Acrodysostosis

Summary

Acrodysostosis (MONDO:0019797) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 53
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000194	Open mouth	Very frequent (80-99%)
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000457	Depressed nasal ridge	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0001831	Short toe	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0005616	Accelerated skeletal maturation	Very frequent (80-99%)
HP:0005916	Abnormal metacarpal morphology	Very frequent (80-99%)
HP:0010049	Short metacarpal	Very frequent (80-99%)
HP:0010579	Cone-shaped epiphysis	Very frequent (80-99%)
HP:0010655	Epiphyseal stippling	Very frequent (80-99%)
HP:0010743	Short metatarsal	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000055	Abnormality of female external genitalia	Frequent (30-79%)
HP:0000248	Brachycephaly	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0000940	Abnormal diaphysis morphology	Frequent (30-79%)
HP:0000944	Abnormal metaphysis morphology	Frequent (30-79%)
HP:0001373	Joint dislocation	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002673	Coxa valga	Frequent (30-79%)
HP:0002818	Abnormal morphology of the radius	Frequent (30-79%)
HP:0002823	Abnormality of femur morphology	Frequent (30-79%)
HP:0002970	Genu varum	Frequent (30-79%)
HP:0002983	Micromelia	Frequent (30-79%)
HP:0002984	Hypoplasia of the radius	Frequent (30-79%)
HP:0003022	Hypoplasia of the ulna	Frequent (30-79%)
HP:0003416	Spinal canal stenosis	Frequent (30-79%)
HP:0006059	Cone-shaped metacarpal epiphyses	Frequent (30-79%)
HP:0006487	Bowing of the long bones	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0010978	Abnormality of immune system physiology	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0040071	Abnormal morphology of ulna	Frequent (30-79%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000858	Irregular menstruation	Occasional (5-29%)
HP:0000995	Melanocytic nevus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acrodysostosis
Mondo ID	MONDO:0019797
MeSH	C538179
OMIM	101800
Orphanet	950
DOID	DOID:14669
ICD-11	477546932
SNOMED CT	66758006
UMLS	C0220659
MedGen	113097
GARD	0005724
NORD	722
Is cancer (heuristic)	no

Also known as: acrodysplasia · Arkless-Graham syndrome · Maroteaux-Malamut syndrome · nasal hypoplasia-peripheral dysostosis-intellectual disability syndrome · peripheral dysostosis-nasal hypoplasia-intellectual disability (PNM) syndrome

Data availability: 2 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 › dysostosis › mandibulofacial dysostosis › acrodysostosis

Related subtypes (5): Treacher-Collins syndrome, otofaciocervical syndrome, X-linked mandibulofacial dysostosis, mandibulofacial dysostosis-macroblepharon-macrostomia syndrome, mandibulofacial dysostosis with alopecia

Subtypes (2): Acrodysostosis 1 with or without hormone resistance, acrodysostosis 2 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 8 · 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
PRKAR1A	Definitive	Autosomal dominant	acrodysostosis with multiple hormone resistance	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE4D	Orphanet:439822	PDE4D haploinsufficiency syndrome
PDE4D	Orphanet:950	Acrodysostosis
PRKAR1A	Orphanet:1359	Carney complex
PRKAR1A	Orphanet:1501	Adrenocortical carcinoma
PRKAR1A	Orphanet:520	Acute promyelocytic leukemia
PRKAR1A	Orphanet:615	Familial atrial myxoma
PRKAR1A	Orphanet:647772	Isolated primary pigmented nodular adrenocortical disease
PRKAR1A	Orphanet:950	Acrodysostosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PDE4D	HGNC:8783	ENSG00000113448	Q08499	3’,5’-cyclic-AMP phosphodiesterase 4D	gencc
PRKAR1A	HGNC:9388	ENSG00000108946	P10644	cAMP-dependent protein kinase type I-alpha regulatory subunit	gencc

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.
PRKAR1A	cAMP-dependent protein kinase type I-alpha regulatory subunit	Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE4D	Enzyme (other)	yes	3.1.4.53	PDEase_catalytic_dom, PDEase, PDEase_CS
PRKAR1A	Other/Unknown	no		cNMP-bd_dom, cAMP_dep_PK_reg_su_I/II_a/b, cAMP_dep_PK_reg_su

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of rectus abdominis	1
germinal epithelium of ovary	1
lateral nuclear group of thalamus	1
mucosa of paranasal sinus	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
PRKAR1A	295	ubiquitous	marker	mucosa of paranasal sinus, germinal epithelium of ovary, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAR1A	3,586
PDE4D	1,533

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE4D	Q08499	122
PRKAR1A	P10644	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 53. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	475.8×	2e-04	PDE4D, PRKAR1A
G alpha (s) signalling events	2	73.2×	0.005	PDE4D, PRKAR1A
ALK mutants bind TKIs	1	475.8×	0.016	PRKAR1A
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	439.2×	0.016	PRKAR1A
PKA activation in glucagon signalling	1	335.9×	0.016	PRKAR1A
PKA activation	1	317.2×	0.016	PRKAR1A
PKA-mediated phosphorylation of CREB	1	285.5×	0.016	PRKAR1A
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.016	PRKAR1A
Leishmania parasite growth and survival	1	196.9×	0.016	PRKAR1A
Calmodulin induced events	1	190.3×	0.016	PRKAR1A
CaM pathway	1	190.3×	0.016	PRKAR1A
Ca-dependent events	1	184.2×	0.016	PRKAR1A
Aquaporin-mediated transport	1	184.2×	0.016	PRKAR1A
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.016	PDE4D
Glucagon signaling in metabolic regulation	1	173.0×	0.016	PRKAR1A
G-protein mediated events	1	163.1×	0.016	PRKAR1A
DAG and IP3 signaling	1	158.6×	0.016	PRKAR1A
Response of endothelial cells to shear stress	1	150.3×	0.016	PRKAR1A
FCGR3A-mediated IL10 synthesis	1	146.4×	0.016	PRKAR1A
Signaling by ALK in cancer	1	135.9×	0.016	PRKAR1A
Opioid Signalling	1	132.8×	0.016	PRKAR1A
PLC beta mediated events	1	132.8×	0.016	PRKAR1A
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	132.8×	0.016	PRKAR1A
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.016	PRKAR1A
Cellular responses to mechanical stimuli	1	129.8×	0.016	PRKAR1A
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.016	PRKAR1A
GPER1 signaling	1	124.1×	0.016	PRKAR1A
Regulation of insulin secretion	1	109.8×	0.017	PRKAR1A
Post NMDA receptor activation events	1	102.0×	0.018	PRKAR1A
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.018	PRKAR1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 cAMP/PKA signal transduction	2	601.9×	9e-05	PDE4D, PRKAR1A
negative regulation of relaxation of cardiac muscle	1	4213.0×	0.004	PDE4D
negative regulation of heart contraction	1	2106.5×	0.005	PDE4D
cAMP catabolic process	1	936.2×	0.005	PDE4D
adrenergic receptor signaling pathway	1	936.2×	0.005	PDE4D
regulation of cell communication by electrical coupling involved in cardiac conduction	1	936.2×	0.005	PDE4D
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	842.6×	0.005	PDE4D
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	842.6×	0.005	PDE4D
positive regulation of interleukin-5 production	1	702.2×	0.005	PDE4D
cellular response to epinephrine stimulus	1	648.1×	0.005	PDE4D
regulation of cardiac muscle cell contraction	1	561.7×	0.005	PDE4D
negative regulation of activated T cell proliferation	1	526.6×	0.005	PRKAR1A
cellular response to glucagon stimulus	1	421.3×	0.006	PRKAR1A
establishment of endothelial barrier	1	383.0×	0.006	PDE4D
vascular endothelial cell response to laminar fluid shear stress	1	366.4×	0.006	PRKAR1A
positive regulation of heart rate	1	351.1×	0.006	PDE4D
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.006	PDE4D
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.006	PRKAR1A
cardiac muscle cell proliferation	1	290.6×	0.006	PRKAR1A
renal water homeostasis	1	255.3×	0.006	PRKAR1A
mesoderm formation	1	247.8×	0.006	PRKAR1A
regulation of heart rate	1	234.1×	0.006	PDE4D
positive regulation of interleukin-2 production	1	234.1×	0.006	PDE4D
sarcomere organization	1	191.5×	0.007	PRKAR1A
cellular response to cAMP	1	145.3×	0.009	PDE4D
positive regulation of insulin secretion	1	127.7×	0.010	PRKAR1A
positive regulation of type II interferon production	1	112.3×	0.011	PDE4D
T cell receptor signaling pathway	1	75.9×	0.015	PDE4D
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.020	PRKAR1A
chemical synaptic transmission	1	38.6×	0.028	PRKAR1A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
PRKAR1A	0	0

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
PRKAR1A	2	Binding: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: 2; 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	1	PRKAR1A

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)
PRKAR1A	2	—

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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford