Larsen syndrome (LS) is a

congenital disorder A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities c ...

discovered in 1950 by Larsen and associates when they observed

dislocation In materials science, a dislocation or Taylor's dislocation is a linear crystallographic defect or irregularity within a crystal structure that contains an abrupt change in the arrangement of atoms. The movement of dislocations allow atoms to s ...

of the large joints and face anomalies in six of their patients.Mitra, N., Kannan, N., Kumar, V.S., Kavita, G. "Larsen Syndrome: A Case Report." Journal of Nepal Paediatric Society. 32.1 (2012): 85-87. Print. Patients with Larsen syndrome normally present with a variety of symptoms, including

congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

of the knees,

of the hips and elbows, flattened facial appearance, prominent foreheads, and depressed nasal bridges.Liang, C.D., Hang, C.L. " Elongation of the Aorta and Multiple Cardiovascular Abnormalities Associated with Larsen Syndrome." Pediatric Cardiology. 22. (2001): 245-246. Print. Larsen syndrome can also cause a variety of

cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

Kiel, E.A., et al. "Cardiovascular Manifestations in the Larsen Syndrome." Pediatrics. 71.6 (1983): 942-946. Print. and

orthopedic Orthopedic surgery or orthopedics ( alternatively spelt orthopaedics), is the branch of surgery concerned with conditions involving the musculoskeletal system. Orthopedic surgeons use both surgical and nonsurgical means to treat musculoskeletal ...

abnormalities.Johnston, C.E., Birch, J.G., Daniels, J.L. "Cervical Kyphosis in Patients Who Have Larsen Syndrome." Journal of Bone and Joint Surgery. 78.4 (1996): 538-545. Print. This rare disorder is caused by a genetic defect in the gene encoding

filamin Filamins are a class of proteins that hold two actin filaments at large angles. Filamin protein in mammals is made up of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules of roughly 95 amino acids. T ...

B, a cytoplasmic protein that is important in regulating the structure and activity of the

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...

.Krakow, D. et al. "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis." Nature Genetics. 36.4 (2004): 405-410. Print. The gene that influences the emergence of Larsen syndrome is found in chromosome region, 3p21.1-14.1, a region containing human type VII

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...

gene.Vujic, M., et al. "Localization of a Gene for Autosomal Dominant Larsen Syndrome to Chromosome Region 3p2I.I-I4.1 in the Proximity of, but Distinct from, the COL7A I Locus." American Journal of Human Genetics. 57. (1995): 1104-1113. Print. Larsen syndrome has recently been described as a

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every ...

disorder that affects the

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

of an individual.

Autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

and

recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

forms of the disorder have been reported, although most cases are autosomal dominant. Reports have found that in Western societies, Larsen syndrome can be found in one in every 100,000 births, but this is most likely an underestimate because the disorder is frequently unrecognized or misdiagnosed.

Signs and symptoms

Common symptoms

Symptoms are related to defects in connective tissue. *

Congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

of the knees * Dislocation of hips and shoulders * Flattened facial appearance * Prominent forehead * Depressed nasal bridge * Club foot * Cervical

kyphosis Kyphosis is an abnormally excessive convex curvature of the spine as it occurs in the thoracic and sacral regions. Abnormal inward concave ''lordotic'' curving of the cervical and lumbar regions of the spine is called lordosis. It can result ...

Cardiac anomalies

Cardiac defects are similar to those associated with

Marfan's syndrome Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints a ...

, a disorder of the connective tissue. * Elongation of

aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes o ...

* Bicuspid aortic valve * Subaortic

stenosis A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' ...

Mitral valve prolapse Mitral valve prolapse (MVP) is a valvular heart disease characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole. It is the primary form of myxomatous degeneration of the valve. Ther ...

with

mitral regurgitation Mitral regurgitation (MR), also known as mitral insufficiency or mitral incompetence, is a form of valvular heart disease in which the mitral valve is insufficient and does not close properly when the heart pumps out blood. Section: Valvular H ...

Atrial septal defect Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

Patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...

Tricuspid valve prolapse In medicine, prolapse is a condition in which organs fall down or slip out of place. It is used for organs protruding through the vagina, rectum, or for the misalignment of the valves of the heart. A spinal disc herniation is also sometimes call ...

Aortic dissection Aortic dissection (AD) occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, this is associated with a sudden onset of severe chest or ...

and

aneurysm An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus ( ...

Aneurysm An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus ( ...

ductus arteriosus The ''ductus arteriosus'', also called the ''ductus Botalli'', named after the Italian physiologist Leonardo Botallo, is a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta. It a ...

Other reported symptoms

These symptoms were found in rare cases of Larsen syndrome. *

Cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble ...

Cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

* Extra bones of wrist *

Malocclusion In orthodontics, a malocclusion is a misalignment or incorrect relation between the teeth of the upper and lower dental arches when they approach each other as the jaws close. The English-language term dates from 1864; Edward Angle (1855-19 ...

* Microdontia and hypodontia * Complete

agenesis In medicine, agenesis () refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue. Many forms of agenesis are referred to by individual names, depending on the organ affected: *A ...

of anus *

Bifid Bifid refers to something that is split or cleft into two parts. It may refer to: * Bifid, a variation in the P wave, R wave, or T wave in an echocardiogram in which a wave which usually has a single peak instead has two separate peaks * Bifid ci ...

uterus * Bifid tongue

Causes

Mutations in gene encoding filamin B

Filamins are cytoplasmic proteins that regulate the structure and activity of the

. These proteins serve as scaffolds on which intracellular signaling and protein trafficking are organized. Filamin B has been found to be expressed in human growth plate

chondrocytes Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...

, which are especially important in vertebrae segmentation and skeleton

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

. Genetic analysis of patients with Larsen syndrome has found the syndrome is caused by

missense mutations In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

in the gene that codes for filamin B. These mutations cause an accelerated rate of

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

in the epiphyseal growth plates of individuals with the mutation. The defects can cause short stature and other symptoms associated with Larsen syndrome.

Localization

Genetic analysis has found that a gene linked to Larsen syndrome, ''LAR1'', is strongly linked to chromosome 3p markers. The locus of this gene is found in a region defined distally by D3S1581 and proximally by D3S1600. This location can be mapped to chromosome region 3p21.1-14.1. Human type VII collagen gene is found within this region in chromosome region 3p21.1. It is reasonable to believe that the joint abnormalities and cardiac anomalies associated with Larsen syndrome are related to the fact that the human type VII collagen gene is found within the same chromosome region as the ''LAR1 ''gene.

Genetics

Both

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

and

forms of Larsen syndrome have been reported. The former is significantly more common than the latter. Symptoms such as

syndactyly Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and diprotodontia, but is an unusual condition in humans. The term is from Greek σύν, ''syn'' 'together' and δά� ...

cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

, short stature, and cardiac defects are seen more commonly in individuals with the autosomal recessive form of the disorder. A lethal form of the disorder has been reported. It is described as being a combination of the Larsen

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

and

pulmonary hypoplasia Pulmonary hypoplasia is incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli. A congenital malformation, it most often occurs secondary to other fetal abnormalities that i ...

Diagnosis

Ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

remains as one of the only effective ways of prenatally diagnosing Larsen syndrome.

Prenatal Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...

diagnosis is extremely important, as it can help families prepare for the arrival of an infant with specifics necessities. Ultrasound can capture prenatal images of multiple joint dislocations, abnormal positioning of legs and knees, depressed nasal bridge, prominent forehead, and

club feet Club may refer to: Arts, entertainment, and media * Club (magazine), ''Club'' (magazine) * Club, a ''Yie Ar Kung-Fu'' character * Clubs (suit), a suit of playing cards * Club music * "Club", by Kelsea Ballerini from the album ''kelsea'' Brands a ...

. These symptoms are all associated with Larsen syndrome, so they can be used to confirm that a

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

has the disorder.Tongsong, T., Wanapirak, C., Pongsatha, S., and Sudasana, J. "Prenatal Sonographic Diagnosis of Larsen Syndrome." Journal of Ultrasound Medicine. 19. (2000): 419-421. Print.

Treatment

Treatment for Larsen syndrome varies according to the symptoms of the individual. Orthopedic surgery can be performed to correct the serious joint defects associated with Larsen syndrome. Reconstructive surgery can be used to treat the facial abnormalities. Cervical kyphosis can be very dangerous to an individual because it can cause the vertebrae to disturb the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...

. Posterior cervical

arthrodesis Arthrodesis, also known as artificial ankylosis or syndesis, is the artificial induction of joint ossification between two bones by surgery. This is done to relieve intractable pain in a joint which cannot be managed by pain medication, spli ...

has been performed on patients with cervical kyphosis, and the results have been successful

Propranolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance an ...

has been used to treat some of the cardiac defects associated with Marfan's syndrome, so the drug also has been suggested to treat cardiac defects associated with Larsen syndrome.

Prognosis

While Larsen syndrome can be lethal if untreated, the prognosis is relatively good if individuals are treated with orthopedic surgery, physical therapy, and other procedures used to treat the symptoms linked with Larsen syndrome.

References

External links

WebMD abstract
{{Cytoskeletal defects Congenital disorders of musculoskeletal system Autosomal dominant disorders Rare syndromes Orthopedic problems