Terminal Osseous Dysplasia

Genetic MONDO:0010279 Pathograph 16 Show in embeddings browser Skeletal Dysplasia

Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare X-linked dominant male-lethal skeletal dysplasia caused by a single recurrent mutation (c.5217G>A) in the FLNA gene. The condition is seen only in females and is characterized by skeletal dysplasia predominantly affecting the hands and feet, pigmentary defects of the skin (particularly punched-out lesions on the face and scalp), and recurrent digital fibromata with onset in female infancy. The mutation activates a cryptic splice site, removing 16 amino acids from filamin repeat 15. X-inactivation plays a major role in determining the range of phenotypic expression, with marked variability between affected individuals. Despite being grouped with OPD spectrum disorders in some classifications, TOD has a distinct molecular mechanism and clinical presentation.

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1
Inheritance
4
Pathophys.
12
Phenotypes
16
Pathograph
1
Genes
2
Medical Actions
🏷

Classifications

ISDS Skeletal Nosology
filamin and related
👪

Inheritance

1
X-linked Dominant HP:0001423
X-linked dominant inheritance
Show evidence (1 reference)
PMID:20598277 SUPPORT Human Clinical
"Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs"
Establishes TOD as an X-linked dominant, male-lethal disorder.
⚙

Pathophysiology

4
FLNA Cryptic Splice Site Activation
A single recurrent mutation (c.5217G>A) at the last nucleotide of exon 31 of FLNA activates a cryptic splice site, removing the last 48 nucleotides from exon 31.
mRNA splicing GO:0000398 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves mRNA splicing, annotated with mRNA splicing, via spliceosome (GO:0000398). GO:0000398 is a biological process from the Gene Ontology.
Downstream
Truncated Filamin A Protein
Show evidence (2 references)
PMID:20598277 SUPPORT Human Clinical
"The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases)"
Identifies the single recurrent FLNA mutation causing TOD.
PMID:20598277 SUPPORT Human Clinical
"The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15."
Defines the molecular mechanism of the TOD mutation.
Truncated Filamin A Protein
At the protein level, the splice site activation results in loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a surface sequence of filamin repeat 15, producing a structurally altered filamin A.
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.
Downstream
Nonrandom X-Inactivation and Tissue-Specific Expression
Show evidence (1 reference)
PMID:20598277 SUPPORT Human Clinical
"At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15."
Describes the truncated filamin A protein produced by the TOD splice mutation.
Nonrandom X-Inactivation and Tissue-Specific Expression
Due to nonrandom X chromosome inactivation, the mutant allele is not expressed in patient fibroblasts but is expressed in cultured fibroma cells. This tissue-specific expression pattern determines the range of phenotypic manifestations.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Dysregulated Elastin Biology and Connective Tissue Manifestations
Recurrent Digital Fibromata Mutant FLNA expression in fibroma cells explains recurrent digital fibromata.
Inclusion Body Fibromatosis Tissue-specific mutant FLNA expression in digital fibroma cells explains inclusion body fibromatosis.
Show evidence (1 reference)
PMID:20598277 SUPPORT Human Clinical
"RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material."
Demonstrates tissue-specific expression of the mutant allele due to X-inactivation patterns.
Dysregulated Elastin Biology and Connective Tissue Manifestations
Mutated filamin A exerts effects through dysregulated elastin biology, with absent elastic fibers in skin lesions, explaining the connective tissue manifestations including skeletal dysplasia and pigmentary defects.
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.
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.
Hand UBERON:0002398 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Hand, annotated with manus (UBERON:0002398). UBERON:0002398 is an anatomical location from the Uberon multi-species anatomy ontology. Foot UBERON:0002387 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Foot, annotated with pes (UBERON:0002387). UBERON:0002387 is an anatomical location from the Uberon multi-species anatomy ontology. Skin UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Skin, annotated with skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Distal Limb Skeletal Dysplasia Dysregulated filamin A/connective-tissue biology disrupts skeletal development in the distal limbs.
Pigmentary Skin Defects Dysregulated elastin biology in skin lesions explains the pigmentary skin-defect component.
Hyperpigmented Papules The skin-lesion branch of the TOD mechanism accounts for hyperpigmented papules.
Flexion Contracture Distal skeletal dysplasia and connective-tissue involvement produce flexion contractures.
Clinodactyly Abnormal digital ossification in TOD produces clinodactyly.
Alopecia The dermatologic component of TOD includes alopecia.
Accessory Oral Frenulum Abnormal connective-tissue development in TOD includes accessory oral frenula.
Scoliosis Generalized skeletal involvement in TOD can produce scoliosis.
Short Stature Broader skeletal dysplasia in TOD can result in short stature.
Hypertelorism Craniofacial connective-tissue and skeletal involvement in TOD can include hypertelorism.
Show evidence (1 reference)
PMID:26059211 SUPPORT Human Clinical
"The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology"
Proposes dysregulated elastin biology as a mechanism for connective tissue manifestations in FLNA disorders including TOD.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Terminal Osseous Dysplasia 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
Eye 1
Hypertelorism OCCASIONAL HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0000316 | Hypertelorism | Occasional (29-5%)"
Orphanet lists hypertelorism as an occasional craniofacial feature of terminal osseous dysplasia-pigmentary defects syndrome.
Head and Neck 1
Accessory Oral Frenulum FREQUENT HP:0000191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Accessory oral frenulum (HP:0000191). HP:0000191 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0000191 | Accessory oral frenulum | Frequent (79-30%)"
Orphanet lists accessory oral frenulum as a frequent feature of terminal osseous dysplasia-pigmentary defects syndrome.
Integument 3
Pigmentary Skin Defects Very frequent Abnormality of skin pigmentation HP:0001000 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of skin pigmentation (HP:0001000). HP:0001000 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20598277 SUPPORT Human Clinical
"pigmentary defects of the skin"
Pigmentary skin defects are a defining feature of TOD.
PMID:26059211 SUPPORT Human Clinical
"deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions"
Confirms the pigmentary skin defect phenotype.
Recurrent Digital Fibromata Very frequent Subungual fibromas HP:0009724 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subungual fibromas (HP:0009724). HP:0009724 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20598277 SUPPORT Human Clinical
"recurrent digital fibroma with onset in female infancy"
Recurrent digital fibromas are a defining feature of TOD.
PMID:20598277 SUPPORT Human Clinical
"RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material."
Demonstrates that the mutant FLNA allele escapes X-inactivation silencing specifically in fibroma tissue.
Alopecia FREQUENT HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0001596 | Alopecia | Frequent (79-30%)"
Orphanet lists alopecia as a frequent feature of terminal osseous dysplasia-pigmentary defects syndrome.
Limbs 2
Distal Limb Skeletal Dysplasia Very frequent Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20598277 SUPPORT Human Clinical
"Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs"
Confirms limb skeletal dysplasia as a defining feature.
Clinodactyly FREQUENT HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0030084 | Clinodactyly | Frequent (79-30%)"
Orphanet lists clinodactyly as a frequent feature of terminal osseous dysplasia-pigmentary defects syndrome.
Musculoskeletal 2
Flexion Contracture FREQUENT HP:0001371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0001371 | Flexion contracture | Frequent (79-30%)"
Orphanet lists flexion contracture as a frequent feature of terminal osseous dysplasia-pigmentary defects syndrome.
Scoliosis OCCASIONAL 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 (2 references)
ORPHA:88630 SUPPORT Human Clinical
"HP:0002650 | Scoliosis | Occasional (29-5%)"
Orphanet lists scoliosis as an occasional feature of terminal osseous dysplasia-pigmentary defects syndrome.
PMID:20301567 SUPPORT Human Clinical
"Monitoring, bracing, and surgical intervention as needed for scoliosis"
The FLNA-OPD GeneReviews entry notes scoliosis as a recognized skeletal complication across FLNA-related disorders including FLNA-TOD.
Growth 1
Short Stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0004322 | Short stature | Occasional (29-5%)"
Orphanet lists short stature as an occasional feature of terminal osseous dysplasia-pigmentary defects syndrome.
Other 2
Hyperpigmented Papules VERY_FREQUENT HP:0025473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperpigmented papule (HP:0025473). HP:0025473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88630 SUPPORT Human Clinical
"HP:0025473 | Hyperpigmented papule | Very frequent (99-80%)"
Orphanet lists hyperpigmented papule as a very frequent feature of terminal osseous dysplasia-pigmentary defects syndrome.
Inclusion Body Fibromatosis VERY_FREQUENT HP:0025197 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inclusion body fibromatosis (HP:0025197). HP:0025197 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:88630 SUPPORT Human Clinical
"HP:0025197 | Inclusion body fibromatosis | Very frequent (99-80%)"
Orphanet lists inclusion body fibromatosis as a very frequent feature of terminal osseous dysplasia-pigmentary defects syndrome.
PMID:26059211 SUPPORT Human Clinical
"Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas."
Confirms digital fibromatosis as one of the three cardinal features of TODPD.
🧬

Genetic Associations

1
FLNA c.5217G>A Recurrent Mutation (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 (2 references)
PMID:20598277 SUPPORT Human Clinical
"Our data show that TOD is caused by this single recurrent mutation in the FLNA gene."
Confirms a single recurrent mutation as the cause of all TOD cases.
PMID:26059211 SUPPORT Human Clinical
"Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing."
Confirms the specific mutation and its diagnostic utility.
💊

Medical Actions

2
Surgical Excision of Digital Fibromas
Action: Surgical excisionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical excision, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Recurrent digital fibromas may require surgical excision, though recurrence is common.
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
Counseling regarding X-linked inheritance, male lethality, and variable expressivity due to X-inactivation patterns.
🔬

Diagnosis

3
Clinical Recognition of the TODPD Triad
Terminal osseous dysplasia with pigmentary defects is recognized clinically by the female-limited combination of distal limb skeletal anomalies, pigmentary skin defects of the face or scalp, and recurrent digital fibromas.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26059211 SUPPORT Human Clinical
"Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas."
Defines the classic clinical triad used to recognize TODPD.
PMID:20598277 SUPPORT Human Clinical
"Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy."
Confirms the same limb, skin-pigment, and digital-fibroma diagnostic pattern with X-linked dominant male lethality.
Molecular Genetic Confirmation
Diagnostic genetic testing can confirm TODPD by identifying the recurrent FLNA c.5217G>A variant, the single recurrent mutation reported across unrelated familial and sporadic cases.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26059211 SUPPORT Human Clinical
"Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing."
Directly supports FLNA c.5217G>A testing as diagnostic for TODPD.
PMID:20598277 SUPPORT Human Clinical
"The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases)"
Establishes recurrence of the FLNA c.5217G>A variant across unrelated cases, supporting targeted molecular confirmation.
Skin Biopsy of Pigmentary Lesions
Skin biopsy of a facial pigmentary lesion can provide supportive histopathology by showing absent papillary dermal elastic fibers consistent with anetoderma.
biopsy of skin NCIT:C51692 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26059211 SUPPORT Human Clinical
"Skin biopsy of the patient's facial lesion revealed absent papillary dermal elastic fibers, consistent with anetoderma"
Supports skin biopsy as a diagnostic adjunct for the characteristic pigmentary lesions in TODPD.
📊

Prevalence

1
Global
Rare Rare
Show evidence (1 reference)
PMID:26059211 SUPPORT Human Clinical
"Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas."
Characterizes TODPD as a rare disorder.
{ }

Source YAML

click to show 
name: Terminal Osseous Dysplasia
synonyms:
- Terminal osseous dysplasia (TOD), FLNA-related
creation_date: "2026-04-04T00:00:00Z"
description: >-
  Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare X-linked
  dominant male-lethal skeletal dysplasia caused by a single recurrent mutation
  (c.5217G>A) in the FLNA gene. The condition is seen only in females and is
  characterized by skeletal dysplasia predominantly affecting the hands and feet,
  pigmentary defects of the skin (particularly punched-out lesions on the face
  and scalp), and recurrent digital fibromata with onset in female infancy.
  The mutation activates a cryptic splice site, removing 16 amino acids from
  filamin repeat 15. X-inactivation plays a major role in determining the range
  of phenotypic expression, with marked variability between affected individuals.
  Despite being grouped with OPD spectrum disorders in some classifications,
  TOD has a distinct molecular mechanism and clinical presentation.
category: Genetic
parents:
- Skeletal Dysplasia
disease_term:
  preferred_term: terminal osseous dysplasia-pigmentary defects syndrome
  term:
    id: MONDO:0010279
    label: terminal osseous dysplasia-pigmentary defects 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"; listed as "Terminal osseous dysplasia (TOD)".
prevalence:
- population: Global
  prevalence_class: RARE
  percentage: Rare
  evidence:
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terminal osseous dysplasia with pigmentary defects (TODPD) is a
      rare, X-linked syndrome classically characterized by distal limb
      anomalies, pigmented skin defects of the face, and recurrent
      digital fibromas.
    explanation: >-
      Characterizes TODPD as a rare disorder.
inheritance:
- name: X-linked Dominant
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal
      disease characterized by skeletal dysplasia of the limbs
    explanation: >-
      Establishes TOD as an X-linked dominant, male-lethal disorder.
pathophysiology:
- name: FLNA Cryptic Splice Site Activation
  description: >-
    A single recurrent mutation (c.5217G>A) at the last nucleotide of exon 31
    of FLNA activates a cryptic splice site, removing the last 48 nucleotides
    from exon 31.
  biological_processes:
  - preferred_term: mRNA splicing
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant c.5217G>A was found in six unrelated cases (three
      families and three sporadic cases)
    explanation: >-
      Identifies the single recurrent FLNA mutation causing TOD.
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant activates a cryptic splice site, removing the last 48
      nucleotides from exon 31. At the protein level, this results in a
      loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove
      a sequence at the surface of filamin repeat 15.
    explanation: >-
      Defines the molecular mechanism of the TOD mutation.
  downstream:
  - target: Truncated Filamin A Protein
- name: Truncated Filamin A Protein
  description: >-
    At the protein level, the splice site activation results in loss of 16
    amino acids (p.Val1724_Thr1739del), predicted to remove a surface
    sequence of filamin repeat 15, producing a structurally altered filamin A.
  biological_processes:
  - preferred_term: Actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the protein level, this results in a loss of 16 amino acids
      (p.Val1724_Thr1739del), predicted to remove a sequence at the
      surface of filamin repeat 15.
    explanation: >-
      Describes the truncated filamin A protein produced by the TOD
      splice mutation.
  downstream:
  - target: Nonrandom X-Inactivation and Tissue-Specific Expression
- name: Nonrandom X-Inactivation and Tissue-Specific Expression
  description: >-
    Due to nonrandom X chromosome inactivation, the mutant allele is not
    expressed in patient fibroblasts but is expressed in cultured fibroma
    cells. This tissue-specific expression pattern determines the range
    of phenotypic manifestations.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA expression of the mutant allele was detected only in cultured
      fibroma cells obtained from 15-year-old surgically removed material.
    explanation: >-
      Demonstrates tissue-specific expression of the mutant allele
      due to X-inactivation patterns.
  downstream:
  - target: Dysregulated Elastin Biology and Connective Tissue Manifestations
  - target: Recurrent Digital Fibromata
    description: Mutant FLNA expression in fibroma cells explains recurrent digital fibromata.
    causal_link_type: DIRECT
  - target: Inclusion Body Fibromatosis
    description: Tissue-specific mutant FLNA expression in digital fibroma cells explains inclusion body fibromatosis.
    causal_link_type: DIRECT
- name: Dysregulated Elastin Biology and Connective Tissue Manifestations
  description: >-
    Mutated filamin A exerts effects through dysregulated elastin biology,
    with absent elastic fibers in skin lesions, explaining the connective
    tissue manifestations including skeletal dysplasia and pigmentary defects.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
  locations:
  - preferred_term: Hand
    term:
      id: UBERON:0002398
      label: manus
  - preferred_term: Foot
    term:
      id: UBERON:0002387
      label: pes
  - preferred_term: Skin
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The finding of absent elastic fibers in the skin lesions suggests
      that mutated filamin A, in part, exerts its effects through
      dysregulated elastin biology
    explanation: >-
      Proposes dysregulated elastin biology as a mechanism for connective
      tissue manifestations in FLNA disorders including TOD.
  downstream:
  - target: Distal Limb Skeletal Dysplasia
    description: Dysregulated filamin A/connective-tissue biology disrupts skeletal development in the distal limbs.
    causal_link_type: DIRECT
  - target: Pigmentary Skin Defects
    description: Dysregulated elastin biology in skin lesions explains the pigmentary skin-defect component.
    causal_link_type: DIRECT
  - target: Hyperpigmented Papules
    description: The skin-lesion branch of the TOD mechanism accounts for hyperpigmented papules.
    causal_link_type: DIRECT
  - target: Flexion Contracture
    description: Distal skeletal dysplasia and connective-tissue involvement produce flexion contractures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - distal limb skeletal dysplasia
  - target: Clinodactyly
    description: Abnormal digital ossification in TOD produces clinodactyly.
    causal_link_type: DIRECT
  - target: Alopecia
    description: The dermatologic component of TOD includes alopecia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Accessory Oral Frenulum
    description: Abnormal connective-tissue development in TOD includes accessory oral frenula.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    description: Generalized skeletal involvement in TOD can produce scoliosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - generalized skeletal dysplasia
  - target: Short Stature
    description: Broader skeletal dysplasia in TOD can result in short stature.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - generalized skeletal dysplasia
  - target: Hypertelorism
    description: Craniofacial connective-tissue and skeletal involvement in TOD can include hypertelorism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Musculoskeletal
  name: Distal Limb Skeletal Dysplasia
  frequency: Very frequent
  description: >-
    Skeletal dysplasia predominantly affecting the hands and feet, including
    brachydactyly and terminal bone abnormalities. Although most striking
    in hands and feet, skeletal involvement can be more generalized.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal
      disease characterized by skeletal dysplasia of the limbs
    explanation: >-
      Confirms limb skeletal dysplasia as a defining feature.
- category: Dermatologic
  name: Pigmentary Skin Defects
  frequency: Very frequent
  description: >-
    Punched-out pigmentary abnormalities over the face and scalp, with
    discolored linear facial lesions. Skin biopsy reveals absent papillary
    dermal elastic fibers (anetoderma).
  phenotype_term:
    preferred_term: Abnormality of skin pigmentation
    term:
      id: HP:0001000
      label: Abnormality of skin pigmentation
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pigmentary defects of the skin
    explanation: >-
      Pigmentary skin defects are a defining feature of TOD.
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      deformities of the hands and feet, craniofacial abnormalities, and
      discolored, linear facial lesions
    explanation: >-
      Confirms the pigmentary skin defect phenotype.
- category: Dermatologic
  name: Hyperpigmented Papules
  frequency: VERY_FREQUENT
  description: >-
    Hyperpigmented papular skin lesions, listed as a very frequent feature
    of terminal osseous dysplasia-pigmentary defects syndrome. These
    represent the characteristic skin pigmentation abnormality in TODPD.
  phenotype_term:
    preferred_term: Hyperpigmented papule
    term:
      id: HP:0025473
      label: Hyperpigmented papule
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0025473 | Hyperpigmented papule | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists hyperpigmented papule as a very frequent feature
      of terminal osseous dysplasia-pigmentary defects syndrome.
- category: Musculoskeletal
  name: Recurrent Digital Fibromata
  frequency: Very frequent
  description: >-
    Recurrent fibromas of the digits with onset in female infancy.
    Surgically removed material shows expression of the mutant FLNA allele
    in fibroma cells.
  phenotype_term:
    preferred_term: Subungual fibromas
    term:
      id: HP:0009724
      label: Subungual fibromas
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent digital fibroma with onset in female infancy
    explanation: >-
      Recurrent digital fibromas are a defining feature of TOD.
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA expression of the mutant allele was detected only in cultured
      fibroma cells obtained from 15-year-old surgically removed material.
    explanation: >-
      Demonstrates that the mutant FLNA allele escapes X-inactivation
      silencing specifically in fibroma tissue.
- category: Musculoskeletal
  name: Inclusion Body Fibromatosis
  frequency: VERY_FREQUENT
  description: >-
    Infantile digital fibromatosis (inclusion body fibromatosis) is
    a hallmark of TODPD. Fibromata containing characteristic cytoplasmic
    inclusion bodies arise on the fingers and toes shortly after birth
    and recur after excision.
  phenotype_term:
    preferred_term: Inclusion body fibromatosis
    term:
      id: HP:0025197
      label: Inclusion body fibromatosis
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0025197 | Inclusion body fibromatosis | Very frequent (99-80%)"
    explanation: >-
      Orphanet lists inclusion body fibromatosis as a very frequent feature
      of terminal osseous dysplasia-pigmentary defects syndrome.
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terminal osseous dysplasia with pigmentary defects (TODPD) is a
      rare, X-linked syndrome classically characterized by distal limb
      anomalies, pigmented skin defects of the face, and recurrent
      digital fibromas.
    explanation: >-
      Confirms digital fibromatosis as one of the three cardinal features
      of TODPD.
- category: Musculoskeletal
  name: Flexion Contracture
  frequency: FREQUENT
  description: >-
    Joint contractures, particularly flexion contractures of the fingers
    and toes, are a frequent feature, contributing to the hand and foot
    deformities in TODPD.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001371 | Flexion contracture | Frequent (79-30%)"
    explanation: >-
      Orphanet lists flexion contracture as a frequent feature of
      terminal osseous dysplasia-pigmentary defects syndrome.
- category: Musculoskeletal
  name: Clinodactyly
  frequency: FREQUENT
  description: >-
    Lateral deviation of one or more digits (clinodactyly) is a
    frequent skeletal feature of TODPD, reflecting the abnormal
    digital ossification in this condition.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0030084 | Clinodactyly | Frequent (79-30%)"
    explanation: >-
      Orphanet lists clinodactyly as a frequent feature of
      terminal osseous dysplasia-pigmentary defects syndrome.
- category: Dermatologic
  name: Alopecia
  frequency: FREQUENT
  description: >-
    Hair loss (alopecia) is a frequent dermatological feature of TODPD,
    reflecting ectodermal involvement by the mutated filamin A protein.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001596 | Alopecia | Frequent (79-30%)"
    explanation: >-
      Orphanet lists alopecia as a frequent feature of terminal osseous
      dysplasia-pigmentary defects syndrome.
- category: Dental
  name: Accessory Oral Frenulum
  frequency: FREQUENT
  description: >-
    Multiple or accessory oral frenula are a frequent mucosal finding
    in TODPD, likely reflecting abnormal fibrous tissue proliferation
    mediated by the FLNA mutation.
  phenotype_term:
    preferred_term: Accessory oral frenulum
    term:
      id: HP:0000191
      label: Accessory oral frenulum
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000191 | Accessory oral frenulum | Frequent (79-30%)"
    explanation: >-
      Orphanet lists accessory oral frenulum as a frequent feature of
      terminal osseous dysplasia-pigmentary defects syndrome.
- category: Musculoskeletal
  name: Scoliosis
  frequency: OCCASIONAL
  description: >-
    Spinal curvature (scoliosis) is an occasional skeletal feature of
    TODPD. Monitoring and bracing or surgical intervention may be
    required as in other FLNA-related disorders.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002650 | Scoliosis | Occasional (29-5%)"
    explanation: >-
      Orphanet lists scoliosis as an occasional feature of terminal
      osseous dysplasia-pigmentary defects syndrome.
  - reference: PMID:20301567
    reference_title: "FLNA-Related Otopalatodigital Spectrum Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Monitoring, bracing, and surgical intervention as needed for
      scoliosis
    explanation: >-
      The FLNA-OPD GeneReviews entry notes scoliosis as a recognized
      skeletal complication across FLNA-related disorders including FLNA-TOD.
- category: Growth
  name: Short Stature
  frequency: OCCASIONAL
  description: >-
    Short stature is an occasional associated feature of TODPD, likely
    secondary to the broader skeletal dysplasia affecting limb growth.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0004322 | Short stature | Occasional (29-5%)"
    explanation: >-
      Orphanet lists short stature as an occasional feature of terminal
      osseous dysplasia-pigmentary defects syndrome.
- category: Craniofacial
  name: Hypertelorism
  frequency: OCCASIONAL
  description: >-
    Increased distance between the orbits (hypertelorism) is an occasional
    craniofacial finding in TODPD, part of the variable craniofacial
    dysmorphism reported in some patients.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:88630
    reference_title: "Terminal osseous dysplasia-pigmentary defects syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000316 | Hypertelorism | Occasional (29-5%)"
    explanation: >-
      Orphanet lists hypertelorism as an occasional craniofacial feature
      of terminal osseous dysplasia-pigmentary defects syndrome.
genetic:
- name: FLNA c.5217G>A Recurrent Mutation
  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
    evidence:
    - reference: PMID:20598277
      reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the families, the variant segregated with the disease, and
        it was transmitted four times from a mildly affected mother to
        a more seriously affected daughter.
      explanation: >-
        Demonstrates X-linked dominant transmission with mother-to-daughter
        segregation and variable expressivity.
  features: >-
    Single recurrent mutation c.5217G>A at the last nucleotide of exon 31.
    X-linked dominant with male lethality. Variable expressivity due to
    nonrandom X chromosome inactivation. Affects only females.
  evidence:
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data show that TOD is caused by this single recurrent mutation
      in the FLNA gene.
    explanation: >-
      Confirms a single recurrent mutation as the cause of all TOD cases.
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies have identified a FLNA c.5217G>A mutation as the
      cause of TODPD, allowing for diagnostic genetic testing.
    explanation: >-
      Confirms the specific mutation and its diagnostic utility.
diagnosis:
- name: Clinical Recognition of the TODPD Triad
  description: >-
    Terminal osseous dysplasia with pigmentary defects is recognized clinically
    by the female-limited combination of distal limb skeletal anomalies,
    pigmentary skin defects of the face or scalp, and recurrent digital fibromas.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare,
      X-linked syndrome classically characterized by distal limb anomalies,
      pigmented skin defects of the face, and recurrent digital fibromas.
    explanation: >-
      Defines the classic clinical triad used to recognize TODPD.
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal
      disease characterized by skeletal dysplasia of the limbs, pigmentary
      defects of the skin, and recurrent digital fibroma with onset in female
      infancy.
    explanation: >-
      Confirms the same limb, skin-pigment, and digital-fibroma diagnostic
      pattern with X-linked dominant male lethality.
- name: Molecular Genetic Confirmation
  description: >-
    Diagnostic genetic testing can confirm TODPD by identifying the recurrent
    FLNA c.5217G>A variant, the single recurrent mutation reported across
    unrelated familial and sporadic cases.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies have identified a FLNA c.5217G>A mutation as the cause of
      TODPD, allowing for diagnostic genetic testing.
    explanation: >-
      Directly supports FLNA c.5217G>A testing as diagnostic for TODPD.
  - reference: PMID:20598277
    reference_title: "Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant c.5217G>A was found in six unrelated cases (three families and
      three sporadic cases)
    explanation: >-
      Establishes recurrence of the FLNA c.5217G>A variant across unrelated
      cases, supporting targeted molecular confirmation.
- name: Skin Biopsy of Pigmentary Lesions
  description: >-
    Skin biopsy of a facial pigmentary lesion can provide supportive
    histopathology by showing absent papillary dermal elastic fibers consistent
    with anetoderma.
  diagnosis_term:
    preferred_term: biopsy of skin
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:26059211
    reference_title: "Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin biopsy of the patient's facial lesion revealed absent papillary dermal
      elastic fibers, consistent with anetoderma
    explanation: >-
      Supports skin biopsy as a diagnostic adjunct for the characteristic
      pigmentary lesions in TODPD.
treatments:
- name: Surgical Excision of Digital Fibromas
  description: >-
    Recurrent digital fibromas may require surgical excision, though
    recurrence is common.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical excision
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Genetic Counseling
  description: >-
    Counseling regarding X-linked inheritance, male lethality, and
    variable expressivity due to X-inactivation patterns.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
datasets: []