Acrodysostosis 2 with or without hormone resistance

Summary

Acrodysostosis 2 with or without hormone resistance (MONDO:0013822) is a disease caused by PDE4D (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PDE4D (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 178

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acrodysostosis 2 with or without hormone resistance
Mondo ID	MONDO:0013822
OMIM	614613
UMLS	C3553250
MedGen	766164
GARD	0015823
Is cancer (heuristic)	no

Also known as: ACRDYS2 · acrodysostosis 2 with or without hormone resistance · acrodysostosis 2, with or without hormone resistance · acrodysostosis caused by mutation in PDE4D · PDE4D acrodysostosis

Data availability: 178 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › mandibulofacial dysostosis › acrodysostosis › acrodysostosis 2 with or without hormone resistance

Related subtypes (1): Acrodysostosis 1 with or without hormone resistance

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

178 retrieved; paginated sample, class counts are floors:

90 uncertain significance, 48 benign, 12 conflicting classifications of pathogenicity, 11 pathogenic, 8 benign/likely benign, 5 likely pathogenic, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
101052	NM_001104631.2(PDE4D):c.677T>G (p.Phe226Cys)	PDE4D	Pathogenic	no assertion criteria provided
101053	NM_001104631.2(PDE4D):c.2033T>C (p.Ile678Thr)	PDE4D	Pathogenic	criteria provided, multiple submitters, no conflicts
2203651	NM_001104631.2(PDE4D):c.674C>T (p.Pro225Leu)	PDE4D	Pathogenic	criteria provided, multiple submitters, no conflicts
2444421	NM_001104631.2(PDE4D):c.998T>C (p.Ile333Thr)	PDE4D	Pathogenic	criteria provided, single submitter
30035	NM_001104631.2(PDE4D):c.673C>A (p.Pro225Thr)	PDE4D	Pathogenic	no assertion criteria provided
30036	NM_001104631.2(PDE4D):c.677T>C (p.Phe226Ser)	PDE4D	Pathogenic	no assertion criteria provided
30037	NM_001104631.2(PDE4D):c.568T>G (p.Ser190Ala)	PDE4D	Pathogenic	no assertion criteria provided
30038	NM_001104631.2(PDE4D):c.1759A>C (p.Thr587Pro)	PDE4D	Pathogenic	no assertion criteria provided
30039	NM_001104631.2(PDE4D):c.682C>G (p.Gln228Glu)	PDE4D	Pathogenic	criteria provided, single submitter
30040	NM_001104631.2(PDE4D):c.1952A>C (p.Glu651Ala)	PDE4D	Pathogenic	no assertion criteria provided
40064	NM_001104631.2(PDE4D):c.911C>T (p.Ala304Val)	PDE4D	Pathogenic	no assertion criteria provided
30041	NM_001104631.2(PDE4D):c.2018G>A (p.Gly673Asp)	PDE4D	Likely pathogenic	criteria provided, single submitter
4531995	NM_001104631.2(PDE4D):c.935T>C (p.Leu312Pro)	PDE4D	Likely pathogenic	criteria provided, single submitter
4814188	NM_001104631.2(PDE4D):c.947T>A (p.Leu316His)	PDE4D	Likely pathogenic	criteria provided, single submitter
982782	NM_001104631.2(PDE4D):c.569C>T (p.Ser190Phe)	PDE4D	Likely pathogenic	criteria provided, single submitter
989238	NM_001104631.2(PDE4D):c.2051A>G (p.Glu684Gly)	PDE4D	Likely pathogenic	criteria provided, single submitter
3236684	NM_001104631.2(PDE4D):c.665T>C (p.Ile222Thr)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353938	NM_001104631.2(PDE4D):c.*2747G>A	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353950	NM_001104631.2(PDE4D):c.*2100C>T	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353985	NM_001104631.2(PDE4D):c.2259C>T (p.Gly753=)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353990	NM_001104631.2(PDE4D):c.1542G>C (p.Leu514=)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354000	NM_001104631.2(PDE4D):c.125C>A (p.Pro42Gln)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3895509	NM_001104631.2(PDE4D):c.671C>T (p.Thr224Ile)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436281	NM_001104631.2(PDE4D):c.1762A>G (p.Met588Val)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
735008	NM_001104631.2(PDE4D):c.240C>G (p.Pro80=)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904304	NM_001104631.2(PDE4D):c.781C>A (p.Pro261Thr)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907635	NM_001104631.2(PDE4D):c.1252C>T (p.Arg418Trp)	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907636	NM_001104631.2(PDE4D):c.1189-4C>G	PDE4D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560134	Single allele	LOC129993944	Uncertain significance	criteria provided, single submitter
1448098	NM_001104631.2(PDE4D):c.235C>T (p.Pro79Ser)	PDE4D	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
PDE4D	Definitive	Autosomal dominant	acrodysostosis 2 with or without hormone resistance	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE4D	Orphanet:439822	PDE4D haploinsufficiency syndrome
PDE4D	Orphanet:950	Acrodysostosis

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
PDE4D	HGNC:8783	ENSG00000113448	Q08499	3’,5’-cyclic-AMP phosphodiesterase 4D	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE4D	3’,5’-cyclic-AMP phosphodiesterase 4D	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE4D	Enzyme (other)	yes	3.1.4.53	PDEase_catalytic_dom, PDEase, PDEase_CS

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
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE4D	283	ubiquitous	marker	gluteal muscle, biceps brachii, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDE4D	1,533

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE4D	Q08499	122

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
DARPP-32 events	1	475.8×	0.004	PDE4D
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.004	PDE4D
G alpha (s) signalling events	1	73.2×	0.014	PDE4D

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 relaxation of cardiac muscle	1	8426.0×	0.002	PDE4D
negative regulation of heart contraction	1	4213.0×	0.002	PDE4D
cAMP catabolic process	1	1872.4×	0.002	PDE4D
adrenergic receptor signaling pathway	1	1872.4×	0.002	PDE4D
regulation of cell communication by electrical coupling involved in cardiac conduction	1	1872.4×	0.002	PDE4D
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	1685.2×	0.002	PDE4D
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	1685.2×	0.002	PDE4D
positive regulation of interleukin-5 production	1	1404.3×	0.002	PDE4D
cellular response to epinephrine stimulus	1	1296.3×	0.002	PDE4D
regulation of cardiac muscle cell contraction	1	1123.5×	0.002	PDE4D
establishment of endothelial barrier	1	766.0×	0.002	PDE4D
positive regulation of heart rate	1	702.2×	0.002	PDE4D
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	674.1×	0.002	PDE4D
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.002	PDE4D
regulation of heart rate	1	468.1×	0.003	PDE4D
positive regulation of interleukin-2 production	1	468.1×	0.003	PDE4D
cellular response to cAMP	1	290.6×	0.004	PDE4D
positive regulation of type II interferon production	1	224.7×	0.005	PDE4D
T cell receptor signaling pathway	1	151.8×	0.007	PDE4D

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
PDE4D	INAMRINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE4D	269	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INAMRINONE	4	PDE4D
THEOPHYLLINE	4	PDE4D
VARDENAFIL	4	PDE4D
MILRINONE	4	PDE4D
LOSARTAN	4	PDE4D
SILDENAFIL	4	PDE4D
ROFLUMILAST	4	PDE4D
ENOXIMONE	4	PDE4D
ENSIFENTRINE	4	PDE4D
CRISABOROLE	4	PDE4D
APREMILAST	4	PDE4D
PENTOXIFYLLINE	4	PDE4D
TADALAFIL	4	PDE4D
DIPYRIDAMOLE	4	PDE4D
CANDESARTAN CILEXETIL	4	PDE4D
TELMISARTAN	4	PDE4D
SIMVASTATIN	4	PDE4D
MORICIZINE	4	PDE4D
AMLEXANOX	4	PDE4D
AMOXAPINE	4	PDE4D
PONATINIB	4	PDE4D
RUCAPARIB	4	PDE4D
CELECOXIB	4	PDE4D
VILANTEROL	4	PDE4D
TIOCONAZOLE	4	PDE4D
UNOPROSTONE ISOPROPYL	4	PDE4D
OLMESARTAN MEDOXOMIL	4	PDE4D
HYDROXYPROGESTERONE CAPROATE	4	PDE4D
NORGESTIMATE	4	PDE4D
THIOTHIXENE	4	PDE4D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PDE4D	863	Binding:805, Functional:33, ADMET:23, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE4D	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PDE4D	863

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

30 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)
INAMRINONE	4	PDE4D
THEOPHYLLINE	4	PDE4D
VARDENAFIL	4	PDE4D
MILRINONE	4	PDE4D
LOSARTAN	4	PDE4D
SILDENAFIL	4	PDE4D
ROFLUMILAST	4	PDE4D
ENOXIMONE	4	PDE4D
ENSIFENTRINE	4	PDE4D
CRISABOROLE	4	PDE4D
APREMILAST	4	PDE4D
PENTOXIFYLLINE	4	PDE4D
TADALAFIL	4	PDE4D
DIPYRIDAMOLE	4	PDE4D
CANDESARTAN CILEXETIL	4	PDE4D
TELMISARTAN	4	PDE4D
SIMVASTATIN	4	PDE4D
MORICIZINE	4	PDE4D
AMLEXANOX	4	PDE4D
AMOXAPINE	4	PDE4D
PONATINIB	4	PDE4D
RUCAPARIB	4	PDE4D
CELECOXIB	4	PDE4D
VILANTEROL	4	PDE4D
TIOCONAZOLE	4	PDE4D
UNOPROSTONE ISOPROPYL	4	PDE4D
OLMESARTAN MEDOXOMIL	4	PDE4D
HYDROXYPROGESTERONE CAPROATE	4	PDE4D
NORGESTIMATE	4	PDE4D
THIOTHIXENE	4	PDE4D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE4D
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.