Clinical characteristics.

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

SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions.

Larsen syndrome is characterized by 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 craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss.

AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support.

Piepkorn osteochondrodysplasia (POCD) is a 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, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.

Diagnosis/testing.

The diagnosis of SCT is established in a proband by identification of biallelic pathogenic variants in FLNB on molecular genetic testing. The diagnosis of other FLNB disorders (Larsen syndrome, AOI, AOIII, and Piepkorn osteochondrodysplasia) is established in a proband by identification of a heterozygous pathogenic variant in FLNB on 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 Larsen syndrome usually requires operative reduction. Scoliosis and clubfeet are managed in a routine manner. Anesthetic agents that exhibit more rapid induction and recovery are preferred in those with laryngotrachiomalacia. 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.

AOI, AOIII, Piepkorn osteochondrodysplasia, and Larsen syndrome are inherited in an autosomal dominant manner. The proportion of autosomal dominant FLNB disorders caused by de novo pathogenic variants is unknown, although the vast majority of lethal FLNB conditions are caused by de novo events. In rare instances, a parent with low-level mosaicism transmits the causative pathogenic variant to an affected offspring. Each child of an individual with an autosomal dominant FLNB disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk for autosomal dominant FLNB disorders is possible if the pathogenic variant in the family is known.

SCT syndrome is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCT syndrome has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for SCT syndrome are possible once the pathogenic variants have been identified in the family.

Suggestive Findings

The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At one end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome and at the severe end are the phenotypic continuum of atelosteogenesis type I (AOI) and type III (AOIII) and Piepkorn osteochondrodysplasia.

Establishing the Diagnosis

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

The diagnosis of other FLNB disorders (Larsen syndrome, AOI, POCD, and AOIII) is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in FLNB on molecular genetic testing (see Table 1).

Note: Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any 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 (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FLNB disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with skeletal dysplasia and/or joint dislocations are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, more than 100 individuals with a pathogenic variant(s) in FLNB have been identified [Daniel et al 2012, Salian et al 2018, Stenson et al 2020]. The following description of the phenotypic features associated with FLNB conditions is based on these reports.

Genotype-Phenotype Correlations

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

Larsen syndrome, AOI, and AOIII. The pathogenic variants associated with Larsen syndrome, AOI, and AOIII are either missense variants or small in-frame deletions and are predicted to encode full-length filamin B protein.

• Larsen syndrome-associated pathogenic variants are spread predominantly over exons 2-5 and 27-33 [Bicknell et al 2007, Daniel et al 2012].
• Atelosteogenesis type III-causing pathogenic variants occur in exons 2-5, 13, and 27-33 [Farrington-Rock et al 2006].
• The large majority of pathogenic variants reported in boomerang dysplasia and AOI are in exons 2-5 [Bicknell et al 2005, Daniel et al 2012].

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

Recurrent pathogenic variants:

• c.5071G>A (p.Gly1691Ser) is 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 (p.Glu227Lys) is associated with Larsen syndrome.

Peipkorn dysplasia. Three individuals with Peipkorn dysplasia have had pathogenic variants in exons 28 and 29.

Penetrance

Germline FLNB pathogenic variants 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]. 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 a variety of chondrodysplasias with multiple joint dislocations and include: the "Reunion Island form of Larsen syndrome" [Bonaventure et al 1992, Laville et al 1994], which is clinically and radiographically distinct from FLNB Larsen syndrome and caused by pathogenic variants in B4GALT7 [Cartault et al 2015]; CHST3-type chondrodysplasia; and two different forms of Desbuquois dysplasia caused by pathogenic variants in CANT1 and XYLT1.

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

Note: Atelosteogenesis type II, one of the sulfate transporter-related osteochondrodysplasias caused by pathogenic variants in SLC26A2 (DTDST), is genetically distinct from AOI and AOIII.

Piepkorn osteochondrodysplasia, although formerly considered to be the same as boomerang dysplasia, has been readdressed by Rehder et al [2018]. A case series of four indicates that a phenotype distinct from boomerang dysplasia and AOI constituting flipper-like limbs, a characteristic form of synpolydactyly, and completely absent ossification of many skeletal elements at mid-gestation defines this entity, a suggestion that is supported by a different distribution of pathogenic variants compared to those underlying boomerang dysplasia and AOI.

Prevalence

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

Spondylocarpotarsal Synostosis (SCT) Syndrome

Larsen Syndrome

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an FLNB 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

Surveillance

Evaluation of Relatives at Risk

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

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.

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

The following FLNB disorders are inherited in an autosomal dominant manner:

• Atelosteogenesis type I (AOI)
• Atelosteogenesis type III (AOIII)
• Boomerang dysplasia
• Larsen syndrome

Spondylocarpotarsal synostosis (SCT) syndrome is inherited in an autosomal recessive manner.

Autosomal Dominant Inheritance ‒ Risk to Family Members

Parents of a proband

• The parents of some individuals diagnosed with an autosomal dominant FLNB disorder are heterozygous for the FLNB pathogenic variant.
• Alternatively, a proband with an autosomal dominant FLNB disorder may have the disorder as the result of a de novo pathogenic variant.
  Although the vast majority of lethal FLNB conditions are the result of de novo events; a proband with AOI, AOIII, or boomerang dysplasia may have the disorder as the result of a pathogenic variant inherited from a mosaic parent with a milder phenotype [Meira et al 2018].
• Recommendations for the evaluation of parents of a proband with an apparent de novo FLNB pathogenic variant include molecular genetic testing and a detailed clinical examination, which may include radiographic examination where indicated.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or somatic and/or germline mosaicism in a parent. Parental somatic and germline mosaicism has been reported [Meira et al 2018].
• The family history of some individuals diagnosed with an autosomal dominant FLNB disorder may appear to be negative 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.

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 Larsen syndrome; a heterozygous sib may have milder or more severe manifestations of the disorder than the proband.
• Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant FLNB disorders [Bernkopf et al 2017]. Most notably, the presentation of a typical Larsen syndrome phenotype in a parent can result from mosaicism for a pathogenic variant which, when present as a germline pathogenic variant in a child, leads to the AOIII phenotype.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or the parents appear to be clinically unaffected, recurrence risk to sibs is slightly greater than that of the general population because of the risk of parental somatic and/or germline mosaicism [Meira et al 2018].

Offspring of a proband

• Each child of a proband who is heterozygous for an autosomal dominant FLNB pathogenic variant has a 50% chance of inheriting the pathogenic variant.
• Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant FLNB disorders. Most notably, the presentation of a typical Larsen syndrome phenotype in a proband can result from mosaicism for a pathogenic variant which, when present as a germline pathogenic variant in offspring, leads to the AOIII phenotype. One approach for the assessment of recurrence risk in offspring of a male proband who is known to have somatic mosaicism for a dominant FLNB pathogenic variant 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.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one 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 allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders.)
• Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 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 being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.

Offspring of a proband. The offspring of an individual with SCT syndrome are obligate heterozygotes (carriers) for a pathogenic variant in FLNB.

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

Carrier (heterozygote) detection. Carrier testing for at-risk family members requires prior identification of the pathogenic variants in the family.

Note: SCT syndrome is inherited in an autosomal recessive manner; heterozygotes for FLNB pathogenic variants causing SCT syndrome are usually asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia. All other FLNB disorders are inherited in an autosomal dominant manner and, thus, carrier testing is not an issue.

Related Genetic Counseling Issues

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

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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular Pathogenesis

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

• 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 disorders can occur either by loss of filamin-B binding to or enhanced filamin-B avidity for actin (see Mechanism of disease causation).

Mechanism of disease causation

• The cause of SCT syndrome is loss of function, which exerts a pathogenic effect at least in part through de-repression of transforming growth factor beta signaling.
• For Larsen syndrome, AOI, POCD, and AOIII, it is not known whether the pathogenic variants disrupt protein interactions or facilitate novel interactions with filamin B.

Author Notes

University of Otago Clinical Genetics Group website

Revision History

• 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

Literature Cited

• Bernkopf M, Hunt D, Koelling N, Morgan T, Collins AL, Fairhurst J, Robertson SP, Douglas AGL, Goriely A. Quantification of transmission risk in a male patient with a FLNB mosaic mutation causing Larsen syndrome: Implications for genetic counseling in postzygotic mosaicism cases. Hum Mutat. 2017;38:1360–4. [PMC free article: PMC5638069] [PubMed: 28639312]
• Bicknell LS, Farrington-Rock C, Shafeghati Y, Rump P, Alanay Y, Alembik Y, Al-Madani N, Firth H, Karimi-Nejad MH, Kim CA, Leask K, Maisenbacher M, Moran E, Pappas JG, Prontera P, de Ravel T, Fryns JP, Sweeney E, Fryer A, Unger S, Wilson LC, Lachman RS, Rimoin DL, Cohn DH, Krakow D, Robertson S. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet. 2007;44:89–98. [PMC free article: PMC2598053] [PubMed: 16801345]
• Bicknell LS, Morgan T, Bonafé L, Wessels MW, Bialer MG, Willems PJ, Cohn DH, Krakow D, Robertson SP. Mutations in FLNB cause boomerang dysplasia. J Med Genet. 2005;42:e43. [PMC free article: PMC1736093] [PubMed: 15994868]
• Bonaventure J, Lasselin C, Mellier J, Cohen-Solal L, Maroteaux P. Linkage studies of four fibrillar collagen genes in three pedigrees with Larsen-like syndrome. J Med Genet. 1992;29:465–70. [PMC free article: PMC1016020] [PubMed: 1640425]
• Cartault F, Munier P, Jacquemont ML, Vellayoudom J, Doray B, Payet C, Randrianaivo H, Laville JM, Munnich A, Cormier-Daire V. Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome. Eur J Hum Genet. 2015;23:49–53. [PMC free article: PMC4266744] [PubMed: 24755949]
• Clayton-Smith J, Donnai D. A further patient with the lethal type of Larsen syndrome. J Med Genet. 1988;25:499–500. [PMC free article: PMC1050530] [PubMed: 3172146]
• Coêlho KE, Ramos ES, Felix TM, Martelli L, de Pina-Neto JM, Niikawa N. Three new cases of spondylocarpotarsal synostosis syndrome: clinical and radiographic studies. Am J Med Genet. 1998;77:12–5. [PubMed: 9557886]
• Daniel PB, Morgan T, Alanay Y, Bijlsma E, Cho TJ, Cole T, Collins F, David A, Devriendt K, Faivre L, Ikegawa S, Jacquemont S, Jesic M, Krakow D, Liebrecht D, Maitz S, Marlin S, Morin G, Nishikubo T, Nishimura G, Prescott T, Scarano G, Shafeghati Y, Skovby F, Tsutsumi S, Whiteford M, Zenker M, Robertson SP. Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity. Hum Mutat. 2012;33:665–73. [PubMed: 22190451]
• Farrington-Rock C, Firestein MH, Bicknell LS, Superti-Furga A, Bacino CA, Cormier-Daire V, Le Merrer M, Baumann C, Roume J, Rump P, Verheij JB, Sweeney E, Rimoin DL, Lachman RS, Robertson SP, Cohn DH, Krakow D. Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat. 2006;27:705–10. [PubMed: 16752402]
• Herrmann HC, Kelly JH, Fried MP, Strome M. The association of a hearing deficit with Larsen’s syndrome. J Otolaryngol. 1981;10:45–8. [PubMed: 7193744]
• Honeywell C, Langer L, Allanson J. Spondylocarpotarsal synostosis with epiphyseal dysplasia. Am J Med Genet. 2002;109:318–22. [PubMed: 11992487]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Johnston CE 2nd, Birch JG, Daniels JL. Cervical kyphosis in patients who have Larsen syndrome. J Bone Joint Surg Am. 1996;78:538–45. [PubMed: 8609132]
• Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C, Wachsmann-Hogiu S, Acuna D, Shapiro SS, Tarafuta T, Aftimos S, Kim CA, Firth H, Steiner CE, Cormier-Daire V, Superti-Furga A, Bonafé L, Graham JM, Grix A, Bacino CA, Allanson J, Bialer MG, Lachman RS, Rimoin DL, Cohn DH. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004;36:405–10. [PubMed: 14991055]
• Langer LO Jr, Gorlin RJ, Donnai D, Hamel BC, Clericuzio C. Spondylocarpotarsal synostosis syndrome (with or without unilateral unsegmented bar). Am J Med Genet. 1994;51:1–8. [PubMed: 8030662]
• Larsen LJ, Schottstaedt ER, Bost FC. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr. 1950’37:574-81. [PubMed: 14779259]
• Laville JM, Lakermance P, Limouzy F. Larsen’s syndrome: review of the literature and analysis of thirty-eight cases. J Pediatr Orthop. 1994;14:63–73. [PubMed: 8113375]
• Maack RW, Muntz HR. Ossicular abnormality in Larsen’s syndrome: a case report. Am J Otolaryngol. 1991;12:51–3. [PubMed: 2029067]
• Madera M, Crawford A, Mangano FT. Management of severe cervical kyphosis in a patient with Larsen syndrome. Case report. J Neurosurg Pediatr. 2008;1:320–4. [PubMed: 18377309]
• Maroteaux P, Spranger J, Stanescu V, Le Marec B, Pfeiffer RA, Beighton P, Mattei JF. Atelosteogenesis. Am J Med Genet. 1982;13:15–25. [PubMed: 7137218]
• Meira JGC, Sarno MAC, Faria ÁCO, Yamamoto GL, Bertola DR, Scheibler GG, Tavares DF, Acosta AX. Diagnosis of atelosteogenesis type i suggested by fetal ultrasonography and atypical paternal phenotype with mosaicism. Rev Bras Ginecol Obstet. 2018;40:570–6. [PMC free article: PMC10316906] [PubMed: 30231296]
• Mitter D, Krakow D, Farrington-Rock C, Meinecke P. Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father. Am J Med Genet A. 2008;146A:779–83. [PubMed: 18257094]
• Petrella R, Rabinowitz JG, Steinmann B, Hirschhorn K. Long-term follow-up of two sibs with Larsen syndrome possibly due to parental germ-line mosaicism. Am J Med Genet. 1993;47:187–97. [PubMed: 8213905]
• Rehder H, Laccone F, Kircher SG, Schild RL, Rapp C, Bald R, Schulze B, Behunova J, Neesen J, Schoner K. Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB-related skeletal disorders in three fetuses and a 106-year-old exhibit. Am J Med Genet A. 2018;176:1559–68. [PMC free article: PMC6585644] [PubMed: 29797497]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Sakaura H, Matsuoka T, Iwasaki M, Yonenobu K, Yoshikawa H. Surgical treatment of cervical kyphosis in Larsen syndrome: Report of 3 cases and review of the literature. Spine. 2007;32:E39–44. [PubMed: 17202879]
• Salian S, Shukla A, Shah H, Bhat SN, Bhat VR, Nampoothiri S, Shenoy R, Phadke SR, Hariharan SV, Girisha KM. Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB. Clin Genet. 2018;94:159–64. [PubMed: 29566257]
• Schultz C, Langer LO, Laxova R, Pauli RM. Atelosteogenesis Type III: long-term survival, prenatal diagnosis, and evidence for dominant transmission. Am J Med Genet. 1999;83:28–42. [PubMed: 10076882]
• Seaver LH, Boyd E. Spondylocarpotarsal synostosis syndrome and cervical instability. Am J Med Genet. 2000;91:340–4. [PubMed: 10766994]
• Sillence DO, Lachman RS, Jenkins T, Riccardi VM, Rimoin DL. Spondlohumerofermoral hypoplasis (giant cell chondrodysplasia): a neonatally lethal short-limb skeletal dysplasia. Am J Med Genet. 1982;13:7–14. [PubMed: 6753583]
• Stanley CS, Thelin JW, Miles JH. Mixed hearing loss in Larsen syndrome. Clin Genet. 1988;33:395–8. [PubMed: 3378369]
• Steiner CE, Torriani M, Norato DY, Marques-de-Faria AP. Spondylocarpotarsal synostosis with ocular findings. Am J Med Genet. 2000;91:131–4. [PubMed: 10748412]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Stern HJ, Graham JM Jr, Lachman RS, Horton W, Bernini PM, Spiegel PK, Bodurtha J, Ives EJ, Bocian M, Rimoin DL. Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet. 1990;36:183–95. [PubMed: 2368807]
• Topley JM, Varady E, Lestringant GG. Larsen syndrome in siblings with consanguineous parents. Clin Dysmorphol. 1994;3:263–5. [PubMed: 7526939]
• Tsutsumi S, Maekawa A, Obata M, Morgan T, Robertson SP, Kurachi H. A case of boomerang dysplasia with a novel causative mutation in filamin B: identification of typical imaging findings on ultrasonography and 3D-CT imaging. Fetal Diagn Ther. 2012;32:216–20. [PubMed: 22354125]
• Ueno K, Tanaka M, Miyakoshi K, Zhao C, Shinmoto H, Nishimura G, Yoshimura Y. Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation. Prenat Diagn. 2002;22:1071–5. [PubMed: 12454961]
• Yamaguchi K, Ogawa Y, Handa T. Brain dysplasia associated with Larsen-like syndrome. Pediatr Neurol. 1996;14:75–9. [PubMed: 8652025]
• Yang H, Zheng Z, Cai H, Li H, Ye X, Zhang X, Wang Z, Fu Q. Three novel missense mutations in the filamin B gene are associated with isolated congenital talipes equinovarus. Hum Genet. 2016;135:1181–9. [PubMed: 27395407]