Acromicric dysplasia

Summary

Acromicric dysplasia (MONDO:0007055) is a disease caused by FBN1 (GenCC Strong), with 3 cohort genes. The dominant Reactome pathway is Elastic fibre formation (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FBN1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 516
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000311	Round face	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000527	Long eyelashes	Very frequent (80-99%)
HP:0000534	Abnormal eyebrow morphology	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0200055	Small hand	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000179	Thick lower lip vermilion	Frequent (30-79%)
HP:0000414	Bulbous nose	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001609	Hoarse voice	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0002823	Abnormality of femur morphology	Occasional (5-29%)
HP:0003300	Ovoid vertebral bodies	Occasional (5-29%)
HP:0005900	Fifth metacarpal with ulnar notch	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)
HP:0010049	Short metacarpal	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Acromicric dysplasia
Mondo ID	MONDO:0007055
MeSH	C535662
OMIM	102370
Orphanet	969
DOID	DOID:0111243
ICD-11	1006372687
SNOMED CT	254090007
UMLS	C0265287
MedGen	78549
GARD	0000007
NORD	725
Is cancer (heuristic)	no

Also known as: ACMICD · Acromicric dysplasia · Acromicric skeletal dysplasia

Data availability: 516 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › acromelic dysplasia › Acromicric dysplasia

Related subtypes (17): geleophysic dysplasia, pseudohypoparathyroidism type 1A, Angel-shaped phalango-epiphyseal dysplasia, Myhre syndrome, Leri pleonosteosis, peripheral dysostosis, short-rib thoracic dysplasia 9 with or without polydactyly, terminal osseous dysplasia-pigmentary defects syndrome, intellectual disability-balding-patella luxation-acromicria syndrome, acrocapitofemoral dysplasia, pseudohypoparathyroidism type 1C, pseudopseudohypoparathyroidism, short stature-brachydactyly-obesity-global developmental delay syndrome, trichorhinophalangeal syndrome, Weill-Marchesani syndrome, craniofacial conodysplasia, acrodysostosis

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

516 retrieved; paginated sample, class counts are floors:

193 conflicting classifications of pathogenicity, 189 uncertain significance, 37 benign/likely benign, 27 pathogenic/likely pathogenic, 23 pathogenic, 22 benign, 14 likely benign, 11 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1451231	NM_000138.5(FBN1):c.4121G>A (p.Cys1374Tyr)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
163462	NM_000138.5(FBN1):c.7754T>C (p.Ile2585Thr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163480	NM_000138.5(FBN1):c.1879C>T (p.Arg627Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
16440	NM_000138.5(FBN1):c.364C>T (p.Arg122Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
16461	NM_000138.5(FBN1):c.718C>T (p.Arg240Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675081	NM_000138.5(FBN1):c.5836del (p.Gln1946fs)	FBN1	Pathogenic	criteria provided, single submitter
1685816	NM_000138.5(FBN1):c.8163_8202dup (p.Glu2735fs)	FBN1	Pathogenic	criteria provided, single submitter
1685817	NM_000138.5(FBN1):c.7249del (p.Glu2417fs)	FBN1	Pathogenic	criteria provided, single submitter
1685818	NM_000138.5(FBN1):c.6629G>A (p.Cys2210Tyr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685819	NM_000138.5(FBN1):c.4684T>C (p.Cys1562Arg)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1707834	NM_000138.5(FBN1):c.2753del (p.Pro918fs)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
180351	NM_000138.5(FBN1):c.1285C>T (p.Arg429Ter)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180352	NM_000138.5(FBN1):c.1633C>T (p.Arg545Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200001	NM_000138.5(FBN1):c.2645C>T (p.Ala882Val)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200022	NM_000138.5(FBN1):c.3712G>A (p.Asp1238Asn)	FBN1	Pathogenic	reviewed by expert panel
200052	NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
200191	NM_000138.5(FBN1):c.6388G>A (p.Glu2130Lys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265401	NM_000138.5(FBN1):c.2581C>T (p.Arg861Ter)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925582	NM_000138.5(FBN1):c.407G>T (p.Cys136Phe)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29696	NM_000138.5(FBN1):c.5096A>G (p.Tyr1699Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
29698	NM_000138.5(FBN1):c.5182G>A (p.Ala1728Thr)	FBN1	Pathogenic	no assertion criteria provided
29700	NM_000138.5(FBN1):c.5250T>G (p.Ser1750Arg)	FBN1	Pathogenic	criteria provided, single submitter
29701	NM_000138.5(FBN1):c.5099A>G (p.Tyr1700Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29702	NM_000138.5(FBN1):c.5202_5204dup (p.Gln1735dup)	FBN1	Pathogenic	no assertion criteria provided
36042	NM_000138.5(FBN1):c.1948C>T (p.Arg650Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36075	NM_000138.5(FBN1):c.4460-8G>A	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36078	NM_000138.5(FBN1):c.4588C>T (p.Arg1530Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36082	NM_000138.5(FBN1):c.4786C>T (p.Arg1596Ter)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
36107	NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42284	NM_000138.5(FBN1):c.1468+5G>A	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 64 · Orphanet: 17 · 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
FBN1	Strong	Autosomal dominant	Acromicric dysplasia	24
LTBP2	Strong	Autosomal dominant	geleophysic dysplasia 3	20
LTBP3	Strong	Autosomal dominant	geleophysic dysplasia 3	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
LTBP3	Orphanet:2623	Geleophysic dysplasia
LTBP3	Orphanet:2899	Brachyolmia-amelogenesis imperfecta syndrome
LTBP3	Orphanet:969	Acromicric dysplasia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	gencc,clinvar
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gencc
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
LTBP3	Latent-transforming growth factor beta-binding protein 3	Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2
decidua	1
skin of hip	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640
LTBP2	2,658
LTBP3	2,339

Intra-cohort edges

A	B	Sources
FBN1	LTBP2	string_interaction
FBN1	LTBP3	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Elastic fibre formation	3	335.9×	1e-07	FBN1, LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	3	326.3×	1e-07	FBN1, LTBP2, LTBP3
Molecules associated with elastic fibres	3	308.6×	1e-07	FBN1, LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	133.6×	2e-04	LTBP2, LTBP3
Signaling by TGFB family members	2	76.9×	5e-04	LTBP2, LTBP3
Extracellular matrix organization	2	42.1×	0.001	LTBP2, LTBP3
Integrin cell surface interactions	1	44.8×	0.033	FBN1
Degradation of the extracellular matrix	1	39.2×	0.033	FBN1
Post-translational protein phosphorylation	1	33.4×	0.033	FBN1
Signal Transduction	2	6.8×	0.033	LTBP2, LTBP3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.034	FBN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
transforming growth factor beta receptor signaling pathway	2	106.0×	0.004	LTBP2, LTBP3
post-embryonic eye morphogenesis	1	1872.4×	0.006	FBN1
obsolete sequestering of BMP in extracellular matrix	1	1404.3×	0.006	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	1404.3×	0.006	FBN1
negative regulation of osteoclast development	1	1123.5×	0.006	FBN1
positive regulation of mesenchymal stem cell differentiation	1	802.5×	0.006	LTBP3
lung saccule development	1	702.2×	0.006	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	702.2×	0.006	LTBP3
embryonic eye morphogenesis	1	510.7×	0.007	FBN1
cellular response to insulin-like growth factor stimulus	1	432.1×	0.007	FBN1
supramolecular fiber organization	1	351.1×	0.007	LTBP2
positive regulation of bone resorption	1	330.4×	0.007	LTBP3
negative regulation of bone mineralization	1	312.1×	0.007	LTBP3
bone remodeling	1	312.1×	0.007	LTBP3
negative regulation of chondrocyte differentiation	1	224.7×	0.009	LTBP3
cell adhesion mediated by integrin	1	224.7×	0.009	FBN1
bone morphogenesis	1	200.6×	0.009	LTBP3
negative regulation of osteoclast differentiation	1	181.2×	0.009	FBN1
metanephros development	1	170.2×	0.010	FBN1
protein targeting	1	122.1×	0.012	LTBP2
camera-type eye development	1	119.5×	0.012	FBN1
lung alveolus development	1	117.0×	0.012	FBN1
chondrocyte differentiation	1	100.3×	0.013	LTBP3
cellular response to transforming growth factor beta stimulus	1	92.1×	0.013	FBN1
bone mineralization	1	90.6×	0.013	LTBP3
protein secretion	1	87.8×	0.013	LTBP2
glucose metabolic process	1	85.1×	0.013	FBN1
glucose homeostasis	1	43.5×	0.025	FBN1
skeletal system development	1	41.9×	0.025	FBN1
gene expression	1	26.6×	0.038	FBN1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
FBN1	0	0
LTBP2	0	0
LTBP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	FBN1, LTBP2, LTBP3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FBN1	0	—
LTBP2	0	—
LTBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.