal and tarsal bones); some of these bones may fuse together during childhood.
The spine is often involved in individuals with Larsen syndrome resulting in abnormal sideways curvature of the spine (scoliosis) or front-to-back curvature of the spinal bones (vertebrae) in the neck (cervical kyphosis). Spinal abnormalities can potentially cause serious complications such as spinal cord compression and partial paralysis.
Individuals with Larsen also have distinctive facial features including eyes that are spaced apart wider than normal (hypertelorism), a prominent forehead, and a depressed bridge of the nose. The middle portion of the face may appear flattened. Incomplete closure of the roof of the mouth (cleft palate) and a cleft in the soft tissue that hangs in the back of the throat (uvula) may also occur.
Some individuals with Larsen syndrome have developed abnormal softening of the cartilage of the windpipe (trachea), a condition known as tracheomalacia. Abnormal softening of the tubes (bronchi) that connect the windpipe to the lungs may also occur (bronchomalacia). These conditions can potentially cause feeding and swallowing difficulties and life-threatening breathing (respiratory) complications.
Additional common symptoms associated with Larsen include a sunken or protruding chest (pectus excavatum or pectus carinatum), short fingernails, underdevelopment (hypoplasia) of the teeth (hypodontia), cleft lip, and shortening and tapering of the long bones of the arms (humerus) near where it meets the elbow. Failure of the testes to descend into the scrotum (cryptorchidism) has been reported in some boys with Larsen syndrome.
The adult height for affected individuals may be normal or mildly reduced (short stature). Hearing loss, usually preceded by ringing in the ears (tinnitus) may also occur in adults with Larsen syndrome.
Many individuals have been reported 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, delays in reaching developmental milestones (developmental delays), severe breathing (respiratory) abnormalities and heart defects.
More serious findings occur in conditions that are similar to Larsen syndrome, but life-threatening in the newborn period due to respiratory insufficiency. These conditions (atelosteogenesis and related disorders) result from different mutations in the FLNB gene. Some of the so-called autosomal recessive forms of Larsen syndrome may represent germline mosaicism for an FLNB mutation (see Causes section below).
The classic form of Larsen syndrome may occur randomly as the result of a spontaneous genetic change (i.e., new mutation) or it may be inherited as an autosomal dominant trait. Some researchers believe that some forms of Larsen syndrome may be inherited as an autosomal recessive trait, but this is unproven and such cases may represent similar, yet distinct, genetic disorders or Larsen syndrome due to germline mosaicism (see below).
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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 autosomal dominant Larsen syndrome occurs due to mutations of 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 body 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". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 3p14" refers to band 14 on the short arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each 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 of the FLNB gene result in dysfunction of this protein. 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 others contain a normal cell line ("mosaicism"). The other cells in a parent's body do not have the mutation. As a result, one or more of the parent's children may inherit the gene mutation, potentially leading to development of Larsen syndrome, while the parent does not have the disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same genetic abnormality. 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, which causes 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, but is less severe than in individuals who have the mutation in all of their cells.
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 apparent recessive form of Larsen syndrome was identified in several large families on the island of La Reunion in the Indian Ocean. However, other researchers have disputed this diagnosis and have suggested that the affected individuals have a similar, yet distinct, genetic disorder.
Symptoms of the following disorders can be similar to those of Larsen syndrome. Comparisons may be useful for a differential diagnosis.
FLNB-related disorders are a group of disorders (including autosomal dominant Larsen syndrome) that occur due to mutations of the filamin B (FLNB) gene (allelic disorders). This group includes atelosteogenesis types I and III, boomerang dysplasia and spondylocarpotarsal syndrome. These disorders are characterized 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.
FLNA-related disorders are a group of disorders that occur due to mutations of the filamin A (FLMA) gene. This group includes otopalataldigita syndromes types I and II, frontometaphyseal dysplasia, and Melnick-Needles syndrome. These disorders are characterized by varying degrees of skeletal malformation (dysplasia). Individuals may develop mild symptoms as is often associated with otopalataldigital syndrome type I or more severe symptoms as may be associated with frontometaphyseal dysplasia and otopalataldigital syndrome type II. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
Larsen-like syndrome is a rare genetic disorder that has been described as a severe variant of Larsen syndrome. The disorder may be characterized by an unusually flattened face, incomplete closure of the roof of the mouth (cleft palate), multiple joint dislocations, severe underdevelopment of the lungs (pulmonary hypoplasia), and/or other associated features, potentially leading to life-threatening complications shortly after birth. Larsen-like syndrome is thought to be inherited as an autosomal recessive trait.
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 (micromelic dwarfism). Affected individuals may have distinctive facial features including prominent eyes, an abnormally small jaw (mircognathia), 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. Some cases of Desbuquois syndrome are caused by mutations of a gene on the long arm of chromosome 17 (17q25.3). The disorder is inherited as an autosomal recessive trait.
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. (For more information, please choose "Ehlers" as your search term in the Rare Disease Database.)
Additional disorders may be characterized by certain facial features, multiple dislocations, additional skeletal abnormalities, and/or other findings similar to those potentially associated with Larsen syndrome. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.)
Diagnosis A diagnosis of Larsen syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. X-ray 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 might rarely be possible through tests such as ultrasound imaging, but because most cases are sporadic, this diagnosis is seldom made. In fetal ultrasonography, reflected sound waves may be used to create an image of the developing fetus, revealing characteristic findings.
Treatment 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, surgeons, specialists who assess and treat skeletal disorders (orthopedists), specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect 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. Physical and occupational therapy or surgery may be necessary to treat clubfoot or skeletal malformations of the hands. Reconstructive surgery is an appropriate treatment for nasal growth deficiency and for cleft palate.
Breathing (respiratory) problems may be supportive therapy including ventilator assistance, special feeding techniques, and chest physiotherapy, a process by which the lungs are cleared of accumulated thick secretions such as mucous or phlegm. Speech therapy may also be beneficial in some cases.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
Under a NORD Research Grant, a team from Cedars-Sinai Medical Center conducted a study that included the establishment of a Larsen syndrome registry as part of 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 may evaluate genetic skeletal surveys on affected individuals and permit sample collection forcontinuing research on affected individuals and members of their families. The Web site will provide information for affected individuals and families, and healthcare professionals.
For information, contact any of the following individuals by phone or e-mail, or write to them at the International Skeletal Dysplasia Registry, Medical Genetics Institute, Cedars-Sinai Medial Center, Los Angeles, CA 90048:
JOHN M. GRAHAM, JR., M.D. Sc.D. Director of Clinical Genetics and Dysmorphology Cedars-Sinai Medical Center 8635 West 3rd Street, Suite #1150 Los Angeles, CA 90048
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JOURNAL ARTICLES Bicknell LS, Farrington-Rock C, Shafeghati Y, et al. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet. 2007;44:89-98.
Zhang, Herring JA, Swaney SS, et al. Mutations responsible for Larsen syndrome cluster in the FLNB protein. J Med Genet. 2006;43:e24.
Krakow D, Robertson SP, King LM, et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004;36:405-410.
Banks JT, Wellons JC, Tubbs RS, et al. Cervical spine involvement in Larsen's syndrome: a case illustration. Pediatrics. 2003;111:199-201.
Debeer P, De Borre LO, De Smet L, Fryns JP. Asymmetrical Larsen syndrome in a young girl: a second example of somatic mosaicism in this syndrome. Genet Couns. 2003;14:95-100.
Becker R, Wegner RD, Kunze J, et al. Clinical variability of Larsen syndrome: diagnosis in a father after sonographic detection of a severely affected fetus. Clin Genet. 2000;57:148-50.
Johnston CE, 2nd, Birch JG, Daniels JL. Cervical kyphosis in patients who have Larsen syndrome. J Bone Joint Surg Am. 1996;78:538-545.
Vujic M, Hallstensson K, Wahlstrom J, et al. Localization of a gene for autosomal dominant Larsen syndrome to chromosome region 3p21.1-14.1 in the proximity of, but distinct from, the COL7A1 locus. Am J Hum Genet. 1995;57:1104-1113.
Petrella R, Rabinowitz JF, Steinmann B, Hirschhorn K. Long-term follow-up of two sibs with Larsen syndrome possibly due to parental germ-line mutation. Am J Med Genet. 1993;47:187-197.
Rock MJ, Green CG, Pauli RM, Peters ME. Tracheomalacia and bronchomalacia associated with Larsen syndrome. Pediatr Pulmonol. 1988;5:55-59.
Larsen LJ, Schottstaedt Er, Bost FC. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediat. 1950;37:574-581.
FROM THE INTERNET McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:150250; Last Update:03/02/2007. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=150250 Accessed on: February 20, 2008.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:2456000; Last Update:03/17/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=245600 Accessed on: February 20, 2008.
MAGIC Foundation for Children's Growth 6645 W. North Avenue Oak Park, IL 60302 Tel: (708)383-0808 Fax: (708)383-0899 Tel: (800)362-4423 Email: mary@magicfoundation.org Internet: http://www.magicfoundation.org
Children's Craniofacial Association 13140 Coit Road Suite 517 Dallas, TX 75240 USA Tel: (214)570-9099 Fax: (214)570-8811 Tel: (800)535-3643 Email: csmith@ccakids.com Internet: http://www.ccakids.com
March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 Tel: (914)428-7100 Fax: (914)997-4763 Tel: (888)663-4637 Email: Askus@marchofdimes.com Internet: http://www.marchofdimes.com
FACES: The National Craniofacial Association P.O. Box 11082 Chattanooga, TN 37401 Tel: (423)266-1632 Fax: (423)267-3124 Tel: (800)332-2373 Email: faces@faces-cranio.org Internet: http://www.faces-cranio.org
The Arc (a national organization on mental retardation) 1010 Wayne Ave Suite 650 Silver Spring, MD 20910 Tel: (301)565-3842 Fax: (301)565-3843 Tel: (800)433-5255 TDD: (817)277-0553 Email: info@thearc.org Internet: http://www.thearc.org/
Little People of America, Inc. 250 El Camino Real Suite 201 Tustin, CA 92780 Tel: (714)368-3689 Tel: (888)572-2001 Email: info@lpaonline.org Internet: http://www.lpaonline.org
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