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.
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.
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.
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.
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.
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.
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.
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
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Hennekam RCM, Allanson J, Krantz I, eds. Gorlin’s Syndromes of the Head and Neck. 5th ed. New York, NY: Oxford University Press; 2010:984-987.
Lachman RS. Taybi and Lachman’s Radiology of Syndromes, Metabolic Disorders and Skeletal Dysplasia. 5th ed. Philadelphia, PA: Mosby Elsevier Co.; 2007:450-452.
Jones KL, Crandall-Jones M, Del Campo, M. Smith’s Recognizable Patterns of Human Malformation, 7th Edition, Philadelphia, Elsevier-W.B. Saunders Co, 2013; 564-567.
Arunrut T, Sabbadini M, Jain M, et al. Corneal clouding, cataract, and colobomas with a novel missense mutation in B4GALT7-a review of eye anomalies in the linkeropathy syndromes. Am J Med Genet A. 2016 Oct;170(10):2711-2718.
Banks JT, Wellons JC, Tubbs RS, et al. Cervical spine involvement in Larsen’s syndrome: a case illustration. Pediatrics. 2003;111:199-201.
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.
Bernkopf M, Hunt D, Koelling N, et al. Quantification of transmission risk in a male patient with a FLNB mosaic mutation causing Larsen syndrome: Implications for genetic counseling in postzygotic mosaicism cases. Hum Mutat. 2017 Oct;38(10):1360-1364.
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.
Cartault F, Munier P, Jacquemont ML, et al.Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome. Eur J Hum Genet. 2015 23:49-53.
Critchley LA, Chan K. General anesthesia in a child with Larsen Syndrome. Anaesth Intensive Care. 2003;31: 217-20.
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.
Girisha KM, Bidchol AM, Graul-Neumann L, et al. Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients. BMC Med Genet. 2016 Apr 6;17:27.
Huber C, Oules B, Bertoli M et al: Identification of CANT1 mutations in Desbuquois dysplasia. Am J Hum Genet 2009; 85: 706–710.
Johnston CE, 2nd, Birch JG, Daniels JL. Cervical kyphosis in patients who have Larsen syndrome. J Bone Joint Surg Am. 1996;78:538-545.
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.
Larsen LJ, Schottstaedt Er, Bost FC. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediat. 1950. 37:574-581.
Malik P, Choudhry DK. Larsen syndrome and its anaesthsia considerations. Paediatr Anaesth. 2002;12:632-6.
Marques LHS, Martins DV, Juares GL, et al. Otologic manifestations of Larsen syndrome. Int J Pediatr Otorhinolaryngol. 2017 Oct;101:223-229.
Mei H, He R, Liu K, et al. Presumed Larsen syndrome in a child: a case with a 12-year follow-up. J Pediatr Orthop B. 2015 24:268-273.
Mizumoto S, Yamada S, Sugahara K. Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias. Biomed Res Int. 2015;2015:861752. doi: 10.1155/2015/861752. Epub 2015 Oct 25.
Patel N, Shamseldin HE, Sakati N, et al. GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome. Am J Hum Genet. 2017 May 4;100(5):831-836.
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.
Salian S, Shukla A, Shah H, et al. Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB. Clin Genet. 2018 Jul;94(1):159-164.
Salter CG, Davies JH, Moon RJ, et al. Further defining the phenotypic spectrum of B4GALT7 mutations. Am J Med Genet A. 2016 Jun;170(6):1556-1563.
Unger S, Lausch E., Rossi A., et al. Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. Am J Med Genet A. 2010;152A:2543-2549.
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.
Winer N, Kyndt F, Paumier A, David A, Isidor B, Quentin M, Jouitteau B, Sanyas P, Philippe HJ, Hernandez A, Krakow D, Le Caignec C. Prenatal diagnosis of Larsen syndrome caused by a mutation in the filamin B gene. Prenat Diagn. 2009;29:172-4.
Zhang, Herring JA, Swaney SS, et al. Mutations responsible for Larsen syndrome cluster in the FLNB protein. J Med Genet. 2006;43:e24.
Robertson S. FLNB-Related Disorders. 2008 Oct 9 [Updated 2013 Oct 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2534/ Accessed Aug. 14, 2018.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Larsen Syndrome; LRS. Entry No: 150250. Last Edited 06/22/2018. Available at: http://omim.org/entry/150250 Accessed Aug. 14, 2018.
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