Cleidocranial Dysplasia

Mendelian MONDO:0007340 Pathograph 10 Show in embeddings browser 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.
23
Phenotypes
10
Pathograph
1
Genes
1
Medical Actions
1
References
1
Deep Research
🏷

Classifications

ISDS Skeletal Nosology
cleidocranial dysplasia and related
👪

Inheritance

1
Autosomal Dominant HP:0000006
Cleidocranial dysplasia is inherited in an autosomal dominant pattern and is associated with heterozygous pathogenic variants affecting RUNX2. Penetrance is complete but expressivity is widely variable, so affected relatives may differ markedly in severity.
Autosomal dominant inheritance Penetrance: COMPLETE
Show evidence (2 references)
PMID:30123273 SUPPORT Human Clinical
"This pathology, autosomal dominant or caused by a spontaneous genetic mutation, is present in one in one million individuals, with complete penetrance and widely variable expressivity."
Direct source for the COMPLETE penetrance value recorded on this inheritance block, together with the variable expressivity that accompanies it.
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 CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
RUNX2 hgnc:10472 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RUNX2 (hgnc:10472). hgnc:10472 is a gene from the HUGO Gene Nomenclature Committee.
Intramembranous Ossification GO:0001957 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Intramembranous Ossification (GO:0001957). GO:0001957 is a biological process from the Gene Ontology. Endochondral Ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Endochondral Ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology.
DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology.
Downstream
Hypertelorism Orphanet records hypertelorism as a very frequent craniofacial phenotype of RUNX2-related cleidocranial dysplasia.
Micrognathia Orphanet records micrognathia as a very frequent craniofacial phenotype of cleidocranial dysplasia.
Narrow Chest Orphanet records narrow chest as a very frequent thoracic skeletal manifestation of cleidocranial dysplasia.
Recurrent Respiratory Infections Orphanet records recurrent respiratory infections as a very frequent clinical phenotype in cleidocranial dysplasia.
Chronic Otitis Media Orphanet records chronic otitis media as a frequent ear phenotype in cleidocranial dysplasia.
Carious Teeth Orphanet records carious teeth as a very frequent dental phenotype in cleidocranial dysplasia.
Abnormality of Dental Enamel Orphanet records dental enamel abnormality as a very frequent dental phenotype in cleidocranial dysplasia.
Down-sloping Shoulders Orphanet records down-sloping shoulders as a very frequent shoulder-girdle phenotype in cleidocranial dysplasia.
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

23
Ear 2
Conductive Hearing Loss Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing loss, annotated with Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
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.
Chronic Otitis Media FREQUENT HP:0000389 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic otitis media (HP:0000389). HP:0000389 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0000389 | Chronic otitis media | Frequent (79-30%)"
Orphanet records chronic otitis media as frequent in CCD.
Eye 1
Hypertelorism VERY_FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0000316 | Hypertelorism | Very frequent (99-80%)"
Orphanet records hypertelorism as very frequent in CCD.
Head and Neck 10
Large Fontanelles VERY_FREQUENT HP:0000239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large fontanelles (HP:0000239). HP:0000239 is a phenotype from the Human Phenotype Ontology.
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 HP:0002645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wormian bones (HP:0002645). HP:0002645 is a phenotype from the Human Phenotype Ontology.
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 HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
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 HP:0000248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachycephaly (HP:0000248). HP:0000248 is a phenotype from the Human Phenotype Ontology.
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 HP:0011069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supernumerary tooth (HP:0011069). HP:0011069 is a phenotype from the Human Phenotype Ontology.
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 HP:0000696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed eruption of permanent teeth (HP:0000696). HP:0000696 is a phenotype from the Human Phenotype Ontology.
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 HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
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.
Micrognathia VERY_FREQUENT HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0000347 | Micrognathia | Very frequent (99-80%)"
Orphanet records micrognathia as very frequent in CCD.
Carious Teeth VERY_FREQUENT HP:0000670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carious teeth (HP:0000670). HP:0000670 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0000670 | Carious teeth | Very frequent (99-80%)"
Orphanet records carious teeth as very frequent in CCD.
Abnormality of Dental Enamel VERY_FREQUENT Abnormal dental enamel morphology HP:0000682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of dental enamel, annotated with Abnormal dental enamel morphology (HP:0000682). HP:0000682 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0000682 | Abnormality of dental enamel | Very frequent (99-80%)"
Orphanet records abnormal dental enamel as very frequent in CCD.
Immune 1
Recurrent Respiratory Infections VERY_FREQUENT HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
Orphanet records recurrent respiratory infections as very frequent in CCD.
Musculoskeletal 4
Aplasia/Hypoplasia of the Clavicles VERY_FREQUENT HP:0006710 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the clavicles (HP:0006710). HP:0006710 is a phenotype from the Human Phenotype Ontology.
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 HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (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 HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
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%).
Narrow Chest VERY_FREQUENT HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow chest (HP:0000774). HP:0000774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0000774 | Narrow chest | Very frequent (99-80%)"
Orphanet records narrow chest as very frequent in CCD.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (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 4
Short Middle Phalanx of the 5th Finger HP:0004220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short middle phalanx of the 5th finger (HP:0004220). HP:0004220 is a phenotype from the Human Phenotype Ontology.
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 HP:0006335 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistence of primary teeth (HP:0006335). HP:0006335 is a phenotype from the Human Phenotype Ontology.
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 HP:0000327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the maxilla (HP:0000327). HP:0000327 is a phenotype from the Human Phenotype Ontology.
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.
Down-sloping Shoulders VERY_FREQUENT HP:0200021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Down-sloping shoulders (HP:0200021). HP:0200021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1452 SUPPORT Other
"HP:0200021 | Down-sloping shoulders | Very frequent (99-80%)"
Orphanet records down-sloping shoulders as very frequent in CCD.
🧬

Genetic Associations

1
RUNX2 Pathogenic Variants (Causative)
Gene: RUNX2 hgnc:10472 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RUNX2 (hgnc:10472). hgnc:10472 is a gene from the HUGO Gene Nomenclature Committee.
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.
💊

Medical Actions

1
Orthopedic and Dental Correction
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
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.
🔬

Diagnosis

1
Clinical, Radiographic, and Molecular Diagnosis
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.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301686 SUPPORT Human Clinical
"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."
GeneReviews defines the combined clinical/radiographic and RUNX2 molecular diagnostic criteria for cleidocranial dysplasia spectrum disorder.
📊

Prevalence

1
Global reported populations
Birth Prevalence 0.1 per 100,000 1–9 per 1,000,000
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.
Show evidence (2 references)
PMID:19063717 SUPPORT Human Clinical
"Cleidocranial dysplasia is very rare in occurrence, incidence being 1: 1,000,000."
This clinical case report explicitly states the accepted incidence estimate for cleidocranial dysplasia.
PMID:34946295 SUPPORT Human Clinical
"Cleidocranial dysplasia (CCD) is a rare, autosomal dominant skeletal dysplasia with a prevalence of one per million births."
This recent review-oriented case report independently gives the same prevalence estimate.
{ }

Source YAML

click to show 
name: Cleidocranial Dysplasia
synonyms:
- Cleidocranial dysplasia, RUNX2-related
creation_date: '2026-03-04T07:37:20Z'
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
classifications:
  isds_skeletal_category:
  - classification_value: cleidocranial_dysplasia_and_related
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 32 "Cleidocranial
      dysplasia and related disorders with maxillary hypoplasia"; listed as
      "Cleidocranial dysplasia".
prevalence:
- population: Global reported populations
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.1
  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
    reference_title: "Clinical spectrum of cleidocranial dysplasia: a case report."
    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
    reference_title: "Genetic Pattern, Orthodontic and Surgical Management of Multiple Supplementary Impacted Teeth in a Rare, Cleidocranial Dysplasia Patient: A Case Report."
    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. Penetrance
    is complete but expressivity is widely variable, so affected relatives may
    differ markedly in severity.
  evidence:
  - reference: PMID:30123273
    reference_title: "Delayed Eruption of Permanent Dentition and Maxillary Contraction in Patients with Cleidocranial Dysplasia: Review and Report of a Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This pathology, autosomal dominant or caused by a spontaneous genetic
      mutation, is present in one in one million individuals, with complete
      penetrance and widely variable expressivity.
    explanation: >-
      Direct source for the COMPLETE penetrance value recorded on this
      inheritance block, together with the variable expressivity that
      accompanies it.
  - 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.
  downstream:
  - target: Hypertelorism
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records hypertelorism as a very frequent craniofacial phenotype
      of RUNX2-related cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000316 | Hypertelorism | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Micrognathia
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records micrognathia as a very frequent craniofacial phenotype
      of cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Narrow Chest
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records narrow chest as a very frequent thoracic skeletal
      manifestation of cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000774 | Narrow chest | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Recurrent Respiratory Infections
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records recurrent respiratory infections as a very frequent
      clinical phenotype in cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Chronic Otitis Media
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records chronic otitis media as a frequent ear phenotype in
      cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000389 | Chronic otitis media | Frequent (79-30%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Carious Teeth
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records carious teeth as a very frequent dental phenotype in
      cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000670 | Carious teeth | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Abnormality of Dental Enamel
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records dental enamel abnormality as a very frequent dental
      phenotype in cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000682 | Abnormality of dental enamel | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
  - target: Down-sloping Shoulders
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records down-sloping shoulders as a very frequent shoulder-girdle
      phenotype in cleidocranial dysplasia.
    evidence:
    - reference: ORPHA:1452
      reference_title: Cleidocranial dysplasia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0200021 | Down-sloping shoulders | Very frequent (99-80%)"
      explanation: >-
        Records the phenotype and its Orphanet frequency band. This row does
        not itself establish the causal link from RUNX2 haploinsufficiency;
        the edge is asserted because this feature belongs to the
        RUNX2-related CCD phenotype, and is typed UNKNOWN accordingly.
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.
- name: Hypertelorism
  description: >
    Hypertelorism is part of the recurrent craniofacial presentation in
    cleidocranial dysplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Very frequent (99-80%)"
    explanation: Orphanet records hypertelorism as very frequent in CCD.
- name: Micrognathia
  description: >
    Micrognathia is a frequent craniofacial skeletal manifestation of
    cleidocranial dysplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
    explanation: Orphanet records micrognathia as very frequent in CCD.
- name: Narrow Chest
  description: >
    Narrow chest reflects thoracic skeletal involvement in cleidocranial
    dysplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000774 | Narrow chest | Very frequent (99-80%)"
    explanation: Orphanet records narrow chest as very frequent in CCD.
- name: Recurrent Respiratory Infections
  description: >
    Recurrent respiratory infections are reported as a common clinical
    manifestation in cleidocranial dysplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
    explanation: Orphanet records recurrent respiratory infections as very frequent in CCD.
- name: Chronic Otitis Media
  description: >
    Chronic otitis media is a frequent ear manifestation reported in
    cleidocranial dysplasia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic otitis media
    term:
      id: HP:0000389
      label: Chronic otitis media
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000389 | Chronic otitis media | Frequent (79-30%)"
    explanation: Orphanet records chronic otitis media as frequent in CCD.
- name: Carious Teeth
  description: >
    Carious teeth are a frequent dental complication in the cleidocranial
    dysplasia dental phenotype.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Carious teeth
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000670 | Carious teeth | Very frequent (99-80%)"
    explanation: Orphanet records carious teeth as very frequent in CCD.
- name: Abnormality of Dental Enamel
  description: >
    Dental enamel abnormality expands the modeled CCD dental phenotype beyond
    eruption and tooth-number abnormalities.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormality of dental enamel
    term:
      id: HP:0000682
      label: Abnormal dental enamel morphology
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000682 | Abnormality of dental enamel | Very frequent (99-80%)"
    explanation: Orphanet records abnormal dental enamel as very frequent in CCD.
- name: Down-sloping Shoulders
  description: >
    Down-sloping shoulders are a common shoulder-girdle manifestation in
    cleidocranial dysplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Down-sloping shoulders
    term:
      id: HP:0200021
      label: Down-sloping shoulders
  evidence:
  - reference: ORPHA:1452
    reference_title: Cleidocranial dysplasia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200021 | Down-sloping shoulders | Very frequent (99-80%)"
    explanation: Orphanet records down-sloping shoulders as very frequent in CCD.
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: NCIT:C19770
      label: Molecular Analysis
  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: NCIT:C15747
      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.