Multiple benign circumferential skin creases on limbs

Summary

Multiple benign circumferential skin creases on limbs (MONDO:0007990) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		32	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000969	Edema	Very frequent (80-99%)
HP:0001072	Thickened skin	Very frequent (80-99%)
HP:0007522	Increased number of skin folds	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0007400	Irregular hyperpigmentation	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000045	Abnormality of the scrotum	Occasional (5-29%)
HP:0000046	Small scrotum	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000271	Abnormality of the face	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0002230	Generalized hirsutism	Occasional (5-29%)
HP:0003011	Abnormality of the musculature	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006768	Localized neuroblastoma	Occasional (5-29%)
HP:0100559	Lower limb asymmetry	Occasional (5-29%)
HP:0100560	Upper limb asymmetry	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple benign circumferential skin creases on limbs
Mondo ID	MONDO:0007990
MeSH	C537575
Orphanet	2505
DOID	DOID:0112241
UMLS	C0473586
MedGen	96881
GARD	0003589
Is cancer (heuristic)	no

Also known as: CCSF · circumferential skin creases, Kunze type · congenital circumferential skin folds · CSCSC · Kunze Riehm syndrome · Kunze-Riehm syndrome · Michelin tyre baby 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 › integumentary system disorder › skin disorder › multiple benign circumferential skin creases on limbs

Related subtypes (71): dermatitis, cutaneous mucinosis, skin neoplasm, pyoderma, chronic ulcer of skin, systemic sclerosis, sunburn, severe cutaneous adverse reaction, paronychia, Achenbach syndrome, erythema multiforme, erythematosquamous dermatosis, exanthem, facial dermatosis, hand dermatosis, keratosis, leg dermatosis, lichen disease, lipodystrophy, mongolian spot, reactive cutaneous fibrous lesion, rosacea, scalp dermatosis, sebaceous gland disorder, skin atrophy, skin sarcoidosis, sweat gland disorder, vesiculobullous skin disease, hyperglobulinemic purpura, ainhum, cheilitis glandularis, erythema palmare hereditarium, actinic prurigo, congenital lethal erythroderma, Parana hard-skin syndrome, Bazex-Dupre-Christol syndrome, nephrogenic systemic fibrosis, erosive pustular dermatosis of the scalp, pseudoxanthoma elasticum-like papillary dermal elastolysis, toxic dermatosis, oral erosive lichen, chronic actinic dermatitis, Jessner lymphocytic infiltration of the skin, acquired kinky hair syndrome, primary cutaneous plasmacytosis, cutaneous pseudolymphoma, corticosteroid-sensitive aseptic abscess syndrome, interstitial granulomatous dermatitis with arthritis, epidermal disease, skin pigmentation disorder, skin vascular disease, Wells syndrome, solar urticaria, pellagra, hereditary epidermal appendage anomaly, keratosis pilaris, dermis disorder, aquagenic pruritus, Boudhina Yedes Khiari syndrome, non-neoplastic nevus, cutaneous sclerosis, pityriasis rotunda, hematohidrosis, skin disorder caused by infection, livedoid vasculopathy, prurigo nodularis, granuloma faciale, sclerema neonatorum, hereditary skin disorder, hand-foot syndrome, Nicolau syndrome

Subtypes (2): skin creases, congenital symmetric circumferential, 2, multiple benign circumferential skin creases on limbs 1

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: 25 · 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
MAPRE2	Definitive	Autosomal recessive	skin creases, congenital symmetric circumferential, 2	18
TUBB	Strong	Autosomal dominant	multiple benign circumferential skin creases on limbs 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB	Orphanet:2505	Multiple benign circumferential skin creases on limbs
MAPRE2	Orphanet:2505	Multiple benign circumferential skin creases on limbs

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
TUBB	HGNC:20778	ENSG00000196230	P07437	Tubulin beta chain	gencc
MAPRE2	HGNC:6891	ENSG00000166974	Q15555	Microtubule-associated protein RP/EB family member 2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB	Tubulin beta chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
MAPRE2	Microtubule-associated protein RP/EB family member 2	Adapter protein that is involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBB	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
MAPRE2	Other/Unknown	no		CH_dom, EB1_C, MAPRE

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
cortical plate	2
ganglionic eminence	1
ventricular zone	1
corpus callosum	1
dorsal root ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB	133	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
MAPRE2	300	ubiquitous	marker	cortical plate, dorsal root ganglion, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAPRE2	2,195
TUBB	1,512

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB	P07437	21

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAPRE2	Q15555	75.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 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
Centrosome maturation	1	253.8×	0.018	TUBB
Loss of Nlp from mitotic centrosomes	1	158.6×	0.018	TUBB
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.018	TUBB
AURKA Activation by TPX2	1	152.3×	0.018	TUBB
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.018	TUBB
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.018	TUBB
Mitotic G2-G2/M phases	1	126.9×	0.018	TUBB
G2/M Transition	1	126.9×	0.018	TUBB
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.018	TUBB
Potential therapeutics for SARS	1	114.2×	0.018	TUBB
Anchoring of the basal body to the plasma membrane	1	113.1×	0.018	TUBB
Cilium Assembly	1	108.8×	0.018	TUBB
Mitotic Prometaphase	1	69.2×	0.024	TUBB
Organelle biogenesis and maintenance	1	66.0×	0.024	TUBB
M Phase	1	66.0×	0.024	TUBB
SARS-CoV Infections	1	55.4×	0.027	TUBB
Cell Cycle, Mitotic	1	48.2×	0.029	TUBB
Cell Cycle	1	36.0×	0.037	TUBB
Viral Infection Pathways	1	30.8×	0.041	TUBB
Innate Immune System	1	25.5×	0.046	TUBB
Infectious disease	1	24.8×	0.046	TUBB
Neutrophil degranulation	1	23.1×	0.047	TUBB
Disease	1	13.1×	0.077	TUBB
Immune System	1	13.0×	0.077	TUBB

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
spindle assembly	2	443.5×	7e-05	TUBB, MAPRE2
positive regulation of ARF protein signal transduction	1	2808.7×	0.002	MAPRE2
cell division	2	46.2×	0.002	TUBB, MAPRE2
odontoblast differentiation	1	1053.2×	0.003	TUBB
positive regulation of focal adhesion disassembly	1	936.2×	0.003	MAPRE2
protein localization to microtubule	1	648.1×	0.003	MAPRE2
positive regulation of keratinocyte migration	1	648.1×	0.003	MAPRE2
regulation of microtubule polymerization or depolymerization	1	526.6×	0.003	MAPRE2
microtubule-based process	1	495.6×	0.003	TUBB
cytoskeleton-dependent intracellular transport	1	468.1×	0.003	TUBB
regulation of synapse organization	1	324.1×	0.004	TUBB
natural killer cell mediated cytotoxicity	1	216.1×	0.005	TUBB
mitotic cell cycle	1	66.9×	0.016	TUBB
microtubule cytoskeleton organization	1	60.6×	0.016	TUBB

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
TUBB	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB	22	4
MAPRE2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB
VINBLASTINE	4	TUBB
LEVOFLOXACIN ANHYDROUS	4	TUBB
DOCETAXEL	4	TUBB
NOSCAPINE	4	TUBB
VINBLASTINE SULFATE	4	TUBB
PACLITAXEL	4	TUBB
LEVOFLOXACIN	4	TUBB
VINORELBINE	4	TUBB
TIRBANIBULIN	4	TUBB
PODOFILOX	4	TUBB
VINCRISTINE	4	TUBB
DOCETAXEL ANHYDROUS	4	TUBB
PATUPILONE	3	TUBB
ABT-751	2	TUBB
MAYTANSINE	2	TUBB
DOLASTATIN-10	2	TUBB
INDIBULIN	2	TUBB
PARBENDAZOLE	2	TUBB
NOCODAZOLE	2	TUBB
MOLIBRESIB	2	TUBB
COMBRETASTATIN	1	TUBB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB	1,780	Binding:1740, Functional:34, ADMET:6
MAPRE2	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB	1,780

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

22 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)
COLCHICINE	4	TUBB
VINBLASTINE	4	TUBB
LEVOFLOXACIN ANHYDROUS	4	TUBB
DOCETAXEL	4	TUBB
NOSCAPINE	4	TUBB
VINBLASTINE SULFATE	4	TUBB
PACLITAXEL	4	TUBB
LEVOFLOXACIN	4	TUBB
VINORELBINE	4	TUBB
TIRBANIBULIN	4	TUBB
PODOFILOX	4	TUBB
VINCRISTINE	4	TUBB
DOCETAXEL ANHYDROUS	4	TUBB
PATUPILONE	3	TUBB
ABT-751	2	TUBB
MAYTANSINE	2	TUBB
DOLASTATIN-10	2	TUBB
INDIBULIN	2	TUBB
PARBENDAZOLE	2	TUBB
NOCODAZOLE	2	TUBB
MOLIBRESIB	2	TUBB
COMBRETASTATIN	1	TUBB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB
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	MAPRE2

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)
MAPRE2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.