Information on the following diseases can be found in the Related Disorders section of this report:

• Larsen-Like Syndrome
• Oto-Palato-Digital Syndrome (General)
• Arthrogryposis Multiplex Congenita (General)
• Ehlers-Danlos Syndrome (General)
• Associated Disorders (General)

Larsen syndrome is present at birth (congenital). The symptoms and severity of the disorder vary from one affected individual to another. Most cases are characterized by a prominent forehead, an upturned nose with a depressed bridge, and slightly protruding wide-spaced eyes. Multiple bone dislocations can occur in the joints of the knees, elbows and hips. The fingers are usually non-tapering and cylindrically shaped. Feet are often clubbed with extremely high arches (pes cavus). Abnormalities of the spine may be present. In males, the testes may be undescended (cryptorchidism).

Some affected individuals may have webbed fingers (syndactyly), low-set ears, short stature, accumulation of fluid in the skull (hydrocephalus), a cleft or high arched palate or lip, fingernail or toenail abnormalities, mild curvature of the spine (scoliosis), or softening of the bones (osteoporosis). Heart or respiratory difficulties may also be present at birth.

Affected individuals may also experience breathing (respiratory) difficulties due to abnormal softening or flaccidness of the cartilage of the voice box (larynx) and the windpipe (trachea), a condition known as laryngotracheomalacia.

Mental retardation has been reported in some cases. Heart (cardiac) abnormalities such as abnormal widening of the aorta (aortic dilatation) and atrial or ventricular septal defects (ASD or VSD) may also be present. The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. ASDs or VSDs are abnormal openings in the corresponding septum. The size and location of the defect determine the severity of the symptoms. A small atrial or ventricular septal defect may close on its own (spontaneously) or become less significant as the child matures and grows. Larger defects may result in a variety of symptoms including an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), failure to grow at the expected rate (failure to thrive), and/or other findings.

In extremely rare cases, hearing loss and dental abnormalities may also be present.
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The specific underlying cause of Larsen syndrome is unknown. However, the disorder is thought to result from a generalized defect of collagen formation. Collagen is a tough, fibrous protein that is the major structural protein in the body. Larsen syndrome may be familial or appear to occur randomly for unknown reasons (sporadically) in the apparent absence of a family history.

In many familial cases, Larsen syndrome appears to be inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disease gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Researchers have conducted genetic analysis of a large Swedish family (kindred) with multiple members affected by autosomal dominant Larsen syndrome. Based on such research, investigators suggest that, in some people with autosomal dominant Larsen Syndrome, a gene for the disorder may be strongly linked to a region on the short arm of chromosome 3 (3p21.1-14.1). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.

In other instances, Larsen syndrome has been reported in more than one child (siblings) of two apparently normal parents. According to some researchers, such cases suggest autosomal recessive inheritance. In addition, a few cases have been reported in which the parents of affected siblings are closely related by blood (consanguineous), further supporting the possibility of autosomal recessive inheritance in some cases of Larsen Syndrome.

In autosomal recessive disorders, the condition may not appear unless a person inherits a defective (mutated) gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

However, some researchers indicate that there is little evidence for autosomal recessive inheritance in some cases in which affected children are born to apparently normal parents. Such investigators suggest that one parent may in fact have extremely mild symptoms, remaining undiagnosed with the disease. Thus, they indicate that such cases may actually represent autosomal dominant transmission with extremely variable expression.

In addition, some researchers suggest that certain apparently recessive cases may represent germline mosaicism. In germline mosaicism, some of a parent's reproductive cells (germ cells) may carry the gene mutation while others contain a normal cell line ("mosaicism"). As a result, one or more of the parent's children may inherit the gene mutation, potentially leading to manifestation of the disorder, while the parent may have no apparent symptoms (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same genetic abnormality.

Further research is necessary to determine the underlying genetic mechanism(s) responsible for transmission and expression of Larsen syndrome.
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Larsen syndrome is named for the investigator Dr. Loren Larsen who originally described the syndrome as a distinct disease entity in 1950. Reported cases include familial and apparently sporadic cases. As noted above, associated symptoms and physical findings may vary greatly among affected individuals, including among members of the same family. The disorder appears to affect males and females in relatively equal numbers.
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Symptoms of the following disorders may be similar to those of Larsen syndrome. Comparisons may be useful for a differential diagnosis:

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.

Oto-palato-digital syndrome refers to a group of hereditary disorders characterized by malformations of the skull and facial (craniofacial) region, defects of the fingers and toes (digits) and additional physical abnormalities. Craniofacial features may include a prominent forehead, flat nasal bridge, cleft palate, downwardly slanting eyelid folds (palpebral fissures), malformed ears, and/or other abnormalities. Some affected individuals may also have hearing loss, small stature, multiple joint dislocations, hand and foot deformities, other skeletal abnormalities, mild mental retardation, and/or other symptoms and physical findings.

Arthrogryposis multiplex congenita refers to a group of congenital conditions characterized by reduced mobility of multiple joints at birth. In those with such conditions, affected joints may be extended or flexed in various fixed postures. The specific joints involved and associated defects may vary greatly from case to case. Arthrogryposis multiplex congenita may be due to many different causes, including various primary neuromuscular diseases.

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.)
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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. Reconstructive surgery is an appropriate treatment for heart valve and spinal abnormalities, and for cleft palate or harelip. Speech therapy may also be beneficial. Services that benefit physically handicapped or mentally retarded individuals and their families may also be of value. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Under a NORD Research Grant, a team from Cedars-Sinai Medical Center is conducting a study that includes establishment of a Larsen syndrome registry and Web site. 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 registry will permit sample collection for long-term follow-up from 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 Medical Genetics Birth Defects Center, Cedars-Sinai Medial Center, Los Angeles, CA 90048:

John M. Graham, MD, ScD
Tel: (310) 423-9914

Jeannie Kreutzman, CPNP
Tel: (310) 423-9906
jeannie.kreutzman@cshs.org

Dawn Earl, CPNP
Tel: (423-9903
dawn.earl@cshs.org

Information about the project is also available online at:

www.cedars-sinai.edu/6015.html

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 150250; 5/24/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?150250.

Online Mendelian Inheritance in Man, OMIM (TM John Hopkins University, Baltimore, MD. MIM Number 245600; 1/14/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?245600.

Online Mendelian Inheritance in Man, OMIM (TM John Hopkins University, Baltimore, MD. MIM Number 245650; 7/8/98. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?245650.

TEXTBOOKS
Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders Company; 2000:1873, 2094.

Jones KL. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, Pa; WB Saunders Company; 1997:270-73, 286-87.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:722-24.

JOURNAL ARTICLES
Critchley LA, Chan L. General anaesthesia in a child with Larsen syndrome. Anaesth Intensive Care. 2003;31:217-20.

Percin EF, et al. Larsen’s syndrome with dental anomalies: report of a case. ASDC J Dent Child. 2002;69:172-4, 125.

Banks JT, et al. Cervical spine involvement in Larsen’s syndrome: a case illustration. Pediatrics. 2003;111:199-201.

Karakas K, et al. Surgical risk factors in Larsen’s syndrome. Acta Orthop Belg. 2000;66:495-98.

Becker R, 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.

Knoblauch H, et al. Autosomal recessive versus autosomal dominant inheritance in Larsen syndrome: report of two affected sisters. Genet Couns. 1999;10:315-20.

Johnston CE 2nd, et al. Cervical kyphosis in patients who have Larsen Syndrome. J Bone Joint Surg Am. 1997;79:1590-91.

Anderson T. Earliest evidence for arthrogryposis multiplex or Larsen syndrome? Am J Med Genet. 1997;71:127-29.

Sty JR, et al. Extraosseous uptake of bone imaging agent. Clin Nuc Med. 1996;21:649-50.

Tobias JD. Anesthetic implications of Larsen syndrome. J Clin Anesth. 1996;8:255-57.

Vujic M, 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;57:1104-13.

Topley JM, et al., Larsen syndrome in consanguineous parents. Clin Dysmorphol. 1994;3:263-65.

Petrella R, et al. Long-term follow-up of two sibs with Larsen syndrome possibly due to parental germ-line mosaicism. Am J Med Genet. 1993;47:187-97.

Larsen LJ, et al. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediat. 1950;37:574-81.