Progressive pseudorheumatoid arthropathy of childhood

Summary

Progressive pseudorheumatoid arthropathy of childhood (MONDO:0008827) is a disease caused by CCN6 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include ganaxolone.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal gene: CCN6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 62
• Phenotypes (HPO): 45
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0002515	Waddling gait	Very frequent (80-99%)
HP:0002655	Spondyloepiphyseal dysplasia	Very frequent (80-99%)
HP:0003301	Irregular vertebral endplates	Very frequent (80-99%)
HP:0004267	Narrow small joints of the hand	Very frequent (80-99%)
HP:0005195	Polyarticular arthropathy	Very frequent (80-99%)
HP:0001225	Wrist swelling	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0001384	Abnormality of the hip joint	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002815	Abnormality of the knee	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003423	Thoracolumbar kyphoscoliosis	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004582	Irregularity of vertebral bodies	Frequent (30-79%)
HP:0004603	Hyperconvex vertebral body endplates	Frequent (30-79%)
HP:0006256	Abnormality of hand joint mobility	Frequent (30-79%)
HP:0008422	Vertebral wedging	Frequent (30-79%)
HP:0009473	Joint contracture of the hand	Frequent (30-79%)
HP:0009811	Abnormality of the elbow	Frequent (30-79%)
HP:0011406	Infancy onset short-trunk short stature	Frequent (30-79%)
HP:0012385	Camptodactyly	Frequent (30-79%)
HP:0000464	Abnormality of the neck	Occasional (5-29%)
HP:0002812	Coxa vara	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0002867	Abnormality of the ilium	Occasional (5-29%)
HP:0002970	Genu varum	Occasional (5-29%)
HP:0003043	Abnormality of the shoulder	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003370	Flat capital femoral epiphysis	Occasional (5-29%)
HP:0003371	Enlargement of the proximal femoral epiphysis	Occasional (5-29%)
HP:0004568	Beaking of vertebral bodies	Occasional (5-29%)
HP:0006247	Enlarged interphalangeal joints	Occasional (5-29%)
HP:0006429	Broad femoral neck	Occasional (5-29%)
HP:0008833	Irregular acetabular roof	Occasional (5-29%)
HP:0010580	Enlarged epiphyses	Occasional (5-29%)
HP:0025477	Periarticular calcification	Occasional (5-29%)
HP:0040160	Generalized osteoporosis	Occasional (5-29%)
HP:0100864	Short femoral neck	Occasional (5-29%)
HP:0002923	Rheumatoid factor positive	Excluded (0%)
HP:0025021	Abnormal erythrocyte sedimentation rate	Excluded (0%)
HP:0032436	Abnormal C-reactive protein level	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive pseudorheumatoid arthropathy of childhood
Mondo ID	MONDO:0008827
MeSH	C535387
OMIM	208230
Orphanet	1159
DOID	DOID:0090004
ICD-11	280808713
SNOMED CT	254065005
UMLS	C0432215
MedGen	96581
GARD	0009184
Is cancer (heuristic)	no

Also known as: arthropathy, progressive pseudorheumatoid, of childhood · PPAC · PPD · progressive pseudorheumatoid arthropathy of childhood · progressive pseudorheumatoid chondrodysplasia · SEDT-PA · spondyloepiphyseal dysplasia tarda - progressive arthropathy · spondyloepiphyseal dysplasia tarda-progressive arthropathy syndrome

Data availability: 62 ClinVar variants · 3 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepiphyseal dysplasia › progressive pseudorheumatoid arthropathy of childhood

Related subtypes (43): hip dysplasia, Beukes type, spondyloepiphyseal dysplasia with congenital joint dislocations, Marshall syndrome, metatropic dysplasia, spondyloepiphyseal dysplasia with punctate corneal dystrophy, spondyloepiphyseal dysplasia, MacDermot type, otospondylomegaepiphyseal dysplasia, Dyggve-Melchior-Clausen disease, dyssegmental dysplasia, Rolland-Desbuquois type, Silverman-Handmaker type dyssegmental dysplasia, Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia, Richieri Costa-da Silva syndrome, Schwartz-Jampel syndrome, X-linked spondyloepimetaphyseal dysplasia, CODAS syndrome, spondyloepiphyseal dysplasia, Reardon type, brachyolmia-amelogenesis imperfecta syndrome, spondyloepiphyseal dysplasia with coronal craniosynostosis, cataracts, cleft palate, and intellectual disability, anauxetic dysplasia, spondyloepiphyseal dysplasia, Kimberley type, spondyloepiphyseal dysplasia, Cantu type, Ehlers-Danlos syndrome, spondylocheirodysplastic type, spondylo-megaepiphyseal-metaphyseal dysplasia, brachydactylous dwarfism, Mseleni type, TMEM165-congenital disorder of glycosylation, Steel syndrome, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Roifman syndrome, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, even-plus syndrome, Smith-McCort dysplasia, cono-spondylar dysplasia, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, Stickler syndrome, spondyloepiphyseal dysplasia tarda, spondyloepiphyseal dysplasia, kondo-fu type, spondyloepiphyseal dysplasia, nishimura type, immunoskeletal dysplasia with neurodevelopmental abnormalities, COL2A1-related spondyloepiphyseal dysplasia, MIR140-related spondyloepiphyseal dysplasia, MGP-related spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia, Holling type

Genetics & variants

GWAS landscape

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

Variant details and genetic-evidence tiers

ClinVar germline variants

62 retrieved; paginated sample, class counts are floors:

21 pathogenic, 10 pathogenic/likely pathogenic, 9 benign, 6 uncertain significance, 6 likely pathogenic, 6 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071874	NM_198239.2(CCN6):c.624dup (p.Cys209fs)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
1323771	NM_198239.2(CCN6):c.626_627del (p.Cys209fs)	CCN6	Pathogenic	criteria provided, single submitter
166615	NM_198239.2(CCN6):c.740_741del (p.Cys247fs)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1680451	NM_198239.2(CCN6):c.1A>G (p.Met1Val)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683480	NM_198239.2(CCN6):c.1011_1014delinsATT (p.Cys337_Gln338delinsTer)	CCN6	Pathogenic	criteria provided, single submitter
1685603	NM_198239.2(CCN6):c.149G>A (p.Trp50Ter)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
1687519	NM_198239.2(CCN6):c.80T>A (p.Leu27Ter)	CCN6	Pathogenic	criteria provided, single submitter
1804751	NM_198239.2(CCN6):c.667T>G (p.Cys223Gly)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
1806291	NM_198239.2(CCN6):c.737del (p.Leu246fs)	CCN6	Pathogenic	criteria provided, single submitter
2136454	NM_198239.2(CCN6):c.197G>A (p.Ser66Asn)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
2445700	NM_198239.2(CCN6):c.40_44del (p.Leu14fs)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
252451	NM_198239.2(CCN6):c.589+1G>A	CCN6	Pathogenic	criteria provided, single submitter
2577398	NM_198239.2(CCN6):c.296_298delinsTTA (p.Tyr99_Cys100delinsPheSer)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734926	NM_198239.2(CCN6):c.49-1G>A	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2965678	NM_198239.2(CCN6):c.116C>A (p.Ser39Ter)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
453263	NM_198239.2(CCN6):c.868_869del (p.Ser290fs)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
521955	NM_198239.2(CCN6):c.1010G>A (p.Cys337Tyr)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
627567	NM_198239.2(CCN6):c.692del (p.Val231fs)	CCN6	Pathogenic	no assertion criteria provided
631969	NM_198239.2(CCN6):c.233G>A (p.Cys78Tyr)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637051	NM_198239.2(CCN6):c.589G>C (p.Ala197Pro)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6380	NM_198239.2(CCN6):c.993G>A (p.Trp331Ter)	CCN6	Pathogenic	no assertion criteria provided
6381	NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6382	NM_198239.2(CCN6):c.232T>C (p.Cys78Arg)	CCN6	Pathogenic	no assertion criteria provided
6383	NM_198239.2(CCN6):c.246del (p.Glu84fs)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts
6384	NM_198239.2(CCN6):c.48+2dup	CCN6	Pathogenic	criteria provided, single submitter
6385	NM_198239.2(CCN6):c.862_863dup (p.Gln289fs)	CCN6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6386	NM_198239.2(CCN6):c.43_44del (p.Ala15fs)	CCN6	Pathogenic	criteria provided, single submitter
6388	NM_198239.2(CCN6):c.1000T>C (p.Ser334Pro)	CCN6	Pathogenic	criteria provided, single submitter
6389	NM_198239.2(CCN6):c.840del (p.Phe280fs)	CCN6	Pathogenic	no assertion criteria provided
817946	NM_198239.2(CCN6):c.707del (p.Ser236fs)	CCN6	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
CCN6	Strong	Autosomal recessive	progressive pseudorheumatoid arthropathy of childhood	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCN6	Orphanet:1159	Progressive pseudorheumatoid dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CCN6	HGNC:12771	ENSG00000112761	O95389	Cellular communication network factor 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCN6	Cellular communication network factor 6	Plays a role in mitochondrial electron transport and mitochondrial respiration.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

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

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCN6	Other/Unknown	no		IGFBP-like, TSP1_rpt, Cys_knot_C

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCN6	162	tissue_specific	yes	tibia, male germ line stem cell (sensu Vertebrata) in testis, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCN6	437

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCN6	O95389	74.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of reactive oxygen species biosynthetic process	1	1872.4×	0.004	CCN6
regulation of mitochondrial membrane potential	1	543.6×	0.007	CCN6
positive regulation of cell differentiation	1	267.5×	0.010	CCN6
negative regulation of angiogenesis	1	168.5×	0.012	CCN6
cell-cell signaling	1	69.6×	0.023	CCN6
negative regulation of cell population proliferation	1	42.1×	0.031	CCN6
cell adhesion	1	37.5×	0.031	CCN6
signal transduction	1	16.1×	0.062	CCN6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCN6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CCN6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CCN6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03228394	PHASE2	COMPLETED	A Clinical Trial of Intravenous (IV) Ganaxolone in Women With Postpartum Depression
NCT03460756	PHASE2	COMPLETED	A Clinical Trial of Oral Ganaxolone in Women With Postpartum Depression

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GANAXOLONE	4	2