Cole-Carpenter syndrome

Mendelian MONDO:0016085 Pathograph 14 Show in embeddings browser Osteogenesis imperfecta Skeletal dysplasia

Cole-Carpenter syndrome (CCS) is an extremely rare Mendelian skeletal dysplasia in the osteogenesis imperfecta spectrum, characterized by severe bone fragility with recurrent fractures, craniosynostosis, ocular proptosis, hydrocephalus, growth failure, and distinctive craniofacial features (frontal bossing, midface hypoplasia, and micrognathia). It is genetically heterogeneous: Cole-Carpenter syndrome 1 (CCS1) is caused by heterozygous (autosomal dominant) missense variants in P4HB, which encodes protein disulfide isomerase (PDI/PDIA1), while Cole-Carpenter syndrome 2 (CCS2) is caused by biallelic (autosomal recessive) variants in SEC24D, a component of the COPII protein-export machinery. Both genetic forms converge on defective type I collagen biosynthesis and secretion, producing a common osteogenesis-imperfecta-like skeletal phenotype.

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1
Mappings
2
Inheritance
5
Pathophys.
11
Phenotypes
14
Pathograph
2
Genes
3
Medical Actions
2
Subtypes
🏷

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
🔗

Mappings

MONDO
MONDO:0016085 Cole-Carpenter syndrome
skos:exactMatch MONDO
MONDO:0016085 is the umbrella Cole-Carpenter syndrome class, cross-referenced to Orphanet ORPHA:2050 and OMIM phenotypic series OMIMPS:112240, and is used here as the top-level disease anchor for the two gene-defined subtypes.
👪

Inheritance

2
Autosomal dominant inheritance (CCS1) HP:0000006
Cole-Carpenter syndrome 1 (P4HB) is inherited in an autosomal dominant manner; the recurrent P4HB p.Tyr393Cys variant occurs de novo or is transmitted from a mosaic carrier parent.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:25683117 SUPPORT Human Clinical
"In one individual, the P4HB mutation had arisen de novo, whereas in the other the mutation was transmitted from the clinically unaffected father who was a mosaic carrier of the variant."
A heterozygous variant that is de novo or transmitted from a mosaic carrier indicates dominant action of the P4HB allele in CCS1.
Autosomal recessive inheritance (CCS2) HP:0000007
Cole-Carpenter syndrome 2 (SEC24D) is inherited in an autosomal recessive manner, with affected individuals carrying biallelic (compound heterozygous) SEC24D variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:25683121 SUPPORT Human Clinical
"Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles"
Biallelic (compound heterozygous) SEC24D genotypes indicate autosomal recessive inheritance of CCS2.
◆

Subtypes

2
Cole-Carpenter syndrome 1 (P4HB) MONDO:0007204
P4HB hgnc:8548 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in P4HB (hgnc:8548). hgnc:8548 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal dominant form caused by a recurrent heterozygous missense variant in P4HB (protein disulfide isomerase, PDI). The two individuals of the original Cole-Carpenter description both carried the same P4HB c.1178A>G (p.Tyr393Cys) variant, arising de novo in one and inherited from a mosaic unaffected father in the other.
Show evidence (1 reference)
PMID:25683117 SUPPORT Human Clinical
"The two unrelated individuals had the same heterozygous missense mutation in exon 9 of P4HB"
Whole-exome sequencing of the two originally described individuals identified the recurrent heterozygous P4HB missense variant defining CCS1.
Cole-Carpenter syndrome 2 (SEC24D) MONDO:0014573
SEC24D hgnc:10706 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SEC24D (hgnc:10706). hgnc:10706 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive form caused by biallelic (compound heterozygous) variants in SEC24D, a component of the COPII complex that mediates procollagen export from the endoplasmic reticulum. Reported patients present with a Cole-Carpenter-like phenotype of disturbed skull ossification, prenatal-onset fractures, short stature, and craniofacial malformation.
Show evidence (2 references)
PMID:30462379 SUPPORT Human Clinical
"We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2."
A compound-heterozygous SEC24D genotype produced Cole-Carpenter syndrome type 2, establishing SEC24D as the CCS2 gene.
PMID:25683121 SUPPORT Human Clinical
"Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles"
The foundational SEC24D cohort was biallelic (compound heterozygous), consistent with autosomal recessive inheritance of CCS2.
⚙

Pathophysiology

5
P4HB/PDI disulfide isomerase dysfunction
In CCS1, the P4HB p.Tyr393Cys variant sits in the C-terminal disulfide isomerase domain of PDI, close to the enzymatic center, and reduces disulfide isomerase activity. Because PDI mediates oxidative folding in the endoplasmic reticulum, the defect perturbs ER proteostasis and provokes ER stress.
P4HB hgnc:8548 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves P4HB (hgnc:8548). hgnc:8548 is a gene from the HUGO Gene Nomenclature Committee.
protein folding GO:0006457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. ↓ DECREASED response to endoplasmic reticulum stress GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ↑ INCREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Defective type I collagen biosynthesis PDI dysfunction and ER stress impair oxidative folding needed for type I collagen production.
Show evidence (2 references)
PMID:25683117 SUPPORT Human Clinical
"The mutation was located in the C-terminal disulfide isomerase domain of PDI, sterically close to the enzymatic center, and affected disulfide isomerase activity in vitro."
The CCS1 variant impairs PDI disulfide isomerase activity, the proximal molecular defect.
PMID:25683117 SUPPORT In Vitro
"Skin fibroblasts showed signs of increased endoplasmic reticulum stress"
Patient fibroblasts show increased ER stress downstream of impaired PDI function.
SEC24D/COPII-dependent procollagen ER export failure
In CCS2, biallelic SEC24D variants disrupt the COPII coat that loads procollagen into transport vesicles, so procollagen export from the endoplasmic reticulum becomes inefficient and ER tubules dilate.
SEC24D hgnc:10706 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SEC24D (hgnc:10706). hgnc:10706 is a gene from the HUGO Gene Nomenclature Committee.
endoplasmic reticulum to Golgi vesicle-mediated transport GO:0006888 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888). GO:0006888 is a biological process from the Gene Ontology. ↓ DECREASED
COPII vesicle coat GO:0030127 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves COPII vesicle coat (GO:0030127). GO:0030127 is a cellular component from the Gene Ontology. endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Defective type I collagen biosynthesis Inefficient COPII export of procollagen reduces effective type I collagen secretion.
Show evidence (1 reference)
PMID:25683121 SUPPORT In Vitro
"ER export of procollagen was inefficient and that ER tubules were dilated"
Fibroblast microscopy shows the COPII-dependent procollagen export defect underlying CCS2.
Defective type I collagen biosynthesis
Both genetic arms converge on defective type I collagen biosynthesis and secretion, the central pathogenic mechanism of CCS. In the P4hb Y393C mouse model, reduced circulating PINP and lower osteoblast collagen expression and secretion quantify the collagen deficit.
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.
collagen biosynthetic process GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced bone quality and skeletal fragility Deficient type I collagen matrix produces osteopenia and brittle bone.
Increased osteoclastic bone resorption The mutant bone environment is associated with increased osteoclast differentiation.
Show evidence (2 references)
PMID:42425402 SUPPORT Model Organism
"CCS mice exhibited reduced circulating levels of procollagen type I N-terminal propeptide (PINP I), indicating decreased type I collagen biosynthesis."
The mouse model shows reduced PINP, a direct biomarker of decreased type I collagen biosynthesis.
PMID:42425402 SUPPORT In Vitro
"primary osteoblasts isolated from CCS mice showed lower expression and secretion of type I collagen, along with decreased expression of osteocalcin and higher mineralization."
Cultured mutant osteoblasts confirm reduced collagen expression and secretion at the cellular level.
Increased osteoclastic bone resorption
Alongside the osteoblast collagen defect, the P4hb Y393C model shows increased osteoclast differentiation, a resorptive component that can further compromise bone mass.
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
osteoclast differentiation GO:0030316 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased osteoclast differentiation (GO:0030316). GO:0030316 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Reduced bone quality and skeletal fragility Excess osteoclastic resorption compounds low bone mass.
Show evidence (1 reference)
PMID:42425402 SUPPORT In Vitro
"On the other hand, osteoclast differentiation was increased."
Increased osteoclast differentiation adds a resorptive contribution to the skeletal phenotype in the model.
Reduced bone quality and skeletal fragility
The collagen-biosynthesis defect yields an osteogenesis-imperfecta-like skeleton with pronounced osteopenia and reduced bone quality, the substrate for recurrent fractures, long-bone bowing, disturbed skull ossification, and craniosynostosis.
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.
ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↕ DYSREGULATED
bone tissue UBERON:0002481 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone tissue (UBERON:0002481). UBERON:0002481 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Recurrent fractures
Reduced bone mineral density
Bowing of the long bones
Craniosynostosis
Show evidence (2 references)
PMID:42425402 SUPPORT Model Organism
"Comprehensive skeletal phenotyping revealed pronounced osteopenia and reduced local bone quality in mutant mice across multiple ages."
The mouse model recapitulates osteopenia and reduced bone quality, linking the collagen defect to the fragile-bone phenotype.
PMID:25683121 SUPPORT Human Clinical
"All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset."
CCS2 patients show disturbed skull ossification and multiple early fractures, the human skeletal-fragility phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Bowing of the long bones' (from 'Reduced bone quality and skeletal fragility') not found in named elements
Pathograph: causal mechanism network for Cole-Carpenter syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Eye 1
Ocular proptosis HP:0000520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proptosis (HP:0000520). HP:0000520 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25683117 SUPPORT Human Clinical
"Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
Ocular proptosis is part of the defining CCS phenotype.
Head and Neck 6
Craniosynostosis HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25683117 SUPPORT Human Clinical
"Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
Craniosynostosis is part of the defining CCS 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:30462379 SUPPORT Human Clinical
"craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia"
Marked frontal bossing is reported as a craniofacial feature in a CCS2 patient.
Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface hypoplasia, annotated with Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30462379 SUPPORT Human Clinical
"craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia"
Midface hypoplasia is reported among the CCS craniofacial features.
Micrognathia 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)
PMID:30462379 SUPPORT Human Clinical
"craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia"
Micrognathia is reported among the CCS craniofacial features.
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25683121 SUPPORT Human Clinical
"craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures"
Macrocephaly is reported among the CCS2 craniofacial malformations.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25683121 SUPPORT Human Clinical
"craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures"
Down-slanting palpebral fissures are reported among the CCS2 craniofacial features.
Musculoskeletal 2
Recurrent fractures HP:0002757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fractures (HP:0002757). HP:0002757 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25683117 SUPPORT Human Clinical
"Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
Frequent fractures are part of the defining CCS phenotype.
Reduced bone mineral density HP:0004349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced bone mineral density (HP:0004349). HP:0004349 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30462379 SUPPORT Human Clinical
"He had low-bone mineral density and basilar impression."
Low bone mineral density is documented in a genetically confirmed CCS2 patient.
Nervous System 1
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25683117 SUPPORT Human Clinical
"Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
Hydrocephalus is part of the defining CCS phenotype.
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 (1 reference)
PMID:25683121 SUPPORT Human Clinical
"The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures."
Short stature is reported in a CCS2-phenotype patient.
🧬

Genetic Associations

2
P4HB (Disease-causing germline variant (CCS1))
Gene: P4HB hgnc:8548 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is P4HB (hgnc:8548). hgnc:8548 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:25683117 SUPPORT Human Clinical
"Cole-Carpenter syndrome is caused by a specific de novo mutation in P4HB that impairs the disulfide isomerase activity of PDI."
This directly establishes P4HB (PDI) loss of disulfide isomerase activity as the cause of CCS1.
PMID:42425402 SUPPORT Human Clinical
"Pathogenic variants in P4HB, encoding protein disulfide isomerase A1 (PDIA1), represent the most frequent cause of CCS."
P4HB is the most frequent causative gene for Cole-Carpenter syndrome.
SEC24D (Disease-causing germline variant (CCS2))
Gene: SEC24D hgnc:10706 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SEC24D (hgnc:10706). hgnc:10706 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:25683121 SUPPORT Human Clinical
"we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER"
SEC24D is a COPII protein-export gene whose mutation causes the syndromic osteogenesis imperfecta underlying CCS2.
💊

Medical Actions

3
Supportive and bone-directed management
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
There is no established disease-modifying therapy for Cole-Carpenter syndrome. Care is supportive and multidisciplinary, directed at fracture management, orthopedic care, monitoring of craniosynostosis and hydrocephalus, and bone-health optimization.
Target Phenotypes: Recurrent fractures HP:0002757 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent fractures (HP:0002757). HP:0002757 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42425402 SUPPORT Other
"Given the lack of disease-modifying therapies for CCS, we explored different therapeutic strategies."
The absence of disease-modifying therapy underlies the current reliance on supportive management.
Allele-specific siRNA silencing (investigational)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Investigational, preclinical allele-specific RNA interference strategy for the dominant P4HB (CCS1) form. siRNA sequences selectively silenced the mutant P4hb allele in vitro and ex vivo without cytotoxicity, aiming to remove the dominant-negative transcript while sparing the wild-type allele.
Mechanism Target:
INHIBITS P4HB/PDI disulfide isomerase dysfunction — Selective knockdown of the mutant P4hb allele is intended to eliminate the dysfunctional PDI while preserving wild-type disulfide isomerase activity.
Show evidence (1 reference)
PMID:42425402 SUPPORT In Vitro
"we developed an allele-specific RNA interference (siRNAs) approach and identified siRNA sequences capable of selectively silencing the mutant P4hb allele in vitro and ex vivo without cytotoxic effects."
Allele-specific siRNA selectively silences the mutant P4hb allele, a targeted strategy against the CCS1 dominant defect.
Show evidence (1 reference)
PMID:42425402 SUPPORT In Vitro
"we developed an allele-specific RNA interference (siRNAs) approach and identified siRNA sequences capable of selectively silencing the mutant P4hb allele in vitro and ex vivo without cytotoxic effects."
Preclinical proof-of-concept only; no in vivo efficacy or human data are established.
Collagen-secretion-enhancing drug repurposing (investigational)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Investigational strategy from a functional screen of an FDA-approved drug library, which identified four compounds that significantly enhanced type I collagen secretion in the CCS cellular model. This is an early, preclinical lead toward correcting the central collagen-biosynthesis defect.
Mechanism Target:
RESTORES Defective type I collagen biosynthesis — The identified compounds enhanced type I collagen secretion, partially countering the central biosynthetic defect in cellular assays.
Show evidence (1 reference)
PMID:42425402 SUPPORT In Vitro
"We performed a functional screen of an FDA-approved drug library identifying four compounds that significantly enhanced type I collagen secretion."
Drug-repurposing hits enhance collagen secretion, targeting the central pathogenic mechanism in vitro.
Show evidence (1 reference)
PMID:42425402 SUPPORT In Vitro
"identifies promising therapeutic strategies with translational potential for this currently untreatable skeletal disorder."
The compounds are promising but preclinical leads without clinical validation.
🔬

Diagnosis

1
Molecular genetic testing
Definitive diagnosis rests on identifying a pathogenic P4HB variant (CCS1) or biallelic SEC24D variants (CCS2), typically by whole-exome sequencing or a skeletal-dysplasia/osteogenesis-imperfecta gene panel.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A pathogenic P4HB or biallelic SEC24D genotype confirms the subtype.
Show evidence (2 references)
PMID:25683117 SUPPORT Human Clinical
"To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we performed whole-exome sequencing"
Whole-exome sequencing established the molecular diagnosis of CCS1.
PMID:30462379 SUPPORT Human Clinical
"Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient."
Whole-exome sequencing identified the biallelic SEC24D genotype diagnostic of CCS2.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Cole-Carpenter syndrome is extremely rare, with only a small number of genetically confirmed cases reported worldwide across the two subtypes.
Show evidence (1 reference)
PMID:30462379 SUPPORT Human Clinical
"Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively."
The small number of reported SEC24D variants and patients illustrates the extreme rarity of Cole-Carpenter syndrome type 2.
{ }

Source YAML

click to show 
name: Cole-Carpenter syndrome
category: Mendelian
creation_date: "2026-07-11T15:00:00Z"
synonyms:
- Cole-Carpenter syndrome
- CCS
- Bone fragility-craniosynostosis-proptosis-hydrocephalus syndrome
- Cole-Carpenter syndrome 1
- Cole-Carpenter syndrome 2
description: >
  Cole-Carpenter syndrome (CCS) is an extremely rare Mendelian skeletal dysplasia
  in the osteogenesis imperfecta spectrum, characterized by severe bone fragility
  with recurrent fractures, craniosynostosis, ocular proptosis, hydrocephalus,
  growth failure, and distinctive craniofacial features (frontal bossing, midface
  hypoplasia, and micrognathia). It is genetically heterogeneous: Cole-Carpenter
  syndrome 1 (CCS1) is caused by heterozygous (autosomal dominant) missense
  variants in P4HB, which encodes protein disulfide isomerase (PDI/PDIA1), while
  Cole-Carpenter syndrome 2 (CCS2) is caused by biallelic (autosomal recessive)
  variants in SEC24D, a component of the COPII protein-export machinery. Both
  genetic forms converge on defective type I collagen biosynthesis and secretion,
  producing a common osteogenesis-imperfecta-like skeletal phenotype.
disease_term:
  preferred_term: Cole-Carpenter syndrome
  term:
    id: MONDO:0016085
    label: Cole-Carpenter syndrome
parents:
- Osteogenesis imperfecta
- Skeletal dysplasia
classifications:
  isds_skeletal_category:
  - classification_value: osteogenesis_imperfecta_and_decreased_bone_density
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 25 "Osteogenesis
      Imperfecta and decreased bone density group"; listed as "Cole-Carpenter
      dysplasia (bone fragility with craniosynostosis)".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016085
      label: Cole-Carpenter syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0016085 is the umbrella Cole-Carpenter syndrome class, cross-referenced
      to Orphanet ORPHA:2050 and OMIM phenotypic series OMIMPS:112240, and is used
      here as the top-level disease anchor for the two gene-defined subtypes.
has_subtypes:
- name: CCS1
  display_name: Cole-Carpenter syndrome 1 (P4HB)
  subtype_term:
    preferred_term: Cole-Carpenter syndrome 1
    term:
      id: MONDO:0007204
      label: Cole-Carpenter syndrome 1
  description: >
    Autosomal dominant form caused by a recurrent heterozygous missense variant in
    P4HB (protein disulfide isomerase, PDI). The two individuals of the original
    Cole-Carpenter description both carried the same P4HB c.1178A>G (p.Tyr393Cys)
    variant, arising de novo in one and inherited from a mosaic unaffected father
    in the other.
  genes:
  - preferred_term: P4HB
    term:
      id: hgnc:8548
      label: P4HB
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two unrelated individuals had the same heterozygous missense mutation in exon 9 of P4HB"
    explanation: Whole-exome sequencing of the two originally described individuals identified the recurrent heterozygous P4HB missense variant defining CCS1.
- name: CCS2
  display_name: Cole-Carpenter syndrome 2 (SEC24D)
  subtype_term:
    preferred_term: Cole-Carpenter syndrome 2
    term:
      id: MONDO:0014573
      label: Cole-Carpenter syndrome 2
  description: >
    Autosomal recessive form caused by biallelic (compound heterozygous) variants
    in SEC24D, a component of the COPII complex that mediates procollagen export
    from the endoplasmic reticulum. Reported patients present with a
    Cole-Carpenter-like phenotype of disturbed skull ossification, prenatal-onset
    fractures, short stature, and craniofacial malformation.
  genes:
  - preferred_term: SEC24D
    term:
      id: hgnc:10706
      label: SEC24D
  evidence:
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2."
    explanation: A compound-heterozygous SEC24D genotype produced Cole-Carpenter syndrome type 2, establishing SEC24D as the CCS2 gene.
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles"
    explanation: The foundational SEC24D cohort was biallelic (compound heterozygous), consistent with autosomal recessive inheritance of CCS2.
inheritance:
- name: Autosomal dominant inheritance (CCS1)
  description: >
    Cole-Carpenter syndrome 1 (P4HB) is inherited in an autosomal dominant manner;
    the recurrent P4HB p.Tyr393Cys variant occurs de novo or is transmitted from a
    mosaic carrier parent.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one individual, the P4HB mutation had arisen de novo, whereas in the other the mutation was transmitted from the clinically unaffected father who was a mosaic carrier of the variant."
    explanation: A heterozygous variant that is de novo or transmitted from a mosaic carrier indicates dominant action of the P4HB allele in CCS1.
- name: Autosomal recessive inheritance (CCS2)
  description: >
    Cole-Carpenter syndrome 2 (SEC24D) is inherited in an autosomal recessive
    manner, with affected individuals carrying biallelic (compound heterozygous)
    SEC24D variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles"
    explanation: Biallelic (compound heterozygous) SEC24D genotypes indicate autosomal recessive inheritance of CCS2.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    Cole-Carpenter syndrome is extremely rare, with only a small number of
    genetically confirmed cases reported worldwide across the two subtypes.
  evidence:
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively."
    explanation: The small number of reported SEC24D variants and patients illustrates the extreme rarity of Cole-Carpenter syndrome type 2.
genetic:
- name: P4HB
  association: Disease-causing germline variant (CCS1)
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: P4HB
    term:
      id: hgnc:8548
      label: P4HB
  features: >
    P4HB encodes protein disulfide isomerase (PDI/PDIA1), a multifunctional
    endoplasmic reticulum enzyme required for oxidative protein folding, including
    type I collagen maturation. The recurrent CCS1 variant p.Tyr393Cys lies in the
    C-terminal disulfide isomerase domain and impairs PDI enzymatic activity.
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cole-Carpenter syndrome is caused by a specific de novo mutation in P4HB that impairs the disulfide isomerase activity of PDI."
    explanation: This directly establishes P4HB (PDI) loss of disulfide isomerase activity as the cause of CCS1.
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in P4HB, encoding protein disulfide isomerase A1 (PDIA1), represent the most frequent cause of CCS."
    explanation: P4HB is the most frequent causative gene for Cole-Carpenter syndrome.
- name: SEC24D
  association: Disease-causing germline variant (CCS2)
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SEC24D
    term:
      id: hgnc:10706
      label: SEC24D
  features: >
    SEC24D encodes a cargo-selective subunit of the COPII vesicle coat that
    packages secretory cargo, including procollagen, for export from the
    endoplasmic reticulum. Biallelic SEC24D variants impair COPII-dependent
    procollagen export and cause the recessive CCS2 form.
  evidence:
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER"
    explanation: SEC24D is a COPII protein-export gene whose mutation causes the syndromic osteogenesis imperfecta underlying CCS2.
pathophysiology:
- name: P4HB/PDI disulfide isomerase dysfunction
  description: >
    In CCS1, the P4HB p.Tyr393Cys variant sits in the C-terminal disulfide
    isomerase domain of PDI, close to the enzymatic center, and reduces disulfide
    isomerase activity. Because PDI mediates oxidative folding in the endoplasmic
    reticulum, the defect perturbs ER proteostasis and provokes ER stress.
  genes:
  - preferred_term: P4HB
    term:
      id: hgnc:8548
      label: P4HB
  biological_processes:
  - preferred_term: protein folding
    modifier: DECREASED
    term:
      id: GO:0006457
      label: protein folding
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation was located in the C-terminal disulfide isomerase domain of PDI, sterically close to the enzymatic center, and affected disulfide isomerase activity in vitro."
    explanation: The CCS1 variant impairs PDI disulfide isomerase activity, the proximal molecular defect.
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Skin fibroblasts showed signs of increased endoplasmic reticulum stress"
    explanation: Patient fibroblasts show increased ER stress downstream of impaired PDI function.
  downstream:
  - target: Defective type I collagen biosynthesis
    description: PDI dysfunction and ER stress impair oxidative folding needed for type I collagen production.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: SEC24D/COPII-dependent procollagen ER export failure
  description: >
    In CCS2, biallelic SEC24D variants disrupt the COPII coat that loads
    procollagen into transport vesicles, so procollagen export from the
    endoplasmic reticulum becomes inefficient and ER tubules dilate.
  genes:
  - preferred_term: SEC24D
    term:
      id: hgnc:10706
      label: SEC24D
  biological_processes:
  - preferred_term: endoplasmic reticulum to Golgi vesicle-mediated transport
    modifier: DECREASED
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
  cellular_components:
  - preferred_term: COPII vesicle coat
    term:
      id: GO:0030127
      label: COPII vesicle coat
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ER export of procollagen was inefficient and that ER tubules were dilated"
    explanation: Fibroblast microscopy shows the COPII-dependent procollagen export defect underlying CCS2.
  downstream:
  - target: Defective type I collagen biosynthesis
    description: Inefficient COPII export of procollagen reduces effective type I collagen secretion.
    causal_link_type: DIRECT
- name: Defective type I collagen biosynthesis
  description: >
    Both genetic arms converge on defective type I collagen biosynthesis and
    secretion, the central pathogenic mechanism of CCS. In the P4hb Y393C mouse
    model, reduced circulating PINP and lower osteoblast collagen expression and
    secretion quantify the collagen deficit.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: collagen biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  evidence:
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CCS mice exhibited reduced circulating levels of procollagen type I N-terminal propeptide (PINP I), indicating decreased type I collagen biosynthesis."
    explanation: The mouse model shows reduced PINP, a direct biomarker of decreased type I collagen biosynthesis.
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "primary osteoblasts isolated from CCS mice showed lower expression and secretion of type I collagen, along with decreased expression of osteocalcin and higher mineralization."
    explanation: Cultured mutant osteoblasts confirm reduced collagen expression and secretion at the cellular level.
  downstream:
  - target: Reduced bone quality and skeletal fragility
    description: Deficient type I collagen matrix produces osteopenia and brittle bone.
    causal_link_type: DIRECT
  - target: Increased osteoclastic bone resorption
    description: The mutant bone environment is associated with increased osteoclast differentiation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased osteoclastic bone resorption
  description: >
    Alongside the osteoblast collagen defect, the P4hb Y393C model shows increased
    osteoclast differentiation, a resorptive component that can further compromise
    bone mass.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0030316
      label: osteoclast differentiation
  evidence:
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "On the other hand, osteoclast differentiation was increased."
    explanation: Increased osteoclast differentiation adds a resorptive contribution to the skeletal phenotype in the model.
  downstream:
  - target: Reduced bone quality and skeletal fragility
    description: Excess osteoclastic resorption compounds low bone mass.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced bone quality and skeletal fragility
  description: >
    The collagen-biosynthesis defect yields an osteogenesis-imperfecta-like
    skeleton with pronounced osteopenia and reduced bone quality, the substrate for
    recurrent fractures, long-bone bowing, disturbed skull ossification, and
    craniosynostosis.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  locations:
  - preferred_term: bone tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  biological_processes:
  - preferred_term: ossification
    modifier: DYSREGULATED
    term:
      id: GO:0001503
      label: ossification
  evidence:
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Comprehensive skeletal phenotyping revealed pronounced osteopenia and reduced local bone quality in mutant mice across multiple ages."
    explanation: The mouse model recapitulates osteopenia and reduced bone quality, linking the collagen defect to the fragile-bone phenotype.
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset."
    explanation: CCS2 patients show disturbed skull ossification and multiple early fractures, the human skeletal-fragility phenotype.
  downstream:
  - target: Recurrent fractures
  - target: Reduced bone mineral density
  - target: Bowing of the long bones
  - target: Craniosynostosis
phenotypes:
- name: Recurrent fractures
  category: Musculoskeletal
  diagnostic: true
  description: Frequent fractures from severe bone fragility are a defining feature of Cole-Carpenter syndrome.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
    explanation: Frequent fractures are part of the defining CCS phenotype.
- name: Craniosynostosis
  category: Craniofacial
  diagnostic: true
  description: Premature cranial suture fusion is a cardinal craniofacial feature of CCS.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
    explanation: Craniosynostosis is part of the defining CCS phenotype.
- name: Ocular proptosis
  category: Ophthalmologic
  diagnostic: true
  description: Ocular proptosis (exophthalmos) is a hallmark craniofacial feature of CCS.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
    explanation: Ocular proptosis is part of the defining CCS phenotype.
- name: Hydrocephalus
  category: Nervous System
  description: Hydrocephalus is a recurrent central nervous system feature of CCS.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features."
    explanation: Hydrocephalus is part of the defining CCS phenotype.
- name: Frontal bossing
  category: Craniofacial
  description: Prominent frontal bossing is a characteristic craniofacial feature.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia"
    explanation: Marked frontal bossing is reported as a craniofacial feature in a CCS2 patient.
- name: Midface retrusion
  category: Craniofacial
  description: Midface hypoplasia/retrusion contributes to the distinctive CCS facial appearance.
  phenotype_term:
    preferred_term: Midface hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia"
    explanation: Midface hypoplasia is reported among the CCS craniofacial features.
- name: Micrognathia
  category: Craniofacial
  description: Micrognathia is part of the distinctive craniofacial gestalt of CCS.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia"
    explanation: Micrognathia is reported among the CCS craniofacial features.
- name: Short stature
  category: Growth
  description: Growth failure with short stature is a frequent feature of CCS.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures."
    explanation: Short stature is reported in a CCS2-phenotype patient.
- name: Macrocephaly
  category: Craniofacial
  description: Macrocephaly is reported among the craniofacial malformations in CCS.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures"
    explanation: Macrocephaly is reported among the CCS2 craniofacial malformations.
- name: Downslanted palpebral fissures
  category: Craniofacial
  description: Down-slanting palpebral fissures are part of the CCS facial phenotype.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:25683121
    reference_title: "Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures"
    explanation: Down-slanting palpebral fissures are reported among the CCS2 craniofacial features.
- name: Reduced bone mineral density
  category: Musculoskeletal
  description: Low bone mineral density reflects the osteopenic, fragile skeleton of CCS.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had low-bone mineral density and basilar impression."
    explanation: Low bone mineral density is documented in a genetically confirmed CCS2 patient.
diagnosis:
- name: Molecular genetic testing
  description: >
    Definitive diagnosis rests on identifying a pathogenic P4HB variant (CCS1) or
    biallelic SEC24D variants (CCS2), typically by whole-exome sequencing or a
    skeletal-dysplasia/osteogenesis-imperfecta gene panel.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: A pathogenic P4HB or biallelic SEC24D genotype confirms the subtype.
  evidence:
  - reference: PMID:25683117
    reference_title: "Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we performed whole-exome sequencing"
    explanation: Whole-exome sequencing established the molecular diagnosis of CCS1.
  - reference: PMID:30462379
    reference_title: "Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient."
    explanation: Whole-exome sequencing identified the biallelic SEC24D genotype diagnostic of CCS2.
treatments:
- name: Supportive and bone-directed management
  description: >
    There is no established disease-modifying therapy for Cole-Carpenter syndrome.
    Care is supportive and multidisciplinary, directed at fracture management,
    orthopedic care, monitoring of craniosynostosis and hydrocephalus, and
    bone-health optimization.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Given the lack of disease-modifying therapies for CCS, we explored different therapeutic strategies."
    explanation: The absence of disease-modifying therapy underlies the current reliance on supportive management.
- name: Allele-specific siRNA silencing (investigational)
  description: >
    Investigational, preclinical allele-specific RNA interference strategy for the
    dominant P4HB (CCS1) form. siRNA sequences selectively silenced the mutant
    P4hb allele in vitro and ex vivo without cytotoxicity, aiming to remove the
    dominant-negative transcript while sparing the wild-type allele.
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: P4HB/PDI disulfide isomerase dysfunction
    treatment_effect: INHIBITS
    description: >
      Selective knockdown of the mutant P4hb allele is intended to eliminate the
      dysfunctional PDI while preserving wild-type disulfide isomerase activity.
    evidence:
    - reference: PMID:42425402
      reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we developed an allele-specific RNA interference (siRNAs) approach and identified siRNA sequences capable of selectively silencing the mutant P4hb allele in vitro and ex vivo without cytotoxic effects."
      explanation: Allele-specific siRNA selectively silences the mutant P4hb allele, a targeted strategy against the CCS1 dominant defect.
  evidence:
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we developed an allele-specific RNA interference (siRNAs) approach and identified siRNA sequences capable of selectively silencing the mutant P4hb allele in vitro and ex vivo without cytotoxic effects."
    explanation: Preclinical proof-of-concept only; no in vivo efficacy or human data are established.
- name: Collagen-secretion-enhancing drug repurposing (investigational)
  description: >
    Investigational strategy from a functional screen of an FDA-approved drug
    library, which identified four compounds that significantly enhanced type I
    collagen secretion in the CCS cellular model. This is an early, preclinical
    lead toward correcting the central collagen-biosynthesis defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Defective type I collagen biosynthesis
    treatment_effect: RESTORES
    description: >
      The identified compounds enhanced type I collagen secretion, partially
      countering the central biosynthetic defect in cellular assays.
    evidence:
    - reference: PMID:42425402
      reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We performed a functional screen of an FDA-approved drug library identifying four compounds that significantly enhanced type I collagen secretion."
      explanation: Drug-repurposing hits enhance collagen secretion, targeting the central pathogenic mechanism in vitro.
  evidence:
  - reference: PMID:42425402
    reference_title: "Generation of a P4hb(Y393C) mouse model of cole-carpenter syndrome and therapeutic proof-of-concept."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "identifies promising therapeutic strategies with translational potential for this currently untreatable skeletal disorder."
    explanation: The compounds are promising but preclinical leads without clinical validation.