Otopalatodigital Spectrum Disorders

Genetic MONDO:0018233 Pathograph 3 Show in embeddings browser Skeletal Dysplasia Craniofacial Disorder

The FLNA-related otopalatodigital (OPD) spectrum disorders are a group of X-linked skeletal dysplasias caused by gain-of-function missense mutations in FLNA (filamin A). The spectrum includes otopalatodigital syndrome type 1 (OPD1), otopalatodigital syndrome type 2 (OPD2), frontometaphyseal dysplasia (FMD), and Melnick-Needles syndrome (MNS). These disorders share overlapping craniofacial, skeletal, and digital anomalies but differ in severity. Mutations are clustered in four regions of FLNA: the actin-binding domain and rod domain repeats 3, 10, and 14/15. Males are typically more severely affected than females; OPD2 and MNS are usually lethal in hemizygous males. The gain-of-function mechanism is distinct from the loss-of-function mutations causing periventricular nodular heterotopia.

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1
Inheritance
2
Pathophys.
8
Phenotypes
3
Pathograph
1
Genes
4
Medical Actions
4
Subtypes
1
References
🏷

Classifications

ISDS Skeletal Nosology
filamin and related
👪

Inheritance

1
X-linked Dominant HP:0001423
X-linked dominant inheritance
◆

Subtypes

4
Otopalatodigital Syndrome Type 1 MONDO:0010704
Mildest form. Most manifestations present at birth. Conductive hearing loss, cleft palate, characteristic facial features, and digital anomalies. Females can present with severity similar to males, although some have mild manifestations.
Otopalatodigital Syndrome Type 2 MONDO:0010571
More severe than OPD1. Males typically die during the first year of life from thoracic hypoplasia and pulmonary insufficiency. Survivors are developmentally delayed and require respiratory support. Females are less severely affected.
Frontometaphyseal Dysplasia MONDO:0024550
Males demonstrate skeletal dysplasia with hearing loss and variable joint contractures, hand and foot malformations. Progressive scoliosis in both sexes. Females less severely affected.
Melnick-Needles Syndrome MONDO:0010650
Wide phenotypic variability in females; some diagnosed in adulthood, others require respiratory support. Male hemizygotes have perinatal lethality in all known cases. Characterized by flared metaphyses, s-curved long bones, and ribbon-like ribs.
⚙

Pathophysiology

2
FLNA Gain-of-Function and Cytoskeletal Signaling Dysregulation
Gain-of-function missense mutations in FLNA cause the OPD spectrum disorders. These mutations are localized, conserve the reading frame, and cluster in four regions: the actin-binding domain and rod domain repeats 3, 10, and 14/15. The mutant filamin A protein shows increased F-actin binding affinity, consistent with a gain-of-function mechanism. This is mechanistically distinct from the loss-of-function mutations causing periventricular nodular heterotopia. The gain-of-function mutations implicate filamin A in signaling pathways that mediate organogenesis in multiple organ systems during embryonic development.
Osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
FLNA hgnc:3754 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FLNA (hgnc:3754). hgnc:3754 is a gene from the HUGO Gene Nomenclature Committee.
Actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. Skeletal system development GO:0001501 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Skeletal system development (GO:0001501). GO:0001501 is a biological process from the Gene Ontology. Intracellular signal transduction GO:0035556 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Intracellular signal transduction (GO:0035556). GO:0035556 is a biological process from the Gene Ontology.
actin filament binding GO:0051015 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves actin filament binding (GO:0051015). GO:0051015 is a molecular function from the Gene Ontology.
Bone UBERON:0002481 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bone, annotated with bone tissue (UBERON:0002481). UBERON:0002481 is an anatomical location from the Uberon multi-species anatomy ontology. Skull UBERON:0003129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Skull (UBERON:0003129). UBERON:0003129 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Craniofacial and Skeletal Malformations
Show evidence (3 references)
PMID:12612583 SUPPORT Human Clinical
"We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders"
Landmark paper identifying gain-of-function FLNA mutations as causative for the OPD spectrum.
PMID:12612583 SUPPORT Human Clinical
"all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15"
Defines the mutational clustering pattern characteristic of OPD spectrum disorders.
PMID:19773341 SUPPORT In Vitro
"recombinant FLNA E254K ABD has increased in vitro F-actin binding (K(d) 13 microm) compared with wild type (WT; K(d) 48 microm). These observations are consistent with a gain-of-function mechanism for OPD."
Provides biochemical evidence that OPD mutations increase actin binding, confirming gain-of-function mechanism.
Craniofacial and Skeletal Malformations
The gain-of-function FLNA mutations disrupt skeletal development, leading to craniofacial dysmorphism, metaphyseal flaring, abnormal ossification, and digital malformations. The severity and pattern of skeletal involvement varies across the OPD spectrum subtypes.
Bone development GO:0060348 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Bone development (GO:0060348). GO:0060348 is a biological process from the Gene Ontology. Cranial suture morphogenesis GO:0060363 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cranial suture morphogenesis (GO:0060363). GO:0060363 is a biological process from the Gene Ontology.
Skeleton UBERON:0004288 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Skeleton (UBERON:0004288). UBERON:0004288 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:12612583 SUPPORT Human Clinical
"The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development."
Establishes that the skeletal malformations result from gain-of-function effects on developmental signaling.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Otopalatodigital Spectrum Disorders 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

8
Ear 1
Conductive Hearing Loss Frequent Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing loss, annotated with Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Males usually, but not always, demonstrate a skeletal dysplasia in association with hearing loss"
GeneReviews confirms hearing loss as a key feature of FLNA-FMD.
Head and Neck 3
Craniofacial Dysmorphism Very frequent Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniofacial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"cosmetic surgery may correct the fronto-orbital deformity"
GeneReviews documents fronto-orbital deformity as a management target, confirming craniofacial dysmorphism as a key feature.
Cleft Palate Frequent HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"surgical correction for orthognathic deformities as needed"
GeneReviews lists orthognathic surgical correction as a management recommendation for the craniofacial/oral spectrum; this supports management of orthognathic (jaw/dental) deformity but does not itself document cleft palate, so it is marked PARTIAL. Cleft palate is a well-established feature of OPD1/OPD2 (the disorder name "otopalatodigital" references the palate), but the available cached source text does not directly state it.
Micrognathia Occasional HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"mandibular distraction can improve airway complications related to micrognathia"
GeneReviews management guidance mentions micrognathia as a cause of airway complications requiring mandibular distraction.
Musculoskeletal 4
Skeletal Dysplasia Very frequent HP:0002652 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal dysplasia (HP:0002652). HP:0002652 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders, characterized primarily by skeletal dysplasia"
GeneReviews defines skeletal dysplasia as the primary feature of the OPD spectrum.
Scoliosis Frequent HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Progressive scoliosis is observed in both affected males and females."
GeneReviews documents progressive scoliosis as a common feature.
Thoracic Hypoplasia Occasional HP:0005257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thoracic hypoplasia (HP:0005257). HP:0005257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Most males with FLNA-OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency."
GeneReviews identifies thoracic hypoplasia as the primary cause of OPD2 male lethality.
Joint Contractures Occasional Flexion contracture HP:0001371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contractures, annotated with Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"variably, joint contractures and hand and foot malformations"
GeneReviews confirms variable joint contractures as a feature of FLNA-FMD within the OPD spectrum.
🧬

Genetic Associations

1
FLNA Gain-of-Function Missense Variants (Causative)
Gene: FLNA hgnc:3754 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLNA (hgnc:3754). hgnc:3754 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
X-linked Dominant
Show evidence (3 references)
PMID:12612583 SUPPORT Human Clinical
"We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations"
Defines the gain-of-function mutation spectrum for OPD spectrum.
PMID:19773341 SUPPORT In Vitro
"These data provide the first biochemical evidence for a gain-of-function mechanism for the OPD disorders, and mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration."
Biochemical confirmation of gain-of-function mechanism, distinguishing from PVNH loss-of-function.
PMID:20301567 SUPPORT Human Clinical
"Penetrance in males with an FLNA pathogenic variant leading to an FLNA-OPD spectrum disorder is complete"
GeneReviews confirms complete penetrance in males.
💊

Medical Actions

4
Orthopedic Surgery
Action: Orthopedic surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgical treatment for hand and foot malformations, scoliosis bracing and surgical intervention, and correction of orthognathic deformities.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Surgical treatment may be required for hand and foot malformations."
GeneReviews management guidance for skeletal anomalies.
Hearing Aids
Action: Hearing aidsNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hearing aids, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Hearing aids for conductive hearing loss, with annual audiology evaluation recommended.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"hearing aids for deafness"
GeneReviews management recommendation for hearing impairment.
Respiratory Support
Action: Respiratory supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Respiratory support, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Continuous positive airway pressure and mandibular distraction for airway complications. Chest expansion surgery for thoracic hypoplasia.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"continuous positive airway pressure and mandibular distraction can improve airway complications related to micrognathia"
GeneReviews details respiratory management strategies.
Genetic Counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling regarding X-linked inheritance, male lethality in severe subtypes, and prenatal testing options.
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders are possible."
GeneReviews genetic counseling guidance.
🔬

Diagnosis

4
Clinical, Radiographic, and Family-History Diagnosis
FLNA-related otopalatodigital spectrum disorders are usually established by characteristic clinical and radiographic features together with a family history consistent with X-linked inheritance. Male and female probands can both be diagnosed this way, with severity varying by sex and subtype.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301567 SUPPORT Human Clinical
"The diagnosis of an FLNA-OPD spectrum disorder is established in a male proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance."
GeneReviews defines the usual diagnostic basis for affected male probands.
PMID:20301567 SUPPORT Human Clinical
"The diagnosis of an FLNA-OPD spectrum disorder is usually established in a female proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance."
GeneReviews defines the usual diagnostic basis for affected female probands.
Molecular Genetic Confirmation
Molecular genetic testing can confirm an FLNA-OPD spectrum disorder when the clinical, radiographic, or family-history pattern is inconclusive. A hemizygous pathogenic FLNA variant confirms diagnosis in a male proband, and a heterozygous pathogenic FLNA variant confirms diagnosis in a female proband.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301567 SUPPORT Human Clinical
"Identification of a hemizygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive."
GeneReviews supports hemizygous FLNA variant detection as confirmatory in male probands when other diagnostic features are inconclusive.
PMID:20301567 SUPPORT Human Clinical
"Identification of a heterozygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive."
GeneReviews supports heterozygous FLNA variant detection as confirmatory in female probands when other diagnostic features are inconclusive.
At-Risk Female Relative Testing
Once the family-specific FLNA pathogenic variant is known, molecular testing can be used to evaluate at-risk female relatives.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Consider molecular genetic testing for the family-specific pathogenic variant in at-risk female relatives."
GeneReviews supports targeted molecular testing for at-risk female relatives when the familial FLNA variant is known.
Prenatal and Preimplantation Genetic Testing
Prenatal and preimplantation genetic testing are possible after identifying the FLNA pathogenic variant in an affected family member.
prenatal genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301567 SUPPORT Human Clinical
"Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders are possible."
GeneReviews supports variant-informed prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders.
📊

Prevalence

1
Global
Rare Rare
{ }

Source YAML

click to show 
name: Otopalatodigital Spectrum Disorders
creation_date: "2026-04-04T00:00:00Z"
description: >-
  The FLNA-related otopalatodigital (OPD) spectrum disorders are a group of
  X-linked skeletal dysplasias caused by gain-of-function missense mutations
  in FLNA (filamin A). The spectrum includes otopalatodigital syndrome type 1
  (OPD1), otopalatodigital syndrome type 2 (OPD2), frontometaphyseal dysplasia
  (FMD), and Melnick-Needles syndrome (MNS). These disorders share overlapping
  craniofacial, skeletal, and digital anomalies but differ in severity.
  Mutations are clustered in four regions of FLNA: the actin-binding domain
  and rod domain repeats 3, 10, and 14/15. Males are typically more severely
  affected than females; OPD2 and MNS are usually lethal in hemizygous males.
  The gain-of-function mechanism is distinct from the loss-of-function mutations
  causing periventricular nodular heterotopia.
category: Genetic
parents:
- Skeletal Dysplasia
- Craniofacial Disorder
disease_term:
  preferred_term: otopalatodigital syndrome spectrum disorder
  term:
    id: MONDO:0018233
    label: otopalatodigital syndrome spectrum disorder
has_subtypes:
- name: OPD1
  display_name: Otopalatodigital Syndrome Type 1
  description: >-
    Mildest form. Most manifestations present at birth. Conductive hearing
    loss, cleft palate, characteristic facial features, and digital anomalies.
    Females can present with severity similar to males, although some have
    mild manifestations.
  subtype_term:
    preferred_term: otopalatodigital syndrome type 1
    term:
      id: MONDO:0010704
      label: otopalatodigital syndrome type 1
- name: OPD2
  display_name: Otopalatodigital Syndrome Type 2
  description: >-
    More severe than OPD1. Males typically die during the first year of life
    from thoracic hypoplasia and pulmonary insufficiency. Survivors are
    developmentally delayed and require respiratory support. Females are
    less severely affected.
  subtype_term:
    preferred_term: otopalatodigital syndrome type 2
    term:
      id: MONDO:0010571
      label: otopalatodigital syndrome type 2
- name: FMD
  display_name: Frontometaphyseal Dysplasia
  description: >-
    Males demonstrate skeletal dysplasia with hearing loss and variable
    joint contractures, hand and foot malformations. Progressive scoliosis
    in both sexes. Females less severely affected.
  subtype_term:
    preferred_term: frontometaphyseal dysplasia 1
    term:
      id: MONDO:0024550
      label: frontometaphyseal dysplasia 1
- name: MNS
  display_name: Melnick-Needles Syndrome
  description: >-
    Wide phenotypic variability in females; some diagnosed in adulthood,
    others require respiratory support. Male hemizygotes have perinatal
    lethality in all known cases. Characterized by flared metaphyses,
    s-curved long bones, and ribbon-like ribs.
  subtype_term:
    preferred_term: Melnick-Needles syndrome
    term:
      id: MONDO:0010650
      label: Melnick-Needles syndrome
classifications:
  isds_skeletal_category:
  - classification_value: filamin_and_related
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 7 "Filamin group and
      related disorders"; this entry corresponds to the FLNA spectrum entries
      otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia, and
      Melnick-Needles syndrome, which this entry lumps.
prevalence:
- population: Global
  prevalence_class: RARE
  percentage: Rare
inheritance:
- name: X-linked Dominant
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
pathophysiology:
- name: FLNA Gain-of-Function and Cytoskeletal Signaling Dysregulation
  description: >-
    Gain-of-function missense mutations in FLNA cause the OPD spectrum
    disorders. These mutations are localized, conserve the reading frame,
    and cluster in four regions: the actin-binding domain and rod domain
    repeats 3, 10, and 14/15. The mutant filamin A protein shows increased
    F-actin binding affinity, consistent with a gain-of-function mechanism.
    This is mechanistically distinct from the loss-of-function mutations
    causing periventricular nodular heterotopia. The gain-of-function
    mutations implicate filamin A in signaling pathways that mediate
    organogenesis in multiple organ systems during embryonic development.
  genes:
  - preferred_term: FLNA
    term:
      id: hgnc:3754
      label: FLNA
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  - preferred_term: Skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
  - preferred_term: Intracellular signal transduction
    term:
      id: GO:0035556
      label: intracellular signal transduction
  locations:
  - preferred_term: Bone
    term:
      id: UBERON:0002481
      label: bone tissue
  - preferred_term: Skull
    term:
      id: UBERON:0003129
      label: skull
  evidence:
  - reference: PMID:12612583
    reference_title: "Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified localized mutations in FLNA that conserve the reading
      frame and lead to a broad range of congenital malformations,
      affecting craniofacial structures, skeleton, brain, viscera and
      urogenital tract, in four X-linked human disorders
    explanation: >-
      Landmark paper identifying gain-of-function FLNA mutations as
      causative for the OPD spectrum.
  - reference: PMID:12612583
    reference_title: "Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all are clustered into four regions of the gene: the actin-binding
      domain and rod domain repeats 3, 10 and 14/15
    explanation: >-
      Defines the mutational clustering pattern characteristic of OPD
      spectrum disorders.
  - reference: PMID:19773341
    reference_title: "Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      recombinant FLNA E254K ABD has increased in vitro F-actin binding
      (K(d) 13 microm) compared with wild type (WT; K(d) 48 microm).
      These observations are consistent with a gain-of-function mechanism
      for OPD.
    explanation: >-
      Provides biochemical evidence that OPD mutations increase actin
      binding, confirming gain-of-function mechanism.
  downstream:
  - target: Craniofacial and Skeletal Malformations
- name: Craniofacial and Skeletal Malformations
  description: >-
    The gain-of-function FLNA mutations disrupt skeletal development,
    leading to craniofacial dysmorphism, metaphyseal flaring, abnormal
    ossification, and digital malformations. The severity and pattern of
    skeletal involvement varies across the OPD spectrum subtypes.
  biological_processes:
  - preferred_term: Bone development
    term:
      id: GO:0060348
      label: bone development
  - preferred_term: Cranial suture morphogenesis
    term:
      id: GO:0060363
      label: cranial suture morphogenesis
  locations:
  - preferred_term: Skeleton
    term:
      id: UBERON:0004288
      label: skeleton
  evidence:
  - reference: PMID:12612583
    reference_title: "Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patterns of mutation, X-chromosome inactivation and phenotypic
      manifestations in the newly described mutations indicate that they
      have gain-of-function effects, implicating filamin A in signaling
      pathways that mediate organogenesis in multiple systems during
      embryonic development.
    explanation: >-
      Establishes that the skeletal malformations result from
      gain-of-function effects on developmental signaling.
phenotypes:
- category: Musculoskeletal
  name: Skeletal Dysplasia
  frequency: Very frequent
  description: >-
    Variable skeletal abnormalities across all subtypes, including
    metaphyseal flaring, bowed long bones, and abnormal ossification.
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders,
      characterized primarily by skeletal dysplasia
    explanation: >-
      GeneReviews defines skeletal dysplasia as the primary feature
      of the OPD spectrum.
- category: Craniofacial
  name: Craniofacial Dysmorphism
  frequency: Very frequent
  description: >-
    Characteristic facial features vary by subtype but commonly include
    frontal bossing, supraorbital hyperostosis, and midface hypoplasia.
  phenotype_term:
    preferred_term: Craniofacial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cosmetic surgery may correct the fronto-orbital deformity
    explanation: >-
      GeneReviews documents fronto-orbital deformity as a management
      target, confirming craniofacial dysmorphism as a key feature.
- category: Hearing
  name: Conductive Hearing Loss
  frequency: Frequent
  description: >-
    Conductive hearing impairment is common, particularly in OPD1 and FMD,
    resulting from ossicular chain anomalies.
  phenotype_term:
    preferred_term: Conductive hearing loss
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males usually, but not always, demonstrate a skeletal dysplasia
      in association with hearing loss
    explanation: >-
      GeneReviews confirms hearing loss as a key feature of FLNA-FMD.
- category: Musculoskeletal
  name: Cleft Palate
  frequency: Frequent
  description: >-
    Cleft palate is a frequent finding, particularly in OPD1 and OPD2.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      surgical correction for orthognathic deformities as needed
    explanation: >-
      GeneReviews lists orthognathic surgical correction as a management
      recommendation for the craniofacial/oral spectrum; this supports
      management of orthognathic (jaw/dental) deformity but does not
      itself document cleft palate, so it is marked PARTIAL. Cleft palate
      is a well-established feature of OPD1/OPD2 (the disorder name
      "otopalatodigital" references the palate), but the available cached
      source text does not directly state it.
- category: Musculoskeletal
  name: Scoliosis
  frequency: Frequent
  description: >-
    Progressive scoliosis is observed in both affected males and females,
    particularly in FMD.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive scoliosis is observed in both affected males and females.
    explanation: >-
      GeneReviews documents progressive scoliosis as a common feature.
- category: Respiratory
  name: Thoracic Hypoplasia
  frequency: Occasional
  subtype: OPD2
  description: >-
    Thoracic hypoplasia resulting in pulmonary insufficiency is a major
    cause of death in OPD2 males during the first year of life.
  phenotype_term:
    preferred_term: Thoracic hypoplasia
    term:
      id: HP:0005257
      label: Thoracic hypoplasia
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most males with FLNA-OPD2 die during the first year of life,
      usually from thoracic hypoplasia resulting in pulmonary
      insufficiency.
    explanation: >-
      GeneReviews identifies thoracic hypoplasia as the primary cause
      of OPD2 male lethality.
- category: Musculoskeletal
  name: Joint Contractures
  frequency: Occasional
  description: >-
    Variable joint contractures, particularly in FMD.
  phenotype_term:
    preferred_term: Joint contractures
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variably, joint contractures and hand and foot malformations
    explanation: >-
      GeneReviews confirms variable joint contractures as a feature of
      FLNA-FMD within the OPD spectrum.
- category: Craniofacial
  name: Micrognathia
  frequency: Occasional
  description: >-
    Small jaw that may contribute to airway complications.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mandibular distraction can improve airway complications related to
      micrognathia
    explanation: >-
      GeneReviews management guidance mentions micrognathia as a cause of
      airway complications requiring mandibular distraction.
genetic:
- name: FLNA Gain-of-Function Missense Variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: FLNA
    term:
      id: hgnc:3754
      label: FLNA
  inheritance:
  - name: X-linked Dominant
    inheritance_term:
      preferred_term: X-linked dominant inheritance
      term:
        id: HP:0001423
        label: X-linked dominant inheritance
  features: >-
    Gain-of-function missense mutations clustered in the actin-binding
    domain and rod domain repeats 3, 10, and 14/15. Several mutations are
    recurrent. Males with OPD2 and MNS mutations typically have perinatal
    lethality. Penetrance in males is complete.
  evidence:
  - reference: PMID:12612583
    reference_title: "Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified localized mutations in FLNA that conserve the reading
      frame and lead to a broad range of congenital malformations
    explanation: >-
      Defines the gain-of-function mutation spectrum for OPD spectrum.
  - reference: PMID:19773341
    reference_title: "Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data provide the first biochemical evidence for a
      gain-of-function mechanism for the OPD disorders, and
      mechanistically distinguishes them from the loss-of-function
      phenotypes that manifest as disorders of neuronal migration.
    explanation: >-
      Biochemical confirmation of gain-of-function mechanism,
      distinguishing from PVNH loss-of-function.
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Penetrance in males with an FLNA pathogenic variant leading to an
      FLNA-OPD spectrum disorder is complete
    explanation: >-
      GeneReviews confirms complete penetrance in males.
diagnosis:
- name: Clinical, Radiographic, and Family-History Diagnosis
  description: >-
    FLNA-related otopalatodigital spectrum disorders are usually established by
    characteristic clinical and radiographic features together with a family
    history consistent with X-linked inheritance. Male and female probands can
    both be diagnosed this way, with severity varying by sex and subtype.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of an FLNA-OPD spectrum disorder is established in a male
      proband with characteristic clinical and radiographic features and a family
      history consistent with X-linked inheritance.
    explanation: >-
      GeneReviews defines the usual diagnostic basis for affected male probands.
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of an FLNA-OPD spectrum disorder is usually established in a
      female proband with characteristic clinical and radiographic features and a
      family history consistent with X-linked inheritance.
    explanation: >-
      GeneReviews defines the usual diagnostic basis for affected female
      probands.
- name: Molecular Genetic Confirmation
  description: >-
    Molecular genetic testing can confirm an FLNA-OPD spectrum disorder when the
    clinical, radiographic, or family-history pattern is inconclusive. A
    hemizygous pathogenic FLNA variant confirms diagnosis in a male proband, and
    a heterozygous pathogenic FLNA variant confirms diagnosis in a female
    proband.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of a hemizygous pathogenic variant in FLNA by molecular
      genetic testing can confirm the diagnosis if clinical features,
      radiographic features, and/or family history are inconclusive.
    explanation: >-
      GeneReviews supports hemizygous FLNA variant detection as confirmatory in
      male probands when other diagnostic features are inconclusive.
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of a heterozygous pathogenic variant in FLNA by molecular
      genetic testing can confirm the diagnosis if clinical features,
      radiographic features, and/or family history are inconclusive.
    explanation: >-
      GeneReviews supports heterozygous FLNA variant detection as confirmatory
      in female probands when other diagnostic features are inconclusive.
- name: At-Risk Female Relative Testing
  description: >-
    Once the family-specific FLNA pathogenic variant is known, molecular testing
    can be used to evaluate at-risk female relatives.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consider molecular genetic testing for the family-specific pathogenic
      variant in at-risk female relatives.
    explanation: >-
      GeneReviews supports targeted molecular testing for at-risk female
      relatives when the familial FLNA variant is known.
- name: Prenatal and Preimplantation Genetic Testing
  description: >-
    Prenatal and preimplantation genetic testing are possible after identifying
    the FLNA pathogenic variant in an affected family member.
  diagnosis_term:
    preferred_term: prenatal genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the FLNA pathogenic variant has been identified in an affected family
      member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum
      disorders are possible.
    explanation: >-
      GeneReviews supports variant-informed prenatal and preimplantation genetic
      testing for FLNA-OPD spectrum disorders.
treatments:
- name: Orthopedic Surgery
  description: >-
    Surgical treatment for hand and foot malformations, scoliosis bracing
    and surgical intervention, and correction of orthognathic deformities.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical treatment may be required for hand and foot malformations.
    explanation: >-
      GeneReviews management guidance for skeletal anomalies.
- name: Hearing Aids
  description: >-
    Hearing aids for conductive hearing loss, with annual audiology
    evaluation recommended.
  treatment_term:
    preferred_term: Hearing aids
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hearing aids for deafness
    explanation: >-
      GeneReviews management recommendation for hearing impairment.
- name: Respiratory Support
  description: >-
    Continuous positive airway pressure and mandibular distraction for
    airway complications. Chest expansion surgery for thoracic hypoplasia.
  treatment_term:
    preferred_term: Respiratory support
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      continuous positive airway pressure and mandibular distraction can
      improve airway complications related to micrognathia
    explanation: >-
      GeneReviews details respiratory management strategies.
- name: Genetic Counseling
  description: >-
    Genetic counseling regarding X-linked inheritance, male lethality
    in severe subtypes, and prenatal testing options.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the FLNA pathogenic variant has been identified in an
      affected family member, prenatal and preimplantation genetic
      testing for FLNA-OPD spectrum disorders are possible.
    explanation: >-
      GeneReviews genetic counseling guidance.
datasets: []
references:
- reference: PMID:20301567
  title: "FLNA-Related Otopalatodigital Spectrum Disorders."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301567
FLNA-Related Otopalatodigital Spectrum Disorders.
No top-level findings curated for this source.