Superficial epidermolytic ichthyosis

Summary

Superficial epidermolytic ichthyosis (MONDO:0007813) is a disease caused by KRT2 (GenCC Definitive), with 1 cohort gene and 48 clinical trials. Top therapeutic interventions include pinaverium, ebastine, and mexiletine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KRT2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 83
• Phenotypes (HPO): 7
• Clinical trials: 48

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0000969	Edema	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0100792	Acantholysis	Very frequent (80-99%)
HP:0010783	Erythema	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	superficial epidermolytic ichthyosis
Mondo ID	MONDO:0007813
MeSH	D053560
OMIM	146800
Orphanet	455
DOID	DOID:0060877
ICD-11	842172475
NCIT	C84777
SNOMED CT	254169002
UMLS	C0432306
MedGen	98153
GARD	0002966
Is cancer (heuristic)	no

Also known as: bullous type of ichthyosis · IBS · ichthyosis bullosa of Siemens · SEI · superficial epidermolytic ichthyosis

Data availability: 83 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › keratinopathic ichthyosis › superficial epidermolytic ichthyosis

Related subtypes (4): epidermolytic ichthyosis, ichthyosis hystrix of Curth-Macklin, congenital reticular ichthyosiform erythroderma, epidermolytic nevus

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

83 retrieved; paginated sample, class counts are floors:

34 benign, 22 uncertain significance, 7 likely benign, 7 pathogenic, 5 conflicting classifications of pathogenicity, 5 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9309	NM_000423.3(KRT2):c.1461G>T (p.Glu487Asp)	KRT2	Pathogenic	no assertion criteria provided
9310	NM_000423.3(KRT2):c.1459G>A (p.Glu487Lys)	KRT2	Pathogenic	criteria provided, multiple submitters, no conflicts
9312	NM_000423.3(KRT2):c.1435A>C (p.Thr479Pro)	KRT2	Pathogenic	no assertion criteria provided
9313	NM_000423.3(KRT2):c.556A>T (p.Asn186Tyr)	KRT2	Pathogenic	no assertion criteria provided
9314	NM_000423.3(KRT2):c.1426G>A (p.Glu476Lys)	KRT2	Pathogenic	no assertion criteria provided
9315	NM_000423.3(KRT2):c.556A>G (p.Asn186Asp)	KRT2	Pathogenic	no assertion criteria provided
9316	NM_000423.3(KRT2):c.558C>A (p.Asn186Lys)	KRT2	Pathogenic	criteria provided, single submitter
3251985	NM_000423.3(KRT2):c.557A>G (p.Asn186Ser)	KRT2	Likely pathogenic	criteria provided, single submitter
66192	NM_000423.3(KRT2):c.1462G>A (p.Glu488Lys)	KRT2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
9311	NM_000423.3(KRT2):c.542A>C (p.Gln181Pro)	KRT2	Likely pathogenic	criteria provided, single submitter
309596	NM_000423.3(KRT2):c.1720G>A (p.Gly574Arg)	KRT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309601	NM_000423.3(KRT2):c.1478G>T (p.Gly493Val)	KRT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309617	NM_000423.3(KRT2):c.633G>A (p.Glu211=)	KRT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309618	NM_000423.3(KRT2):c.536G>A (p.Arg179His)	KRT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880953	NM_000423.3(KRT2):c.1699G>A (p.Gly567Ser)	KRT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309586	NM_000423.3(KRT2):c.*301G>A	KRT2	Uncertain significance	criteria provided, single submitter
309588	NM_000423.3(KRT2):c.*289C>A	KRT2	Uncertain significance	criteria provided, single submitter
309590	NM_000423.3(KRT2):c.*248C>T	KRT2	Uncertain significance	criteria provided, single submitter
309594	NM_000423.3(KRT2):c.1869G>T (p.Lys623Asn)	KRT2	Uncertain significance	criteria provided, single submitter
309595	NM_000423.3(KRT2):c.1829G>T (p.Gly610Val)	KRT2	Uncertain significance	criteria provided, single submitter
309603	NM_000423.3(KRT2):c.1355C>G (p.Ala452Gly)	KRT2	Uncertain significance	criteria provided, single submitter
309610	NM_000423.3(KRT2):c.1051G>A (p.Glu351Lys)	KRT2	Uncertain significance	criteria provided, single submitter
309612	NM_000423.3(KRT2):c.864C>T (p.Asp288=)	KRT2	Uncertain significance	criteria provided, single submitter
309614	NM_000423.3(KRT2):c.768C>T (p.Asn256=)	KRT2	Uncertain significance	criteria provided, single submitter
309630	NM_000423.3(KRT2):c.52G>A (p.Gly18Arg)	KRT2	Uncertain significance	criteria provided, single submitter
3891523	NM_000423.3(KRT2):c.101G>A (p.Arg34Gln)	KRT2	Uncertain significance	criteria provided, single submitter
3891525	NM_000423.3(KRT2):c.731C>A (p.Thr244Asn)	KRT2	Uncertain significance	criteria provided, single submitter
881005	NM_000423.3(KRT2):c.346G>C (p.Gly116Arg)	KRT2	Uncertain significance	criteria provided, single submitter
882264	NM_000423.3(KRT2):c.*438A>G	KRT2	Uncertain significance	criteria provided, single submitter
882362	NM_000423.3(KRT2):c.290G>A (p.Gly97Glu)	KRT2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
KRT2	Definitive	Autosomal dominant	superficial epidermolytic ichthyosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT2	Orphanet:455	Superficial epidermolytic ichthyosis

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
KRT2	HGNC:6439	ENSG00000172867	P35908	Keratin, type II cytoskeletal 2 epidermal	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT2	Keratin, type II cytoskeletal 2 epidermal	Probably contributes to terminal cornification.

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)
KRT2	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

Expression context

Cohort genes with no expression data: 0.

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
skin of hip	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT2	162	tissue_specific	yes	upper arm skin, upper leg skin, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT2	1,783

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT2	P35908	67.38

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
Formation of the cornified envelope	1	87.8×	0.027	KRT2
Keratinization	1	55.7×	0.027	KRT2
Developmental Biology	1	14.5×	0.069	KRT2

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
keratinocyte activation	1	8426.0×	0.001	KRT2
positive regulation of epidermis development	1	3370.4×	0.001	KRT2
keratinocyte migration	1	2407.4×	0.001	KRT2
keratinocyte development	1	1532.0×	0.001	KRT2
cornification	1	1053.2×	0.002	KRT2
keratinocyte proliferation	1	581.1×	0.003	KRT2
intermediate filament organization	1	240.7×	0.005	KRT2
keratinization	1	234.1×	0.005	KRT2
epidermis development	1	210.7×	0.005	KRT2

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
KRT2	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	KRT2

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)
KRT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 48.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	37
PHASE4	5
PHASE3	2
PHASE1/PHASE2	1
PHASE2	1
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07426705	PHASE4	NOT_YET_RECRUITING	Effect of Multispecies Probiotic Supplementation on the Efficacy of Rifaximin α Therapy in Patients With Small Intestinal Bacterial Overgrowth (SIBO): a Randomized Placebo-controlled Trial
NCT01667627	PHASE4	COMPLETED	Probiotic in Irritable Bowel Syndrome (IBS) Patients With Diarrhea
NCT01779765	PHASE4	UNKNOWN	The Efficacy of Hydrolyzed Guar Gum ( PHGG) in the Treatment of Patients With Irritable Bowel Syndrome (IBS)
NCT02937506	PHASE4	COMPLETED	Patient Satisfaction With Propofol for Out Patient Colonoscopy
NCT05995899	PHASE4	COMPLETED	Effect of Tenapanor on the Metagenomics and Metabolomics of Patients With Irritable Bowel Syndrome With Constipation
NCT05815602	PHASE3	RECRUITING	Ebastine Versus Mebeverine in IBS Patients
NCT07168434	PHASE3	RECRUITING	Saccharomyces Boulardii CNCM I-745 in Irritable Bowel Syndrome
NCT06727422	PHASE2	RECRUITING	Efficacy of Rifaximin With NAC in IBS-D
NCT01276626	PHASE1/PHASE2	COMPLETED	Study of Bacteria on Mood and Bowel Symptoms in Patients With Irritable Bowel Syndrome
NCT01717404	PHASE1	COMPLETED	Effects of Mexiletine on Colonic Transit in a Patient With Irritable Bowel Syndrome - Constipation (IBS-C)
NCT07238790	EARLY_PHASE1	NOT_YET_RECRUITING	Use of A Complex Gut Bacterial Consortium (MITI 001) for the Treatment of Irritable Bowel Syndrome With Diarrhea
NCT01912313	Not specified	RECRUITING	Measuring Nerve Activity in Small Human Intestinal Biopsies in IBS (Irritable Bowel Syndrome)
NCT02421705	Not specified	RECRUITING	Visceral Sensitivity in IBD (Irritable Bowel Disease) and IBS (Irritable Bowel Syndrome)
NCT06757491	Not specified	RECRUITING	Lf-rTMS Attenuates Visceral Pain in Irritable Bowel Syndrome With Diarrhea
NCT06889779	Not specified	RECRUITING	Study Evaluating the Efficacy of Different Mixes of HMO-2FL + Humiome® Post LB on IBS Gastrointestinal Symptoms
NCT07172139	Not specified	NOT_YET_RECRUITING	Transcranial Magnetic Stimulation and Pharmacologic/Probiotic Interventions for Diarrhea-Predominant IBS
NCT07424898	Not specified	ENROLLING_BY_INVITATION	Lactose Intolerance and Intestinal Permability
NCT07471490	Not specified	ENROLLING_BY_INVITATION	Specimen and Data Collection for a Novel Biomarker Combination for the Differential Diagnosis of Inflammatory Bowel Disease and Irritable Bowel Syndrome.
NCT07534930	Not specified	ACTIVE_NOT_RECRUITING	Personalised Multidisciplinary Treatment in Moderate to Severe IBS
NCT07540312	Not specified	RECRUITING	A Prospective Trial of a Variable Compression System for Moderate to Severe Irritable Bowel Syndrome
NCT07584473	Not specified	RECRUITING	NCWS or IBS/FD in Relatives of CD Patients
NCT07591584	Not specified	RECRUITING	A Study Evaluating the Impact of Regular FODMAP-targeting Digestive Enzyme Blend Use on Gastrointestinal Symptoms in Individuals With Self-Reported Bloating
NCT00179582	Not specified	TERMINATED	Dose Ranging Study With the Probiotic Combination (VSL#3) in Diarrhea IBS
NCT00248586	Not specified	COMPLETED	Development of Limited Contact CBT Treatment for IBS
NCT02009618	Not specified	COMPLETED	The Effects of Rifaximin Therapy in Irritable Bowel Syndrome
NCT02293343	Not specified	COMPLETED	24 Hrs Histamine Profile in Healthy Persons and Patients With Food Intolerance
NCT02313207	Not specified	WITHDRAWN	Confocal Laser Endomicroscopy in IBS Patients
NCT02419963	Not specified	COMPLETED	Analyzing IBS to Identify Biomarkers and Microbiome Signatures
NCT02436603	Not specified	COMPLETED	Integrative Approaches to Managing Irritable Bowel Syndrome (IBS)
NCT02536131	Not specified	COMPLETED	Intestinal Microbiome and Psychological Correlates in Irritable Bowel Syndrome and Inflammatory Bowel Disease
NCT02681666	Not specified	COMPLETED	Mindfulness-Based Eating in Patients With Irritable Bowel Syndrome
NCT02920268	Not specified	COMPLETED	Just in TIME - Intervention With Dance and Yoga for Girls With Recurrent Abdominal Pain
NCT02981888	Not specified	COMPLETED	Fecal Metabolome and the Intestinal Microbiota in Irritable Bowel Syndrome
NCT03482765	Not specified	COMPLETED	A Study of Probiotics in IBS Subjects
NCT03986476	Not specified	COMPLETED	The Effect of Two Probiotic Products on the Intestinal Barrier Function in Patients With Irritable Bowel Syndrome
NCT04031469	Not specified	SUSPENDED	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Disease
NCT04122586	Not specified	UNKNOWN	Mechanism of PERK - eIF2a Pathways in Intestinal Mucosal Barrier of IBS-D and the Role Metabolism Ingredients of Tongxieyaofang
NCT04677881	Not specified	COMPLETED	Health Effects of Different Types of Bread
NCT04953728	Not specified	COMPLETED	Optimization of Transcutaneous Electrical Acustimulation (TEA) Modalities for Treatment of IBS-C
NCT05579444	Not specified	TERMINATED	Systems Biology of Gastrointestinal and Related Diseases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PINAVERIUM	4	3
EBASTINE	4	1
MEXILETINE	4	1
RIFAXIMIN	4	1
SULFALENE	4	1
TENAPANOR	4	1
BIFIDOBACTERIUM SPP.	3	2
MALTODEXTRIN	3	2
CHEMBL4303383	0	1