Pyle disease

Summary

Pyle disease (MONDO:0009943) is a disease caused by SFRP4 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SFRP4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0002857	Genu valgum	Very frequent (80-99%)
HP:0004975	Erlenmeyer flask deformity of the femurs	Very frequent (80-99%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000411	Protruding ear	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000689	Dental malocclusion	Frequent (30-79%)
HP:0002659	Increased susceptibility to fractures	Frequent (30-79%)
HP:0003051	Enlarged metaphyses	Frequent (30-79%)
HP:0005464	Craniofacial osteosclerosis	Frequent (30-79%)
HP:0006599	Medial widening of clavicles	Frequent (30-79%)
HP:0000696	Delayed eruption of permanent teeth	Occasional (5-29%)
HP:0000926	Platyspondyly	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0002645	Wormian bones	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0010539	Thin calvarium	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Pyle disease
Mondo ID	MONDO:0009943
MeSH	C536252
OMIM	265900
Orphanet	3005
DOID	DOID:0080019
ICD-10-CM	Q78.5
ICD-11	651364947
SNOMED CT	27837003
UMLS	C0265294
MedGen	82704
GARD	0004612
Is cancer (heuristic)	no

Also known as: Bakwin-Krida syndrome · metaphyseal dysplasia · metaphyseal dysplasia Pyle type · metaphyseal dysplasia, Pyle type · Pyle disease · Pyle’s disease · Pyle’s syndrome · Pyle-Cohn syndrome

Data availability: 14 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › Pyle disease

Related subtypes (49): atelosteogenesis, midface dysplasia, Kashin-Beck disease, achondroplasia, Boomerang dysplasia, campomelic dysplasia, cleidocranial dysplasia 1, Leri-Weill dyschondrosteosis, hypochondroplasia, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, Kniest dysplasia, pseudoachondroplasia, ulna metaphyseal dysplasia syndrome, acheiropody, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, bone dysplasia, lethal Holmgren type, cleidocranial dysplasia, recessive form, diastrophic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, lethal Kniest-like dysplasia, metaphyseal chondrodysplasia, Kaitila type, metaphyseal chondrodysplasia, Spahr type, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, pycnodysostosis, pyknoachondrogenesis, schneckenbecken dysplasia, mesomelia-synostoses syndrome, lethal chondrodysplasia, Seller type, acrocapitofemoral dysplasia, brachyolmia, Desbuquois dysplasia, fibrochondrogenesis, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, thanatophoric dysplasia, Blount disease, osteogenesis imperfecta, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

Subtypes (2): metaphyseal chondrodysplasia, chondrodysplasia calcificans Metaphysealis

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

14 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 benign, 3 likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
242995	NM_003014.4(SFRP4):c.499dup (p.Asp167fs)	SFRP4	Pathogenic	no assertion criteria provided
242996	NM_003014.3(SFRP4):c.694C>T	SFRP4	Pathogenic	no assertion criteria provided
242997	NM_003014.4(SFRP4):c.481_487del (p.Val161fs)	SFRP4	Pathogenic	criteria provided, single submitter
3893232	NM_003014.4(SFRP4):c.433del (p.Asp145fs)	SFRP4	Pathogenic	criteria provided, single submitter
4819365	NM_003014.4(SFRP4):c.180del (p.Gln60fs)	SFRP4	Pathogenic	criteria provided, single submitter
3775097	NM_003014.4(SFRP4):c.445+1G>A	SFRP4	Likely pathogenic	criteria provided, single submitter
989454	NM_003014.4(SFRP4):c.161C>A (p.Ala54Asp)	SFRP4	Likely pathogenic	criteria provided, single submitter
989455	NM_003014.4(SFRP4):c.373T>A (p.Cys125Ser)	SFRP4	Likely pathogenic	criteria provided, single submitter
1374436	NM_003014.4(SFRP4):c.566C>T (p.Thr189Met)	SFRP4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2052702	NM_003014.4(SFRP4):c.514C>T (p.Arg172Cys)	SFRP4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1287094	NM_003014.4(SFRP4):c.958C>A (p.Pro320Thr)	SFRP4	Benign	criteria provided, multiple submitters, no conflicts
1332946	NM_003014.4(SFRP4):c.1019G>A (p.Arg340Lys)	SFRP4	Benign	criteria provided, multiple submitters, no conflicts
1332947	NM_003014.4(SFRP4):c.786C>T (p.Arg262=)	SFRP4	Benign	criteria provided, multiple submitters, no conflicts
1332948	NM_003014.4(SFRP4):c.567G>A (p.Thr189=)	SFRP4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SFRP4	Strong	Autosomal recessive	Pyle disease	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SFRP4	Orphanet:3005	Pyle disease

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
SFRP4	HGNC:10778	ENSG00000106483	Q6FHJ7	Secreted frizzled-related protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SFRP4	Secreted frizzled-related protein 4	Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts.

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)
SFRP4	Other/Unknown	no		Netrin_domain, TIMP-like_OB-fold, Frizzled/SFRP

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
ectocervix	1
endocervix	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SFRP4	221	broad	marker	right uterine tube, endocervix, ectocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SFRP4	2,002

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SFRP4	Q6FHJ7	78.60

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
negative regulation of sodium-dependent phosphate transport	1	16852.0×	0.001	SFRP4
positive regulation of keratinocyte apoptotic process	1	4213.0×	0.002	SFRP4
negative regulation of non-canonical Wnt signaling pathway	1	3370.4×	0.002	SFRP4
positive regulation of epidermal cell differentiation	1	2106.5×	0.002	SFRP4
regulation of BMP signaling pathway	1	1203.7×	0.003	SFRP4
phosphate ion homeostasis	1	1053.2×	0.003	SFRP4
positive regulation of receptor internalization	1	702.2×	0.004	SFRP4
bone morphogenesis	1	601.9×	0.004	SFRP4
non-canonical Wnt signaling pathway	1	581.1×	0.004	SFRP4
response to hormone	1	432.1×	0.004	SFRP4
negative regulation of Wnt signaling pathway	1	343.9×	0.005	SFRP4
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.010	SFRP4
canonical Wnt signaling pathway	1	153.2×	0.010	SFRP4
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.012	SFRP4
positive regulation of apoptotic process	1	56.7×	0.022	SFRP4
negative regulation of cell population proliferation	1	42.1×	0.028	SFRP4
positive regulation of gene expression	1	38.7×	0.029	SFRP4
cell differentiation	1	29.1×	0.036	SFRP4
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	SFRP4

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
SFRP4	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	SFRP4

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)
SFRP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05046977	Not specified	UNKNOWN	Double Osteotomy for Deformity Correction in Pyle Disease