Ask OpenScientist

Ask a research question about Osteochondritis of Tarsal/Metatarsal Bone. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Pathophys.
5
Phenotypes
7
Pathograph
3
Treatments
1
Deep Research

Pathophysiology

2
Disturbed Navicular Ossification and Circulation
Kohler disease belongs to the pediatric foot osteochondroses, a group of self-limited conditions in which disturbed ossification and reduced local circulation affect developing foot bones. In MONDO:0016086, the affected ossification center is the tarsal navicular.
Chondrocyte link Osteocyte link
Ossification link Cartilage Development link
Tarsal navicular bone link Bone tissue link
Show evidence (2 references)
PMID:23254328 SUPPORT Human Clinical
"Osteochondrosis is a heterogeneous group of self-limiting conditions characterized by disturbance of enchondral ossification caused by a lack of circulation."
This pediatric foot osteochondrosis review supports disturbed endochondral ossification with reduced circulation as the broader disease-process frame.
PMID:31083875 SUPPORT Human Clinical
"Other locations of osteochondrosis include the second metatarsal head (i.e., Freiberg disease), the navicular bone (i.e., Köhler bone disease), the femoral head (i.e., Legg-Calvé-Perthes disease), and the capitellum (i.e., Panner disease)."
This review identifies the navicular bone as the site of Kohler bone disease within the osteochondrosis family.
Navicular Osteonecrosis and Structural Remodeling
The developing tarsal navicular undergoes osteochondrosis or avascular necrosis, producing increased sclerosis, flattening, fragmentation, or rarefaction on imaging. These structural changes explain medial midfoot pain, limping, and transient inability to bear weight.
Osteocyte link
Bone Mineralization link
Tarsal navicular bone link
Show evidence (2 references)
PMID:30685015 SUPPORT Human Clinical
"Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular."
This directly links the pediatric clinical syndrome to tarsal navicular osteochondrosis or avascular necrosis.
PMID:30685015 SUPPORT Human Clinical
"Radiographs show increased sclerosis and sometimes flattening and fragmentation of the navicular."
This directly supports the characteristic structural radiographic changes.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Osteochondritis of Tarsal/Metatarsal Bone 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

5
Nervous System 1
Limping Gait and Difficulty Bearing Weight Gait disturbance (HP:0001288)
Show evidence (3 references)
PMID:28801039 SUPPORT Human Clinical
"It usually presents as sudden and unexplained foot pain and limping."
This directly supports limping as a usual presentation.
PMID:25783595 SUPPORT Human Clinical
"intermittent or continuous limping may be the only clinical manifestation"
This supports limping as a prominent and sometimes isolated clinical sign.
PMID:28801039 SUPPORT Human Clinical
"foot pain and inability to bear weight for two days after overactivity and acute foot injury"
This case report documents inability to bear weight at presentation.
Other 4
Medial Midfoot Pain Foot pain (HP:0025238)
Show evidence (2 references)
PMID:30685015 SUPPORT Human Clinical
"Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular."
This review identifies pain in the medial midfoot as a core clinical manifestation.
PMID:25783595 SUPPORT Human Clinical
"Typically the child reports pain with mechanical characteristics in the medial region of the foot"
This case-based clinical report supports medial foot pain as a typical symptom.
Medial Midfoot Swelling Localized soft-tissue swelling on extremity (HP:6000840)
Show evidence (1 reference)
PMID:30685015 SUPPORT Human Clinical
"Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular."
This definition identifies swelling of the medial midfoot as a core manifestation alongside pain.
Navicular Avascular Necrosis Avascular necrosis (HP:0010885)
Show evidence (2 references)
PMID:28801039 SUPPORT Human Clinical
"The patient was eventually diagnosed with Kohler's disease (avascular necrosis of the navicular bone)."
This explicitly equates Kohler disease with avascular necrosis of the navicular bone.
PMID:30685015 SUPPORT Human Clinical
"associated osteochondrosis or avascular necrosis of the tarsal navicular"
This confirms the disease process and anatomic site.
Navicular Sclerosis, Flattening, and Fragmentation Abnormality of the tarsal bones (HP:0001850)
Show evidence (2 references)
PMID:30685015 SUPPORT Human Clinical
"Radiographs show increased sclerosis and sometimes flattening and fragmentation of the navicular."
This directly supports the characteristic radiographic phenotype.
PMID:25783595 SUPPORT Human Clinical
"The radiologic evaluation showed flattening, sclerosis and irregular rarefaction of both navicular bones."
This case report supports flattening, sclerosis, and rarefaction of the navicular bones on imaging.
💊

Treatments

3
Relative Rest and Offloading
Action: supportive care MAXO:0000950
Relative rest, reduction of painful loading, and monitoring are conservative first-line approaches for pediatric osteochondrosis including Kohler disease.
Target Phenotypes: Foot pain
Show evidence (1 reference)
PMID:31083875 SUPPORT Human Clinical
"Osteochondrosis generally resolves with relative rest, but close monitoring is needed to ensure resolution."
This supports relative rest and monitoring as conservative management for osteochondrosis.
Short-Leg Walking Cast Immobilization
Action: orthopedic procedure MAXO:0000477
Short-leg walking cast immobilization can reduce symptom duration in symptomatic children while long-term recovery remains favorable.
Target Phenotypes: Foot pain Painful limping and weight-bearing difficulty
Show evidence (2 references)
PMID:30685015 SUPPORT Human Clinical
"Long-term outcomes for Köhler disease are favorable regardless of the type of treatment, although a short period of immobilization with a short leg walking cast may reduce the duration of symptoms."
This review supports cast immobilization as a symptom-duration-reducing conservative option.
PMID:7273526 SUPPORT Human Clinical
"Whereas patients who were not treated in a short-leg cast had symptoms for an average duration of 15 months, treated patients had symptoms for less than three months."
This clinical series directly reports shorter symptom duration with a short-leg cast.
Navicular Decompression and Micro-Circulation Reconstruction
Action: surgical procedure MAXO:0000004
Surgery is not routine for Kohler disease, but a small refractory pediatric series reported navicular decompression with micro-circulation reconstruction after unsuccessful conservative treatment.
Mechanism Target:
MODULATES Navicular Osteonecrosis and Structural Remodeling — The operation is intended to decompress the navicular and improve local microcirculation in refractory ischemic navicular disease.
Target Phenotypes: Foot pain
Show evidence (2 references)
PMID:38491143 PARTIAL Human Clinical
"From October 2013 to July 2015, 3 children with Kohler's disease underwent navicular decompression and micro-circulation reconstruction surgery in our hospital."
This supports the existence of a refractory-case surgical approach, but the evidence is limited to three children.
PMID:38491143 PARTIAL Human Clinical
"Navicular decompression and micro-circulation reconstruction surgery may quickly improve the ischemic status of navicular bone, alleviate pain symptom and enable patients to resume normal activity as soon as possible."
The abstract itself uses cautious language, so this is treated as partial support for benefit in refractory cases.
🌍

Environmental Factors

1
Mechanical and Vascular Susceptibility
The immediate cause is not established. Reviews of osteochondrosis describe possible contributions from mechanical factors, repetitive trauma, and vascular abnormalities; these remain mechanistic hypotheses rather than confirmed single causes for Kohler disease.
Show evidence (1 reference)
PMID:31083875 PARTIAL Human Clinical
"Multiple possible etiologies have been explored, including genetic causes, hormonal imbalances, mechanical factors, repetitive trauma, and vascular abnormalities."
This supports broad osteochondrosis etiologic hypotheses but does not establish a single Kohler-specific cause, so support is partial.
{ }

Source YAML

click to show
name: Osteochondritis of Tarsal/Metatarsal Bone
creation_date: "2026-05-09T13:22:43Z"
updated_date: "2026-05-09T22:27:56Z"
category: Complex
description: >
  Osteochondritis of tarsal/metatarsal bone, also known as Kohler disease, is a
  pediatric osteochondrosis of the tarsal navicular. The curated MONDO term maps
  to childhood navicular osteochondrosis/avascular necrosis rather than to adult
  Muller-Weiss disease or metatarsal-head Freiberg disease.
disease_term:
  preferred_term: osteochondritis of tarsal/metatarsal bone
  term:
    id: MONDO:0016086
    label: osteochondritis of tarsal/metatarsal bone
parents:
- Osteochondrosis
- Pediatric Foot Disease
synonyms:
- Kohler disease
- Kohler's disease
- Osteochondrosis of the tarsal bone
- Aseptic necrosis of the tarsal bone
prevalence:
- population: Pediatric foot-pain literature
  percentage: Rare; population-level prevalence not established
  notes: >
    Published abstracts characterize Kohler disease as uncommon or rare, but no
    population incidence or prevalence estimate was found in the Falcon report or
    PubMed abstracts used for this entry.
  evidence:
  - reference: PMID:28801039
    reference_title: "Kohler's disease presenting as acute foot injury."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kohler's disease is rare cause of foot pain and limping in the pediatric population."
    explanation: >
      A pediatric emergency case report explicitly characterizes Kohler disease
      as rare in the pediatric foot-pain differential.
progression:
- phase: Childhood Presentation
  age_range: 2 to 10 years
  notes: >
    Typical onset is in early childhood, with a male predominance in published
    pediatric series and reviews.
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at presentation is between 2 and 10 years, with boys more likely to be affected than girls."
    explanation: >
      This review supports early-childhood presentation and male predominance.
- phase: Self-Limited Remodeling
  notes: >
    Symptoms and radiographic abnormalities usually improve over time, with
    short-leg walking cast immobilization shortening morbidity in symptomatic
    children.
  evidence:
  - reference: PMID:7273526
    reference_title: "Köhler's disease of the tarsal navicular."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notwithstanding the decrease in morbidity with the use of a short-leg walking cast, the long-term results suggest that all of our patients eventually had spontaneous reconstitution of the navicular and excellent recovery of function."
    explanation: >
      This classic clinical series supports eventual navicular reconstitution and
      favorable functional recovery.
pathophysiology:
- name: Disturbed Navicular Ossification and Circulation
  description: >
    Kohler disease belongs to the pediatric foot osteochondroses, a group of
    self-limited conditions in which disturbed ossification and reduced local
    circulation affect developing foot bones. In MONDO:0016086, the affected
    ossification center is the tarsal navicular.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: Ossification
    term:
      id: GO:0001503
      label: ossification
  - preferred_term: Cartilage Development
    term:
      id: GO:0051216
      label: cartilage development
  locations:
  - preferred_term: Tarsal navicular bone
    term:
      id: UBERON:0001451
      label: navicular bone of pes
  - preferred_term: Bone tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  evidence:
  - reference: PMID:23254328
    reference_title: "[Osteochondrosis of the pediatric foot]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Osteochondrosis is a heterogeneous group of self-limiting conditions characterized by disturbance of enchondral ossification caused by a lack of circulation."
    explanation: >
      This pediatric foot osteochondrosis review supports disturbed endochondral
      ossification with reduced circulation as the broader disease-process frame.
  - reference: PMID:31083875
    reference_title: "Apophysitis and Osteochondrosis: Common Causes of Pain in Growing Bones."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other locations of osteochondrosis include the second metatarsal head (i.e., Freiberg disease), the navicular bone (i.e., Köhler bone disease), the femoral head (i.e., Legg-Calvé-Perthes disease), and the capitellum (i.e., Panner disease)."
    explanation: >
      This review identifies the navicular bone as the site of Kohler bone disease
      within the osteochondrosis family.
  downstream:
  - target: Navicular Osteonecrosis and Structural Remodeling
    description: >
      Reduced local circulation and altered ossification lead to osteochondrosis
      or avascular necrosis of the tarsal navicular with later radiographic
      remodeling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - vascular insufficiency
    - delayed or disturbed ossification
- name: Navicular Osteonecrosis and Structural Remodeling
  description: >
    The developing tarsal navicular undergoes osteochondrosis or avascular
    necrosis, producing increased sclerosis, flattening, fragmentation, or
    rarefaction on imaging. These structural changes explain medial midfoot pain,
    limping, and transient inability to bear weight.
  cell_types:
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: Bone Mineralization
    term:
      id: GO:0030282
      label: bone mineralization
  locations:
  - preferred_term: Tarsal navicular bone
    term:
      id: UBERON:0001451
      label: navicular bone of pes
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular."
    explanation: >
      This directly links the pediatric clinical syndrome to tarsal navicular
      osteochondrosis or avascular necrosis.
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs show increased sclerosis and sometimes flattening and fragmentation of the navicular."
    explanation: >
      This directly supports the characteristic structural radiographic changes.
phenotypes:
- category: Clinical
  name: Medial Midfoot Pain
  phenotype_term:
    preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  description: >
    Pain localizes to the medial midfoot or foot, reflecting symptomatic navicular
    osteochondrosis.
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular."
    explanation: >
      This review identifies pain in the medial midfoot as a core clinical
      manifestation.
  - reference: PMID:25783595
    reference_title: "Köhler disease: an infrequent or underdiagnosed cause of child's limping?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically the child reports pain with mechanical characteristics in the medial region of the foot"
    explanation: >
      This case-based clinical report supports medial foot pain as a typical
      symptom.
- category: Clinical
  name: Limping Gait and Difficulty Bearing Weight
  phenotype_term:
    preferred_term: Painful limping and weight-bearing difficulty
    term:
      id: HP:0001288
      label: Gait disturbance
  description: >
    Children may limp, sometimes as the only obvious manifestation, and can have
    acute difficulty bearing weight because loading through the painful navicular
    is avoided.
  evidence:
  - reference: PMID:28801039
    reference_title: "Kohler's disease presenting as acute foot injury."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It usually presents as sudden and unexplained foot pain and limping."
    explanation: >
      This directly supports limping as a usual presentation.
  - reference: PMID:25783595
    reference_title: "Köhler disease: an infrequent or underdiagnosed cause of child's limping?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intermittent or continuous limping may be the only clinical manifestation"
    explanation: >
      This supports limping as a prominent and sometimes isolated clinical sign.
  - reference: PMID:28801039
    reference_title: "Kohler's disease presenting as acute foot injury."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "foot pain and inability to bear weight for two days after overactivity and acute foot injury"
    explanation: >
      This case report documents inability to bear weight at presentation.
- category: Clinical
  name: Medial Midfoot Swelling
  phenotype_term:
    preferred_term: Medial midfoot swelling
    term:
      id: HP:6000840
      label: Localized soft-tissue swelling on extremity
  description: >
    Localized swelling over the medial midfoot accompanies the painful navicular
    osteochondrosis presentation.
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular."
    explanation: >
      This definition identifies swelling of the medial midfoot as a core
      manifestation alongside pain.
- category: Clinical
  name: Navicular Avascular Necrosis
  phenotype_term:
    preferred_term: Avascular necrosis of the tarsal navicular
    term:
      id: HP:0010885
      label: Avascular necrosis
  description: >
    The tarsal navicular is the focal bone undergoing osteochondrosis/ischemic
    necrosis.
  evidence:
  - reference: PMID:28801039
    reference_title: "Kohler's disease presenting as acute foot injury."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was eventually diagnosed with Kohler's disease (avascular necrosis of the navicular bone)."
    explanation: >
      This explicitly equates Kohler disease with avascular necrosis of the
      navicular bone.
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated osteochondrosis or avascular necrosis of the tarsal navicular"
    explanation: >
      This confirms the disease process and anatomic site.
- category: Radiographic
  name: Navicular Sclerosis, Flattening, and Fragmentation
  phenotype_term:
    preferred_term: Abnormality of the tarsal navicular
    term:
      id: HP:0001850
      label: Abnormality of the tarsal bones
  description: >
    Plain radiographs may show increased navicular density/sclerosis with
    flattening, fragmentation, or irregular rarefaction.
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs show increased sclerosis and sometimes flattening and fragmentation of the navicular."
    explanation: >
      This directly supports the characteristic radiographic phenotype.
  - reference: PMID:25783595
    reference_title: "Köhler disease: an infrequent or underdiagnosed cause of child's limping?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiologic evaluation showed flattening, sclerosis and irregular rarefaction of both navicular bones."
    explanation: >
      This case report supports flattening, sclerosis, and rarefaction of the
      navicular bones on imaging.
diagnosis:
- name: Plain Radiography
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  description: >
    Plain radiographs support diagnosis by showing navicular sclerosis,
    flattening, fragmentation, or related ossification abnormalities. Clinical
    correlation is needed because asymptomatic navicular ossification variants can
    resemble Kohler osteochondrosis.
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs show increased sclerosis and sometimes flattening and fragmentation of the navicular."
    explanation: >
      This supports radiography as the imaging modality showing characteristic
      diagnostic features.
  - reference: PMID:7273526
    reference_title: "Köhler's disease of the tarsal navicular."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic or true Köhler's disease must be differentiated clinically from asymptomatic roentgenographic changes resembling Köhler's osteochondrosis."
    explanation: >
      This supports the need to interpret radiographs together with symptoms.
- name: Magnetic Resonance Imaging
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >
    MRI is a secondary imaging option when early radiographs are normal or when
    more sensitive detection of early osteochondrosis changes is needed.
  evidence:
  - reference: PMID:31083875
    reference_title: "Apophysitis and Osteochondrosis: Common Causes of Pain in Growing Bones."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiography results may be normal initially; magnetic resonance imaging is more sensitive to early changes."
    explanation: >
      This review supports MRI as a more sensitive secondary imaging modality
      for early osteochondrosis changes.
environmental:
- name: Mechanical and Vascular Susceptibility
  presence: Possible
  description: >
    The immediate cause is not established. Reviews of osteochondrosis describe
    possible contributions from mechanical factors, repetitive trauma, and
    vascular abnormalities; these remain mechanistic hypotheses rather than
    confirmed single causes for Kohler disease.
  evidence:
  - reference: PMID:31083875
    reference_title: "Apophysitis and Osteochondrosis: Common Causes of Pain in Growing Bones."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple possible etiologies have been explored, including genetic causes, hormonal imbalances, mechanical factors, repetitive trauma, and vascular abnormalities."
    explanation: >
      This supports broad osteochondrosis etiologic hypotheses but does not
      establish a single Kohler-specific cause, so support is partial.
treatments:
- name: Relative Rest and Offloading
  description: >
    Relative rest, reduction of painful loading, and monitoring are conservative
    first-line approaches for pediatric osteochondrosis including Kohler disease.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: PMID:31083875
    reference_title: "Apophysitis and Osteochondrosis: Common Causes of Pain in Growing Bones."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Osteochondrosis generally resolves with relative rest, but close monitoring is needed to ensure resolution."
    explanation: >
      This supports relative rest and monitoring as conservative management for
      osteochondrosis.
- name: Short-Leg Walking Cast Immobilization
  description: >
    Short-leg walking cast immobilization can reduce symptom duration in
    symptomatic children while long-term recovery remains favorable.
  treatment_term:
    preferred_term: orthopedic procedure
    term:
      id: MAXO:0000477
      label: orthopedic procedure
  target_phenotypes:
  - preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  - preferred_term: Painful limping and weight-bearing difficulty
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:30685015
    reference_title: "Köhler Disease: Avascular Necrosis in the Child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term outcomes for Köhler disease are favorable regardless of the type of treatment, although a short period of immobilization with a short leg walking cast may reduce the duration of symptoms."
    explanation: >
      This review supports cast immobilization as a symptom-duration-reducing
      conservative option.
  - reference: PMID:7273526
    reference_title: "Köhler's disease of the tarsal navicular."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whereas patients who were not treated in a short-leg cast had symptoms for an average duration of 15 months, treated patients had symptoms for less than three months."
    explanation: >
      This clinical series directly reports shorter symptom duration with a
      short-leg cast.
- name: Navicular Decompression and Micro-Circulation Reconstruction
  description: >
    Surgery is not routine for Kohler disease, but a small refractory pediatric
    series reported navicular decompression with micro-circulation reconstruction
    after unsuccessful conservative treatment.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_mechanisms:
  - target: Navicular Osteonecrosis and Structural Remodeling
    treatment_effect: MODULATES
    description: >
      The operation is intended to decompress the navicular and improve local
      microcirculation in refractory ischemic navicular disease.
  target_phenotypes:
  - preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: PMID:38491143
    reference_title: "Clinical report of microsurgical treatment of Kohler's disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "From October 2013 to July 2015, 3 children with Kohler's disease underwent navicular decompression and micro-circulation reconstruction surgery in our hospital."
    explanation: >
      This supports the existence of a refractory-case surgical approach, but the
      evidence is limited to three children.
  - reference: PMID:38491143
    reference_title: "Clinical report of microsurgical treatment of Kohler's disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Navicular decompression and micro-circulation reconstruction surgery may quickly improve the ischemic status of navicular bone, alleviate pain symptom and enable patients to resume normal activity as soon as possible."
    explanation: >
      The abstract itself uses cautious language, so this is treated as partial
      support for benefit in refractory cases.
review_notes: >
  Falcon deep research completed on 2026-05-09. The report discussed the broader
  umbrella of tarsal/metatarsal osteochondroses, including Freiberg disease and
  adult Muller-Weiss disease, but MONDO:0016086 specifically defines the Kohler
  disease/tarsal navicular phenotype; this YAML is scoped accordingly.
📚

References & Deep Research

Deep Research

1
Falcon
Disease Characteristics Research Template
Edison Scientific Literature 31 citations 2026-05-09T09:37:33.833932

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Osteochondritis of Tarsal/Metatarsal Bone
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on Osteochondritis of Tarsal/Metatarsal Bone covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.


1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive disease characteristics report: Osteochondritis/Osteochondrosis of tarsal/metatarsal bone

Scope and entity mapping (important nosology note)

The umbrella phrase “osteochondritis of tarsal/metatarsal bone” is not a single well-defined disease entity in the retrieved literature; rather, it most consistently maps to a group of osteochondroses/osteonecroses affecting (i) the tarsal navicular in children (Köhler disease), (ii) the metatarsal head (classically the 2nd) in adolescents (Freiberg disease / Freiberg infraction), and (iii) the tarsal navicular in adults (Müller–Weiss disease, spontaneous adult navicular osteonecrosis). (liu2024footpainin pages 8-10, goncalvesdos2024necrosisavasculardel pages 2-4, maruszczak2024lowerlimbosteochondrosis pages 9-10)

Because no ontology/terminology databases (MONDO/Orphanet/MeSH/ICD) were directly queried in the available toolchain for this run, definitive MONDO IDs, MeSH IDs, Orphanet IDs, and ICD-10/ICD-11 codes could not be verified from primary evidence in the retrieved texts. The report therefore focuses on evidence-backed clinical entities and their characteristics.

Entity Primary bone/joint Typical age Sex predominance Key synonyms Key imaging features Notes on etiology/risk factors Key sources with DOI and year
Freiberg disease Usually 2nd metatarsal head / 2nd metatarsophalangeal joint; less often 3rd, 4th metatarsal head Adolescence; often adolescent athletes Female predominance; reported ~5:1 female:male Freiberg infraction; osteochondrosis/avascular necrosis of the metatarsal head Radiographs: widening of MTP joint, then subchondral flattening/collapse, sclerosis, fragmentation; MRI: bone marrow edema and subchondral/cartilage defects; US: flattened/fragmented metatarsal head, irregular bony surface, synovial hyperplasia/effusion Multifactorial; trauma/repetitive microtrauma, mechanical overload, possible vascular insufficiency/watershed supply, mechanical arterial compression; associated systemic disorders reported include hypercoagulability, SLE, diabetes Carmont et al., 2009, DOI: 10.3113/fai-2009-0167; Kim et al., 2024, DOI: 10.7547/22-025; Liu et al., 2024, DOI: 10.14366/usg.24002 (liu2024footpainin pages 8-10, kim2024shorttermoutcomesof pages 1-2, carmont2009currentconceptsreview pages 1-2)
Köhler disease Tarsal navicular Usually children; commonly 4–7 years; also described in children <10 years Male predominance; boys affected about 4 times more often; bilateral in up to 25% Köhler’s disease; navicular osteochondrosis; avascular necrosis of the navicular in childhood Radiographs: wafer-thin navicular, bony collapse, fragmentation, patchy sclerosis/increased radiodensity, flattening and loss of normal trabecular pattern; US: unsmooth/bumpy/fragmented navicular ossification center, possible deformity Self-limited osteochondrosis in skeletally immature children; thought related to delayed/late ossification with increased mechanical compression/loading before complete ossification; trauma and ischemia also implicated Maruszczak et al., 2024, DOI: 10.3390/app142411795; Liu et al., 2024, DOI: 10.14366/usg.24002; Steinborn & Glaser, 2019, DOI: 10.1055/s-0039-1695721 (liu2024footpainin pages 1-2, steinborn2019normalvariationsand pages 1-2, maruszczak2024lowerlimbosteochondrosis pages 9-10)
Müller-Weiss disease Adult tarsal navicular / midfoot Adults, typically 4th–6th decades; many diagnosed in 4th–5th decades Female predominance; about 70% female in reviewed series Müller-Weiss disease; spontaneous osteonecrosis/avascular necrosis of the navicular Radiographs: condensation/sclerosis, fragmentation, dorsolateral fragmentation, deformity; may show osteophytes and paradoxical flatfoot; MRI may mimic osteonecrosis Rare adult navicular osteonecrosis; proposed factors include delayed ossification plus abnormal force distribution, vascular compromise, bone dysplasia/uneven compressive stress, trauma/stress fracture history, childhood physical/nutritional stress; may be unilateral or bilateral Gonçalves-dos Santos et al., 2024, DOI: 10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4, santos2024avascularnecrosisof pages 1-2)

Table: This table maps the umbrella concept of osteochondritis/osteochondrosis affecting tarsal or metatarsal bones to the main clinical entities encountered in practice. It summarizes age/sex patterns, synonymous names, imaging hallmarks, and supported etiologic notes using only the gathered evidence.

1. Disease information

1.1 Definitions (current understanding)

  • Freiberg disease (Freiberg infraction): described as osteochondrosis/avascular necrosis of the (usually) second metatarsal head, presenting at the metatarsophalangeal (MTP) joint. (liu2024footpainin pages 8-10, carmont2009currentconceptsreview pages 1-2)
  • Köhler disease: osteochondrosis/avascular necrosis of the tarsal navicular in children; described as a self-limited osteochondrosis of an ossification center in skeletally immature patients. (liu2024footpainin pages 1-2, tuthill2014imagingoftarsal pages 8-9, maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Müller–Weiss disease: adult navicular avascular necrosis/osteonecrosis characterized by deformation, fragmentation, and sclerosis/condensation of the navicular and associated midfoot pain and deformity patterns. (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4)

1.2 Synonyms / alternate names (examples from the literature)

  • Freiberg disease has multiple historical terms (e.g., “Kohler’s second disease”, “eggshell fracture”, “metatarsal epiphysitis”, “osteochondritis deformans metatarsojuvenilis”). (schade2015surgicalmanagementof pages 1-2, carmont2009currentconceptsreview pages 1-2)
  • Köhler disease is also explicitly called “avascular necrosis of the navicular bone” in a 2024 review. (maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Müller–Weiss is consistently referred to as “avascular necrosis of the navicular” / “spontaneous osteonecrosis of the navicular” in 2024 systematic-review material. (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4, santos2024avascularnecrosisof pages 1-2)

1.3 Evidence source type

The retrieved evidence is mostly aggregated disease-level clinical literature (reviews and systematic reviews) plus a retrospective surgical cohort for Freiberg disease; it is not derived from EHR-scale datasets in the retrieved corpus. (goncalvesdos2024necrosisavasculardel pages 1-2, kim2024shorttermoutcomesof pages 1-2, schade2015surgicalmanagementof pages 1-2)

2. Etiology

2.1 Causal factors and risk factors

Freiberg disease - Etiology is described as multifactorial, with proposed roles for trauma/microtrauma, mechanical arterial compression, possible vascular “watershed” vulnerability, and systemic disorders including hypercoagulability, systemic lupus erythematosus, and diabetes. (liu2024footpainin pages 8-10, carmont2009currentconceptsreview pages 1-2) - Vascular anatomy studies in a systematic review context: one cadaveric study reported 65% of second metatarsals lacked a vascular branch from the first web-space artery; another noted the epiphysis is supplied by small vessels near the joint capsule, hypothesized to be vulnerable to compression. (schade2015surgicalmanagementof pages 1-2)

Köhler disease - 2024 review synthesis suggests the likely driver is increased mechanical compression/loading of the navicular before complete ossification, disrupting blood supply and leading to ischemia/avascular necrosis; trauma is also discussed as a possible contributor. (maruszczak2024lowerlimbosteochondrosis pages 9-10)

Müller–Weiss disease - Proposed etiologies in a 2024 systematic review include: delayed ossification plus abnormal force distribution, bone dysplasia/uneven compressive stress, and vascular compromise, with possible contributors such as intensive childhood physical stress, nutritional/environmental/metabolic factors, and trauma/stress fractures. (goncalvesdos2024necrosisavasculardel pages 1-2)

2.2 Protective factors / GxE

No specific protective genetic variants, environmental protective factors, or formal gene–environment interaction studies were identified in the retrieved evidence set.

3. Phenotypes

Across entities, pain and functional limitation are dominant, with entity-specific location and imaging findings.

Entity Phenotype (plain language) Phenotype type (symptom/sign/imaging) Typical onset/age Frequency (if available) Suggested HPO term(s) (best-effort) Supporting citation (with DOI/year)
Freiberg disease Forefoot chronic pain Symptom Adolescence; often adolescent athletic females not reported HP:0001836 Pain in the metatarsal region; HP:0001767 Foot pain Liu et al., 2024, DOI:10.14366/usg.24002 (liu2024footpainin pages 8-10)
Freiberg disease Swelling around the metatarsophalangeal joint Sign Adolescence not reported HP:0001389 Arthritis; HP:0011463 Swelling of joint Liu et al., 2024, DOI:10.14366/usg.24002 (liu2024footpainin pages 8-10)
Freiberg disease Tenderness over affected metatarsal head Sign Adolescence not reported HP:0033748 Tenderness Liu et al., 2024, DOI:10.14366/usg.24002; Gillespie, 2010, DOI:10.1249/jsr.0b013e3181f19488 (liu2024footpainin pages 8-10, gillespie2010osteochondrosesandapophyseal pages 1-2)
Freiberg disease Restricted metatarsophalangeal joint motion Sign Adolescence not reported HP:0031372 Reduced joint range of motion Liu et al., 2024, DOI:10.14366/usg.24002 (liu2024footpainin pages 8-10)
Freiberg disease Focal pain and tenderness Symptom/sign Adolescent girls not reported HP:0001767 Foot pain; HP:0033748 Tenderness Reginelli et al., 2018, DOI:10.23750/abm.v89i1-s.7009 (steinborn2019normalvariationsand pages 1-2)
Freiberg disease Widening of the MTP joint, followed by metatarsal head collapse and sclerosis on radiographs Imaging Adolescence not reported HP:0001363 Osteonecrosis; HP:0100807 Abnormality of the metatarsal bones Gillespie, 2010, DOI:10.1249/jsr.0b013e3181f19488 (gillespie2010osteochondrosesandapophyseal pages 1-2)
Freiberg disease Flattened/fragmented metatarsal head with rough irregular bony surface on ultrasound Imaging Adolescence not reported HP:0100807 Abnormality of the metatarsal bones; HP:0001363 Osteonecrosis Liu et al., 2024, DOI:10.14366/usg.24002 (liu2024footpainin pages 8-10)
Freiberg disease Bone marrow edema and subchondral/cartilage defects on MRI Imaging Adolescence to adulthood not reported HP:0011849 Abnormality of the epiphysis; HP:0001363 Osteonecrosis Kim et al., 2024, DOI:10.7547/22-025 (kim2024shorttermoutcomesof pages 1-2)
Köhler disease Dorsomedial midfoot pain Symptom Children, usually 4–7 years not reported HP:0001767 Foot pain Maruszczak et al., 2024, DOI:10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
Köhler disease Local swelling over navicular region Sign Children, usually 4–7 years not reported HP:0001389 Arthritis; HP:0011463 Swelling of joint Maruszczak et al., 2024, DOI:10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
Köhler disease Tenderness over navicular Sign Children <10 years; commonly 4–7 years not reported HP:0033748 Tenderness Maruszczak et al., 2024, DOI:10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
Köhler disease Limp favoring the lateral side of the foot Sign Children, usually 4–7 years not reported HP:0002204 Abnormal gait; HP:0002515 Limping Maruszczak et al., 2024, DOI:10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
Köhler disease Bilateral involvement Sign/distribution Children younger than 10 years up to 25% HP:0012832 Bilateral Liu et al., 2024, DOI:10.14366/usg.24002 (liu2024footpainin pages 1-2)
Köhler disease Unsmooth, bumpy, fragmented, sometimes deformed navicular ossification center on ultrasound Imaging Children younger than 10 years not reported HP:0000925 Abnormality of the skeletal system; HP:0011849 Abnormality of the epiphysis Liu et al., 2024, DOI:10.14366/usg.24002 (liu2024footpainin pages 1-2)
Köhler disease Wafer-thin navicular with collapse, fragmentation, patchy sclerosis, and increased radiodensity on radiographs Imaging Children, usually 4–7 years not reported HP:0001363 Osteonecrosis; HP:0000925 Abnormality of the skeletal system Maruszczak et al., 2024, DOI:10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
Köhler disease Navicular flattening, increased density, and fragmentation on radiographs Imaging Children aged ~3–9 years not reported HP:0001363 Osteonecrosis; HP:0000925 Abnormality of the skeletal system Steinborn & Glaser, 2019, DOI:10.1055/s-0039-1695721 (steinborn2019normalvariationsand pages 1-2)
Müller-Weiss disease Chronic midfoot pain Symptom Adults, typically 4th–6th decades not reported HP:0001767 Foot pain Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 1-2)
Müller-Weiss disease Long-term mechanical dorsal foot pain Symptom Adults, usually diagnosed in 4th–5th decades not reported HP:0001767 Foot pain Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)
Müller-Weiss disease Midfoot varus deformity Sign Adults, 4th–6th decades not reported HP:0004689 Varus deformity of foot Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 1-2)
Müller-Weiss disease Ankle instability Sign/symptom Adults not reported HP:0002141 Ankle instability Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)
Müller-Weiss disease Reduced subtalar mobility Sign Adults not reported HP:0031372 Reduced joint range of motion Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)
Müller-Weiss disease Peroneal tendonitis Sign Adults not reported HP:0100526 Tendinitis Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)
Müller-Weiss disease Condensation/sclerosis and fragmentation of the navicular on radiographs Imaging Adults, 4th–6th decades not reported HP:0001363 Osteonecrosis; HP:0000925 Abnormality of the skeletal system Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 1-2, santos2024avascularnecrosisof pages 1-2)
Müller-Weiss disease Osteophytes and dorsolateral fragmentation of the navicular Imaging Adults not reported HP:0002808 Osteophyte; HP:0001363 Osteonecrosis Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)
Müller-Weiss disease Paradoxical flatfoot Sign/imaging Adults not reported HP:0001762 Flat feet Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)
Müller-Weiss disease Bilateral or unilateral involvement Sign/distribution Adults not reported HP:0012832 Bilateral Gonçalves-dos Santos et al., 2024, DOI:10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 2-4)

Table: This table summarizes key clinical and imaging phenotypes reported in context for Freiberg disease, Köhler disease, and Müller-Weiss disease. It is useful for building phenotype annotations and suggested HPO mappings while clearly marking where frequencies were not reported.

4. Genetic / molecular information

  • The pediatric imaging-focused review describes Freiberg’s disease etiology as including possible “genetic susceptibility” among multiple factors, but no specific genes/variants, inheritance patterns, or ClinVar-grade pathogenic variants were identified in the retrieved corpus. (liu2024footpainin pages 8-10)
  • Consequently, no causal genes can be asserted from the retrieved evidence. The current retrieved literature supports predominantly biomechanical/vascular/ossification-timing hypotheses rather than a monogenic etiology for these specific entities. (goncalvesdos2024necrosisavasculardel pages 1-2, maruszczak2024lowerlimbosteochondrosis pages 9-10, carmont2009currentconceptsreview pages 1-2)

5. Environmental information

The evidence base emphasizes mechanical load/repetitive stress and (for adult navicular osteonecrosis) systemic/metabolic contributors as possible factors, rather than discrete toxins or infectious causes. (goncalvesdos2024necrosisavasculardel pages 1-2, maruszczak2024lowerlimbosteochondrosis pages 9-10)

6. Mechanism / pathophysiology (causal chains)

6.1 Osteochondrosis as a process (general)

A sports-medicine review describes osteochondroses as “bone-cartilage conditions” associated with disturbed endochondral ossification and a typical sequence of necrosis → revascularization → granulation/invasion → osteoclast resorption → osteoid replacement and lamellar bone formation. (gillespie2010osteochondrosesandapophyseal pages 1-2)

6.2 Entity-specific mechanistic hypotheses

  • Freiberg disease: proposed chain includes repetitive microtrauma/overload in a vulnerable epiphysis during growth, plus compromised blood supply (e.g., anatomically variable arterial supply) leading to subchondral necrosis/structural collapse and degenerative changes. (carmont2009currentconceptsreview pages 1-2)
  • Köhler disease: mechanical compression/loading of the navicular during incomplete ossification is proposed to disrupt blood supply, causing ischemia and transient osteonecrosis with later resolution (self-limited course). (maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Müller–Weiss disease: overload and compressive deformation of the navicular within the medial arch, plus vascular obstruction and stress fracture/trauma contributions, are proposed to lead to chronic fragmentation/deformity and arthritic changes with pain and gait alteration. (goncalvesdos2024necrosisavasculardel pages 2-4)

Suggested GO biological processes (best-effort, not explicitly asserted in retrieved texts): endochondral ossification; bone remodeling; angiogenesis; response to mechanical stress.

Suggested CL cell types (best-effort): osteoblast; osteoclast; chondrocyte; endothelial cell.

7. Anatomical structures affected

  • Freiberg: metatarsal head and MTP joint (classically 2nd). (carmont2009currentconceptsreview pages 1-2)
  • Köhler: tarsal navicular in the midfoot. (liu2024footpainin pages 1-2, maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Müller–Weiss: tarsal navicular with associated perinavicular arthritis and midfoot deformity (e.g., midfoot varus; paradoxical flatfoot). (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4)

UBERON suggestions (best-effort): navicular bone of foot; metatarsal bone; metatarsophalangeal joint; midfoot.

8. Temporal development

  • Köhler: pediatric onset (commonly ~4–7 years in 2024 review). (maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Freiberg: onset typically during adolescence/skeletal growth; clinical series included Smillie stages I–V at treatment. (kim2024shorttermoutcomesof pages 1-2, carmont2009currentconceptsreview pages 1-2)
  • Müller–Weiss: adult onset/diagnosis primarily in 4th–6th decades; systematic review reports ages 28–69 with most patients >40. (goncalvesdos2024necrosisavasculardel pages 2-4)

9. Inheritance and population / epidemiology

9.1 Demographics (from retrieved sources)

  • Köhler: male predominance; bilateral involvement up to 25%. (liu2024footpainin pages 1-2)
  • Freiberg: strong predilection for adolescent athletic females; female:male ratio reported as ~5:1. (liu2024footpainin pages 8-10, carmont2009currentconceptsreview pages 1-2)
  • Müller–Weiss: systematic review across included studies reports 134 patients (138 feet) with female predominance ~70% and typical diagnosis in the 4th–5th decades. (goncalvesdos2024necrosisavasculardel pages 2-4)

9.2 Prevalence/incidence

No population-based prevalence/incidence estimates for these entities were identified in the retrieved evidence set.

10. Diagnostics

10.1 Imaging and clinical workup

  • Radiography is repeatedly identified as front-line for Köhler and Freiberg; Freiberg commonly uses radiographs for Smillie staging. (kim2024shorttermoutcomesof pages 2-6, maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • MRI is emphasized for detecting bone marrow edema and subchondral/cartilage abnormalities (Freiberg), and for evaluating navicular osteonecrosis-like changes (Müller–Weiss). (liu2024footpainin pages 8-10, kim2024shorttermoutcomesof pages 2-6, goncalvesdos2024necrosisavasculardel pages 2-4)
  • High-frequency musculoskeletal ultrasound is described as a useful pediatric modality for diagnosis and monitoring, capable of visualizing bone surfaces and adjacent soft tissues in real time; ultrasonographic patterns are described for Köhler and Freiberg. (liu2024footpainin pages 1-2, liu2024footpainin pages 8-10)

10.2 Freiberg staging/classification (Smillie)

A 2024 retrospective arthroscopy cohort restates Smillie I–V definitions (I fissure+sclerosis; II cancellous absorption with dorsal sinking; III absorption with bony projections; IV loose body; V arthrosis with flattening/deformity) and reports surgical outcomes across stages. (kim2024shorttermoutcomesof pages 1-2)

11. Outcome / prognosis

  • Köhler: characterized as self-limiting in a 2024 review, supporting a generally favorable prognosis with conservative management. (maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Freiberg: surgical literature suggests many procedures can relieve pain and restore activity; systematic review notes joint-sparing procedures are reported more often and appear to have better prognosis for symptom resolution and return to activity. (schade2015surgicalmanagementof pages 1-2)
  • Müller–Weiss: chronic course with long-term mechanical pain; treatment selection is stage-dependent, and classification/consensus limitations are noted in 2024 systematic review material. (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4)

12. Treatment

A consolidated treatment-and-outcomes table is provided below.

Entity First-line diagnostics Key staging/classification Conservative treatments Surgical options Reported outcomes/statistics (with numbers, follow-up) when available Suggested MAXO terms (best-effort) Supporting citations
Freiberg disease Plain radiographs for diagnosis and Smillie staging; follow-up radiographs; MRI to assess bone marrow edema, subchondral cortical irregularity, and cartilage defects; ultrasound can show flattened/fragmented metatarsal head, irregular bony surface, synovial hyperplasia, effusion, Doppler angiogenesis Smillie I-V: I fissure+sclerosis; II cancellous absorption with dorsal cartilage sinking; III further absorption with medial/lateral projections; IV central loose body; V arthrosis with flattening/deformity Rest, activity modification, footwear modification, orthosis/padding, NSAIDs, immobilization Arthroscopic synovectomy/debridement/chondroplasty/microfracture; core decompression; debridement; perichondral grafting; dorsal closing-wedge osteotomy; osteochondral autologous transplantation (OAT); arthroplasty; metatarsal head restoration/resection Arthroscopy series: 13 patients/15 feet, 12-month radiographs showed no progression; AOFAS improved from 39.67±5.04 pre-op to 93.07±1.83 at 12 months; VAS 7.20±1.42 to 1.80±0.41; ROM 33.67°±4.81° to 51.67°±5.23°; return to normal activities in 4-6 weeks (12-month follow-up) (kim2024shorttermoutcomesof pages 2-6, kim2024shorttermoutcomesof pages 6-7). Systematic review: 257 joint-sparing procedures, mean follow-up 30.4 months, >90% pain resolution/full return to activity; 70 joint-destructive procedures, mean follow-up 15.0 months, >70% pain resolution/full return to activity (schade2015surgicalmanagementof pages 1-2). Adult late-stage comparative study: OAT AOFAS 95.7 vs DCWMO 87.9 at final follow-up; fewer complications with OAT (kim2020comparisonofosteochondral pages 7-7) MAXO: physical activity modification; orthopedic insole/orthotic use; NSAID therapy; immobilization/casting; arthroscopic debridement; microfracture surgery; osteotomy; osteochondral graft transplantation; arthroplasty (liu2024footpainin pages 8-10, kim2024shorttermoutcomesof pages 1-2, schade2015surgicalmanagementof pages 1-2, kim2020comparisonofosteochondral pages 7-7, kim2024shorttermoutcomesof pages 2-6, kim2024shorttermoutcomesof pages 6-7)
Köhler disease Radiographs are the diagnostic method of choice; ultrasound can show unsmooth/bumpy/fragmented or deformed navicular ossification center; CT or MRI if symptoms fail to improve or more detail is needed No formal staging/classification identified in retrieved context Rest, ice, firm-soled shoes, arch supports, non-weight-bearing crutches, immobilization with cast (~6 weeks) or controlled-ankle-motion shoe, NSAIDs Usually no surgery indicated; refractory pediatric cases reported with navicular decompression and microcirculation reconstruction Disease is self-limiting; bilateral involvement reported in up to 25% (diagnostic/epidemiologic statistic). Small surgical series: 3 pediatric patients had pain resolution within 3 months and restoration of navicular density after decompression/microcirculation reconstruction (liu2024footpainin pages 1-2, maruszczak2024lowerlimbosteochondrosis pages 9-10) MAXO: rest; cryotherapy; shoe modification; arch support; assistive device use/crutches; non-weight-bearing; cast immobilization; NSAID therapy; navicular decompression surgery (liu2024footpainin pages 1-2, maruszczak2024lowerlimbosteochondrosis pages 9-10)
Müller-Weiss disease Radiographs showing osteophytes, sclerosis/condensation, fragmentation, dorsolateral navicular fragmentation; MRI when radiographs are equivocal and for osteonecrosis-like changes; functional assessment often with AOFAS and VAS in studies Early vs advanced stages referenced; early stages noted as S1-S2 in review context, but no full staging scheme provided in retrieved text Conservative treatment may be used in early stages; reported as giving acute symptomatic improvement and favorable evaluation in S1-S2; biomechanical offloading considerations implied by altered plantar pressures Arthrodesis most common (isolated talonavicular, double, triple/perinavicular), calcaneal osteotomy, grafting Systematic review included 17 studies with 134 patients (138 feet); ages 28-69 years; most >40 years; females ~70%; conservative treatment favorable in early S1-S2, surgery preferred in remaining stages; outcomes commonly measured with AOFAS and VAS, but pooled quantitative response rates not available in retrieved context (goncalvesdos2024necrosisavasculardel pages 2-4). Another review states isolated talonavicular arthrodesis gives good results in early stages, with double/triple arthrodesis used in advanced disease (goncalvesdos2024necrosisavasculardel pages 1-2, santos2024avascularnecrosisof pages 1-2) MAXO: activity modification; analgesic/NSAID therapy; orthotic/offloading support; talonavicular arthrodesis; double arthrodesis; triple arthrodesis; calcaneal osteotomy; bone grafting (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4, santos2024avascularnecrosisof pages 1-2)

Table: This table summarizes diagnostic approaches, staging systems, conservative care, surgical options, and reported outcomes for Freiberg disease, Köhler disease, and Müller-Weiss disease. It is useful for comparing how these related tarsal/metatarsal osteochondroses are diagnosed and managed in current evidence.

Visual evidence from recent clinical series (Freiberg)

A cropped outcome table and outcome figure from the 2024 arthroscopic Freiberg series provide visual confirmation of the AOFAS/VAS/ROM improvements summarized in Artifact-02. (kim2024shorttermoutcomesof media 28b80a18, kim2024shorttermoutcomesof media 2d3231ac)

13. Prevention

No disease-specific primary prevention programs or screening protocols were identified in the retrieved evidence set. Practical prevention concepts implied by etiology include load management / activity modification and early evaluation of persistent forefoot/midfoot pain in at-risk groups (adolescent athletes; active children; adults with chronic midfoot pain). (liu2024footpainin pages 8-10, maruszczak2024lowerlimbosteochondrosis pages 9-10, goncalvesdos2024necrosisavasculardel pages 2-4)

14. Other species / natural disease

No veterinary/natural disease evidence specific to these tarsal/metatarsal entities was retrieved in this run.

15. Model organisms

No model-organism–based mechanistic studies specific to these entities were retrieved in this run.

Recent developments (2023–2024 emphasis)

  • Broader adoption/positioning of musculoskeletal ultrasound in pediatric foot pain evaluation (including osteochondroses such as Köhler and Freiberg) is emphasized in a 2024 review, highlighting real-time imaging and monitoring potential beyond radiography/MRI in young patients. Publication: May 2024; URL: https://doi.org/10.14366/usg.24002 (liu2024footpainin pages 1-2, liu2024footpainin pages 8-10)
  • Updated synthesis of lower-limb osteochondroses in young athletes includes a dedicated Köhler section with practical conservative treatment recommendations and radiographic hallmarks. Publication: Dec 2024; URL: https://doi.org/10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Stage-inclusive arthroscopic management data for Freiberg disease: a 2024 retrospective study reports significant improvements in validated clinical scores and motion at 12 months across Smillie stages, supporting arthroscopy (debridement/microfracture-based) as a real-world option even across radiographic stages (short-term evidence). Publication: May/June 2024; URL: https://doi.org/10.7547/22-025 (kim2024shorttermoutcomesof pages 2-6, kim2024shorttermoutcomesof pages 6-7)
  • Müller–Weiss evidence remains limited and heterogeneous: a 2024 systematic review notes limited studies, variable approaches, and the need for long-term outcomes/complication data; it also summarizes available demographic patterns (female predominance; typical 4th–6th decade). Publication: Jan 2024; URL: https://doi.org/10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4)

Expert opinion / evidence-quality considerations

  • The Freiberg systematic review concludes that joint-sparing procedures are more commonly reported and appear to have better prognosis for symptom resolution/return to activity, but also highlights inconsistency in staging usage (“Smillie stage was not consistently …”). This reflects a broader limitation: most data are case series and retrospective cohorts rather than randomized trials. (schade2015surgicalmanagementof pages 1-2)
  • For Müller–Weiss, the 2024 systematic review characterizes the disease as rare with small study samples and notes that additional classifications might be needed/validated, again reflecting evidence scarcity and the importance of standardized staging/outcome reporting. (goncalvesdos2024necrosisavasculardel pages 2-4)

Key statistics (from the retrieved evidence)

  • Köhler disease: bilateral involvement up to 25%. (liu2024footpainin pages 1-2)
  • Freiberg disease: female:male ratio reported ~5:1. (carmont2009currentconceptsreview pages 1-2)
  • Müller–Weiss systematic review: 134 patients (138 feet); age range 28–69; ~70% female. (goncalvesdos2024necrosisavasculardel pages 2-4)
  • Freiberg arthroscopy cohort (n=13 patients/15 feet): AOFAS improved 39.67±5.04 → 93.07±1.83 at 12 months; VAS 7.20±1.42 → 1.80±0.41; ROM 33.67°±4.81° → 51.67°±5.23°, P=.001. (kim2024shorttermoutcomesof pages 2-6, kim2024shorttermoutcomesof pages 6-7)
  • Freiberg systematic review: 257 joint-sparing procedures (mean follow-up 30.4 months) with >90% pain resolution/return to activity; 70 joint-destructive procedures (mean follow-up 15.0 months) with >70% pain resolution/return to activity. (schade2015surgicalmanagementof pages 1-2)

Evidence gaps relative to knowledge-base template

  • Ontology identifiers (MONDO/MeSH/ICD/Orphanet/OMIM): not extractable from the retrieved texts in this run.
  • Genetics/variants: no specific genes/variants identified; only nonspecific “genetic susceptibility” mentioned for Freiberg among multifactorial risk factors. (liu2024footpainin pages 8-10)
  • Incidence/prevalence: no population-level estimates found in retrieved evidence.
  • Clinical trials: no clearly relevant interventional trials were identified from the clinical-trials search results used in this run.

Primary source URL list (publication date when available)

  • Liu L, Wang T, Qi H. Ultrasonography May 2024. https://doi.org/10.14366/usg.24002 (liu2024footpainin pages 1-2, liu2024footpainin pages 8-10)
  • Maruszczak K, Madej T, Gawda P. Applied Sciences Dec 2024. https://doi.org/10.3390/app142411795 (maruszczak2024lowerlimbosteochondrosis pages 9-10)
  • Kim J-K et al. J Am Podiatr Med Assoc May/June 2024. https://doi.org/10.7547/22-025 (kim2024shorttermoutcomesof pages 2-6, kim2024shorttermoutcomesof pages 6-7)
  • Gonçalves-dos Santos R et al. Acta Ortopédica Mexicana Jan 2024. https://doi.org/10.35366/117381 (goncalvesdos2024necrosisavasculardel pages 1-2, goncalvesdos2024necrosisavasculardel pages 2-4)
  • Schade VL. Foot & Ankle Specialist May 2015. https://doi.org/10.1177/1938640015585966 (schade2015surgicalmanagementof pages 1-2)
  • Carmont MR et al. Foot & Ankle International Feb 2009. https://doi.org/10.3113/fai-2009-0167 (carmont2009currentconceptsreview pages 1-2)

PMID note: PMIDs were not present in the retrieved text excerpts for these articles; therefore PMID-based citations could not be provided from the available evidence context.

References

  1. (liu2024footpainin pages 8-10): Lihua Liu, Tiezheng Wang, and Hengtao Qi. Foot pain in children and adolescents: a problem-based approach in musculoskeletal ultrasonography. Ultrasonography, 43:193-208, May 2024. URL: https://doi.org/10.14366/usg.24002, doi:10.14366/usg.24002. This article has 7 citations.

  2. (goncalvesdos2024necrosisavasculardel pages 2-4): Santos R Gonçalves-dos, V. Furtuoso-Junior, W. L. Pinto de Barros-Moreira, A. Assunção-Tostes, F. Caixeta, and T. dos Santos-Carneiro. Necrosis avascular del navicular (müller-weiss). una revisión sistemática. Acta Ortopédica Mexicana, 38:333-339, Jan 2024. URL: https://doi.org/10.35366/117381, doi:10.35366/117381. This article has 0 citations.

  3. (maruszczak2024lowerlimbosteochondrosis pages 9-10): Krystian Maruszczak, Tomasz Madej, and Piotr Gawda. Lower limb osteochondrosis and apophysitis in young athletes—a comprehensive review. Applied Sciences, 14:11795, Dec 2024. URL: https://doi.org/10.3390/app142411795, doi:10.3390/app142411795. This article has 2 citations.

  4. (kim2024shorttermoutcomesof pages 1-2): Jong-Kil Kim, Do-Yeon Kim, Jong-Sung Oh, Dong-ill Ko, and Kwang-Bok Lee. Short-term outcomes of arthroscopic treatment of freiberg disease. Journal of the American Podiatric Medical Association, May 2024. URL: https://doi.org/10.7547/22-025, doi:10.7547/22-025. This article has 0 citations and is from a peer-reviewed journal.

  5. (carmont2009currentconceptsreview pages 1-2): Michael R. Carmont, Robin J. Rees, and Christopher M. Blundell. Current concepts review: freiberg's disease. Foot & Ankle International, 30:167-176, Feb 2009. URL: https://doi.org/10.3113/fai-2009-0167, doi:10.3113/fai-2009-0167. This article has 139 citations and is from a peer-reviewed journal.

  6. (liu2024footpainin pages 1-2): Lihua Liu, Tiezheng Wang, and Hengtao Qi. Foot pain in children and adolescents: a problem-based approach in musculoskeletal ultrasonography. Ultrasonography, 43:193-208, May 2024. URL: https://doi.org/10.14366/usg.24002, doi:10.14366/usg.24002. This article has 7 citations.

  7. (steinborn2019normalvariationsand pages 1-2): Marc Steinborn and Christian Glaser. Normal variations and pathologic disorders of chondrification and ossification of the foot and related diseases. Seminars in Musculoskeletal Radiology, 23:497-510, Sep 2019. URL: https://doi.org/10.1055/s-0039-1695721, doi:10.1055/s-0039-1695721. This article has 7 citations and is from a peer-reviewed journal.

  8. (goncalvesdos2024necrosisavasculardel pages 1-2): Santos R Gonçalves-dos, V. Furtuoso-Junior, W. L. Pinto de Barros-Moreira, A. Assunção-Tostes, F. Caixeta, and T. dos Santos-Carneiro. Necrosis avascular del navicular (müller-weiss). una revisión sistemática. Acta Ortopédica Mexicana, 38:333-339, Jan 2024. URL: https://doi.org/10.35366/117381, doi:10.35366/117381. This article has 0 citations.

  9. (santos2024avascularnecrosisof pages 1-2): RG Santos, VF Furtuoso-Junior, and WL Moreira. Avascular necrosis of the navicular (müller-weiss). a systematic review. Unknown journal, 2024.

  10. (tuthill2014imagingoftarsal pages 8-9): Heidi L. Tuthill, Evan R. Finkelstein, Allen M. Sanchez, Paul D. Clifford, Ty K. Subhawong, and Jean Jose. Imaging of tarsal navicular disorders. Foot & Ankle Specialist, 7:210-224, Mar 2014. URL: https://doi.org/10.1177/1938640014528042, doi:10.1177/1938640014528042. This article has 49 citations.

  11. (schade2015surgicalmanagementof pages 1-2): Valerie L. Schade. Surgical management of freiberg’s infraction. Foot & Ankle Specialist, 8:498-519, May 2015. URL: https://doi.org/10.1177/1938640015585966, doi:10.1177/1938640015585966. This article has 49 citations.

  12. (gillespie2010osteochondrosesandapophyseal pages 1-2): Heather Gillespie. Osteochondroses and apophyseal injuries of the foot in the young athlete. Current Sports Medicine Reports, 9:265-268, Sep 2010. URL: https://doi.org/10.1249/jsr.0b013e3181f19488, doi:10.1249/jsr.0b013e3181f19488. This article has 103 citations and is from a peer-reviewed journal.

  13. (kim2024shorttermoutcomesof pages 2-6): Jong-Kil Kim, Do-Yeon Kim, Jong-Sung Oh, Dong-ill Ko, and Kwang-Bok Lee. Short-term outcomes of arthroscopic treatment of freiberg disease. Journal of the American Podiatric Medical Association, May 2024. URL: https://doi.org/10.7547/22-025, doi:10.7547/22-025. This article has 0 citations and is from a peer-reviewed journal.

  14. (kim2024shorttermoutcomesof pages 6-7): Jong-Kil Kim, Do-Yeon Kim, Jong-Sung Oh, Dong-ill Ko, and Kwang-Bok Lee. Short-term outcomes of arthroscopic treatment of freiberg disease. Journal of the American Podiatric Medical Association, May 2024. URL: https://doi.org/10.7547/22-025, doi:10.7547/22-025. This article has 0 citations and is from a peer-reviewed journal.

  15. (kim2020comparisonofosteochondral pages 7-7): Sung Jae Kim, Young Woo Kim, Jin Ho Park, and Gab Lae Kim. Comparison of osteochondral autologous transplantation and dorsiflexion closing wedge metatarsal osteotomy for late-stage freiberg disease in adults. Foot & Ankle International, 41:529-535, Feb 2020. URL: https://doi.org/10.1177/1071100720904363, doi:10.1177/1071100720904363. This article has 14 citations and is from a peer-reviewed journal.

  16. (kim2024shorttermoutcomesof media 28b80a18): Jong-Kil Kim, Do-Yeon Kim, Jong-Sung Oh, Dong-ill Ko, and Kwang-Bok Lee. Short-term outcomes of arthroscopic treatment of freiberg disease. Journal of the American Podiatric Medical Association, May 2024. URL: https://doi.org/10.7547/22-025, doi:10.7547/22-025. This article has 0 citations and is from a peer-reviewed journal.

  17. (kim2024shorttermoutcomesof media 2d3231ac): Jong-Kil Kim, Do-Yeon Kim, Jong-Sung Oh, Dong-ill Ko, and Kwang-Bok Lee. Short-term outcomes of arthroscopic treatment of freiberg disease. Journal of the American Podiatric Medical Association, May 2024. URL: https://doi.org/10.7547/22-025, doi:10.7547/22-025. This article has 0 citations and is from a peer-reviewed journal.