Stiff skin syndrome

Summary

Stiff skin syndrome (MONDO:0008492) is a disease caused by FBN1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FBN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 508
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		54	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001072	Thickened skin	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0100679	Lack of skin elasticity	Very frequent (80-99%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0000998	Hypertrichosis	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001482	Subcutaneous nodule	Occasional (5-29%)
HP:0003011	Abnormality of the musculature	Occasional (5-29%)
HP:0003119	Abnormal circulating lipid concentration	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0004325	Decreased body weight	Occasional (5-29%)
HP:0005978	Type II diabetes mellitus	Occasional (5-29%)
HP:0007328	Impaired pain sensation	Occasional (5-29%)
HP:0008065	Aplasia/Hypoplasia of the skin	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)
HP:0100578	Lipoatrophy	Occasional (5-29%)
HP:0030057	Autoimmune antibody positivity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	stiff skin syndrome
Mondo ID	MONDO:0008492
MeSH	C566112
OMIM	184900
Orphanet	2833
DOID	DOID:0111561
ICD-11	642409035
NCIT	C118636
SNOMED CT	765187004
UMLS	C1861456
MedGen	348877
GARD	0005025
Is cancer (heuristic)	no

Also known as: SSKS · stiff skin syndrome

Data availability: 508 ClinVar variants · 2 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary skin disorder › stiff skin syndrome

Related subtypes (113): alopecia, isolated, reticulate pigment disorder, dyschromatosis universalis hereditaria, psoriasis, porokeratosis, hereditary papulotranslucent acrokeratoderma, acrokeratosis verruciformis, Tietz syndrome, familial primary localized cutaneous amyloidosis, isolated anhidrosis with normal sweat glands, aplasia cutis congenita, blue rubber bleb nevus, Darier disease, dermatosis papulosa nigra, autosomal dominant vibratory urticaria, absence of fingerprints-congenital milia syndrome, pilomatrixoma, spinocerebellar ataxia type 34, isolated congenital adermatoglyphia, isolated hyperchlorhidrosis, hyperkeratosis-hyperpigmentation syndrome, hyperpigmentation with or without hypopigmentation, familial progressive, lichen sclerosus et atrophicus, lichen planus, familial, monilethrix, hereditary mucoepithelial dysplasia, schwannomatosis, nevus, epidermal, familial multiple nevi flammei, linear nevus sebaceous syndrome, progressive osseous heteroplasia, Hailey-Hailey disease, piebaldism, familial pityriasis rubra pilaris, scalp defects-postaxial polydactyly syndrome, seborrheic keratosis, Sneddon syndrome, sebocystomatosis, familial multiple discoid fibromas, urticaria, aquagenic, urticaria, familial localized heat, vasculitis, lymphocytic, nodular, VPS13A-related neurodegenerative disease, acrogeria, anhidrosis, familial generalized, with abnormal or absent sweat glands, deafness, congenital, with total albinism, epidermodysplasia verruciformis, combined immunodeficiency with skin granulomas, lipoid proteinosis, neurocutaneous melanocytosis, neutrophil actin dysfunction, albinism-hearing loss syndrome, X-linked reticulate pigmentary disorder, CHILD syndrome, linear skin defects with multiple congenital anomalies, dermatitis herpetiformis, familial, keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome, H syndrome, hydroa vacciniforme, familial, poikiloderma with neutropenia, acne, infundibulocystic basal cell carcinoma, Becker nevus syndrome, generalized basaloid follicular hamartoma syndrome, sweet syndrome, MEDNIK syndrome, seborrhea-like dermatitis with psoriasiform elements, DK1-congenital disorder of glycosylation, body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency, Legius syndrome, CLOVES syndrome, encephalocraniocutaneous lipomatosis, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, hereditary sclerosing poikiloderma with tendon and pulmonary involvement, cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, skin creases, congenital symmetric circumferential, 2, nevus comedonicus syndrome, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, chronic mucocutaneous candidiasis, segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome, hereditary mucosal leukokeratosis, inherited ichthyosis, hereditary photodermatosis, Cowden disease, juvenile hyaline fibromatosis, osteopathia striata-pigmentary dermopathy-white forelock syndrome, syndromic oculocutaneous albinism, phakomatosis pigmentokeratotica, neonatal inflammatory skin and bowel disease, lamellar ichthyosis, PENS syndrome, familial multiple fibrofolliculoma, autosomal recessive cutis laxa type 2A, familial chilblain lupus, familial keratoacanthoma, keratosis pilaris atrophicans, Cobb syndrome, oculocutaneous albinism, hereditary palmoplantar keratoderma, inherited epidermolysis bullosa, ectodermal dysplasia syndrome, subcutaneous panniculitis-like T-cell lymphoma, hereditary angioedema, hereditary lipodystrophy, X-linked chondrodysplasia punctata 2, multiple benign circumferential skin creases on limbs 1, lentigo, familial acne inversa, familial acanthosis nigricans, large congenital melanocytic nevus, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, inflammatory poikiloderma with hair abnormalities and acral keratoses

Subtypes (1): fascial dystrophy, congenital

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

508 retrieved; paginated sample, class counts are floors:

191 conflicting classifications of pathogenicity, 186 uncertain significance, 37 benign/likely benign, 26 pathogenic/likely pathogenic, 22 benign, 21 pathogenic, 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
16469	NM_000138.5(FBN1):c.4710G>T (p.Trp1570Cys)	FBN1	Pathogenic	no assertion criteria provided
16470	NM_000138.5(FBN1):c.4710G>C (p.Trp1570Cys)	FBN1	Pathogenic	no assertion criteria provided
16471	NM_000138.5(FBN1):c.4691G>C (p.Cys1564Ser)	FBN1	Pathogenic	no assertion criteria provided
16472	NM_000138.5(FBN1):c.4729T>G (p.Cys1577Gly)	FBN1	Pathogenic	criteria provided, single submitter
1675081	NM_000138.5(FBN1):c.5836del (p.Gln1946fs)	FBN1	Pathogenic	criteria provided, single submitter
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
200017	NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn)	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
36042	NM_000138.5(FBN1):c.1948C>T (p.Arg650Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36043	NM_000138.5(FBN1):c.2055C>G (p.Cys685Trp)	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
42295	NM_000138.5(FBN1):c.184C>T (p.Arg62Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
42340	NM_000138.5(FBN1):c.368G>A (p.Cys123Tyr)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
42351	NM_000138.5(FBN1):c.4222T>C (p.Cys1408Arg)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 11 · 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	stiff skin syndrome	24

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

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
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	gencc,clinvar

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.

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)
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Elastic fibre formation	1	335.9×	0.008	FBN1
TGF-beta receptor signaling activates SMADs	1	326.3×	0.008	FBN1
Molecules associated with elastic fibres	1	308.6×	0.008	FBN1
Integrin cell surface interactions	1	134.3×	0.012	FBN1
Degradation of the extracellular matrix	1	117.7×	0.012	FBN1
Post-translational protein phosphorylation	1	100.2×	0.012	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
post-embryonic eye morphogenesis	1	5617.3×	0.001	FBN1
obsolete sequestering of BMP in extracellular matrix	1	4213.0×	0.001	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	4213.0×	0.001	FBN1
negative regulation of osteoclast development	1	3370.4×	0.001	FBN1
embryonic eye morphogenesis	1	1532.0×	0.002	FBN1
cellular response to insulin-like growth factor stimulus	1	1296.3×	0.002	FBN1
cell adhesion mediated by integrin	1	674.1×	0.004	FBN1
negative regulation of osteoclast differentiation	1	543.6×	0.004	FBN1
metanephros development	1	510.7×	0.004	FBN1
camera-type eye development	1	358.6×	0.004	FBN1
lung alveolus development	1	351.1×	0.004	FBN1
cellular response to transforming growth factor beta stimulus	1	276.3×	0.005	FBN1
glucose metabolic process	1	255.3×	0.005	FBN1
glucose homeostasis	1	130.6×	0.009	FBN1
skeletal system development	1	125.8×	0.009	FBN1
gene expression	1	79.9×	0.013	FBN1
heart development	1	78.8×	0.013	FBN1

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
FBN1	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	FBN1

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)
FBN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.