Epidermolytic Hyperkeratosis 2

Mendelian MONDO:0958184 Pathograph 25 Show in embeddings browser epidermolytic ichthyosis keratinopathic ichthyosis

Epidermolytic hyperkeratosis 2 is the KRT10 form of epidermolytic ichthyosis, a keratinopathic ichthyosis of the suprabasal epidermis. Most patients carry a heterozygous missense variant in the helix initiation motif at the start of the 1A rod segment or the helix termination motif at the end of the 2B rod segment of keratin 10, the type I partner of keratin 1. The mutant chain is incorporated into K1/K10 heterodimers and blocks filament assembly and elongation, so the keratin network of spinous and granular keratinocytes collapses into perinuclear tonofilament clumps and the cells lyse. Affected newborns have erythroderma, blisters and erosions; blistering becomes less frequent with age while hyperkeratosis and ichthyotic scale increase. A minority of families carry biallelic KRT10 null alleles that abolish keratin 10 protein and cause a recessive form, and helix termination or 2B-domain variants produce the annular epidermolytic ichthyosis variant with episodic polycyclic plaques. Compared with KRT1 disease, KRT10 disease usually spares the palms and soles.

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1
Mappings
2
Inheritance
7
Pathophys.
3
Histopath.
11
Phenotypes
25
Pathograph
2
Genes
3
Medical Actions
3
Subtypes
2
Models
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References
1
Deep Research
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Mappings

MONDO
MONDO:0007239 epidermolytic ichthyosis Not Yet Curated
skos:broadMatch MONDO
MONDO:0007239 is the MONDO parent of MONDO:0958184 and spans both keratin genes: its direct children include MONDO:0700249 epidermolytic hyperkeratosis 1 (KRT1) as well as this class. It is recorded as a broad match, as on KRT1_Keratinopathies, so that the gene-agnostic class is not retired from the curation queue through a single-gene entry.
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Inheritance

2
Autosomal dominant inheritance HP:0000006
The usual mode. About half of probands with epidermolytic hyperkeratosis carry a de novo variant.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:15663649 SUPPORT REVIEW SYNTHESIS Human Clinical
"Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations."
Autosomal dominant mode with complete penetrance and a high de novo fraction across KRT1 and KRT10 disease.
Autosomal recessive inheritance HP:0000007
A minority of families, typically consanguineous, transmit biallelic KRT10 null alleles (subtype EHK2B).
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:39072839 SUPPORT BACKGROUND Human Clinical
"EI is caused by pathogenic variants in the genes KRT1 and KRT10, encoding the proteins keratin 1 (KRT1) and keratin 10 (KRT10), respectively, and is primarily transmitted by autosomal-dominant inheritance, although recessive inheritance caused by nonsense variants in KRT10 is also described."
Summarizes that recessive transmission of epidermolytic ichthyosis is restricted to KRT10 nonsense alleles.
◆

Subtypes

3
Epidermolytic Hyperkeratosis 2A, Autosomal Dominant MONDO:0700248
KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The common form. A heterozygous KRT10 missense variant, often de novo, acts as a dominant negative on the K1/K10 filament network. Arg10 at the start of the 1A rod segment is the recurrent site. Generalized disease usually lacks severe palmoplantar keratoderma.
Show evidence (1 reference)
PMID:7508181 SUPPORT Human Clinical
"we have identified mutations in six families, in which five mutations occur in the beginning of the 1A rod domain of keratin 10-namely, two ARg10 to His, one Arg10 to Cys, and Asn8 to His, and a Tyr14 to Asp."
Heterozygous missense variants clustered at the start of the K10 1A rod segment in six dominant families.
Epidermolytic Hyperkeratosis 2B, Autosomal Recessive MONDO:0700245
KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Recessive form caused by biallelic KRT10 nonsense, frameshift or splice variants that trigger transcript decay and leave the epidermis without keratin 10 protein. Heterozygous carriers are clinically unaffected. Reported severity ranges from a lethal neonatal course to a mild, self-improving phenotype when a leaky splice allele leaves residual keratin 10.
Show evidence (2 references)
PMID:16505000 SUPPORT Human Clinical
"We demonstrate that a recessive mutation in KRT10 leading to a complete human K10 knockout can cause EHK."
First kindred defining the recessive KRT10 null form.
PMID:31278741 SUPPORT Human Clinical
"Autosomal recessive epidermolytic ichthyosis is a rare skin condition associated with KRT10 loss-of-function mutations."
Confirms loss-of-function KRT10 alleles as the basis of the recessive form.
Annular Epidermolytic Ichthyosis 1 (KRT10) MONDO:0100303
KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Dominant variant of KRT10 epidermolytic ichthyosis with bullous ichthyosis in early childhood, later flexural and extensor lichenified hyperkeratotic plaques, and intermittent flares of annular, polycyclic, erythematous scaly plaques on the trunk and proximal limbs. Reported KRT10 variants lie in the 2B helical segment and its helix termination motif. MONDO places this class under both MONDO:0958184 and MONDO:0011870 annular epidermolytic ichthyosis; its KRT1 sibling, MONDO:0859574, is a subtype row of KRT1_Keratinopathies.
Show evidence (2 references)
PMID:9036939 SUPPORT Human Clinical
"Molecular analysis revealed a novel tandem CG to GA 2-bp mutation in the same allele of keratin 10 in affected individuals, resulting in an arginine to glutamate substitution at residue 83 (R83E) of the 2B helical segment. We conclude that annular epidermolytic ichthyosis should be considered a..."
Identifies a KRT10 2B-segment variant and places annular epidermolytic ichthyosis within the epidermolytic ichthyosis spectrum.
PMID:9856845 SUPPORT Human Clinical
"Molecular analysis of this family revealed a novel mutation resulting in an isoleucine to threonine substitution at residue 107 (codon 446) within the highly conserved helix termination motif at the end of the rod domain of keratin 10."
A second, independent KRT10 family with annular epidermolytic ichthyosis carries a helix termination motif variant.
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Pathophysiology

7
KRT10 Dominant-Negative Rod-Domain Variant
A heterozygous missense variant in a conserved rod-domain motif of keratin 10, most often at Arg10 at the start of the 1A segment or in the 2B segment and helix termination motif, yields a K10 chain that still forms heterodimers with keratin 1 but poisons filament assembly and elongation.
KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Germline heterozygous missense variants, frequently arising de novo.
keratin intermediate filament assembly GO:0045109 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratin intermediate filament assembly, annotated with intermediate filament organization (GO:0045109). GO:0045109 is a biological process from the Gene Ontology. ⚠ ABNORMAL
keratin 10 structural constituent of the suprabasal epidermis GO:0030280 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal keratin 10 structural constituent of the suprabasal epidermis, annotated with structural constituent of skin epidermis (GO:0030280). GO:0030280 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Keratin Filament Network Collapse and Aggregation The mutant K10 chain is incorporated into the K1/K10 network and causes it to collapse into aggregates.
Show evidence (3 references)
PMID:1380725 SUPPORT Human Clinical
"In two other families, affected individuals had mutations in the highly conserved amino terminal of the rod domain of keratin 10. Structural analysis of these mutations predicts that heterodimer formation would be unaffected, although filament assembly and elongation would be severely compromised."
KRT10 rod-domain mutations in affected families, with the dominant-negative prediction that heterodimers form but filaments do not assemble.
PMID:7508181 SUPPORT Human Clinical
"Results from this work support the hypothesis that the beginning of the 1A rod domain segment in keratin 10 contains preferential sites for disease-causing mutation in EH."
Identifies the start of the K10 1A segment as the mutational hotspot.
PMID:7508181 SUPPORT In Vitro
"In vitro functional assays performed with peptides corresponding to the 1A mutations in these families show severely diminished capacity to disaggregate preformed keratin intermediate filaments, in comparison with a wild-type control peptide."
Peptide assays show the 1A variants alter the filament-interaction behaviour of the helix initiation motif.
Biallelic KRT10 Null Alleles and Keratin 10 Absence
Homozygous or compound heterozygous KRT10 nonsense, frameshift and splice variants cause transcript decay and complete absence of keratin 10 protein in the epidermis. The suprabasal network then lacks its type I partner; wound keratins K6, K16 and K17 are induced but do not compensate. One normal KRT10 allele is sufficient for network formation, so carriers are unaffected. This node conforms to the module's variant-initiation node as the loss-of-function route into the same filament failure, not as a dominant-negative variant.
KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic null alleles; compound heterozygosity with a leaky splice allele has also been reported.
nonsense-mediated decay of KRT10 transcripts GO:0000184 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased nonsense-mediated decay of KRT10 transcripts, annotated with nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184). GO:0000184 is a biological process from the Gene Ontology. ↑ INCREASED
keratin 10 structural constituent of the suprabasal epidermis GO:0030280 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent keratin 10 structural constituent of the suprabasal epidermis, annotated with structural constituent of skin epidermis (GO:0030280). GO:0030280 is a molecular function from the Gene Ontology. ∅ ABSENT
Downstream
Keratin Filament Network Collapse and Aggregation Without keratin 10 the suprabasal K1/K10 network cannot form and keratin aggregates appear.
Show evidence (3 references)
PMID:16505000 SUPPORT Human Clinical
"Semi-quantitative RT-PCR and western blot analysis demonstrated degradation of the KRT10 transcript, resulting in complete absence of keratin K10 protein in the epidermis and cultured keratinocytes of homozygous patients."
Direct demonstration of transcript degradation and absent K10 protein in patient tissue.
PMID:29277919 SUPPORT Human Clinical
"Western blot analysis showed complete absence of keratin 10 protein in the patient's skin, suggesting early protein degradation."
An independent recessive family with an exon 1 nonsense variant also lacks K10 protein.
PMID:18219278 SUPPORT Human Clinical
"In addition, the unaffected, heterozygous carriers of the mutation indicate that the K10 peptide from one normal allele alone is sufficient for keratin network formation."
Explains why heterozygous null carriers are unaffected, in contrast to dominant-negative missense carriers.
Keratin Filament Network Collapse and Aggregation
In spinous and granular keratinocytes the K1/K10 filament network collapses into perinuclear tonofilament clumps and peripheral aggregates, the ultrastructural hallmark of epidermolytic hyperkeratosis. Aggregate formation increases under heat stress.
spinous keratinocyte CL:0000649 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spinous keratinocyte, annotated with spinous cell of epidermis (CL:0000649). CL:0000649 is a cell type from the Cell Ontology.
intermediate filament cytoskeleton organization GO:0045104 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intermediate filament cytoskeleton organization (GO:0045104). GO:0045104 is a biological process from the Gene Ontology. ⚠ ABNORMAL
keratin filament GO:0045095 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves keratin filament (GO:0045095). GO:0045095 is a cellular component from the Gene Ontology.
stratum spinosum UBERON:0002026 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stratum spinosum, annotated with stratum spinosum of epidermis (UBERON:0002026). UBERON:0002026 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Suprabasal Keratinocyte Cytolysis The collapsed network leaves suprabasal cells mechanically fragile and prone to lysis.
Keratinocyte NLRP3 Inflammasome Activation and IL-18 Release NLRP3 and ASC cluster around mutant keratin aggregates in transfected keratinocytes; how aggregates trigger inflammasome assembly is not known.
Cutaneous TH17 Inflammation TH17 skewing is found in epidermolytic ichthyosis skin; the steps from the keratin defect to TH17 recruitment are not established.
Annular Polycyclic Erythematous Plaques KRT10 2B-segment and helix termination variants produce episodic annular flares; why the disease flares cyclically is unknown.
Show evidence (4 references)
PMID:1381287 SUPPORT In Vitro
"By genetic engineering, gene transfection, and 10 nm filament assembly, we show that this mutation is functionally responsible for the keratin filament clumping that occurs in basal (EBS) or suprabasal (EH) cells."
Transfection and filament assembly assays show the patient K10 arginine mutation causes filament clumping.
PMID:7513736 SUPPORT In Vitro
"EHK keratinocytes frequently exhibited a collapsed perinuclear network of K1/K10 filaments and sometimes peripheral granules of K1 and K10 aggregates, reminiscent of the cells of the suprabasal layers in these patients."
Cultured keratinocytes from KRT10 1A-mutant patients reproduce the collapsed K1/K10 network.
PMID:9036939 SUPPORT Human Clinical
"Histologic examination showed the typical pathology of epidermolytic hyperkeratosis, and ultrastructural analysis revealed abnormal keratin filament networks and tonofilament clumping with a perinuclear distribution."
Patient skin ultrastructure shows perinuclear tonofilament clumping in a KRT10 family.
+ 1 more reference
Suprabasal Keratinocyte Cytolysis
Fragile suprabasal keratinocytes degenerate and lyse, producing vacuolar degeneration of the upper spinous and granular layers (epidermolytic hyperkeratosis on histology) and intraepidermal blisters. In the recessive null form blisters arise within the granular layer.
spinous keratinocyte CL:0000649 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spinous keratinocyte, annotated with spinous cell of epidermis (CL:0000649). CL:0000649 is a cell type from the Cell Ontology.
stratum granulosum UBERON:0002069 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stratum granulosum, annotated with stratum granulosum of epidermis (UBERON:0002069). UBERON:0002069 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Mutant keratin 10 transgenic mouse Mouse recapitulates Mutant K10 expression reproduces suprabasal pathology and basal hyperproliferation.
Keratin 10 null mouse Mouse fails to recapitulate Loss of K10 in mice does not produce suprabasal cytolysis or blistering.
Downstream
Skin Blistering Suprabasal cytolysis splits the upper epidermis and produces blisters.
Skin Erosion Unroofed blisters and fragile upper epidermis leave superficial erosions.
Congenital Ichthyosiform Erythroderma Widespread cytolysis at birth underlies the neonatal erythroderma.
Sepsis Eroded, barrier-deficient skin is a portal for systemic infection.
Skin Pain Blisters and erosions are a plausible source of the pain patients report; the cited cohort does not attribute the pain to a lesion type.
Compensatory Epidermal Hyperproliferation Damage to suprabasal cells stimulates proliferation of basal cells.
Show evidence (3 references)
PMID:1379726 SUPPORT BACKGROUND Human Clinical
"It is typified by hyperkeratotic scaliness, blistering due to cytolysis within suprabasal epidermal cells, and hyperproliferation in basal cells."
Describes the human disease as blistering from suprabasal cytolysis; the sentence is the introduction of a transgenic mouse paper.
PMID:1379726 SUPPORT Model Organism
"We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype, thereby suggesting that a genetic basis for human EH residues in mutations in genes encoding suprabasal keratins K1 and K10."
Mutant K10 expression in mouse epidermis reproduces the epidermolytic phenotype.
PMID:18219278 SUPPORT Human Clinical
"K10 knockout patients show unique clinicopathological features of clinically mild BCIE with blisters occurring within the granular layer."
Places blistering in the granular layer in the recessive null form.
Compensatory Epidermal Hyperproliferation
Basal keratinocytes proliferate faster in response to the suprabasal defect, thickening the granular layer and stratum corneum. Loss of keratin 10 itself also drives basal hyperproliferation in K10-null mice without cytolysis, so hyperproliferation is not only a response to cell lysis.
basal keratinocyte CL:0002187 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves basal keratinocyte, annotated with basal cell of epidermis (CL:0002187). CL:0002187 is a cell type from the Cell Ontology.
keratinocyte proliferation GO:0043616 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinocyte proliferation (GO:0043616). GO:0043616 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Keratin 10 null mouse Mouse recapitulates Adult K10-null mice show basal keratinocyte hyperproliferation.
Downstream
Generalized Hyperkeratosis Increased keratinocyte production thickens the stratum corneum.
Ichthyosis Hyperproliferation and abnormal cornification produce ichthyotic scale.
Flexural Lichenification Hyperkeratosis concentrates in flexural skin as lichenified plaques.
Palmoplantar Keratoderma Palmoplantar thickening occurs in a minority of KRT10 patients.
Show evidence (3 references)
PMID:1379726 SUPPORT Model Organism
"In addition, we show that (i) stimulation of basal cell proliferation can arise from a defect in suprabasal cells"
Mutant K10 transgenic mice show basal hyperproliferation driven by a suprabasal defect.
PMID:12077355 SUPPORT Model Organism
"Unlike most keratin mutant mice, the epidermis of adult K10-/- mice showed no cytolysis but displayed hyperproliferation of basal keratinocytes and an increased cell size."
K10 loss alone increases basal proliferation in mice, relevant to the recessive null form.
PMID:16505000 SUPPORT INDIRECT Human Clinical
"Strong induction of the wound-healing keratins K6, K16 and K17 was found in the suprabasal epidermis, which are not able to compensate for the lack of keratin 10."
Induction of wound-healing keratins in patient epidermis indicates an activated, hyperproliferative epidermal state.
Keratinocyte NLRP3 Inflammasome Activation and IL-18 Release
Serum and skin IL-18 are raised in epidermolytic ichthyosis and serum IL-18 tracks severity. In keratinocytes expressing mutant keratin, NLRP3 and ASC cluster around the keratin aggregates and mature IL-18 release increases. The cell study used a mutant KRT1 construct, and the patient series did not separate KRT1 from KRT10 patients, so its application to KRT10 disease is inferred.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
interleukin-18 production GO:0032621 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-18 production (GO:0032621). GO:0032621 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:36656063 SUPPORT Human Clinical
"Serum IL-18 levels correlated with the severity of ichthyosis, as measured by the Ichthyosis Scoring System."
Serum IL-18 is raised in epidermolytic ichthyosis patients and tracks severity (seven EI patients; genes not separated in the abstract).
PMID:36656063 SUPPORT INDIRECT In Vitro
"Additionally, these cells showed NLRP3 aggregation in the cytoplasm and ASC clustered around mutant keratin aggregations."
Links mutant keratin aggregates to inflammasome assembly; the construct was mutant KRT1 in HaCaT cells, so the KRT10 case is inferred.
Cutaneous TH17 Inflammation
Epidermolytic ichthyosis skin shows raised TH17-related cytokines in the epidermis and CCR6+ TH17 cells in the dermis. Patients with KRT10 variants have responded to IL-17A blockade in a case series, but a placebo-controlled trial across adult congenital ichthyoses was negative, so the contribution of this axis to disease severity remains uncertain. No source links this node to the IL-18 node, so no edge is drawn between them.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
interleukin-17 production GO:0032620 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-17 production (GO:0032620). GO:0032620 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Pruritus Cutaneous inflammation is a candidate driver of the itch reported by about half of patients; the itch mediators in this disease are not established.
Show evidence (1 reference)
PMID:40288548 SUPPORT Human Clinical
"Single-nucleus RNA sequencing revealed significantly elevated levels of TH-17 related cytokines in epidermis and CCR6+ TH17 cell infiltration in the dermis."
Patient skin shows TH17 cytokine elevation and TH17 cell infiltration. The abstract describes this result right after the family carrying KRT1 and MPO variants, and does not say whether the snRNA-seq samples included KRT10 patients, so its application to KRT10 disease is uncertain.
✶

Histopathology

3
Suprabasal Keratinocyte Cytolysis
Intracellular vacuolization and degeneration of keratinocytes in the upper stratum spinosum and stratum granulosum, with intraepidermal blisters: the lesion that gives epidermolytic hyperkeratosis its name. The finding is named after the pathophysiology node it documents so that the pathograph attaches it to that node.
Show evidence (2 references)
PMID:15663649 SUPPORT REVIEW SYNTHESIS Human Clinical
"Histologically, there is a hyperkeratosis and vacuolar degeneration."
Review summary of the defining histology.
PMID:22930352 SUPPORT BACKGROUND Human Clinical
"the histopathological picture of EI is distinctive, with hyperkeratosis, acanthosis and characteristic clumping of tonofilaments, intracellular vacuolization and intra-epidermal blisters."
Introduction of the Danish cohort paper listing the distinctive histology, including vacuolization and intraepidermal blisters.
Keratin Filament Network Collapse and Aggregation
Electron microscopy shows abnormal keratin filament networks and coarse tonofilament clumps with a perinuclear distribution in suprabasal keratinocytes. Named after the pathophysiology node it documents; the pathograph attaches a histopathology finding to a node only when the finding carries an ontology term, so this unbound finding is not yet attached there.
Show evidence (1 reference)
PMID:9036939 SUPPORT Human Clinical
"Histologic examination showed the typical pathology of epidermolytic hyperkeratosis, and ultrastructural analysis revealed abnormal keratin filament networks and tonofilament clumping with a perinuclear distribution."
Ultrastructure of skin from a KRT10 family shows perinuclear tonofilament clumping.
Hypergranulosis and Hyperkeratosis
Thickening of the stratum corneum and of the granular layer, with enlarged, irregular suprabasal cells. Hypergranulosis (HP:0025114) has no admissible term in the histopathology enum, so the finding is bound to hyperkeratosis and the granular-layer change is carried in the preferred term.
Show evidence (1 reference)
PMID:1379726 SUPPORT BACKGROUND Human Clinical
"Histologically, EH epidermis exhibits a thickened stratum corneum and granular layer, with enlarged and irregular-shaped cells."
Introduction of the transgenic mouse paper describing human epidermolytic hyperkeratosis histology.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Epidermolytic Hyperkeratosis 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Immune 1
Sepsis HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15663649 SUPPORT REVIEW SYNTHESIS Human Clinical
"It can lead to life-threatening complications, such as sepsis."
Sepsis is a recognized life-threatening complication.
Integument 9
Congenital Ichthyosiform Erythroderma HP:0007431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital ichthyosiform erythroderma (HP:0007431). HP:0007431 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15663649 SUPPORT REVIEW SYNTHESIS Human Clinical
"This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."
Neonatal erythema is a cardinal feature.
PMID:16505000 SUPPORT Human Clinical
"This K10 null mutation leads to a severe phenotype, clinically resembling autosomal-dominant EHK, but differing in form and distribution of keratin aggregates on ultrastructural analysis."
The recessive null form shares the dominant clinical picture.
Skin Blistering Abnormal blistering of the skin HP:0008066 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal blistering of the skin (HP:0008066). HP:0008066 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1380725 SUPPORT Human Clinical
"Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum."
Blistering is a defining feature.
Skin Erosion HP:0200041 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin erosion (HP:0200041). HP:0200041 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31278741 SUPPORT Human Clinical
"Mild scaling on the neck and skin fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew."
Superficial erosions persist as the residual feature in a mild recessive case.
Generalized Hyperkeratosis HP:0000962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperkeratosis (HP:0000962). HP:0000962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1380725 SUPPORT Human Clinical
"Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum."
Marked stratum corneum thickening is a defining feature.
Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21271994 SUPPORT Human Clinical
"Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes."
Ichthyosis defines the disorder caused by KRT10 mutations.
Palmoplantar Keratoderma OCCASIONAL HP:0000982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palmoplantar keratoderma (HP:0000982). HP:0000982 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:11558869 SUPPORT Human Clinical
"Those with mutated keratin 1 (K1) invariably had associated keratoderma (n=6). In contrast, only 1 of 7 patients with K10 mutations had this problem (p = 0.0047)."
Keratoderma occurred in 1 of 7 KRT10 patients against all KRT1 patients.
PMID:8053700 SUPPORT Human Clinical
"In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types."
In a 21-family series, KRT10 families fell in the types without severe palm/sole hyperkeratosis.
PMID:21271994 SUPPORT Human Clinical
"The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants."
KRT10 disease usually spares the palms and soles.
Flexural Lichenification HP:0007453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flexural lichenification (HP:0007453). HP:0007453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9856845 SUPPORT Human Clinical
"Individuals with this variant present with bullous ichthyosis in early childhood and hyperkeratotic lichenified plaques in the flexural areas and extensor surfaces at later ages."
Describes flexural lichenified plaques in annular epidermolytic ichthyosis.
Annular Polycyclic Erythematous Plaques Annular cutaneous lesion HP:0025528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Annular cutaneous lesion (HP:0025528). HP:0025528 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9856845 SUPPORT Human Clinical
"Characteristically, they also develop intermittent bouts of annular and polycyclic, erythematous, scaly plaques on the trunk and proximal extremities."
Defines the episodic annular plaques.
PMID:9036939 SUPPORT Human Clinical
"The proband suffered from bullous ichthyosis and had bouts of disease activity associated with the development of numerous annular and polycyclic erythematous, hyperkeratotic plaques on the trunk and the proximal extremities."
Independent KRT10 family with the same flaring annular plaques.
Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38741524 SUPPORT Human Clinical
"The study highlights that around half of the patients with EI experienced itch and severe pain."
Itch in about half of a 48-patient cohort that includes KRT1 and KRT10 patients.
Constitutional 1
Skin Pain HP:0012531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin pain, annotated with Pain (HP:0012531). HP:0012531 is a phenotype from the Human Phenotype Ontology.
Bound to the general HPO term because OLS searches of HP for "skin pain", "cutaneous pain" and "painful skin" returned no skin-specific pain term; the nearest hit, HP:0025803 Mucocutaneous lesion painful, names a painful lesion rather than pain across the skin.
Show evidence (1 reference)
PMID:38741524 SUPPORT Human Clinical
"The study highlights that around half of the patients with EI experienced itch and severe pain."
Severe pain in about half of a mixed KRT1/KRT10 cohort.
🧬

Genetic Associations

2
KRT10 heterozygous dominant-negative variants (Causative)
Gene: KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal Dominant
Show evidence (4 references)
PMID:21271994 SUPPORT Human Clinical
"In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation."
Heterozygous point mutations at KRT10 helix boundary motifs cause severe epidermolytic ichthyosis.
PMID:39072839 SUPPORT Human Clinical
"We report three different novel missense variants in the L12 linker domain of KRT10 in patients with an atypical, milder form of EI resembling peeling skin syndrome."
Extends the allelic series to linker variants with a milder phenotype.
PMID:38741524 SUPPORT Human Clinical
"Patients with keratin 1 mutations tended to have severe EI, while the three forms were evenly distributed in those with keratin 10 mutations."
In a 48-patient cohort graded localized, intermediate or severe, KRT10 patients spread evenly across the three severity forms, unlike KRT1 patients.
+ 1 more reference
KRT10 biallelic null variants (Causative)
Gene: KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal Recessive
Show evidence (2 references)
PMID:29277919 SUPPORT Human Clinical
"Direct sequencing of the patient's genomic DNA revealed a novel homozygous nonsense mutation residing within the proximal part KRT10 first exon. The mutation was found to co-segregate with the disease phenotype in an autosomal recessive fashion."
Homozygous KRT10 nonsense variant co-segregating recessively.
PMID:31278741 SUPPORT Human Clinical
"The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3."
Compound heterozygous null and leaky splice alleles in a mild case.
💊

Medical Actions

3
Emollients
Action: topical emollient therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is topical emollient therapy, annotated with Skin-Directed Therapy (NCIT:C121969). NCIT:C121969 is a clinical intervention from the NCI Thesaurus. Ontology label: Skin-Directed Therapy NCIT:C121969
Platform: Other
Regular emollients to hydrate the skin and reduce scale; the mainstay of symptomatic care.
Mechanism Target:
Generalized Hyperkeratosis
Show evidence (1 reference)
PMID:15663649 SUPPORT REVIEW SYNTHESIS Human Clinical
"We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids."
Emollients are part of standard symptomatic therapy.
Retinoids
Action: retinoid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is retinoid therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: acitretin CHEBI:50172 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acitretin (CHEBI:50172). CHEBI:50172 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral acitretin or topical retinoids reduce hyperkeratosis. In a Scandinavian series patients with KRT10 variants responded more often than those with KRT1 variants. Retinoids can increase skin fragility.
Mechanism Target:
Compensatory Epidermal Hyperproliferation
Show evidence (2 references)
PMID:11558869 SUPPORT Human Clinical
"Five out of 6 patients with KRT10 mutations benefited from treatment with oral acitretin (5-25mg/day) or topical tretinoin/tazarotene, but none of the patients with KRT1 mutations derived any benefit."
Gene-stratified response favouring retinoid use in KRT10 disease.
PMID:22504942 SUPPORT INDIRECT In Vitro
"When cells were pre-incubated with all-trans-retinoic acid (ATRA) or retinoic acid receptor (RAR)-α agonists the aggregates decreased in a dose-dependent manner."
Offers a mechanistic rationale in KRT10-mutant patient keratinocytes.
IL-17A Blockade
Action: anti-IL-17A biologic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anti-IL-17A biologic therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: secukinumab NCIT:C152315 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses secukinumab (NCIT:C152315). NCIT:C152315 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-IL-17A antibodies such as secukinumab have been reported to help individual patients, including patients with KRT10 variants, but a randomized trial across adult congenital ichthyoses did not show efficacy.
Mechanism Target:
Cutaneous TH17 Inflammation
Show evidence (2 references)
PMID:40288548 SUPPORT Human Clinical
"The treatment efficacy was also confirmed in patients with KRT10 mutations."
Reports response to anti-IL-17A treatment in KRT10 patients.
PMID:35218370 REFUTE Human Clinical
"IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses."
A placebo-controlled trial including epidermolytic ichthyosis did not show efficacy overall.
🔬

Diagnosis

2
Skin Biopsy with Light and Electron Microscopy
Biopsy shows epidermolytic hyperkeratosis on light microscopy, and electron microscopy shows perinuclear tonofilament clumps. In the Danish cohort new biopsies were taken when the diagnosis was in doubt.
skin biopsy NCIT:C51692 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:22930352 SUPPORT Human Clinical
"new skin biopsies for light or electron microscopy were taken in case of diagnostic doubt."
Skin biopsy for light and electron microscopy was part of the diagnostic work-up.
PMID:22930352 SUPPORT BACKGROUND Human Clinical
"In contrast to most other ichthyoses, the histopathological picture of EI is distinctive"
The histology distinguishes epidermolytic ichthyosis from other ichthyoses.
KRT10 Sequencing
Sequencing of KRT1 and KRT10 identifies the causal variant and separates KRT10 disease from KRT1 disease.
KRT1 and KRT10 gene sequencing NCIT:C153598 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:22930352 SUPPORT Human Clinical
"All patients were initially screened for mutations in hotspot regions of KRT1 and KRT10 by denaturing high-performance liquid chromatography"
Hotspot screening of KRT1 and KRT10, followed by DNA sequencing, was the genetic diagnostic step.
📈

Progression

2
Neonatal
Age: Birth
Erythroderma, blistering and erosions are present at or shortly after birth.
Show evidence (1 reference)
PMID:15663649 SUPPORT REVIEW SYNTHESIS Human Clinical
"This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."
Congenital onset with erythema and blistering.
Childhood to adulthood
Age: Infancy onward
Blistering becomes less frequent while hyperkeratosis increases.
Show evidence (1 reference)
PMID:20302579 SUPPORT BACKGROUND Human Clinical
"is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases."
Describes the shift from neonatal blistering to later hyperkeratosis.
📊

Prevalence

1
Denmark
Point Prevalence 0.29 per 100,000 1–9 per 1,000,000
Approximately 1 in 350,000 for epidermolytic ichthyosis as a whole, of which the KRT10 form is a part: six of the eleven genotyped Danish families carried a KRT10 variant and five a KRT1 variant. No KRT10-specific population estimate was found.
Show evidence (2 references)
PMID:22930352 SUPPORT Human Clinical
"In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%)."
National cohort prevalence estimate for epidermolytic ichthyosis, both keratin genes combined.
PMID:22930352 SUPPORT Human Clinical
"Five families had mutations in K1 and 6 families had mutations in K10."
KRT10 accounts for roughly half of genotyped families in the same cohort.
🐁

Animal Models

2
Mutant keratin 10 transgenic mouse
Transgenic mice expressing a mutant keratin 10 gene develop the epidermolytic hyperkeratosis phenotype, the first in vivo evidence that suprabasal keratin mutations underlie the human disease.
Species
Mouse
Genotype
Transgene expressing a mutant human keratin 10 in the suprabasal epidermis
Publication
PMID:1379726
Pathograph links
Suprabasal Keratinocyte Cytolysis recapitulates fidelity: moderate observes: tissue Mutant K10 expression reproduces suprabasal pathology and basal hyperproliferation.
Limitations: Transgenic overexpression of an engineered mutant rather than a heterozygous knock-in of a patient allele at the endogenous locus.
Show evidence (1 reference)
PMID:1379726 SUPPORT Model Organism
"We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype"
The dominant mutant K10 transgene reproduces the epidermolytic phenotype.
Keratin 10 null mouse
Mice lacking keratin 10 form a normal epidermis without fragility at birth because K5/K14 persist suprabasally; adults show basal hyperproliferation without cytolysis. This contrasts with human biallelic KRT10 null patients, who have epidermolytic ichthyosis with blistering.
Species
Mouse
Genotype
Krt10 -/-
Publication
PMID:11408568
Pathograph links
Suprabasal Keratinocyte Cytolysis fails to recapitulate fidelity: low observes: tissue Loss of K10 in mice does not produce suprabasal cytolysis or blistering.
Limitations: Species difference in keratin redundancy: mouse epidermis compensates for K10 loss with suprabasal K5/K14 and novel K1/K14/K15 filaments, whereas human K10-null epidermis blisters despite induction of K6, K16 and K17.
Show evidence (2 references)
PMID:11408568 SUPPORT Model Organism
"Here, we show that the loss of K10, the most prominent epidermal protein, allowed the formation of a normal epidermis in neonatal mice without signs of fragility or wound-healing response."
Neonatal K10-null mice lack the fragility seen in human recessive disease.
+ 1 more reference
Compensatory Epidermal Hyperproliferation recapitulates fidelity: moderate observes: tissue Adult K10-null mice show basal keratinocyte hyperproliferation.
Show evidence (1 reference)
PMID:12077355 SUPPORT Model Organism
"Unlike most keratin mutant mice, the epidermis of adult K10-/- mice showed no cytolysis but displayed hyperproliferation of basal keratinocytes and an increased cell size."
Basal hyperproliferation occurs without cytolysis in adult K10-null mice.
{ }

Source YAML

click to show 
name: Epidermolytic Hyperkeratosis 2
creation_date: "2026-09-28T12:49:03Z"
category: Mendelian
description: >-
  Epidermolytic hyperkeratosis 2 is the KRT10 form of epidermolytic ichthyosis, a
  keratinopathic ichthyosis of the suprabasal epidermis. Most patients carry a
  heterozygous missense variant in the helix initiation motif at the start of the
  1A rod segment or the helix termination motif at the end of the 2B rod segment
  of keratin 10, the type I partner of keratin 1. The mutant chain is incorporated
  into K1/K10 heterodimers and blocks filament assembly and elongation, so the
  keratin network of spinous and granular keratinocytes collapses into perinuclear
  tonofilament clumps and the cells lyse. Affected newborns have erythroderma,
  blisters and erosions; blistering becomes less frequent with age while
  hyperkeratosis and ichthyotic scale increase. A minority of families carry
  biallelic KRT10 null alleles that abolish keratin 10 protein and cause a
  recessive form, and helix termination or 2B-domain variants produce the annular
  epidermolytic ichthyosis variant with episodic polycyclic plaques. Compared with
  KRT1 disease, KRT10 disease usually spares the palms and soles.
disease_term:
  preferred_term: epidermolytic hyperkeratosis 2
  term:
    id: MONDO:0958184
    label: epidermolytic hyperkeratosis 2
parents:
- epidermolytic ichthyosis
- keratinopathic ichthyosis
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007239
      label: epidermolytic ichthyosis
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0007239 is the MONDO parent of MONDO:0958184 and spans both keratin
      genes: its direct children include MONDO:0700249 epidermolytic
      hyperkeratosis 1 (KRT1) as well as this class. It is recorded as a broad
      match, as on KRT1_Keratinopathies, so that the gene-agnostic class is not
      retired from the curation queue through a single-gene entry.
synonyms:
- KRT10-related epidermolytic ichthyosis
- keratin 10 epidermolytic hyperkeratosis
- bullous congenital ichthyosiform erythroderma, KRT10 type
references:
- reference: PMID:31335043
  title: "Epidermolytic Hyperkeratosis."
  tags:
  - StatPearls
has_subtypes:
- name: EHK2A
  display_name: Epidermolytic Hyperkeratosis 2A, Autosomal Dominant
  subtype_term:
    preferred_term: epidermolytic hyperkeratosis 2A, autosomal dominant
    term:
      id: MONDO:0700248
      label: epidermolytic hyperkeratosis 2A, autosomal dominant
  description: >-
    The common form. A heterozygous KRT10 missense variant, often de novo, acts
    as a dominant negative on the K1/K10 filament network. Arg10 at the start of
    the 1A rod segment is the recurrent site. Generalized disease usually lacks
    severe palmoplantar keratoderma.
  genes:
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  inheritance:
  - name: Autosomal dominant inheritance
    description: >-
      Heterozygous KRT10 variants segregate with disease and are absent from
      unaffected individuals.
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:7508181
      reference_title: "Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epidermolytic hyperkeratosis (EH) is a rare autosomal dominant skin disease."
      explanation: States the autosomal dominant mode in a family series whose mutations are all in KRT10.
  evidence:
  - reference: PMID:7508181
    reference_title: "Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified mutations in six families, in which five mutations occur in the beginning of the 1A rod domain of keratin 10-namely, two ARg10 to His, one Arg10 to Cys, and Asn8 to His, and a Tyr14 to Asp."
    explanation: Heterozygous missense variants clustered at the start of the K10 1A rod segment in six dominant families.
- name: EHK2B
  display_name: Epidermolytic Hyperkeratosis 2B, Autosomal Recessive
  subtype_term:
    preferred_term: epidermolytic hyperkeratosis 2B, autosomal recessive
    term:
      id: MONDO:0700245
      label: epidermolytic hyperkeratosis 2B, autosomal recessive
  description: >-
    Recessive form caused by biallelic KRT10 nonsense, frameshift or splice
    variants that trigger transcript decay and leave the epidermis without keratin
    10 protein. Heterozygous carriers are clinically unaffected. Reported
    severity ranges from a lethal neonatal course to a mild, self-improving
    phenotype when a leaky splice allele leaves residual keratin 10.
  genes:
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  inheritance:
  - name: Autosomal recessive inheritance
    description: >-
      Affected children are homozygous or compound heterozygous for KRT10 null
      alleles and their heterozygous parents are unaffected.
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:16505000
      reference_title: "A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis revealed a homozygous nonsense mutation of the KRT10 gene in the affected family members, leading to a premature termination codon (p.Q434X), whereas the clinically unaffected consanguineous parents were both heterozygous carriers of the mutation."
      explanation: Homozygous affected children with heterozygous unaffected parents establishes recessive transmission.
  evidence:
  - reference: PMID:16505000
    reference_title: "A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that a recessive mutation in KRT10 leading to a complete human K10 knockout can cause EHK."
    explanation: First kindred defining the recessive KRT10 null form.
  - reference: PMID:31278741
    reference_title: "Skin fragility caused by biallelic KRT10 mutations: an intriguing form of self-improving epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive epidermolytic ichthyosis is a rare skin condition associated with KRT10 loss-of-function mutations."
    explanation: Confirms loss-of-function KRT10 alleles as the basis of the recessive form.
- name: AEI1
  display_name: Annular Epidermolytic Ichthyosis 1 (KRT10)
  subtype_term:
    preferred_term: annular epidermolytic ichthyosis, KRT10 type
    term:
      id: MONDO:0100303
      label: ichthyosis, annular epidermolytic 1
  description: >-
    Dominant variant of KRT10 epidermolytic ichthyosis with bullous ichthyosis in
    early childhood, later flexural and extensor lichenified hyperkeratotic
    plaques, and intermittent flares of annular, polycyclic, erythematous scaly
    plaques on the trunk and proximal limbs. Reported KRT10 variants lie in the 2B
    helical segment and its helix termination motif. MONDO places this class under
    both MONDO:0958184 and MONDO:0011870 annular epidermolytic ichthyosis; its
    KRT1 sibling, MONDO:0859574, is a subtype row of KRT1_Keratinopathies.
  genes:
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  inheritance:
  - name: Autosomal dominant inheritance
    description: >-
      Annular epidermolytic ichthyosis segregates as a dominant trait across two
      affected generations.
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:9036939
      reference_title: "A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The pattern of inheritance of the disorder is consistent with an autosomal dominant mode of transmission."
      explanation: States the dominant mode for annular epidermolytic ichthyosis in a KRT10 family.
  evidence:
  - reference: PMID:9036939
    reference_title: "A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis revealed a novel tandem CG to GA 2-bp mutation in the same allele of keratin 10 in affected individuals, resulting in an arginine to glutamate substitution at residue 83 (R83E) of the 2B helical segment. We conclude that annular epidermolytic ichthyosis should be considered a variant of bullous congenital ichthyosiform erythroderma."
    explanation: Identifies a KRT10 2B-segment variant and places annular epidermolytic ichthyosis within the epidermolytic ichthyosis spectrum.
  - reference: PMID:9856845
    reference_title: "A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis of this family revealed a novel mutation resulting in an isoleucine to threonine substitution at residue 107 (codon 446) within the highly conserved helix termination motif at the end of the rod domain of keratin 10."
    explanation: A second, independent KRT10 family with annular epidermolytic ichthyosis carries a helix termination motif variant.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The usual mode. About half of probands with epidermolytic hyperkeratosis
    carry a de novo variant.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations."
    explanation: Autosomal dominant mode with complete penetrance and a high de novo fraction across KRT1 and KRT10 disease.
- name: Autosomal recessive inheritance
  description: >-
    A minority of families, typically consanguineous, transmit biallelic KRT10
    null alleles (subtype EHK2B).
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:39072839
    reference_title: "Variants in the L12 linker domain of KRT10 are causal to atypical epidermolytic ichthyosis."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "EI is caused by pathogenic variants in the genes KRT1 and KRT10, encoding the proteins keratin 1 (KRT1) and keratin 10 (KRT10), respectively, and is primarily transmitted by autosomal-dominant inheritance, although recessive inheritance caused by nonsense variants in KRT10 is also described."
    explanation: Summarizes that recessive transmission of epidermolytic ichthyosis is restricted to KRT10 nonsense alleles.
prevalence:
- population: Denmark
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.29
  notes: >-
    Approximately 1 in 350,000 for epidermolytic ichthyosis as a whole, of which
    the KRT10 form is a part: six of the eleven genotyped Danish families carried
    a KRT10 variant and five a KRT1 variant. No KRT10-specific population
    estimate was found.
  evidence:
  - reference: PMID:22930352
    reference_title: "Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%)."
    explanation: National cohort prevalence estimate for epidermolytic ichthyosis, both keratin genes combined.
  - reference: PMID:22930352
    reference_title: "Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five families had mutations in K1 and 6 families had mutations in K10."
    explanation: KRT10 accounts for roughly half of genotyped families in the same cohort.
progression:
- phase: Neonatal
  age_range: Birth
  notes: Erythroderma, blistering and erosions are present at or shortly after birth.
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."
    explanation: Congenital onset with erythema and blistering.
- phase: Childhood to adulthood
  age_range: Infancy onward
  notes: Blistering becomes less frequent while hyperkeratosis increases.
  evidence:
  - reference: PMID:20302579
    reference_title: "Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice-site mutation in KRT10."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases."
    explanation: Describes the shift from neonatal blistering to later hyperkeratosis.
pathophysiology:
- name: KRT10 Dominant-Negative Rod-Domain Variant
  conforms_to: "keratin_intermediate_filament_fragility#Dominant-Negative Keratin Variant in a Filament Assembly Domain"
  biological_scale: MOLECULAR
  description: >-
    A heterozygous missense variant in a conserved rod-domain motif of keratin 10,
    most often at Arg10 at the start of the 1A segment or in the 2B segment and
    helix termination motif, yields a K10 chain that still forms heterodimers with
    keratin 1 but poisons filament assembly and elongation.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    gene:
      preferred_term: KRT10
      term:
        id: hgnc:6413
        label: KRT10
    description: >-
      Germline heterozygous missense variants, frequently arising de novo.
  genes:
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  molecular_functions:
  - preferred_term: keratin 10 structural constituent of the suprabasal epidermis
    term:
      id: GO:0030280
      label: structural constituent of skin epidermis
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: keratin intermediate filament assembly
    term:
      id: GO:0045109
      label: intermediate filament organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:1380725
    reference_title: "Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two other families, affected individuals had mutations in the highly conserved amino terminal of the rod domain of keratin 10. Structural analysis of these mutations predicts that heterodimer formation would be unaffected, although filament assembly and elongation would be severely compromised."
    explanation: KRT10 rod-domain mutations in affected families, with the dominant-negative prediction that heterodimers form but filaments do not assemble.
  - reference: PMID:7508181
    reference_title: "Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results from this work support the hypothesis that the beginning of the 1A rod domain segment in keratin 10 contains preferential sites for disease-causing mutation in EH."
    explanation: Identifies the start of the K10 1A segment as the mutational hotspot.
  - reference: PMID:7508181
    reference_title: "Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional assays performed with peptides corresponding to the 1A mutations in these families show severely diminished capacity to disaggregate preformed keratin intermediate filaments, in comparison with a wild-type control peptide."
    explanation: Peptide assays show the 1A variants alter the filament-interaction behaviour of the helix initiation motif.
  downstream:
  - target: Keratin Filament Network Collapse and Aggregation
    causal_link_type: DIRECT
    description: The mutant K10 chain is incorporated into the K1/K10 network and causes it to collapse into aggregates.
- name: Biallelic KRT10 Null Alleles and Keratin 10 Absence
  conforms_to: "keratin_intermediate_filament_fragility#Dominant-Negative Keratin Variant in a Filament Assembly Domain"
  biological_scale: MOLECULAR
  subtypes:
  - EHK2B
  description: >-
    Homozygous or compound heterozygous KRT10 nonsense, frameshift and splice
    variants cause transcript decay and complete absence of keratin 10 protein in
    the epidermis. The suprabasal network then lacks its type I partner; wound
    keratins K6, K16 and K17 are induced but do not compensate. One normal KRT10
    allele is sufficient for network formation, so carriers are unaffected. This
    node conforms to the module's variant-initiation node as the loss-of-function
    route into the same filament failure, not as a dominant-negative variant.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    gene:
      preferred_term: KRT10
      term:
        id: hgnc:6413
        label: KRT10
    description: >-
      Biallelic null alleles; compound heterozygosity with a leaky splice allele
      has also been reported.
  genes:
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  molecular_functions:
  - preferred_term: keratin 10 structural constituent of the suprabasal epidermis
    term:
      id: GO:0030280
      label: structural constituent of skin epidermis
    modifier: ABSENT
  biological_processes:
  - preferred_term: nonsense-mediated decay of KRT10 transcripts
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  evidence:
  - reference: PMID:16505000
    reference_title: "A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semi-quantitative RT-PCR and western blot analysis demonstrated degradation of the KRT10 transcript, resulting in complete absence of keratin K10 protein in the epidermis and cultured keratinocytes of homozygous patients."
    explanation: Direct demonstration of transcript degradation and absent K10 protein in patient tissue.
  - reference: PMID:29277919
    reference_title: "Recessive epidermolytic ichthyosis results from loss of keratin 10 expression, regardless of the mutation location."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot analysis showed complete absence of keratin 10 protein in the patient's skin, suggesting early protein degradation."
    explanation: An independent recessive family with an exon 1 nonsense variant also lacks K10 protein.
  - reference: PMID:18219278
    reference_title: "Mild recessive bullous congenital ichthyosiform erythroderma due to a previously unidentified homozygous keratin 10 nonsense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, the unaffected, heterozygous carriers of the mutation indicate that the K10 peptide from one normal allele alone is sufficient for keratin network formation."
    explanation: Explains why heterozygous null carriers are unaffected, in contrast to dominant-negative missense carriers.
  downstream:
  - target: Keratin Filament Network Collapse and Aggregation
    causal_link_type: DIRECT
    description: Without keratin 10 the suprabasal K1/K10 network cannot form and keratin aggregates appear.
- name: Keratin Filament Network Collapse and Aggregation
  conforms_to: "keratin_intermediate_filament_fragility#Keratin Filament Network Collapse and Aggregation"
  biological_scale: CELLULAR
  description: >-
    In spinous and granular keratinocytes the K1/K10 filament network collapses
    into perinuclear tonofilament clumps and peripheral aggregates, the
    ultrastructural hallmark of epidermolytic hyperkeratosis. Aggregate formation
    increases under heat stress.
  cell_types:
  - preferred_term: spinous keratinocyte
    term:
      id: CL:0000649
      label: spinous cell of epidermis
  biological_processes:
  - preferred_term: intermediate filament cytoskeleton organization
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: keratin filament
    term:
      id: GO:0045095
      label: keratin filament
  locations:
  - preferred_term: stratum spinosum
    term:
      id: UBERON:0002026
      label: stratum spinosum of epidermis
  evidence:
  - reference: PMID:1381287
    reference_title: "The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By genetic engineering, gene transfection, and 10 nm filament assembly, we show that this mutation is functionally responsible for the keratin filament clumping that occurs in basal (EBS) or suprabasal (EH) cells."
    explanation: Transfection and filament assembly assays show the patient K10 arginine mutation causes filament clumping.
  - reference: PMID:7513736
    reference_title: "Abnormal keratin 1 and 10 cytoskeleton in cultured keratinocytes from epidermolytic hyperkeratosis caused by keratin 10 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "EHK keratinocytes frequently exhibited a collapsed perinuclear network of K1/K10 filaments and sometimes peripheral granules of K1 and K10 aggregates, reminiscent of the cells of the suprabasal layers in these patients."
    explanation: Cultured keratinocytes from KRT10 1A-mutant patients reproduce the collapsed K1/K10 network.
  - reference: PMID:9036939
    reference_title: "A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic examination showed the typical pathology of epidermolytic hyperkeratosis, and ultrastructural analysis revealed abnormal keratin filament networks and tonofilament clumping with a perinuclear distribution."
    explanation: Patient skin ultrastructure shows perinuclear tonofilament clumping in a KRT10 family.
  - reference: PMID:22504942
    reference_title: "Retinoids reduce formation of keratin aggregates in heat-stressed immortalized keratinocytes from an epidermolytic ichthyosis patient with a KRT10 mutation*."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "K10 aggregates were detected in 5% of cells in the resting state, whereas heat stress increased this proportion to 25%."
    explanation: Immortalized KRT10-mutant patient keratinocytes form K10 aggregates that increase under stress.
  downstream:
  - target: Suprabasal Keratinocyte Cytolysis
    causal_link_type: DIRECT
    description: The collapsed network leaves suprabasal cells mechanically fragile and prone to lysis.
  - target: Keratinocyte NLRP3 Inflammasome Activation and IL-18 Release
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      NLRP3 and ASC cluster around mutant keratin aggregates in transfected
      keratinocytes; how aggregates trigger inflammasome assembly is not known.
  - target: Cutaneous TH17 Inflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      TH17 skewing is found in epidermolytic ichthyosis skin; the steps from
      the keratin defect to TH17 recruitment are not established.
  - target: Annular Polycyclic Erythematous Plaques
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      KRT10 2B-segment and helix termination variants produce episodic annular
      flares; why the disease flares cyclically is unknown.
- name: Suprabasal Keratinocyte Cytolysis
  conforms_to: "keratin_intermediate_filament_fragility#Keratinocyte Cytolysis Within the Keratin Expression Domain"
  biological_scale: CELLULAR
  description: >-
    Fragile suprabasal keratinocytes degenerate and lyse, producing vacuolar
    degeneration of the upper spinous and granular layers (epidermolytic
    hyperkeratosis on histology) and intraepidermal blisters. In the recessive
    null form blisters arise within the granular layer.
  cell_types:
  - preferred_term: spinous keratinocyte
    term:
      id: CL:0000649
      label: spinous cell of epidermis
  locations:
  - preferred_term: stratum granulosum
    term:
      id: UBERON:0002069
      label: stratum granulosum of epidermis
  evidence:
  - reference: PMID:1379726
    reference_title: "Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "It is typified by hyperkeratotic scaliness, blistering due to cytolysis within suprabasal epidermal cells, and hyperproliferation in basal cells."
    explanation: Describes the human disease as blistering from suprabasal cytolysis; the sentence is the introduction of a transgenic mouse paper.
  - reference: PMID:1379726
    reference_title: "Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype, thereby suggesting that a genetic basis for human EH residues in mutations in genes encoding suprabasal keratins K1 and K10."
    explanation: Mutant K10 expression in mouse epidermis reproduces the epidermolytic phenotype.
  - reference: PMID:18219278
    reference_title: "Mild recessive bullous congenital ichthyosiform erythroderma due to a previously unidentified homozygous keratin 10 nonsense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "K10 knockout patients show unique clinicopathological features of clinically mild BCIE with blisters occurring within the granular layer."
    explanation: Places blistering in the granular layer in the recessive null form.
  downstream:
  - target: Skin Blistering
    causal_link_type: DIRECT
    description: Suprabasal cytolysis splits the upper epidermis and produces blisters.
  - target: Skin Erosion
    causal_link_type: DIRECT
    description: Unroofed blisters and fragile upper epidermis leave superficial erosions.
  - target: Congenital Ichthyosiform Erythroderma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neonatal epidermal barrier disruption and inflammatory erythema.
    description: Widespread cytolysis at birth underlies the neonatal erythroderma.
  - target: Sepsis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Barrier breach through erosions permits bacterial entry.
    description: Eroded, barrier-deficient skin is a portal for systemic infection.
  - target: Skin Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Blisters and erosions are a plausible source of the pain patients report; the cited cohort does not attribute the pain to a lesion type.
  - target: Compensatory Epidermal Hyperproliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Damage to suprabasal cells stimulates proliferation of basal cells.
- name: Compensatory Epidermal Hyperproliferation
  conforms_to: "epidermal_cornification_failure#Compensatory Epidermal Hyperproliferation and Retention Hyperkeratosis"
  biological_scale: TISSUE
  description: >-
    Basal keratinocytes proliferate faster in response to the suprabasal defect,
    thickening the granular layer and stratum corneum. Loss of keratin 10 itself
    also drives basal hyperproliferation in K10-null mice without cytolysis,
    so hyperproliferation is not only a response to cell lysis.
  cell_types:
  - preferred_term: basal keratinocyte
    term:
      id: CL:0002187
      label: basal cell of epidermis
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:1379726
    reference_title: "Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, we show that (i) stimulation of basal cell proliferation can arise from a defect in suprabasal cells"
    explanation: Mutant K10 transgenic mice show basal hyperproliferation driven by a suprabasal defect.
  - reference: PMID:12077355
    reference_title: "Hyperproliferation, induction of c-Myc and 14-3-3sigma, but no cell fragility in keratin-10-null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unlike most keratin mutant mice, the epidermis of adult K10-/- mice showed no cytolysis but displayed hyperproliferation of basal keratinocytes and an increased cell size."
    explanation: K10 loss alone increases basal proliferation in mice, relevant to the recessive null form.
  - reference: PMID:16505000
    reference_title: "A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strong induction of the wound-healing keratins K6, K16 and K17 was found in the suprabasal epidermis, which are not able to compensate for the lack of keratin 10."
    explanation: Induction of wound-healing keratins in patient epidermis indicates an activated, hyperproliferative epidermal state.
  downstream:
  - target: Generalized Hyperkeratosis
    causal_link_type: DIRECT
    description: Increased keratinocyte production thickens the stratum corneum.
  - target: Ichthyosis
    causal_link_type: DIRECT
    description: Hyperproliferation and abnormal cornification produce ichthyotic scale.
  - target: Flexural Lichenification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hyperkeratosis concentrates in flexural skin as lichenified plaques.
  - target: Palmoplantar Keratoderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Palmoplantar thickening occurs in a minority of KRT10 patients.
- name: Keratinocyte NLRP3 Inflammasome Activation and IL-18 Release
  biological_scale: CELLULAR
  description: >-
    Serum and skin IL-18 are raised in epidermolytic ichthyosis and serum IL-18
    tracks severity. In keratinocytes expressing mutant keratin, NLRP3 and ASC
    cluster around the keratin aggregates and mature IL-18 release increases.
    The cell study used a mutant KRT1 construct, and the patient series did not
    separate KRT1 from KRT10 patients, so its application to KRT10 disease is
    inferred.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: interleukin-18 production
    term:
      id: GO:0032621
      label: interleukin-18 production
    modifier: INCREASED
  evidence:
  - reference: PMID:36656063
    reference_title: "Interleukin-18 as a severity marker and novel potential therapeutic target for epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum IL-18 levels correlated with the severity of ichthyosis, as measured by the Ichthyosis Scoring System."
    explanation: Serum IL-18 is raised in epidermolytic ichthyosis patients and tracks severity (seven EI patients; genes not separated in the abstract).
  - reference: PMID:36656063
    reference_title: "Interleukin-18 as a severity marker and novel potential therapeutic target for epidermolytic ichthyosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Additionally, these cells showed NLRP3 aggregation in the cytoplasm and ASC clustered around mutant keratin aggregations."
    explanation: Links mutant keratin aggregates to inflammasome assembly; the construct was mutant KRT1 in HaCaT cells, so the KRT10 case is inferred.
- name: Cutaneous TH17 Inflammation
  biological_scale: TISSUE
  description: >-
    Epidermolytic ichthyosis skin shows raised TH17-related cytokines in the
    epidermis and CCR6+ TH17 cells in the dermis. Patients with KRT10 variants
    have responded to IL-17A blockade in a case series, but a placebo-controlled
    trial across adult congenital ichthyoses was negative, so the contribution
    of this axis to disease severity remains uncertain. No source links this
    node to the IL-18 node, so no edge is drawn between them.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: interleukin-17 production
    term:
      id: GO:0032620
      label: interleukin-17 production
    modifier: INCREASED
  evidence:
  - reference: PMID:40288548
    reference_title: "Exploring T(H)17-mediated inflammation in epidermolytic ichthyosis: Clinical and mechanistic insight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Single-nucleus RNA sequencing revealed significantly elevated levels of TH-17 related cytokines in epidermis and CCR6+ TH17 cell infiltration in the dermis."
    explanation: >-
      Patient skin shows TH17 cytokine elevation and TH17 cell infiltration. The
      abstract describes this result right after the family carrying KRT1 and MPO
      variants, and does not say whether the snRNA-seq samples included KRT10
      patients, so its application to KRT10 disease is uncertain.
  downstream:
  - target: Pruritus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cutaneous inflammation is a candidate driver of the itch reported by about half of patients; the itch mediators in this disease are not established.
phenotypes:
- category: Dermatologic
  name: Congenital Ichthyosiform Erythroderma
  description: Generalized erythroderma present at or shortly after birth.
  phenotype_term:
    preferred_term: Congenital ichthyosiform erythroderma
    term:
      id: HP:0007431
      label: Congenital ichthyosiform erythroderma
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."
    explanation: Neonatal erythema is a cardinal feature.
  - reference: PMID:16505000
    reference_title: "A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This K10 null mutation leads to a severe phenotype, clinically resembling autosomal-dominant EHK, but differing in form and distribution of keratin aggregates on ultrastructural analysis."
    explanation: The recessive null form shares the dominant clinical picture.
- category: Dermatologic
  name: Skin Blistering
  description: Superficial blisters, most frequent in the neonatal period and in infancy.
  phenotype_term:
    preferred_term: Abnormal blistering of the skin
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:1380725
    reference_title: "Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum."
    explanation: Blistering is a defining feature.
- category: Dermatologic
  name: Skin Erosion
  description: Superficial erosions from fragile upper epidermis, persisting after scratching in milder forms.
  phenotype_term:
    preferred_term: Skin erosion
    term:
      id: HP:0200041
      label: Skin erosion
  evidence:
  - reference: PMID:31278741
    reference_title: "Skin fragility caused by biallelic KRT10 mutations: an intriguing form of self-improving epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild scaling on the neck and skin fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew."
    explanation: Superficial erosions persist as the residual feature in a mild recessive case.
- category: Dermatologic
  name: Generalized Hyperkeratosis
  description: Thickening of the stratum corneum that increases with age.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:1380725
    reference_title: "Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum."
    explanation: Marked stratum corneum thickening is a defining feature.
- category: Dermatologic
  name: Ichthyosis
  description: Ichthyotic scaling, the chronic manifestation after infancy.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes."
    explanation: Ichthyosis defines the disorder caused by KRT10 mutations.
- category: Dermatologic
  name: Palmoplantar Keratoderma
  frequency: OCCASIONAL
  description: >-
    Palmoplantar keratoderma is uncommon with KRT10 variants and is the main
    clinical feature that points to KRT1 instead.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:11558869
    reference_title: "Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those with mutated keratin 1 (K1) invariably had associated keratoderma (n=6). In contrast, only 1 of 7 patients with K10 mutations had this problem (p = 0.0047)."
    explanation: Keratoderma occurred in 1 of 7 KRT10 patients against all KRT1 patients.
  - reference: PMID:8053700
    reference_title: "Clinical heterogeneity in epidermolytic hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types."
    explanation: In a 21-family series, KRT10 families fell in the types without severe palm/sole hyperkeratosis.
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants."
    explanation: KRT10 disease usually spares the palms and soles.
- category: Dermatologic
  name: Flexural Lichenification
  subtype: AEI1
  description: Lichenified hyperkeratotic plaques in flexures and on extensor surfaces in later childhood.
  phenotype_term:
    preferred_term: Flexural lichenification
    term:
      id: HP:0007453
      label: Flexural lichenification
  evidence:
  - reference: PMID:9856845
    reference_title: "A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with this variant present with bullous ichthyosis in early childhood and hyperkeratotic lichenified plaques in the flexural areas and extensor surfaces at later ages."
    explanation: Describes flexural lichenified plaques in annular epidermolytic ichthyosis.
- category: Dermatologic
  name: Annular Polycyclic Erythematous Plaques
  subtype: AEI1
  description: >-
    Intermittent flares of annular and polycyclic erythematous scaly plaques on
    the trunk and proximal limbs, the defining feature of the annular variant.
  phenotype_term:
    preferred_term: Annular cutaneous lesion
    term:
      id: HP:0025528
      label: Annular cutaneous lesion
  evidence:
  - reference: PMID:9856845
    reference_title: "A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristically, they also develop intermittent bouts of annular and polycyclic, erythematous, scaly plaques on the trunk and proximal extremities."
    explanation: Defines the episodic annular plaques.
  - reference: PMID:9036939
    reference_title: "A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband suffered from bullous ichthyosis and had bouts of disease activity associated with the development of numerous annular and polycyclic erythematous, hyperkeratotic plaques on the trunk and the proximal extremities."
    explanation: Independent KRT10 family with the same flaring annular plaques.
- category: Dermatologic
  name: Pruritus
  description: Itch reported by about half of patients with epidermolytic ichthyosis.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:38741524
    reference_title: "Epidermolytic ichthyosis: Clinical spectrum and burden of disease in a large German cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study highlights that around half of the patients with EI experienced itch and severe pain."
    explanation: Itch in about half of a 48-patient cohort that includes KRT1 and KRT10 patients.
- category: Dermatologic
  name: Skin Pain
  description: Severe skin pain reported by about half of patients with epidermolytic ichthyosis.
  notes: >-
    Bound to the general HPO term because OLS searches of HP for "skin pain",
    "cutaneous pain" and "painful skin" returned no skin-specific pain term;
    the nearest hit, HP:0025803 Mucocutaneous lesion painful, names a painful
    lesion rather than pain across the skin.
  phenotype_term:
    preferred_term: Skin pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:38741524
    reference_title: "Epidermolytic ichthyosis: Clinical spectrum and burden of disease in a large German cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study highlights that around half of the patients with EI experienced itch and severe pain."
    explanation: Severe pain in about half of a mixed KRT1/KRT10 cohort.
- category: Infectious
  name: Sepsis
  description: Life-threatening systemic infection, a risk in neonates with eroded skin.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "It can lead to life-threatening complications, such as sepsis."
    explanation: Sepsis is a recognized life-threatening complication.
genetic:
- name: KRT10 heterozygous dominant-negative variants
  gene_term:
    preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    Heterozygous missense variants and small in-frame changes in the conserved
    1A helix initiation motif (Arg10 recurrent), the 2B segment and the helix
    termination motif. Mild atypical disease resembling peeling skin syndrome has
    been reported with L12 linker variants. Severity is more variable than with
    KRT1: in a German cohort KRT10 patients were spread evenly across localized,
    intermediate and severe forms. This row covers subtypes EHK2A and
    AEI1; `Genetic.subtype` is single-valued, so those rows carry the reciprocal
    link through their own `genes` descriptors. KRT10 frameshifts into the
    alternative arginine-rich reading frame cause ichthyosis with confetti,
    which is a different disease and is not covered here.
  evidence:
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation."
    explanation: Heterozygous point mutations at KRT10 helix boundary motifs cause severe epidermolytic ichthyosis.
  - reference: PMID:39072839
    reference_title: "Variants in the L12 linker domain of KRT10 are causal to atypical epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report three different novel missense variants in the L12 linker domain of KRT10 in patients with an atypical, milder form of EI resembling peeling skin syndrome."
    explanation: Extends the allelic series to linker variants with a milder phenotype.
  - reference: PMID:38741524
    reference_title: "Epidermolytic ichthyosis: Clinical spectrum and burden of disease in a large German cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with keratin 1 mutations tended to have severe EI, while the three forms were evenly distributed in those with keratin 10 mutations."
    explanation: In a 48-patient cohort graded localized, intermediate or severe, KRT10 patients spread evenly across the three severity forms, unlike KRT1 patients.
  - reference: PMID:20798280
    reference_title: "Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, no revertant clones have been reported, or seen in our clinics, in patients with dominant negative or recessive mutations in keratin 10 that cause a distinct disease, epidermolytic ichthyosis (also known as epidermolytic hyperkeratosis)"
    explanation: Distinguishes KRT10 epidermolytic ichthyosis, without revertant clones, from ichthyosis with confetti.
- name: KRT10 biallelic null variants
  gene_term:
    preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EHK2B
  inheritance:
  - name: Autosomal Recessive
  notes: >-
    Homozygous nonsense or splice variants, and compound heterozygosity for a
    nonsense variant and a leaky splice variant, abolish or reduce keratin 10.
  evidence:
  - reference: PMID:29277919
    reference_title: "Recessive epidermolytic ichthyosis results from loss of keratin 10 expression, regardless of the mutation location."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct sequencing of the patient's genomic DNA revealed a novel homozygous nonsense mutation residing within the proximal part KRT10 first exon. The mutation was found to co-segregate with the disease phenotype in an autosomal recessive fashion."
    explanation: Homozygous KRT10 nonsense variant co-segregating recessively.
  - reference: PMID:31278741
    reference_title: "Skin fragility caused by biallelic KRT10 mutations: an intriguing form of self-improving epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3."
    explanation: Compound heterozygous null and leaky splice alleles in a mild case.
treatments:
- name: Emollients
  description: Regular emollients to hydrate the skin and reduce scale; the mainstay of symptomatic care.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: topical emollient therapy
    term:
      id: NCIT:C121969
      label: Skin-Directed Therapy
  target_mechanisms:
  - target: Generalized Hyperkeratosis
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids."
    explanation: Emollients are part of standard symptomatic therapy.
- name: Retinoids
  description: >-
    Oral acitretin or topical retinoids reduce hyperkeratosis. In a Scandinavian
    series patients with KRT10 variants responded more often than those with
    KRT1 variants. Retinoids can increase skin fragility.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: retinoid therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_mechanisms:
  - target: Compensatory Epidermal Hyperproliferation
  evidence:
  - reference: PMID:11558869
    reference_title: "Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five out of 6 patients with KRT10 mutations benefited from treatment with oral acitretin (5-25mg/day) or topical tretinoin/tazarotene, but none of the patients with KRT1 mutations derived any benefit."
    explanation: Gene-stratified response favouring retinoid use in KRT10 disease.
  - reference: PMID:22504942
    reference_title: "Retinoids reduce formation of keratin aggregates in heat-stressed immortalized keratinocytes from an epidermolytic ichthyosis patient with a KRT10 mutation*."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "When cells were pre-incubated with all-trans-retinoic acid (ATRA) or retinoic acid receptor (RAR)-α agonists the aggregates decreased in a dose-dependent manner."
    explanation: Offers a mechanistic rationale in KRT10-mutant patient keratinocytes.
- name: IL-17A Blockade
  description: >-
    Anti-IL-17A antibodies such as secukinumab have been reported to help
    individual patients, including patients with KRT10 variants, but a
    randomized trial across adult congenital ichthyoses did not show efficacy.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: anti-IL-17A biologic therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: secukinumab
      term:
        id: NCIT:C152315
        label: Secukinumab
  target_mechanisms:
  - target: Cutaneous TH17 Inflammation
  evidence:
  - reference: PMID:40288548
    reference_title: "Exploring T(H)17-mediated inflammation in epidermolytic ichthyosis: Clinical and mechanistic insight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment efficacy was also confirmed in patients with KRT10 mutations."
    explanation: Reports response to anti-IL-17A treatment in KRT10 patients.
  - reference: PMID:35218370
    reference_title: "Secukinumab responses vary across the spectrum of congenital ichthyosis in adults."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses."
    explanation: A placebo-controlled trial including epidermolytic ichthyosis did not show efficacy overall.
histopathology:
- name: Suprabasal Keratinocyte Cytolysis
  finding_term:
    preferred_term: vacuolar degeneration of upper spinous and granular keratinocytes
    term:
      id: NCIT:C96302
      label: Cytoplasmic Vacuolation
  description: >-
    Intracellular vacuolization and degeneration of keratinocytes in the upper
    stratum spinosum and stratum granulosum, with intraepidermal blisters: the
    lesion that gives epidermolytic hyperkeratosis its name. The finding is
    named after the pathophysiology node it documents so that the pathograph
    attaches it to that node.
  diagnostic: true
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologically, there is a hyperkeratosis and vacuolar degeneration."
    explanation: Review summary of the defining histology.
  - reference: PMID:22930352
    reference_title: "Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "the histopathological picture of EI is distinctive, with hyperkeratosis, acanthosis and characteristic clumping of tonofilaments, intracellular vacuolization and intra-epidermal blisters."
    explanation: Introduction of the Danish cohort paper listing the distinctive histology, including vacuolization and intraepidermal blisters.
- name: Keratin Filament Network Collapse and Aggregation
  finding_term:
    preferred_term: perinuclear tonofilament clumping on electron microscopy
  description: >-
    Electron microscopy shows abnormal keratin filament networks and coarse
    tonofilament clumps with a perinuclear distribution in suprabasal
    keratinocytes. Named after the pathophysiology node it documents; the
    pathograph attaches a histopathology finding to a node only when the
    finding carries an ontology term, so this unbound finding is not yet
    attached there.
  diagnostic: true
  notes: >-
    Left unbound. HP:0034067 Tonofilament clumping is the matching concept but
    lies outside the HistopathologyFindingTerm enum (it is not under
    HP:0025461 Abnormal cell morphology). The nearest NCIT ultrastructural
    term found by OLS search for "intermediate filament aggregate",
    NCIT:C45956 Concentric Aggregates of Intermediate Filaments Present,
    names a concentric arrangement that the sources do not describe.
  evidence:
  - reference: PMID:9036939
    reference_title: "A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic examination showed the typical pathology of epidermolytic hyperkeratosis, and ultrastructural analysis revealed abnormal keratin filament networks and tonofilament clumping with a perinuclear distribution."
    explanation: Ultrastructure of skin from a KRT10 family shows perinuclear tonofilament clumping.
- name: Hypergranulosis and Hyperkeratosis
  finding_term:
    preferred_term: thickened granular layer and stratum corneum
    term:
      id: NCIT:C35541
      label: Hyperkeratosis
  description: >-
    Thickening of the stratum corneum and of the granular layer, with enlarged,
    irregular suprabasal cells. Hypergranulosis (HP:0025114) has no admissible
    term in the histopathology enum, so the finding is bound to hyperkeratosis
    and the granular-layer change is carried in the preferred term.
  evidence:
  - reference: PMID:1379726
    reference_title: "Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologically, EH epidermis exhibits a thickened stratum corneum and granular layer, with enlarged and irregular-shaped cells."
    explanation: Introduction of the transgenic mouse paper describing human epidermolytic hyperkeratosis histology.
diagnosis:
- name: Skin Biopsy with Light and Electron Microscopy
  description: >-
    Biopsy shows epidermolytic hyperkeratosis on light microscopy, and electron
    microscopy shows perinuclear tonofilament clumps. In the Danish cohort new
    biopsies were taken when the diagnosis was in doubt.
  diagnosis_term:
    preferred_term: skin biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:22930352
    reference_title: "Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "new skin biopsies for light or electron microscopy were taken in case of diagnostic doubt."
    explanation: Skin biopsy for light and electron microscopy was part of the diagnostic work-up.
  - reference: PMID:22930352
    reference_title: "Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to most other ichthyoses, the histopathological picture of EI is distinctive"
    explanation: The histology distinguishes epidermolytic ichthyosis from other ichthyoses.
- name: KRT10 Sequencing
  description: >-
    Sequencing of KRT1 and KRT10 identifies the causal variant and separates
    KRT10 disease from KRT1 disease.
  diagnosis_term:
    preferred_term: KRT1 and KRT10 gene sequencing
    term:
      id: NCIT:C153598
      label: DNA Sequencing
  evidence:
  - reference: PMID:22930352
    reference_title: "Generalized and naevoid epidermolytic ichthyosis in Denmark: clinical and mutational findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients were initially screened for mutations in hotspot regions of KRT1 and KRT10 by denaturing high-performance liquid chromatography"
    explanation: Hotspot screening of KRT1 and KRT10, followed by DNA sequencing, was the genetic diagnostic step.
animal_models:
- name: Mutant keratin 10 transgenic mouse
  species: Mouse
  genotype: Transgene expressing a mutant human keratin 10 in the suprabasal epidermis
  publication: PMID:1379726
  description: >-
    Transgenic mice expressing a mutant keratin 10 gene develop the
    epidermolytic hyperkeratosis phenotype, the first in vivo evidence that
    suprabasal keratin mutations underlie the human disease.
  modeled_mechanisms:
  - target: Suprabasal Keratinocyte Cytolysis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Mutant K10 expression reproduces suprabasal pathology and basal hyperproliferation.
    limitations: >-
      Transgenic overexpression of an engineered mutant rather than a
      heterozygous knock-in of a patient allele at the endogenous locus.
    evidence:
    - reference: PMID:1379726
      reference_title: "Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype"
      explanation: The dominant mutant K10 transgene reproduces the epidermolytic phenotype.
- name: Keratin 10 null mouse
  species: Mouse
  genotype: Krt10 -/-
  publication: PMID:11408568
  description: >-
    Mice lacking keratin 10 form a normal epidermis without fragility at birth
    because K5/K14 persist suprabasally; adults show basal hyperproliferation
    without cytolysis. This contrasts with human biallelic KRT10 null patients,
    who have epidermolytic ichthyosis with blistering.
  modeled_mechanisms:
  - target: Suprabasal Keratinocyte Cytolysis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: Loss of K10 in mice does not produce suprabasal cytolysis or blistering.
    limitations: >-
      Species difference in keratin redundancy: mouse epidermis compensates for
      K10 loss with suprabasal K5/K14 and novel K1/K14/K15 filaments, whereas
      human K10-null epidermis blisters despite induction of K6, K16 and K17.
    evidence:
    - reference: PMID:11408568
      reference_title: "Formation of a normal epidermis supported by increased stability of keratins 5 and 14 in keratin 10 null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that the loss of K10, the most prominent epidermal protein, allowed the formation of a normal epidermis in neonatal mice without signs of fragility or wound-healing response."
      explanation: Neonatal K10-null mice lack the fragility seen in human recessive disease.
    - reference: PMID:12077355
      reference_title: "Hyperproliferation, induction of c-Myc and 14-3-3sigma, but no cell fragility in keratin-10-null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Unlike most keratin mutant mice, the epidermis of adult K10-/- mice showed no cytolysis but displayed hyperproliferation of basal keratinocytes and an increased cell size."
      explanation: Adult K10-null mice also lack cytolysis.
  - target: Compensatory Epidermal Hyperproliferation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Adult K10-null mice show basal keratinocyte hyperproliferation.
    evidence:
    - reference: PMID:12077355
      reference_title: "Hyperproliferation, induction of c-Myc and 14-3-3sigma, but no cell fragility in keratin-10-null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Unlike most keratin mutant mice, the epidermis of adult K10-/- mice showed no cytolysis but displayed hyperproliferation of basal keratinocytes and an increased cell size."
      explanation: Basal hyperproliferation occurs without cytolysis in adult K10-null mice.
notes: >-
  Scope. This entry covers the germline KRT10 epidermolytic ichthyoses that MONDO
  places under MONDO:0958184: the dominant form MONDO:0700248, the recessive null
  form MONDO:0700245, and annular epidermolytic ichthyosis 1 MONDO:0100303, each
  a has_subtypes row. It mirrors KRT1_Keratinopathies, which covers the KRT1
  allelic series. Ichthyosis with confetti (MONDO:0012208, congenital reticular
  ichthyosiform erythroderma) is not a subtype here: MONDO places it under
  keratinopathic ichthyosis rather than under MONDO:0958184, it is caused by
  either KRT10 or KRT1 frameshifts into an arginine-rich alternative reading
  frame that sends keratin 10 to the nucleolus, and its revertant mosaicism is a
  mechanism the epidermolytic forms lack (PMID:20798280); it needs its own entry.
  Epidermolytic epidermal nevi due to postzygotic KRT10 variants are likewise
  outside this entry. Several sources cited here (the Danish prevalence, the
  German cohort itch and pain figures, the IL-18 study) pool KRT1 and KRT10
  patients, and the NLRP3 aggregation result used a mutant KRT1 construct.
  The 2026-09-10 Bookshelf index read by `just check-genereviews` lists no
  GeneReviews chapter for epidermolytic ichthyosis, so the clinical baseline is
  the StatPearls chapter and the primary literature.
📚

References & Deep Research

References

1
PMID:31335043
Epidermolytic Hyperkeratosis.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Epidermolytic Hyperkeratosis 2 · 2026-09-28T13:06:44Z · View source

New entry for the KRT10 form of epidermolytic ichthyosis (MONDO:0958184), structured in parallel with KRT1_Keratinopathies. Three has_subtypes rows bind the MONDO children of MONDO:0958184: MONDO:0700248 (autosomal dominant), MONDO:0700245 (autosomal recessive null) and MONDO:0100303 (annular epidermolytic ichthyosis 1). Ichthyosis with confetti (MONDO:0012208) was left out because MONDO does not place it under MONDO:0958184, it is caused by KRT10 or KRT1, and its frameshift and revertant-mosaicism mechanism differs. Six pathophysiology nodes (dominant-negative and null KRT10 alleles, filament collapse, suprabasal cytolysis, compensatory hyperproliferation, IL-18/IL-17 inflammation) connect to all 11 phenotypes. A Perplexity deep-research report was produced: the first run failed with a server disconnect, and a rerun with a streaming request succeeded (research/Epidermolytic_Hyperkeratosis_2-deep-research-perplexity.md). The entry was first curated from PubMed abstracts fetched with just fetch-reference, and the report was then screened as leads only. Its body stops after section 7. just preflight-dr could not run because the local MONDO build is absent. Its Term Validation section flags UBERON:0001510 and UBERON:0001509 as named for other structures (skin of knee, triceps brachii, called palm and sole), and UBERON:0001511, UBERON:0002330 and UBERON:0007798 as loose matches; none of its CURIEs were used. Several claims it attributes to PMID:21271994 (17 of 28 de novo, 87% missense, recessive collodion cases, p.Gln434X) are not in that abstract, and its Danish prevalence of 1 in 2,300,000-4,350,000 contradicts the cited 1 in 350,000 (PMID:22930352). The one lead taken from it is the keratin 10 null mouse (PMID:11408568), added with the mutant K10 transgenic mouse as an animal_models section; the null mouse is recorded as FAILS_TO_RECAPITULATE suprabasal cytolysis, a species difference from human recessive disease. Validated with just validate-disorders (schema, terms, 62/62 snippets), check-causal-targets, check-entity-refs, list-disconnected-phenotypes (11/11 connected), check-genereviews (no GeneReviews chapter in the Bookshelf index; StatPearls chapter tagged) and list-gene-term-mismatches.

Perplexity ▸
1. Disease Information
sonar-deep-research 21 citations 2026-09-28T13:15:49.715226

1. Disease Information

1.1 Definition, Nosology, and Disease Concept

Epidermolytic Hyperkeratosis 2 is best understood within the broader family of keratinopathic ichthyoses, which are inherited disorders of epidermal cornification caused by pathogenic variants in suprabasal keratin genes KRT1, KRT10, and KRT2.[13][4][20] The principal clinical entity is epidermolytic ichthyosis (EI), historically named bullous congenital ichthyosiform erythroderma (BCIE), characterized by generalized erythema, blistering, erosions, and later hyperkeratosis, with histopathology revealing epidermolytic hyperkeratosis in the upper epidermal layers.[4][9][12][13][20] Within this umbrella, EHK1 denotes disease due to KRT1 mutations on chromosome 12q13.13, whereas EHK2 refers to disease caused by KRT10 mutations on chromosome 17q21.2–q21.3, with autosomal dominant EHK2A (OMIM 620150) and autosomal recessive EHK2B (OMIM 620707) distinguished by inheritance mode and mutational mechanism.[1][6][8][11][12][13][20] Orphanet classifies autosomal dominant epidermolytic ichthyosis (EI) as a rare keratinopathic ichthyosis with neonatal blistering that progressively becomes hyperkeratotic, caused by mutations in KRT1 or KRT10 and assigned Orphanet ID 312.[20] Autosomal recessive epidermolytic ichthyosis, often collodion at birth and lacking palmoplantar keratoderma, is recognized separately (Orphanet ID 512103) and is consistently associated with KRT10 loss-of-function variants.[2][12][13][14]

EHK2 is part of the ICD-10 category Q80.3 “Other congenital ichthyosis,” shared with epidermolytic ichthyosis broadly, and ICD-11 includes EC20.03 for epidermolytic ichthyosis.[4][5][6][20] MedlinePlus Genetics describes epidermolytic hyperkeratosis as a skin disorder present at birth, with red, blistering skin evolving to thickened, often malodorous hyperkeratotic plaques, and specifies that KRT1 mutations are associated with palmoplantar hyperkeratosis (PS-type) whereas KRT10 mutations usually produce non-palmoplantar (NPS-type) disease.[3][8] Orphanet and OMIM note that keratinopathic ichthyoses have very low prevalence, with estimates of EI ranging from 1 in 100,000–300,000 in some studies and between 1/2,300,000–4,350,000 in Japanese and Danish populations.[4][9][20][13] Within these, EHK2 cases are a subset but likely represent a substantial fraction due to the mutational hotspot in KRT10 and the predominance of KRT10 mutations in some cohorts.[14][13][20]

From a disease ontological perspective, EHK2 would be mapped as a child of MONDO terms for epidermolytic ichthyosis and keratinopathic ichthyosis, and the user’s suggested MONDO:0958184 appears to correspond to “epidermolytic hyperkeratosis 2” or “epidermolytic ichthyosis due to KRT10,” although this mapping should be cross-checked against up-to-date MONDO releases.[20] At the level of Human Phenotype Ontology (HPO), EHK2 is associated with phenotypes such as congenital erythroderma, skin blistering, erosions, hyperkeratosis, palmoplantar keratoderma (in some cases), and recurrent skin infections, among others.[3][4][9][13][20] Disease information for EHK2 is derived from aggregated case series, registries, and genetic databases, rather than isolated electronic health records, with major resources including OMIM entries for EHK2A and recessive EI, Orphanet disease summaries, DermNet clinical reviews, and peer-reviewed cohort analyses.[1][2][4][11][12][13][14][20]

1.2 Identifiers, Synonyms, and Coding Systems

EHK2 is embedded in a complex synonymy reflecting historical terminology and evolving molecular classification. OMIM lists “epidermolytic hyperkeratosis 2A, autosomal dominant” under entry 620150, linked to KRT10 at 17q21.2, and references older generic terms for epidermolytic ichthyosis and bullous congenital ichthyosiform erythroderma.[11][1][10][20] Orphanet’s entry for autosomal dominant epidermolytic ichthyosis (ORPHA:312) and MedlinePlus identify numerous synonyms, including BCIE, BIE, Bullous congenital ichthyosiform erythroderma, Bullous erythroderma ichthyosiformis congenita of Brocq, Bullous ichthyosis, epidermolytic ichthyosis, epidermolytic hyperkeratosis, and Ichthyosis hystrix Brocq type.[3][4][9][20] The KRT10-associated recessive entity is often referred to as autosomal recessive epidermolytic ichthyosis, recessive EI, or lethal autosomal recessive epidermolytic ichthyosis when neonatally fatal, and has Orphanet ID 512103.[2][12][13][14]

ICD-10 includes EHK/EI within Q80.3 “Other congenital ichthyosis,” and DermNet explicitly associates epidermolytic ichthyosis (formerly epidermolytic hyperkeratosis) with Q80.3 and ICD-11 code EC20.03.[4][5][6][20] Superficial epidermolytic ichthyosis (SEI, Ichthyosis bullosa of Siemens), which is due to KRT2 mutations, is classified separately under ICD-10 Q80.8 and ICD-11 EC20.03.[7][13] SNOMED CT concepts such as 254167000 have been linked to epidermolytic hyperkeratosis and related entities.[1][4][5][20] MedGen, GARD, and UMLS also provide concepts for epidermolytic ichthyosis and bullous congenital ichthyosiform erythroderma, and ClinVar uses these disease names when annotating KRT10 variants.[19][8][20]

From a structured data perspective, the disease can be annotated with the following key identifiers and ontology concepts, though exact mappings should be verified in current releases: Orphanet:312 (AD EI), Orphanet:512103 (AR EI), OMIM:620150 (EHK2A), OMIM:148080 (KRT10 gene), ICD-10:Q80.3, ICD-11:EC20.03, SNOMED CT:254167000 (epidermolytic hyperkeratosis or epidermolytic ichthyosis), UMLS C0079153 (epidermolytic hyperkeratosis), and a MONDO term for epidermolytic ichthyosis, with MONDO:0958184 as a candidate for the KRT10-specific subtype.[1][3][4][5][6][8][11][19][20] The disease-level knowledge summarized here is derived from aggregated resources (OMIM, Orphanet, DermNet, MedlinePlus, peer-reviewed clinical cohorts), rather than individual patient records, though many primary studies analyze detailed phenotypic and genotypic information at the patient level.[3][4][9][12][13][14][20]

1.3 Relation to Broader Disease Categories

Conceptually, EHK2 resides at the intersection of ichthyoses, genodermatoses, and disorders of cornification. MedlinePlus emphasizes that epidermolytic hyperkeratosis is part of the group of conditions called ichthyoses, which classically show scaly skin, but notes that in EHK the skin is thick but not necessarily scaly, highlighting its distinct clinical pattern.[3] DermNet identifies epidermolytic ichthyosis as one of the five main types of ichthyosis alongside lamellar ichthyosis, ichthyosis vulgaris, congenital ichthyosiform erythroderma, and X-linked ichthyosis, and categorizes it as a genetic disorder of keratinization.[4] Orphanet groups EHK/EI under keratinopathic ichthyoses, distinguished by a blistering neonatal presentation followed by hyperkeratosis, and links them to mutations in suprabasal keratin genes.[13][20]

Within keratin disorders, EHK/EI is unique in several respects. DermNet notes that epidermolytic ichthyosis is the only keratin disease with well-documented genetic mosaicism, manifesting clinically as epidermolytic nevi when postzygotic mutations occur, and posing a risk of generalized disease in offspring if germ cells are involved.[4][13][14] Superficial epidermolytic ichthyosis, due to KRT2 mutations, is recognized as a distinct but closely related entity with more superficial blistering and erosions.[7][13] Among disorders of cornification, EHK2 offers a clear example of how single amino acid substitutions in conserved helix boundary motifs of structural proteins can dramatically perturb tissue architecture and function, providing a model system for broader principles of intermediate filament biology and skin barrier physiology.[12][14][15][16]

In summary, Epidermolytic Hyperkeratosis 2 represents a molecularly defined subtype of epidermolytic ichthyosis, anchored in the KRT10 gene, distinguished clinically by a non-palmoplantar-predominant pattern in most autosomal dominant cases and distinct recessive phenotypes, and situated within the broader conceptual frameworks of keratinopathic ichthyoses, genodermatoses, and Mendelian disorders of epidermal cornification.[3][4][9][12][13][14][20]

2. Etiology

2.1 Genetic Causal Factors

The primary etiologic factor in Epidermolytic Hyperkeratosis 2 is the presence of pathogenic variants in the KRT10 gene, which encodes keratin 10 (K10), a type I intermediate filament protein abundantly expressed in suprabasal keratinocytes of the epidermis.[8][11][12][13][14] OMIM entry 620150 explicitly states that autosomal dominant epidermolytic hyperkeratosis 2A is caused by heterozygous mutation in KRT10 on chromosome 17q21, and Orphanet confirms that autosomal dominant EI/EHK can be due to mutations in either KRT1 or KRT10.[11][20] MedlinePlus Genetics notes that dozens of mutations in KRT10 have been found in people with epidermolytic hyperkeratosis, most often associated with the non-palmoplantar subtype and featuring widespread thick skin on many parts of the body but sparing palms and soles.[3][8] DermNet similarly reports that epidermolytic ichthyosis is caused by missense mutations in keratin genes KRT1 and KRT10, with KRT10 mutations leading to variable disruption and decreased stability of K1/K10 tonofilaments and hyperkeratosis due to impaired desquamation.[4]

Extensive mutational catalogs underscore the genetic heterogeneity within EHK2. A British Journal of Dermatology cohort study analyzing 28 patients with EI identified 14 different mutations in KRT1 and KRT10, of which four were novel, and noted that approximately 87% of reported mutations are heterozygous missense changes in conserved helix boundary motifs critical for filament formation.[14] That study highlighted that palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to non-palmoplantar variants, reinforcing the clinical distinction between EHK1 and EHK2.[14] More recently, a large clinical spectrum study of keratinopathic ichthyoses documented autosomal dominant EI due to KRT10 variants clustered in the rod domain and autosomal recessive EI caused by null mutations that abolish keratin 10 expression, with recessive cases manifesting collodion presentation at birth and sometimes lethal erythroderma.[13][12][14]

Autosomal recessive epidermolytic ichthyosis due to KRT10 represents a distinct etiologic scenario characterized by loss-of-function. A 2010 British Journal of Dermatology report described a lethal autosomal recessive epidermolytic ichthyosis caused by a novel donor splice-site mutation in KRT10 (c.1155+5G>A), with the affected neonate homozygous and both parents heterozygous, and emphasized that three inbred pedigrees with recessive EI due to KRT10 null mutations had previously been described.[12] In the recent clinical spectrum study, recessive EI is attributed to loss of keratin 10 expression regardless of mutation location, underscoring a consistent pathogenic mechanism across different truncating or frameshift variants.[13]

Thus, EHK2 arises from germline KRT10 mutations—heterozygous, typically missense or small in-frame changes exerting dominant-negative effects in autosomal dominant disease, and biallelic loss-of-function mutations in autosomal recessive disease—against a background of normal KRT1 and KRT2 function.[11][12][13][14] Postzygotic KRT10 mutations lead to mosaic manifestations (epidermolytic nevi), which can have reproductive consequences if gonadal tissue is involved.[4][13][14] No non-genetic primary causal factors have been documented, confirming EHK2 as a purely Mendelian, monogenic disorder of structural protein function.[3][4][11][13][20]

2.2 Genetic Risk Factors and Susceptibility

Within the context of EHK2, genetic risk is essentially synonymous with carrying a pathogenic KRT10 variant, either heterozygous (dominant) or biallelic (recessive).[11][12][13][14] ClinVar reports numerous KRT10 variants interpreted as pathogenic or likely pathogenic for epidermolytic ichthyosis, including missense changes at conserved residues in the rod domain and truncating variants associated with recessive EI.[19][8][13][14] For autosomal dominant EHK2A, each child of an affected heterozygous individual has a 50% probability of inheriting the mutation and therefore the disease, assuming full penetrance.[3][4][11][13][20] De novo mutations are common; DermNet indicates spontaneous mutation occurs in approximately 50% of EI cases, and the genotype–phenotype study noted that 17 of 28 patients had de novo mutations, illustrating that parental family history may be absent despite high genetic risk to offspring once the mutation arises.[4][9][14][13]

For autosomal recessive EHK2B, consanguinity and carrier status in both parents constitute major genetic risk factors. The lethal recessive EI case report and the genotype–phenotype study both involved consanguineous families with homozygous KRT10 truncating mutations, and the authors emphasized that the existence of a recessive form increases recurrence risk from ≤1% (for new dominant mutations) to 25% in consanguineous couples carrying the same KRT10 null variant.[12][14] This has important implications for genetic counseling in communities where consanguineous marriage is common, as recessive KRT10 mutations may be enriched and carrier frequency elevated. Population-level allele frequencies for specific KRT10 variants in gnomAD or ExAC are not provided in the current search results, but given the extreme rarity of EI/EHK, pathogenic alleles are expected to be very infrequent in general populations.[13][20]

Modifier genes affecting EHK2 severity have not been definitively identified, but variation in other keratin genes (KRT1, KRT2, KRT5, KRT14) and in genes controlling epidermal differentiation, inflammation, or desquamation could plausibly modulate phenotype, as suggested by animal models where suprabasal keratin composition changes compensate for K10 loss.[15][16][13] The clinical spectrum study documented striking inter-individual variability even among patients sharing the same KRT10 mutation, indicating that epigenetic, environmental, or polygenic background effects may influence susceptibility to severe blistering, infection, or psychosocial impact.[13][14]

2.3 Environmental and Lifestyle Risk Factors

Although EHK2 is fundamentally genetic, several environmental and lifestyle factors exacerbate disease manifestations or precipitate acute complications. Clinical reviews and cohort reports consistently highlight mechanical friction, minor trauma, heat, humidity, and occlusion as triggers of blistering and erosions, particularly in infancy and early childhood when the skin is fragile.[3][4][9][13][20] DermNet describes peeling, erosions, and denuded skin occurring after minor friction or trauma in epidermolytic ichthyosis, and emphasizes that blisters and superficial ulcerations at birth can be worsened by physical stress.[4] MedlinePlus notes that newborns with EHK lack the protection of normal skin and are at risk of dehydration and infection, with sepsis being a serious risk, implying that environmental exposures such as high ambient temperature and inadequate hydration can increase morbidity.[3]

Secondary infections represent another key environmental risk factor. Thick hyperkeratotic skin in older individuals often harbors bacteria that can proliferate and cause a distinct malodor; DermNet mentions that bleach baths and antiseptic washes are used to reduce microbial colonization and prevent infections.[4][17] Recurrent bacterial skin infections can worsen erythema, pain, and systemic symptoms, and septicemia remains a life-threatening complication in severely affected neonates and infants.[3][4][13] Hygienic conditions, access to medical care, and cultural practices regarding bathing and emollient use therefore influence disease course.

Lifestyle factors such as clothing choice, occupational activities, and climate also modulate symptom burden. In hot climates, sweating and occlusion under clothing can increase maceration and blistering, whereas in cold, dry environments xerosis may aggravate fissuring and pain.[4][13][18] Patients often adopt strategies to minimize friction and heat—such as wearing soft, loose garments, avoiding vigorous physical contact sports, and living in temperature-controlled environments—to reduce disease flares.[13][17][18] No data currently implicate toxins, radiation, or specific dietary components as primary causes, but nutritional status and hydration are clearly important in managing skin barrier dysfunction and preventing complications.[4][17][18]

2.4 Protective Factors and Gene–Environment Interactions

Documented protective factors in EHK2 primarily relate to optimized skin care and avoidance of physical stress rather than intrinsic genetic protection. Systematic reviews and European guidelines on congenital ichthyoses emphasize that multidimensional therapy—including hydration, lubrication, keratolytic agents, and careful infection control—can substantially reduce symptoms and improve quality of life, thereby functioning as environmental modifiers that protect against disease exacerbation.[17][18] Long baths to hydrate and soften hyperkeratotic skin, lubrication with oils and ointments, humidification of indoor environments, and routine antiseptic measures (e.g., bleach baths) are described as critical interventions that limit skin damage and infection in ichthyoses, including epidermolytic ichthyosis.[4][17][18]

At the genetic level, complete absence of K10 appears, paradoxically, to confer relative protection against the severe dominant phenotype, as demonstrated in K10-null mice that develop a structurally intact epidermis without significant fragility, in contrast to transgenic mice expressing mutant K10 that show epidermolytic hyperkeratosis and neonatal lethality.[15][16] The K10-null mouse study concluded that “the deletion of K10, which is the most abundant epidermal protein, does not lead to epidermal fragility,” suggesting that persistence of K5/K14 suprabasally and altered keratin filament composition can maintain epidermal integrity in the absence of K10.[15] In humans, recessive K10-null mutations cause a distinct EI phenotype that may be severe but mechanistically lacks dominant-negative filament disruption, illustrating a gene–environment interplay in which the cellular keratin network adapts to loss-of-function but not to misfolded, aggregation-prone proteins.[12][13][15][16]

Gene–environment interactions in EHK2 thus involve the interplay between keratin network resilience or compensatory expression and external mechanical and microbial stressors. Dominant-negative KRT10 variants predispose suprabasal keratinocytes to cytolysis under mechanical load, and environmental friction directly tests the integrity of these compromised cell layers, resulting in blistering.[4][16] Conversely, in recessive K10 loss-of-function, cellular compensatory mechanisms involving K5/K14 and K1 may be sufficient to withstand moderate stress, but extreme environmental challenges such as infection or severe dehydration can reveal vulnerability, particularly in neonates with collodion-like presentation.[12][13][15] Future multi-omics studies may uncover additional molecular protective factors, such as upregulation of stress keratins or barrier lipids, that buffer disease severity under different environmental conditions.[13][15][16]

Overall, the etiologic picture of EHK2 is dominated by KRT10 mutations, with de novo and inherited variants conferring high genetic risk, consanguinity amplifying recessive risk, and environmental factors—especially friction, heat, and infection—modulating clinical expression within the constraints imposed by the underlying keratin network pathology.[3][4][11][12][13][14][17][18][20]

3. Phenotypes

3.1 Neonatal and Early-Life Phenotypic Presentation

The neonatal phenotype of Epidermolytic Hyperkeratosis 2 is characterized by generalized skin fragility, erythema, and blistering, accompanied by erosions and superficial ulceration. MedlinePlus reports that affected babies may have very red skin (erythroderma) and severe blisters at birth, and notes that because they lack the protection provided by normal skin, they are at risk of dehydration and infections, including potentially life-threatening sepsis.[3] DermNet similarly describes that epidermolytic ichthyosis typically presents at birth with widespread erythroderma, skin fragility, blisters, and peeling or denuded skin after minor friction; the lesions are often superficial but can be extensive and painful.[4] Orphanet’s summary of autosomal dominant EI emphasizes a blistering phenotype at birth that progressively becomes hyperkeratotic over time, and the clinical spectrum study of keratinopathic ichthyoses corroborates that EI manifests with congenital blistering and erosions with variable erythroderma.[13][20]

In autosomal recessive EHK2B, neonatal presentation can be even more dramatic. The BJD report on lethal autosomal recessive EI due to a KRT10 donor splice-site mutation described a newborn with severe generalized erythroderma, erosions, and skin breakdown; the infant died early despite intensive care, underscoring the potential for neonatal lethality.[12] The genotype–phenotype study documented several recessive EI cases with collodion presentation at birth, characterized by a tight, shiny membrane encasing the neonate, which later evolves into hyperkeratotic plaques, reflecting a severe disturbance of cornification from the earliest developmental stages.[14][2][13] In clinical practice, such presentations require differential diagnosis against other congenital ichthyoses, epidermolysis bullosa, and syndromic genodermatoses, making histopathology and genetic testing crucial.[4][20]

Age of onset for EHK2 is thus neonatal, with lesions apparent at or soon after birth. Symptom severity in the first days and weeks is typically moderate to severe, depending on the specific KRT10 mutation and inheritance pattern, with recessive null variants tending toward more severe and sometimes lethal phenotypes.[12][13][14] The progression during infancy involves partial healing of erosions and diminished blistering, but persistent erythema and initiation of hyperkeratosis along flexural surfaces, neck, and other high-friction regions.[3][4][9][13] From an HPO standpoint, key neonatal phenotypes include erythroderma, skin blistering, erosions, collodion baby in recessive forms, and neonatal skin fragility—all of which significantly impair barrier function and homeostasis.[3][4][12][13][20]

3.2 Evolution to Hyperkeratosis and Later Cutaneous Manifestations

As affected individuals with EHK2 age, the phenotype undergoes a well-documented shift from fragility and blistering toward persistent hyperkeratosis. MedlinePlus notes that in subsequent months after birth, erythema and blistering improve, but patients develop hyperkeratotic thickening especially along joint flexures, on areas where skin comes into contact with itself, and on the scalp or neck.[3] DermNet describes that hyperkeratosis gradually replaces erosions, with thickened, verrucous or ridged plaques in flexural areas, often accompanied by palmoplantar keratoderma in many EI cases, though palm involvement is less common in KRT10-associated EHK2.[4][13][14] The clinical spectrum study confirms that blistering becomes less frequent later in life while hyperkeratosis increases, and that the distribution and severity of hyperkeratosis vary with genotype, including more localized or intermediate patterns.[13]

Hyperkeratotic skin in EHK2 tends to be thick, darkened, and malodorous, with a texture that may be ridged or verrucous. MedlinePlus notes that thickened skin is usually darker than normal, and bacteria can grow in the thick skin, often causing a distinct odor, contributing to social stigmatization and quality-of-life impairment.[3] DermNet lists typical features such as hyperkeratosis of flexural folds, trunk, and extremities, sometimes with spiky or hystrix-like scaling, and palmoplantar keratoderma particularly in KRT1-mutant cases.[4] In KRT10-driven EHK2, the non-palmoplantar subtype is common, but exceptions exist, and some patients show focal palmoplantar hyperkeratosis or keratotic papules on hands and feet.[3][14]

Symptom progression in EHK2 is generally chronic and lifelong, with blistering episodes becoming episodic and less frequent but hyperkeratosis persisting or worsening with age.[3][4][9][13] Severity can range from mild localized keratosis with occasional erosions to extensive, disabling hyperkeratotic plaques with recurrent infections and pain. The clinical spectrum study quantified disease burden using scoring tools and found substantial heterogeneity, with some individuals reporting moderate impact and others severe disability.[13] Quality-of-life impact is considerable: patients may require daily intensive skin care, face social isolation due to appearance and odor, experience limitations in physical activities, and suffer from chronic discomfort or pruritus.[4][13][17][18]

Suggested HPO terms for these later phenotypes include hyperkeratosis, hyperpigmented skin lesions, palmoplantar keratoderma (when present), recurrent skin infections, malodor, and pruritus, each with variable frequency among affected individuals.[3][4][9][13][20] For EHK2 specifically, non-palmoplantar generalized hyperkeratosis is a hallmark in most autosomal dominant cases, while collodion baby with subsequent hyperkeratosis without palmoplantar involvement defines autosomal recessive K10-null disease.[2][12][13][14]

3.3 Variability, Subtypes, and Mosaic Manifestations

Phenotypic expression in EHK2 is notably variable, influenced by mutation type, zygosity, mosaicism, and environmental factors. The genotype–phenotype correlation study observed a broad spectrum of manifestations and severity across patients with KRT10 mutations, ranging from superficial blistering with mild keratosis to extensive hyperkeratosis with severe blistering and erythroderma.[14] The authors identified mutational hotspots in KRT10 and found that helix boundary mutations typically produce more severe phenotypes, whereas some rod domain or tail variants lead to milder disease, reflecting differences in dominant-negative impact on filament assembly.[14][13]

Mosaic manifestations, known clinically as epidermolytic nevi, arise when postzygotic KRT10 mutations occur in keratinocyte progenitors during embryogenesis. DermNet notes that epidermolytic ichthyosis is the only keratin disease associated with genetic mosaicism, and that offspring of parents with epidermolytic epidermal nevi can develop generalized EI if gonadal tissue is involved, representing germline mosaicism.[4] The genotype–phenotype study included patients with epidermolytic nevi harboring KRT10 mutations such as p.Arg156His, who exhibited linear keratotic papules along Blaschko’s lines, reflecting somatic mosaic patterns.[14] These mosaic forms often present with localized hyperkeratotic streaks or plaques, without generalized disease, but they pose a reproductive risk when the mutation is present in germ cells, effectively making the parent a somatic–gonadal mosaic.[4][13][14]

Phenotypic expressivity in autosomal dominant EHK2A is therefore highly variable, from mild localized keratosis to severe generalized disease, while penetrance is generally complete—i.e., individuals carrying heterozygous KRT10 mutations typically show some clinical features.[4][9][13][14][20] In autosomal recessive EHK2B, expressivity includes lethal neonatal erythroderma, collodion presentation, and intermediate localized disease, but phenotype remains distinct from dominant forms because loss-of-function removes K10 without producing aberrant filaments.[12][13][14][15]

3.4 Quality of Life and Psychosocial Impact

The quality-of-life impact of EHK2 is profound and multifaceted. Orphanet and DermNet emphasize that patients who survive the neonatal period continue to experience episodes of infection, skin fragility, and blistering throughout their lives, along with psychological stress and social isolation associated with visible skin lesions and malodor.[4][13][20] The clinical spectrum and burden study explicitly aimed to quantify disease burden, demonstrating that keratinopathic ichthyoses exert significant physical, emotional, and social impacts, including limitations in mobility, daily activities, interpersonal relationships, and employment.[13]

Thick, malodorous hyperkeratotic plaques interfere with clothing, heat regulation, and body image, while chronic erosions and blistering cause pain and limit physical activity, particularly in children.[3][4][13][17][18] Recurrent infections necessitate frequent medical visits and sometimes hospitalizations, and the fear of sepsis in neonates imposes emotional strain on families.[3][12][13] Parents of affected infants must perform intensive caregiving tasks, including daily bathing, application of emollients and keratolytics, infection surveillance, and coordination of multidisciplinary care, which can be exhausting and financially burdensome.[17][18]

Validated quality-of-life instruments such as the Dermatology Life Quality Index (DLQI), SF-36, or disease-specific ichthyosis QoL scales have been applied in some cohorts, demonstrating reductions across domains of physical functioning, emotional well-being, and social participation.[13][18] HPO terms related to quality of life, such as impaired quality of life, social isolation, and chronic pain, are appropriate for annotating the broader phenotypic impact of EHK2 beyond cutaneous signs.[13][17][18]

Taken together, the phenotypic profile of Epidermolytic Hyperkeratosis 2 encompasses congenital erythroderma, blistering, erosions, and collodion presentation in some recessive cases, evolving into variable patterns of hyperkeratosis, pigmentary change, malodor, infection, and psychosocial distress, with significant impairment of daily functioning and quality of life that persists across the lifespan.[3][4][9][12][13][14][17][18][20]

4. Genetic and Molecular Information

4.1 The KRT10 Gene and Keratin 10 Protein

The KRT10 gene encodes keratin 10, a type I intermediate filament protein that pairs with keratin 1 (K1, encoded by KRT1) to form heterodimeric filaments in suprabasal layers of the epidermis.[8][4][13][14] MedlinePlus Genetics identifies KRT10 as a gene on chromosome 17, and OMIM places autosomal dominant EHK2A at 17q21.2, with KRT10 as the causative gene.[8][11] Keratin 10 is synthesized in spinous and granular layer keratinocytes and contributes to the dense network of tonofilaments that provide mechanical resilience to suprabasal cells; this network is critical for withstanding mechanical stress and maintaining epidermal integrity.[4][12][14][16]

Structurally, K10—like other type I keratins—features a central α-helical rod domain flanked by non-helical head and tail domains, with conserved helix boundary motifs at the 1A/1B and 2A/2B transitions that are crucial for filament assembly.[14][15][16] Mutations in these boundary motifs disrupt coiled-coil formation and heterodimerization with K1, leading to disorganized filaments, keratin clumping, and cell fragility.[12][14][16] The K10 protein is highly expressed, making up a substantial fraction of epidermal protein content, and its loss or dysfunction has major consequences for terminal differentiation and cornification.[15][16]

The KRT10 gene is catalogued in many genomic databases, with OMIM entry 148080 (“KERATIN 10, TYPE I; KRT10”) listing associated conditions such as epidermolytic ichthyosis and ichthyosis with confetti.[8][10][11][13][14] ClinVar contains numerous variant entries for KRT10 associated with epidermolytic ichthyosis, many classified as pathogenic or likely pathogenic based on clinical and functional evidence.[19][8][13][14] Genomic sequencing in EI cohorts typically covers exons 1–7 of KRT10, which contain most known pathogenic variants, particularly in the rod domain.[14]

From a Gene Ontology perspective, K10 participates in biological processes such as keratinization, epidermis development, and response to mechanical stimulus, and localizes to the cytoplasmic intermediate filament network (GO:0005882, intermediate filament; GO:0005829, cytosol). Keratin 10 is expressed in keratinocytes (CL:0000312), especially suprabasal epidermal keratinocytes located in skin (UBERON:0002097) and the epidermis (UBERON:0001003).[13][14][15][16]

4.2 Pathogenic Variant Classes in KRT10

Pathogenic variants in KRT10 causing EHK2 fall into two main mechanistic classes: dominant-negative missense or in-frame variants and loss-of-function (null) variants. DermNet and OMIM report that autosomal dominant EI/EHK 2A is caused by heterozygous missense mutations in KRT10, often at highly conserved residues in the helix boundary motifs.[4][11][14] The genotype–phenotype study identified multiple KRT10 missense mutations (e.g., p.Met150Thr, p.Met150Arg, p.Arg156His, p.Tyr449Cys) that affect critical sites in the rod domain and result in dominant disease.[14] These missense changes produce structurally aberrant K10 proteins that incorporate into filaments and disrupt their architecture, leading to keratin clumping and cytolysis—classic dominant-negative behavior.[12][14][16]

In contrast, autosomal recessive EI/EHK2B arises from frameshift, nonsense, or splice-site mutations that abolish K10 expression. The lethal recessive EI case report identified a homozygous G>A substitution affecting the donor splice site of intron 5 (c.1155+5G>A), predicted to impair mRNA splicing and generate a truncated or unstable transcript.[12] The genotype–phenotype study documented recessive EI cases with KRT10 truncating variants such as c.1300C>T (p.Gln434X) and c.1325insC (p.Lys439fsX6), both found in consanguineous families, and concluded that recessive EI results from loss of keratin 10 expression regardless of mutation location.[14][13]

ClinVar provides specific examples of pathogenic KRT10 variants, such as NM_000421.5(KRT10):c.376G>A (p.Gly126Ser), annotated as associated with epidermolytic ichthyosis and epidemic hyperkeratosis.[19] Many ClinVar variants are classified according to ACMG/AMP criteria as pathogenic or likely pathogenic, based on segregation, de novo occurrence, functional data, and consistency with known mutational hotspots.[19][13][14] Variant types include missense, nonsense, frameshift, splice-site, and occasionally small in-frame insertions or deletions, with most autosomal dominant disease arising from missense alterations in helix boundaries and most recessive disease arising from truncating or splice-disrupting changes that lead to nonsense-mediated decay or non-functional protein.[12][14][15][16]

Allele frequencies of these pathogenic variants in population databases such as gnomAD are not detailed in the current search results, but given their severe phenotypic consequences and early detection, they are expected to be extremely rare (minor allele frequencies far below 0.001).[13][20] The distinction between germline and somatic (postzygotic) origin is crucial in mosaic EHK2; epidermolytic nevi result from somatic mutations in KRT10 confined to skin segments, while generalized EI/EHK arises from germline mutations present in all cells.[4][13][14]

4.3 Functional Consequences: Dominant-Negative vs Loss-of-Function

Functional studies in animal models and human tissues demonstrate that dominant-negative K10 mutations and loss-of-function K10 mutations have markedly different biological consequences. In transgenic mice expressing a mutant keratin 10 gene, researchers observed an epidermolytic hyperkeratosis phenotype, including cytolysis of suprabasal keratinocytes, induction of hyperproliferative keratins, and perinatal lethality, suggesting that a defect in suprabasal cells can stimulate basal cell proliferation and that intermediate filament perturbation has profound effects on nuclear morphology and cytokinesis.[16] The authors concluded that transgenic mice expressing mutant K10 recapitulate the human EH phenotype and strongly implicate KRT10 and KRT1 mutations as the likely genetic basis of epidermolytic hyperkeratosis.[16]

In contrast, K10-null mice engineered to completely lack keratin 10 expression formed a normal stratified epidermis without signs of fragility or wound-healing response; suprabasal keratin filaments were composed of K5/K14 that persisted suprabasally at elevated protein levels despite mRNAs remaining restricted to basal keratinocytes, indicating a novel mechanism regulating keratin turnover and filament composition.[15] The authors noted that the amount of K1 was reduced and a small amount of novel K1/14/15 filaments formed, but epidermal integrity was maintained and cytolysis absent, leading to the conclusion that filaments with K1/K10 are not essential for suprabasal integrity in mice and that deletion of K10 does not induce epidermal fragility or up-regulation of hyperproliferative keratins K6 and K17.[15]

These findings align with human clinical observations. Dominant missense KRT10 mutations cause EI/EHK2 by producing mutant K10 that destabilizes the K1/K10 filament network, leading to keratin clumps, perinuclear aggregates, and cell lysis in suprabasal layers—classic dominant-negative behavior.[4][5][12][14][16] Recessive KRT10 mutations, in contrast, abolish K10 expression and allow compensatory expression of other keratins, producing a distinct phenotype with collodion presentation and later hyperkeratosis but without the same degree of cytolysis, at least in mice; human recessive EI can be severe due to additional factors such as inflammatory responses or impaired cornification pathways.[12][13][15]

Quoting the K10-null mouse study:

“In conclusion, we have demonstrated that the deletion of K10, which is the
most abundant epidermal protein, does not lead to epidermal fragility or to the
up-regulation of the hyperproliferative keratins 6 and 17.”[15]

and the transgenic mutant K10 study:

“We have discovered that transgenic mice expressing a mutant keratin 10 gene
have the EH phenotype, thereby suggesting that a genetic basis for human EH
resides in mutations in genes encoding suprabasal keratins K1 and K10.”[16]

These experimental observations provide strong functional evidence that the pathogenic mechanism in autosomal dominant EHK2A is dominant-negative disruption of K1/K10 filaments, whereas autosomal recessive EHK2B arises from loss-of-function and altered compensatory keratin expression, explaining differences in phenotype, inheritance, and severity.[12][13][14][15][16]

4.4 Modifier Genes, Epigenetics, and Chromosomal Abnormalities

To date, no specific modifier genes have been conclusively shown to alter EHK2 severity, although the diversity of clinical manifestations among individuals with identical KRT10 mutations suggests the presence of genetic or epigenetic modifiers.[13][14] Potential candidates include other keratin genes (KRT1, KRT2, KRT5, KRT14) and genes involved in desmosomal adhesion, cornified envelope formation, or lipid barrier synthesis, but direct evidence remains lacking in the current literature.[13][15][16] Epigenetic regulation of keratin gene expression, such as DNA methylation or histone modifications affecting KRT10 transcription, may also influence disease expression, particularly in mosaic forms, but specific epigenetic patterns have not been described in EI/EHK2 studies.[13]

No large-scale chromosomal abnormalities (aneuploidy, translocations, inversions) have been linked to EHK2; disease arises from point mutations or small indels in KRT10 within otherwise normal karyotypes.[11][14][19] Cytogenetic locations are well defined (17q21.2 for KRT10), and there is no evidence of structural genomic rearrangements contributing to this condition.[10][11][13]

Thus, genetic and molecular information in EHK2 centers on KRT10 variants and their dominant-negative or loss-of-function effects, with potential but as yet undefined contributions from modifier genes and epigenetic regulation that may shape the spectrum of keratin expression and filament architecture in affected skin.[12][13][14][15][16][19]

5. Environmental Information

5.1 Non-Genetic Factors Influencing Disease Expression

EHK2 itself is not caused by environmental insults, but non-genetic factors substantially modulate symptom severity and complication risk. Clinical reviews and guidelines highlight that environmental humidity, temperature, clothing, and mechanical trauma influence skin fragility and blistering episodes.[4][13][17][18] High temperatures and humidity can promote sweating, maceration, and bacterial growth, exacerbating erosions and infections, while low humidity and cold climates may worsen xerosis and fissuring, leading to pain and impaired mobility.[4][13][18]

Mechanical trauma, including rubbing, scratching, and pressure from clothing or shoes, is particularly important in early life, as suprabasal keratinocytes in EHK2 are prone to cytolysis under mechanical load due to compromised filament networks.[4][16] Caregivers are advised to minimize friction through soft clothing, careful handling, and avoidance of adhesive dressings that might tear fragile skin.[17][18] In older children and adults, physical activities that involve repetitive friction or trauma, such as contact sports or manual labor, may precipitate erosions and require adaptation of lifestyle and occupational choices.[13][17][18]

5.2 Infectious and Microbial Influences

Infections, particularly bacterial skin infections, represent a key environmental factor in EHK2. MedlinePlus notes that bacteria can grow in thickened hyperkeratotic skin, often causing a distinct odor, and DermNet recommends antiseptic measures such as chlorhexidine washes and sodium hypochlorite (bleach) baths to reduce microbial load and prevent infection.[3][4] The systemic retinoids review and European guidelines emphasize that infection control is central to managing ichthyoses, including prophylactic or therapeutic use of topical and systemic antibiotics when necessary, and that unchecked infection can evolve into sepsis, especially in neonates with extensive erosions.[17][18]

The skin microbiome in EHK2 has not been extensively profiled, but the presence of thick plaques, impaired barrier function, and recurrent erosions likely alters microbial composition and may predispose to colonization by Staphylococcus aureus and other opportunistic pathogens.[4][13][17] In neonates, hospital-acquired infections may occur if barrier care is inadequate, and management in specialized neonatal intensive care settings with infection control protocols can substantially influence survival.[12][18]

5.3 Lifestyle, Nutrition, and Care Environment

Lifestyle factors such as bathing practices, emollient use, and ambient humidity strongly affect EHK2 manifestation and long-term outcomes. The systemic retinoids review notes that therapy for ichthyoses is usually multidimensional, including humidification with long baths, scale removal by gentle abrasives, lubrication with oils and creams applied to wet skin, and environmental humidification.[17] European guidelines stress the importance of structured topical therapy plans and caregiver education in congenital ichthyoses, advocating for regular follow-up and adjustment of regimens as patients age.[18] These practices directly modulate disease expression, reducing fissuring, pain, and infection risk, and thus can be considered environmental protective factors.

Nutrition and hydration also play roles. Adequate hydration is crucial in neonates with extensive skin loss to prevent dehydration and electrolyte imbalance, and energy requirements may be increased in severe EI due to hypermetabolism associated with chronic skin inflammation and repair.[3][12][17][18] Malnutrition or failure to thrive can exacerbate overall morbidity and should be addressed in multidisciplinary care frameworks. No specific dietary components are known to alter keratin expression or disease severity, but general nutritional support remains fundamental to resilience against infection and wound healing.[17][18]

In summary, environmental influences in EHK2 revolve around mechanical, thermal, microbial, and care-related factors that do not cause the disease but substantially shape its clinical trajectory, highlighting the necessity of comprehensive supportive environments to minimize disease burden.[3][4][13][17][18]

6. Mechanism / Pathophysiology

6.1 Ordered Causal Chain from Mutation to Clinical Manifestation

The mechanistic sequence leading from KRT10 mutation to EHK2 clinical features can be summarized as follows within a single causal chain. First, pathogenic germline or postzygotic variants in KRT10 arise, either heterozygous dominant-negative missense mutations or biallelic loss-of-function changes in the gene encoding keratin 10, which alters keratin 10 protein structure or expression and thereby perturbs the formation of K1/K10 heterodimers in suprabasal keratinocytes.[11][12][13][14][15][16] Second, the resulting defective or absent K1/K10 complexes lead to disorganized intermediate filament networks, keratin clumping, and impaired cytoskeletal integrity in suprabasal cells, which in turn causes mechanical fragility and cytolysis under physiological stress, as demonstrated in human histopathology and transgenic mouse models; this step is directly observed in electron microscopy and inferred from filament assembly studies.[4][5][12][15][16] Third, the cytolysis of suprabasal keratinocytes results in epidermolytic changes characterized by vacuolization, perinuclear keratin aggregates, and breakdown of the spinous and granular layers, leading to clinical blistering, erosions, and erythema, particularly in neonates exposed to mechanical friction; this process is well documented histologically and clinically.[4][5][12][13][20] Fourth, the epidermal damage and barrier disruption elicit inflammatory and wound-healing responses, including induction of hyperproliferative keratins (such as K6 and K16), altered differentiation programs, and increased keratinocyte turnover, which over time produces thickened hyperkeratotic stratum corneum and scaling, as inferred from gene expression studies and animal models.[15][16][13] Fifth, chronic hyperkeratosis, coupled with persistent barrier defects and recurrent microtrauma, fosters microbial colonization, particularly by bacteria, resulting in malodor, recurrent infections, and risk of systemic sepsis, especially in early life, which contributes to morbidity and sometimes mortality.[3][4][13][17] Finally, these cumulative cutaneous changes and complications interfere with thermoregulation, hydration, mobility, and social functioning, causing chronic pain, psychosocial distress, and reduced quality of life, as demonstrated in clinical burden studies and patient-reported outcomes.[13][17][18]

This causal chain underscores that mutations in KRT10 are upstream events that initiate a cascade of molecular, cellular, tissue, and systemic processes culminating in the characteristic clinical manifestations of Epidermolytic Hyperkeratosis 2.[11][12][13][14][15][16]

6.2 Keratin Intermediate Filament Biology and Molecular Pathways

At the molecular level, EHK2 pathophysiology centers on disruption of the epidermal intermediate filament network. Keratins are the major structural proteins of epithelial cells, assembling into obligate heterodimers of type I and type II keratins that polymerize into filaments providing mechanical resilience.[4][12][14][15][16] In suprabasal epidermis, K1 (type II) and K10 (type I) form the principal heterodimer, replacing basal K5/K14 as keratinocytes differentiate and migrate outward.[4][14][15][16] Mutations in KRT10, particularly in conserved helix boundary motifs of the rod domain, alter the ability of K10 to form proper coiled-coil structures with K1 and thereby impair filament assembly.[12][14][16]

DermNet notes that mutations in KRT1 and KRT10 lead to “variable disruption and decreased stability of the K1/K10 tonofilaments and hyperkeratosis due to lack of desquamation,” emphasizing that impaired filament stability both compromises mechanical function and alters terminal differentiation.[4] In autosomal dominant EHK2A, mutant K10 incorporates into filaments, leading to misaligned, clumped, or fragmented filaments and creating large perinuclear aggregates observed in electron microscopy.[4][5][12][15][16] This disorganization affects cytoskeletal linkage to desmosomes and other cell–cell junctions, weakening tissue cohesion and making suprabasal layers prone to mechanical failure.

Molecular pathways downstream of filament disruption include activation of stress and differentiation pathways. Transgenic mice expressing mutant K10 show induction of hyperproliferative keratins (e.g., K6/16), increased basal cell proliferation, and evidence of aberrant cytokinesis and nuclear shape distortion, indicating that intermediate filament perturbation can signal to cell cycle machinery and nuclear architecture.[16] These changes likely involve pathways such as MAPK and NF-κB, which respond to mechanical and inflammatory stress, though direct mapping in EI is not yet fully elaborated. The K10-null mouse study revealed compensatory persistence of K5/K14 in suprabasal layers at elevated protein levels, suggesting upregulation of basal keratin expression or altered protein turnover to restore filament networks in the absence of K10.[15]

From a Gene Ontology perspective, the key biological processes implicated include epidermis development, keratinization, cornification, response to mechanical stimulus, cell adhesion, and regulation of cell proliferation.[13][14][15][16] At the signaling pathway level (KEGG, Reactome), intermediate filament perturbations may intersect with pathways regulating cytoskeletal dynamics, cell junctions, and inflammatory responses, though specific pathway mapping (e.g., Wnt, MAPK, PI3K-AKT) in EHK2 remains an area for future research.[13][15][16]

6.3 Cellular Processes: Cytolysis, Differentiation, and Inflammation

At the cellular level, EHK2 is characterized by cytolysis of suprabasal keratinocytes, altered differentiation, and chronic mild inflammation. Histopathology of epidermolytic hyperkeratosis shows hyperkeratosis with orthokeratosis, hypergranulosis, and cytolysis in the upper stratum spinosum and granular layers, with characteristic intracellular vacuolization and perinuclear keratin clumps.[5][20][13] Electron microscopy reveals suprabasal keratinocytes filled with coarse keratin filament aggregates and vacuoles, and perinuclear clumps in the upper epidermis.[5][20][13] These findings indicate that the intermediate filament cytoskeleton is severely disrupted, leading to structural failure and cell death.

Cytolysis can occur through mechanical rupture when weakened cells are subjected to friction or shear forces, or through apoptosis triggered by cytoskeletal damage and stress signaling. Transgenic mutant K10 mice show strong induction of wound-healing responses and hyperproliferative keratins, implying that epidermal damage stimulates basal cell proliferation and possibly inflammatory cytokine release.[16] Hypergranulosis and thickened stratum corneum in human EI/EHK reflect altered differentiation programs, with keratinocytes undergoing abnormal cornification and retention in the cornified layer, contributing to hyperkeratosis and scaling.[4][5][13]

Inflammation in EHK2 is generally mild to moderate but can be exacerbated by infections and erosions. Erythema in neonates and older individuals likely reflects vascular and immunologic responses to barrier disruption and microbial stimuli, involving cytokines such as IL-1, TNF-α, and chemokines that recruit immune cells to damaged skin.[3][4][13] Although EI/EHK is not primarily an inflammatory dermatosis like psoriasis or atopic dermatitis, chronic barrier defects and mechanical injury may induce a low-grade inflammatory milieu that influences itch, pain, and secondary tissue remodeling.[13][17][18]

Cell types involved include suprabasal epidermal keratinocytes (CL:0000312) as primary cells affected by K10 dysfunction, basal keratinocytes that proliferate in response to suprabasal damage, immune cells such as neutrophils and macrophages that respond to infection and tissue injury, and fibroblasts that support dermal repair.[13][15][16] Desmosomes and cornified envelope proteins (e.g., involucrin, loricrin) may be secondarily affected by filament disruption, altering cell–cell adhesion and barrier function.[4][13]

6.4 Tissue-Level Pathology and Barrier Dysfunction

At the tissue level, EHK2 produces a distinctive pattern of epidermal pathology termed epidermolytic hyperkeratosis, captured in the name of the condition. DermNet’s pathology description notes that epidermolytic hyperkeratosis is characterized by marked hyperkeratosis in the stratum corneum, hypergranulosis, and vacuolization with clumped keratin filaments in the upper spinous and granular layers.[5] Orphanet reports that histological examination in EI shows hyperkeratosis with orthokeratosis, hypergranulosis, and cytolysis in the upper layers, and electron microscopy reveals perinuclear keratin clumps.[20]

These tissue-level changes translate to barrier dysfunction. Although the stratum corneum is thickened, its structural organization is abnormal, with disrupted lipid lamellae and corneocyte cohesion, resulting in increased transepidermal water loss and vulnerability to trauma and infection.[3][4][13][17] Neonates with EI/EHK lack effective barrier function, leading to rapid dehydration and high risk of electrolyte derangement; management centers on hydration, lubrication, and careful monitoring.[3][4][17][18] As hyperkeratosis develops, barrier function improves somewhat, but fissures and erosions remain, and the thick superficial layers impede normal desquamation and can trap heat and microbes.[4][13]

Tissue damage mechanisms in EHK2 encompass mechanical stress leading to cytolysis, microbial invasion through erosions, and chronic frictional trauma in flexural sites and areas of skin-to-skin contact. DermNet notes that minor friction can cause peeling, erosions, and denuded skin, and emphasizes that palmoplantar keratoderma may develop, particularly in KRT1-mutant disease, but is less typical in pure KRT10 EHK2.[4] The clinical spectrum study documented localized and generalized patterns of hyperkeratosis, with flexural, truncal, and extremity involvement variably affecting function and comfort.[13]

Suggested UBERON terms for anatomical localization include skin (UBERON:0002097), epidermis (UBERON:0001003), palm of hand (UBERON:0001510), sole of foot (UBERON:0001509), and scalp skin (UBERON:0001511), reflecting common sites of involvement.[4][13][20] Tissue-level pathology in EHK2 is thus characterized by epidermolytic changes in suprabasal layers, hyperkeratosis, hypergranulosis, and barrier impairment that collectively underpin the clinical picture of fragility, blistering, and thickened plaques.[4][5][13][20]

6.5 Biochemical Abnormalities and Metabolic Changes

Biochemical abnormalities in EHK2 are largely structural and protein-based rather than enzymatic or metabolic per se. K10 mutations disrupt protein folding and assembly into intermediate filaments, leading to protein aggregation and altered proteostasis.[4][12][14][15][16] These aggregates may be poorly degraded by proteasomes or autophagy pathways, contributing to cytosolic stress and potential activation of unfolded protein response mechanisms, although specific evidence for UPR activation in EI is limited.[13][15][16]

Keratins themselves are not enzymes, but their misfolding may alter cellular metabolism indirectly, for example by changing cytoskeletal organization and intracellular trafficking, or by promoting inflammatory signaling that affects energy metabolism in skin.[13][16] The thickened stratum corneum may have altered lipid composition and desquamation dynamics, with accumulation of corneocyte aggregates and retained corneodesmosomes, but detailed lipidomics or metabolomics signatures for EHK2 have not been reported.[4][13]

No clear epigenetic changes have been documented specifically in EHK2, but given the regulatory complexity of keratin gene expression, DNA methylation and histone modifications likely play roles in tissue-specific expression patterns and compensatory responses to K10 loss, especially in recessive disease where K5/K14 persist suprabasally.[15][16][13] Future multi-omics integration, including transcriptomics and proteomics of EI skin, may elucidate gene expression changes beyond keratins—for example, upregulation of stress-response genes, cytokines, and cornified envelope proteins—that contribute to disease mechanisms.[13]

6.6 Immune System Involvement and Inflammatory Mechanisms

The immune system plays a secondary but important role in EHK2, primarily through responses to barrier disruption and microbial invasion. Erythema and erosions in neonates and older patients reflect vasodilation and infiltration of inflammatory cells such as neutrophils, macrophages, and lymphocytes into damaged skin.[3][4][13] Infections superimposed on erosions can trigger robust inflammatory responses, leading to pain, swelling, and systemic symptoms, and sepsis in severe cases.[3][12][17][18]

While EHK2 is not classically considered an autoimmune or primary inflammatory dermatosis, chronic low-grade inflammation is a feature of hyperkeratotic skin exposed to constant microtrauma and colonized by bacteria. This inflammatory milieu can influence keratinocyte proliferation and differentiation, potentially exacerbating hyperkeratosis and pruritus.[13][17][18] Cytokines such as IL-1β, TNF-α, and IL-6, as well as chemokines, are likely involved in these responses, though specific profiling in EI/EHK has not yet been extensively published.[13]

Immune cells thus act downstream of keratin defects, responding to tissue damage rather than initiating disease. CL ontology terms for relevant cell types include keratinocyte (CL:0000312), neutrophil (CL:0000775), macrophage (CL:0000235), and T cell (CL:0000084), which may be recruited to EHK lesions.[13][17][18] Immune-mediated treatments such as systemic immunosuppressants are not standard in EHK2; instead, infection control and barrier repair remain the primary methods of modulating inflammation.[4][17][18]

6.7 Advanced Molecular Profiling and Future Mechanistic Insights

Advanced technologies such as transcriptomics, proteomics, and single-cell analysis have only begun to be applied to keratinopathic ichthyoses but hold promise for deeper mechanistic understanding. The recent clinical spectrum study of EI hints at broader gene expression changes and burden but does not yet detail multi-omics data.[13] Single-cell RNA sequencing of lesional and non-lesional skin could reveal cell-type-specific alterations in keratinocyte states, immune infiltration, and barrier gene expression, while spatial transcriptomics could map the topography of mutant versus wild-type keratin expression in mosaic cases.[13][15][16]

Functional genomics screens using CRISPR or RNAi in cultured keratinocytes could identify modifier genes whose knockdown or overexpression alters the impact of mutant K10 on filament assembly, pointing to potential therapeutic targets.[13][15][16] Proteomics studies may detect changes in desmosomal proteins, cornified envelope components, and stress-response proteins, while lipidomics could characterize alterations in epidermal lipid barrier composition in EI/EHK.[4][13]

In summary, the mechanistic pathophysiology of Epidermolytic Hyperkeratosis 2 involves KRT10 mutations disrupting K1/K10 filament assembly, leading to suprabasal cytolysis, epidermolytic histopathology, barrier dysfunction, hyperkeratosis, infection susceptibility, and inflammatory responses that collectively give rise to the clinical phenotype, with dominant-negative and loss-of-function variants producing distinct but overlapping mechanistic cascades.[4][5][11][12][13][14][15][16][17][20]

7. Anatomical Structures Affected

7.1 Organ-Level Involvement

EHK2 predominantly affects the skin, particularly the epidermis, across the entire body. DermNet and Orphanet note that epidermolytic ichthyosis presents with generalized erythroderma and blistering at birth, implying widespread cutaneous involvement.[4][13][20] Hyperkeratosis later in life typically affects the trunk, flexural regions, extremities, and in some cases palms and soles, with variability depending on genotype and subtype.[3][4][13][14] There is no direct involvement of internal organs such as heart, lungs, liver, or nervous system; however, systemic complications like dehydration, electrolyte imbalance, and sepsis can indirectly affect multiple organ systems.[3][12][18]

From an anatomical ontology perspective, primary organ-level terms include skin (UBERON:0002097), integumentary system (UBERON:0002330), and epidermis (UBERON:0001003).[4][13][20] Secondary involvement arises in the immune system (UBERON:0002405) due to infection and inflammation, and circulatory system (UBERON:0007798) when sepsis occurs, but these are downstream consequences rather than direct targets of KRT10 mutations.[3][12][17][18]

7.2 Tissue and Cell-Level Involvement

At the tissue level, EHK2 primarily affects the stratum spinosum and stratum granulosum of the epidermis, where suprabasal keratinocytes express K1 and K10 and form the main intermediate filament network.[4][5][13][14][15][16] Histopathology in EHK shows cytolysis and vacuolization in these layers, with hypergranulosis and hyperkeratosis in the stratum corneum.[5][20][13] The dermis is relatively spared, though chronic inflammation may induce some dermal changes such as fibrosis or vascular dilation.

Cell populations targeted include suprabasal keratinocytes, which express K10 and are directly affected by its mutation or absence, and basal keratinocytes, which respond to suprabasal damage by proliferating and sometimes expressing stress keratins.[4][13][15][16] The CL ontology term *epid

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 2
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 21
Resolved 15
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 6
Terms whose name was checked 12
Terms named correctly 4
Terms named as a different term 2
Terms whose name is worth a second look 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • UBERON:0001510 (1 mention) - the report calls it "palm of hand"; UBERON calls it skin of knee
  • UBERON:0001509 (1 mention) - the report calls it "sole of foot"; UBERON calls it triceps brachii

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • CL:0000312 (3 mentions) - the report calls it "suprabasal epidermal keratinocytes", "keratinocyte"; CL calls it keratinocyte
  • UBERON:0002097 (3 mentions) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other names
  • UBERON:0001003 (3 mentions) - the report calls it "epidermis"; UBERON calls it skin epidermis, and lists "epidermis" among its other names
  • UBERON:0001511 (1 mention) - the report calls it "scalp skin"; UBERON calls it skin of leg, and lists "leg skin" among its other names
  • UBERON:0002330 (1 mention) - the report calls it "integumentary system"; UBERON calls it exocrine system, and lists "exocrine glandular system" among its other names
  • UBERON:0007798 (1 mention) - the report calls it "circulatory system"; UBERON calls it vascular system

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • CL:0000312 - called "suprabasal epidermal keratinocytes", "keratinocyte"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Orphanet, OMIM, CT.