Clinical Diagnosis

The FLNB-related disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome and at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and boomerang dysplasia.

Spondylocarpotarsal synostosis (SCT) syndrome is characterized by the following [Langer et al 1994]:

• Disproportionate short stature

• Vertebral anomalies with block vertebrae

• Scoliosis, lordosis

• Carpal and tarsal synostosis

• Club feet

• Mild facial dysmorphisms with round face, frontal bossing, anteverted nostrils

Other manifestations can include the following:

• Midline cleft palate

• Conductive hearing loss

• Joint laxity

• Dental enamel hypoplasia

Diagnostic radiographic features:

• Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine.
  Note: (1) Asymmetric fusion of the posterior elements can result in “a unilateral unsegmented vertebral bar.” (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as “segmentation defects,” it is probable that the process of segmentation is normal in SCT syndrome and that the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development.

• Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [Langer et al 1994].

• Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur were reported in two patients [Honeywell et al 2002, Mitter et al 2008].

Larsen syndrome is characterized by the following [Larsen et al 1950]:

• Congenital dislocations of the hip, knee, and elbow

• Club feet (equinovarus or equinovalgus foot deformities)

• Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy

• Short, broad, spatulate distal phalanges, particularly of the thumb

• Craniofacial anomalies (prominent forehead, depressed nasal bridge, flattened midface, and ocular hypertelorism)

Other manifestations can include the following:

• Midline cleft palate

• Hearing loss, often resulting from malformations of the ossicles

Diagnostic radiographic features in early childhood:

• Supernumerary (accessory) carpal and tarsal bone ossification centers, which may be a universal finding [Bicknell et al 2007].

Atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII), once thought to represent distinct entities, now appear to be part of a phenotypic continuum [Farrington-Rock et al 2006].

• AOIII is milder than AOI, commonly with survival beyond the neonatal period. Clinical findings are dislocated hips, knees, and elbows and club feet.
  Radiographic features include distal tapering of the humeri and femora, short and broad tubular bones of the hands and feet, and mild vertebral hypoplasia.

• AOI is characterized by perinatal lethality with severe short-limbed dwarfism, dislocated hips, knees, and elbows, and club feet. Radiographic features include marked platyspondyly; hypoplastic pelvis; incomplete or absent, shortened, or distally-tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae; and unossified or partially ossified metacarpals and middle and proximal phalanges.

Boomerang dysplasia is a perinatal lethal bone dysplasia with close similarities to AOI, distinguished primarily by characteristic bowing of the femora and, occasionally, extraskeletal manifestations including encephalocele and omphalocele [Bicknell et al 2005].

Molecular Genetic Testing

Gene. FLNB is the only gene currently known to be associated with the FLNB-related disorders [Krakow et al 2004].

Clinical testing

• Sequence analysis. Sequencing of the coding exons including the exon-intron boundaries:

  • SCT syndrome. Mutations are spread throughout the gene; there are no hot-spot regions.

  • Larsen syndrome. Mutations are spread over exons 2-5 and 27-33 [Bicknell et al 2007].

  • Atelosteogenesis type III. Mutations are in exons 2-5, 13, and 27-33 [Farrington-Rock et al 2006].

  • Boomerang dysplasia or atelosteogenesis type I. The large majority of reported mutations are in exons 2-5 [Bicknell et al 2005].

Several recurrent mutations have been reported (see Genotype/Phenotype Correlations and Molecular Genetics).

Table 1. Summary of Molecular Genetic Testing Used in FLNB-Related Disorders

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
FLNB	Sequencing of exons and intron-exon boundaries	Point mutations; small deletions	100% 2,3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Because this disorder is defined by the presence of a mutation in the causative gene, the mutation detection rate is 100%.

3. Mutation detection frequency for Larsen syndrome and AOI and AOIII is 100%. In several instances individuals with typical SCT syndrome have had no FLNB mutation identified on sequence analysis; the proportion of such cases that could be explained by either exonic or whole-gene deletions or locus heterogeneity is unknown; however, some cases of SCT syndrome do not map to the FLNB locus using linkage analysis [unpublished data].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband. Clinical findings guide the order of testing of FLNB exons:

• Mutations associated with the most severe phenotypes almost invariably occur in exons 2-5.

• Mutations associated with the milder phenotype, Larsen syndrome, can occur in exons 2-5 and exons 27-33.

• Sequencing of the entire FLNB coding may be appropriate when clinical suspicion is high and a mutation was not identified in select exons.

Carrier testing for relatives at risk for SCT syndrome requires prior identification of the disease-causing mutations in the family.

Note: SCT syndrome is inherited in an autosomal recessive manner; heterozygotes for FLNB mutations causing SCT syndrome are asymptomatic. All other FLNB-related disorders are inherited in an autosomal dominant manner and, thus, carrier testing is not an issue.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation(s) in the family.

Note: It is the policy of GeneReviews to include in GeneReviews^TM chapters any clinical uses of testing available from laboratories listed in the GeneTests^TM Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in FLNB.

Natural History

Boomerang dysplasia or atelosteogenesis type I. On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is seldom possible. Polyhydramnios can complicate the pregnancy. Neonates with boomerang dysplasia or AOI die soon after birth from cardiorespiratory insufficiency.

Atelosteogenesis type III. The most conspicuous finding of AOIII is joint dislocations. A specific diagnosis of AOIII is seldom possible by ultrasound examination alone.

Infants with AOIII can survive the neonatal period but can require intensive and invasive support to do so. The infant reported by Schultz et al [1999] had significant problems with respiratory insufficiency as a result of laryngotracheomalacia and thoracic hypoplasia. Her mother, who was intellectually normal, had similar but milder respiratory problems in the neonatal period.

Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). In these instances, the parents probably have a mild phenotype associated with somatic mosaicism, whereas their offspring with a non-mosaic germline mutation have a severe phenotype.

Developmental delay, present in some long-term survivors with AOIII, is assumed to be a secondary consequence of orthopedic and respiratory complications of the primary disorder

Spondylocarpotarsal synostosis syndrome. Individuals with spondylocarpotarsal syndrome have normal or near-normal birth length; however, progressive vertebral fusion results in poor growth of the trunk and short stature becomes evident postnatally. Stature is typically -3 to -4 SD.

Scoliosis is common, but variable in severity and time of onset because of the extent and pattern of vertebral fusion. Some authors have observed deformity at birth although the phenotype and, hence the diagnosis, has only become evident later in childhood. The irregular nature of the vertebral anomalies can also give rise to other complications such as cervical spine instability [Seaver & Boyd 2000].

SCT syndrome has been associated with retinal anomalies [Steiner et al 2000] and sensorineural deafness [Langer et al 1994, Coêlho et al 1998]. The cataracts and retinal abnormalities described in one family with SCT syndrome were not severe enough to impair vision [Steiner et al 2000].

Other findings can include pes planus, dental enamel hypoplasia, and unilateral conductive hearing loss [Mitter et al 2008].

Intelligence is normal.

Larsen syndrome. Larsen syndrome is compatible with survival into adulthood [Bicknell et al 2007]. Intelligence is normal.

Intrafamilial variation in Larsen syndrome can be remarkable. In a large family segregating one of the recurring mutations leading to Larsen syndrome, some individuals had cleft palate and multiple large joint dislocations, whereas others who had no major anomalies had short stature and very mild clinical and radiographic features, such as short distal phalanges and supernumerary carpal and tarsal bones [Bicknell et al 2007]. Clinical variability can also result from the presence of somatic mosaicism for a causative mutation in a mildly affected parent and the presence of a germline mutation in more severely affected offspring.

In their study of 20 unrelated families with a total of 52 affected individuals, Bicknell et al [2007] determined that all probands had dislocations or subluxations of the large joints (80% hip, 80% knee, and 65% elbow). The most mildly affected proband had subluxation of the shoulders as her only large joint manifestation. Clubfoot was present in 75% of affected individuals.

Stature is mildly affected. In 14 of 20 probands height was below the tenth centile; height less than the first centile was rare and one individual was greater than the 97^th centile [Bicknell et al 2007].

Spinal abnormalities were observed on x-rays in 16 of 19 (84%) probands. Cervical kyphosis was noted in 50%, usually from subluxation or fusion of the bodies of C2, C3, and C4, which was commonly 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 of cervical cord myelopathy and secondary tetraparesis [Bicknell et al 2007]. The incidence of myelopathy is at least 15%.

Cleft palate occurs in 15% of affected individuals.

Deafness is common [Herrmann et al 1981, Stanley et al 1988, Maack & Muntz 1991]. Conductive deafness, often with malformation of the ossicles of the middle ear, was observed in four of 19 probands (21%) [Bicknell et al 2007].

Although laryngotracheomalacia has been reported in association with Larsen syndrome, few individuals with Larsen syndrome and a documented FLNB mutation are severely affected. Of note, individuals with more severe skeletal manifestations consistent with a diagnosis of AOIII can have severe laryngotracheomalacia [Rock et al 1988, Schultz et al 1999].

Genotype-Phenotype Correlations

SCT syndrome. Homozygosity or compound heterozygosity for frameshift or nonsense mutations in FLNB causes SCT syndrome [Krakow et al 2004]. Mutations associated with SCT syndrome are associated with loss of protein expression and hence are true null alleles [Farrington-Rock et al 2006].

Larsen syndrome and atelosteogenesis I and III. The mutations associated with Larsen syndrome and AOII and AOIII are either missense or small in-frame deletions and are predicted to encode full-length filamin B protein.

In some instances the same mutation is associated with different phenotypes (e.g., c.502G>A leading to the substitution p.Gly168Ser is associated with both AOI and AOIII).

Recurrent mutations:

• p.Gly1691Ser, the most common recurrent substitution, associated with phenotypes ranging from mild Larsen syndrome (isolated bilateral dislocation of the knees and digital and craniofacial anomalies) to AOIII [Bicknell et al 2005, Farrington-Rock et al 2006]

• c.679G>A, predicting the substitution p.Glu227Lys, associated with Larsen syndrome

Mosaicism. Clinical evidence suggests that somatic mosaicism can complicate the presentation of these conditions [Petrella et al 1993]. Most notably, somatic mosaicism for a FLNB mutation can be associated with Larsen syndrome, whereas the same mutation in the germline state can be associated with AOIII.

Penetrance

Germline FLNB mutations are fully penetrant but show variable expressivity, leading to the range of phenotypes described in this GeneReview.

Nomenclature

Larsen syndrome. Some authors described what appeared to be autosomal recessive Larsen syndrome [Clayton-Smith & Donnai 1988, Bonaventure et al 1992, Laville et al 1994, Yamaguchi et al 1996]; however, some of these families had sib recurrence of Larsen syndrome as a result of germline mosaicism in an unaffected parent [Petrella et al 1993].

In contrast, other recessive disorders with multiple joint dislocations called Larsen syndrome in the past but not sharing other clinical characteristics of Larsen syndrome are best not referred to as Larsen syndrome [Topley et al 1994]. These conditions include the “Reunion Island form of Larsen syndrome” [Bonaventure et al 1992, Laville et al 1994], which is clinically and radiographically distinct from FLNB-related Larsen syndrome.

Atelosteogenesis types I and III were so named because the major manifestation is incomplete and disordered ossification of the skeleton [Maroteaux et al 1982, Sillence et al 1982, Stern et al 1990].

Note: AOII, one of the sulfate transporter-related osteochondrodysplasias caused by mutations in SLC26A2 (DTDST), is genetically distinct from AOI and AOIII (see Atelosteogenesis Type 2).

Piepkorn dysplasia is considered to be the same as boomerang dysplasia and, thus, the name has fallen out of use.

Prevalence

No prevalence figures are available for any of the FLNB-related conditions.

SCT Syndrome

Other vertebral dysplasias with similarities to SCT syndrome, such as spondylocostal dysplasia and multiple synostosis, are inherited in an autosomal dominant manner. Absence of rib anomalies in SCT syndrome distinguishes it from spondylocostal dysplasia; lack of progressive symphalangism and different facial findings in SCT syndrome distinguish it from multiple synostoses syndrome.

Some individuals with vertebral, carpal, and tarsal fusions similar to the findings of SCT syndrome, previously identified as having Klippel-Feil syndrome, have been shown to be heterozygous for mutations in GDF6 [Tassabehji et al 2008].

Individuals with autosomal dominant inheritance of a phenotype similar to FLNB-associated SCT syndrome but without identifiable FLNB mutations were recently reported [Isidor et al 2008].

Larsen Syndrome

Otopalatodigital syndrome type 1 (OPD1) (see Otopalatodigital Spectrum Disorders) differs chiefly from Larsen syndrome in the following ways:

• X-linked inheritance of OPD1

• Absence of dislocation of the large joints (except dislocation of the radial heads) and cervical spine dysplasia in OPD1

• Absence of radiologically supernumerary ossification centers within the carpus and/or tarsus in OPD1

Spondyloepiphyseal dysplasia (SED), Omani type [Thiele et al 2004], like Larsen syndrome, is characterized by congenital joint dislocations and supernumerary ossification centers in the carpus and tarsus. The chief differences are the presence of the following in SED Omani type and not in Larsen syndrome:

• Epiphyseal dysplasia

• Progressive spondylodysplasia in early and mid childhood

• Rhizomelic shortening of the limbs

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with FLNB-related disorders, the following evaluations are recommended:

Spondylocarpotarsal synostosis syndrome

• Ophthalmologic examination for retinal anomalies

• Audiometry to assess for sensorineural hearing loss

• Spine films to evaluate for vertebral abnormalities that predispose to scoliosis

• Cervical spine films to evaluate for cervical dysplasia

Larsen syndrome

• Lateral cervical spine films in flexion and extension to look for dysplasia that can lead to cervical cord myelopathy.
  Note: Early diagnosis of cervical kyphosis may influence the surgical approach used to stabilize the spine (see Treatment of Manifestations).

• Audiometry to assess hearing

• Assessment of the hips for dislocation

Treatment of Manifestations

Cervical spine instability. Case series indicate that early intervention to improve cervical spine stability in asymptomatic infants using posterior arthrodesis is successful. In infants with myelopathic signs function can be stabilized, if not improved, by a combination of anterior decompression and circumferential arthrodesis [Johnston et al 1996, Sakaura et al 2007, Madera et al 2008].

Large joint dislocations. Conservative, nonsurgical management of hip dislocation in Larsen syndrome is often unsuccessful and operative reduction is usually required.

Scoliosis is treated medically; no effective surgical intervention has been described.

Club feet are managed in a routine manner.

Cleft palate should be treated by a multidisciplinary craniofacial team when possible.

Hearing loss. Ideally, the team evaluating and treating the deaf individual should consist of an otolaryngologist with expertise in the management of early childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a clinical geneticist, and a pediatrician. The expertise of an educator of the Deaf may also be required. An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, and cochlear implantation (see Deafness and Hereditary Hearing Loss Overview).

Prevention of Secondary Complications

Evidence suggests that preemptive posterior stabilization of the cervical spine in individuals with Larsen syndrome with cervical spine dysplasia may prevent this complication and that combined anterior and posterior stabilization can lead to clinical improvement in individuals with evidence of myelopathy [Sakaura et al 2007].

Because of the cervical vertebral abnormalities observed in both SCT syndrome and Larsen syndrome, the cervical spine should be evaluated for features of instability prior to general anesthesia. Care must be taken intraoperatively to minimize extension of the cervical spine [Malik & Choudhry 2002, Critchley & Chan 2003]. Additionally, individuals with Larsen syndrome are at increased risk for airway complications related to laryngotracheomalacia; thus, it has been suggested that anesthetic agents that exhibit more rapid induction and recovery are preferred [Morishima et al 2004].

Surveillance

Vertebral anomalies can lead to progressive scoliosis; orthopedic monitoring is therefore indicated.

If an individual with Larsen syndrome is born without dislocated hips, careful surveillance should be maintained to ensure that the hips remain enlocated.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

The FLNB-related disorders, AOI, AOIII, boomerang dysplasia, and Larsen syndrome, are inherited in an autosomal dominant manner.

SCT syndrome is inherited in an autosomal recessive manner.

Risk to Family Members - Autosomal Dominant Inheritance

Parents of a proband

• Some individuals diagnosed with an autosomal dominant FLNB-related disorder have an affected parent.

• A proband with an autosomal dominant FLNB-related disorder may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown, although the vast majority of lethal FLNB-related conditions are the result of de novo events, the exception being a low-grade mosaic parent transmitting the causative mutation to their affected offspring.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Germline mosaicism has been reported; its incidence is unknown [Petrella et al 1993]

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a thorough clinical examination, which may include radiographic examination where indicated. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although many individuals diagnosed with an autosomal dominant FLNB-related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

• Germline mosaicism has been reported; its incidence is unknown [Petrella et al 1993].

Offspring of a proband. Each child of an individual with an autosomal dominant FLNB-related disorder has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Risk to Family Members- Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic, although one case report has made an argument for the presence of mild manifestations in one instance.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are generally asymptomatic.

Offspring of a proband. The offspring of an individual with SCT syndrome are obligate heterozygotes (carriers) for a disease-causing mutation in the FLNB gene.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the family.

Related Genetic Counseling Issues

Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with these conditions. Most notably, the presentation of a typical Larsen syndrome phenotype can result from mosaicism for a mutation which, when present as a germline mutation, leads to the AOIII phenotype.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

A priori high-risk pregnancies. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

A priori low-risk pregnancies. Routine prenatal ultrasound examination may identify skeletal findings such as limb changes consistent with multiple joint dislocations that raise the possibility of Larsen syndrome in a fetus not known to be at increased risk. Detection of fetuses affected with AOI by ultrasound examination during the second trimester is possible because of the multiple anomalies present including shortening of the limbs and thoracic hypoplasia [Ueno et al 2002].

Consideration of molecular genetic testing for an FLNB mutation in these situations is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews^TM chapters any clinical uses of testing available from laboratories listed in the GeneTests^TM Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The molecular pathogenesis of SCT syndrome results from a lack of expression of FLNB protein [Farrington-Rock et al 2008]. This mechanism differs from that of the Larsen syndrome – AO spectrum of conditions, which are caused by normal expression of a structurally abnormal FLNB protein. The mechanism by which abnormal FLNB proteins lead to the Larsen syndrome-AO spectrum disorders is not understood.

In the developing murine embryo Flnb is widely expressed, particularly in endothelial cells and chondrocytes. In keeping with this pattern of expression, Flnb-deficient mice are growth retarded with mild shortening of the limbs. Postnatally they develop fusion of the ribs and vertebrae, kyphoscoliosis, and malformations of the calvaria and facial bones. The possible mechanisms underlying this effect include diminished cell-matrix adhesion or de-repression of transforming growth factor beta signaling [Lu et al 2007, Zheng et al 2007, Zhou et al 2007, Farrington-Rock et al 2008].

Normal allelic variants. The mRNA transcript of FLNB is 9463 nucleotides in length and comprises 46 exons.

Pathologic allelic variants. Mutations associated with SCT syndrome are associated with loss of protein expression and hence are true null alleles [Farrington-Rock et al 2006]. The mutations associated with Larsen syndrome and AOI and AOIII are either missense or small in-frame deletions and are predicted to encode full-length filamin B protein. Mutations that lead to Larsen syndrome are clustered in exons 2-5 and 27-33 [Bicknell et al 2007]. Three recurrent mutations have been reported, the most common of which is p.Gly1691Ser (Table 2) [Bicknell et al 2007].

Normal gene product. The filamin-B protein comprises 2,602 amino acids. The N terminus has an actin-binding domain. The rest of the protein comprises 24 filamin repeats. There are two “hinge” regions between filamin repeats 15 and 16 and 23 and 24, which are thought to confer flexibility to the protein.

Abnormal gene product. For Larsen syndrome and AOI and AOIII, it is not known whether the mutations disrupt protein interactions or facilitate novel interactions with filamin B. The cause of SCT syndrome is a complete loss of filamin B protein.

Literature Cited

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Author Notes

Web: dnmeds.otago.ac.nz/departments/womens/paediatrics/research/cgg/

Revision History

• 9 October 2008 (me) Review posted live

• 20 May 2008 (sr) Original submission