Larsen Syndrome

Mendelian MONDO:0007875 Pathograph 2 Skeletal Dysplasia

Larsen syndrome is an FLNB-associated autosomal dominant skeletal dysplasia characterized by congenital large-joint dislocations, craniofacial dysmorphism, and high-risk cervical spine deformity.

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1
Inheritance
4
Pathophys.
12
Phenotypes
2
Pathograph
1
Genes
5
Treatments
1
References
1
Deep Research
👪

Inheritance

1
Autosomal Dominant HP:0000006
Larsen syndrome is inherited in an autosomal dominant pattern and is caused by heterozygous FLNB missense or small in-frame deletion variants.
Autosomal dominant inheritance De novo rate: Common in simplex cases
Show evidence (2 references)
PMID:16801345 SUPPORT Human Clinical
"BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies."
This directly supports autosomal dominant inheritance and core syndrome definition.
PMID:27048506 SUPPORT Human Clinical
"Larsen syndrome is an autosomal dominant skeletal dysplasia characterized by large joint dislocations and craniofacial dysmorphism."
This independently confirms autosomal dominant inheritance and canonical phenotype.
⚙

Pathophysiology

4
FLNB Variant Clustering in Functional Protein Domains
Causative Larsen syndrome variants are non-randomly clustered in specific FLNB domains, especially the actin-binding domain and selected filamin repeat regions.
Chondrocyte link
actin filament organization link
Show evidence (2 references)
PMID:16801345 SUPPORT Human Clinical
"The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome."
This supports domain-specific mutation clustering in Larsen syndrome.
PMID:16648377 SUPPORT Human Clinical
"They appear to occur in specific functional domains of the filamin B protein."
This supports mutation enrichment in functionally important FLNB regions.
Gain-of-Function Actin-Binding Dysregulation
Actin-binding domain FLNB substitutions promote increased actin-binding behavior and cytoplasmic actin-filamin accumulation; variants near hinge regions can produce similar phenotypes through distinct mechanisms.
Chondrocyte link
FLNB link
actin filament organization link
actin filament binding link
Show evidence (3 references)
PMID:19505475 SUPPORT In Vitro
"These mutations cluster in particular FLNB protein domains and act in a presumptive gain-of-function mechanism."
This explicitly supports gain-of-function behavior of disease-associated variants.
PMID:19505475 SUPPORT In Vitro
"Characterisation of the wild type and mutant ABD F-actin binding activities via co-sedimentation assays shows that the mutant FLNB ABDs have increased F-actin binding affinities, with dissociation constants of 2.0 microM (W148R) and 0.56 microM (M202V), compared to the wild type ABD K(d) of 7.0 microM."
This provides direct biochemical evidence of increased actin-binding affinity.
PMID:22190451 SUPPORT In Vitro
"These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism."
This supports actin-binding perturbation as a core mechanism in FLNB dysplasia.
Comparator FLNB Deficiency Model: Impaired Chondrocyte Differentiation
Larsen syndrome is caused by monoallelic gain-of-function or altered-function FLNB variants. This deficiency-model node is retained only as comparator skeletal-biology evidence showing that FLNB dosage and function are required for chondrocyte differentiation; it should not be read as the primary FLNB-Larsen disease mechanism.
Chondrocyte link
Cartilage Development link
Show evidence (1 reference)
PMID:17510210 SUPPORT Model Organism
"No changes in the initial proliferative rate of chondrocytes were observed, but the progressive differentiation of chondrocyte precursors was impaired, consistent with reduced bone length."
This model-organism evidence supports FLNB dependence of chondrocyte maturation.
Comparator FLNB Deficiency Model: Disrupted Endochondral Ossification
FLNB-deficient model and comparative human data indicate that loss of FLNB disrupts endochondral ossification and vertebral/limb skeletal patterning. This is comparator context for the FLNB-related disorder spectrum; biallelic loss-of-function FLNB causes spondylocarpotarsal synostosis rather than classic FLNB-Larsen syndrome.
Chondrocyte link
Endochondral Ossification link
Show evidence (1 reference)
PMID:17510210 SUPPORT Model Organism
"Here we show that Flnb deficient mice have shortened distal limbs with small body size, and develop fusion of the ribs and vertebrae, abnormal spinal curvatures, and dysmorphic facial/calvarial bones, similar to the human phenotype."
This model-organism evidence links FLNB perturbation to skeletal patterning defects.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Larsen Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Ear 1
Conductive Hearing Loss Conductive hearing impairment (HP:0000405)
Show evidence (1 reference)
PMID:20301736 PARTIAL Human Clinical
"Individuals with FLNB-LS may also present with midline cleft palate and hearing loss."
GeneReviews supports hearing loss in FLNB-Larsen syndrome; the linked HPO term captures the conductive form emphasized in clinical surveillance.
Eye 1
Hypertelorism Hypertelorism (HP:0000316)
Show evidence (1 reference)
PMID:11837607 SUPPORT Human Clinical
"Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence."
This directly supports hypertelorism in classical Larsen syndrome.
Head and Neck 3
Prominent Forehead Prominent forehead (HP:0011220)
Show evidence (1 reference)
PMID:11837607 SUPPORT Human Clinical
"Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence."
This directly supports prominent forehead as part of classical facial morphology.
Depressed Nasal Bridge Depressed nasal bridge (HP:0005280)
Show evidence (1 reference)
PMID:11837607 SUPPORT Human Clinical
"Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence."
This directly supports depressed nasal bridge in the craniofacial phenotype.
Malar Flattening Malar flattening (HP:0000272)
Show evidence (1 reference)
PMID:20301736 SUPPORT Human Clinical
"distinctive craniofacial features (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes);"
GeneReviews directly lists malar flattening among FLNB-Larsen craniofacial features.
Limbs 3
Multiple Carpal Ossification Centers Multiple carpal ossification centers (HP:0006067)
Show evidence (2 references)
PMID:16801345 SUPPORT Human Clinical
"The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb."
This supports excess carpal ossification elements as a frequent feature.
PMID:27048506 SUPPORT Human Clinical
"Contrary to the widely described advanced carpal ossification, we noted delay in two patients."
This supports variability in the timing and direction of carpal ossification abnormalities.
Broad Distal Phalanx of Finger Broad distal phalanx of finger (HP:0009836)
Show evidence (1 reference)
PMID:16801345 SUPPORT Human Clinical
"The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb."
This directly supports broad/spatulate distal phalangeal morphology.
Talipes Equinovarus Talipes equinovarus (HP:0001762)
Show evidence (1 reference)
PMID:11837607 SUPPORT Human Clinical
"Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence."
This supports equinovarus deformity among characteristic foot findings.
Musculoskeletal 4
Large Joint Dislocations Large joint dislocations (HP:0005008)
Show evidence (2 references)
PMID:27048506 SUPPORT Human Clinical
"All patients exhibited typical facial features and joint dislocations."
This directly supports recurrent large-joint dislocations.
PMID:20301736 SUPPORT Human Clinical
"FLNB-LS is characterized by combinations of congenital dislocations of the hip, knee, and elbow;"
GeneReviews specifies the hallmark hip, knee, and elbow dislocation pattern within FLNB-related Larsen syndrome.
Cervical Kyphosis Cervical kyphosis (HP:0002947)
Show evidence (2 references)
PMID:17202879 SUPPORT Human Clinical
"SUMMARY OF BACKGROUND DATA: Cervical kyphosis is the most hazardous and serious manifestation of Larsen syndrome due to the risk of life-threatening paralysis, and thus usually requires surgical treatment."
This directly establishes cervical kyphosis as a severe hallmark manifestation.
PMID:8609132 SUPPORT Human Clinical
"We believe that cervical kyphosis is sometimes present but not diagnosed in patients who have Larsen syndrome."
This supports the need for active surveillance for cervical kyphosis.
Kyphoscoliosis Kyphoscoliosis (HP:0002751)
Show evidence (1 reference)
PMID:18377309 SUPPORT Human Clinical
"Larsen syndrome is a rare genetic disorder of the connective tissue that is characterized by multiple joint dislocations, distinctive deformities of the hands and feet, characteristic facial features, kyphoscoliosis, and segmentation anomalies of the vertebrae."
This directly supports kyphoscoliosis in the Larsen phenotype profile.
Scoliosis Scoliosis (HP:0002650)
Show evidence (1 reference)
PMID:20301736 SUPPORT Human Clinical
"scoliosis and cervical kyphosis (which can be associated with a cervical myelopathy);"
GeneReviews lists scoliosis as part of FLNB-Larsen syndrome and links the cervical spine phenotype to myelopathy risk.
🧬

Genetic Associations

1
FLNB Pathogenic Variants (Causative)
Show evidence (3 references)
PMID:16801345 SUPPORT Human Clinical
"All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions."
This directly supports the causative variant class and zygosity pattern.
PMID:16648377 SUPPORT Human Clinical
"Mutations in FLNB may be responsible for all cases of Larsen syndrome."
This supports FLNB as the principal causative gene.
PMID:27048506 SUPPORT Human Clinical
"It is caused by missense or small in-frame deletions in the FLNB gene."
This independently confirms FLNB variant classes associated with Larsen syndrome.
💊

Treatments

5
Cervical Spine Surgical Stabilization
Action: surgical procedure MAXO:0000004
Management of cervical kyphosis includes early radiographic screening and, when indicated, operative stabilization/decompression strategies to reduce risk of neurologic deterioration.
Show evidence (3 references)
PMID:17202879 SUPPORT Human Clinical
"SUMMARY OF BACKGROUND DATA: Cervical kyphosis is the most hazardous and serious manifestation of Larsen syndrome due to the risk of life-threatening paralysis, and thus usually requires surgical treatment."
This supports operative management in severe cervical deformity.
PMID:17202879 SUPPORT Human Clinical
"Therefore, all patients with Larsen syndrome should be screened with radiographs at the first visit to detect cervical kyphosis early so that posterior alone fusion is possible."
This supports early surveillance and intervention planning.
PMID:8609132 SUPPORT Human Clinical
"Early diagnosis followed by operative stabilization should help such patients avoid neurological deficits."
This supports early surgical stabilization to mitigate neurologic risk.
Conservative and Supportive Management for Nonoperative Cases
Action: supportive care MAXO:0000950
Conservative observation and supportive multidisciplinary care are used in selected patients depending on spine severity and neurologic status.
Show evidence (1 reference)
PMID:18377309 SUPPORT Human Clinical
"Diverse treatment options, including conservative observation and surgical correction, have been reported for patients who present with cervical spine pathophysiology."
This supports conservative/supportive management pathways in selected patients.
Orthopedic Management of Hip Dislocation, Scoliosis, and Clubfeet
Action: surgical procedure MAXO:0000004
Orthopedic care should address hip dislocation, clubfeet, scoliosis, and other limb/spine manifestations, with operative reduction or routine clubfoot/scoliosis management when indicated.
Show evidence (1 reference)
PMID:20301736 SUPPORT Human Clinical
"Hip dislocation in individuals with FLNB-LS usually requires operative reduction. Scoliosis and clubfeet are managed in a routine manner."
GeneReviews supports explicit orthopedic management beyond cervical spine stabilization.
Physical Therapy and Joint Rehabilitation
Action: physical therapy MAXO:0000011
Physical therapy and rehabilitation are used to support mobility, strength, and functional recovery around joint dislocation management and orthopedic surgery.
Show evidence (1 reference)
PMID:27048506 PARTIAL Human Clinical
"All patients exhibited typical facial features and joint dislocations."
The evidence supports the joint-dislocation target for rehabilitation, but does not evaluate a specific physical-therapy protocol.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Counseling should explain autosomal dominant inheritance, de novo and mosaic parent possibilities, severity variability across the FLNB gain-of-function spectrum, and prenatal or preimplantation testing options when the familial variant is known.
Show evidence (2 references)
PMID:20301736 SUPPORT Human Clinical
"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."
GeneReviews supports counseling about heterozygous and mosaic parental transmission.
PMID:20301736 SUPPORT Human Clinical
"Offspring who inherit an FLNB pathogenic variant from a proband with somatic mosaicism may be more severely affected than the proband."
This supports the specific mosaicism severity-risk counseling point.
{ }

Source YAML

click to show 
name: Larsen Syndrome
creation_date: '2026-03-04T19:58:20Z'
updated_date: '2026-05-31T11:30:00Z'
category: Mendelian
description: >
  Larsen syndrome is an FLNB-associated autosomal dominant skeletal dysplasia
  characterized by congenital large-joint dislocations, craniofacial dysmorphism,
  and high-risk cervical spine deformity.
disease_term:
  preferred_term: Larsen syndrome
  term:
    id: MONDO:0007875
    label: Larsen syndrome
parents:
- Skeletal Dysplasia
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: Common in simplex cases
  description: >
    Larsen syndrome is inherited in an autosomal dominant pattern and is caused
    by heterozygous FLNB missense or small in-frame deletion variants.
  evidence:
  - reference: PMID:16801345
    reference_title: "A molecular and clinical study of Larsen syndrome caused by mutations in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies.
    explanation: >-
      This directly supports autosomal dominant inheritance and core syndrome definition.
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larsen syndrome is an autosomal dominant skeletal dysplasia characterized by large joint dislocations and craniofacial dysmorphism.
    explanation: >-
      This independently confirms autosomal dominant inheritance and canonical phenotype.
prevalence:
- population: Live births
  percentage: 1 in 100,000
  notes: >-
    The available prevalence statement located in the PubMed literature is an
    estimated live-birth frequency rather than a population-registry estimate.
  evidence:
  - reference: PMID:25536406
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of Larsen syndrome is estimated to be one in 100,000 live
      births .
    explanation: >-
      This abstract provides an explicit estimated live-birth prevalence for
      Larsen syndrome.
pathophysiology:
- name: FLNB Variant Clustering in Functional Protein Domains
  description: >
    Causative Larsen syndrome variants are non-randomly clustered in specific
    FLNB domains, especially the actin-binding domain and selected filamin repeat
    regions.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: actin filament organization
    term:
      id: GO:0007015
      label: actin filament organization
  evidence:
  - reference: PMID:16801345
    reference_title: "A molecular and clinical study of Larsen syndrome caused by mutations in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome.
    explanation: >-
      This supports domain-specific mutation clustering in Larsen syndrome.
  - reference: PMID:16648377
    reference_title: "Mutations responsible for Larsen syndrome cluster in the FLNB protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They appear to occur in specific functional domains of the filamin B protein.
    explanation: >-
      This supports mutation enrichment in functionally important FLNB regions.
- name: Gain-of-Function Actin-Binding Dysregulation
  description: >
    Actin-binding domain FLNB substitutions promote increased actin-binding
    behavior and cytoplasmic actin-filamin accumulation; variants near hinge
    regions can produce similar phenotypes through distinct mechanisms.
  genes:
  - preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: actin filament organization
    term:
      id: GO:0007015
      label: actin filament organization
  evidence:
  - reference: PMID:19505475
    reference_title: "Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These mutations cluster in particular FLNB protein domains and act in a presumptive gain-of-function mechanism.
    explanation: >-
      This explicitly supports gain-of-function behavior of disease-associated variants.
  - reference: PMID:19505475
    reference_title: "Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Characterisation of the wild type and mutant ABD F-actin binding activities via co-sedimentation assays shows that the mutant FLNB ABDs have increased F-actin binding affinities, with dissociation constants of 2.0 microM (W148R) and 0.56 microM (M202V), compared to the wild type ABD K(d) of 7.0 microM.
    explanation: >-
      This provides direct biochemical evidence of increased actin-binding affinity.
  - reference: PMID:22190451
    reference_title: "Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.
    explanation: >-
      This supports actin-binding perturbation as a core mechanism in FLNB dysplasia.
- name: "Comparator FLNB Deficiency Model: Impaired Chondrocyte Differentiation"
  description: >
    Larsen syndrome is caused by monoallelic gain-of-function or altered-function
    FLNB variants. This deficiency-model node is retained only as comparator
    skeletal-biology evidence showing that FLNB dosage and function are required
    for chondrocyte differentiation; it should not be read as the primary
    FLNB-Larsen disease mechanism.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Cartilage Development
    term:
      id: GO:0051216
      label: cartilage development
  evidence:
  - reference: PMID:17510210
    reference_title: "Filamin B mutations cause chondrocyte defects in skeletal development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      No changes in the initial proliferative rate of chondrocytes were observed, but the progressive differentiation of chondrocyte precursors was impaired, consistent with reduced bone length.
    explanation: >-
      This model-organism evidence supports FLNB dependence of chondrocyte maturation.
- name: "Comparator FLNB Deficiency Model: Disrupted Endochondral Ossification"
  description: >
    FLNB-deficient model and comparative human data indicate that loss of FLNB
    disrupts endochondral ossification and vertebral/limb skeletal patterning.
    This is comparator context for the FLNB-related disorder spectrum; biallelic
    loss-of-function FLNB causes spondylocarpotarsal synostosis rather than
    classic FLNB-Larsen syndrome.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Endochondral Ossification
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:17510210
    reference_title: "Filamin B mutations cause chondrocyte defects in skeletal development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show that Flnb deficient mice have shortened distal limbs with small body size, and develop fusion of the ribs and vertebrae, abnormal spinal curvatures, and dysmorphic facial/calvarial bones, similar to the human phenotype.
    explanation: >-
      This model-organism evidence links FLNB perturbation to skeletal patterning defects.
genetic:
- name: FLNB Pathogenic Variants
  association: Causative
  gene_term:
    preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  notes: >
    Heterozygous missense and small in-frame deletion variants in FLNB are
    causative in dominant Larsen syndrome.
  evidence:
  - reference: PMID:16801345
    reference_title: "A molecular and clinical study of Larsen syndrome caused by mutations in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions.
    explanation: >-
      This directly supports the causative variant class and zygosity pattern.
  - reference: PMID:16648377
    reference_title: "Mutations responsible for Larsen syndrome cluster in the FLNB protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in FLNB may be responsible for all cases of Larsen syndrome.
    explanation: >-
      This supports FLNB as the principal causative gene.
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by missense or small in-frame deletions in the FLNB gene.
    explanation: >-
      This independently confirms FLNB variant classes associated with Larsen syndrome.
phenotypes:
- name: Large Joint Dislocations
  description: >
    Congenital dislocations of large joints are a defining clinical feature,
    classically involving the hips, knees, and elbows.
  phenotype_term:
    preferred_term: Large joint dislocations
    term:
      id: HP:0005008
      label: Large joint dislocations
  evidence:
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients exhibited typical facial features and joint dislocations.
    explanation: >-
      This directly supports recurrent large-joint dislocations.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FLNB-LS is characterized by combinations of congenital dislocations of the
      hip, knee, and elbow;
    explanation: >-
      GeneReviews specifies the hallmark hip, knee, and elbow dislocation
      pattern within FLNB-related Larsen syndrome.
- name: Prominent Forehead
  description: >
    A prominent forehead is part of the characteristic Larsen craniofacial
    pattern.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:11837607
    reference_title: "Larsen syndrome associated with severe congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence.
    explanation: >-
      This directly supports prominent forehead as part of classical facial morphology.
- name: Depressed Nasal Bridge
  description: >
    Depressed nasal bridge is a recurrent craniofacial feature in classical
    Larsen syndrome descriptions.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:11837607
    reference_title: "Larsen syndrome associated with severe congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence.
    explanation: >-
      This directly supports depressed nasal bridge in the craniofacial phenotype.
- name: Hypertelorism
  description: >
    Increased interorbital distance is part of the classical facial presentation.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:11837607
    reference_title: "Larsen syndrome associated with severe congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence.
    explanation: >-
      This directly supports hypertelorism in classical Larsen syndrome.
- name: Malar Flattening
  description: >
    Malar flattening is part of the characteristic FLNB-Larsen craniofacial
    gestalt.
  phenotype_term:
    preferred_term: Malar flattening
    term:
      id: HP:0000272
      label: Malar flattening
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinctive craniofacial features (prominent forehead, depressed nasal
      bridge, malar flattening, and widely spaced eyes);
    explanation: >-
      GeneReviews directly lists malar flattening among FLNB-Larsen craniofacial
      features.
- name: Multiple Carpal Ossification Centers
  description: >
    Carpal ossification abnormalities are common; advanced/supernumerary carpal
    ossification is classic, though delayed ossification can also be observed.
  phenotype_term:
    preferred_term: Multiple carpal ossification centers
    term:
      id: HP:0006067
      label: Multiple carpal ossification centers
  evidence:
  - reference: PMID:16801345
    reference_title: "A molecular and clinical study of Larsen syndrome caused by mutations in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb.
    explanation: >-
      This supports excess carpal ossification elements as a frequent feature.
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Contrary to the widely described advanced carpal ossification, we noted delay in two patients.
    explanation: >-
      This supports variability in the timing and direction of carpal ossification abnormalities.
- name: Broad Distal Phalanx of Finger
  description: >
    Broad spatulate distal phalanges, especially involving thumbs, are frequent.
  phenotype_term:
    preferred_term: Broad distal phalanx of finger
    term:
      id: HP:0009836
      label: Broad distal phalanx of finger
  evidence:
  - reference: PMID:16801345
    reference_title: "A molecular and clinical study of Larsen syndrome caused by mutations in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb.
    explanation: >-
      This directly supports broad/spatulate distal phalangeal morphology.
- name: Talipes Equinovarus
  description: >
    Equinovarus foot deformity is a recurrent appendicular finding in classical
    Larsen syndrome descriptions.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:11837607
    reference_title: "Larsen syndrome associated with severe congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence.
    explanation: >-
      This supports equinovarus deformity among characteristic foot findings.
- name: Cervical Kyphosis
  description: >
    Cervical kyphosis is a high-risk spinal manifestation associated with
    myelopathy and paralysis risk.
  phenotype_term:
    preferred_term: Cervical kyphosis
    term:
      id: HP:0002947
      label: Cervical kyphosis
  evidence:
  - reference: PMID:17202879
    reference_title: "Surgical treatment of cervical kyphosis in Larsen syndrome: report of 3 cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SUMMARY OF BACKGROUND DATA: Cervical kyphosis is the most hazardous and serious manifestation of Larsen syndrome due to the risk of life-threatening paralysis, and thus usually requires surgical treatment.
    explanation: >-
      This directly establishes cervical kyphosis as a severe hallmark manifestation.
  - reference: PMID:8609132
    reference_title: "Cervical kyphosis in patients who have Larsen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We believe that cervical kyphosis is sometimes present but not diagnosed in patients who have Larsen syndrome.
    explanation: >-
      This supports the need for active surveillance for cervical kyphosis.
- name: Kyphoscoliosis
  description: >
    Combined kyphotic and scoliotic spinal deformity can occur as part of the
    skeletal phenotype.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:18377309
    reference_title: "Management of severe cervical kyphosis in a patient with Larsen syndrome. Case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larsen syndrome is a rare genetic disorder of the connective tissue that is characterized by multiple joint dislocations, distinctive deformities of the hands and feet, characteristic facial features, kyphoscoliosis, and segmentation anomalies of the vertebrae.
    explanation: >-
      This directly supports kyphoscoliosis in the Larsen phenotype profile.
- name: Scoliosis
  description: >
    Progressive scoliosis is an important spinal manifestation requiring
    orthopedic surveillance.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      scoliosis and cervical kyphosis (which can be associated with a cervical
      myelopathy);
    explanation: >-
      GeneReviews lists scoliosis as part of FLNB-Larsen syndrome and links the
      cervical spine phenotype to myelopathy risk.
- name: Conductive Hearing Loss
  description: >
    Hearing loss can occur in FLNB-Larsen syndrome and should prompt audiologic
    surveillance and management.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with FLNB-LS may also present with midline cleft palate and
      hearing loss.
    explanation: >-
      GeneReviews supports hearing loss in FLNB-Larsen syndrome; the linked HPO
      term captures the conductive form emphasized in clinical surveillance.
diagnosis:
- name: Clinical-Radiographic Pattern with FLNB Molecular Confirmation
  description: >
    Diagnosis integrates characteristic clinical and radiographic findings with
    molecular confirmation of a heterozygous FLNB variant.
  evidence:
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The seven patients from six unrelated families were clinically and radiologically evaluated.
    explanation: >-
      This supports the central role of clinical-radiographic assessment.
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients were screened for mutations in selected exons and exon-intron boundaries of the FLNB gene by Sanger sequencing.
    explanation: >-
      This supports molecular diagnostic confirmation via FLNB sequencing.
  - reference: PMID:16648377
    reference_title: "Mutations responsible for Larsen syndrome cluster in the FLNB protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A molecular screen would be valuable for diagnosis and genetic counselling.
    explanation: >-
      This reinforces use of molecular screening in diagnostic workup and counseling.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      GeneReviews baseline: Larsen syndrome (LS) is confirmed by a heterozygous
      gain-of-function FLNB variant, distinguishing it from the recessive
      loss-of-function FLNB disorders.
- name: Cervical Spine and Airway/Anesthesia Surveillance
  description: >
    Cervical spine imaging and neurologic review should be performed early and
    before anesthesia or major orthopedic procedures because cervical kyphosis
    and instability can be under-recognized and can cause myelopathy or
    paralysis. Airway planning should account for laryngotracheomalacia when
    present.
  diagnosis_term:
    preferred_term: clinical imaging procedure
    term:
      id: MAXO:0000005
      label: clinical imaging procedure
  results: >
    Radiographs or other cervical spine imaging may identify cervical kyphosis or
    instability requiring urgent surgical planning; airway assessment guides
    anesthesia strategy when laryngotracheomalacia is present.
  evidence:
  - reference: PMID:17202879
    reference_title: "Surgical treatment of cervical kyphosis in Larsen syndrome: report of 3 cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, all patients with Larsen syndrome should be screened with radiographs at the first visit to detect cervical kyphosis early so that posterior alone fusion is possible.
    explanation: >-
      This directly supports early cervical spine imaging surveillance in
      Larsen syndrome.
  - reference: PMID:8609132
    reference_title: "Cervical kyphosis in patients who have Larsen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We believe that cervical kyphosis is sometimes present but not diagnosed in patients who have Larsen syndrome.
    explanation: >-
      This supports active surveillance because cervical kyphosis can be missed
      clinically.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anesthetic agents that allow more rapid induction and recovery are
      preferred in those with laryngotracheomalacia.
    explanation: >-
      GeneReviews supports anesthesia planning around airway complications in
      FLNB-related Larsen syndrome.
- name: Orthopedic and Audiologic Surveillance
  description: >
    Ongoing evaluation should monitor progressive scoliosis, joint/foot
    complications, dental needs, and hearing loss.
  diagnosis_term:
    preferred_term: hearing examination
    term:
      id: MAXO:0000873
      label: hearing examination
  results: >
    Surveillance may identify progressive scoliosis, treatable hearing loss,
    dental issues, and orthopedic problems requiring intervention.
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      GeneReviews directly supports annual orthopedic, audiologic, and dental
      surveillance for FLNB-related disorders.
treatments:
- name: Cervical Spine Surgical Stabilization
  description: >
    Management of cervical kyphosis includes early radiographic screening and,
    when indicated, operative stabilization/decompression strategies to reduce
    risk of neurologic deterioration.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:17202879
    reference_title: "Surgical treatment of cervical kyphosis in Larsen syndrome: report of 3 cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SUMMARY OF BACKGROUND DATA: Cervical kyphosis is the most hazardous and serious manifestation of Larsen syndrome due to the risk of life-threatening paralysis, and thus usually requires surgical treatment.
    explanation: >-
      This supports operative management in severe cervical deformity.
  - reference: PMID:17202879
    reference_title: "Surgical treatment of cervical kyphosis in Larsen syndrome: report of 3 cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, all patients with Larsen syndrome should be screened with radiographs at the first visit to detect cervical kyphosis early so that posterior alone fusion is possible.
    explanation: >-
      This supports early surveillance and intervention planning.
  - reference: PMID:8609132
    reference_title: "Cervical kyphosis in patients who have Larsen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early diagnosis followed by operative stabilization should help such patients avoid neurological deficits.
    explanation: >-
      This supports early surgical stabilization to mitigate neurologic risk.
- name: Conservative and Supportive Management for Nonoperative Cases
  description: >
    Conservative observation and supportive multidisciplinary care are used in
    selected patients depending on spine severity and neurologic status.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:18377309
    reference_title: "Management of severe cervical kyphosis in a patient with Larsen syndrome. Case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diverse treatment options, including conservative observation and surgical correction, have been reported for patients who present with cervical spine pathophysiology.
    explanation: >-
      This supports conservative/supportive management pathways in selected patients.
- name: Orthopedic Management of Hip Dislocation, Scoliosis, and Clubfeet
  description: >
    Orthopedic care should address hip dislocation, clubfeet, scoliosis, and
    other limb/spine manifestations, with operative reduction or routine
    clubfoot/scoliosis management when indicated.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hip dislocation in individuals with FLNB-LS usually requires operative
      reduction. Scoliosis and clubfeet are managed in a routine manner.
    explanation: >-
      GeneReviews supports explicit orthopedic management beyond cervical spine
      stabilization.
- name: Physical Therapy and Joint Rehabilitation
  description: >
    Physical therapy and rehabilitation are used to support mobility, strength,
    and functional recovery around joint dislocation management and orthopedic
    surgery.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:27048506
    reference_title: "Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients exhibited typical facial features and joint dislocations.
    explanation: >-
      The evidence supports the joint-dislocation target for rehabilitation, but
      does not evaluate a specific physical-therapy protocol.
- name: Genetic Counseling
  description: >
    Counseling should explain autosomal dominant inheritance, de novo and mosaic
    parent possibilities, severity variability across the FLNB gain-of-function
    spectrum, and prenatal or preimplantation testing options when the familial
    variant is known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      GeneReviews supports counseling about heterozygous and mosaic parental
      transmission.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Offspring who inherit an FLNB pathogenic variant from a proband with
      somatic mosaicism may be more severely affected than the proband.
    explanation: >-
      This supports the specific mosaicism severity-risk counseling point.
notes: >-
  FLNB-related dominant skeletal dysplasias form a gain-of-function severity
  spectrum ranging from apparently isolated clubfoot through FLNB-related Larsen
  syndrome to atelosteogenesis type 3 and perinatal-lethal atelosteogenesis type
  1. Biallelic FLNB loss-of-function causes spondylocarpotarsal synostosis and
  should be kept mechanistically distinct from classic FLNB-Larsen syndrome,
  although deficiency models remain useful comparator evidence for FLNB skeletal
  biology.
references:
- reference: PMID:20301736
  title: "FLNB-Related Disorders."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301736
FLNB-Related Disorders.
No top-level findings curated for this source.

Deep Research

1
Manual Pubmed Review ▸
Larsen Syndrome (FLNB): Mechanistic Summary
n/a 9 citations 2026-03-04T20:35:00Z

Larsen Syndrome (FLNB): Mechanistic Summary

Genetics and inheritance

Larsen syndrome is an autosomal dominant skeletal dysplasia most commonly caused by heterozygous missense or small in-frame deletion variants in FLNB (PMID:16801345; PMID:27048506). Mutation distribution is non-random, with hotspot clustering in the actin-binding domain and filamin repeat regions (PMID:16648377; PMID:16801345; PMID:27048506).

Pathophysiology

FLNB encodes filamin B, an actin-crosslinking cytoskeletal protein. Disease-associated dominant variants generally preserve protein expression and act via gain-of-function mechanisms rather than null alleles (PMID:19505475; PMID:27048506; PMID:22190451). Experimental work shows increased F-actin binding affinity for key mutant actin-binding-domain constructs (PMID:19505475), and mutation-specific cytoplasmic actin-filamin focal accumulations that correlate with severity for ABD variants (PMID:22190451). Model data further support disturbed chondrocyte maturation and endochondral skeletal development pathways (PMID:17510210).

Hallmark phenotype profile

Core clinical features include congenital large-joint dislocations and characteristic craniofacial dysmorphism (PMID:16801345; PMID:27048506). Classical facial descriptions include prominent forehead, depressed nasal bridge, and hypertelorism, with associated equinovarus/valgus foot deformity (PMID:11837607). Frequently reported FLNB-associated findings include supernumerary carpal/tarsal elements and broad spatulate distal phalanges (PMID:16801345). Cervical spine involvement is clinically critical; cervical kyphosis is repeatedly reported as a high-risk manifestation with potential for neurologic compromise (PMID:17202879; PMID:8609132; PMID:18377309).

Diagnosis and management implications

Diagnostic confirmation combines clinical and radiographic pattern recognition with targeted molecular testing of FLNB (PMID:16801345; PMID:27048506). Because cervical deformity may be occult early and can progress to severe neurologic risk, early cervical imaging surveillance and timely orthopedic/neurosurgical stabilization are emphasized in the literature (PMID:17202879; PMID:8609132).

References

  • PMID:16648377
  • PMID:11837607
  • PMID:16801345
  • PMID:17202879
  • PMID:18377309
  • PMID:8609132
  • PMID:19505475
  • PMID:22190451
  • PMID:27048506