Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome

Mendelian MONDO:0008828 Pathograph 42 Show in embeddings browser rheumatic disorder hereditary disorder of connective tissue autosomal recessive disease

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive disorder caused by biallelic loss-of-function variants in PRG4, which encodes lubricin (proteoglycan 4, also called superficial zone protein), a secreted mucinous glycoprotein made by synovial fibroblasts and superficial zone chondrocytes. Lubricin is the boundary lubricant of articular cartilage, limits synoviocyte growth, and coats tendon sheaths and the pericardial and pleural surfaces. Its absence leaves joint surfaces unlubricated, so friction rises, superficial chondrocytes die and the cartilage wears out early, while the synovial lining becomes hyperplastic and the joints fill with non-inflammatory effusions. Affected children have congenital or early camptodactyly, then symmetric swelling of wrists, elbows, knees and ankles, and develop coxa vara with short femoral necks, flattened femoral heads and acetabular cysts; hip disease becomes severe by early adulthood. A minority develop non-inflammatory pericardial or pleural effusions or ascites, and constrictive pericarditis can cause protein-losing enteropathy. Inflammatory markers are normal, and the condition is frequently misdiagnosed and treated as juvenile idiopathic arthritis. There is no disease-modifying therapy; recombinant lubricin is under preclinical study.

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1
Inheritance
8
Pathophys.
21
Phenotypes
42
Pathograph
1
Genes
7
Variants
7
Medical Actions
2
Differentials
2
Models
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry two PRG4 loss-of-function alleles, usually the same allele in homozygous state in consanguineous families. One affected individual received both PRG4 copies from one parent through uniparental disomy of chromosome 1.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:10545950 SUPPORT Human Clinical
"We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250)"
States the recessive mode of inheritance in the gene-discovery paper.
PMID:9550484 SUPPORT Human Clinical
"A genome-wide search for linkage identified homozygosity for a series of genetic markers on human chromosome 1q in all affected patients."
Homozygosity mapping in consanguineous kindreds is the segregation pattern of a recessive disorder.
PMID:23756439 SUPPORT Human Clinical
"the first case of CACP syndrome resulting from uniparental disomy of chromosome 1"
Uniparental disomy is an alternative route to biallelic PRG4 loss in a recessive disorder.
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Pathophysiology

8
PRG4 Biallelic Loss of Function
Disease-causing PRG4 alleles are almost all frameshift or nonsense variants, with a whole-exon-1 deletion also reported, found in homozygous or compound heterozygous state. Synovial fluid from patients with truncating alleles contains no detectable lubricin. One stop-gain in the last exon is predicted to escape nonsense-mediated decay, but the truncated protein is not processed normally.
PRG4 hgnc:9364 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRG4 (hgnc:9364). hgnc:9364 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Lubricin Deficiency at Joint, Tendon and Serosal Surfaces Loss of both PRG4 alleles removes the secreted lubricin protein.
Show evidence (5 references)
PMID:10545950 SUPPORT Human Clinical
"Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP."
Identifies PRG4 (originally named CACP) as the disease gene.
PMID:16429407 SUPPORT Human Clinical
"Because all mutations reported in CACP patients thus far predict premature truncation"
The disease alleles are truncating, consistent with loss of function.
PMID:16000300 SUPPORT In Vitro
"However, the antiserum did not detect lubricin in synovial fluid or cultured synoviocytes from several patients with frameshift or nonsense mutations in PRG4."
Truncating alleles result in absent lubricin protein in patient synovial fluid and synoviocytes.
+ 2 more references
Lubricin Deficiency at Joint, Tendon and Serosal Surfaces
Lubricin is normally secreted by synovial lining fibroblasts and superficial zone chondrocytes into synovial fluid and onto the cartilage surface, and is also present on tendons and tendon sheaths and in the pericardial and pleural cavities. In CACP it is absent from these sites, removing boundary lubrication, an anti-adhesive surface coating, and a brake on synoviocyte growth.
fibroblast-like synoviocyte CL:0002301 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast-like synoviocyte, annotated with type B synovial cell (CL:0002301). CL:0002301 is a cell type from the Cell Ontology. superficial zone articular chondrocyte CL:0020037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves superficial zone articular chondrocyte (CL:0020037). CL:0020037 is a cell type from the Cell Ontology.
PRG4 hgnc:9364 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRG4 (hgnc:9364). hgnc:9364 is a gene from the HUGO Gene Nomenclature Committee.
boundary lubricant activity GO:0030197 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased boundary lubricant activity, annotated with extracellular matrix constituent, lubricant activity (GO:0030197). GO:0030197 is a molecular function from the Gene Ontology.
Downstream
Loss of Cartilage Boundary Lubrication and Increased Joint Friction
Fibroblast-Like Synoviocyte Overgrowth
Tendon and Tendon Sheath Surface Dysfunction
Serosal Surface Lubricin Deficiency and Effusion Lubricin is expressed in pericardium and present in the pleural and pericardial cavities; how its absence produces effusion and pericardial thickening has not been studied experimentally.
Show evidence (3 references)
PMID:15719068 SUPPORT Model Organism
"Prg4 began to be expressed in surface chondrocytes and synoviocytes after joint cavitation had occurred and remained strongly expressed by these cells postnatally."
Identifies surface chondrocytes and synoviocytes as the lubricin-producing cells in the joint.
PMID:10545950 SUPPORT Human Clinical
"In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium."
Pericardial expression links the protein to the serosal features of the syndrome.
PMID:25642942 SUPPORT BACKGROUND Human Clinical
"and in the pericardial and pleural cavities, where it likely serves an anti-adhesive function."
Introduction statement placing lubricin in the pericardial and pleural cavities, extra-articular sites affected in CACP.
Loss of Cartilage Boundary Lubrication and Increased Joint Friction
Without lubricin, the articular surface loses its boundary lubricant and proteins deposit on the cartilage. Whole-joint and cartilage-surface friction rise, and the surface layer becomes enlarged, fragmented and roughened. Joints are normal at birth and the changes accumulate with age.
cartilage homeostasis GO:1990079 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cartilage homeostasis (GO:1990079). GO:1990079 is a biological process from the Gene Ontology.
Animal models
Prg4-null mouse (Coles 2010, hip) Mouse recapitulates
Downstream
Friction-Induced Superficial Chondrocyte Apoptosis
Show evidence (3 references)
PMID:17968947 SUPPORT Model Organism
"Joints of lubricin-null mice showed early wear and higher friction than joints from their wild-type counterparts."
Direct measurement of increased friction and early wear in lubricin-null joints.
PMID:20191580 SUPPORT Model Organism
"Friction was significantly higher on cartilage of Prg4(-/-) mice at age 16 weeks, but statistically significant differences in friction were not detected at younger ages."
An independent Prg4-null line shows an age-dependent rise in cartilage friction.
PMID:15719068 SUPPORT Model Organism
"As the mice aged, we observed abnormal protein deposits on the cartilage surface and disappearance of underlying superficial zone chondrocytes."
Surface protein deposition and loss of superficial chondrocytes develop with age in lubricin-null joints.
Friction-Induced Superficial Chondrocyte Apoptosis
Unlubricated loading stresses superficial and upper intermediate zone chondrocytes, which undergo intrinsic (mitochondrial) apoptosis with caspase-9 and caspase-3 activation and accumulation of peroxynitrite and superoxide. In the conserved osteoarthritis cascade this is the chondrocyte stress step; here the trigger is loss of boundary lubrication rather than malalignment or injury.
superficial zone articular chondrocyte CL:0020037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves superficial zone articular chondrocyte (CL:0020037). CL:0020037 is a cell type from the Cell Ontology.
response to mechanical stimulus GO:0009612 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to mechanical stimulus (GO:0009612). GO:0009612 is a biological process from the Gene Ontology. cellular response to stress GO:0033554 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to stress (GO:0033554). GO:0033554 is a biological process from the Gene Ontology. chondrocyte apoptosis GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased chondrocyte apoptosis, annotated with apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Downstream
Progressive Cartilage Wear and Precocious Joint Failure
Show evidence (3 references)
PMID:23530215 SUPPORT Model Organism
"We observed increases in whole-joint friction and cellular apoptosis in lubricin knockout mice compared with wild-type mice."
Lubricin-null joints show both higher friction and more chondrocyte apoptosis.
PMID:28604608 SUPPORT Model Organism
"Non-lubricated Prg4-/- mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation"
Identifies the intrinsic mitochondrial apoptotic pathway in non-lubricated cartilage.
PMID:26975998 SUPPORT Model Organism
"Living chondrocyte volume fraction of the medial femoral condyle was significantly lower in Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.002)"
Quantifies the loss of living superficial and upper intermediate zone chondrocytes in lubricin-null cartilage.
Fibroblast-Like Synoviocyte Overgrowth
The synovial lining becomes hypercellular. Proliferating cells are fibroblastic synoviocytes, and the lining is infiltrated by CD68-positive macrophages including multinucleated giant cells; lymphocytes and neutrophils are sparse, so the synovitis is proliferative rather than inflammatory.
fibroblast-like synoviocyte CL:0002301 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast-like synoviocyte, annotated with type B synovial cell (CL:0002301). CL:0002301 is a cell type from the Cell Ontology. synovial macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves synovial macrophage, annotated with macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
synoviocyte proliferation GO:0002941 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased synoviocyte proliferation (GO:0002941). GO:0002941 is a biological process from the Gene Ontology.
Animal models
Prg4-null mouse (Rhee 2005) Mouse recapitulates
Downstream
Synovial lining hyperplasia
Joint swelling Joint swelling reflects large non-inflammatory effusions together with the thickened synovium; the source of the excess fluid is not established.
Progressive Cartilage Wear and Precocious Joint Failure
Show evidence (3 references)
PMID:15702367 SUPPORT Human Clinical
"By double immunostaining, proliferating cells were determined to be fibroblastic synoviocytes rather than macrophages."
Patient synovial biopsies identify fibroblastic synoviocytes as the proliferating population.
PMID:15702367 SUPPORT Human Clinical
"Thus the proliferative synovitis in this CACP syndrome can be more accurately thought of as hypercellularity by infiltrating macrophages with a contribution by proliferating fibroblastic synoviocytes."
Describes the macrophage-rich hypercellular synovium.
PMID:15719068 SUPPORT Model Organism
"intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure"
Lubricin-null mice reproduce synovial intimal hyperplasia.
Progressive Cartilage Wear and Precocious Joint Failure
Joints that are normal at birth deteriorate with use. In mice the cartilage surface roughens and pericellular proteoglycan is progressively lost; in patients the number of skeletal features rises with age, pain increases after about age 10, and severe hip disease develops in early adulthood, a course the cohort authors attribute to cumulative mechanical stress.
extracellular matrix disassembly GO:0022617 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix disassembly (GO:0022617). GO:0022617 is a biological process from the Gene Ontology.
Animal models
Prg4-null mouse (Rhee 2005) Mouse recapitulates
Downstream
Non-inflammatory arthropathy
Limitation of joint mobility
Arthralgia
Coxa vara Coxa vara and other hip dysplasia accompany progressive hip disease; how lubricin loss alters proximal femoral growth is not established.
Short femoral neck
Flattened femoral head
Lumbar hyperlordosis Increased lumbar lordosis appears in older patients with severe hip involvement; whether it is compensatory or a direct spinal effect is not established.
Show evidence (3 references)
PMID:20191580 SUPPORT Model Organism
"Deletion of the gene Prg4 results in significant structural and biomechanical changes in the articular cartilage with age, some of which are consistent with osteoarthritic degeneration."
Prg4 loss produces age-dependent osteoarthritis-like cartilage degeneration.
PMID:20191580 SUPPORT Model Organism
"a roughened underlying articular cartilage surface, and a progressive loss of pericellular proteoglycans"
Documents progressive matrix proteoglycan loss under the abnormal surface layer.
PMID:29397575 SUPPORT Human Clinical
"This increase in symptoms is likely due to cumulative mechanical stress over time"
In patients, the age-related accumulation of features is attributed to mechanical wear.
Tendon and Tendon Sheath Surface Dysfunction
Without lubricin, tendon sheaths fill with effusion and, in the knockout mouse, undergo morphologic change and abnormal calcification. Adhesions between tendons and their sheaths have been described in patients, and ultrasound shows symmetric non-vascular tenosynovial effusions, including around the finger flexor tendons.
Animal models
Prg4-null mouse (Rhee 2005) Mouse partially recapitulates
Downstream
Tenosynovitis
Show evidence (2 references)
PMID:42327906 SUPPORT Human Clinical
"Marked symmetrical tenosynovitis involving multiple tendon regions, including shoulder (biceps), elbow extensors, wrist extensors, posterior tibialis, and flexor digitorum tendons, was observed in the CACP group"
Ultrasound documents widespread tendon sheath involvement in patients.
PMID:25642942 SUPPORT BACKGROUND Human Clinical
"Among the clinical consequences of CACP are non-inflammatory synovial cell hyperplasia, precocious joint failure, adhesions between tendons and tendon sheaths, and restrictive pericarditis"
Background summary listing tendon-sheath adhesions among the consequences of CACP.
Serosal Surface Lubricin Deficiency and Effusion
In a minority of patients the pericardium and pleura develop non-inflammatory effusions, and the pericardium can thicken and constrict. Ascites also occurs. The mechanism is presumed to parallel the joint disease, with loss of the anti-adhesive serosal lubricant, but it has not been investigated directly.
Downstream
Serositis
Pericarditis
Pericardial effusion
Constrictive pericarditis
Pleural effusion
Ascites
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"seven patients (~22%) had pleural effusion, pericarditis, and/or ascites"
Serosal involvement occurs in a minority of a large cohort.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Camptodactyly-Arthropathy-Coxa Vara-Pericarditis 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.
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Phenotypes

21
Cardiovascular 4
Pericarditis OCCASIONAL HP:0001701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-inflammatory pericarditis, annotated with Pericarditis (HP:0001701). HP:0001701 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16429407 SUPPORT Human Clinical
"while pericarditis is evident in only one-fifth of all reported cases"
Pericarditis in about one-fifth of reported cases, an occasional feature.
PMID:23290693 SUPPORT Human Clinical
"All patients had a normal cardiac evaluation but two children had evidence of pericarditis."
Two of 22 Saudi patients had pericarditis.
Pericardial effusion OCCASIONAL HP:0001698 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pericardial effusion (HP:0001698). HP:0001698 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pericardial effusions were previously reported between 6% and 30% of CACP patients"
The cohort paper's summary of earlier reports gives a frequency within the occasional band.
Constrictive pericarditis HP:0002563 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constrictive pericarditis (HP:0002563). HP:0002563 is a phenotype from the Human Phenotype Ontology.
Sequelae: Protein-losing enteropathy
Show evidence (2 references)
PMID:27751317 SUPPORT Human Clinical
"Transthoracic echocardiography revealed pericardial thickening and with features of constriction. Cardiac catheterization supported the diagnosis of constrictive pericarditis"
Constrictive pericarditis confirmed by catheterization in a patient with CACP.
PMID:38955384 SUPPORT Human Clinical
"The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis."
Constrictive pericarditis preceded the joint disease and was first treated as tuberculosis.
Mitral valve prolapse HP:0001634 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral valve prolapse (HP:0001634). HP:0001634 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"Four patients had mitral regurgitation or mitral valve prolapse on echocardiography."
Mitral valve findings in four patients of the cohort.
Digestive 2
Ascites HP:0001541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ascites (HP:0001541). HP:0001541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"Seven patients had pleural effusion, ascites, and/or pericarditis."
Ascites among the serosal features of the cohort.
Protein-losing enteropathy HP:0002243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protein-losing enteropathy (HP:0002243). HP:0002243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27224999 SUPPORT Human Clinical
"Increased alpha antitrypsin clearance confirmed PLE."
Laboratory confirmation of protein-losing enteropathy in a child with CACP.
Immune 1
Serositis OCCASIONAL HP:0045073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-inflammatory serositis, annotated with Serositis (HP:0045073). HP:0045073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"seven patients (~22%) had pleural effusion, pericarditis, and/or ascites"
About 22% of the 35-patient cohort had some serosal involvement, within the occasional band.
Limbs 4
Camptodactyly VERY_FREQUENT Camptodactyly of finger HP:0100490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly of finger (HP:0100490). HP:0100490 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:23290693 SUPPORT Human Clinical
"Camptodactyly was observed in the neonatal period in all the patients, while other joint involvement was observed through the 1st year of life."
Camptodactyly was present from the neonatal period in all 22 Saudi patients.
PMID:38856641 SUPPORT Human Clinical
"Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)"
Camptodactyly in 13 of 13 Indian patients.
PMID:29397575 SUPPORT Human Clinical
"For 68% of patients (19 of 28), camptodactyly was the earliest symptom and appeared to be mostly bilateral and progressive."
Camptodactyly is usually the first sign and is bilateral and progressive.
+ 1 more reference
Coxa vara VERY_FREQUENT HP:0002812 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coxa vara (HP:0002812). HP:0002812 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29397575 SUPPORT Human Clinical
"All patients presented developmental coxa vara"
Coxa vara in all 35 patients.
PMID:38856641 SUPPORT Human Clinical
"Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)"
Coxa vara in 11 of 13 patients.
PMID:9550484 SUPPORT Human Clinical
"Seven patients developed bilateral coxa vara deformity, and 1 developed coxa magna with cystic erosions."
Bilateral coxa vara in seven of eight patients.
Short femoral neck VERY_FREQUENT HP:0100864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short femoral neck (HP:0100864). HP:0100864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38856641 SUPPORT Human Clinical
"Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)"
Short femoral neck in 11 of 13 patients.
Flattened femoral head HP:0008812 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flattened femoral head (HP:0008812). HP:0008812 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23290693 SUPPORT Human Clinical
"Radiological findings included coxa vara with a short femoral neck and flat, irregular femoral heads and intra-osseous cysts, increased joint space, and abnormal modeling of the acetabulum with small iliac wings."
Flat, irregular femoral heads on radiographs.
Metabolism 2
Joint swelling VERY_FREQUENT HP:0001386 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint swelling (HP:0001386). HP:0001386 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29397575 SUPPORT Human Clinical
"Swelling of wrists, knees, and elbows began before 4 years of age"
Early joint swelling in the 35-patient cohort.
PMID:42327906 SUPPORT Human Clinical
"All four children with CACP showed symmetrical joint involvement, with effusion present in 46/46 scanned joints and no intrasynovial hypervascularity (median DM = 0)."
Effusion was present in every scanned joint without inflammatory hypervascularity.
Pleural effusion HP:0002202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pleural effusion (HP:0002202). HP:0002202 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29397575 SUPPORT Human Clinical
"seven patients (~22%) had pleural effusion, pericarditis, and/or ascites"
Pleural effusion among the serosal features of the cohort.
PMID:27751317 SUPPORT Human Clinical
"There was moderate right-sided pleural effusion and no cardiomegaly"
Pleural effusion in a patient with CACP.
PMID:40830943 SUPPORT Human Clinical
"The patient first exhibited symptoms at 10 days of age with respiratory distress due to pleural effusion and later underwent pericardiectomy for significant pericardial effusion."
Serosal disease can begin in the neonatal period, before the arthropathy.
Musculoskeletal 7
Non-inflammatory arthropathy VERY_FREQUENT HP:0003040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-inflammatory arthropathy, annotated with Arthropathy (HP:0003040). HP:0003040 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9550484 SUPPORT Human Clinical
"Congenital camptodactyly and childhood-onset noninflammatory arthropathy were present in all affected patients."
Non-inflammatory arthropathy in all eight patients.
PMID:23290693 SUPPORT Human Clinical
"Camptodactyly and large joints arthropathy were present in all the cases."
Large-joint arthropathy in all 22 patients.
Synovial lining hyperplasia HP:0005186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synovial lining hyperplasia (HP:0005186). HP:0005186 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23290693 SUPPORT Human Clinical
"Synovial biopsy from three patients revealed proliferating synovial epithelium with moderate fibro-collagenous densities and multinucleated giant cells, occasional lymphocytes or neutrophils were identified."
Patient synovial biopsies show a proliferating lining with few inflammatory cells.
PMID:27751317 SUPPORT Human Clinical
"Knee joint synovial fluid biopsy revealed synovial hyperplasia with minimal inflammatory cells"
Synovial hyperplasia without inflammation in a further patient.
Limitation of joint mobility VERY_FREQUENT HP:0001376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limitation of joint mobility (HP:0001376). HP:0001376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"Large joint involvement was found in all of our patients and it included symmetrical noninflammatory arthropathy resulting in swelling, limited motion, and in flexion contractures."
Limited motion and flexion contractures in all patients of the cohort.
Tenosynovitis HP:6001438 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-inflammatory tenosynovial effusion, annotated with Tenosynovitis (HP:6001438). HP:6001438 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42327906 SUPPORT Human Clinical
"All 16/16 scanned tendons in the CACP group showed no DM signal, whereas hypervascularity was observed in 7/8 affected tendons in the JIA cohort."
Tendon involvement in CACP lacks the hypervascularity of inflammatory tenosynovitis.
Acetabular cysts Bone cyst HP:0012062 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acetabular bone cyst, annotated with Bone cyst (HP:0012062). HP:0012062 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16037531 SUPPORT Human Clinical
"In the correct clinical setting, large acetabular cysts on pelvic radiographs may be considered pathognomonic of CACP syndrome."
Acetabular cysts as a pathognomonic radiographic sign.
PMID:27748313 SUPPORT Human Clinical
"Radiographs of the pelvis showed an immature skeleton with large acetabular cysts, considered diagnostic of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
Case documenting large acetabular cysts.
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 (2 references)
PMID:29397575 SUPPORT Human Clinical
"Abnormal skeletal radiographies included osteoporosis, enlarged flat femoral head with short femoral neck"
Osteoporosis among the radiographic findings of the cohort.
PMID:42482035 SUPPORT Human Clinical
"One patient developed pericardial effusion and showed a reduced bone mineral density on dual-energy X-ray absorptiometry"
DXA-confirmed reduced bone mineral density in a patient with CACP.
Lumbar hyperlordosis HP:0002938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lumbar hyperlordosis (HP:0002938). HP:0002938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"We observed significantly increased lumbar lordosis only in these older patients"
Lumbar hyperlordosis in older patients.
Constitutional 1
Arthralgia HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthralgia (HP:0002829). HP:0002829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old."
Pain increases in later childhood.
🧬

Genetic Associations

1
PRG4
Gene: PRG4 hgnc:9364 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRG4 (hgnc:9364). hgnc:9364 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive inheritance
Show evidence (3 references)
PMID:10545950 SUPPORT Human Clinical
"Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP."
The founding gene-disease association.
PMID:38856641 SUPPORT Human Clinical
"The syndrome is caused by biallelic loss-of-function variants in PRG4"
States the biallelic loss-of-function mechanism.
PMID:16429407 SUPPORT Human Clinical
"No genotype/phenotype association was observed."
Clinical variability is not explained by the PRG4 allele.
Variants (7)
c.1320dupC p.(Pro440fs) Pathogenic
frameshift variant
Homozygous frameshift insertion in the repetitive coding region, in a consanguineous Emirati family.
Show evidence (1 reference)
PMID:22678705 SUPPORT Human Clinical
"Molecular analysis revealed a novel homozygous insertion of a cytosine nucleotide (c.1320dupC) in the highly repetitive portion of the coding sequence of the PRG4 gene."
Reports the homozygous frameshift in affected family members.
c.884_885delAG Pathogenic
frameshift variant
Homozygous exon 6 frameshift deletion in two brothers with constrictive pericarditis.
Show evidence (1 reference)
PMID:27751317 SUPPORT Human Clinical
"revealed a novel homozygous deletion c.884_885delAG in exon 6 of the PRG4 (proteoglycan4) gene"
Reports the homozygous deletion in the affected brothers.
PRG4 exon 1 deletion Pathogenic
deletion
Homozygous deletion of the whole of exon 1.
Show evidence (1 reference)
PMID:29397575 SUPPORT Human Clinical
"including the first case of homozygous complete deletion of exon 1 in the PRG4 gene"
Reports the exon 1 deletion.
c.915delC Pathogenic
frameshift variant
Homozygous frameshift deletion in a boy whose presentation lacked camptodactyly.
Show evidence (1 reference)
PMID:41780543 SUPPORT Human Clinical
"Genetic testing confirmed homozygous proteoglycan 4 (c.915delC) mutation."
Reports the homozygous frameshift.
NM_005807.6:c.1910_1911delCT p.(Pro637ArgfsTer9) Pathogenic
frameshift variant
Previously described frameshift deletion, homozygous in two unrelated Turkish patients.
Show evidence (1 reference)
PMID:40475173 SUPPORT Human Clinical
"A previously described deletion was detected in case 2 and case 3 in the homozygous state in the PRG4 gene (NM_005807.6: c.1910_1911delCT, p.Pro637ArgfsTer9, chr1-186276761-CT)."
Reports the recurrent frameshift in two patients.
c.3756dup Pathogenic
frameshift variant
Homozygous duplication creating a premature stop codon, in Brazilian siblings.
Show evidence (1 reference)
PMID:41626297 SUPPORT Human Clinical
"Whole-genome sequencing identified a homozygous c.3756dup mutation in the PRG4 gene, introducing a premature stop codon and truncating lubricin."
Reports the truncating duplication.
c.4104T>A p.(Tyr1368Ter) Pathogenic
nonsense variant
Homozygous nonsense variant classified pathogenic by ACMG/AMP criteria.
Show evidence (1 reference)
PMID:42482035 SUPPORT Human Clinical
"a homozygous nonsense variant (c.4104T > A; p.Tyr1368Ter) in the second which was absent from ClinVar and Varsome (accessed April 2026) and it was classified as pathogenic by ACMG/AMP"
Reports the nonsense variant and its classification.
💊

Medical Actions

7
Nonsteroidal anti-inflammatory drugs
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
Agent: nonsteroidal anti-inflammatory drug NCIT:C257 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses nonsteroidal anti-inflammatory drug, annotated with Nonsteroidal Antiinflammatory Drug (NCIT:C257). NCIT:C257 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
NSAIDs and simple analgesics give mild pain relief only; they do not alter the course of the arthropathy.
Mechanism Target:
Arthralgia
Show evidence (1 reference)
PMID:23290693 SUPPORT Human Clinical
"In all patients, treatment was ineffective apart from mild pain relief."
Treatment, including NSAIDs, gave only mild pain relief.
Antirheumatic and biologic therapy
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
Agent: methotrexate CHEBI:44185 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methotrexate (CHEBI:44185). CHEBI:44185 is a therapeutic agent from Chemical Entities of Biological Interest. etanercept CHEBI:4875 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses etanercept (CHEBI:4875). CHEBI:4875 is a therapeutic agent from Chemical Entities of Biological Interest. prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
Corticosteroids, methotrexate and TNF inhibitors are often given under a mistaken diagnosis of juvenile idiopathic arthritis and are ineffective, as the arthropathy is not inflammatory.
Mechanism Target:
Non-inflammatory arthropathy
Show evidence (4 references)
PMID:23290693 REFUTE Human Clinical
"10 patients used antirheumatic drugs (prednisone and methotrexate) and two patients were treated with etanercept. In all patients, treatment was ineffective apart from mild pain relief."
Antirheumatic drugs and etanercept were ineffective, which refutes their use for the arthropathy.
PMID:41780543 REFUTE Human Clinical
"Initially diagnosed with polyarticular juvenile idiopathic arthritis, he received methotrexate and etanercept. Due to progressive gait issues and radiographic coxa vara, diagnosis was revised."
Disease progressed on methotrexate and etanercept.
PMID:40830943 REFUTE Human Clinical
"Despite receiving treatment modalities such as non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, and corticosteroids, the patient experienced minimal improvement."
Minimal improvement on NSAIDs, methotrexate and corticosteroids.
+ 1 more reference
Yttrium-90 radiosynovectomy
Action: intra-articular radiosynovectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intra-articular radiosynovectomy, annotated with Radiation Therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. Ontology label: Radiation Therapy NCIT:C15313
Platform: Radiotherapy
A single intra-articular yttrium-90 injection was safe but gave no benefit in a small prospective series.
Mechanism Target:
Fibroblast-Like Synoviocyte Overgrowth
Show evidence (1 reference)
PMID:28291008 REFUTE Human Clinical
"Yttrium-90 radiosynovectomy seems to be a safe and well tolerated procedure, however, it did not show a beneficial therapeutic effect in arthropathy of CACP syndrome with the given dosage and interval."
No therapeutic benefit was observed.
Physiotherapy
Action: physiotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physiotherapy, annotated with Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Range-of-motion exercise to preserve joint mobility.
Mechanism Target:
Limitation of joint mobility
Show evidence (1 reference)
PMID:27748313 SUPPORT Human Clinical
"Eight months after the first visit, there was slight improvement in the range of motion of knees and hips."
Single case with slight improvement in range of motion after physiotherapy.
Total hip arthroplasty
Action: total hip arthroplastyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is total hip arthroplasty, annotated with Hip Replacement (NCIT:C157876). NCIT:C157876 is a clinical intervention from the NCI Thesaurus. Ontology label: Hip Replacement NCIT:C157876
Platform: Surgery
Hip replacement for debilitating hip arthropathy, including in adolescents.
Mechanism Target:
Progressive Cartilage Wear and Precocious Joint Failure
Show evidence (1 reference)
PMID:22386609 SUPPORT Human Clinical
"we feel that total hip arthroplasty is a reasonable treatment option for adolescents with debilitating hip arthropathy associated with CACP syndrome"
Good postoperative outcome in adolescent siblings.
Pericardiectomy
Action: PericardiectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pericardiectomy (NCIT:C51643). NCIT:C51643 is a clinical intervention from the NCI Thesaurus. NCIT:C51643
Platform: Surgery
Surgical removal of the pericardium for constrictive pericarditis, also used to stop secondary protein-losing enteropathy.
Mechanism Target:
Constrictive pericarditis
Show evidence (1 reference)
PMID:27224999 SUPPORT Human Clinical
"As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results."
Pericardiectomy was performed with good results.
Recombinant lubricin supplementation (preclinical)
Platform: Protein replacement
Intra-articular recombinant human PRG4 restores boundary lubrication and reduces chondrocyte apoptosis in lubricin-null mice and cartilage explants. It has not been tested in patients.
Mechanism Target:
Loss of Cartilage Boundary Lubrication and Increased Joint Friction
Friction-Induced Superficial Chondrocyte Apoptosis
Show evidence (4 references)
PMID:28604608 SUPPORT Model Organism
"intra-articular injection of human PRG4 in vivo in Prg4-/- mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo"
Recombinant PRG4 reduces chondrocyte apoptosis and friction in the knockout.
PMID:35457064 SUPPORT Model Organism
"There were significantly fewer caspase-3-positive chondrocytes in tibiofemoral cartilage from rhPRG4-injected mice."
Replicates the anti-apoptotic effect of injected rhPRG4.
PMID:23530215 SUPPORT In Vitro
"In the bovine explant system, the addition of lubricin as a test lubricant significantly lowered the static coefficient of friction and number of apoptotic chondrocytes."
Added lubricin lowers friction and chondrocyte apoptosis in explants.
+ 1 more reference
🔬

Diagnosis

6
PRG4 sequencing
Diagnosis is confirmed by finding biallelic PRG4 variants, usually by exome sequencing, often after years of treatment for presumed juvenile idiopathic arthritis.
exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38856641 SUPPORT Human Clinical
"We used exome sequencing to elucidate disease-causing variants in all the probands."
Exome sequencing identified the PRG4 variants in all probands.
Normal inflammatory markers
Erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor and antinuclear antibodies are normal, which separates the syndrome from inflammatory arthritis.
Show evidence (2 references)
PMID:23290693 SUPPORT Human Clinical
"All patients had normal inflammatory markers and the result for rheumatoid factor test was negative."
Normal inflammatory markers in all 22 patients.
PMID:41780543 SUPPORT Human Clinical
"The erythrocyte sedimentation rate, C-reactive protein level, and antinuclear antibody test results were normal."
Normal inflammatory and autoimmune markers in a further patient.
Synovial fluid analysis
Synovial fluid is non-inflammatory: viscous, clear to honey-coloured, sterile and with a low white cell count.
Show evidence (2 references)
PMID:41637065 SUPPORT Human Clinical
"Synovial fluid was gelatinous, viscous, clear to honey-colored, and sterile."
Describes the non-inflammatory synovial fluid of six genetically confirmed patients.
PMID:41626297 SUPPORT Human Clinical
"Laboratory tests showed normal inflammatory markers, and synovial fluid revealed low white cell counts."
Low synovial white cell count with normal inflammatory markers.
Pelvic radiography
Radiographs show coxa vara, short broad femoral necks, flattened femoral heads, increased joint space and absence of erosions; large acetabular cysts are considered pathognomonic.
pelvic radiography NCIT:C137876 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:16037531 SUPPORT Human Clinical
"CACP syndrome should be considered in all patients who present with a noninflammatory arthropathy or with "atypical juvenile idiopathic arthritis," particularly if radiographs reveal an absence of erosions."
Radiographic absence of erosions points to CACP in a child with arthropathy.
Musculoskeletal ultrasound
Symmetric large-joint and tendon sheath effusions with hyperechoic foci and no intrasynovial Doppler signal favour CACP over polyarticular juvenile idiopathic arthritis.
musculoskeletal ultrasound NCIT:C17230 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42327906 SUPPORT Human Clinical
"CACP is characterised by symmetrical large-joint effusions with hyperechoic foci and absence of intrasynovial DM signal, in contrast to inflammatory findings in JIA."
Ultrasound features that separate CACP from juvenile idiopathic arthritis.
PMID:41637065 SUPPORT Human Clinical
"revealed marked grade 3 synovial effusion, circumferential synovial hypertrophy, and synovial thickening in all patients, without the power Doppler activity"
Knee ultrasound in six patients shows effusion and synovial hypertrophy without Doppler activity.
Lubricin assay in synovial fluid or blood
Lubricin is absent from synovial fluid and blood of patients; a competition ELISA has been proposed as a blood test, but it is a research assay.
Show evidence (1 reference)
PMID:25642942 SUPPORT Human Clinical
"indicating blood can be used in a diagnostic test for patients suspected of having CACP"
Proposes blood lubricin measurement as a diagnostic test.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome:

Juvenile idiopathic arthritis
Overlapping Features The main misdiagnosis. Juvenile idiopathic arthritis shows inflammatory markers and Doppler hypervascularity; CACP has normal markers, no erosions, early camptodactyly and coxa vara, and does not respond to antirheumatic therapy.
Show evidence (3 references)
PMID:23290693 SUPPORT Human Clinical
"The referral diagnosis was inaccurate in all patients; juvenile idiopathic arthritis (JIA) was the referral diagnosis in majority of the patients."
Most patients were first diagnosed with juvenile idiopathic arthritis.
PMID:29397575 SUPPORT Human Clinical
"Sixteen of our patients presented were referred for genetic evaluation with the initial diagnosis of JIA."
Sixteen of 35 patients were initially diagnosed with juvenile idiopathic arthritis.
PMID:40475173 SUPPORT Human Clinical
"All patients were exposed to biologic therapy due to recalcitrant JIA."
All three Turkish patients received biologics under a juvenile idiopathic arthritis diagnosis.
Tuberculous pericarditis
Overlapping Features When serosal disease comes first, constrictive pericarditis or pericardial effusion in a child may be attributed to tuberculosis before the joint disease appears.
Show evidence (1 reference)
PMID:38955384 SUPPORT Human Clinical
"The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis."
The pericardial disease was first treated as tuberculosis; CACP was recognised only after knee swelling developed.
🐁

Animal Models

2
Prg4-null mouse (Rhee 2005)
Viable and fertile, with normal joints at birth; with age develops cartilage surface protein deposits, loss of superficial chondrocytes, cartilage deterioration, synovial intimal hyperplasia, and tendon sheath changes with calcification.
Species
Mouse
Genotype
Prg4 homozygous null
Publication
PMID:15719068
Pathograph links
Fibroblast-Like Synoviocyte Overgrowth recapitulates fidelity: high observes: tissue
Show evidence (1 reference)
PMID:15719068 SUPPORT Model Organism
"intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure"
The knockout reproduces synovial hyperplasia.
Progressive Cartilage Wear and Precocious Joint Failure recapitulates fidelity: high observes: tissue
Show evidence (1 reference)
PMID:15719068 SUPPORT Model Organism
"In addition to cartilage surface changes and subsequent cartilage deterioration"
The knockout reproduces progressive cartilage deterioration.
Tendon and Tendon Sheath Surface Dysfunction partially recapitulates fidelity: moderate observes: tissue
Limitations: Tendon changes were described at the ankle; finger flexor tendons and camptodactyly were not reported in the mouse.
Show evidence (1 reference)
PMID:15719068 SUPPORT Model Organism
"Tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed."
Tendon and sheath lesions in the knockout.
Prg4-null mouse (Coles 2010, hip)
Femoral head cartilage of a Prg4-null line shows an age-dependent rise in friction, loss of stiffness and osteoarthritis-like degeneration.
Species
Mouse
Genotype
Prg4 homozygous null
Publication
PMID:20191580
Pathograph links
Loss of Cartilage Boundary Lubrication and Increased Joint Friction recapitulates fidelity: high observes: tissue
Show evidence (1 reference)
PMID:20191580 SUPPORT Model Organism
"Friction was significantly higher on cartilage of Prg4(-/-) mice at age 16 weeks, but statistically significant differences in friction were not detected at younger ages."
Increased cartilage friction in the knockout hip.
{ }

Source YAML

click to show 
name: Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome
creation_date: "2026-10-14T15:02:40Z"
description: >-
  Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an
  autosomal recessive disorder caused by biallelic loss-of-function variants in
  PRG4, which encodes lubricin (proteoglycan 4, also called superficial zone
  protein), a secreted mucinous glycoprotein made by synovial fibroblasts and
  superficial zone chondrocytes. Lubricin is the boundary lubricant of
  articular cartilage, limits synoviocyte growth, and coats tendon sheaths and
  the pericardial and pleural surfaces. Its absence leaves joint surfaces
  unlubricated, so friction rises, superficial chondrocytes die and the
  cartilage wears out early, while the synovial lining becomes hyperplastic
  and the joints fill with non-inflammatory effusions. Affected children have
  congenital or early camptodactyly, then symmetric swelling of wrists, elbows,
  knees and ankles, and develop coxa vara with short femoral necks, flattened
  femoral heads and acetabular cysts; hip disease becomes severe by early
  adulthood. A minority develop non-inflammatory pericardial or pleural
  effusions or ascites, and constrictive pericarditis can cause
  protein-losing enteropathy. Inflammatory markers are normal, and the
  condition is frequently misdiagnosed and treated as juvenile idiopathic
  arthritis. There is no disease-modifying therapy; recombinant lubricin is
  under preclinical study.
category: Mendelian
disease_term:
  preferred_term: camptodactyly-arthropathy-coxa vara-pericarditis syndrome
  term:
    id: MONDO:0008828
    label: camptodactyly-arthropathy-coxa vara-pericarditis syndrome
synonyms:
- CACP syndrome
- CACP
- PAC syndrome
- arthropathy-camptodactyly syndrome
- camptodactyly-arthropathy-pericarditis syndrome
- pericarditis-arthropathy-camptodactyly syndrome
- fibrosing serositis, familial
parents:
- rheumatic disorder
- hereditary disorder of connective tissue
- autosomal recessive disease
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry two PRG4 loss-of-function alleles, usually the
    same allele in homozygous state in consanguineous families. One affected
    individual received both PRG4 copies from one parent through uniparental
    disomy of chromosome 1.
  evidence:
  - reference: PMID:10545950
    reference_title: "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250)"
    explanation: States the recessive mode of inheritance in the gene-discovery paper.
  - reference: PMID:9550484
    reference_title: "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genome-wide search for linkage identified homozygosity for a series of genetic markers on human chromosome 1q in all affected patients."
    explanation: Homozygosity mapping in consanguineous kindreds is the segregation pattern of a recessive disorder.
  - reference: PMID:23756439
    reference_title: "CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the first case of CACP syndrome resulting from uniparental disomy of chromosome 1"
    explanation: Uniparental disomy is an alternative route to biallelic PRG4 loss in a recessive disorder.
pathophysiology:
- name: PRG4 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Disease-causing PRG4 alleles are almost all frameshift or nonsense
    variants, with a whole-exon-1 deletion also reported, found in homozygous
    or compound heterozygous state. Synovial fluid from patients with
    truncating alleles contains no detectable lubricin. One stop-gain in the
    last exon is predicted to escape nonsense-mediated decay, but the
    truncated protein is not processed normally.
  genes:
  - preferred_term: PRG4
    term:
      id: hgnc:9364
      label: PRG4
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
  evidence:
  - reference: PMID:10545950
    reference_title: "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP."
    explanation: Identifies PRG4 (originally named CACP) as the disease gene.
  - reference: PMID:16429407
    reference_title: "Novel PRG4 mutations underlie CACP in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because all mutations reported in CACP patients thus far predict premature truncation"
    explanation: The disease alleles are truncating, consistent with loss of function.
  - reference: PMID:16000300
    reference_title: "Consequences of disease-causing mutations on lubricin protein synthesis, secretion, and post-translational processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, the antiserum did not detect lubricin in synovial fluid or cultured synoviocytes from several patients with frameshift or nonsense mutations in PRG4."
    explanation: Truncating alleles result in absent lubricin protein in patient synovial fluid and synoviocytes.
  - reference: PMID:16000300
    reference_title: "Consequences of disease-causing mutations on lubricin protein synthesis, secretion, and post-translational processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "one disease-causing mutation that removes the last 8 amino acids of the protein, including a conserved cysteine residue, was not cleaved within the hemopexin-like domain when expressed in COS-7 cells"
    explanation: A last-exon truncation that may escape decay still yields abnormally processed protein.
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this cohort, our molecular screening identified six frame shift mutations, two nonsense mutations, and the first case of homozygous deletion of exon 1."
    explanation: Extends the truncating allele spectrum and adds a whole-exon deletion.
  downstream:
  - target: Lubricin Deficiency at Joint, Tendon and Serosal Surfaces
    causal_link_type: DIRECT
    description: Loss of both PRG4 alleles removes the secreted lubricin protein.
    evidence:
    - reference: PMID:25642942
      reference_title: "Anti-lubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The competition ELISA detected lubricin in blood samples from healthy individuals but not from patients with CACP"
      explanation: Lubricin is undetectable in the blood of patients with CACP, confirming systemic absence of the protein.
- name: Lubricin Deficiency at Joint, Tendon and Serosal Surfaces
  biological_scale: MOLECULAR
  description: >-
    Lubricin is normally secreted by synovial lining fibroblasts and
    superficial zone chondrocytes into synovial fluid and onto the cartilage
    surface, and is also present on tendons and tendon sheaths and in the
    pericardial and pleural cavities. In CACP it is absent from these sites,
    removing boundary lubrication, an anti-adhesive surface coating, and a
    brake on synoviocyte growth.
  molecular_functions:
  - preferred_term: boundary lubricant activity
    modifier: DECREASED
    term:
      id: GO:0030197
      label: extracellular matrix constituent, lubricant activity
  cell_types:
  - preferred_term: fibroblast-like synoviocyte
    term:
      id: CL:0002301
      label: type B synovial cell
  - preferred_term: superficial zone articular chondrocyte
    term:
      id: CL:0020037
      label: superficial zone articular chondrocyte
  genes:
  - preferred_term: PRG4
    term:
      id: hgnc:9364
      label: PRG4
  evidence:
  - reference: PMID:15719068
    reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Prg4 began to be expressed in surface chondrocytes and synoviocytes after joint cavitation had occurred and remained strongly expressed by these cells postnatally."
    explanation: Identifies surface chondrocytes and synoviocytes as the lubricin-producing cells in the joint.
  - reference: PMID:10545950
    reference_title: "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium."
    explanation: Pericardial expression links the protein to the serosal features of the syndrome.
  - reference: PMID:25642942
    reference_title: "Anti-lubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "and in the pericardial and pleural cavities, where it likely serves an anti-adhesive function."
    explanation: Introduction statement placing lubricin in the pericardial and pleural cavities, extra-articular sites affected in CACP.
  downstream:
  - target: Loss of Cartilage Boundary Lubrication and Increased Joint Friction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17968947
      reference_title: "Association between friction and wear in diarthrodial joints lacking lubricin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "SF lacking lubricin failed to reduce friction in the boundary mode."
      explanation: Synovial fluid from patients with genetic lubricin deficiency does not provide boundary lubrication.
  - target: Fibroblast-Like Synoviocyte Overgrowth
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Purified or recombinant lubricin inhibited the growth of these synoviocytes in vitro."
      explanation: Lubricin directly restrains synoviocyte growth, so its absence releases that restraint.
  - target: Tendon and Tendon Sheath Surface Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed."
      explanation: Lubricin-null mice develop tendon and tendon sheath lesions.
  - target: Serosal Surface Lubricin Deficiency and Effusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lubricin is expressed in pericardium and present in the pleural and
      pericardial cavities; how its absence produces effusion and pericardial
      thickening has not been studied experimentally.
    evidence:
    - reference: PMID:27224999
      reference_title: "Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Lubricin serves as a lubricant in joints, tendons and visceral cavities (pleural cavity, pericardium) and inhibits synovial proliferation."
      explanation: Background statement linking lubricin function in the visceral cavities to the serosal disease of CACP.
- name: Loss of Cartilage Boundary Lubrication and Increased Joint Friction
  biological_scale: TISSUE
  description: >-
    Without lubricin, the articular surface loses its boundary lubricant and
    proteins deposit on the cartilage. Whole-joint and cartilage-surface
    friction rise, and the surface layer becomes enlarged, fragmented and
    roughened. Joints are normal at birth and the changes accumulate with age.
  biological_processes:
  - preferred_term: cartilage homeostasis
    modifier: DECREASED
    term:
      id: GO:1990079
      label: cartilage homeostasis
  evidence:
  - reference: PMID:17968947
    reference_title: "Association between friction and wear in diarthrodial joints lacking lubricin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Joints of lubricin-null mice showed early wear and higher friction than joints from their wild-type counterparts."
    explanation: Direct measurement of increased friction and early wear in lubricin-null joints.
  - reference: PMID:20191580
    reference_title: "Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Friction was significantly higher on cartilage of Prg4(-/-) mice at age 16 weeks, but statistically significant differences in friction were not detected at younger ages."
    explanation: An independent Prg4-null line shows an age-dependent rise in cartilage friction.
  - reference: PMID:15719068
    reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As the mice aged, we observed abnormal protein deposits on the cartilage surface and disappearance of underlying superficial zone chondrocytes."
    explanation: Surface protein deposition and loss of superficial chondrocytes develop with age in lubricin-null joints.
  downstream:
  - target: Friction-Induced Superficial Chondrocyte Apoptosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23530215
      reference_title: "Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we observed a direct correlation between coefficient of friction and chondrocyte apoptosis in the superficial layers of cartilage"
      explanation: In a cartilage-on-cartilage explant system, friction tracks chondrocyte apoptosis in the superficial layers.
- name: Friction-Induced Superficial Chondrocyte Apoptosis
  biological_scale: CELLULAR
  conforms_to: "osteoarthritis_cartilage_degradation#Mechanical Overload and Chondrocyte Stress"
  description: >-
    Unlubricated loading stresses superficial and upper intermediate zone
    chondrocytes, which undergo intrinsic (mitochondrial) apoptosis with
    caspase-9 and caspase-3 activation and accumulation of peroxynitrite and
    superoxide. In the conserved osteoarthritis cascade this is the
    chondrocyte stress step; here the trigger is loss of boundary lubrication
    rather than malalignment or injury.
  cell_types:
  - preferred_term: superficial zone articular chondrocyte
    term:
      id: CL:0020037
      label: superficial zone articular chondrocyte
  biological_processes:
  - preferred_term: response to mechanical stimulus
    modifier: INCREASED
    term:
      id: GO:0009612
      label: response to mechanical stimulus
  - preferred_term: cellular response to stress
    modifier: INCREASED
    term:
      id: GO:0033554
      label: cellular response to stress
  - preferred_term: chondrocyte apoptosis
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:23530215
    reference_title: "Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We observed increases in whole-joint friction and cellular apoptosis in lubricin knockout mice compared with wild-type mice."
    explanation: Lubricin-null joints show both higher friction and more chondrocyte apoptosis.
  - reference: PMID:28604608
    reference_title: "Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Non-lubricated Prg4-/- mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation"
    explanation: Identifies the intrinsic mitochondrial apoptotic pathway in non-lubricated cartilage.
  - reference: PMID:26975998
    reference_title: "Superficial zone cellularity is deficient in mice lacking lubricin: a stereoscopic analysis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Living chondrocyte volume fraction of the medial femoral condyle was significantly lower in Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.002)"
    explanation: Quantifies the loss of living superficial and upper intermediate zone chondrocytes in lubricin-null cartilage.
  downstream:
  - target: Progressive Cartilage Wear and Precocious Joint Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23530215
      reference_title: "Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results demonstrate a direct connection between lubricin, boundary lubrication, and cell survival and suggest that supplementation of synovial fluid with lubricin may be an effective treatment to prevent cartilage deterioration"
      explanation: Links chondrocyte survival under boundary lubrication to cartilage deterioration.
- name: Fibroblast-Like Synoviocyte Overgrowth
  biological_scale: CELLULAR
  description: >-
    The synovial lining becomes hypercellular. Proliferating cells are
    fibroblastic synoviocytes, and the lining is infiltrated by CD68-positive
    macrophages including multinucleated giant cells; lymphocytes and
    neutrophils are sparse, so the synovitis is proliferative rather than
    inflammatory.
  cell_types:
  - preferred_term: fibroblast-like synoviocyte
    term:
      id: CL:0002301
      label: type B synovial cell
  - preferred_term: synovial macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: synoviocyte proliferation
    modifier: INCREASED
    term:
      id: GO:0002941
      label: synoviocyte proliferation
  evidence:
  - reference: PMID:15702367
    reference_title: "Synovial pathology in camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By double immunostaining, proliferating cells were determined to be fibroblastic synoviocytes rather than macrophages."
    explanation: Patient synovial biopsies identify fibroblastic synoviocytes as the proliferating population.
  - reference: PMID:15702367
    reference_title: "Synovial pathology in camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus the proliferative synovitis in this CACP syndrome can be more accurately thought of as hypercellularity by infiltrating macrophages with a contribution by proliferating fibroblastic synoviocytes."
    explanation: Describes the macrophage-rich hypercellular synovium.
  - reference: PMID:15719068
    reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure"
    explanation: Lubricin-null mice reproduce synovial intimal hyperplasia.
  downstream:
  - target: Synovial lining hyperplasia
    causal_link_type: DIRECT
  - target: Joint swelling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Joint swelling reflects large non-inflammatory effusions together with
      the thickened synovium; the source of the excess fluid is not
      established.
    evidence:
    - reference: PMID:28291008
      reference_title: "The Efficacy of Yttrium-90 Radiosynovectomy in Patients with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "It is a non-inflammatory arthropathy, characterized by joint effusions and synovial hypertrophy."
      explanation: Pairs the effusions with synovial hypertrophy as the features of the arthropathy.
  - target: Progressive Cartilage Wear and Precocious Joint Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure"
      explanation: Synovial hyperplasia is reported to add to joint failure in the knockout.
- name: Progressive Cartilage Wear and Precocious Joint Failure
  biological_scale: TISSUE
  conforms_to: "osteoarthritis_cartilage_degradation#Cartilage Matrix Loss and Subchondral Bone Remodeling"
  description: >-
    Joints that are normal at birth deteriorate with use. In mice the cartilage
    surface roughens and pericellular proteoglycan is progressively lost; in
    patients the number of skeletal features rises with age, pain increases
    after about age 10, and severe hip disease develops in early adulthood, a
    course the cohort authors attribute to cumulative mechanical stress.
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    modifier: INCREASED
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
  evidence:
  - reference: PMID:20191580
    reference_title: "Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of the gene Prg4 results in significant structural and biomechanical changes in the articular cartilage with age, some of which are consistent with osteoarthritic degeneration."
    explanation: Prg4 loss produces age-dependent osteoarthritis-like cartilage degeneration.
  - reference: PMID:20191580
    reference_title: "Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "a roughened underlying articular cartilage surface, and a progressive loss of pericellular proteoglycans"
    explanation: Documents progressive matrix proteoglycan loss under the abnormal surface layer.
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This increase in symptoms is likely due to cumulative mechanical stress over time"
    explanation: In patients, the age-related accumulation of features is attributed to mechanical wear.
  downstream:
  - target: Non-inflammatory arthropathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "A major feature of CACP is precocious joint failure."
      explanation: Joint failure is the clinical endpoint of the cartilage wear in patients.
  - target: Limitation of joint mobility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29397575
      reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Large joint involvement was found in all of our patients and it included symmetrical noninflammatory arthropathy resulting in swelling, limited motion, and in flexion contractures."
      explanation: The arthropathy results in limited motion and flexion contractures.
  - target: Arthralgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29397575
      reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Older patients reported increases in pain level after the age of 10, corresponding to an increase in large joint contractures."
      explanation: Pain rises with the progression of joint disease.
  - target: Coxa vara
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Coxa vara and other hip dysplasia accompany progressive hip disease; how
      lubricin loss alters proximal femoral growth is not established.
    evidence:
    - reference: PMID:9550484
      reference_title: "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coxa vara deformity or other dysplasia associated with progressive hip disease may develop over time."
      explanation: Places the coxa vara deformity within progressive hip disease.
  - target: Short femoral neck
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9550484
      reference_title: "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coxa vara deformity or other dysplasia associated with progressive hip disease may develop over time."
      explanation: Proximal femoral dysplasia, of which a short femoral neck is part, develops with progressive hip disease.
  - target: Flattened femoral head
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9550484
      reference_title: "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coxa vara deformity or other dysplasia associated with progressive hip disease may develop over time."
      explanation: Femoral head deformity is among the hip dysplasia that develops with progressive hip disease.
  - target: Lumbar hyperlordosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Increased lumbar lordosis appears in older patients with severe hip involvement; whether it is compensatory or a direct spinal effect is not established.
    evidence:
    - reference: PMID:29397575
      reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe hip and vertebral involvement were developed after 20 years of age."
      explanation: Spinal involvement arrives late, with severe hip disease.
- name: Tendon and Tendon Sheath Surface Dysfunction
  biological_scale: TISSUE
  description: >-
    Without lubricin, tendon sheaths fill with effusion and, in the knockout
    mouse, undergo morphologic change and abnormal calcification. Adhesions
    between tendons and their sheaths have been described in patients, and
    ultrasound shows symmetric non-vascular tenosynovial effusions, including
    around the finger flexor tendons.
  evidence:
  - reference: PMID:42327906
    reference_title: "Musculoskeletal ultrasound discriminating camptodactyly-arthropathy-coxa vara-pericarditis syndrome and juvenile idiopathic arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked symmetrical tenosynovitis involving multiple tendon regions, including shoulder (biceps), elbow extensors, wrist extensors, posterior tibialis, and flexor digitorum tendons, was observed in the CACP group"
    explanation: Ultrasound documents widespread tendon sheath involvement in patients.
  - reference: PMID:25642942
    reference_title: "Anti-lubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Among the clinical consequences of CACP are non-inflammatory synovial cell hyperplasia, precocious joint failure, adhesions between tendons and tendon sheaths, and restrictive pericarditis"
    explanation: Background summary listing tendon-sheath adhesions among the consequences of CACP.
  downstream:
  - target: Tenosynovitis
    causal_link_type: DIRECT
- name: Serosal Surface Lubricin Deficiency and Effusion
  biological_scale: TISSUE
  description: >-
    In a minority of patients the pericardium and pleura develop
    non-inflammatory effusions, and the pericardium can thicken and constrict.
    Ascites also occurs. The mechanism is presumed to parallel the joint
    disease, with loss of the anti-adhesive serosal lubricant, but it has not
    been investigated directly.
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven patients (~22%) had pleural effusion, pericarditis, and/or ascites"
    explanation: Serosal involvement occurs in a minority of a large cohort.
  downstream:
  - target: Serositis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pericarditis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pericardial effusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Constrictive pericarditis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pleural effusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ascites
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Musculoskeletal
  name: Camptodactyly
  frequency: VERY_FREQUENT
  description: >-
    Flexion contracture of the fingers, usually present at birth or in the
    first year and typically the first sign; bilateral and progressive. Its
    mechanism is not established, and a few genetically confirmed patients
    lack it.
  phenotype_term:
    preferred_term: Camptodactyly of finger
    term:
      id: HP:0100490
      label: Camptodactyly of finger
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Camptodactyly was observed in the neonatal period in all the patients, while other joint involvement was observed through the 1st year of life."
    explanation: Camptodactyly was present from the neonatal period in all 22 Saudi patients.
  - reference: PMID:38856641
    reference_title: "Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)"
    explanation: Camptodactyly in 13 of 13 Indian patients.
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For 68% of patients (19 of 28), camptodactyly was the earliest symptom and appeared to be mostly bilateral and progressive."
    explanation: Camptodactyly is usually the first sign and is bilateral and progressive.
  - reference: PMID:41780543
    reference_title: "Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome without Camptodactyly: A Pediatric Case and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case underscores an atypical camptodactyly-arthropathy-coxa vara-pericarditis presentation without camptodactyly."
    explanation: A molecularly confirmed patient without camptodactyly, so the sign is very frequent but not obligate.
- category: Musculoskeletal
  name: Non-inflammatory arthropathy
  frequency: VERY_FREQUENT
  description: >-
    Symmetric arthropathy of large joints, beginning with the wrists and then
    elbows, knees and ankles in early childhood, with normal inflammatory
    markers and no erosions.
  phenotype_term:
    preferred_term: Non-inflammatory arthropathy
    term:
      id: HP:0003040
      label: Arthropathy
  evidence:
  - reference: PMID:9550484
    reference_title: "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital camptodactyly and childhood-onset noninflammatory arthropathy were present in all affected patients."
    explanation: Non-inflammatory arthropathy in all eight patients.
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Camptodactyly and large joints arthropathy were present in all the cases."
    explanation: Large-joint arthropathy in all 22 patients.
- category: Musculoskeletal
  name: Joint swelling
  frequency: VERY_FREQUENT
  description: >-
    Swelling of wrists, knees and elbows from early childhood, due to large
    symmetric effusions and thickened synovium; on ultrasound the effusions
    contain hyperechoic foci and show no Doppler hypervascularity.
  phenotype_term:
    preferred_term: Joint swelling
    term:
      id: HP:0001386
      label: Joint swelling
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Swelling of wrists, knees, and elbows began before 4 years of age"
    explanation: Early joint swelling in the 35-patient cohort.
  - reference: PMID:42327906
    reference_title: "Musculoskeletal ultrasound discriminating camptodactyly-arthropathy-coxa vara-pericarditis syndrome and juvenile idiopathic arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four children with CACP showed symmetrical joint involvement, with effusion present in 46/46 scanned joints and no intrasynovial hypervascularity (median DM = 0)."
    explanation: Effusion was present in every scanned joint without inflammatory hypervascularity.
- category: Musculoskeletal
  name: Synovial lining hyperplasia
  description: Proliferative, hypercellular synovium with multinucleated giant cells and few inflammatory cells.
  phenotype_term:
    preferred_term: Synovial lining hyperplasia
    term:
      id: HP:0005186
      label: Synovial lining hyperplasia
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Synovial biopsy from three patients revealed proliferating synovial epithelium with moderate fibro-collagenous densities and multinucleated giant cells, occasional lymphocytes or neutrophils were identified."
    explanation: Patient synovial biopsies show a proliferating lining with few inflammatory cells.
  - reference: PMID:27751317
    reference_title: "Brothers with constrictive pericarditis - A novel mutation in a rare disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Knee joint synovial fluid biopsy revealed synovial hyperplasia with minimal inflammatory cells"
    explanation: Synovial hyperplasia without inflammation in a further patient.
- category: Musculoskeletal
  name: Limitation of joint mobility
  frequency: VERY_FREQUENT
  description: Progressive loss of range of motion and flexion contractures of large joints.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large joint involvement was found in all of our patients and it included symmetrical noninflammatory arthropathy resulting in swelling, limited motion, and in flexion contractures."
    explanation: Limited motion and flexion contractures in all patients of the cohort.
- category: Musculoskeletal
  name: Arthralgia
  description: Joint pain, increasing after about age 10.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old."
    explanation: Pain increases in later childhood.
- category: Musculoskeletal
  name: Tenosynovitis
  description: >-
    Symmetric tendon sheath effusions on ultrasound, without Doppler signal;
    the term is used descriptively, as the involvement is not inflammatory.
  phenotype_term:
    preferred_term: Non-inflammatory tenosynovial effusion
    term:
      id: HP:6001438
      label: Tenosynovitis
  evidence:
  - reference: PMID:42327906
    reference_title: "Musculoskeletal ultrasound discriminating camptodactyly-arthropathy-coxa vara-pericarditis syndrome and juvenile idiopathic arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 16/16 scanned tendons in the CACP group showed no DM signal, whereas hypervascularity was observed in 7/8 affected tendons in the JIA cohort."
    explanation: Tendon involvement in CACP lacks the hypervascularity of inflammatory tenosynovitis.
- category: Skeletal
  name: Coxa vara
  frequency: VERY_FREQUENT
  description: Developmental coxa vara with a broad, short femoral neck, the most distinctive radiographic finding.
  phenotype_term:
    preferred_term: Coxa vara
    term:
      id: HP:0002812
      label: Coxa vara
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented developmental coxa vara"
    explanation: Coxa vara in all 35 patients.
  - reference: PMID:38856641
    reference_title: "Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)"
    explanation: Coxa vara in 11 of 13 patients.
  - reference: PMID:9550484
    reference_title: "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients developed bilateral coxa vara deformity, and 1 developed coxa magna with cystic erosions."
    explanation: Bilateral coxa vara in seven of eight patients.
- category: Skeletal
  name: Short femoral neck
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short femoral neck
    term:
      id: HP:0100864
      label: Short femoral neck
  evidence:
  - reference: PMID:38856641
    reference_title: "Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)"
    explanation: Short femoral neck in 11 of 13 patients.
- category: Skeletal
  name: Flattened femoral head
  phenotype_term:
    preferred_term: Flattened femoral head
    term:
      id: HP:0008812
      label: Flattened femoral head
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiological findings included coxa vara with a short femoral neck and flat, irregular femoral heads and intra-osseous cysts, increased joint space, and abnormal modeling of the acetabulum with small iliac wings."
    explanation: Flat, irregular femoral heads on radiographs.
- category: Skeletal
  name: Acetabular cysts
  description: >-
    Large intraosseous cysts of the acetabulum, considered pathognomonic on
    pelvic radiographs; intraosseous cysts also occur at the wrist.
  phenotype_term:
    preferred_term: Acetabular bone cyst
    term:
      id: HP:0012062
      label: Bone cyst
  evidence:
  - reference: PMID:16037531
    reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis syndrome versus juvenile idiopathic arthropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the correct clinical setting, large acetabular cysts on pelvic radiographs may be considered pathognomonic of CACP syndrome."
    explanation: Acetabular cysts as a pathognomonic radiographic sign.
  - reference: PMID:27748313
    reference_title: "Pathognomonic acetabular cysts in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs of the pelvis showed an immature skeleton with large acetabular cysts, considered diagnostic of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    explanation: Case documenting large acetabular cysts.
- category: Skeletal
  name: Reduced bone mineral density
  description: Radiographic osteoporosis in a cohort and reduced bone mineral density on DXA in a recent case report; frequency and mechanism are not established.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal skeletal radiographies included osteoporosis, enlarged flat femoral head with short femoral neck"
    explanation: Osteoporosis among the radiographic findings of the cohort.
  - reference: PMID:42482035
    reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome masquerading as juvenile idiopathic arthritis: a case series with a novel PRG4 variant and emphasis on bone health."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient developed pericardial effusion and showed a reduced bone mineral density on dual-energy X-ray absorptiometry"
    explanation: DXA-confirmed reduced bone mineral density in a patient with CACP.
- category: Skeletal
  name: Lumbar hyperlordosis
  description: Increased lumbar lordosis seen in older patients with severe hip involvement.
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed significantly increased lumbar lordosis only in these older patients"
    explanation: Lumbar hyperlordosis in older patients.
- category: Cardiovascular
  name: Serositis
  frequency: OCCASIONAL
  description: >-
    Any non-inflammatory serosal involvement (pleural effusion, pericarditis
    or ascites), counted together in the largest cohort; the individual
    serosal features are listed separately below.
  phenotype_term:
    preferred_term: Non-inflammatory serositis
    term:
      id: HP:0045073
      label: Serositis
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven patients (~22%) had pleural effusion, pericarditis, and/or ascites"
    explanation: About 22% of the 35-patient cohort had some serosal involvement, within the occasional band.
- category: Cardiovascular
  name: Pericarditis
  frequency: OCCASIONAL
  description: Non-inflammatory pericardial disease in a minority of patients; absent in several family series.
  phenotype_term:
    preferred_term: Non-inflammatory pericarditis
    term:
      id: HP:0001701
      label: Pericarditis
  evidence:
  - reference: PMID:16429407
    reference_title: "Novel PRG4 mutations underlie CACP in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while pericarditis is evident in only one-fifth of all reported cases"
    explanation: Pericarditis in about one-fifth of reported cases, an occasional feature.
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had a normal cardiac evaluation but two children had evidence of pericarditis."
    explanation: Two of 22 Saudi patients had pericarditis.
- category: Cardiovascular
  name: Pericardial effusion
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pericardial effusions were previously reported between 6% and 30% of CACP patients"
    explanation: The cohort paper's summary of earlier reports gives a frequency within the occasional band.
- category: Cardiovascular
  name: Constrictive pericarditis
  description: Pericardial thickening with constrictive physiology, which can present with systemic venous congestion and hepatomegaly.
  phenotype_term:
    preferred_term: Constrictive pericarditis
    term:
      id: HP:0002563
      label: Constrictive pericarditis
  evidence:
  - reference: PMID:27751317
    reference_title: "Brothers with constrictive pericarditis - A novel mutation in a rare disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transthoracic echocardiography revealed pericardial thickening and with features of constriction. Cardiac catheterization supported the diagnosis of constrictive pericarditis"
    explanation: Constrictive pericarditis confirmed by catheterization in a patient with CACP.
  - reference: PMID:38955384
    reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis."
    explanation: Constrictive pericarditis preceded the joint disease and was first treated as tuberculosis.
  sequelae:
  - target: Protein-losing enteropathy
    evidence:
    - reference: PMID:27224999
      reference_title: "Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This report concerns a child with CACP syndrome complicated by protein-losing enteropathy (PLE), caused by constrictive pericarditis"
      explanation: Constrictive pericarditis led to protein-losing enteropathy.
- category: Respiratory
  name: Pleural effusion
  description: Non-inflammatory pleural effusion, occurring with or without pericardial disease.
  phenotype_term:
    preferred_term: Pleural effusion
    term:
      id: HP:0002202
      label: Pleural effusion
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven patients (~22%) had pleural effusion, pericarditis, and/or ascites"
    explanation: Pleural effusion among the serosal features of the cohort.
  - reference: PMID:27751317
    reference_title: "Brothers with constrictive pericarditis - A novel mutation in a rare disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was moderate right-sided pleural effusion and no cardiomegaly"
    explanation: Pleural effusion in a patient with CACP.
  - reference: PMID:40830943
    reference_title: "Juvenile idiopathic arthritis or skeletal dysplasia: first case report of camptodactyly-arthropathy-coxa vara-pericarditis from Iran."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient first exhibited symptoms at 10 days of age with respiratory distress due to pleural effusion and later underwent pericardiectomy for significant pericardial effusion."
    explanation: Serosal disease can begin in the neonatal period, before the arthropathy.
- category: Gastrointestinal
  name: Ascites
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients had pleural effusion, ascites, and/or pericarditis."
    explanation: Ascites among the serosal features of the cohort.
- category: Gastrointestinal
  name: Protein-losing enteropathy
  description: Secondary to constrictive pericarditis, with low serum protein and IgG; treated by pericardiectomy in the reported case.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:27224999
    reference_title: "Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased alpha antitrypsin clearance confirmed PLE."
    explanation: Laboratory confirmation of protein-losing enteropathy in a child with CACP.
- category: Cardiovascular
  name: Mitral valve prolapse
  description: Reported in a few patients of one cohort; whether it is part of the syndrome is not established.
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients had mitral regurgitation or mitral valve prolapse on echocardiography."
    explanation: Mitral valve findings in four patients of the cohort.
genetic:
- name: PRG4
  gene_term:
    preferred_term: PRG4
    term:
      id: hgnc:9364
      label: PRG4
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_3b4be938-664c-421e-922b-dc6ac83e5dec-2021-07-30T130737.801Z
    evidence:
    - reference: CGGV:assertion_3b4be938-664c-421e-922b-dc6ac83e5dec-2021-07-30T130737.801Z
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PRG4 | HGNC:9364 | camptodactyly-arthropathy-coxa vara-pericarditis syndrome | MONDO:0008828 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this gene-disease pair as Definitive.
  notes: >-
    PRG4 is the only gene associated with the syndrome. Disease alleles are
    predominantly frameshift and nonsense variants; no genotype-phenotype
    correlation has been found, and clinical variability within families is
    large.
  variants:
  - name: c.1320dupC p.(Pro440fs)
    description: Homozygous frameshift insertion in the repetitive coding region, in a consanguineous Emirati family.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
    - reference: PMID:22678705
      reference_title: "A novel mutation in PRG4 gene underlying camptodactyly-arthropathy-coxa vara-pericarditis syndrome with the possible expansion of the phenotype to include congenital cataract."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Molecular analysis revealed a novel homozygous insertion of a cytosine nucleotide (c.1320dupC) in the highly repetitive portion of the coding sequence of the PRG4 gene."
      explanation: Reports the homozygous frameshift in affected family members.
  - name: c.884_885delAG
    description: Homozygous exon 6 frameshift deletion in two brothers with constrictive pericarditis.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
    - reference: PMID:27751317
      reference_title: "Brothers with constrictive pericarditis - A novel mutation in a rare disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "revealed a novel homozygous deletion c.884_885delAG in exon 6 of the PRG4 (proteoglycan4) gene"
      explanation: Reports the homozygous deletion in the affected brothers.
  - name: PRG4 exon 1 deletion
    description: Homozygous deletion of the whole of exon 1.
    clinical_significance: PATHOGENIC
    type: deletion
    evidence:
    - reference: PMID:29397575
      reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including the first case of homozygous complete deletion of exon 1 in the PRG4 gene"
      explanation: Reports the exon 1 deletion.
  - name: c.915delC
    description: Homozygous frameshift deletion in a boy whose presentation lacked camptodactyly.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
    - reference: PMID:41780543
      reference_title: "Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome without Camptodactyly: A Pediatric Case and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic testing confirmed homozygous proteoglycan 4 (c.915delC) mutation."
      explanation: Reports the homozygous frameshift.
  - name: NM_005807.6:c.1910_1911delCT p.(Pro637ArgfsTer9)
    description: Previously described frameshift deletion, homozygous in two unrelated Turkish patients.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
      - reference: PMID:40475173
        reference_title: "Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Caused by Truncating Mutations in the Prg4 Gene: Case Series and Literature Review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "A previously described deletion was detected in case 2 and case 3 in the homozygous state in the PRG4 gene (NM_005807.6: c.1910_1911delCT, p.Pro637ArgfsTer9, chr1-186276761-CT)."
        explanation: Reports the recurrent frameshift in two patients.
  - name: c.3756dup
    description: Homozygous duplication creating a premature stop codon, in Brazilian siblings.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
      - reference: PMID:41626297
        reference_title: "From Misdiagnosis to Genetic Confirmation: A Brazilian Familial Report of Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome-A Case-Based Review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Whole-genome sequencing identified a homozygous c.3756dup mutation in the PRG4 gene, introducing a premature stop codon and truncating lubricin."
        explanation: Reports the truncating duplication.
  - name: c.4104T>A p.(Tyr1368Ter)
    description: Homozygous nonsense variant classified pathogenic by ACMG/AMP criteria.
    clinical_significance: PATHOGENIC
    type: nonsense_variant
    evidence:
      - reference: PMID:42482035
        reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome masquerading as juvenile idiopathic arthritis: a case series with a novel PRG4 variant and emphasis on bone health."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "a homozygous nonsense variant (c.4104T > A; p.Tyr1368Ter) in the second which was absent from ClinVar and Varsome (accessed April 2026) and it was classified as pathogenic by ACMG/AMP"
        explanation: Reports the nonsense variant and its classification.
  evidence:
  - reference: PMID:10545950
    reference_title: "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP."
    explanation: The founding gene-disease association.
  - reference: PMID:38856641
    reference_title: "Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The syndrome is caused by biallelic loss-of-function variants in PRG4"
    explanation: States the biallelic loss-of-function mechanism.
  - reference: PMID:16429407
    reference_title: "Novel PRG4 mutations underlie CACP in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No genotype/phenotype association was observed."
    explanation: Clinical variability is not explained by the PRG4 allele.
diagnosis:
- name: PRG4 sequencing
  description: >-
    Diagnosis is confirmed by finding biallelic PRG4 variants, usually by
    exome sequencing, often after years of treatment for presumed juvenile
    idiopathic arthritis.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:38856641
    reference_title: "Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used exome sequencing to elucidate disease-causing variants in all the probands."
    explanation: Exome sequencing identified the PRG4 variants in all probands.
- name: Normal inflammatory markers
  description: >-
    Erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor and
    antinuclear antibodies are normal, which separates the syndrome from
    inflammatory arthritis.
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had normal inflammatory markers and the result for rheumatoid factor test was negative."
    explanation: Normal inflammatory markers in all 22 patients.
  - reference: PMID:41780543
    reference_title: "Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome without Camptodactyly: A Pediatric Case and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The erythrocyte sedimentation rate, C-reactive protein level, and antinuclear antibody test results were normal."
    explanation: Normal inflammatory and autoimmune markers in a further patient.
- name: Synovial fluid analysis
  description: >-
    Synovial fluid is non-inflammatory: viscous, clear to honey-coloured,
    sterile and with a low white cell count.
  evidence:
  - reference: PMID:41637065
    reference_title: "From Synovial Fluid to Musculoskeletal Ultrasound: A Portrayal of Joint Involvement in Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Synovial fluid was gelatinous, viscous, clear to honey-colored, and sterile."
    explanation: Describes the non-inflammatory synovial fluid of six genetically confirmed patients.
  - reference: PMID:41626297
    reference_title: "From Misdiagnosis to Genetic Confirmation: A Brazilian Familial Report of Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome-A Case-Based Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory tests showed normal inflammatory markers, and synovial fluid revealed low white cell counts."
    explanation: Low synovial white cell count with normal inflammatory markers.
- name: Pelvic radiography
  description: >-
    Radiographs show coxa vara, short broad femoral necks, flattened femoral
    heads, increased joint space and absence of erosions; large acetabular
    cysts are considered pathognomonic.
  diagnosis_term:
    preferred_term: pelvic radiography
    term:
      id: NCIT:C137876
      label: Bone Radiography
  evidence:
  - reference: PMID:16037531
    reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis syndrome versus juvenile idiopathic arthropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CACP syndrome should be considered in all patients who present with a noninflammatory arthropathy or with \"atypical juvenile idiopathic arthritis,\" particularly if radiographs reveal an absence of erosions."
    explanation: Radiographic absence of erosions points to CACP in a child with arthropathy.
- name: Musculoskeletal ultrasound
  description: >-
    Symmetric large-joint and tendon sheath effusions with hyperechoic foci
    and no intrasynovial Doppler signal favour CACP over polyarticular juvenile
    idiopathic arthritis.
  diagnosis_term:
    preferred_term: musculoskeletal ultrasound
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:42327906
    reference_title: "Musculoskeletal ultrasound discriminating camptodactyly-arthropathy-coxa vara-pericarditis syndrome and juvenile idiopathic arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CACP is characterised by symmetrical large-joint effusions with hyperechoic foci and absence of intrasynovial DM signal, in contrast to inflammatory findings in JIA."
    explanation: Ultrasound features that separate CACP from juvenile idiopathic arthritis.
  - reference: PMID:41637065
    reference_title: "From Synovial Fluid to Musculoskeletal Ultrasound: A Portrayal of Joint Involvement in Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed marked grade 3 synovial effusion, circumferential synovial hypertrophy, and synovial thickening in all patients, without the power Doppler activity"
    explanation: Knee ultrasound in six patients shows effusion and synovial hypertrophy without Doppler activity.
- name: Lubricin assay in synovial fluid or blood
  description: >-
    Lubricin is absent from synovial fluid and blood of patients; a
    competition ELISA has been proposed as a blood test, but it is a research
    assay.
  evidence:
  - reference: PMID:25642942
    reference_title: "Anti-lubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "indicating blood can be used in a diagnostic test for patients suspected of having CACP"
    explanation: Proposes blood lubricin measurement as a diagnostic test.
differential_diagnoses:
- name: Juvenile idiopathic arthritis
  description: >-
    The main misdiagnosis. Juvenile idiopathic arthritis shows inflammatory
    markers and Doppler hypervascularity; CACP has normal markers, no
    erosions, early camptodactyly and coxa vara, and does not respond to
    antirheumatic therapy.
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The referral diagnosis was inaccurate in all patients; juvenile idiopathic arthritis (JIA) was the referral diagnosis in majority of the patients."
    explanation: Most patients were first diagnosed with juvenile idiopathic arthritis.
  - reference: PMID:29397575
    reference_title: "Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen of our patients presented were referred for genetic evaluation with the initial diagnosis of JIA."
    explanation: Sixteen of 35 patients were initially diagnosed with juvenile idiopathic arthritis.
  - reference: PMID:40475173
    reference_title: "Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Caused by Truncating Mutations in the Prg4 Gene: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients were exposed to biologic therapy due to recalcitrant JIA."
    explanation: All three Turkish patients received biologics under a juvenile idiopathic arthritis diagnosis.
- name: Tuberculous pericarditis
  description: >-
    When serosal disease comes first, constrictive pericarditis or pericardial
    effusion in a child may be attributed to tuberculosis before the joint
    disease appears.
  evidence:
  - reference: PMID:38955384
    reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis."
    explanation: The pericardial disease was first treated as tuberculosis; CACP was recognised only after knee swelling developed.
treatments:
- name: Nonsteroidal anti-inflammatory drugs
  description: >-
    NSAIDs and simple analgesics give mild pain relief only; they do not alter
    the course of the arthropathy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nonsteroidal anti-inflammatory drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Arthralgia
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, treatment was ineffective apart from mild pain relief."
    explanation: Treatment, including NSAIDs, gave only mild pain relief.
- name: Antirheumatic and biologic therapy
  description: >-
    Corticosteroids, methotrexate and TNF inhibitors are often given under a
    mistaken diagnosis of juvenile idiopathic arthritis and are ineffective,
    as the arthropathy is not inflammatory.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
    - preferred_term: etanercept
      term:
        id: CHEBI:4875
        label: etanercept
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Non-inflammatory arthropathy
  evidence:
  - reference: PMID:23290693
    reference_title: "Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "10 patients used antirheumatic drugs (prednisone and methotrexate) and two patients were treated with etanercept. In all patients, treatment was ineffective apart from mild pain relief."
    explanation: Antirheumatic drugs and etanercept were ineffective, which refutes their use for the arthropathy.
  - reference: PMID:41780543
    reference_title: "Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome without Camptodactyly: A Pediatric Case and Review of the Literature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Initially diagnosed with polyarticular juvenile idiopathic arthritis, he received methotrexate and etanercept. Due to progressive gait issues and radiographic coxa vara, diagnosis was revised."
    explanation: Disease progressed on methotrexate and etanercept.
  - reference: PMID:40830943
    reference_title: "Juvenile idiopathic arthritis or skeletal dysplasia: first case report of camptodactyly-arthropathy-coxa vara-pericarditis from Iran."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite receiving treatment modalities such as non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, and corticosteroids, the patient experienced minimal improvement."
    explanation: Minimal improvement on NSAIDs, methotrexate and corticosteroids.
  - reference: PMID:42482035
    reference_title: "Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome masquerading as juvenile idiopathic arthritis: a case series with a novel PRG4 variant and emphasis on bone health."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Both received multiple disease-modifying and biologic agents without clinical response."
    explanation: No response to disease-modifying and biologic agents in two further patients.
- name: Yttrium-90 radiosynovectomy
  description: A single intra-articular yttrium-90 injection was safe but gave no benefit in a small prospective series.
  treatment_term:
    preferred_term: intra-articular radiosynovectomy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  therapeutic_modality: RADIOTHERAPY
  target_mechanisms:
  - target: Fibroblast-Like Synoviocyte Overgrowth
  evidence:
  - reference: PMID:28291008
    reference_title: "The Efficacy of Yttrium-90 Radiosynovectomy in Patients with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Yttrium-90 radiosynovectomy seems to be a safe and well tolerated procedure, however, it did not show a beneficial therapeutic effect in arthropathy of CACP syndrome with the given dosage and interval."
    explanation: No therapeutic benefit was observed.
- name: Physiotherapy
  description: Range-of-motion exercise to preserve joint mobility.
  treatment_term:
    preferred_term: physiotherapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Limitation of joint mobility
  evidence:
  - reference: PMID:27748313
    reference_title: "Pathognomonic acetabular cysts in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight months after the first visit, there was slight improvement in the range of motion of knees and hips."
    explanation: Single case with slight improvement in range of motion after physiotherapy.
- name: Total hip arthroplasty
  description: Hip replacement for debilitating hip arthropathy, including in adolescents.
  treatment_term:
    preferred_term: total hip arthroplasty
    term:
      id: NCIT:C157876
      label: Hip Replacement
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Progressive Cartilage Wear and Precocious Joint Failure
  evidence:
  - reference: PMID:22386609
    reference_title: "Total hip arthroplasty in adolescents with severe hip arthropathy and dysplasia associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we feel that total hip arthroplasty is a reasonable treatment option for adolescents with debilitating hip arthropathy associated with CACP syndrome"
    explanation: Good postoperative outcome in adolescent siblings.
- name: Pericardiectomy
  description: Surgical removal of the pericardium for constrictive pericarditis, also used to stop secondary protein-losing enteropathy.
  treatment_term:
    preferred_term: Pericardiectomy
    term:
      id: NCIT:C51643
      label: Pericardiectomy
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Constrictive pericarditis
  evidence:
  - reference: PMID:27224999
    reference_title: "Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results."
    explanation: Pericardiectomy was performed with good results.
- name: Recombinant lubricin supplementation (preclinical)
  description: >-
    Intra-articular recombinant human PRG4 restores boundary lubrication and
    reduces chondrocyte apoptosis in lubricin-null mice and cartilage
    explants. It has not been tested in patients.
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Loss of Cartilage Boundary Lubrication and Increased Joint Friction
  - target: Friction-Induced Superficial Chondrocyte Apoptosis
  evidence:
  - reference: PMID:28604608
    reference_title: "Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "intra-articular injection of human PRG4 in vivo in Prg4-/- mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo"
    explanation: Recombinant PRG4 reduces chondrocyte apoptosis and friction in the knockout.
  - reference: PMID:35457064
    reference_title: "Quadruped Gait and Regulation of Apoptotic Factors in Tibiofemoral Joints following Intra-Articular rhPRG4 Injection in Prg4 Null Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "There were significantly fewer caspase-3-positive chondrocytes in tibiofemoral cartilage from rhPRG4-injected mice."
    explanation: Replicates the anti-apoptotic effect of injected rhPRG4.
  - reference: PMID:23530215
    reference_title: "Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the bovine explant system, the addition of lubricin as a test lubricant significantly lowered the static coefficient of friction and number of apoptotic chondrocytes."
    explanation: Added lubricin lowers friction and chondrocyte apoptosis in explants.
  - reference: PMID:28129516
    reference_title: "Intra-articular Recombinant Human Proteoglycan 4 Mitigates Cartilage Damage After Destabilization of the Medial Meniscus in the Yucatan Minipig."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The rhPRG4 group had significantly less macroscopic cartilage damage in the medial tibial plateau compared with the PBS group"
    explanation: In a large-animal post-traumatic model, intra-articular rhPRG4 reduced cartilage damage; indirect for CACP because the minipigs were not lubricin deficient.
animal_models:
- name: Prg4-null mouse (Rhee 2005)
  species: Mouse
  genotype: Prg4 homozygous null
  publication: PMID:15719068
  description: >-
    Viable and fertile, with normal joints at birth; with age develops
    cartilage surface protein deposits, loss of superficial chondrocytes,
    cartilage deterioration, synovial intimal hyperplasia, and tendon sheath
    changes with calcification.
  modeled_mechanisms:
  - target: Fibroblast-Like Synoviocyte Overgrowth
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure"
      explanation: The knockout reproduces synovial hyperplasia.
  - target: Progressive Cartilage Wear and Precocious Joint Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In addition to cartilage surface changes and subsequent cartilage deterioration"
      explanation: The knockout reproduces progressive cartilage deterioration.
  - target: Tendon and Tendon Sheath Surface Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: Tendon changes were described at the ankle; finger flexor tendons and camptodactyly were not reported in the mouse.
    evidence:
    - reference: PMID:15719068
      reference_title: "The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed."
      explanation: Tendon and sheath lesions in the knockout.
- name: Prg4-null mouse (Coles 2010, hip)
  species: Mouse
  genotype: Prg4 homozygous null
  publication: PMID:20191580
  description: Femoral head cartilage of a Prg4-null line shows an age-dependent rise in friction, loss of stiffness and osteoarthritis-like degeneration.
  modeled_mechanisms:
  - target: Loss of Cartilage Boundary Lubrication and Increased Joint Friction
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    evidence:
    - reference: PMID:20191580
      reference_title: "Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Friction was significantly higher on cartilage of Prg4(-/-) mice at age 16 weeks, but statistically significant differences in friction were not detected at younger ages."
      explanation: Increased cartilage friction in the knockout hip.
notes: >-
  No GeneReviews chapter exists for this disease (PubMed searches for
  camptodactyly[TI], PRG4 and CACP, each restricted to genereviews[book],
  returned no records). The broader Camptodactyly entry covers camptodactyly
  as a sign across syndromes and also discusses PRG4; this entry is the
  disease-level record for CACP syndrome. A congenital cataract reported in
  one Emirati patient (PMID:22678705) is a single observation and is not
  listed as a phenotype. MONDO also lists the eponym Jacobs syndrome as a
  synonym; it is left out of the synonyms here because the same name is in
  common use for 47,XYY syndrome (the StatPearls chapter titled Jacobs
  Syndrome is about 47,XYY). Mitral stenosis requiring commissurotomy has
  been reported in a single child (PMID:38523390) and is not listed as a
  phenotype.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome · 2026-10-14T15:37:49Z · View source

Created the entry for CACP syndrome (MONDO:0008828, PRG4) from primary literature found by PubMed search, replacing the stub. Pathophysiology is an eight-node chain: biallelic PRG4 loss of function, lubricin deficiency at joint, tendon and serosal surfaces, loss of cartilage boundary lubrication with raised friction, friction-induced superficial chondrocyte apoptosis (conforms_to osteoarthritis_cartilage_degradation#Mechanical Overload and Chondrocyte Stress), fibroblast-like synoviocyte overgrowth, progressive cartilage wear (conforms_to osteoarthritis_cartilage_degradation#Cartilage Matrix Loss and Subchondral Bone Remodeling), tendon sheath dysfunction and serosal effusion. Mechanistic edges rest on the Prg4-null mouse papers (PMID:15719068, 20191580, 17968947, 23530215, 28604608) and on patient synovial pathology and protein studies (PMID:15702367, 16000300, 25642942). Twenty-one HP-bound phenotypes with cohort frequencies from the Saudi (PMID:23290693), Turkish (PMID:29397575) and Indian (PMID:38856641) series. ClinGen Definitive validity recorded from the CGGV assertion. Treatments include REFUTE evidence for antirheumatic and biologic drugs and for yttrium-90 radiosynovectomy, plus pericardiectomy, hip arthroplasty and preclinical recombinant lubricin. Camptodactyly, acetabular cysts, reduced bone mineral density and mitral valve prolapse are left without an inbound causal edge because no source states their mechanism. Not cited: PMID:26508154 (no quotable text cached), PMID:24834922 (temporomandibular joint mouse phenotype, not needed), PMID:36252540 (surface-chemistry study of recombinant lubricin), PMID:34012381 and PMID:39705621 (no claim not already covered by primary series). The MONDO synonym Jacobs syndrome was omitted because it names 47,XYY in common use. No GeneReviews chapter exists. Deep research: research/Camptodactyly-Arthropathy-Coxa_Vara-Pericarditis_Syndrome-deep-research-openscientist.md (second run, after the first timed out) was used as leads after the initial curation. All 24 of its references resolved. Its term suggestions were not used: five HP/NCIT CURIEs are mislabelled (HP:0005750, HP:0001644, HP:0100658, HP:0100763, NCIT:C15431), HP:0002102 is Pleuritis rather than pleural effusion, GO:0005615 is obsolete, and it gives PRG4 as HGNC:9361 where the binding is hgnc:9364. just preflight-dr could not run because the local MONDO build is absent, so identity was checked by hand: PRG4 is named throughout, OMIM 208250 and MONDO:0008828 are cited, and WISP3/CCN6 progressive pseudorheumatoid dysplasia appears only as a differential. Taken from the report, each re-verified against the cached abstract: superficial-zone chondrocyte loss in Prg4-null mice (PMID:26975998); constrictive pericarditis first treated as tuberculosis, added as evidence and as a differential (PMID:38955384); neonatal pleural effusion (PMID:40830943); further REFUTE evidence for NSAIDs, methotrexate, corticosteroids and biologics (PMID:40830943, 42482035); misdiagnosis as JIA with biologic exposure (PMID:40475173); non-inflammatory synovial fluid and ultrasound findings (PMID:41637065, 41626297); DXA-confirmed reduced bone mineral density, which replaced the Osteoporosis phenotype with Reduced bone mineral density (PMID:42482035); variants c.1910_1911delCT, c.3756dup and c.4104T>A (PMID:40475173, 41626297, 42482035); and the minipig rhPRG4 study as INDIRECT treatment evidence (PMID:28129516). A Serositis phenotype (HP:0045073, OCCASIONAL) was added from the 22% serosal-involvement figure in PMID:29397575. Not used from the report: the TMJ hedgehog and BMP mouse papers (PMID:26945615, 26534931, 24834922), which concern ectopic TMJ cartilage rather than the human disease; the Turkish rheumatic-mimic series (PMID:40626694), a referral cohort giving no prevalence; the mutation count (PMID:36694203) and case reviews (PMID:40874560, 42074176, 25297354), which add nothing not already sourced; the single mitral stenosis case (PMID:38523390), mentioned in notes only; and the report's suggested ORPHA identifier, which no resolver checks. Validation: just validate, validate-terms, count-verified-snippets (119/119), check-entity-refs, check-causal-targets, check-duplicate-keys, check-block-scalar-comments, check-genereviews and validate-disorders all passed.

OpenScientist ▸
Camptodactyly–Arthropathy–Coxa Vara–Pericarditis (CACP) Syndrome: A Comprehensive Disease Characteristics Report
openscientist-autonomous 24 citations 2026-10-14T16:19:42.287641

Camptodactyly–Arthropathy–Coxa Vara–Pericarditis (CACP) Syndrome: A Comprehensive Disease Characteristics Report

Disease: Camptodactyly–Arthropathy–Coxa Vara–Pericarditis Syndrome MONDO ID: MONDO:0008828 · OMIM: 208250 · Causal gene: PRG4 (lubricin / proteoglycan 4) Category: Mendelian (autosomal recessive)

Summary

Camptodactyly–Arthropathy–Coxa Vara–Pericarditis (CACP) syndrome is an ultra-rare, autosomal recessive Mendelian disorder caused by biallelic loss-of-function mutations in PRG4, the gene encoding lubricin (also known as proteoglycan 4, superficial zone protein, or megakaryocyte-stimulating factor precursor). Lubricin is a large secreted, mucin-like glycoprotein that provides boundary lubrication to articular cartilage and serosal (pericardial, pleural, tendon-sheath) surfaces and simultaneously suppresses the overgrowth of synovial intimal cells. When lubricin is absent, two coupled pathological processes occur: friction-driven death of superficial-zone chondrocytes and uncontrolled synovial intimal hyperplasia. Together these drive the disease's characteristic non-inflammatory tetrad: congenital camptodactyly (flexion contractures of the fingers), early-childhood non-inflammatory large-joint arthropathy with synovial hyperplasia, progressive coxa vara with a short femoral neck, and non-inflammatory serosal (pericardial/pleural) effusions.

A central clinical theme — recurring across essentially every modern case series — is that CACP is repeatedly misdiagnosed as juvenile idiopathic arthritis (JIA) and treated, ineffectively, with NSAIDs, methotrexate, corticosteroids, and biologic TNF inhibitors. The key distinguishing features are persistently normal inflammatory markers (ESR/CRP), non-inflammatory synovial fluid (low white-cell count), absence of erosions on imaging, and the presence of coxa vara/short femoral neck. Definitive diagnosis is made by PRG4 sequencing (whole-exome/whole-genome or single-gene), which typically reveals homozygous (or compound heterozygous) truncating variants in consanguineous families, supported by an antibody-based assay showing lubricin absence in blood and synovial fluid.

There is no approved disease-modifying treatment; management is supportive (physiotherapy, orthopedic correction of coxa vara, joint replacement for end-stage disease, pericardiectomy for constrictive pericarditis). The most mechanistically rational investigational therapy is recombinant human PRG4 (rhPRG4) replacement, supported by preclinical large-animal and in vitro data. Prognosis is dominated by progressive joint deformity/disability, with cardiac serositis (constrictive pericarditis) representing the principal life-threatening complication; cognition and lifespan are otherwise generally preserved.

Key Findings

Finding 1 — CACP is caused by biallelic loss-of-function mutations in PRG4 (lubricin)

CACP was mapped and cloned by positional-candidate methods to chromosome 1q25–q31, where mutations in a gene designated CACP (now PRG4) encoding a secreted proteoglycan were identified as the cause of the autosomal recessive syndrome (PMID: 10545950): "we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP." PRG4 had previously been identified independently as the precursor of megakaryocyte-stimulating factor and as the articular cartilage "superficial zone protein," unifying several research threads under one gene.

Across subsequent case series the inheritance mechanism is uniform: biallelic loss-of-function variants. A large cohort of 13 Indian patients explicitly states the syndrome "is caused by biallelic loss-of-function variants in PRG4" (PMID: 38856641), and multiple independent reports describe homozygous truncating variants such as c.1290del (p.T431Lfs*481) in consanguineous families (PMID: 40874560).

Gene annotation: HGNC PRG4; OMIM gene 605602; OMIM phenotype 208250. Suggested MONDO: MONDO:0008828.

Finding 2 — Mechanism: lubricin lubricates cartilage AND restrains synovial overgrowth; its loss produces friction-driven chondrocyte apoptosis plus synovial hyperplasia

Lubricin has a dual protective role, and CACP pathology reflects the loss of both functions. In lubricin-mutant mice, abnormal protein deposits accumulate on the cartilage surface, superficial-zone chondrocytes are lost, and — critically — "intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure. Purified or recombinant lubricin inhibited the growth of these synoviocytes in vitro" (PMID: 15719068). This single observation explains both the cartilage failure and the synovial hyperplasia that clinically mimics inflammatory arthritis.

The friction–apoptosis link is mechanistically demonstrated: lubricin-knockout joints show elevated whole-joint friction and increased chondrocyte apoptosis, and in a bovine cartilage-on-cartilage explant system "we observed a direct correlation between coefficient of friction and chondrocyte apoptosis in the superficial layers of cartilage," an effect reversed by adding lubricin (PMID: 23530215). Downstream, friction induces chondrocyte mitochondrial dysregulation and caspase-3 activation (PMID: 28604608), identifying apoptosis as the terminal tissue-damage step.

Suggested GO/CL terms: GO:0006915 (apoptotic process), GO:0005615 (extracellular space), GO:0008285 (negative regulation of cell proliferation); CL:0000138 (chondrocyte), CL:0000214 (synovial cell).

Finding 3 — The clinical tetrad is non-inflammatory and is frequently misdiagnosed as JIA

CACP presents as a tetrad: congenital/early-onset camptodactyly, childhood-onset non-inflammatory arthropathy with synovial hyperplasia, progressive coxa vara, and non-inflammatory pericardial (± pleural) effusion (PMID: 40830943). Phenotype frequencies from the 13-patient Indian cohort are: "Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13)" (PMID: 38856641), with wrists (11/13), ankles (11/13), elbows (10/13) and knees (10/13) most affected.

Because synovial hyperplasia superficially resembles inflammatory arthritis but inflammatory markers are normal and synovial fluid is non-inflammatory (low WBC), misdiagnosis as JIA is the rule rather than the exception. In one series "all patients were exposed to biologic therapy due to recalcitrant JIA" (PMID: 40475173), and multiple independent reports describe prolonged, ineffective immunosuppression before genetic confirmation (PMID: 41626297; PMID: 42074176; PMID: 42482035).

Suggested HPO terms: HP:0100490 (camptodactyly of finger), HP:0005750 (coxa vara), HP:0001367 (abnormal joint morphology), HP:0001644 (pericardial effusion), HP:0002102 (pleural effusion), HP:0100658 (joint effusion), HP:0100763 (synovial hypertrophy).

Finding 4 — Serosal (pericardial/pleural) involvement is variable, often later, and can be life-threatening

Pericarditis/pericardial effusion is the most variable and least penetrant element of the tetrad. It is described as occurring "rarely" in some cohorts (PMID: 40475173: "early-onset camptodactyly, noninflammatory arthropathy, coxa vara deformity, and, rarely, pericardial effusion"), reflecting lubricin's role on visceral serosal surfaces. When present and severe, it progresses to constrictive pericarditis requiring pericardiectomy, and has been misattributed to tuberculosis: "the elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis" (PMID: 38955384). Neonatal pleural effusion with respiratory distress followed by later pericardiectomy has also been reported (PMID: 40830943), and a unique association with mitral stenosis requiring commissurotomy was documented, hypothesized to relate to the proteoglycan content of the mitral valve (PMID: 38523390).

Finding 5 — No cure exists; management is supportive; rhPRG4 replacement is the rational investigational therapy

No approved disease-modifying treatment exists. Because the arthropathy is non-inflammatory, anti-inflammatory/immunosuppressive regimens fail: a patient "despite receiving treatment modalities such as non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, and corticosteroids... experienced minimal improvement" (PMID: 40830943). The mechanistically rational strategy is lubricin (rhPRG4) replacement: intra-articular full-length recombinant human PRG4 reduced cartilage damage in a Yucatan minipig model of medial-meniscus destabilization — "the rhPRG4 group had significantly less macroscopic cartilage damage in the medial tibial [plateau]" (PMID: 28129516) — and purified/recombinant lubricin inhibits synoviocyte overgrowth and reduces chondrocyte apoptosis in vitro (PMID: 15719068; PMID: 23530215). Supportive care includes physiotherapy, orthopedic correction of coxa vara (e.g., valgus osteotomy), joint replacement for end-stage arthropathy, and pericardiectomy for constrictive pericarditis.

Suggested NCIT terms: NCIT:C15431 (Physical Therapy), NCIT:C15329 (Surgery), protein replacement therapy (rhPRG4, investigational).

Finding 6 — Mutational spectrum: predominantly truncating (frameshift/nonsense) loss-of-function variants, with strong consanguinity/homozygosity

As of 2023 only "36 pathogenic mutations have been reported in this gene" (PMID: 36694203), underscoring the disease's rarity. The spectrum is overwhelmingly truncating:

Variant Type Reference
c.1290del (p.T431Lfs*481) Frameshift PMID: 40874560
c.3756dup Frameshift (duplication) PMID: 41626297
c.2208del (p.Thr737ProfsTer175) Frameshift PMID: 42482035
c.4104T>A (p.Tyr1368Ter) Nonsense PMID: 42482035
c.3636G>T, c.1935del, c.1134dup, c.1699del, c.962T>A 5 novel PMID: 38856641
c.2645_2646delGA; c.2883_2886delAAGA Frameshift deletions PMID: 25297354

The 13-patient Indian cohort reported "five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A)" (PMID: 38856641). Variants are typically homozygous in consanguineous families, consistent with autosomal recessive inheritance. Most truncating variants are predicted to trigger nonsense-mediated decay or yield non-functional truncated protein (PMID: 40874560). Under ACMG/AMP these are generally classified pathogenic/likely pathogenic (null variant in a gene where LOF is the established mechanism).

Finding 7 — The Prg4-null mouse recapitulates key CACP features

The lubricin-deficient (Prg4⁻/⁻) mouse is the primary disease model. Mice are viable and fertile with normal joints at birth, then develop age-dependent cartilage-surface protein deposits, superficial-zone chondrocyte loss, synovial intimal hyperplasia, and periarticular pathology: "tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed" (PMID: 15719068) — relevant to the camptodactyly/contracture phenotype. Stereological analysis confirms deficient superficial/upper-intermediate-zone chondrocyte cellularity with caspase-3/TUNEL-positive apoptosis (PMID: 26975998). In the temporomandibular joint, "as early as 2 weeks of age, mutant mice exhibited hyperplasia in the glenoid fossa articular cartilage, articular disc, and synovial membrane" progressing to osteoarthritic degradation, ectopic cartilage, and mineralization (PMID: 24834922; PMID: 26945615; PMID: 26534931). Ectopic cartilage in Prg4-null TMJ discs is associated with excess BMP signaling and ectopic hedgehog signaling, candidate downstream pathways.

Finding 8 — Protein-level consequence: truncating mutations abolish lubricin synthesis/secretion; normal lubricin requires disulfide-dependent SPC processing

In patients carrying frameshift or nonsense PRG4 mutations, "the antiserum did not detect lubricin in synovial fluid or cultured synoviocytes from several patients with frameshift or nonsense mutations in PRG4" (PMID: 16000300) — direct evidence that the disease mechanism is loss of protein (absent synthesis/secretion). The same work showed that wild-type lubricin undergoes post-translational cleavage within its C-terminal hemopexin-like domain by a subtilisin-like proprotein convertase (SPC), and that "formation of an intrachain disulfide bond is required for SPC-mediated cleavage and that SPC-mediated cleavage is essential to protein function." Epitope mapping localizes key monoclonal-antibody epitopes to O-linked oligosaccharides on the mucin-domain KEPAPTTT motif (PMID: 25642942).

Finding 9 — Diagnostic biomarker: lubricin is absent from blood and synovial fluid, enabling an antibody-based test alongside sequencing

Epitope-specific anti-lubricin monoclonal antibodies (raised in Prg4⁻/⁻ mice) detect lubricin in healthy individuals but not in CACP patients: "the competition ELISA detected lubricin in blood samples from healthy individuals but not from patients with CACP, indicating blood can be used in a diagnostic test for patients suspected of having CACP" (PMID: 25642942). This provides a blood-based screening/confirmation assay. Definitive diagnosis remains PRG4 sequencing (WES/WGS/single-gene) (PMID: 38856641). Supporting distinguishing labs/imaging: normal ESR/CRP; non-inflammatory synovial fluid (gelatinous, viscous, low WBC, sterile — PMID: 41637065); musculoskeletal ultrasound shows marked synovial effusion and circumferential synovial hypertrophy without power Doppler activity (PMID: 41637065); radiographs show joint effusion/synovial debris without erosions, coxa vara, short femoral neck, and metaphyseal flaring (PMID: 42074176).

Finding 10 — Epidemiology/inheritance: ultra-rare autosomal recessive, consanguinity-linked, complete joint penetrance with variable expressivity, no strong sex bias

CACP is an ultra-rare monogenic autosomal recessive disorder (OMIM 208250) with no established population prevalence; only a few hundred cases and ~36 catalogued mutations are reported worldwide (PMID: 36694203). Cases cluster in consanguineous families and populations (Middle East, Turkey, South Asia, North Africa). The 13-patient cohort derived from "eight consanguineous Indian families" with 7 females and 6 males (PMID: 38856641), indicating no strong sex predilection. Penetrance of the joint phenotype is essentially complete in biallelic carriers, while expressivity — especially the cardiac/serosal component — is variable. Regionally, a Southeastern Turkey series identified CACP in 12 of 47 individuals evaluated for non-inflammatory musculoskeletal complaints mimicking rheumatic disease (PMID: 40626694), underscoring its relative frequency among genetic JIA mimics in consanguineous populations.

Finding 11 — Natural history/prognosis: congenital onset, chronic progressive non-inflammatory arthropathy; cardiac serositis is the main life-threatening risk; cognition and lifespan usually preserved

Onset is congenital/early (camptodactyly at birth/infancy; arthropathy in early childhood). The course is chronic and progressive: "deficiency of PRG4 results in progressive worsening of joint deformity with age" (PMID: 38856641), producing large-joint contractures, coxa vara/short femoral neck, and "precocious joint failure" (PMID: 15719068). Reduced bone mineral density has been reported as part of a broader phenotypic burden (PMID: 42482035). Serosal disease can present even in adulthood as a first episode of constrictive pericarditis and represents the principal cause of serious morbidity/mortality; most patients have normal intelligence and near-normal lifespan when cardiac disease is managed.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic truncating mutation in PRG4 (frameshift/nonsense) leads to loss of full-length lubricin mRNA/protein via nonsense-mediated decay or non-functional truncated product (demonstrated: lubricin undetectable in patient synovial fluid/synoviocytes, PMID 16000300).
  2. Absent lubricin results in loss of boundary lubrication at articular cartilage and serosal surfaces, and in parallel loss of the normal inhibitory signal that restrains synovial intimal cell proliferation (demonstrated in mouse/in vitro, PMID 15719068).

→ Branch A (cartilage/joint): - 3a. Loss of lubrication leads to an elevated coefficient of friction at the cartilage surface (demonstrated, PMID 23530215; 28604608). - 4a. Increased friction results in superficial-zone chondrocyte mitochondrial dysregulation and caspase-3–mediated apoptosis, leading to depletion of superficial-zone chondrocytes and surface protein deposition (demonstrated, PMID 23530215, 26975998, 28604608). - 5a. In parallel, de-repressed synovial intimal cells undergo hyperplasia, producing non-inflammatory synovial thickening and effusion (demonstrated, PMID 15719068). - 6a. Progressive cartilage failure + synovial hyperplasia leads to precocious large-joint arthropathy, contractures (camptodactyly, inferred from tendon/sheath involvement), and, at the hip, coxa vara with short femoral neck (clinical, PMID 38856641, 15719068).

→ Branch B (serosa): - 3b. Absent lubricin on pericardial/pleural serosal surfaces leads to non-inflammatory serosal effusion, which can result in fibrosis/constrictive pericarditis (clinical, variable expressivity; PMID 40475173, 38955384).

Upstream vs downstream

  • Upstream (initiating): PRG4-null genotype → absent lubricin protein.
  • Midstream (mechanistic): increased friction + loss of synoviocyte growth inhibition.
  • Downstream (effector): chondrocyte apoptosis, synovial hyperplasia, serosal effusion.
  • Terminal (clinical): camptodactyly, arthropathy, coxa vara, pericarditis, reduced BMD.

Cell types, tissues, and compartments

Level Entities Suggested ontology
Cells Superficial-zone chondrocyte; synovial intimal cell (synoviocyte) CL:0000138; CL:0000214
Tissue Articular cartilage, synovial membrane, tendon/sheath, pericardium, pleura UBERON:0002418, 0002103, 0000043, 0002407, 0000977
Organ/system Joints (hip, knee, wrist, ankle, elbow, fingers, TMJ), heart (pericardium), lung (pleura), skeleton (femoral neck) Musculoskeletal + cardiovascular + respiratory
Subcellular Extracellular space (secreted lubricin); chondrocyte mitochondria (apoptotic signaling) GO:0005615; GO:0005739
Processes Boundary lubrication, apoptotic process, negative regulation of cell proliferation GO:0006915; GO:0008285

Mechanistic nuances

  • CACP is not inflammatory: synovial hyperplasia is a direct consequence of lost lubricin growth-inhibition, not immune-driven synovitis — explaining the universal failure of immunosuppression and the normal CRP/ESR.
  • Mouse models reveal downstream signaling perturbations (ectopic hedgehog and excess BMP signaling driving ectopic cartilage/osteophytes in the TMJ; PMID 26945615, 26534931), which are candidate secondary pathways best characterized in the TMJ model rather than in human CACP tissue.

Evidence Base

PMID Title (abbrev.) Source type Contribution
10545950 CACP, encoding a secreted proteoglycan, is mutated in CACP Human genetics Establishes PRG4 as causal gene (positional cloning)
38856641 Thirteen Indians with CACP syndrome Human cohort Biallelic LOF; phenotype frequencies; 5 novel variants; progression
15719068 Lubricin protects cartilage and inhibits synovial overgrowth Mouse / in vitro Dual mechanism; precocious joint failure; tendon pathology
23530215 Lubricin and prevention of chondrocyte apoptosis In vitro / mouse Friction ↔ apoptosis causal link
28604608 Friction-induced mitochondrial dysregulation in Prg4 KO Mouse Caspase-3/mitochondrial chondrocyte death
16000300 Consequences of disease-causing mutations on lubricin In vitro / human Truncating mutations abolish protein; SPC/disulfide processing
25642942 Anti-lubricin monoclonal antibodies In vitro / human Blood-based diagnostic assay (lubricin absent in CACP)
28129516 Intra-articular rhPRG4 in Yucatan minipig Large-animal Preclinical rationale for rhPRG4 replacement
40475173 CACP caused by truncating mutations (JIA mimic) Human Misdiagnosis as JIA; biologic exposure; pericarditis variable
40830943 First Iranian CACP case Human Tetrad; failure of NSAIDs/MTX/steroids; pleural effusion
38955384 CACP syndrome review/cases Human Constrictive pericarditis → pericardiectomy; TB misdiagnosis
38523390 CACP with mitral stenosis Human Rare cardiac valve association
36694203 Novel PRG4 mutation, two sisters Human Quantifies ~36 known mutations (rarity)
26975998 Superficial-zone cellularity deficient in lubricin-null mice Mouse Stereological chondrocyte loss + caspase-3
24834922 Lubricin required for TMJ integrity Mouse TMJ hyperplasia model recapitulation
26945615 / 26534931 Ectopic hedgehog / excess BMP in Prg4-null TMJ Mouse Downstream signaling pathways
41637065 MSUS of CACP joints Human Synovial hypertrophy/effusion without power Doppler; sterile fluid
42482035 CACP with bone-health emphasis Human Novel variants; reduced BMD; JIA mimic
40626694 Genetic diseases mimicking rheumatic disorders (Turkey) Human CACP among JIA mimics in consanguineous population
25297354 Novel PRG4 mutations in Indian families Human Early frameshift variants from India

Consistency: All human and model-organism evidence converges on a single, coherent loss-of-function mechanism. No source contradicts the core model; the main variability is clinical expressivity of the cardiac/serosal component.

Section-by-Section Compendium

1. Disease information. CACP (MONDO:0008828; OMIM 208250; ORPHA:1236). Synonyms: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome; CACP syndrome; arthropathy-camptodactyly syndrome; familial arthropathy. Information is derived from aggregated disease-level case reports/series and model-organism studies (no large EHR datasets; the disease is ultra-rare).

2. Etiology. Purely genetic — biallelic LOF of PRG4. The principal non-genetic contributor is consanguinity (increases probability of homozygous inheritance). No environmental, infectious, toxic, or lifestyle causes; no known protective alleles or gene–environment interactions. Not applicable: GWAS loci, common susceptibility SNPs.

3. Phenotypes. Camptodactyly (congenital physical manifestation, ~100% — HP:0100490); non-inflammatory large-joint arthropathy with synovial hyperplasia (clinical sign, childhood onset, progressive, ~92–100% — HP:0100658/HP:0100763); coxa vara (radiographic, childhood, progressive, ~85% — HP:0005750); short femoral neck (~85%); pericardial effusion (variable onset, variable/less frequent — HP:0001644); pleural effusion (HP:0002102); reduced bone mineral density (HP:0004349). Labs: normal ESR/CRP (key distinguisher), non-inflammatory synovial fluid. Quality of life: progressive contractures and hip deformity impair mobility and daily functioning; cardiac tamponade/constriction is the severe-impact phenotype.

4. Genetic/molecular. Causal gene PRG4 (HGNC:9361; 1q31.1; OMIM 605602). Variant classes: predominantly frameshift and nonsense (truncating); ACMG class pathogenic/likely pathogenic; germline, homozygous; functional consequence loss of function (absent secreted protein). Allele frequencies: individually very rare/absent in gnomAD (private family mutations). No established modifier genes, disease-specific epigenetic signatures, or large chromosomal abnormalities.

5. Environmental. None causal. No toxins, infectious agents, or lifestyle factors. (Serosal effusions are sometimes clinically mistaken for tuberculous pericarditis — a diagnostic pitfall, not an etiology.)

6. Mechanism. See causal chain above. Core pathways: boundary-lubrication failure → friction → mitochondrial/caspase-3 apoptosis of superficial-zone chondrocytes; loss of synoviocyte growth suppression → hyperplasia; downstream ectopic hedgehog/BMP signaling in the model TMJ.

7. Anatomical structures. Primary: synovial joints (hip/coxa vara, knee, wrist, ankle, elbow, fingers, TMJ), articular cartilage, synovium, tendon sheaths. Secondary: pericardium, pleura (serosal), occasionally cardiac valves; skeleton (femoral neck, reduced BMD). Bilateral/symmetrical joint involvement. UBERON: 0002418 (cartilage), 0002103 (synovial membrane), 0000977 (pleura), 0002407 (pericardium).

8. Temporal development. Onset congenital (camptodactyly) → early childhood (arthropathy, coxa vara) → variable, sometimes adult-onset serosal disease. Course: chronic, progressive, non-remitting joint disease; serosal episodes may be episodic. Lifelong. The critical window for potential lubricin-replacement intervention is likely early, before irreversible cartilage loss.

9. Inheritance & population. Autosomal recessive; ultra-rare (no established prevalence); consanguinity-associated; complete joint penetrance, variable expressivity (cardiac); no strong sex bias; founder/private mutations in consanguineous families (South Asia, Middle East, Turkey, North Africa). Carrier frequency not established.

10. Diagnostics. Normal ESR/CRP; non-inflammatory, sterile, viscous synovial fluid; radiographs show effusion/synovial debris without erosions, coxa vara, short femoral neck, metaphyseal flaring; MSUS shows synovial hypertrophy/effusion without power Doppler; lubricin absent on blood/synovial-fluid immunoassay; definitive = PRG4 sequencing (WES/WGS/single-gene). Differential: JIA (key mimic), skeletal dysplasias (progressive pseudorheumatoid dysplasia, mucopolysaccharidoses), other familial arthropathies.

11. Prognosis. Progressive disability from joint deformity; constrictive pericarditis is the main mortality risk (manageable with pericardiectomy); normal cognition; near-normal lifespan with cardiac management. Main prognostic factor: presence/severity of cardiac involvement.

12. Treatment. No cure. Supportive: physiotherapy/occupational therapy, analgesia, orthopedic surgery (valgus osteotomy for coxa vara, joint replacement), pericardiectomy for constriction, valve surgery if indicated. Immunosuppressants/biologics are ineffective and should be discontinued once CACP is confirmed. Investigational: rhPRG4 replacement (preclinical). NCIT: physical therapy, orthopedic surgery, protein replacement therapy.

13. Prevention. No primary prevention. Genetic counseling and carrier/cascade testing in consanguineous families; prenatal/preimplantation genetic testing feasible once the familial variant is known. Tertiary prevention: regular echocardiographic surveillance for pericardial/valvular disease; bone-health monitoring (DXA).

14. Other species / natural disease. Orthologous gene: mouse Prg4 (NCBI Gene 56689). The Prg4⁻/⁻ mouse is an engineered (not natural) model; no well-established spontaneous CACP-equivalent natural disease in companion animals is documented in this knowledge base. The lubricin boundary-lubrication mechanism is evolutionarily conserved across mammals (bovine, equine, porcine lubricin all studied).

15. Model organisms. Primary: mouse (Prg4 knockout — mammalian genetic model) recapitulating synovial hyperplasia, superficial-zone chondrocyte loss/apoptosis, tendon/sheath pathology, and TMJ degeneration. Large-animal pharmacology: Yucatan minipig (rhPRG4 intra-articular efficacy). In vitro: bovine cartilage explants, synoviocyte cultures. Limitations: mice are born with normal joints and develop disease postnatally (age-dependent), and the human cardiac/serosal phenotype is not a prominent reported feature of the mouse. Resource: MGI (Prg4).

Limitations and Knowledge Gaps

  1. No epidemiological denominator. Prevalence/incidence, carrier frequency, and population-specific rates are unknown; all data derive from small case series biased toward consanguineous populations.
  2. Cardiac mechanism under-characterized. Why serosal/pericardial involvement is variable and sometimes adult-onset — and the basis of the rare mitral-valve association — is not mechanistically established.
  3. Weak genotype–phenotype correlation. With predominantly null alleles, the determinants of variable expressivity (modifier genes, environment) are unknown.
  4. rhPRG4 is preclinical only for CACP; no human CACP clinical-trial outcome data (NCT identifiers) were identified in this investigation.
  5. Mouse-model gaps. The knockout does not clearly reproduce human cardiac serositis; camptodactyly is inferred from tendon-sheath pathology rather than directly modeled.
  6. No omics in CACP patients. Patient transcriptomic/proteomic/metabolomic profiling is largely absent; mechanistic signaling data (hedgehog/BMP) derive from the TMJ mouse model, not human CACP tissue.
  7. Bone-health phenotype newly emerging. Reduced BMD is reported in isolated cases (PMID: 42482035) but frequency and mechanism are undefined.

Proposed Follow-up Experiments / Actions

  1. Establish an international CACP registry / natural-history cohort to define prevalence, phenotype frequencies (especially cardiac penetrance by age), and progression rates.
  2. Advance rhPRG4 toward a first-in-human CACP trial — intra-articular dosing informed by minipig data (PMID: 28129516); define outcome measures (MSUS synovial hypertrophy, friction surrogates, joint function).
  3. Validate the lubricin blood immunoassay (PMID: 25642942) as a first-line, low-cost diagnostic screen to shorten the diagnostic odyssey and curb inappropriate biologic use.
  4. Deploy early PRG4 sequencing in any child with non-inflammatory, immunosuppression-refractory arthritis plus normal CRP/ESR and/or coxa vara — codify this as a diagnostic pathway/guideline.
  5. Interrogate downstream signaling (hedgehog/BMP) in human CACP synovium/cartilage to test whether pathway inhibitors (e.g., BMP-receptor kinase inhibitors) could serve as adjunct therapies, building on TMJ-model findings (PMID: 26534931).
  6. Systematically assess cardiac and bone health (serial echocardiography; DXA) across cohorts to quantify constrictive-pericarditis risk and the newly reported low-BMD phenotype.
  7. Explore gene/cell-based correction (AAV PRG4 delivery, or lubricin-secreting cell therapy) as a durable alternative to repeated protein replacement.

Report compiled from 11 confirmed findings and 37 reviewed publications over 5 investigation iterations. Evidence types are indicated per citation (human clinical, mouse/model organism, in vitro, large-animal preclinical). Primary literature PMIDs are provided throughout; direct abstract quotes are used verbatim to support key mechanistic and clinical claims.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 24
On topic 20
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 20
Resolved 17
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 14
Terms named correctly 6
Terms named as a different term 5
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0005750 (2 mentions) - the report calls it "coxa vara"; HP calls it Lower-limb joint contracture
  • HP:0001644 (2 mentions) - the report calls it "pericardial effusion"; HP calls it Dilated cardiomyopathy
  • HP:0100658 (2 mentions) - the report calls it "joint effusion"; HP calls it Cellulitis
  • HP:0100763 (2 mentions) - the report calls it "synovial hypertrophy"; HP calls it Abnormality of the lymphatic system
  • NCIT:C15431 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Hematopoietic Cell Transplantation

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (2 mentions) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0005615 (2 mentions) - the report calls it "extracellular space"; GO calls it obsolete extracellular space, and lists "intercellular space" among its other names
  • GO:0008285 (2 mentions) - the report calls it "negative regulation of cell proliferation"; GO calls it negative regulation of cell population proliferation, and lists "negative regulation of cell proliferation" among its other names
  • HP:0002102 (2 mentions) - the report calls it "pleural effusion"; HP calls it Pleuritis, and lists "Pleurisy" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.