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). 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.

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.

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.

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. 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. 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.

Suggestive Findings

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).

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.

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 [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].
• c.679G>A (p.Glu227Lys) is associated with FLNB-LS.

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].

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.

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).

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.

Evaluation of Relatives at Risk

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

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.

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 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 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 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 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 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 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.
  • 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 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 (see Clinical Description, Somatic Mosaicism). One approach for the assessment of recurrence risk in offspring of a male 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.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

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.

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.

Author Notes

University of Otago Clinical Genetics Group website

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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