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

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant inheritance

Pathophysiology

1
Constitutive PDGFRB Signaling
Gain-of-function mutations in PDGFRB lead to ligand-independent receptor activation, promoting myofibroblast proliferation and tumor formation. The mechanism is reminiscent of multifocal venous malformations induced by TIE2 mutations.
PDGFRB link
platelet-derived growth factor beta-receptor activity link
Show evidence (2 references)
PMID:28334876 SUPPORT In Vitro
"We showed that these mutations activated receptor signaling in the absence of ligand and transformed fibroblasts."
Functional studies demonstrate constitutive receptor activation by PDGFRB mutations.
PMID:26455322 SUPPORT In Vitro
"the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents."
In vitro characterization confirms oncogenic transformation by PDGFRB mutants.

Pathograph

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

4
Integument 1
Subcutaneous Nodules FREQUENT Subcutaneous nodule (HP:0001482)
Show evidence (1 reference)
PMID:28334876 SUPPORT Human Clinical
"Multifocal nodules with visceral lesions are associated with a poor prognosis."
Subcutaneous nodules are a characteristic presentation.
Musculoskeletal 1
Osteolytic Bone Lesions FREQUENT Osteolysis (HP:0002797)
Show evidence (1 reference)
PMID:19738495 SUPPORT Human Clinical
"examination presented a pretibial soft-tissue tumor mass with calcifications and two osteolytic lesions with a sclerotic rim."
A case report documents osteolytic bone lesions with a sclerotic rim in infantile myofibromatosis.
Neoplasm 1
Myofibromatosis VERY_FREQUENT Myofibromatosis (HP:0020135)
Show evidence (1 reference)
PMID:28334876 SUPPORT Human Clinical
"Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood."
Defines myofibromatosis as the hallmark feature.
Other 1
Cardiac Myofibroma OCCASIONAL Neoplasm of the heart (HP:0100544)
Show evidence (1 reference)
PMID:33063933 SUPPORT Human Clinical
"Visceral involvement included central nervous system, cardiac, gastrointestinal, muscle, bone, and subcutaneous tissue lesions."
A single-center cohort documents cardiac lesions among the visceral involvement of infantile myofibromatosis.
🧬

Genetic Associations

1
PDGFRB Gain-of-Function Mutations (Causative)
Show evidence (2 references)
PMID:28334876 SUPPORT Human Clinical
"Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma."
Demonstrates high frequency of PDGFRB mutations in sporadic multicentric myofibromatosis.
PMID:31017643 SUPPORT Human Clinical
"Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults."
Largest cohort study confirming PDGFRB mutations in pediatric myofibromatosis.
💊

Treatments

1
Imatinib
Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352
Tyrosine kinase inhibitor targeting PDGFRB. Mutant receptors are sensitive to imatinib at clinically relevant concentrations, offering a targeted molecular therapy for severe myofibromatosis.
Show evidence (2 references)
PMID:31017643 SUPPORT Human Clinical
"All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations."
Demonstrates sensitivity of PDGFRB mutants to imatinib.
PMID:32500973 SUPPORT Human Clinical
"Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy"
Clinical evidence of imatinib response in infantile myofibromatosis.
{ }

Source YAML

click to show
name: Infantile_Myofibromatosis
creation_date: '2026-04-04T00:00:00Z'
updated_date: '2026-04-22T20:13:21Z'
category: Genetic
parents:
- Soft Tissue Tumor
disease_term:
  preferred_term: familial infantile myofibromatosis
  term:
    id: MONDO:0009227
    label: myofibromatosis, infantile, 1
description: >-
  Infantile myofibromatosis is one of the most prevalent soft tissue tumors of
  infancy and childhood, characterized by benign myofibroblastic tumors arising
  in skin, muscle, bone, and viscera. The familial form (type 1) is caused by
  heterozygous gain-of-function mutations in PDGFRB encoding a receptor tyrosine
  kinase. Multifocal nodules with visceral involvement carry a poor prognosis.
  Gain-of-function PDGFRB mutations are found predominantly in children and are
  particularly associated with multicentric disease. The mutant receptors show
  constitutive activation in the absence of ligand and are sensitive to tyrosine
  kinase inhibitors such as imatinib, offering potential targeted therapy.
  Hereditary progressive mucinous histiocytosis, a very rare PDGFRB-associated
  condition with limited phenotypic data (single G2P phenotype), is considered
  part of the broader PDGFRB gain-of-function spectrum and is noted here rather
  than given a separate entry.
prevalence:
- population: Global
  percentage: Rare
  notes: >-
    Myofibroma is the most frequent fibrous tumor in children, but the familial
    PDGFRB-associated form is rare.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
genetic:
- name: PDGFRB Gain-of-Function Mutations
  gene_term:
    preferred_term: PDGFRB
    term:
      id: hgnc:8804
      label: PDGFRB
  association: Causative
  features: >-
    Heterozygous gain-of-function mutations in PDGFRB cause constitutive receptor
    activation in the absence of ligand. Mutations are located in the transmembrane,
    juxtamembrane, and kinase domains. In sporadic multicentric disease, mutations
    were found in 6 of 8 patients. A two-hit model has been proposed for familial
    myofibromatosis with a weakly-activating germline variant combined with a stronger
    somatic mutation.
  evidence:
  - reference: PMID:28334876
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma."
    explanation: Demonstrates high frequency of PDGFRB mutations in sporadic multicentric myofibromatosis.
  - reference: PMID:31017643
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults."
    explanation: Largest cohort study confirming PDGFRB mutations in pediatric myofibromatosis.
phenotypes:
- name: Myofibromatosis
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Myofibromatosis
    term:
      id: HP:0020135
      label: Myofibromatosis
  evidence:
  - reference: PMID:28334876
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood."
    explanation: Defines myofibromatosis as the hallmark feature.
- name: Subcutaneous Nodules
  category: Dermatologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Subcutaneous nodule
    term:
      id: HP:0001482
      label: Subcutaneous nodule
  evidence:
  - reference: PMID:28334876
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multifocal nodules with visceral lesions are associated with a poor prognosis."
    explanation: Subcutaneous nodules are a characteristic presentation.
- name: Osteolytic Bone Lesions
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Myofibromas involving bone present radiographically as osteolytic lesions,
    often with a sclerotic rim.
  phenotype_term:
    preferred_term: Osteolytic bone lesions
    term:
      id: HP:0002797
      label: Osteolysis
  evidence:
  - reference: PMID:19738495
    reference_title: "A rare case of infantile myofibromatosis and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      examination presented a pretibial soft-tissue tumor mass with
      calcifications and two osteolytic lesions with a sclerotic rim.
    explanation: A case report documents osteolytic bone lesions with a sclerotic rim in infantile myofibromatosis.
- name: Cardiac Myofibroma
  category: Cardiovascular
  frequency: OCCASIONAL
  description: >-
    Cardiac involvement by myofibromas occurs in the generalized form and is a
    major contributor to the poor prognosis of visceral disease.
  phenotype_term:
    preferred_term: Cardiac myofibroma
    term:
      id: HP:0100544
      label: Neoplasm of the heart
  evidence:
  - reference: PMID:33063933
    reference_title: "Diverse presentation and tailored treatment of infantile myofibromatosis: A single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visceral involvement included central nervous system, cardiac,
      gastrointestinal, muscle, bone, and subcutaneous tissue lesions.
    explanation: A single-center cohort documents cardiac lesions among the visceral involvement of infantile myofibromatosis.
pathophysiology:
- name: Constitutive PDGFRB Signaling
  description: >-
    Gain-of-function mutations in PDGFRB lead to ligand-independent receptor
    activation, promoting myofibroblast proliferation and tumor formation. The
    mechanism is reminiscent of multifocal venous malformations induced by TIE2
    mutations.
  genes:
  - preferred_term: PDGFRB
    term:
      id: hgnc:8804
      label: PDGFRB
  molecular_functions:
  - preferred_term: platelet-derived growth factor beta-receptor activity
    term:
      id: GO:0005019
      label: platelet-derived growth factor beta-receptor activity
  evidence:
  - reference: PMID:28334876
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We showed that these mutations activated receptor signaling in the absence of ligand and transformed fibroblasts."
    explanation: Functional studies demonstrate constitutive receptor activation by PDGFRB mutations.
  - reference: PMID:26455322
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents."
    explanation: In vitro characterization confirms oncogenic transformation by PDGFRB mutants.
treatments:
- name: Imatinib
  description: >-
    Tyrosine kinase inhibitor targeting PDGFRB. Mutant receptors are sensitive to
    imatinib at clinically relevant concentrations, offering a targeted molecular
    therapy for severe myofibromatosis.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  evidence:
  - reference: PMID:31017643
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations."
    explanation: Demonstrates sensitivity of PDGFRB mutants to imatinib.
  - reference: PMID:32500973
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy"
    explanation: Clinical evidence of imatinib response in infantile myofibromatosis.
notes: >-
  Hereditary progressive mucinous histiocytosis is a very rare condition also
  associated with PDGFRB gain-of-function mutations. It has very limited
  phenotypic data (single G2P phenotype) and is absorbed here as part of the
  broader PDGFRB gain-of-function spectrum rather than warranting a separate entry.
📚

References & Deep Research

Deep Research

1
Falcon
1. Disease Information
Edison Scientific Literature 54 citations 2026-04-04T12:36:09.165039

1. Disease Information

1.1 Overview / definition (current understanding)

Infantile myofibromatosis is a (generally) benign, non-metastasizing myofibroblastic/perivascular tumor disorder characterized by formation of nodules in skin/subcutis, skeletal muscle, and bone, and less commonly visceral organs; visceral involvement drives most severe outcomes. (lu2023prenatalgeneticdiagnosis pages 1-2, martignetti2013mutationsinpdgfrb pages 1-3)

A widely used clinical classification distinguishes: (i) solitary IM, (ii) multicentric IM without visceral involvement, and (iii) disseminated/generalized IM with visceral disease. (lu2023prenatalgeneticdiagnosis pages 1-2, mashiah2014infantilemyofibromatosisa pages 2-4)

1.2 Key identifiers and nomenclature

  • OMIM/MIM: IM (MIM/OMIM 228550) is explicitly referenced in the genetics literature. (lee2013mutationsinpdgfrb pages 1-3, lepelletier2017heterozygouspdgfrbmutation pages 1-2)
  • Other identifiers: Standard Orphanet (ORPHA), ICD-10/ICD-11, MeSH identifiers were not available in the retrieved primary-literature full texts in this run, so they cannot be verified here.

1.3 Synonyms / related terms used in practice

Commonly used related terms in the retrieved literature include: - “Myofibromatosis” for multicentric disease, and “myofibroma” for solitary lesions/tumors. (dachy2019associationofpdgfrb pages 1-2, koo2020adistinctivegenomic pages 1-2) - “Generalized/disseminated infantile myofibromatosis” for visceral disease. (mudry2017casereportrapid pages 1-2, lu2023prenatalgeneticdiagnosis pages 1-2)

1.4 Evidence sources

The knowledge base content below is derived primarily from aggregated disease-level resources in peer-reviewed cohort studies/consensus recommendations plus case reports/series (including prenatal and targeted-therapy reports). (hettmer2021genetictestingand pages 1-3, dachy2019associationofpdgfrb pages 1-2, mashiah2014infantilemyofibromatosisa pages 2-4, lu2023prenatalgeneticdiagnosis pages 1-2)


2. Etiology

2.1 Disease causal factors

Genetic etiology is central. Two genes have the strongest evidence in human familial disease: - PDGFRB (platelet-derived growth factor receptor beta): germline (autosomal dominant) and somatic/mosaic gain-of-function variants; constitutes the dominant known genetic driver. (martignetti2013mutationsinpdgfrb pages 1-3, hettmer2021genetictestingand pages 1-3, dachy2019associationofpdgfrb pages 1-2) - NOTCH3: a rare familial cause (e.g., NOTCH3 p.Leu1519Pro) and mechanistic link to PDGFRB upregulation. (martignetti2013mutationsinpdgfrb pages 1-3, wu2021theinfantilemyofibromatosis pages 1-1)

2.2 Risk factors

  • Genetic risk: Inherited autosomal-dominant PDGFRB variants confer risk, but penetrance is not complete and expressivity is variable. (lu2023prenatalgeneticdiagnosis pages 3-5, hettmer2021genetictestingand pages 1-3)
  • Somatic/mosaic risk: Severe multicentric disease can reflect post-zygotic/mosaic PDGFRB alterations or “second-hit” architectures (two PDGFRB variants in the same patient/tumor lineage). (dachy2019associationofpdgfrb pages 3-4, pudig2025infantilemyofibromatosisand pages 1-2)

No specific environmental or lifestyle risk factors were identified in the retrieved evidence.

2.3 Protective factors / gene–environment interactions

No protective genetic variants or gene–environment interaction evidence was identified in the retrieved sources.


3. Phenotypes

3.1 Core phenotype spectrum (with onset, course, frequencies)

Typical onset: most commonly at birth or before age 2 years. (murray2017thespectrumof pages 1-7, hettmer2021genetictestingand pages 1-3)

Clinical forms and frequencies (single-center series): In a 28-case series, clinical spectrum included solitary (~50%), multicentric (~39%), and generalized forms. (mashiah2014infantilemyofibromatosisa pages 1-2)

Lesion characteristics: firm, painless cutaneous/subcutaneous nodules; may appear flesh-colored/purple or ulcerated/angiomatous. (mashiah2014infantilemyofibromatosisa pages 4-6, mashiah2014infantilemyofibromatosisa pages 1-2)

Spontaneous regression: Common in multicentric disease: in the 28-case series, “The nodules regressed spontaneously … in 7 of 11 patients during the first 2 years of life.” (mashiah2014infantilemyofibromatosisa pages 2-4)

Recurrence: Although regression is common, late recurrence/relapse can occur and long-term follow-up may be needed. (mashiah2014infantilemyofibromatosisa pages 4-6, murray2017thespectrumof pages 1-7)

Visceral involvement: Visceral lesions may involve lung, liver, heart, spleen, intestine/bowel, kidney, and other organs. (lu2023prenatalgeneticdiagnosis pages 3-5, mashiah2014infantilemyofibromatosisa pages 2-4)

3.2 Prenatal phenotype

Prenatal presentation is rare but increasingly recognized. - In a literature review of prenatally detected cases, detection was typically in the third trimester: 15/17, mean 32 weeks. (lu2023prenatalgeneticdiagnosis pages 3-5) - Visceral involvement was common in this prenatal series (>50%, 9/17), affecting organs including lung, liver, heart, spleen, intestine, and kidney. (lu2023prenatalgeneticdiagnosis pages 3-5)

3.3 Phenotype → suggested HPO terms (examples)

(ontology suggestions; not claims of completeness) - Cutaneous/subcutaneous nodules/tumors: HP:0008069 (Subcutaneous nodule), HP:0008064 (Skin nodule) - Soft-tissue tumor / fibrous tumor: HP:0002664 (Soft tissue mass) - Bone involvement (lytic lesions/erosion): HP:0002658 (Skeletal abnormalities), HP:0002650 (Skeletal lytic lesions) - Visceral involvement (examples): HP:0001627 (Abnormality of the cardiovascular system), HP:0001740 (Abnormality of the gastrointestinal system), HP:0001507 (Failure to thrive) (for severe systemic disease) - Prenatal ultrasound-detected masses: HP:0000918 (Abnormal prenatal ultrasound)

3.4 Quality-of-life impact

QoL impact is driven by number/location of lesions and organ compromise. A targeted-therapy case report emphasizes that sunitinib-based therapy produced response “without toxicities or limitations to daily life activities” in a refractory case. (mudry2017casereportrapid pages 1-2)


4. Genetic / Molecular Information

4.1 Causal genes

  • PDGFRB (major): Germline AD familial IM and somatic/mosaic IM. (martignetti2013mutationsinpdgfrb pages 1-3, hettmer2021genetictestingand pages 1-3, dachy2019associationofpdgfrb pages 1-2)
  • NOTCH3 (rare): identified in a family and functionally characterized as ligand-independent gain-of-function with downstream PDGFRB upregulation. (martignetti2013mutationsinpdgfrb pages 1-3, wu2021theinfantilemyofibromatosis pages 1-1)

4.2 Pathogenic variant classes and examples

PDGFRB gain-of-function variants cluster in key regulatory regions: - Juxtamembrane domain hotspot: p.Arg561Cys (R561C) and nearby residues. (hettmer2021genetictestingand pages 1-3, lee2013mutationsinpdgfrb pages 1-3) - Kinase domain hotspot: p.Asn666Lys (N666K); also p.Pro660Thr (P660T). (lee2013mutationsinpdgfrb pages 1-3, koo2020adistinctivegenomic pages 1-2) - Prenatal DFIM example: PDGFRB c.1681C>T (p.R561C) inherited from an asymptomatic father; authors highlight incomplete penetrance/variable expressivity and severe visceral disease leading to fetal demise in their case. (lu2023prenatalgeneticdiagnosis pages 1-2, lu2023prenatalgeneticdiagnosis pages 5-6)

NOTCH3: - Familial NOTCH3 c.4556T>C (p.Leu1519Pro; L1519P) was identified in a PDGFRB-negative family. (lee2013mutationsinpdgfrb pages 1-3, martignetti2013mutationsinpdgfrb pages 1-3)

Recent 2024 expansion of PDGFRB genotype/phenotype: Corneal infantile myofibromatosis was associated with novel activating PDGFRB variants including c.1766A>G (p.Tyr589Cys) and c.1949C>G (p.Ser650Trp / S650W). (howaldt2024cornealinfantilemyofibromatosis pages 4-6, howaldt2024cornealinfantilemyofibromatosis pages 8-9)

4.3 Somatic vs germline architecture

  • Familial IM typically follows autosomal-dominant inheritance linked to PDGFRB germline variants. (hettmer2021genetictestingand pages 1-3)
  • Somatic PDGFRB variants occur in solitary and multicentric lesions; multicentric lesions may share post-zygotic variants or show “second-hit” patterns. (dachy2019associationofpdgfrb pages 3-4, hettmer2021genetictestingand pages 6-7)

4.4 Molecular mechanisms (pathophysiology)

PDGFRB activation as upstream driver: PDGFRB gain-of-function variants produce ligand-independent receptor activation and downstream growth signaling; in a 69-patient pediatric-focused cohort, functional characterization supported constitutive activation across identified variants. (dachy2019associationofpdgfrb pages 1-2, dachy2019associationofpdgfrb pages 3-4)

NOTCH3–PDGFRB axis: Wu et al. functionally showed NOTCH3L1519P is ligand-independent gain-of-function and “upregulates PDGFRB expression in fibroblasts,” concluding they “define a NOTCH3–PDGFRB axis in IMF.” (wu2021theinfantilemyofibromatosis pages 1-1)

4.5 Suggested GO (biological process) and CL (cell type) terms

(ontology suggestions) - GO processes: GO:0007173 (epidermal growth factor receptor signaling pathway) (as an RTK analog), GO:0007169 (transmembrane receptor protein tyrosine kinase signaling pathway), GO:0008283 (cell population proliferation), GO:0001525 (angiogenesis) - CL (cell types): CL:0000186 (myofibroblast); pericytic lineage supported by genomic/IHC profiling. (koo2020adistinctivegenomic pages 1-2)


5. Environmental Information

No validated environmental, lifestyle, or infectious triggers were identified in the retrieved evidence base.


6. Mechanism / Pathophysiology (causal chains)

6.1 PDGFRB-driven disease

Causal chain (simplified): 1) Activating PDGFRB variant (germline, somatic, or mosaic) → 2) Constitutive PDGFRB kinase signaling → 3) Increased proliferation/survival of perivascular/myofibroblastic progenitors → 4) Myofibromas in skin/soft tissue/bone ± viscera → 5) Mass effect/organ dysfunction in severe disseminated disease. (dachy2019associationofpdgfrb pages 1-2, mashiah2014infantilemyofibromatosisa pages 2-4)

Downstream pathways referenced in the clinical genetics literature include RAS/RAF/ERK and PI3K/AKT/mTOR signaling. (pudig2025infantilemyofibromatosisand pages 1-2)

6.2 NOTCH3-driven disease (rare)

Causal chain (simplified): 1) NOTCH3 L1519P → 2) ligand-independent NOTCH activation with altered trafficking/processing → 3) PDGFRB upregulation (epistatic axis) → 4) enhanced PDGF responsiveness and proliferation signatures → 5) IM lesions. (wu2021theinfantilemyofibromatosis pages 7-8, wu2021theinfantilemyofibromatosis pages 8-9)


7. Anatomical Structures Affected

7.1 Organ/system involvement

  • Integumentary/soft tissue: skin/subcutis, skeletal muscle (common). (lu2023prenatalgeneticdiagnosis pages 1-2, mashiah2014infantilemyofibromatosisa pages 4-6)
  • Skeletal system: bone involvement (~50% in multicentric series; lytic lesions/erosions). (mashiah2014infantilemyofibromatosisa pages 4-6, mashiah2014infantilemyofibromatosisa pages 1-2)
  • Viscera (severe/generalized): lung, liver, heart, spleen, bowel/intestine, kidney (reported). (lu2023prenatalgeneticdiagnosis pages 3-5, mashiah2014infantilemyofibromatosisa pages 2-4)
  • Ocular surface (recently expanded phenotype): corneal/conjunctival “pterygium-like” lesions with recurrence post-surgery in PDGFRB-variant families. (howaldt2024cornealinfantilemyofibromatosis pages 3-4, howaldt2024cornealinfantilemyofibromatosis pages 6-8)

7.2 Suggested UBERON terms (examples)

  • Skin: UBERON:0002097
  • Subcutaneous tissue: UBERON:0002072
  • Skeletal muscle: UBERON:0001134
  • Bone: UBERON:0002481
  • Heart: UBERON:0000948
  • Liver: UBERON:0002107
  • Lung: UBERON:0002048
  • Kidney: UBERON:0002113
  • Cornea: UBERON:0000964

8. Temporal Development

8.1 Onset and course

  • Most cases present in infancy (≤2 years), but recurrence in later life can occur in familial disease. (murray2017thespectrumof pages 1-7)
  • Multicentric lesions often regress within the first few years; severe disseminated disease can be rapidly lethal, including prenatal/neonatal deaths. (mashiah2014infantilemyofibromatosisa pages 2-4, lu2023prenatalgeneticdiagnosis pages 3-5)

8.2 Remission patterns

Spontaneous regression is characteristic, especially in multicentric non-visceral disease. (mashiah2014infantilemyofibromatosisa pages 2-4, murray2017thespectrumof pages 1-7)


9. Inheritance and Population

9.1 Epidemiology

  • Incidence: A commonly cited estimate is ~1 in 150,000. (lu2023prenatalgeneticdiagnosis pages 1-2, hettmer2021genetictestingand pages 1-3)
  • Sex ratio: Male predominance has been reported (e.g., M:F 1.55:1 overall in a 28-case series; higher in multicentric). (mashiah2014infantilemyofibromatosisa pages 4-6)

9.2 Inheritance

  • Autosomal dominant inheritance is well supported for familial PDGFRB-driven IM; incomplete penetrance and variable expressivity are documented. (lu2023prenatalgeneticdiagnosis pages 3-5, hettmer2021genetictestingand pages 1-3)
  • In prenatal PDGFRB-variant disease, a 50% recurrence risk was noted for an inherited heterozygous pathogenic PDGFRB variant. (lu2023prenatalgeneticdiagnosis pages 2-3)

10. Diagnostics

10.1 Clinical evaluation and imaging

  • Prenatal ultrasound characteristics: lesions described as hypoechogenic/moderately echogenic, relatively homogeneous/with slight heterogeneity, clearly demarcated, and with absent/poor vascularity; detection typically in third trimester. (lu2023prenatalgeneticdiagnosis pages 2-3, lu2023prenatalgeneticdiagnosis pages 3-5)

  • Postnatal staging/work-up (series recommendations): After histopathologic confirmation, suggested evaluation includes clinical exam, ECG, chest/skeletal radiographs, and thoracoabdominal ultrasound/CT. (mashiah2014infantilemyofibromatosisa pages 6-7)

  • Expert consensus (SIOPE): recommends screening for multicentric and visceral disease with whole-body MRI and/or PET and targeted cardiac/abdominal imaging. (hettmer2021genetictestingand pages 5-6)

10.2 Pathology and immunohistochemistry

Characteristic histology includes a biphasic lesion with peripheral spindle-cell myofibroblastic proliferation and central hemangiopericytoma-like vascular areas (“staghorn” vessels). (mashiah2014infantilemyofibromatosisa pages 2-4)

Immunophenotype in series/case contexts: - Strong smooth muscle actin (SMA) positivity is commonly reported. (mashiah2014infantilemyofibromatosisa pages 2-4, lu2023prenatalgeneticdiagnosis pages 2-3) - In one familial-spectrum report, tumors were actin-positive and desmin-negative. (murray2017thespectrumof pages 1-7) - In corneal PDGFRB-variant lesions: SMA-positive, low Ki-67 (<5%), variable/marginal desmin; negative caldesmon and CD34 in described cases. (howaldt2024cornealinfantilemyofibromatosis pages 1-2, howaldt2024cornealinfantilemyofibromatosis pages 3-4)

10.3 Genetic testing (real-world implementation)

Tumor-first deep sequencing is increasingly used, given high prevalence of PDGFRB gain-of-function variants in pediatric disease and mosaicism/second-hit architectures. - In a 69-patient cohort, deep targeted sequencing identified PDGFRB gain-of-function variants in pediatric cases and supported their diagnostic/prognostic/therapeutic utility. (dachy2019associationofpdgfrb pages 1-2) - SIOPE recommendations emphasize NGS with sufficient depth; most pathogenic PDGFRB variants cluster in exons 12 and 14, but up to one-third occur elsewhere; for suspected mosaicism, testing multiple lesions is recommended. (hettmer2021genetictestingand pages 6-7)

10.4 Differential diagnosis (high level)

The main diagnostic challenge is morphologic overlap with other pericytic/myofibroblastic lesions (e.g., myopericytoma spectrum). Genomic + NOTCH3 IHC patterns can help in difficult cases. (koo2020adistinctivegenomic pages 1-2, dachy2019associationofpdgfrb pages 4-5)


11. Outcome / Prognosis

11.1 Prognosis by subtype

  • Solitary / multicentric (no viscera): generally good; spontaneous regression common. (lu2023prenatalgeneticdiagnosis pages 1-2, mashiah2014infantilemyofibromatosisa pages 4-6)
  • Disseminated/generalized with visceral involvement: poor prognosis with high mortality.
  • Review-level statements cite high mortality “up to” ~70% in visceral disease. (lee2013mutationsinpdgfrb pages 1-3)
  • In a prenatal review, fetal mortality was 29% (5/17) overall and 67% (4/6) in disseminated DFIM; 3/17 (18%) neonates died within one month due to severe visceral involvement. (lu2023prenatalgeneticdiagnosis pages 3-5)

11.2 Prognostic factors (supported)

  • Visceral involvement is the dominant adverse prognostic factor. (murray2017thespectrumof pages 1-7, lu2023prenatalgeneticdiagnosis pages 3-5)
  • Genotype may be prognostic/therapeutic (e.g., PDGFRB mutations commonly imatinib-sensitive, but specific alleles can be resistant). (dachy2019associationofpdgfrb pages 4-5, hettmer2021genetictestingand pages 3-5)

12. Treatment

12.1 Standard management in current practice

  • Observation is often appropriate for uncomplicated lesions expected to regress (especially multicentric non-visceral). (lu2023prenatalgeneticdiagnosis pages 1-2, mashiah2014infantilemyofibromatosisa pages 2-4)
  • Surgical excision is commonly used for solitary lesions or lesions causing local complications. (mashiah2014infantilemyofibromatosisa pages 2-4, lu2023prenatalgeneticdiagnosis pages 3-5)
  • Chemotherapy is used in severe/refractory disease; regimens in case literature include vinblastine/methotrexate metronomic therapy and multi-agent chemotherapy (e.g., VAC variants). (mudry2017casereportrapid pages 1-2)

12.2 Targeted therapy (major recent development)

PDGFRB as an actionable target: - Large cohort functional testing supports broad PDGFRB mutant sensitivity: “all but one” PDGFRB mutant were imatinib-sensitive at clinically relevant concentrations in vitro, with a resistant activation-loop allele noted in that cohort. (dachy2019associationofpdgfrb pages 1-2, dachy2019associationofpdgfrb pages 4-5)

Clinical targeted-therapy implementation (case evidence): - A refractory generalized IM case with germline PDGFRB mutation had “unexpected and durable response” to sunitinib plus low-dose vinblastine after chemotherapy toxicity/limited response. (mudry2017casereportrapid pages 1-2)

2024 ocular/corneal targeted-therapy concept: - Novel activating PDGFRB variants causing corneal IM were blocked by imatinib (1 μM) in vitro, motivating targeted therapy concepts including topical imatinib (investigational). (howaldt2024cornealinfantilemyofibromatosis pages 6-8, howaldt2024cornealinfantilemyofibromatosis pages 8-9)

12.3 MAXO term suggestions

  • Observation/active surveillance: MAXO:0000127 (clinical monitoring)
  • Surgical excision: MAXO:0000467 (surgical excision)
  • Chemotherapy: MAXO:0000647 (chemotherapy)
  • Tyrosine kinase inhibitor therapy (imatinib/sunitinib): MAXO:0000747 (protein kinase inhibitor therapy)
  • Prenatal diagnosis/genetic testing: MAXO:0000741 (genetic testing)

12.4 Clinical trials

A clinicaltrials.gov search during this run did not retrieve an IM-specific interventional trial; retrieved trials were broader pediatric solid tumor studies (e.g., selpercatinib trial NCT03899792) and are not disease-targeted for IM. (tool output not cited; no IM-specific NCT evidence in retrieved text set)


13. Prevention

No primary prevention exists for a genetic tumor predisposition of this type. Secondary/tertiary prevention is primarily genetic counseling + early surveillance in at-risk infants. - Genetic counseling and prenatal approaches: authors recommend genetic counseling and consideration of prenatal or preimplantation genetic diagnosis in families with pathogenic PDGFRB variants. (lu2023prenatalgeneticdiagnosis pages 2-3)


14. Other Species / Natural Disease

No veterinary or cross-species natural disease evidence was identified in the retrieved sources.


15. Model Organisms / Model Systems

While whole-animal models were not identified in the retrieved evidence, mechanistic and functional work uses cell-based systems: - NOTCH3 L1519P functional characterization in fibroblasts and signaling assays defining NOTCH3→PDGFRB axis. (wu2021theinfantilemyofibromatosis pages 1-1, wu2021theinfantilemyofibromatosis pages 7-8) - PDGFRB variant functional assays in transfected cells, including imatinib inhibition experiments for corneal IM variants. (howaldt2024cornealinfantilemyofibromatosis pages 2-3, howaldt2024cornealinfantilemyofibromatosis pages 6-8)


Recent developments & “expert opinions” (authoritative analyses)

2023–2024 highlights (prioritized)

1) Prenatal genetic diagnosis and outcome quantification (2023): Lü et al. emphasize that “Prenatal IM diagnosis is difficult. Initial detection is always based on ultrasound. DFIM has high mortality” and report a severe fetal case with PDGFRB p.R561C. (lu2023prenatalgeneticdiagnosis pages 1-2) 2) Novel PDGFRB variants expanding the phenotype to corneal disease (2024): Howaldt et al. identify novel activating PDGFRB variants in corneal IM and show imatinib blockade in vitro, proposing targeted therapeutic avenues to prevent recurrences. (howaldt2024cornealinfantilemyofibromatosis pages 6-8, howaldt2024cornealinfantilemyofibromatosis pages 1-2)

Consensus/working-group recommendations

The SIOPE Host Genome Working Group report frames PDGFRB testing and surveillance as an emerging standard because mutant receptors are typically imatinib-sensitive and because early-life visceral disease can be life-threatening. (hettmer2021genetictestingand pages 1-3, hettmer2021genetictestingand pages 6-7)


Visual evidence (prenatal cases)

Table 1 from Lü et al. (2023) summarizes prenatally detected IM cases, including gestational age at detection, clinical subtype, outcomes, and treatments (including chemotherapy and imatinib in specific cases). (lu2023prenatalgeneticdiagnosis media ef3ffef0)


Genetics and therapy summary table

Gene Variant examples / hotspots Inheritance / origin Mechanistic implication Therapeutic implication / evidence Key quantitative findings Key studies
PDGFRB R561C (juxtamembrane hotspot, exon 12) Germline autosomal dominant familial IM; can require second cis-acting hit; also reported as likely germline/de novo in sporadic pediatric disease Disrupts juxtamembrane autoinhibition, causing ligand-independent kinase activation; weaker germline activation may need second hit for full activation Mutant receptors are typically imatinib-sensitive; PDGFR inhibitors also include sunitinib; targeted therapy supported by clinical case responses and in vitro sensitivity (lee2013mutationsinpdgfrb pages 1-3, hettmer2021genetictestingand pages 1-3, mudry2017casereportrapid pages 1-2, dachy2019associationofpdgfrb pages 1-2) In pediatric series, PDGFRB GOF mutations in 13/19 myofibromatosis cases (68%); 3/25 (12%) PDGFRB-mutant pediatric cases were likely germline, all involving R561 (dachy2019associationofpdgfrb pages 1-2, dachy2019associationofpdgfrb pages 3-4) Martignetti 2013 Am J Hum Genet; Dachy 2019 JAMA Dermatol; Hettmer 2021 Familial Cancer
PDGFRB N666K (kinase domain hotspot) Often somatic second hit; also reported in sporadic lesions/mosaic contexts Kinase-domain activating mutation favoring active receptor conformation; can cooperate with R561C in a second-hit model Generally imatinib-sensitive in functional studies; PDGFRB-mutant lesions may respond to TKIs, though resistance depends on allele Seen among recurrent hotspots in IM/myofibroma; second-hit combinations support multicentric disease biology (lee2013mutationsinpdgfrb pages 1-3, lepelletier2017heterozygouspdgfrbmutation pages 1-2, dachy2019associationofpdgfrb pages 3-4) Lee 2013 Clinical Genetics; Lepelletier 2017 Acta Derm Venereol; Dachy 2019 JAMA Dermatol
PDGFRB P560L (exon 12) Germline autosomal dominant familial IM Juxtamembrane-domain activation analogous to other exon 12 PDGFRB variants Likely TKI-sensitive by class effect; cited among actionable PDGFRB familial variants Novel segregating variant in a 3-generation AD IM family (lepelletier2017heterozygouspdgfrbmutation pages 1-2, hettmer2021genetictestingand pages 1-3) Lepelletier 2017 Acta Derm Venereol; Hettmer 2021 Familial Cancer
PDGFRB P660T (exon 14) Germline AD in single reported family Kinase-domain mutation predicted to stabilize active conformation / constitutive signaling Supports genotype-guided TKI consideration; included among IM-causing activating alleles Rare compared with exon 12 hotspots (lee2013mutationsinpdgfrb pages 1-3, hettmer2021genetictestingand pages 1-3) Lee 2013 Clinical Genetics; Hettmer 2021 Familial Cancer
PDGFRB Y589C and S650W (novel corneal IM variants) Familial autosomal dominant transmission in two unrelated families Constitutive ligand-independent activation in vitro; corneal myofibromatosis / pterygium-like phenotype Imatinib at 1 μM completely blocked mutant activation in vitro; authors propose topical/systemic imatinib as targeted strategy for recurrent corneal disease (howaldt2024cornealinfantilemyofibromatosis pages 1-2, howaldt2024cornealinfantilemyofibromatosis pages 8-9, howaldt2024cornealinfantilemyofibromatosis pages 4-6, howaldt2024cornealinfantilemyofibromatosis pages 6-8) 4 affected individuals from 2 families; all had recurrence after corneal surgery (howaldt2024cornealinfantilemyofibromatosis pages 1-2, howaldt2024cornealinfantilemyofibromatosis pages 3-4) Howaldt 2024 Ophthalmology Science
PDGFRB Broad pediatric mutation spectrum (including juxtamembrane duplication and multiple activating alleles) Somatic, germline/de novo, and mosaic forms all reported All identified pediatric PDGFRB variants in cohort caused ligand-independent receptor activation All but one tested mutants were imatinib-sensitive at clinically relevant concentrations; one activation-loop allele (D850V) was resistant (dachy2019associationofpdgfrb pages 1-2, dachy2019associationofpdgfrb pages 4-5, hettmer2021genetictestingand pages 3-5) 25 PDGFRB-mutant children among 69 patients; 0 adults had PDGFRB mutations in that series (dachy2019associationofpdgfrb pages 1-2) Dachy 2019 JAMA Dermatol; Hettmer 2021 Familial Cancer
PDGFRB c.1681C>A germline variant in refractory generalized IM Germline familial case; sister shared genotype/histology Elevated intratumoral PDGFRβ phosphokinase activity Sunitinib + low-dose vinblastine produced rapid, durable responses after chemotherapy failure/toxicity (mudry2017casereportrapid pages 1-2) Real-world response in 2 siblings with severe disease; quality-of-life preserved during targeted therapy (mudry2017casereportrapid pages 1-2) Mudry 2017 BMC Cancer
NOTCH3 L1519P Germline autosomal dominant in one familial kindred lacking PDGFRB mutation Hyperactivated ligand-independent Notch signaling; mutant receptor mislocalized to ER/lysosomal pathway; upregulates PDGFRB, defining a NOTCH3→PDGFRB axis (wu2021theinfantilemyofibromatosis pages 7-8, wu2021theinfantilemyofibromatosis pages 1-1, wu2021theinfantilemyofibromatosis pages 1-3, wu2021theinfantilemyofibromatosis pages 8-9) Suggests potential benefit from targeting downstream PDGFRB and/or Notch processing/signaling; ligand-blocking strategies may be less effective because activation is ligand-independent Rare compared with PDGFRB-driven IM; found in 1/10 sequenced myofibroma cases in one genomic/IHC series (koo2020adistinctivegenomic pages 1-2) Wu 2021 Dis Model Mech; Koo 2020 Int J Surg Pathol
PDGFRB / NOTCH3 pathway PDGFRB hotspots plus NOTCH3 L1519P Familial AD, somatic, and mosaic architectures all contribute to disease heterogeneity Convergent activation of pericytic / myofibroblastic growth signaling; NOTCH3 activation can increase PDGFRB expression, while PDGFRB GOF directly activates downstream signaling Supports molecular testing-first management: deep NGS of tumor and blood, hotspot focus on exons 12 and 14, and genotype-guided TKI consideration; multiple lesions may need testing when mosaicism is suspected (hettmer2021genetictestingand pages 6-7, hettmer2021genetictestingand pages 1-3) SIOPE report notes most variants cluster in exons 12 and 14, but up to one-third occur elsewhere; testing of multiple lesions recommended if blood is negative and mosaicism suspected (hettmer2021genetictestingand pages 6-7) Hettmer 2021 Familial Cancer; Koo 2020 Int J Surg Pathol; Wu 2021 Dis Model Mech

Table: This table summarizes the main disease genes, recurrent variants, inheritance patterns, pathogenic mechanisms, and therapeutic implications in infantile myofibromatosis. It highlights the predominance of PDGFRB-driven disease, the rarer NOTCH3-driven subtype, and the evidence supporting genotype-guided use of tyrosine kinase inhibitors such as imatinib and sunitinib.


Key statistics (quick reference)

  • Incidence often cited: ~1:150,000 (lu2023prenatalgeneticdiagnosis pages 1-2, hettmer2021genetictestingand pages 1-3)
  • Multicentric regression in a case series: 7/11 regressed spontaneously within first 2 years (mashiah2014infantilemyofibromatosisa pages 2-4)
  • Prenatal series outcomes: 71% recovered, fetal mortality 29% (5/17) overall; 67% (4/6) in DFIM; neonatal death within one month 18% (3/17) (lu2023prenatalgeneticdiagnosis pages 3-5)
  • PDGFRB mutation frequency in pediatric cohort: 13/19 (68%) in myofibromatosis cases; likely germline 3/25 (12%) among PDGFRB-mutant pediatric cases (dachy2019associationofpdgfrb pages 1-2, dachy2019associationofpdgfrb pages 3-4)

Primary literature used (URLs and publication dates)

  • Lü Y et al. Aug 2023. BMC Medical Genomics. “Prenatal genetic diagnosis of disseminated infantile myofibromatosis.” https://doi.org/10.1186/s12920-023-01612-w (lu2023prenatalgeneticdiagnosis pages 1-2)
  • Howaldt A et al. May 2024. Ophthalmology Science. “Corneal Infantile Myofibromatosis … imatinib-responsive variants in PDGFRB.” https://doi.org/10.1016/j.xops.2023.100444 (howaldt2024cornealinfantilemyofibromatosis pages 1-2)
  • Dachy G et al. Aug 2019. JAMA Dermatology. “Association of PDGFRB Mutations With Pediatric Myofibroma and Myofibromatosis.” https://doi.org/10.1001/jamadermatol.2019.0114 (dachy2019associationofpdgfrb pages 1-2)
  • Hettmer S et al. Sep 2021. Familial Cancer. “Genetic testing and surveillance in infantile myofibromatosis … SIOPE Host Genome Working Group.” https://doi.org/10.1007/s10689-020-00204-2 (hettmer2021genetictestingand pages 1-3)
  • Wu D et al. Feb 2021. Disease Models & Mechanisms. “NOTCH3 L1519P … increased PDGFRB expression.” https://doi.org/10.1242/dmm.046300 (wu2021theinfantilemyofibromatosis pages 1-1)
  • Mashiah J et al. Aug 2014. Journal of the American Academy of Dermatology. “Infantile myofibromatosis: a series of 28 cases.” https://doi.org/10.1016/j.jaad.2014.03.035 (mashiah2014infantilemyofibromatosisa pages 2-4)
  • Mudry P et al. Feb 2017. BMC Cancer. “Rapid and durable response to PDGFR targeted therapy …” https://doi.org/10.1186/s12885-017-3115-x (mudry2017casereportrapid pages 1-2)
  • Murray N et al. Jul 2017. European Journal of Medical Genetics. “Spectrum … non-penetrance and adult recurrence.” https://doi.org/10.1016/j.ejmg.2017.02.005 (murray2017thespectrumof pages 1-7)
  • Martignetti JA et al. Jun 2013. American Journal of Human Genetics. “Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.” https://doi.org/10.1016/j.ajhg.2013.04.024 (martignetti2013mutationsinpdgfrb pages 1-3)

References

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