Cleidocranial Dysplasia

Mendelian MONDO:0007340 Pathograph 2 Skeletal Dysplasia

Cleidocranial dysplasia is a RUNX2-related skeletal dysplasia characterized by clavicular hypoplasia/aplasia, delayed cranial suture closure, and dental abnormalities. Pathogenesis is driven by RUNX2 haploinsufficiency with impaired osteoblast differentiation affecting intramembranous and endochondral ossification.

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1
Inheritance
1
Pathophys.
15
Phenotypes
2
Pathograph
1
Genes
1
Treatments
1
References
1
Deep Research
👪

Inheritance

1
Autosomal Dominant HP:0000006
Cleidocranial dysplasia is inherited in an autosomal dominant pattern and is associated with heterozygous pathogenic variants affecting RUNX2.
Autosomal dominant inheritance Penetrance: COMPLETE
Show evidence (1 reference)
PMID:10204840 SUPPORT Human Clinical
"Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes."
This sentence directly supports autosomal dominant inheritance and the core clinical spectrum.
⚙

Pathophysiology

1
RUNX2 Haploinsufficiency and Osteoblast Differentiation Failure
RUNX2 (CBFA1) haploinsufficiency impairs osteoblast differentiation, causing defective ossification with prominent intramembranous skeletal involvement (clavicles/skull) and additional endochondral effects.
Osteoblast link Chondrocyte link
RUNX2 link
Intramembranous Ossification link Endochondral Ossification link
DNA-binding transcription factor activity, RNA polymerase II-specific link
Show evidence (2 references)
PMID:10204840 SUPPORT Model Organism
"Loss of both alleles (-/-) leads to a complete absence of bone owing to a lack of osteoblast differentiation."
This model-organism evidence directly supports RUNX2-dependent osteoblast differentiation as a causal mechanism.
PMID:10204840 SUPPORT Model Organism
"CBFA1 controls differentiation of precursor cells into osteoblasts and is thus essential for membranous as well as endochondral bone formation."
This supports the dual intramembranous and endochondral ossification defects in RUNX2-related disease.
⬡

Pathograph

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

Phenotypes

15
Ear 1
Conductive Hearing Loss Conductive hearing impairment (HP:0000405)
Show evidence (1 reference)
PMID:32894534 SUPPORT Human Clinical
"A slight conductive hearing loss was diagnosed in 3 out of 4 patients."
This dedicated audiology cohort directly supports a conductive hearing-loss phenotype in CCD, but no global disease-wide frequency is assigned because the study was limited to four selected children.
Head and Neck 7
Large Fontanelles VERY_FREQUENT Large fontanelles (HP:0000239)
Show evidence (2 references)
PMID:10204840 SUPPORT Human Clinical
"Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes."
This supports persistent patent sutures/fontanelles as core CCD features.
PMID:35638029 SUPPORT Human Clinical
"Open fontanels or cranial sutures, the presence of at least one of the typical CCD facies (frontal bossing, brachycephaly, hypertelorism, or depression of the nasal bridge), and supernumerary teeth were reported in 92%, 85%, and 88% of cases, respectively."
In the ordered list in the abstract, open fontanels or cranial sutures correspond to the first percentage (92%), which falls in the VERY_FREQUENT band (80-99%).
Wormian Bones Wormian bones (HP:0002645)
Show evidence (1 reference)
PMID:23633875 SUPPORT Human Clinical
"The skull findings are brachycephaly, delayed or failed closure of the fontanelles, presence of open skull sutures and multiple wormian bones with pronounced frontal bossing."
This abstract directly documents multiple wormian bones as part of the characteristic cranial phenotype.
Frontal Bossing Frontal bossing (HP:0002007)
Show evidence (1 reference)
PMID:23633875 SUPPORT Human Clinical
"The skull findings are brachycephaly, delayed or failed closure of the fontanelles, presence of open skull sutures and multiple wormian bones with pronounced frontal bossing."
This abstract directly supports frontal bossing as part of the cranial phenotype.
Brachycephaly Brachycephaly (HP:0000248)
Show evidence (1 reference)
PMID:23633875 SUPPORT Human Clinical
"The skull findings are brachycephaly, delayed or failed closure of the fontanelles, presence of open skull sutures and multiple wormian bones with pronounced frontal bossing."
This abstract directly supports brachycephaly as a cranial manifestation of CCD.
Supernumerary Tooth VERY_FREQUENT Supernumerary tooth (HP:0011069)
Show evidence (2 references)
PMID:10204840 SUPPORT Human Clinical
"Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes."
This directly supports supernumerary dentition as a hallmark CCD feature.
PMID:35638029 SUPPORT Human Clinical
"Open fontanels or cranial sutures, the presence of at least one of the typical CCD facies (frontal bossing, brachycephaly, hypertelorism, or depression of the nasal bridge), and supernumerary teeth were reported in 92%, 85%, and 88% of cases, respectively."
In the ordered list in the abstract, supernumerary teeth correspond to the third percentage (88%), which falls in the VERY_FREQUENT band (80-99%).
Delayed Eruption of Permanent Teeth Delayed eruption of permanent teeth (HP:0000696)
Show evidence (1 reference)
PMID:25206109 SUPPORT Human Clinical
"prolonged retention of primary teeth and delayed eruption of permanent teeth were evident."
This provides direct clinical evidence for delayed permanent tooth eruption in CCD.
High Palate High palate (HP:0000218)
Show evidence (1 reference)
PMID:23633875 SUPPORT Human Clinical
"Oral manifestations exhibit a hypoplastic maxilla with high-arched palate."
This abstract directly supports high-arched palate as an oral manifestation of CCD.
Musculoskeletal 3
Aplasia/Hypoplasia of the Clavicles VERY_FREQUENT Aplasia/Hypoplasia of the clavicles (HP:0006710)
Show evidence (2 references)
PMID:10204840 SUPPORT Human Clinical
"Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes."
This directly supports clavicular abnormalities as a defining phenotype.
PMID:35638029 SUPPORT Human Clinical
"Clavicular dysplasia was present in 98.6% of cases"
The 72-case systematic review reports clavicular dysplasia in 98.6% of cases, which falls in the VERY_FREQUENT band (80-99%).
Scoliosis Scoliosis (HP:0002650)
Show evidence (1 reference)
PMID:35638029 SUPPORT Human Clinical
"other skeletal abnormalities such as scoliosis, pubic symphysis diastasis, and flat feet were found"
This systematic review explicitly lists scoliosis among the associated skeletal abnormalities seen in CCD.
Osteoporosis FREQUENT Osteoporosis (HP:0000939)
Show evidence (1 reference)
PMID:28027977 SUPPORT Human Clinical
"Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%."
In this 15-patient cohort, osteoporosis was reported in 57.1% of cases, which falls in the FREQUENT band (30-79%).
Growth 1
Short Stature Short stature (HP:0004322)
Show evidence (2 references)
PMID:35638029 SUPPORT Human Clinical
"short stature was present in 71% of cases"
This systematic review supports short stature as part of the CCD phenotype, but the reported proportion varies across cohorts, so no single frequency band is assigned.
PMID:28027977 SUPPORT Human Clinical
"short stature present at a rate of 28.6%"
This smaller 15-patient cohort reported a substantially lower rate than the systematic review, reinforcing that short stature is variable in CCD.
Other 3
Short Middle Phalanx of the 5th Finger Short middle phalanx of the 5th finger (HP:0004220)
Show evidence (1 reference)
PMID:38534443 SUPPORT Human Clinical
"short middle phalanx of the fifth fingers"
This recent CCD clinical/genetic report explicitly includes shortening of the fifth-finger middle phalanx in the characteristic skeletal phenotype.
Persistence of Primary Teeth Persistence of primary teeth (HP:0006335)
Show evidence (1 reference)
PMID:25206109 SUPPORT Human Clinical
"prolonged retention of primary teeth and delayed eruption of permanent teeth were evident."
This abstract directly supports persistent retention of primary teeth in CCD.
Hypoplasia of the Maxilla Hypoplasia of the maxilla (HP:0000327)
Show evidence (1 reference)
PMID:23633875 SUPPORT Human Clinical
"Oral manifestations exhibit a hypoplastic maxilla with high-arched palate."
This abstract directly supports maxillary hypoplasia as an oral-facial manifestation in CCD.
🧬

Genetic Associations

1
RUNX2 Pathogenic Variants (Causative)
Show evidence (2 references)
PMID:25206109 SUPPORT Human Clinical
"is a rare autosomal dominant skeletal dysplasia caused by CBAF1 gene"
This report links the RUNX2 locus (historically CBFA1/CBAF1 notation) with autosomal dominant CCD.
PMID:10204840 SUPPORT Human Clinical
"Mutations in the CBFA1 gene that presumably lead to synthesis of an inactive gene product were identified in patients with CCD."
This identifies pathogenic RUNX2/CBFA1 mutations in affected CCD patients.
💊

Treatments

1
Orthopedic and Dental Correction
Action: supportive care MAXO:0000950
Management is primarily supportive and multidisciplinary, with long-term orthopedic and dental correction for skeletal and dentofacial complications.
Show evidence (1 reference)
PMID:25206109 SUPPORT Human Clinical
"Medical treatment is mainly directed at orthopedic and dental correction."
This directly supports supportive orthopedic/dental management in CCD.
{ }

Source YAML

click to show 
name: Cleidocranial Dysplasia
creation_date: '2026-03-04T07:37:20Z'
updated_date: '2026-04-19T06:45:02Z'
category: Mendelian
description: >
  Cleidocranial dysplasia is a RUNX2-related skeletal dysplasia characterized by
  clavicular hypoplasia/aplasia, delayed cranial suture closure, and dental
  abnormalities. Pathogenesis is driven by RUNX2 haploinsufficiency with impaired
  osteoblast differentiation affecting intramembranous and endochondral
  ossification.
disease_term:
  preferred_term: cleidocranial dysplasia 1
  term:
    id: MONDO:0007340
    label: cleidocranial dysplasia 1
parents:
- Skeletal Dysplasia
prevalence:
- population: Global reported populations
  percentage: 1 in 1,000,000 births
  notes: >-
    Cleidocranial dysplasia is consistently described in the clinical literature
    as an ultra-rare skeletal dysplasia with incidence or prevalence around 1
    per 1,000,000 births.
  evidence:
  - reference: PMID:19063717
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cleidocranial dysplasia is very rare in occurrence, incidence being 1: 1,000,000."
    explanation: This clinical case report explicitly states the accepted incidence estimate for cleidocranial dysplasia.
  - reference: PMID:34946295
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cleidocranial dysplasia (CCD) is a rare, autosomal dominant skeletal dysplasia with a prevalence of one per million births."
    explanation: This recent review-oriented case report independently gives the same prevalence estimate.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  description: >
    Cleidocranial dysplasia is inherited in an autosomal dominant pattern and is
    associated with heterozygous pathogenic variants affecting RUNX2.
  evidence:
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant
      skeletal dysplasia characterised by abnormal clavicles, patent sutures and
      fontanelles, supernumerary teeth, short stature, and a variety of other
      skeletal changes.
    explanation: >-
      This sentence directly supports autosomal dominant inheritance and the
      core clinical spectrum.
pathophysiology:
- name: RUNX2 Haploinsufficiency and Osteoblast Differentiation Failure
  description: >
    RUNX2 (CBFA1) haploinsufficiency impairs osteoblast differentiation, causing
    defective ossification with prominent intramembranous skeletal involvement
    (clavicles/skull) and additional endochondral effects.
  genes:
  - preferred_term: RUNX2
    term:
      id: hgnc:10472
      label: RUNX2
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Intramembranous Ossification
    term:
      id: GO:0001957
      label: intramembranous ossification
  - preferred_term: Endochondral Ossification
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of both alleles (-/-) leads to a complete absence of bone owing to a
      lack of osteoblast differentiation.
    explanation: >-
      This model-organism evidence directly supports RUNX2-dependent osteoblast
      differentiation as a causal mechanism.
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CBFA1 controls differentiation of precursor cells into osteoblasts and is
      thus essential for membranous as well as endochondral bone formation.
    explanation: >-
      This supports the dual intramembranous and endochondral ossification
      defects in RUNX2-related disease.
genetic:
- name: RUNX2 Pathogenic Variants
  gene_term:
    preferred_term: RUNX2
    term:
      id: hgnc:10472
      label: RUNX2
  association: Causative
  notes: >
    Pathogenic variants in RUNX2 are causative for Cleidocranial Dysplasia.
  evidence:
  - reference: PMID:25206109
    reference_title: "Cleidocranial dysplasia: case report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is a rare autosomal dominant skeletal dysplasia caused by CBAF1 gene
    explanation: >-
      This report links the RUNX2 locus (historically CBFA1/CBAF1 notation) with
      autosomal dominant CCD.
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the CBFA1 gene that presumably lead to synthesis of an
      inactive gene product were identified in patients with CCD.
    explanation: >-
      This identifies pathogenic RUNX2/CBFA1 mutations in affected CCD patients.
phenotypes:
- name: Aplasia/Hypoplasia of the Clavicles
  description: >
    Clavicular hypoplasia or aplasia is a hallmark skeletal manifestation of
    cleidocranial dysplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the clavicles
    term:
      id: HP:0006710
      label: Aplasia/Hypoplasia of the clavicles
  evidence:
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant
      skeletal dysplasia characterised by abnormal clavicles, patent sutures and
      fontanelles, supernumerary teeth, short stature, and a variety of other
      skeletal changes.
    explanation: >-
      This directly supports clavicular abnormalities as a defining phenotype.
  - reference: PMID:35638029
    reference_title: "Demographic, clinical, and radiological characteristics of cleidocranial dysplasia: A systematic review of cases reported in south America."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clavicular dysplasia was present in 98.6% of cases"
    explanation: >-
      The 72-case systematic review reports clavicular dysplasia in 98.6% of
      cases, which falls in the VERY_FREQUENT band (80-99%).
- name: Large Fontanelles
  description: >
    Persistent large fontanelles with delayed cranial suture closure reflect the
    impaired intramembranous ossification of CCD.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Large fontanelles
    term:
      id: HP:0000239
      label: Large fontanelles
  evidence:
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant
      skeletal dysplasia characterised by abnormal clavicles, patent sutures and
      fontanelles, supernumerary teeth, short stature, and a variety of other
      skeletal changes.
    explanation: >-
      This supports persistent patent sutures/fontanelles as core CCD features.
  - reference: PMID:35638029
    reference_title: "Demographic, clinical, and radiological characteristics of cleidocranial dysplasia: A systematic review of cases reported in south America."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Open fontanels or cranial sutures, the presence of at least one of the
      typical CCD facies (frontal bossing, brachycephaly, hypertelorism, or
      depression of the nasal bridge), and supernumerary teeth were reported in
      92%, 85%, and 88% of cases, respectively.
    explanation: >-
      In the ordered list in the abstract, open fontanels or cranial sutures
      correspond to the first percentage (92%), which falls in the
      VERY_FREQUENT band (80-99%).
- name: Wormian Bones
  description: >
    Wormian bones are a recurrent radiographic manifestation in the persistently
    open cranial sutures of CCD.
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:23633875
    reference_title: "Cleidocranial dysplasia with hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skull findings are brachycephaly, delayed or failed closure of the
      fontanelles, presence of open skull sutures and multiple wormian bones
      with pronounced frontal bossing.
    explanation: >-
      This abstract directly documents multiple wormian bones as part of the
      characteristic cranial phenotype.
- name: Frontal Bossing
  description: >
    Frontal bossing contributes to the typical craniofacial appearance of CCD.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:23633875
    reference_title: "Cleidocranial dysplasia with hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skull findings are brachycephaly, delayed or failed closure of the
      fontanelles, presence of open skull sutures and multiple wormian bones
      with pronounced frontal bossing.
    explanation: >-
      This abstract directly supports frontal bossing as part of the cranial
      phenotype.
- name: Brachycephaly
  description: >
    Brachycephaly is part of the characteristic craniofacial phenotype in CCD.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:23633875
    reference_title: "Cleidocranial dysplasia with hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skull findings are brachycephaly, delayed or failed closure of the
      fontanelles, presence of open skull sutures and multiple wormian bones
      with pronounced frontal bossing.
    explanation: >-
      This abstract directly supports brachycephaly as a cranial manifestation
      of CCD.
- name: Short Stature
  description: >
    Short stature is a variably expressed but recurrent component of the CCD
    skeletal phenotype.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35638029
    reference_title: "Demographic, clinical, and radiological characteristics of cleidocranial dysplasia: A systematic review of cases reported in south America."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature was present in 71% of cases"
    explanation: >-
      This systematic review supports short stature as part of the CCD
      phenotype, but the reported proportion varies across cohorts, so no single
      frequency band is assigned.
  - reference: PMID:28027977
    reference_title: "Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature present at a rate of 28.6%"
    explanation: >-
      This smaller 15-patient cohort reported a substantially lower rate than
      the systematic review, reinforcing that short stature is variable in CCD.
- name: Scoliosis
  description: >
    Scoliosis is a clinically important associated skeletal manifestation in
    some affected individuals.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35638029
    reference_title: "Demographic, clinical, and radiological characteristics of cleidocranial dysplasia: A systematic review of cases reported in south America."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other skeletal abnormalities such as scoliosis, pubic symphysis
      diastasis, and flat feet were found
    explanation: >-
      This systematic review explicitly lists scoliosis among the associated
      skeletal abnormalities seen in CCD.
- name: Short Middle Phalanx of the 5th Finger
  description: >
    Brachymesophalangy of the fifth finger is part of the characteristic hand
    skeletal phenotype described in CCD.
  phenotype_term:
    preferred_term: Short middle phalanx of the 5th finger
    term:
      id: HP:0004220
      label: Short middle phalanx of the 5th finger
  evidence:
  - reference: PMID:38534443
    reference_title: "New Genetic Variants of RUNX2 in Mexican Families Cause Cleidocranial Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short middle phalanx of the fifth fingers"
    explanation: >-
      This recent CCD clinical/genetic report explicitly includes shortening of
      the fifth-finger middle phalanx in the characteristic skeletal phenotype.
- name: Supernumerary Tooth
  description: >
    Supernumerary teeth contribute to the complex eruption abnormalities of
    CCD.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Supernumerary tooth
    term:
      id: HP:0011069
      label: Supernumerary tooth
  evidence:
  - reference: PMID:10204840
    reference_title: "Cleidocranial dysplasia: clinical and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant
      skeletal dysplasia characterised by abnormal clavicles, patent sutures and
      fontanelles, supernumerary teeth, short stature, and a variety of other
      skeletal changes.
    explanation: >-
      This directly supports supernumerary dentition as a hallmark CCD feature.
  - reference: PMID:35638029
    reference_title: "Demographic, clinical, and radiological characteristics of cleidocranial dysplasia: A systematic review of cases reported in south America."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Open fontanels or cranial sutures, the presence of at least one of the
      typical CCD facies (frontal bossing, brachycephaly, hypertelorism, or
      depression of the nasal bridge), and supernumerary teeth were reported in
      92%, 85%, and 88% of cases, respectively.
    explanation: >-
      In the ordered list in the abstract, supernumerary teeth correspond to the
      third percentage (88%), which falls in the VERY_FREQUENT band (80-99%).
- name: Persistence of Primary Teeth
  description: >
    Failure to shed retained primary teeth is a characteristic dental
    manifestation in CCD.
  phenotype_term:
    preferred_term: Persistence of primary teeth
    term:
      id: HP:0006335
      label: Persistence of primary teeth
  evidence:
  - reference: PMID:25206109
    reference_title: "Cleidocranial dysplasia: case report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prolonged retention of primary teeth and delayed eruption of permanent
      teeth were evident.
    explanation: >-
      This abstract directly supports persistent retention of primary teeth in
      CCD.
- name: Delayed Eruption of Permanent Teeth
  description: >
    Delayed eruption of permanent dentition is a characteristic oral
    manifestation in CCD.
  phenotype_term:
    preferred_term: Delayed eruption of permanent teeth
    term:
      id: HP:0000696
      label: Delayed eruption of permanent teeth
  evidence:
  - reference: PMID:25206109
    reference_title: "Cleidocranial dysplasia: case report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prolonged retention of primary teeth and delayed eruption of permanent
      teeth were evident.
    explanation: >-
      This provides direct clinical evidence for delayed permanent tooth eruption
      in CCD.
- name: Hypoplasia of the Maxilla
  description: >
    Maxillary hypoplasia contributes to the characteristic dentofacial
    phenotype of CCD.
  phenotype_term:
    preferred_term: Hypoplasia of the maxilla
    term:
      id: HP:0000327
      label: Hypoplasia of the maxilla
  evidence:
  - reference: PMID:23633875
    reference_title: "Cleidocranial dysplasia with hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral manifestations exhibit a hypoplastic maxilla with high-arched palate."
    explanation: >-
      This abstract directly supports maxillary hypoplasia as an oral-facial
      manifestation in CCD.
- name: High Palate
  description: >
    High-arched palate is part of the characteristic oral phenotype in CCD.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:23633875
    reference_title: "Cleidocranial dysplasia with hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral manifestations exhibit a hypoplastic maxilla with high-arched palate."
    explanation: >-
      This abstract directly supports high-arched palate as an oral manifestation
      of CCD.
- name: Osteoporosis
  description: >
    Reduced bone density with osteoporosis is a clinically relevant skeletal
    manifestation in some CCD cohorts.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:28027977
    reference_title: "Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our clinical evaluations revealed that short stature present at a rate of
      28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%.
    explanation: >-
      In this 15-patient cohort, osteoporosis was reported in 57.1% of cases,
      which falls in the FREQUENT band (30-79%).
- name: Conductive Hearing Loss
  description: >
    Audiologic evaluation in CCD can demonstrate a conductive component of
    hearing impairment.
  phenotype_term:
    preferred_term: Conductive hearing loss
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:32894534
    reference_title: "Audiological evaluation of patients with cleidocranial dysplasia (CCD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A slight conductive hearing loss was diagnosed in 3 out of 4 patients."
    explanation: >-
      This dedicated audiology cohort directly supports a conductive hearing-loss
      phenotype in CCD, but no global disease-wide frequency is assigned because
      the study was limited to four selected children.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    Cleidocranial dysplasia spectrum disorder is diagnosed from typical clinical
    and radiographic findings (clavicular hypoplasia/aplasia, delayed fontanelle
    closure, dental anomalies with supernumerary teeth) and/or confirmed by
    identification of a heterozygous RUNX2 pathogenic variant on molecular
    genetic testing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301686
    reference_title: "Cleidocranial Dysplasia Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CCD spectrum disorder is established in an individual with typical clinical and radiographic findings and/or a heterozygous pathogenic variant in RUNX2 identified by molecular genetic testing."
    explanation: >-
      GeneReviews defines the combined clinical/radiographic and RUNX2 molecular
      diagnostic criteria for cleidocranial dysplasia spectrum disorder.
treatments:
- name: Orthopedic and Dental Correction
  description: >
    Management is primarily supportive and multidisciplinary, with long-term
    orthopedic and dental correction for skeletal and dentofacial complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:25206109
    reference_title: "Cleidocranial dysplasia: case report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical treatment is mainly directed at orthopedic and dental correction.
    explanation: >-
      This directly supports supportive orthopedic/dental management in CCD.
datasets: []
references:
- reference: PMID:20301686
  title: "Cleidocranial Dysplasia Spectrum Disorder."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301686
Cleidocranial Dysplasia Spectrum Disorder.
No top-level findings curated for this source.

Deep Research

1
OpenAI ▸
Overview and Genetic Basis
o3-deep-research-2025-06-26 17 citations 2026-03-03T23:40:48.749264

Overview and Genetic Basis

Cleidocranial dysplasia (CCD) is a rare (~1 in 1,000,000) autosomal dominant skeletal disorder caused by loss-of-function mutations in the RUNX2 gene (formerly CBFA1) (pubmed.ncbi.nlm.nih.gov). RUNX2 encodes a “master” osteogenic transcription factor essential for osteoblast differentiation and skeletal development (pmc.ncbi.nlm.nih.gov). Haploinsufficiency of RUNX2 disrupts bone formation – particularly intramembranous ossification (as in skull and clavicles) and also chondrocyte maturation in endochondral ossification (www.ncbi.nlm.nih.gov). Consequently, patients cannot fully ossify certain bones. In mouse models, complete RUNX2 knockout blocks bone formation entirely (cartilage forms normally), and RUNX2^+/− mice recapitulate CCD features like open skull sutures (pmc.ncbi.nlm.nih.gov). In humans, most CCD cases result from a heterozygous RUNX2 mutation, inherited in an autosomal dominant pattern (often de novo) with complete penetrance but variable expressivity (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov).

Hallmark Skeletal Phenotypes

Classic CCD is defined by a triad of: (1) delayed closure of cranial sutures with persistent open fontanelles, (2) hypoplastic or absent clavicles, and (3) multiple dental anomalies (www.ncbi.nlm.nih.gov). Newborns often have large, wide-open anterior fontanelles that may remain open into adulthood (www.ncbi.nlm.nih.gov). Clavicular underdevelopment leads to narrow, sloping shoulders that can be opposed at the midline (due to the ability to bring shoulders together) (www.ncbi.nlm.nih.gov). Dental features are prominent: prolonged retention of primary teeth, failure of secondary (adult) teeth to erupt on time, and formation of supernumerary teeth are common (www.ncbi.nlm.nih.gov). Moderate short stature is frequently noted, though intellect is normal (www.ncbi.nlm.nih.gov). Additional skeletal findings include Wormian bones (small sutural bones in skull sutures), a narrowed thorax, delayed ossification of pelvic bones (with a wide pubic symphysis), and hand anomalies like short distal phalanges (www.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These phenotypes reflect the underlying developmental bone defects caused by insufficient RUNX2 function.

References: Cleidocranial dysplasia has been extensively described in genetic and medical literature. For example, a 1999 study by Mundlos et al. first detailed the RUNX2/CBFA1 mutations in CCD (pubmed.ncbi.nlm.nih.gov). More recently, GeneReviews (updated 2023) provides a comprehensive overview of CCD’s clinical spectrum and genetics (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Current research (e.g. Thaweesapphithak et al., 2024) is exploring genotype–phenotype correlations of various RUNX2 mutations (pubmed.ncbi.nlm.nih.gov). These resources, alongside case reports and animal studies, underpin our mechanistic understanding of how RUNX2 haploinsufficiency produces the hallmark skeletal features of cleidocranial dysplasia.