Penttinen_Premature_Aging_Syndrome

Genetic MONDO:0011150 Pathograph 8 Show in embeddings browser Premature Aging Syndrome Connective Tissue Disorder

Penttinen premature aging syndrome is an autosomal dominant disorder caused by heterozygous gain-of-function mutations in PDGFRB, most commonly the c.1994T>A p.Val665Ala variant. Affected individuals present shortly after birth with a prematurely aged appearance, distinctive facial features, cutaneous atrophy with hypertrophic scar-like or keloid-like lesions, lipodystrophy, brachydactyly with acro-osteolysis, and flexion contractures. Cognitive impairment is typically absent. The condition is part of a spectrum of PDGFRB gain-of-function disorders that includes infantile myofibromatosis and Kosaki overgrowth syndrome. Tyrosine kinase inhibitors including imatinib and dasatinib have shown clinical efficacy.

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1
Inheritance
3
Pathophys.
4
Phenotypes
8
Pathograph
1
Genes
2
Medical Actions
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant inheritance
⚙

Pathophysiology

3
Constitutive PDGFRB Activation
The Val665Ala mutation in the kinase domain of PDGFRB leads to constitutive ligand-independent receptor activation, resulting in dysregulated signaling through downstream pathways including AKT and STAT.
PDGFRB hgnc:8804 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PDGFRB (hgnc:8804). hgnc:8804 is a gene from the HUGO Gene Nomenclature Committee.
platelet-derived growth factor beta-receptor activity GO:0005019 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves platelet-derived growth factor beta-receptor activity (GO:0005019). GO:0005019 is a molecular function from the Gene Ontology.
Downstream
Connective Tissue Degeneration Constitutive signaling drives premature aging of connective tissues.
Osteopenia Altered skeletal stem cell fate leads to osteopenia.
Brachydactyly with Acro-osteolysis Constitutive PDGFRB signaling produces the distal skeletal phenotype with generalized brachydactyly and acro-osteolysis.
Show evidence (1 reference)
PMID:34894066 SUPPORT In Vitro
"in vitro molecular studies with imatinib and dasatinib showed that the Val665Ala variant had greater sensitivity to dasatinib than imatinib."
Molecular studies confirm constitutive activation of the Val665Ala variant.
Connective Tissue Degeneration
Constitutive PDGFRB signaling causes premature aging of connective tissues, resulting in cutaneous atrophy and keloid-like lesions.
Downstream
Prematurely Aged Appearance Connective tissue degeneration clinically manifests as the characteristic premature-aged appearance.
Cutaneous Atrophy The same connective tissue degeneration produces cutaneous atrophy and hypertrophic scar-like lesions.
Limitation of Joint Mobility Fibrotic/connective-tissue contractures restrict joint mobility and limit daily activities.
Show evidence (1 reference)
PMID:34894066 SUPPORT Human Clinical
"A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
Clinical description of connective tissue degeneration phenotype.
Osteopenia
PDGFRB gain-of-function mutations cause osteopenia associated with intrinsic changes in skeletal stem cells, promoting chondrogenesis over osteogenesis.
Show evidence (1 reference)
PMID:34738614 SUPPORT Model Organism
"Mice with PDGFRβD849V exhibit osteopenia."
Mouse model demonstrates osteopenic skeletal phenotype from PDGFRB gain-of-function.
⬡

Pathograph

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

Phenotypes

4
Integument 2
Prematurely Aged Appearance VERY_FREQUENT HP:0007495 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prematurely aged appearance (HP:0007495). HP:0007495 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34894066 SUPPORT Human Clinical
"A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
Prematurely aged appearance is the hallmark feature.
Cutaneous Atrophy VERY_FREQUENT Dermal atrophy HP:0004334 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous atrophy, annotated with Dermal atrophy (HP:0004334). HP:0004334 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34894066 SUPPORT Human Clinical
"A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
Cutaneous atrophy is a hallmark dermatologic feature of Penttinen syndrome.
Limbs 1
Brachydactyly with Acro-osteolysis VERY_FREQUENT 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:34894066 SUPPORT Human Clinical
"Generalized brachydactyly with acro-osteolysis was observed."
Brachydactyly with acro-osteolysis is a characteristic finding.
Musculoskeletal 1
Limitation of Joint Mobility FREQUENT HP:0001376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limitation of joint mobility (HP:0001376). HP:0001376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34894066 SUPPORT Human Clinical
"Flexion contractures limited his daily activities."
Flexion contractures causing joint limitation are a prominent feature.
🧬

Genetic Associations

1
PDGFRB Gain-of-Function Mutations (Causative)
Gene: PDGFRB hgnc:8804 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDGFRB (hgnc:8804). hgnc:8804 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:34894066 SUPPORT Human Clinical
"Penttinen type of premature aging syndrome is an autosomal-dominant disorder that can be caused by the c.1994T>A pVal665Ala pathogenic variant in platelet-derived growth factor receptor-B (PDGFRB)."
Identifies the causative variant in PDGFRB.
PMID:33449152 SUPPORT Other
"gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome."
Review confirms PDGFRB gain-of-function mutations cause Penttinen syndrome.
💊

Medical Actions

2
Imatinib
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
First-line tyrosine kinase inhibitor used in Penttinen syndrome, targeting constitutively activated PDGFRB with partial clinical response.
Show evidence (1 reference)
PMID:34894066 SUPPORT Human Clinical
"Imatinib, a receptor tyrosine kinase (RTK) inhibitor, has been used in Penttinen syndrome (PS) patients with good results."
Clinical evidence of imatinib efficacy.
Dasatinib
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Second-generation tyrosine kinase inhibitor with greater potency against the Val665Ala variant than imatinib. Used when imatinib response is incomplete.
Show evidence (1 reference)
PMID:34894066 SUPPORT Human Clinical
"Improved clinical response was observed after treatment with dasatinib."
Demonstrates clinical improvement with dasatinib after incomplete imatinib response.
📊

Prevalence

1
Global
Cases In Literature Rare
Extremely rare; fewer than 15 cases reported in the literature.
{ }

Source YAML

click to show 
name: Penttinen_Premature_Aging_Syndrome
creation_date: '2026-04-04T00:00:00Z'
category: Genetic
parents:
- Premature Aging Syndrome
- Connective Tissue Disorder
disease_term:
  preferred_term: premature aging syndrome, Penttinen type
  term:
    id: MONDO:0011150
    label: acroosteolysis-keloid-like lesions-premature aging syndrome
description: >-
  Penttinen premature aging syndrome is an autosomal dominant disorder caused
  by heterozygous gain-of-function mutations in PDGFRB, most commonly the
  c.1994T>A p.Val665Ala variant. Affected individuals present shortly after
  birth with a prematurely aged appearance, distinctive facial features,
  cutaneous atrophy with hypertrophic scar-like or keloid-like lesions,
  lipodystrophy, brachydactyly with acro-osteolysis, and flexion contractures.
  Cognitive impairment is typically absent. The condition is part of a spectrum
  of PDGFRB gain-of-function disorders that includes infantile myofibromatosis
  and Kosaki overgrowth syndrome. Tyrosine kinase inhibitors including imatinib
  and dasatinib have shown clinical efficacy.
prevalence:
- population: Global
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    Extremely rare; fewer than 15 cases reported in the literature.
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: >-
    The recurrent c.1994T>A p.Val665Ala variant in exon 14 of PDGFRB is the most
    common cause of Penttinen syndrome. This variant leads to constitutive activation
    of the receptor tyrosine kinase. The Val665Ala variant shows greater sensitivity
    to dasatinib than imatinib in molecular studies.
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penttinen type of premature aging syndrome is an autosomal-dominant disorder that can be caused by the c.1994T>A pVal665Ala pathogenic variant in platelet-derived growth factor receptor-B (PDGFRB)."
    explanation: Identifies the causative variant in PDGFRB.
  - reference: PMID:33449152
    reference_title: "PDGF receptor mutations in human diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome."
    explanation: Review confirms PDGFRB gain-of-function mutations cause Penttinen syndrome.
phenotypes:
- name: Prematurely Aged Appearance
  category: Dermatologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Prematurely aged appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
    explanation: Prematurely aged appearance is the hallmark feature.
- name: Brachydactyly with Acro-osteolysis
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized brachydactyly with acro-osteolysis was observed."
    explanation: Brachydactyly with acro-osteolysis is a characteristic finding.
- name: Limitation of Joint Mobility
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flexion contractures limited his daily activities."
    explanation: Flexion contractures causing joint limitation are a prominent feature.
- name: Cutaneous Atrophy
  category: Dermatologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cutaneous atrophy
    term:
      id: HP:0004334
      label: Dermal atrophy
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
    explanation: Cutaneous atrophy is a hallmark dermatologic feature of Penttinen syndrome.
pathophysiology:
- name: Constitutive PDGFRB Activation
  description: >-
    The Val665Ala mutation in the kinase domain of PDGFRB leads to constitutive
    ligand-independent receptor activation, resulting in dysregulated signaling
    through downstream pathways including AKT and STAT.
  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
  downstream:
  - target: Connective Tissue Degeneration
    description: Constitutive signaling drives premature aging of connective tissues.
  - target: Osteopenia
    description: Altered skeletal stem cell fate leads to osteopenia.
  - target: Brachydactyly with Acro-osteolysis
    description: >-
      Constitutive PDGFRB signaling produces the distal skeletal phenotype with
      generalized brachydactyly and acro-osteolysis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34894066
      reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Generalized brachydactyly with acro-osteolysis was observed."
      explanation: >-
        The clinical case report documents the brachydactyly and acro-osteolysis
        phenotype downstream of PDGFRB-associated Penttinen syndrome.
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in vitro molecular studies with imatinib and dasatinib showed that the Val665Ala variant had greater sensitivity to dasatinib than imatinib."
    explanation: Molecular studies confirm constitutive activation of the Val665Ala variant.
- name: Connective Tissue Degeneration
  description: >-
    Constitutive PDGFRB signaling causes premature aging of connective tissues,
    resulting in cutaneous atrophy and keloid-like lesions.
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
    explanation: Clinical description of connective tissue degeneration phenotype.
  downstream:
  - target: Prematurely Aged Appearance
    description: >-
      Connective tissue degeneration clinically manifests as the characteristic
      premature-aged appearance.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34894066
      reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
      explanation: The case report identifies premature-aged appearance as an early clinical manifestation.
  - target: Cutaneous Atrophy
    description: >-
      The same connective tissue degeneration produces cutaneous atrophy and
      hypertrophic scar-like lesions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34894066
      reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions."
      explanation: The case report directly documents cutaneous atrophy in Penttinen syndrome.
  - target: Limitation of Joint Mobility
    description: >-
      Fibrotic/connective-tissue contractures restrict joint mobility and limit
      daily activities.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Flexion contractures
    evidence:
    - reference: PMID:34894066
      reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Flexion contractures limited his daily activities."
      explanation: The case report links flexion contractures to functional limitation.
- name: Osteopenia
  description: >-
    PDGFRB gain-of-function mutations cause osteopenia associated with intrinsic
    changes in skeletal stem cells, promoting chondrogenesis over osteogenesis.
  evidence:
  - reference: PMID:34738614
    reference_title: "Skeletal stem cell fate defects caused by Pdgfrb activating mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with PDGFRβD849V exhibit osteopenia."
    explanation: Mouse model demonstrates osteopenic skeletal phenotype from PDGFRB gain-of-function.
treatments:
- name: Imatinib
  description: >-
    First-line tyrosine kinase inhibitor used in Penttinen syndrome, targeting
    constitutively activated PDGFRB with partial clinical response.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imatinib, a receptor tyrosine kinase (RTK) inhibitor, has been used in Penttinen syndrome (PS) patients with good results."
    explanation: Clinical evidence of imatinib efficacy.
- name: Dasatinib
  description: >-
    Second-generation tyrosine kinase inhibitor with greater potency against the
    Val665Ala variant than imatinib. Used when imatinib response is incomplete.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  evidence:
  - reference: PMID:34894066
    reference_title: "Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Improved clinical response was observed after treatment with dasatinib."
    explanation: Demonstrates clinical improvement with dasatinib after incomplete imatinib response.