Larsen Syndrome

A number sign (#) is used with this entry because autosomal dominant Larsen syndrome (LRS) is caused by heterozygous mutation in the gene encoding filamin B (FLNB; 603381) on chromosome 3p14.

An autosomal recessive syndrome with overlapping features (multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects; 245600) has been found to be caused by mutation in the B3GAT3 gene (606374) on chromosome 11q12.

Description

Larsen syndrome is an osteochondrodysplasia characterized by large-joint dislocations and characteristic craniofacial abnormalities. The cardinal features of the condition are dislocations of the hip, knee and elbow joints, with equinovarus or equinovalgus foot deformities. Spatula-shaped fingers, most marked in the thumb, are also present. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge, and a flattened midface. Cleft palate and short stature are often associated features. Spinal anomalies include scoliosis and cervical kyphosis. Hearing loss is a well-recognized complication (summary by Bicknell et al., 2007).

Clinical Features

Larsen et al. (1950) called attention to a syndrome of multiple congenital dislocations and characteristic facies (prominent forehead, depressed nasal bridge, wide-spaced eyes). Clubfoot, bilateral dislocation of elbows, hips and knees (most characteristically, anterior dislocation of the tibia on the femur), and short metacarpals with cylindrical fingers lacking the usual tapering were the skeletal features of note. Cleft palate, hydrocephalus, and abnormalities of spinal segmentation were found in some patients.

Harris and Cullen (1971) described affected mother and daughter. Bilateral dislocation of the knees, pes cavus, cylindrically shaped fingers, and characteristic facies (wide-spaced eyes, flattened nasal bridge and prominent forehead) were present in both. The maternal grandfather was said to have had similar facies. One of the original cases of Larsen et al. (1950), 23 years of age in 1972, had an affected child. Features in addition to knee dislocations included flat face, accessory carpal bones, and short terminal phalanges creating pseudoclubbing. Multiple congenital dislocations with osseous anomalies and unusual facies are characteristic. Anterior dislocation of the tibia on the femur is usual. A juxtacalcaneal accessory ossification center and abnormality of vertebrae are observed.

Latta et al. (1971) made a point of a juxtacalcaneal accessory bone which may be specific for this entity.

Tsang et al. (1986) reported 'new' oral and craniofacial findings in a patient with Larsen syndrome.

Stanley et al. (1988) described mixed hearing loss in a child with Larsen syndrome. On the basis of this and other cases, the authors suggested that there may be involvement of the ossicular joints in this disorder.

Le Marec et al. (1994) described a male infant who, in addition to the typical manifestations of Larsen syndrome, had laryngomalacia with apnea and multiple abnormalities of the cervical spine (segmentation defects, kyphosis, atlantoaxial dislocation, and narrowing of subdural space at the apex of the kyphosis).

Although abnormalities of the cervical spine were not emphasized in the original description of the syndrome (Larsen et al., 1950), they may be the most serious manifestation. Cervical kyphosis in particular may be life-threatening because of the impingement on the spinal cord at the apex of the kyphosis. Of the 9 affected infants followed by Johnston et al. (1996), 5 were noted to have cervical kyphosis because of marked hypoplasia of 1 or 2 vertebral bodies (usually the fourth or fifth cervical vertebra, or both) at the apex of the kyphosis; the infants were successfully managed by posterior cervical arthrodesis alone. Johnston et al. (1996) suggested that the prevalence of cervical kyphosis in Larsen syndrome has probably been underestimated but may easily be documented because no dynamic studies or cooperation by the patients are necessary. They concluded that early diagnosis followed by operative stabilization should help such patients avoid neurologic deficits.

Becker et al. (2000) reported the case of a mildly affected father and a severe form of Larsen syndrome in a fetus detected by sonography. The mother had requested prenatal diagnosis on the grounds of an unknown congenital disorder in her husband. His height was 172 cm. He presented with a flat palate and craniofacial dysmorphism (small teeth, hypertelorism, and a prominent forehead). The fingers and toes had short terminal phalanges creating pseudoclubbing. Congenital bilateral clubfoot had required orthopedic correction. Sonographic examination in the man's pregnant wife showed that both legs of the fetus were fixed in an extended position at the knee joints with overstretching of the joints, consistent with genua recurvata. Irregularities of the knee joints and clubfeet were noted. The elbows were flexed and mobile. The fingers seemed to be thickened and in a constantly flexed position. The facial profile showed dysmorphism including a prominent forehead, flat nose, and micrognathia. The parents opted to terminate the pregnancy. Autopsy of the fetus confirmed the sonographic findings in the female fetus with a normal 46,XX karyotype. The diagnosis of Larsen syndrome in the father had been missed by highly skilled genetic counselors. A similar experience of misdiagnosis was reported by Vujic et al. (1995), who reported that none of 26 family members with Larsen syndrome who had received medical treatment had been diagnosed correctly. Becker et al. (2000) raised the possibility that the mild manifestation of Larsen syndrome in the father was due to mosaicism.

Inheritance

Dominant inheritance of Larsen syndrome seemed certain from the reports of Latta et al. (1971) and of McFarlane (1947). The mother of the patient reported by Latta et al. (1971) had a saddle nose which developed at age 18 after tennis-ball trauma. McFarlane (1947) reported a woman with saddle nose, congenital dislocation of the knees, and hyperextensibility of the elbows. By each of 3 different mates she produced an affected child with bilateral knee dislocations.

Hall (1978) followed up on the 2-generation family reported by Latta et al. (1971); she was convinced that the mother was affected and made the further observation that in her 30s the mother had developed polychondritis of her tracheobronchial cartilage with recurrent pulmonary problems because of airway stenosis.

Sugarman (1975) described affected black mother and daughter. The diagnosis in the cases of Henriksson et al. (1977) and of Marques (1980) is doubtful (Gorlin, 1982). Gorlin (1982) observed affected mother and son.

Petrella et al. (1993) provided follow-up on 2 sibs with Larsen syndrome reported by Bloch and Peck (1965). This family had been cited as a possible example of the recessive form of Larsen syndrome. Congenital dislocation of the knees with unilateral cataract and unilateral undescended testis was present in a newborn male; a sister was born with bilateral dislocation of the knees and hips and cleft palate. The parents were unaffected. However, reinterpretation as the autosomal dominant form of Larsen syndrome with germline mosaicism was required because the sister gave birth to an affected daughter (Petrella et al., 1993).

Frints et al. (2000) and Debeer et al. (2003) described cases of asymmetric Larsen syndrome which they interpreted as examples of unilateral somatic mosaicism.

Mapping

In a large Swedish kindred with autosomal dominant Larsen syndrome, Vujic et al. (1995) found that the gene, which they symbolized LAR1, is strongly linked to a region of 3p defined distally by D3S1581 and proximally by D3S1600, which cytogenetically maps to 3p21.1-p14.1. Linkage and recombination analysis using a COL7A1 (120120) PvuII intragenic polymorphism versus Larsen syndrome and chromosome 3 markers indicated that COL7A1 is located close to, but separate from, the LAR1 locus. The kindred contained a total of 49 individuals thought to be carriers of the mutant gene. Altogether, 48 family members, of whom 26 were affected, were included in the DNA study.

Molecular Genetics

In 4 individuals with sporadically occurring Larsen syndrome and 1 family with a dominantly inherited form of the condition, Krakow et al. (2004) found heterozygosity for de novo missense mutations in the FLNB gene (603381.0004; 603381.0005).

Bicknell et al. (2007) identified several different heterozygous mutations in the FLNB gene (see, e.g., 603381.0011; 603381.0012) in 20 unrelated patients with Larsen syndrome. One of the mutations was detected in 6 unrelated probands.

History

One of the earliest reports of Larsen syndrome may have been that of McFarland (1929).