Pycnodysostosis

Summary

Pycnodysostosis (MONDO:0009940) is a disease caused by CTSK (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: CTSK (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 175
• Phenotypes (HPO): 66

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 1 000 000	0.13	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

66 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0004474	Persistent open anterior fontanelle	Very frequent (80-99%)
HP:0005446	Obtuse angle of mandible	Very frequent (80-99%)
HP:0005906	Delayed pneumatization of the mastoid process	Very frequent (80-99%)
HP:0008873	Disproportionate short-limb short stature	Very frequent (80-99%)
HP:0009839	Osteolytic defects of the distal phalanges of the hand	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0030353	Decreased serum insulin-like growth factor 1	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000444	Convex nasal ridge	Frequent (30-79%)
HP:0000448	Prominent nose	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000592	Blue sclerae	Frequent (30-79%)
HP:0000824	Decreased response to growth hormone stimulation test	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002659	Increased susceptibility to fractures	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0005789	Generalized osteosclerosis	Frequent (30-79%)
HP:0008598	Mild conductive hearing impairment	Frequent (30-79%)
HP:0009381	Short finger	Frequent (30-79%)
HP:0011800	Midface retrusion	Frequent (30-79%)
HP:0012532	Chronic pain	Frequent (30-79%)
HP:0200055	Small hand	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000668	Hypodontia	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0000680	Delayed eruption of primary teeth	Occasional (5-29%)
HP:0000689	Dental malocclusion	Occasional (5-29%)
HP:0000696	Delayed eruption of permanent teeth	Occasional (5-29%)
HP:0000889	Abnormality of the clavicle	Occasional (5-29%)
HP:0001601	Laryngomalacia	Occasional (5-29%)
HP:0001807	Ridged nail	Occasional (5-29%)
HP:0002164	Nail dysplasia	Occasional (5-29%)
HP:0002645	Wormian bones	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002866	Hypoplastic iliac wing	Occasional (5-29%)
HP:0003027	Mesomelia	Occasional (5-29%)
HP:0003302	Spondylolisthesis	Occasional (5-29%)
HP:0003304	Spondylolysis	Occasional (5-29%)
HP:0006297	Enamel hypoplasia	Occasional (5-29%)
HP:0006335	Persistence of primary teeth	Occasional (5-29%)
HP:0008905	Rhizomelia	Occasional (5-29%)
HP:0010307	Stridor	Occasional (5-29%)
HP:0010884	Acromelia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pycnodysostosis
Mondo ID	MONDO:0009940
MeSH	D058631
OMIM	265800
Orphanet	763
DOID	DOID:0080038
ICD-11	1329974152
NCIT	C131187
SNOMED CT	89647000
UMLS	C0238402
MedGen	116061
GARD	0004611
NORD	1637
Is cancer (heuristic)	no

Also known as: PKND · pycnodysostosis · Pyknodysostosis

Data availability: 175 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › lysosomal storage disease › pycnodysostosis

Related subtypes (10): lysosomal acid phosphatase deficiency, glycoprotein storage disease, hereditary spastic paraplegia 48, late infantile neuronal ceroid lipofuscinosis, glycoproteinosis, disorder of sialic acid metabolism, lysosomal glycogen storage disease, lysosomal lipid storage disorder, inborn disorder of lysosomal amino acid transport, mucopolysaccharidosis

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

175 retrieved; paginated sample, class counts are floors:

60 likely pathogenic, 51 uncertain significance, 27 pathogenic/likely pathogenic, 20 pathogenic, 8 likely benign, 5 conflicting classifications of pathogenicity, 3 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073787	NM_000396.4(CTSK):c.190_200del (p.Ala64fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073792	NM_000396.4(CTSK):c.493del (p.Gln165fs)	CTSK	Pathogenic	criteria provided, multiple submitters, no conflicts
1076504	NM_000396.4(CTSK):c.419G>A (p.Trp140Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076677	NM_000396.4(CTSK):c.364C>T (p.Arg122Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332709	NM_000396.4(CTSK):c.399+1G>A	CTSK	Pathogenic	criteria provided, single submitter
1332837	NM_000396.4(CTSK):c.120+1G>T	CTSK	Pathogenic	criteria provided, single submitter
1451614	NM_000396.4(CTSK):c.894G>A (p.Trp298Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685684	NM_000396.4(CTSK):c.83dup (p.Trp29fs)	CTSK	Pathogenic	criteria provided, multiple submitters, no conflicts
1724741	NM_000396.4(CTSK):c.658A>T (p.Lys220Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1949482	NM_000396.4(CTSK):c.457A>T (p.Lys153Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1961646	NM_000396.4(CTSK):c.818del (p.Asn273fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2126304	NM_000396.4(CTSK):c.290del (p.Leu97fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202838	NM_000396.4(CTSK):c.908G>A (p.Gly303Glu)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202839	NM_000396.4(CTSK):c.737_738del (p.Ser246fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687837	NM_000396.4(CTSK):c.150G>A (p.Trp50Ter)	CTSK	Pathogenic	criteria provided, single submitter
3384131	NM_000396.4(CTSK):c.338del (p.Gly113fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370345	NM_000396.4(CTSK):c.213T>A (p.Tyr71Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370473	NM_000396.4(CTSK):c.426del (p.Phe142fs)	CTSK	Pathogenic	criteria provided, multiple submitters, no conflicts
370558	NM_000396.4(CTSK):c.121-2A>G	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370625	NM_000396.4(CTSK):c.679_680insAA (p.Ile227fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370816	NM_000396.4(CTSK):c.48del (p.Tyr17fs)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371328	NM_000396.4(CTSK):c.568C>T (p.Gln190Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371426	NM_000396.4(CTSK):c.934C>T (p.Arg312Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371447	NM_000396.4(CTSK):c.120+1G>A	CTSK	Pathogenic	criteria provided, single submitter
4818303	NM_000396.4(CTSK):c.282dup (p.Val95fs)	CTSK	Pathogenic	criteria provided, single submitter
551507	NM_000396.4(CTSK):c.876G>A (p.Trp292Ter)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551777	NM_000396.4(CTSK):c.3G>A (p.Met1Ile)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553560	NM_000396.4(CTSK):c.136C>T (p.Arg46Trp)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
623333	NM_000396.4(CTSK):c.891-1G>T	CTSK	Pathogenic	criteria provided, single submitter
649051	NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr)	CTSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
CTSK	Definitive	Autosomal recessive	pycnodysostosis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTSK	Orphanet:763	Pycnodysostosis

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
CTSK	HGNC:2536	ENSG00000143387	P43235	Cathepsin K	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTSK	Cathepsin K	Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTSK	Protease	yes	3.4.22.38	Pept_cys_AS, Peptidase_C1A_C, Peptidase_C1A

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
periodontal ligament	1
skin of hip	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTSK	254	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTSK	2,790

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTSK	P43235	70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX1 regulates transcription of genes involved in differentiation of keratinocytes	1	1142.0×	0.009	CTSK
Trafficking and processing of endosomal TLR	1	815.7×	0.009	CTSK
Activation of Matrix Metalloproteinases	1	308.6×	0.016	CTSK
Collagen degradation	1	175.7×	0.018	CTSK
Transcriptional regulation by RUNX1	1	146.4×	0.018	CTSK
Toll-like Receptor Cascades	1	124.1×	0.018	CTSK
Degradation of the extracellular matrix	1	117.7×	0.018	CTSK
MHC class II antigen presentation	1	89.2×	0.021	CTSK
Extracellular matrix organization	1	63.1×	0.026	CTSK
Adaptive Immune System	1	29.8×	0.050	CTSK
Innate Immune System	1	25.5×	0.053	CTSK
RNA Polymerase II Transcription	1	22.5×	0.055	CTSK
Gene expression (Transcription)	1	17.8×	0.065	CTSK
Generic Transcription Pathway	1	15.1×	0.071	CTSK
Immune System	1	13.0×	0.077	CTSK

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
negative regulation of cartilage development	1	2106.5×	0.004	CTSK
thyroid hormone generation	1	991.3×	0.004	CTSK
bone resorption	1	581.1×	0.004	CTSK
obsolete proteolysis involved in protein catabolic process	1	526.6×	0.004	CTSK
collagen catabolic process	1	391.9×	0.004	CTSK
extracellular matrix disassembly	1	366.4×	0.004	CTSK
mitophagy	1	318.0×	0.004	CTSK
proteolysis	1	34.2×	0.029	CTSK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CTSK	BOCEPREVIR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CTSK	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BOCEPREVIR	4	CTSK
TELAPREVIR	4	CTSK
NIRMATRELVIR	4	CTSK
ODANACATIB	3	CTSK
RELACATIB	2	CTSK
BALICATIB	2	CTSK
ATUZAGINSTAT	2	CTSK
IBUZATRELVIR	2	CTSK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTSK	376	Binding:365, ADMET:5, Toxicity:5, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTSK	3.4.22.38	cathepsin K

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CTSK	376

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

8 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.

Compound	Max phase	Cohort target (bioactivity)
BOCEPREVIR	4	CTSK
TELAPREVIR	4	CTSK
NIRMATRELVIR	4	CTSK
ODANACATIB	3	CTSK
RELACATIB	2	CTSK
BALICATIB	2	CTSK
ATUZAGINSTAT	2	CTSK
IBUZATRELVIR	2	CTSK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CTSK
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.