FLNB-Related Disorders

Stephen Robertson; Joanna Meira

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FLNB-Related Disorders

Stephen Robertson, FRACP, DPhil and Joanna Meira, MD, MSc.

Author Information and Affiliations

Initial Posting: October 9, 2008; Last Update: September 11, 2025.

Estimated reading time: 34 minutes

Summary

Clinical characteristics.

The FLNB-related disorders can be divided into two groups of conditions caused by loss of function or gain of function of filamin-B. Biallelic loss-of-function pathogenic variants in FLNB cause spondylocarpotarsal synostosis syndrome (FLNB-SCT) VSports注册入口. Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal. For the purposes of this GeneReview, the previously described entities Piepkorn dysplasia and boomerang dysplasia are subsumed under the FLNB-AO1 spectrum.

FLNB-SCT is characterized by postnatal disproportionate short stature; scoliosis and lordosis due to vertebral fusions; carpal and tarsal synostosis; and, variably, clubfeet, hearing loss, and dental enamel hypoplasia.

FLNB-LS is characterized by combinations of congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis (which can be associated with a cervical myelopathy); short, broad, spatulate distal phalanges; distinctive craniofacial features (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal ossification centers. Individuals with FLNB-LS may also present with midline cleft palate and hearing loss VSports在线直播.

FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. FLNB-AO1 is lethal in the perinatal period. At its most severe, the spectrum of phenotypes assigned FLNB-AO1 can present with perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges); macrobrachycephaly; prominent forehead; hypertelorism; and proptosis. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support V体育2025版.

Diagnosis/testing.

The diagnosis of FLNB-SCT is established in a proband by identification of biallelic loss-of-function pathogenic variants in FLNB by molecular genetic testing. The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is established in a proband by identification of a heterozygous gain-of-function pathogenic variant in FLNB by molecular genetic testing VSports.

Management.

Treatment of manifestations: Cervical spine instability in asymptomatic infants can be successfully managed with posterior arthrodesis. Function can be stabilized (if not improved) in infants with myelopathic signs by a combination of anterior decompression and circumferential arthrodesis VSports app下载. Hip dislocation in individuals with FLNB-LS usually requires operative reduction. Scoliosis and clubfeet are managed in a routine manner. Anesthetic agents that allow more rapid induction and recovery are preferred in those with laryngotracheomalacia. When possible, cleft palate and hearing loss are best managed by multidisciplinary teams.

Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations.

Pregnancy management: Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees.

Genetic counseling.

FLNB-SCT is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FLNB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial FLNB pathogenic variants V体育安卓版. Heterozygous sibs of a proband with FLNB-SCT can exhibit mild reductions in stature but no other medically significant phenotypic manifestations. Once the FLNB pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

FLNB-LS, FLNB-AO1, FLNB-AO3, and FLNB-related apparently isolated clubfoot are inherited in an autosomal dominant manner. Comparatively mild (e.g., FLNB-LS) and severe (e.g., FLNB-AO3) forms of the autosomal dominant FLNB-related disorders can occur in the same family. Some individuals diagnosed with an autosomal dominant FLNB-related disorder have the disorder as the result of a pathogenic variant inherited from a heterozygous or mosaic parent. Some individuals have the disorder as the result of a de novo pathogenic variant (the vast majority of lethal FLNB conditions are the result of de novo pathogenic variants). Each child of a proband who is heterozygous for an FLNB pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of a proband with somatic mosaicism for an FLNB pathogenic variant has up to a 50% chance of inheriting the pathogenic variant. Offspring who inherit an FLNB pathogenic variant from a proband with somatic mosaicism may be more severely affected than the proband. Once the FLNB pathogenic variant has been identified in an affected family member, prenatal/preimplantation genetic testing are possible.

"V体育ios版" GeneReview Scope

FLNB-Related Disorders: Phenotypic Spectrum
Spondylocarpotarsal synostosis syndrome (FLNB-SCT) Larsen syndrome (FLNB-LS) Atelosteogenesis type 1 (FLNB-AO1) Including boomerang dysplasia, Piepkorn dysplasia, & spondylohumerofemoral (giant cell) dysplasia Atelosteogenesis type 3 (FLNB-AO3) Apparently isolated clubfoot

: For synonyms and outdated names see Nomenclature.

"V体育ios版" Diagnosis

Formal diagnostic criteria for FLNB-related disorders have not been established.

"V体育官网" Suggestive Findings

FLNB-Related Spondylocarpotarsal Synostosis Syndrome (FLNB-SCT)

FLNB-SCT should be suspected in individuals with the following clinical and radiographic features [Langer et al 1994].

Clinical features

Postnatal disproportionate short stature
Scoliosis and lordosis
Clubfeet
Other manifestations: midline cleft palate, conductive and/or sensorineural hearing loss, joint stiffness, dental enamel hypoplasia

Radiographic features

Fusion of adjacent vertebrae and posterior elements, which 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" [Langer et al 1994]. (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in individuals with FLNB-SCT and the fusion of adjacent vertebral elements is related to a defect in a separate pathologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis has been described.
Carpal and tarsal synostosis. Carpal synostosis is usually between the capitate and hamate, or the lunate and triquetrum ["V体育官网" Langer et al 1994].
Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur have been reported in two individuals [Honeywell et al 2002, Mitter et al 2008].

FLNB-Related Larsen Syndrome (FLNB-LS)

FLNB-LS should be suspected in individuals with the following clinical and radiographic features [Larsen et al 1950].

Clinical features

Congenital dislocations of the hip, knee, elbow, and occasionally the shoulder
Clubfoot (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals ["V体育2025版" Yang et al 2016, Quiggle et al 2022].
Scoliosis and cervical kyphosis, which can be associated with cervical myelopathy
Short, broad, spatulate distal phalanges, particularly of the thumb
Distinctive craniofacial features (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)

Radiographic features in early childhood

Vertebral anomalies: hypoplastic vertebrae, hemivertebrae, spondylolisthesis, bifid posterior processes
Supernumerary (accessory) carpal and tarsal bone ossification centers
Note: Possibly a universal finding [Bicknell et al 2007].

FLNB-Related Atelosteogenesis Type 3 (FLNB-AO3)

FLNB-AO3 should be suspected in individuals with the following clinical and radiographic features.

Clinical features

Dislocated hips, knees, and elbows
Clubfoot
Milder than FLNB-AO1; survival beyond the neonatal period is possible with intensive and invasive respiratory support [Schultz et al 1999].
Laryngotracheobronchomalacia

Radiographic features

Mild vertebral hypoplasia
Distal tapering of the humeri and femora
Short and broad tubular bones of the hands and feet

Note: There are no qualitative diagnostic differences between FLNB-AO3 and FLNB-LS. The prime distinction lies in the severity of the disorder in individuals with FLNB-AO3, such that survival beyond the first year of life is rare.

FLNB-Related Atelosteogenesis Type 1 (FLNB-AO1)

FLNB-AO1 should be suspected in individuals with the following clinical and radiographic features.

Clinical features

Perinatal-lethal short-limbed dwarfism
Severe dislocations of the hips, knees, and elbows; clubfoot

Radiographic features

Marked platyspondyly
Hypoplastic pelvis
Thoracic hypoplasia
Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
Unossified or partially ossified metacarpals and middle and proximal phalanges
Occasionally, extraskeletal manifestations including encephalocele and/or omphalocele [V体育官网入口 - Bicknell et al 2005]

Note: Individuals with a diagnosis of boomerang dysplasia or Piepkorn dysplasia (both entities being perinatal-lethal bone dysplasias with close similarities to FLNB-AO1) are now best subsumed under a diagnosis of FLNB-AO1. Bowing of the femora was previously considered a differentiating feature between boomerang dysplasia and FLNB-AO1, but following the definition of their molecular pathogenesis, it is unlikely that this clinical sign adequately differentiates these two conditions. Similarly, Piepkorn dysplasia exhibits significant phenotypic overlap with FLNB-AO1, with oligosyndactyly possibly representing the only differentiating feature. For the purposes of this review, boomerang dysplasia and Piepkorn dysplasia are subsumed under the FLNB-AO1 spectrum.

FLNB-Related Apparently Isolated Clubfoot

Preliminary evidence suggests that a minimal manifestation of the autosomal dominant FLNB-related disorders is apparently isolated clubfoot [Yang et al 2016, Quiggle et al 2022]. Some individuals in these series had other mild manifestations of Larsen syndrome, but in pedigrees where the identified variants segregated, manifestations were mild, if not monosymptomatic. Studies of larger cohorts are necessary to fully define the phenotypic manifestations of these presentations.

Establishing the Diagnosis

FLNB-SCT. The diagnosis of FLNB-SCT is established in a proband by identification of biallelic pathogenic (or likely pathogenic) loss-of-function variants in FLNB by molecular genetic testing (see Table 1).

Autosomal dominant FLNB-related disorders. The diagnosis of other FLNB-related disorders (LS, AO1, and AO3, and isolated clubfoot) is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) gain-of-function variant in FLNB by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of FLNB-related disorders, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of FLNB is performed first to detect missense, nonsense, and splice-site variants and small intragenic deletions/insertions. Note: (1) Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no pathogenic variant is found (or only one pathogenic variant is identified in a proband with features characteristic of FLNB-SCT), the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. (2) Multiexon FLNB deletions have been identified in two individuals with FLNB-SCT [Fukushima et al 2021] but have not been reported to cause FLNB-LS, FLNB-AO1, or FLNB-AO3. (see Table 1).
A multigene panel that includes FLNB and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other skeletal dysplasias, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in FLNB-Related Disorders

Gene ¹	Method	Proportion of Pathogenic Variants ² Identified by Method
FLNB	Sequence analysis ³	<100% ⁴
FLNB	Gene-targeted deletion/duplication analysis ⁵	See footnote 6.

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in the interpretation of sequence analysis results, click here.
4.: Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may also be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than that of gene-targeted deletion/duplication analysis.
6.: To date, deletions/duplications have not been identified as a cause of FLNB-LS, FLNB-AO1, or FLNB-AO3. Two individuals with FLNB-SCT were homozygous for large multiexon deletions of FLNB [Fukushima et al 2021].

Clinical Characteristics

Clinical Description

The FLNB-related disorders can be divided into two groups of conditions caused by loss of function or gain of function of filamin-B. Biallelic loss-of-function pathogenic variants in FLNB cause spondylocarpotarsal synostosis syndrome (FLNB-SCT). Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal. For the purposes of this GeneReview, the previously described entities Piepkorn dysplasia, boomerang dysplasia, and spondylohumerofemoral (giant cell) dysplasia are subsumed under the FLNB-AO1 spectrum. To date, more than 100 individuals with pathogenic variants in FLNB have been identified [Daniel et al 2012, Girisha et al 2016, Yang et al 2016, Salian et al 2018, Stenson et al 2020, Quiggle et al 2022]. The following description of the phenotypic features associated with FLNB-related conditions is based on these reports.

FLNB-Related Spondylocarpotarsal Synostosis Syndrome (FLNB-SCT)

Individuals with FLNB-SCT 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 3-6 standard deviations (SD) below the mean [Salian et al 2018, Ramos-Mejía et al 2022].

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 may only become evident later in childhood [Salian et al 2018, Ramos-Mejía et al 2022]. The irregular nature of the vertebral anomalies can also give rise to other complications such as cervical spine instability [Seaver & Boyd 2000] and basilar impression.

Clubfeet, pes planus, and cleft palate have been described in a small number of individuals with FLNB-SCT. Some authors have reported mild craniofacial dysmorphism as part of this condition, but the majority of individuals do not exhibit these features [Ramos-Mejía et al 2022].

FLNB-SCT has also been associated with retinal anomalies [Steiner et al 2000] and sensorineural deafness [Langer et al 1994, Coêlho et al 1998, Yasin et al 2021, Ramos-Mejía et al 2022]. The cataracts and retinal abnormalities were not severe enough to impair vision [Steiner et al 2000] and have not been observed in subsequently described individuals, so they may not represent primary manifestations of the condition [Ramos-Mejía et al 2022].

Dental enamel hypoplasia has been reported in at least two unrelated individuals [Brunetti-Pierri et al 2008, Mitter et al 2008].

Intelligence is normal.

In keeping with the observation that common variation at the FLNB locus contributes modestly to the genetic basis of stature in healthy humans [Yengo et al 2022], individuals with a heterozygous loss-of-function pathogenic variant in FLNB can exhibit mild reductions in stature but no other medically significant phenotypic manifestations.

FLNB-Related Larsen Syndrome (FLNB-LS)

FLNB-LS is compatible with survival into adulthood [Bicknell et al 2007, Girisha et al 2016]. Intelligence is normal.

Intrafamilial variation in FLNB-LS can be remarkable. In a large family segregating one of the recurring pathogenic variants leading to FLNB-LS, 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]. These mild phenotypes may be analogous to reports that isolated clubfoot may be a minimal manifestation of this spectrum of conditions [Yang et al 2016, Quiggle et al 2022]. Clinical variability can also result from the presence of somatic mosaicism for a causative pathogenic variant in a mildly affected parent and the presence of a germline pathogenic variant in more severely affected offspring [Bernkopf et al 2017].

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). Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees. 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 was rarely below the first centile and in one individual was above the 97th centile [Bicknell et al 2007].

Spinal abnormalities were observed on radiographs in 16 (84%) of 19 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 FLNB-LS and cervical spine dysplasia are at significant risk for cervical cord myelopathy and secondary tetraparesis [Bicknell et al 2007]. The incidence of myelopathy is at least 15%. Evidence suggests that preemptive posterior stabilization of the cervical spine in individuals with FLNB-LS 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].

Craniofacial anomalies are found in all individuals with FLNB-LS. These include a prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes. 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 (21%) of 19 probands [Bicknell et al 2007].

Although laryngotracheomalacia has been reported in association with FLNB-LS, few individuals with FLNB-LS and a documented FLNB pathogenic variant are severely affected.

Short, broad, spatulate distal phalanges, particularly of the thumb, are a common but not invariable manifestation (67%) of FLNB-LS [Bicknell et al 2007].

FLNB-Related Atelosteogenesis Type 3 (FLNB-AO3)

The most conspicuous finding of FLNB-AO3 is joint dislocations. A specific clinical diagnosis of FLNB-AO3 is seldom possible by prenatal ultrasound examination alone. Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees.

Infants with FLNB-AO3 can survive the neonatal period but may require intensive and invasive support to do so. The infant reported by Schultz et al [1999] had significant 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. The manifestations of FLNB-AO3 overlap with those of FLNB-LS: large joint dislocations, clubfeet, short stature, and spinal anomalies. The observation of a distally tapering humerus on radiographs is indicative of FLNB-AO3, and suggests a stronger likelihood of significant laryngotracheobronchomalacia, the major differentiating feature between these two diagnoses.

Infants with FLNB-AO3 have been born to parents with milder phenotypes (similar to FLNB-LS). In these instances, the parents probably present a mild phenotype associated with somatic mosaicism, whereas their offspring with a non-mosaic germline pathogenic variant present a severe phenotype.

Neurodevelopment is mildly affected in some long-term survivors with FLNB-AO3 [Schultz et al 1999], although the authors assumed this to be a secondary consequence of orthopedic and respiratory complications of the primary disorder.

FLNB-Related Atelosteogenesis Type 1 (FLNB-AO1) (including boomerang dysplasia and Piepkorn dysplasia)

On prenatal ultrasound examination, the findings of FLNB-AO1 consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive clinical diagnosis by ultrasound examination alone is possible [Tsutsumi et al 2012]. Polyhydramnios can complicate the pregnancy. Neonates with FLNB-AO1 die soon after birth from cardiorespiratory insufficiency. Occasionally, extraskeletal manifestations including encephalocele and omphalocele are encountered [Bicknell et al 2005].

A severe form of the FLNB-AO1 spectrum characterized by perinatal-lethal micromelic dwarfism has been described in fewer than five individuals in the literature and was formerly referred to as Piepkorn dysplasia. It is characterized by flipper-like limbs, a characteristic form of polysyndactyly with complete syndactyly of all fingers and toes. The thumbs and halluces are either hypoplastic or absent. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octadactyly. Occasional features include cleft palate, omphalocele, cardiac anomalies, and genitourinary defects including sex reversal. The radiographic features of this condition are largely supportive of it being a severe form of FLNB-AO1.

FLNB-Related Apparently Isolated Clubfoot

Clubfoot is the most common congenital malformation, affecting 1-2 in 1,000 live births, with multifactorial causes including genetic and environmental factors. Pathogenic variants in FLNB (one of them recurrent [Quiggle et al 2022]) have been associated with apparently isolated clubfoot in two recent studies involving a small number of individuals from a large cohort with this phenotype [Yang et al 2016, Quiggle et al 2022]. These observations may represent minimal manifestations of a spectrum that extends to FLNB-LS, and a deeper study of the phenotype of these individuals is required to address this question.

Genotype-Phenotype Correlations

FLNB-SCT. Homozygosity or compound heterozygosity for pathogenic frameshift or nonsense variants in FLNB causes FLNB-SCT [Krakow et al 2004]. Pathogenic variants associated with FLNB-SCT are associated with loss of protein expression and hence constitute true null alleles [Farrington-Rock et al 2006]. Consequently, no genotype-phenotype association has been described.

FLNB-LS, FLNB-AO1, and FLNB-AO3. The FLNB pathogenic variants associated with LS, AO1, and AO3 are either missense variants or small in-frame deletions and are predicted to encode full-length filamin-B protein.

LS-associated FLNB pathogenic variants are spread predominantly across exons 2-5 and 27-33 [Bicknell et al 2007, Daniel et al 2012, Girisha et al 2016].
AO3-causing FLNB pathogenic variants occur in exons 2-5, 13, and 27-33 [Farrington-Rock et al 2006].
The large majority of FLNB pathogenic variants reported in individuals with FLNB-AO1 are in exons 2-5 [V体育官网入口 - Bicknell et al 2005, Daniel et al 2012]. Three individuals with Piepkorn dysplasia have had pathogenic variants in exons 28 and 29.

In some instances, the same FLNB pathogenic variant is associated with different phenotypes (e.g., c.502G>A [p.Gly168Ser] is associated with both AO1 and AO3).

Recurrent FLNB pathogenic variants:

c.5071G>A (p.Gly1691Ser) is the most common recurrent substitution, associated with phenotypes ranging from mild FLNB-LS (isolated bilateral dislocation of the knees with digital and craniofacial anomalies) to FLNB-AO3 [Bicknell et al 2005, Farrington-Rock et al 2006].
V体育ios版 - c.679G>A (p.Glu227Lys) is associated with FLNB-LS.

Somatic Mosaicism

Clinical evidence suggests that somatic mosaicism can complicate the presentation of these conditions [Petrella et al 1993, Bicknell et al 2007, Bernkopf et al 2017]. Somatic mosaicism for an FLNB pathogenic variant can result in an asymmetric or milder clinical presentation suggestive of LS in a mosaic parent, whereas the same pathogenic variant in the germline state can be associated with AO1, leading to perinatal lethality [Meira et al 2018].

Penetrance

Germline FLNB pathogenic variants associated with syndromic FLNB-related disorders are fully penetrant but show variable expressivity, leading to the range of phenotypes described in this GeneReview. Although most individuals with idiopathic congenital clubfoot presented with the malformation in isolation, and some kindreds seemed to indicate reduced penetrance [Yang et al 2016], in some individuals, subtle phenotypic signs – such as elbow and thumb hypermobility, as well as wide, flat thumbs – have been identified that suggest mild manifestations within the clinical spectrum of LS [Quiggle et al 2022].

Nomenclature

Larsen syndrome. Some authors have described what they termed "autosomal recessive Larsen syndrome" [Clayton-Smith & Donnai 1988, Bonaventure et al 1992, Laville et al 1994, Yamaguchi et al 1996]; however, these disorders are phenotypically heterogeneous and are not typical of the FLNB-related phenotype [Topley et al 1994]. The conditions (which likely include a variety of chondrodysplasias with multiple joint dislocations) include: the "Reunion Island form of Larsen syndrome" [Bonaventure et al 1992, Laville et al 1994], which is clinically and radiographically distinct from FLNB-LS and is caused by pathogenic variants in B4GALT7 [Cartault et al 2015]; CHST3-related chondrodysplasia with congenital joint dislocations; and two different forms of Desbuquois dysplasia caused by pathogenic variants in CANT1 and XYLT1.

Atelosteogenesis types 1 and 3 were so named because the major manifestation was disordered and incomplete ossification of the skeleton [Maroteaux et al 1982, Sillence et al 1982, Stern et al 1990].

Note: Atelosteogenesis type 2, one of the sulfate transporter-related osteochondrodysplasias caused by pathogenic variants in SLC26A2 (DTDST), is genetically distinct from FLNB-AO1 and FLNB-AO3 (see SLC26A2-Related Atelosteogenesis).

Piepkorn dysplasia, formerly considered to be the same disorder as boomerang dysplasia, has been readdressed by Rehder et al [2018], who described a phenotype that was more severe but with significant overlap with FLNB-AO1. This severe phenotype included flipper-like limbs, a characteristic form of synpolydactyly, and completely absent ossification of many skeletal elements at mid-gestation.

Boomerang dysplasia was so named due to the distinctive bowing of the femora in the original descriptions. The definition of its pathogenesis has confirmed that this condition is best subsumed under the FLNB-AO1 spectrum.

Prevalence

No prevalence figures are available for any of the FLNB-related conditions. To date, more than 100 individuals with a pathogenic variant(s) in FLNB have been identified [Daniel et al 2012, Girisha et al 2016, Salian et al 2018, Stenson et al 2020].

Genetically Related (Allelic) Disorders (VSports注册入口)

No mendelian phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in FLNB.

In one study, variants in FLNB were implicated as potential contributory factors in the context of a proposed oligogenic etiology for some instances of adolescent idiopathic scoliosis [Jiang et al 2020]. Corroborative studies are required to explore this proposition.

"VSports app下载" Differential Diagnosis

FLNB-related spondylocarpotarsal synostosis syndrome. See Table 2.

Table 2.

Genes of Interest in the Differential Diagnosis of FLNB-Related Spondylocarpotarsal Synostosis Syndrome

Gene(s)	Disorder	MOI	Features of Disorder
Gene(s)	Disorder	MOI	Overlapping w/FLNB-SCT	Distinguishing from FLNB-SCT
DLL3 HES7 LFNG MESP2 RIPPLY2 TBX6	Spondylocostal dysostosis (See Spondylocostal Dysostosis, Autosomal Recessive.)	AR (AD) ¹	Vertebral dysplasia	Vertebral segmentation defects (as opposed to vertebral fusions in FLNB-SCT) Rib anomalies
FGF9 GDF5 GDF6 NOG	Multiple synostoses syndrome (OMIM PS186500)	AD	Vertebral dysplasia	Progressive symphalangism & distinct facial findings
GDF6	GDF6-related Klippel-Feil syndrome (OMIM 118100)	AD	Vertebral, carpal, & tarsal fusions	No carpal or tarsal fusions Isolated cervical fusions do not occur in FLNB-SCT.
MYH3	MYH3-related SCT w/contractures & pterygia (OMIM 178110 & 618469)	AD AR	Vertebral, carpal, & tarsal fusions	Pterygia
RFLNA	RFLNA-related SCT ²	AR	Vertebral, carpal, & tarsal fusions

: AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SCT = spondylocarpotarsal synostosis syndrome
1.: Autosomal dominant inheritance of TBX6-related spondylocostal dysplasia has been reported in a three-generation family.
2.: One affected individual has been described to date [Shimizu et al 2019].

FLNB-related Larsen syndrome. See Table 3.

Table 3.

Genes of Interest in the Differential Diagnosis of FLNB-Related Larsen Syndrome

Gene	Disorder	MOI	Features of Disorder
Gene	Disorder	MOI	Overlapping w/FLNB-LS	Distinguishing from FLNB-LS
B3GAT3	B3GAT3-related multiple joint dislocations, short stature, craniofacial dysmorphisms, & skeletal dysplasia, w/ or w/o heart defects (OMIM 245600)	AR	Joint dislocations	Brachydactyly & cardiac defects (incl bicuspid aortic valve & dilatation of aorta) More significant short stature
B4GALT7	B4GALT7-related Ehlers-Danlos syndrome, spondylodysplastic type 1 (OMIM 130070)	AR	Joint dislocations	Short stature (>3 SD below mean)
BPNT2 (IMPAD1)	BPNT2-related chondrodysplasia w/congenital joint dislocations (OMIM 614078)	AR	Joint dislocations	Pronounced brachydactyly, asymmetry in hands, & short stature
CANT1	CANT1-related Desbuquois dysplasia (w/accessory ossification center in digit 2) (OMIM 251450)	AR	Joint dislocations	Short stature (>3 SD below mean) Advanced carpal bone age Characteristic radiographic manifestations in hips, pelvis, & hands
CANT1	CANT1-related Desbuquois dysplasia (w/short metacarpals & elongated phalanges, Kim type) (OMIM 251450)	AR	Joint dislocations
CHST3	CHST3-related chondrodysplasia w/congenital joint dislocations ¹	AR	Joint dislocations	Epiphyseal dysplasia Progressive spondylodysplasia in early & mid-childhood Rhizomelic shortening of limbs Short stature
COL27A1	Steel syndrome (OMIM 615155)	AR	Joint dislocations Scoliosis Cervical anomalies Craniofacial dysmorphism (prominent forehead, hypertelorism)	Carpal coalition Sensorineural deafness Short stature May be assoc w/developmental delay Not assoc w/cleft palate (a characteristic of FLNB-LS)
FLNA	FLNA-related otopalatodigital syndrome type 1 (See FLNA-Related Otopalatodigital Spectrum Disorders.)	XL	Spatulate fingers Craniofacial dysmorphism	Not assoc w/dislocation of large joints (except of the radial heads), cervical spine dysplasia, or radiologically supernumerary ossification centers w/in carpus &/or tarsus
GZF1	GZF1-related joint laxity, short stature, & myopia (OMIM "VSports" 617662)	AR	Joint dislocations	Myopia, short stature, & excessive joint laxity (seldom a characteristic of FLNB-LS)

: AR = autosomal recessive; LS = Larsen syndrome; MOI = mode of inheritance; SD = standard deviations; XL = X-linked
1.: Also known as spondyloepiphyseal dysplasia, Omani type

Management

No clinical practice guidelines for FLNB-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an FLNB-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

FLNB-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Orthopedic	Lateral cervical spine radiographs in flexion & extension	To evaluate for cervical dysplasia, which can be associated w/cervical cord myelopathy Evaluate cervical spine for instability prior to general anesthesia.
	Spine radiographs	To evaluate for vertebral abnormalities that predispose to scoliosis
	Clinical & ultrasound assessment of hips for dislocation	Development of dislocations postnatally has not been described.
	Clinical exam for joint dislocation, clubfoot
ENT	Eval for cleft palate
Pulmonology	Respiratory exam	For evidence of laryngotracheobronchomalacia
Audiology	Audiologic eval	To assess for sensorineural &/or conductive hearing loss
Ophthalmology	Ophthalmologic exam	To evaluate for retinal anomalies in those w/FLNB-SCT
Dental	Eval for enamel hypoplasia & need for sealants
Genetic counseling	By genetics professionals ¹	To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of FLNB-related disorders to facilitate medical & personal decision making

: MOI = mode of inheritance; SCT = spondylocarpotarsal synostosis syndrome
1.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5. (V体育官网)

FLNB-Related Disorders: Treatment of Manifestations

Manifestation/ Concern	Treatment	Considerations/Other
Cervical spine instability	Asymptomatic infants: early intervention to improve cervical spine stability using posterior arthrodesis is successful. Infants w/myelopathic signs: function can be stabilized &/or improved by combination of anterior decompression & circumferential arthrodesis. ¹	Care must be taken to minimize extension of cervical spine intraoperatively. ²
Scoliosis	Medical treatment per orthopedist	No effective surgical intervention has been described.
Large joint dislocations	Operative reduction is usually required.	Conservative, nonsurgical mgmt of hip dislocation in FLNB-LS is often unsuccessful.
Clubfeet	Routine mgmt per orthopedist
Cleft palate	Treated by multidisciplinary craniofacial team when possible
Laryngo- tracheomalacia	Anesthetic agents that allow more rapid induction & recovery are preferred.	Due to ↑ risk for airway complications in persons w/FLNB-LS
Hearing loss	Possible treatments include hearing aids, vibrotactile devices, & cochlear implantation (see Genetic Hearing Loss Overview).	Ideally, mgmt by otolaryngologist & audiologist w/expertise in early-childhood otologic disorders The expertise of an educator of the Deaf may be required. An important part of eval is determining appropriate habilitation option.
Enamel hypoplasia	Dental sealants & treatment per dentist

: LS = Larsen syndrome
1.: "V体育2025版" Armouti et al [2022]
2.: Singh et al [2020], "V体育2025版" Armouti et al [2022]

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

FLNB-Related Disorders: Recommended Surveillance

System/Concern	Evaluation	Frequency
Vertebral anomalies	Orthopedic eval for development of progressive scoliosis	Annually from birth
Feeding for those w/cleft palate	Feeding & growth assessment	Per multidisciplinary craniofacial team
Audiologic	Audiologic exam	Annually
Enamel hypoplasia	Dental eval	Annually

Evaluation of Relatives at Risk (VSports注册入口)

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

"VSports app下载" Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FLNB-related spondylocarpotarsal synostosis syndrome (FLNB-SCT) is caused by biallelic FLNB pathogenic variants and is inherited in an autosomal recessive manner.

FLNB-related Larsen syndrome (FLNB-LS), FLNB-related atelosteogenesis type 1 (FLNB-AO1), FLNB-related atelosteogenesis type 3 (FLNB-AO3), and FLNB-related apparently isolated clubfoot are inherited in an autosomal dominant manner. Note: Comparatively mild (e.g., FLNB-LS) and severe (e.g., FLNB-AO3) forms of the autosomal dominant FLNB-related disorders can occur in the same family.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

The parents of a child with FLNB-SCT are presumed to be heterozygous for an FLNB pathogenic variant.
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FLNB pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multi-exon deletion in the proband that was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
- Uniparental isodisomy for the parental "VSports最新版本" chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygous parents of a child with FLNB-SCT can exhibit mild reductions in stature but no other medically significant phenotypic manifestations. One report described a parent of a child with typical FLNB-SCT who had a height 2.2 standard deviations (SD) below the mean and mild unilateral hip dysplasia.

Sibs of a proband

If both parents are known to be heterozygous for an FLNB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial FLNB pathogenic variants.
Heterozygous sibs of a "VSports最新版本" proband with FLNB-SCT can exhibit mild reductions in stature but no other medically significant phenotypic manifestations.

Offspring of a proband. The offspring of an individual with FLNB-SCT are obligate heterozygotes for a pathogenic variant in FLNB.

Other family members. Each sib of the proband’s parents is at 50% risk of being heterozygous for an FLNB pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives of a proband with FLNB-SCT requires prior identification of the FLNB pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Some individuals diagnosed with an autosomal dominant (V体育官网) FLNB-related disorder have the disorder as the result of a pathogenic variant inherited from a heterozygous or mosaic parent.
- The heterozygous parent of an individual with FLNB-LS may have a milder or more severe phenotype. Significant clinical variability can be seen among heterozygous family members with FLNB-LS.
- The parent of an individual with FLNB-AO1 or FLNB-AO3 may have a milder VSports手机版 - phenotype associated with somatic mosaicism [Meira et al 2018]. Somatic mosaicism for an FLNB pathogenic variant can be associated with FLNB-LS in a mosaic parent, whereas the same pathogenic variant in the constitutional state can be associated with a more severe VSports手机版 - phenotype such as FLNB-AO1 [Meira et al 2018] or FLNB-AO3.
Some individuals diagnosed with an autosomal dominant FLNB-related disorder have the disorder as the result of a de novo pathogenic variant. The vast majority of lethal FLNB conditions are the result of de novo pathogenic variants.
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Detailed clinical examination (including radiographic examination if indicated) may also be recommended.
Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members and/or a milder phenotypic presentation. Therefore, de novo occurrence of an FLNB pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the FLNB pathogenic variant.
If the pathogenic variant (VSports app下载) identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- The proband has a de novo pathogenic variant (VSports app下载).
- The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
  * A parent with somatic and gonadal mosaicism for an FLNB pathogenic variant may be mildly/minimally affected (see Clinical Description, Somatic Mosaicism).

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 and/or is known to have the FLNB pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Significant intrafamilial clinical variability is observed in FLNB-LS; a heterozygous sib may have milder or more severe manifestations of the disorder than the proband.
Clinical evidence suggests that somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant FLNB-related disorders [Bernkopf et al 2017]. Most notably, the presentation of a typical FLNB-LS phenotype in a parent can result from mosaicism for a pathogenic variant that, when present as a constitutional pathogenic variant in a child, leads to the FLNB-AO3 phenotype.
If the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent and/or the parents appear to be clinically unaffected based on detailed clinical examination, the recurrence risk to sibs is slightly greater than that of the general population because of the risk of parental gonadal (or somatic and gonadal) mosaicism [Meira et al 2018].

Offspring of a proband

Each child of a V体育ios版 - proband who is heterozygous for an FLNB pathogenic variant has a 50% chance of inheriting the pathogenic variant.
Each child of a "V体育官网入口" proband with somatic mosaicism for an FLNB pathogenic variant has up to a 50% chance of inheriting the pathogenic variant. Offspring who inherit an FLNB pathogenic variant from a "V体育官网入口" proband with somatic mosaicism may be more severely affected than the "V体育官网入口" proband (see Clinical Description, Somatic Mosaicism). One approach for the assessment of recurrence risk in offspring of a male "V体育官网入口" proband with an autosomal dominant FLNB-related disorder who is known to have somatic mosaicism is to measure the degree of gonadal mosaicism in sperm [Bernkopf et al 2017].

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the FLNB pathogenic variant, the parent's family members may be at risk.

V体育官网入口 - Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing (V体育ios版) 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.

"VSports在线直播" Prenatal Testing and Preimplantation Genetic Testing

A priori high-risk pregnancies. Once the FLNB pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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 FLNB-LS in a fetus not known to be at increased risk. Detection of fetuses with FLNB-AO1 by ultrasound examination during the second trimester is possible because of the multiple anomalies present including shortening of the limbs and thoracic hypoplasia [Tsutsumi et al 2012]. Consideration of FLNB molecular genetic testing in these situations is appropriate.

Note: Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources (V体育官网)

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Children's Craniofacial Association
Phone: 800-535-3643
Email: contactCCA@qiuluzeuv.cn
"VSports注册入口" ccakids.org
Compassionate Friends
Supporting Family After a Child Dies
Phone: 877-969-0010
"VSports手机版" compassionatefriends.org
Helping After Neonatal Death (HAND)
Phone: 650-367-6993
Email: info@qiuluzeuv.cn
VSports最新版本 - handonline.org
Little People of America
Phone: 888-LPA-2001; 714-368-3689
Email: info@qiuluzeuv.cn
lpaonline.org
Medline Plus
VSports在线直播 - Scoliosis
Medline Plus
VSports在线直播 - Clubfoot
National Scoliosis Foundation
Phone: 800-673-6922
Email: nsf@qiuluzeuv.cn
scoliosis.org
UCLA International Skeletal Dysplasia Registry (ISDR)
Phone: 310-825-8998
International Skeletal Dysplasia Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

FLNB-Related Disorders: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
FLNB	3p14.3	Filamin-B	FLNB database	FLNB	FLNB

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for FLNB-Related Disorders (View All in OMIM)

108720	ATELOSTEOGENESIS, TYPE I; AO1
108721	ATELOSTEOGENESIS, TYPE III; AO3
112310	BOOMERANG DYSPLASIA; BOOMD
150250	LARSEN SYNDROME; LRS
272460	SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME; SCT
603381	FILAMIN B; FLNB

Molecular Pathogenesis

FLNB encodes filamin-B, which connects cell membrane components, including transmembrane proteins, to the actin cytoskeleton. Features of filamin-B include:

An N-terminal actin-binding domain;
24 filamin repeats;
Two "hinge" regions between filamin repeats 15 and 16 and 23 and 24, which are thought to confer flexibility to the protein.

Filamin-B is expressed by endothelial cells and chondrocytes during development, playing an important role in embryonal skeletal development. FLNB-related disorders can occur either through loss of filamin-B binding to actin or enhanced filamin-B avidity for actin.

Mechanism of disease causation

The cause of FLNB-related spondylocarpotarsal synostosis syndrome is loss of function, which exerts a pathogenic effect at least in part through derepression of transforming growth factor beta signaling.
It is not known whether the gain-of-function pathogenic variants that cause FLNB-related Larsen syndrome, FLNB-related atelosteogenesis type 1, and FLNB-related atelosteogenesis type 3 disrupt protein interactions or facilitate novel interactions with filamin-B.

Table 7.

FLNB Pathogenic Variants Referenced in This GeneReview

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_001457.4 NP_001448.2	c.502G>A	p.Gly168Ser	Assoc w/both FLNB-AO1 & FLNB-AO3 ¹
	c.679G>A	p.Glu227Lys	Recurrent pathogenic variant assoc w/FLNB-LS ¹
	c.5071G>A	p.Gly1691Ser	Recurrent variant assoc w/a range of FLNB-related phenotypes ¹

: AO1 = atelosteogenesis type 1; AO3 = atelosteogenesis type 3; LS = Larsen syndrome
: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
1.: See Genotype-Phenotype Correlations.

"VSports最新版本" Chapter Notes

Author Notes (VSports注册入口)

University of Otago Clinical Genetics Group website

"VSports在线直播" Revision History

11 September 2025 (sw) Comprehensive update posted live
13 February 2020 (sw) Comprehensive update posted live
17 October 2013 (me) Comprehensive update posted live
9 October 2008 (me) Review posted live
20 May 2008 (sr) Original submission

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Robertson S, Meira J. FLNB-Related Disorders. 2008 Oct 9 [Updated 2025 Sep 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
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