Caffey disease

Summary

Caffey disease (MONDO:0007244) is a disease caused by COL1A1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: COL1A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 212
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0005731	Cortical irregularity	Very frequent (80-99%)
HP:0100658	Cellulitis	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0006465	Periosteal thickening of long tubular bones	Frequent (30-79%)
HP:0100963	Hyperesthesia	Frequent (30-79%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0004490	Calvarial hyperostosis	Occasional (5-29%)
HP:0005791	Cortical thickening of long bone diaphyses	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0010702	Increased circulating antibody level	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Caffey disease
Mondo ID	MONDO:0007244
MeSH	D006958
OMIM	114000
Orphanet	1310
DOID	DOID:4257
NCIT	C118423
SNOMED CT	24752008
UMLS	C0020497
MedGen	43781
GARD	0001051
Is cancer (heuristic)	no

Also known as: Caffey disease · infantile cortical hyperostosis

Data availability: 212 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › hyperostosis › Caffey disease

Related subtypes (8): exostosis, bone Paget disease, diffuse idiopathic skeletal hyperostosis, autosomal dominant osteosclerosis, Worth type, craniodiaphyseal dysplasia, hyperostosis corticalis generalisata, X-linked calvarial hyperostosis, sclerosteosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

212 retrieved; paginated sample, class counts are floors:

83 conflicting classifications of pathogenicity, 42 uncertain significance, 26 benign/likely benign, 25 pathogenic, 13 pathogenic/likely pathogenic, 13 benign, 9 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076006	NM_000088.4(COL1A1):c.288del (p.Asp97fs)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1254747	NM_000088.4(COL1A1):c.1177C>T (p.Gln393Ter)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342741	NM_000088.4(COL1A1):c.1444G>A (p.Gly482Arg)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1431093	NM_000088.4(COL1A1):c.1667del (p.Pro556fs)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685271	NM_000088.4(COL1A1):c.608G>A (p.Gly203Asp)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685647	NM_000088.4(COL1A1):c.1192G>C (p.Gly398Arg)	COL1A1	Pathogenic	criteria provided, single submitter
17285	NM_000088.4(COL1A1):c.814G>T (p.Gly272Cys)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17312	NM_000088.4(COL1A1):c.994G>A (p.Gly332Arg)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17313	NM_000088.4(COL1A1):c.3541G>A (p.Gly1181Ser)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17343	NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17347	NM_000088.4(COL1A1):c.3040C>T (p.Arg1014Cys)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1805989	NM_000088.4(COL1A1):c.3540del (p.Gly1181fs)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2772795	NM_000088.4(COL1A1):c.2597del (p.Gly866fs)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2780397	NM_000088.4(COL1A1):c.598G>A (p.Gly200Ser)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287320	NM_000088.4(COL1A1):c.2089C>T (p.Arg697Ter)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
3256564	NM_000088.4(COL1A1):c.2752C>T (p.Arg918Cys)	COL1A1	Pathogenic	criteria provided, single submitter
3382929	NM_000088.4(COL1A1):c.635G>A (p.Gly212Glu)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35907	NM_000088.4(COL1A1):c.2062C>T (p.Gln688Ter)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35920	NM_000088.4(COL1A1):c.3076C>T (p.Arg1026Ter)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
425580	NM_000088.4(COL1A1):c.1821+1G>A	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
425583	NM_000088.4(COL1A1):c.2343+1G>A	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
425589	NM_000088.4(COL1A1):c.3505G>A (p.Gly1169Ser)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
425597	NM_000088.4(COL1A1):c.1243C>T (p.Arg415Ter)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
425599	NM_000088.4(COL1A1):c.1299+1G>A	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
425606	NM_000088.4(COL1A1):c.2155G>A (p.Gly719Ser)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
425618	NM_000088.4(COL1A1):c.3226G>A (p.Gly1076Ser)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
425639	NM_000088.4(COL1A1):c.769G>A (p.Gly257Arg)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
447141	NM_000088.4(COL1A1):c.2362G>A (p.Gly788Ser)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
450546	NM_000088.4(COL1A1):c.985G>C (p.Gly329Arg)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
456724	NM_000088.4(COL1A1):c.1012G>A (p.Gly338Ser)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
COL1A1	Definitive	Autosomal dominant	Caffey disease	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	gencc,clinvar
A4GALT	HGNC:18149	ENSG00000128274	Q9NPC4	Lactosylceramide 4-alpha-galactosyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
A4GALT	Lactosylceramide 4-alpha-galactosyltransferase	Glycosyltransferase involved in biosynthesis of P1, P(k) and the rare NOR antigens of P1PK histo-blood group system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
A4GALT	Enzyme (other)	yes	2.4.1.228	GlycoTrfase_DXD_sugar-bd_CS, A1-4-GlycosylTfrase_dom, Nucleotide-diphossugar_trans

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
periodontal ligament	1
skin of hip	1
stromal cell of endometrium	1
apex of heart	1
olfactory segment of nasal mucosa	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
A4GALT	186	ubiquitous	marker	apex of heart, olfactory segment of nasal mucosa, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
A4GALT	814

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL1A1	P02452	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
A4GALT	Q9NPC4	89.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective VWF binding to collagen type I	1	1903.3×	0.007	COL1A1
Enhanced cleavage of VWF variant by ADAMTS13	1	1427.5×	0.007	COL1A1
Defective VWF cleavage by ADAMTS13 variant	1	1427.5×	0.007	COL1A1
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	815.7×	0.008	COL1A1
Defective binding of VWF variant to GPIb:IX:V	1	815.7×	0.008	COL1A1
GP1b-IX-V activation signalling	1	475.8×	0.009	COL1A1
Anchoring fibril formation	1	380.7×	0.009	COL1A1
Platelet Adhesion to exposed collagen	1	335.9×	0.009	COL1A1
Scavenging by Class A Receptors	1	300.5×	0.009	COL1A1
Glycosphingolipid biosynthesis	1	300.5×	0.009	A4GALT
Fibronectin matrix formation	1	285.5×	0.009	COL1A1
Crosslinking of collagen fibrils	1	285.5×	0.009	COL1A1
RUNX2 regulates osteoblast differentiation	1	228.4×	0.010	COL1A1
Platelet Aggregation (Plug Formation)	1	219.6×	0.010	COL1A1
Syndecan interactions	1	211.5×	0.010	COL1A1
MET activates PTK2 signaling	1	190.3×	0.010	COL1A1
GPVI-mediated activation cascade	1	154.3×	0.011	COL1A1
Glycosphingolipid metabolism	1	150.3×	0.011	A4GALT
Collagen chain trimerization	1	129.8×	0.013	COL1A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.014	COL1A1
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.015	COL1A1
Collagen degradation	1	87.8×	0.015	COL1A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.015	COL1A1
Sphingolipid metabolism	1	84.0×	0.015	A4GALT
Non-integrin membrane-ECM interactions	1	77.2×	0.016	COL1A1
ECM proteoglycans	1	75.1×	0.016	COL1A1
Integrin cell surface interactions	1	67.2×	0.017	COL1A1
Cell surface interactions at the vascular wall	1	47.6×	0.023	COL1A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.024	COL1A1
Metabolism of lipids	1	15.8×	0.064	A4GALT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to vitamin E	1	8426.0×	0.004	COL1A1
cellular response to fluoride	1	4213.0×	0.004	COL1A1
globoside biosynthetic process	1	2808.7×	0.004	A4GALT
tooth mineralization	1	2808.7×	0.004	COL1A1
cellular response to acetaldehyde	1	1685.2×	0.005	COL1A1
intramembranous ossification	1	1404.3×	0.005	COL1A1
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.005	COL1A1
bone trabecula formation	1	1053.2×	0.005	COL1A1
skin morphogenesis	1	702.2×	0.006	COL1A1
collagen-activated tyrosine kinase receptor signaling pathway	1	648.1×	0.006	COL1A1
response to hyperoxia	1	561.7×	0.006	COL1A1
negative regulation of cell-substrate adhesion	1	526.6×	0.006	COL1A1
collagen biosynthetic process	1	526.6×	0.006	COL1A1
plasma membrane organization	1	443.5×	0.007	A4GALT
response to steroid hormone	1	421.3×	0.007	COL1A1
glycosphingolipid biosynthetic process	1	300.9×	0.009	A4GALT
endochondral ossification	1	271.8×	0.009	COL1A1
cellular response to fibroblast growth factor stimulus	1	271.8×	0.009	COL1A1
response to cAMP	1	255.3×	0.009	COL1A1
face morphogenesis	1	247.8×	0.009	COL1A1
response to hydrogen peroxide	1	234.1×	0.009	COL1A1
embryonic skeletal system development	1	195.9×	0.010	COL1A1
blood vessel development	1	187.2×	0.010	COL1A1
protein localization to nucleus	1	175.5×	0.010	COL1A1
positive regulation of epithelial to mesenchymal transition	1	159.0×	0.011	COL1A1
cellular response to epidermal growth factor stimulus	1	159.0×	0.011	COL1A1
cellular response to amino acid stimulus	1	153.2×	0.011	COL1A1
cellular response to transforming growth factor beta stimulus	1	138.1×	0.011	COL1A1
cellular response to glucose stimulus	1	133.8×	0.011	COL1A1
cellular response to retinoic acid	1	117.0×	0.012	COL1A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL1A1	0	0
A4GALT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
COL1A1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
A4GALT	2.4.1.228	lactosylceramide 4-alpha-galactosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	A4GALT
E	Difficult family or no structure, no drug	1	COL1A1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL1A1	8	—
A4GALT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.