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Larsen syndrome
Larsen syndrome is a rare inherited disorder affecting the skeleton. Individuals typically present with multiple joint dislocations, particularly in the knees, hips, and elbows, along with characteristic facial features and spinal curvature. It is often apparent at birth.
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Overview
Larsen syndrome is a rare genetic condition characterised by multiple joint dislocations, particularly of the knees, hips, and elbows, often present from birth. Affected individuals may also have distinctive facial features, such as a prominent forehead, flattened midface, and widely spaced eyes [PMID:10729707]. Other skeletal issues, including spinal curvature (scoliosis or kyphosis) and abnormalities of the hands and feet, are also common.
This condition can vary in its severity, even among individuals in the same family. While some may experience relatively mild symptoms, others may have more significant health challenges requiring ongoing medical management. Larsen syndrome is named after Dr. Loren J. Larsen, who first described a series of cases in 1950.
Symptoms & clinical features
The primary clinical features of Larsen syndrome are multiple large joint dislocations, which are usually evident at birth. These commonly affect the knees (often with the kneecap dislocated outwards), hips, and elbows [PMID:10729707]. Clubfoot (talipes equinovarus) or other foot deformities are also frequently observed.
Characteristic facial features often include a prominent forehead, a flattened appearance of the middle of the face (midface hypoplasia), and widely spaced eyes (hypertelorism). Some individuals may have a depressed nasal bridge. Skeletal findings can extend to the spine, with conditions like scoliosis (sideways curvature of the spine) or kyphosis (outward curvature of the upper back) [PMID:24816029]. Other possible features include short stature, a short neck, and, in rare cases, cardiovascular or respiratory problems.
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Affected organs
Larsen syndrome predominantly affects the skeletal system, impacting bones, joints, and connective tissues throughout the body. The most commonly affected joints are the knees, hips, and elbows, where dislocations occur. The spine can also be affected, leading to curvatures such as scoliosis or kyphosis. The bones of the hands and feet may show abnormalities.
While primarily a skeletal disorder, the condition can sometimes have implications for other body systems. For example, severe spinal curvature can, in some instances, affect respiratory function. Facial bone development is also altered, contributing to the characteristic facial appearance.
Risks & severity
The severity of Larsen syndrome can vary considerably. Some individuals experience mild joint dislocations that can be managed with physical therapy and surgical correction, allowing for a good quality of life. In more severe cases, extensive joint dislocations, significant spinal deformities, and potential respiratory complications due to spinal issues may lead to more significant challenges [PMID:24816029].
The condition is present from birth (congenital). The exact prevalence of Larsen syndrome is not well established, but it is estimated to affect approximately 1 in 100,000 live births. Lifelong orthopaedic management is typically required, and early intervention can often improve outcomes.
Genetic causes
Larsen syndrome is most commonly caused by pathogenic variants in the *FLNB* gene. The *FLNB* gene provides instructions for making a protein called filamin B. This protein is essential for maintaining cell structure and allowing cells to change shape, playing a crucial role in the proper development of the skeleton before birth.
Pathogenic variants in *FLNB* can alter the structure or function of filamin B, disrupting its normal role in bone and cartilage formation. This leads to the characteristic skeletal abnormalities and joint laxity seen in Larsen syndrome. Other genes, though less commonly, have also been associated with conditions that share features with Larsen syndrome.
- FLNB filamin BThe FLNB gene encodes filamin B, a protein essential for cellular structure, mobility, and the proper development of the skeleton.
Inheritance pattern
Larsen syndrome is typically inherited in an autosomal dominant pattern. This means that a person only needs one copy of an altered *FLNB* gene in each cell to develop the condition. In most cases, a child inherits the altered gene from an affected parent.
However, in approximately 50% of cases, the condition results from a new (de novo) pathogenic variant in the *FLNB* gene that occurs spontaneously and is not inherited from either parent. If a parent has Larsen syndrome, each of their children has a 50% chance of inheriting the altered gene and developing the condition. If the condition is due to a de novo variant, the chance of future siblings being affected is very low, although genetic counselling is recommended to discuss specific family risks.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of Larsen syndrome is usually suspected based on the characteristic clinical features observed at birth, such as multiple joint dislocations and distinctive facial appearance. Imaging studies, including X-rays, can help confirm skeletal abnormalities, joint dislocations, and spinal curvature.
Confirmation of Larsen syndrome is typically achieved through genetic testing, which can identify pathogenic variants in the *FLNB* gene. Genetic testing for skeletal dysplasias, including Larsen syndrome, can be accessed via the NHS Genomic Medicine Service (GMS) following a referral from a specialist clinician. The relevant R-code for genomic testing would be discussed by the clinical genetics team.
Management & lifestyle
Management of Larsen syndrome focuses on addressing the orthopaedic and other clinical issues to improve function and quality of life. This often involves a multidisciplinary team of healthcare professionals, including orthopaedic surgeons, physiotherapists, occupational therapists, and clinical geneticists.
Treatment strategies typically include early intervention with physical therapy to improve joint mobility and muscle strength. Surgical procedures may be necessary to correct joint dislocations, manage clubfoot, or stabilise spinal deformities. Regular monitoring of spinal curvature and respiratory function is also important. Genetic counselling is an integral part of management, providing information about inheritance, recurrence risks, and support for affected individuals and families.
UK care pathway
In the UK, individuals suspected of having Larsen syndrome would typically be referred to a clinical genetics service through their GP or a specialist paediatrician. Clinical geneticists and genetic counsellors can provide diagnosis, information about the condition, and discuss the inheritance pattern and implications for family members. Genetic testing for Larsen syndrome is available through the NHS Genomic Medicine Service (GMS) following appropriate clinical referral. Patients may also be supported by multidisciplinary teams in regional centres, including orthopaedic specialists and physiotherapists.
Frequently asked questions
Is Larsen syndrome always inherited from a parent?
No, about half of all cases of Larsen syndrome result from a new genetic change (de novo variant) that occurs spontaneously, meaning neither parent carries the altered gene. In other cases, it is inherited from an affected parent.
What kind of medical specialists will be involved in managing Larsen syndrome?
Management often involves a team of specialists, including orthopaedic surgeons for joint and bone issues, physiotherapists and occupational therapists for mobility, and clinical geneticists for diagnosis and genetic counselling. Other specialists may be involved depending on specific symptoms.
Can Larsen syndrome be detected before birth?
In some cases, severe joint dislocations or skeletal abnormalities associated with Larsen syndrome may be detected during prenatal ultrasound scans. If there is a known family history, prenatal genetic testing can also be an option.
Will people with Larsen syndrome have learning difficulties?
Larsen syndrome primarily affects the skeletal system. Intellectual development is typically unaffected, and most individuals with Larsen syndrome have normal cognitive abilities.
Are there any specific exercises or activities that should be avoided?
Individuals with Larsen syndrome often benefit from physical therapy. However, specific activities may need to be adapted or avoided to protect fragile joints. A physiotherapist or orthopaedic specialist can provide personalised advice based on an individual's specific joint stability and overall condition.
References
- Adam MP, Bick S, Mirzaa GM. FLNB-Related Disorders. 1993. PMID: 20301736
- Siafaka A, Angelis S, Piagkou M. Larsen Syndrome and Associated Spinal Deformities. Cureus. 2023. PMID: 37565102
- Raff ML, Byers PH. Joint hypermobility syndromes. Current opinion in rheumatology. 1996. PMID: 8941450
- Alessandri JL, Celse T, Spodenkiewicz M. Prenatal and neonatal phenotype of Larsen of La Réunion Island syndrome (B4GALT7-linkeropathy). European journal of medical genetics. 2024. PMID: 38705458
- Adam MP, Bick S, Mirzaa GM. Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related. 1993. PMID: 21882400
- Yasunaga M, Ishikawa H, Yanagita K. An orthodontic perspective on Larsen syndrome. BMC oral health. 2021. PMID: 33691679
- Xu Q, Wu N, Cui L. Filamin B: The next hotspot in skeletal research? Journal of genetics and genomics = Yi chuan xue bao. 2017. PMID: 28739045
- Singh S, Sardhara J, Raiyani V. Craniovertebral junction instability in Larsen syndrome: An institutional series and review of literature. Journal of craniovertebral junction & spine. 2020. PMID: 33824557