Loricrin keratoderma

Summary

Loricrin keratoderma (MONDO:0011396) is a disease caused by LORICRIN (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LORICRIN (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000972	Palmoplantar hyperkeratosis	Very frequent (80-99%)
HP:0007503	Generalized ichthyosis	Very frequent (80-99%)
HP:0010491	Digital constriction ring	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0000982	Palmoplantar keratoderma	Frequent (30-79%)
HP:0001036	Parakeratosis	Frequent (30-79%)
HP:0007465	Honeycomb palmoplantar keratoderma	Frequent (30-79%)
HP:0007479	Congenital nonbullous ichthyosiform erythroderma	Frequent (30-79%)
HP:0025114	Hypergranulosis	Frequent (30-79%)
HP:0025525	Scaling skin on fingertip	Frequent (30-79%)
HP:0032541	Knuckle pad	Frequent (30-79%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0001805	Onychogryposis	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)
HP:0025092	Epidermal acanthosis	Occasional (5-29%)
HP:0040162	Orthokeratosis	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Excluded (0%)
HP:0000707	Abnormality of the nervous system	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	loricrin keratoderma
Mondo ID	MONDO:0011396
MeSH	C565826
OMIM	604117
Orphanet	79395
SNOMED CT	717183001
UMLS	C1858805
MedGen	395099
GARD	0016719
Is cancer (heuristic)	no

Also known as: Camisa disease · keratoderma hereditarium mutilans with ichthyosis · keratoderma-ichthyosiform dermatosis-elevated beta-glucuronidase syndrome · loricrin keratoderma · Vohwinkel syndrome with ichthyosis

Data availability: 9 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › loricrin keratoderma

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, Clouston syndrome, epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Bart-Pumphrey syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, diffuse nonepidermolytic palmoplantar keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, erythrokeratodermia variabilis, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

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

9 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic, 2 uncertain significance, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14419	NM_000427.3(LORICRIN):c.664dup (p.Gln222fs)	LORICRIN	Pathogenic	no assertion criteria provided
1805407	NM_000427.3(LORICRIN):c.515dup (p.Gly173fs)	LORICRIN	Pathogenic	criteria provided, single submitter
279841	NM_000427.3(LORICRIN):c.684dup (p.Ser229fs)	LORICRIN	Pathogenic	criteria provided, multiple submitters, no conflicts
1324671	NM_000427.3(LORICRIN):c.624C>G (p.Tyr208Ter)	LORICRIN	Likely pathogenic	criteria provided, single submitter
1810236	NM_000427.3(LORICRIN):c.484G>T (p.Gly162Ter)	LORICRIN	Likely pathogenic	criteria provided, single submitter
587580	NM_000427.3(LORICRIN):c.112GGC[5] (p.Gly41dup)	LORICRIN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431419	NM_000427.3(LORICRIN):c.736G>C (p.Gly246Arg)	LORICRIN	Uncertain significance	criteria provided, single submitter
3779817	NM_000427.3(LORICRIN):c.34C>T (p.Pro12Ser)	LORICRIN	Uncertain significance	criteria provided, single submitter
2035667	NM_000427.3(LORICRIN):c.272C>T (p.Ser91Phe)	LORICRIN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
LORICRIN	Strong	Autosomal dominant	loricrin keratoderma	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LORICRIN	Orphanet:316	Progressive symmetric erythrokeratodermia
LORICRIN	Orphanet:79395	Keratoderma hereditarium mutilans with 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
LORICRIN	HGNC:6663	ENSG00000203782	P23490	Loricrin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LORICRIN	Loricrin	Major keratinocyte cell envelope protein.

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)
LORICRIN	Other/Unknown	no		Loricrin

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
nipple	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LORICRIN	155	tissue_specific	yes	upper arm skin, upper leg skin, nipple

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LORICRIN	960

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LORICRIN	P23490	44.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.011	LORICRIN
Developmental Cell Lineages	1	223.9×	0.011	LORICRIN
Formation of the cornified envelope	1	87.8×	0.019	LORICRIN
Keratinization	1	55.7×	0.022	LORICRIN
Developmental Biology	1	14.5×	0.069	LORICRIN

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
peptide cross-linking	1	1404.3×	0.002	LORICRIN
keratinocyte differentiation	1	247.8×	0.004	LORICRIN
keratinization	1	234.1×	0.004	LORICRIN

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
LORICRIN	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	LORICRIN

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)
LORICRIN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.