KLICK Syndrome

Mendelian MONDO:0011169 Pathograph 18 Show in embeddings browser Hereditary Palmoplantar Keratoderma Inherited Ichthyosis

KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma) is a rare autosomal recessive keratinization disorder. It combines congenital ichthyosiform scaling, sclerosing palmoplantar keratoderma with constricting digital bands, and keratotic papules arranged in linear, cord-like bands in the flexures, especially the arm folds and wrists. Every genetically studied patient has been homozygous for the same single nucleotide deletion in the 5' untranslated region of POMP, which encodes the proteasome maturation chaperone. The deletion shifts POMP transcription toward long 5' UTR isoforms and reduces effective POMP in differentiating keratinocytes, producing proteasome insufficiency, endoplasmic reticulum stress and defective profilaggrin processing in the upper epidermis. Disease is confined to the skin; whether mild dermal inflammation reflects an autoinflammatory component is debated.

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1
Inheritance
8
Pathophys.
1
Histopath.
7
Phenotypes
1
Hypotheses
1
Gaps
18
Pathograph
1
Genes
1
Variants
1
Medical Actions
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals are homozygous for the POMP c.-95delC deletion; the first family was consanguineous and the later single case had no prior family history.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20226437 SUPPORT Human Clinical
"KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling."
States the recessive inheritance in the gene-identification study.
PMID:2521286 SUPPORT Human Clinical
"Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
Affected relatives in a consanguineous family, consistent with recessive transmission.
◈

Mechanistic Hypotheses

1
ER stress-driven autoinflammation in KLICK skin
klick_er_stress_autoinflammation EMERGING
Evidence balance 1 support
Chronic ER stress in POMP-deficient keratinocytes may activate innate immunity and drive dermal inflammation, placing KLICK among autoinflammatory keratinization diseases. Contested: no inflammatory pathway has been measured in patients.
Pathograph links
Keratinocyte ER Stress and Unfolded Protein Response -> ER Stress-Driven Cutaneous Autoinflammation INDIRECT UNKNOWN INTERMEDIATES Hypothesized link from keratinocyte ER stress to cutaneous autoinflammation; not tested in KLICK.
Show evidence (1 reference)
PMID:32425927 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome."
States the autoinflammation hypothesis.
?

Discussions and Knowledge Gaps

1
Does chronic keratinocyte ER stress in KLICK drive innate-immune or type 1 interferon activation, or is the mild dermal infiltrate a nonspecific consequence of hyperkeratosis?
KNOWLEDGE GAP OPEN gap_klick_autoinflammation
Attached to
pathophysiology#ER Stress-Driven Cutaneous Autoinflammation
One review proposes KLICK as an autoinflammatory keratinization disease, while the PRAAS2 gene-discovery paper describes KLICK as non-inflammatory. No inflammatory pathway has been measured in KLICK patient skin, and the answer determines whether anti-inflammatory therapy is a rational option.
⚙

Pathophysiology

8
Homozygous POMP 5' UTR Deletion
Mechanism confidence: Established
The initiating lesion is homozygosity for a single-nucleotide deletion at c.-95 in the 5' untranslated region of POMP. It lies in the long 5' UTR used by a subset of POMP transcript variants and does not alter the coding sequence.
POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee. Variant type: deletion allele_type: single-nucleotide deletion in the 5' untranslated region variant_origin: GERMLINE zygosity: HOMOZYGOUS
Downstream
POMP Transcriptional Switch to Long 5' UTR Variants
Show evidence (1 reference)
PMID:20226437 SUPPORT Human Clinical
"Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands."
Homozygous c.-95 deletion found in all eight European probands.
POMP Transcriptional Switch to Long 5' UTR Variants
Mechanism confidence: Provisional
Keratinocytes from patients show a marked increase in POMP transcripts with long 5' UTRs. How this switch lowers the amount of functional POMP in differentiating epidermis has not been characterized at the level of translation or protein stability.
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.
POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced POMP in Differentiating Keratinocytes The step from altered transcript isoforms to reduced POMP is inferred from patient immunostaining and from knockdown experiments that reproduce the patient pattern; the molecular intermediate is not shown.
Show evidence (1 reference)
PMID:20226437 SUPPORT Human Clinical
"The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients."
Direct measurement in patient keratinocytes.
Reduced POMP in Differentiating Keratinocytes
Mechanism confidence: Provisional
Patient epidermis shows altered POMP distribution. Silencing POMP in organotypic human epidermis by about half reproduced the patient staining pattern for POMP, proteasome subunits and filaggrin, supporting reduced POMP as the causal intermediate. POMP acts as a proteasome assembly chaperone by binding proteasome precursor subunits; GO has no molecular-function term for assembly-chaperone activity, so the binding activity is recorded with the general protein binding term, which is POMP's experimentally supported GO function.
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.
POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee.
proteasome precursor subunit binding (assembly chaperone) GO:0005515 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased proteasome precursor subunit binding (assembly chaperone), annotated with protein binding (GO:0005515). GO:0005515 is a molecular function from the Gene Ontology.
epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epidermis, annotated with skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Epidermal Proteasome Insufficiency
Show evidence (2 references)
PMID:20226437 SUPPORT Human Clinical
"Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP."
Patient skin biopsies show altered POMP distribution.
PMID:22235297 SUPPORT In Vitro
"Immunohistochemical analysis of the tissue constructs revealed aberrant staining of POMP, proteasome subunits and the skin differentiation marker filaggrin when compared to control tissue constructs."
Knockdown in organotypic epidermis reproduces the patient staining pattern.
Epidermal Proteasome Insufficiency
Mechanism confidence: Provisional
POMP is the chaperone for proteasome assembly. Reducing it lowers the amount of the alpha 7 and beta 5 proteasome subunits, with compensatory up-regulation of their transcripts; the same subunits are weakly or patchily stained in KLICK epidermis.
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.
POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee.
proteasome assembly GO:0043248 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome assembly (GO:0043248). GO:0043248 is a biological process from the Gene Ontology.
proteasome complex GO:0000502 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves proteasome complex (GO:0000502). GO:0000502 is a cellular component from the Gene Ontology.
Downstream
Keratinocyte ER Stress and Unfolded Protein Response
Defective Profilaggrin Processing
Show evidence (2 references)
PMID:22235297 SUPPORT In Vitro
"Knock-down of POMP expression in regular cell cultures resulted in decreased amounts of proteasome subunits."
Direct cell-culture result linking POMP loss to reduced proteasome subunits.
PMID:22235297 SUPPORT In Vitro
"The effect of POMP knock-down on proteasome subunits explains the weaker expression of α7 and β5 in KLICK epidermis."
Connects the cell-culture effect to the patient biopsy finding.
Keratinocyte ER Stress and Unfolded Protein Response
Mechanism confidence: Provisional
CHOP staining is increased in the differentiated layers of patient epidermis, and prolonged POMP silencing induces CHOP in HeLa and HaCaT cells, with a slight BiP increase in HaCaT keratinocytes only. ER stress is proposed as the route by which proteasome insufficiency disturbs terminal differentiation; its exact contribution relative to the profilaggrin defect is not resolved.
ER stress-driven autoinflammation in KLICK skin
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.
endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology.
Downstream
Perturbed Terminal Epidermal Differentiation
ER Stress-Driven Cutaneous Autoinflammation Hypothesized link from keratinocyte ER stress to cutaneous autoinflammation; not tested in KLICK. ER stress-driven autoinflammation in KLICK skin
Show evidence (2 references)
PMID:22235297 SUPPORT BACKGROUND Human Clinical
"Furthermore, differentiated epidermal layers of patient skin biopsies show increased staining of the unfolded protein response (UPR) protein CHOP, suggesting that ER stress is a pathophysiological mechanism in KLICK [4]."
Restates the earlier patient-biopsy CHOP finding from the gene-identification study.
PMID:22235297 SUPPORT In Vitro
"Furthermore, POMP knock-down caused a slight increase in the ER chaperone BiP in keratinocyte derived HaCaT cells, but not in HeLa cells, supporting tissue specific sensitivity to ER stress, as suggested previously [18]."
Keratinocyte-specific ER stress response to POMP loss.
Defective Profilaggrin Processing
Mechanism confidence: Provisional
KLICK epidermis shows patchy staining of the cornified layer with retained profilaggrin granules in the outermost cells. POMP-silenced tissue constructs show the same retention and altered profilaggrin cleavage products. The large keratohyaline granules seen by electron microscopy in the 1997 case fit this defect.
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.
epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epidermis, annotated with skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Perturbed Terminal Epidermal Differentiation
Show evidence (2 references)
PMID:22235297 SUPPORT In Vitro
"Similar to what was observed in skin from KLICK patients the POMP siRNA treated tissue constructs also showed a retention of profilaggrin granules in the cornified cell layer"
Organotypic knockdown reproduces the patient profilaggrin retention.
PMID:9188877 SUPPORT INDIRECT Human Clinical
"Electron microscopy disclosed numerous large keratohyaline granules in superficial keratinocytes."
Ultrastructural keratohyaline abnormality in patient skin, consistent with disturbed profilaggrin handling.
Perturbed Terminal Epidermal Differentiation
Mechanism confidence: Provisional
The outermost epidermal layers form abnormally, giving marked acanthosis, hypergranulosis and hyperkeratosis on biopsy. This is the shared tissue-level basis of the scaling, keratoderma and linear keratoses. Why lesions concentrate in palms, soles and flexures is not explained.
keratinocyte differentiation GO:0030216 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratinocyte differentiation (GO:0030216). GO:0030216 is a biological process from the Gene Ontology.
epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epidermis, annotated with skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ichthyosis
Sclerosing palmoplantar keratoderma
Linear keratotic flexural papules
Hyperkeratosis
Hypergranulosis
Epidermal acanthosis
Show evidence (1 reference)
PMID:20226437 SUPPORT INDIRECT Human Clinical
"These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis."
Gene-identification study links the POMP defect to terminal epidermal differentiation.
ER Stress-Driven Cutaneous Autoinflammation
Mechanism confidence: Hypothetical
Proposed: chronic keratinocyte ER stress triggers innate-immune or type 1 interferon activation, which would make KLICK an autoinflammatory keratinization disease and explain the mild upper dermal infiltrate seen on biopsy. No inflammatory pathway has been measured in KLICK patients, and the PRAAS2 discovery paper describes KLICK as non-inflammatory. The observed infiltrate itself is recorded under histopathology.
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:32425927 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"As we have cited that prolonged ER stress is known to induce inflammation in numerous chronic inflammatory skin diseases (23), the inflammation seen in KLICK syndrome could be considered to result from continuous abnormal ER stress in keratinocytes."
Hypothesis that keratinocyte ER stress drives the dermal inflammation.
PMID:32425927 REFUTE REVIEW SYNTHESIS Other
"Although there are no reports of hyperactivation of innate immunity or of the induction of a type 1 interferon response in KLICK patients, the chronic ER stress present in the epidermis of KLICK patients may eventually trigger autoinflammation (16)."
The same review states that innate-immune or interferon activation has not been shown in patients.
PMID:29805043 REFUTE BACKGROUND Other
"AR deletions in the 5′ UTR of an alternative POMP transcript give rise to a longer-lived transcript that leads to a keratinization disorder of the skin ... with no inflammatory component."
The PRAAS2 gene-discovery paper characterizes KLICK as non-inflammatory.
✶

Histopathology

1
Mild upper dermal inflammatory infiltrate
Mild, sparse nonspecific or lymphohistiocytic inflammatory infiltrates in the upper dermis of lesional skin. Whether they reflect autoinflammation is unresolved; see the ER stress-driven autoinflammation hypothesis.
Show evidence (1 reference)
PMID:32425927 SUPPORT REVIEW SYNTHESIS Other
"In addition, mild, spare nonspecific/lymphohistiocytic infiltrates of inflammatory cells are seen in the upper dermis"
Review summary of the biopsy findings in reported patients.
⬡

Pathograph

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

Phenotypes

7
Integument 6
Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital ichthyosis, annotated with Ichthyosis (HP:0008064), qualified as congenital onset. HP:0008064 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (4 references)
PMID:2521286 SUPPORT Human Clinical
"Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
Congenital ichthyosiform dermatosis in the original family.
PMID:9188877 SUPPORT Human Clinical
"We report a 32-year-old man with an unusual combination of congenital ichthyosis, sclerosing palmoplantar keratoderma with pseudoainhum, and bizarre striate hyperkeratosis in the fixtures, but no systemic involvement."
Congenital ichthyosis in the case that named the syndrome.
PMID:20226437 SUPPORT Human Clinical
"KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling."
Ichthyosiform scaling is a defining feature.
+ 1 more reference
Sclerosing palmoplantar keratoderma Diffuse palmoplantar hyperkeratosis HP:0007447 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sclerosing diffuse palmoplantar keratoderma, annotated with Diffuse palmoplantar hyperkeratosis (HP:0007447). HP:0007447 is a phenotype from the Human Phenotype Ontology.
Sequelae: Constricting digital bands (pseudoainhum)
Show evidence (2 references)
PMID:2521286 SUPPORT Human Clinical
"Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
Sclerosing palmoplantar keratoderma in the original family.
PMID:31334055 SUPPORT REVIEW SYNTHESIS Other
"KLICK syndrome (keratosis linearis with ichthyosis) | AR | POMP (POMP) | Diffuse, mutilating PPK"
Review table classifying the KLICK keratoderma as diffuse and mutilating.
Linear keratotic flexural papules Hyperkeratotic papule HP:0045059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Linear keratotic papules in flexural areas, annotated with Hyperkeratotic papule (HP:0045059). HP:0045059 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:2521286 SUPPORT Human Clinical
"Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
Linear, cord-like keratotic papules in the original family.
PMID:32425927 SUPPORT REVIEW SYNTHESIS Other
"Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules..."
Places the linear papules in the arm folds and on the wrists.
PMID:32147745 SUPPORT REVIEW SYNTHESIS Other
"Flexural linear and starfish keratoses overlying large joints are distinctive"
Review identifies the flexural linear keratoses as a distinctive sign.
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:9188877 SUPPORT Human Clinical
"On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis."
Lesional histology in the index case.
Hypergranulosis HP:0025114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergranulosis (HP:0025114). HP:0025114 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9188877 SUPPORT Human Clinical
"On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis."
Hypergranulosis on lesional histology.
Epidermal acanthosis HP:0025092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epidermal acanthosis (HP:0025092). HP:0025092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9188877 SUPPORT Human Clinical
"On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis."
Acanthosis on lesional histology.
Other 1
Constricting digital bands (pseudoainhum)
Show evidence (2 references)
PMID:9188877 SUPPORT Human Clinical
"We report a 32-year-old man with an unusual combination of congenital ichthyosis, sclerosing palmoplantar keratoderma with pseudoainhum, and bizarre striate hyperkeratosis in the fixtures, but no systemic involvement."
Pseudoainhum accompanying the sclerosing keratoderma.
PMID:32425927 SUPPORT REVIEW SYNTHESIS Other
"Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules..."
Review lists circular finger constrictions among the defining features.
🧬

Genetic Associations

1
POMP
Gene: POMP hgnc:20330 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:20226437 SUPPORT Human Clinical
"Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q."
Homozygosity mapping localized the gene before POMP sequencing.
Variants (1)
c.-95delC
deletion
Single-nucleotide deletion at c.-95 in the 5' UTR present in the long-UTR POMP transcript variants; homozygous in every reported KLICK patient.
Show evidence (2 references)
PMID:20226437 SUPPORT Human Clinical
"Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands."
The variant was homozygous in all eight probands of the discovery study.
PMID:32425927 SUPPORT REVIEW SYNTHESIS Other
"There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion."
All reported patients share this one allele.
💊

Medical Actions

1
Oral retinoids
Action: oral retinoid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is oral retinoid therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: etretinate CHEBI:4913 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses etretinate (CHEBI:4913). CHEBI:4913 is a therapeutic agent from Chemical Entities of Biological Interest. 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
Systemic retinoids are the only reported symptomatic therapy with an observed effect. The index case improved on etretinate, and a keratoderma review recommends acitretin for both the ichthyosis and the keratoderma. Evidence is limited to case experience.
Target Phenotypes: Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology. Diffuse palmoplantar keratoderma HP:0007447 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Diffuse palmoplantar keratoderma, annotated with Diffuse palmoplantar hyperkeratosis (HP:0007447). HP:0007447 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9188877 SUPPORT Human Clinical
"The condition, which improved on oral etretinate therapy, had not appeared previously in the family."
Single-case report of improvement on etretinate.
PMID:32147745 SUPPORT REVIEW SYNTHESIS Other
"Acitretin can be helpful for both the ichthyosis and keratoderma"
Review-level recommendation of acitretin for KLICK.
🔬

Diagnosis

1
POMP 5' UTR testing
Molecular confirmation is homozygosity for the recurrent POMP 5' UTR deletion. Because the variant is noncoding, the assay must cover the 5' UTR; an exon-only test can miss it.
POMP 5' UTR sequencing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20226437 SUPPORT Human Clinical
"Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands."
The diagnostic variant lies at c.-95, in the 5' UTR.
📊

Prevalence

2
France (capture-recapture study of inherited ichthyosis)
Point Prevalence 0.023 per 100,000 (0.019–0.03) <1 in 1,000,000
0.23 per million (95% CI 0.19-0.30), derived from two recorded KLICK patients in a national French survey. The estimate rests on two cases and should not be read as a precise or global figure.
Show evidence (1 reference)
PMID:24393603 SUPPORT Human Clinical
"| KLICK syndrome | 2 (1.7) | 0.23 [0.19 – 0.30] |"
Table row from the French capture-recapture study: two KLICK patients, prevalence 0.23 per million with its confidence interval.
Published literature
Cases In Literature Ultra Rare
Fourteen genetically characterized patients were described in the literature by 2020.
Show evidence (1 reference)
PMID:32425927 SUPPORT REVIEW SYNTHESIS Other
"There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion."
Review count of reported patients; a literature count, not a population rate.
{ }

Source YAML

click to show 
name: KLICK Syndrome
creation_date: "2026-10-09T12:00:00Z"
description: >-
  KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma) is a rare autosomal
  recessive keratinization disorder. It combines congenital ichthyosiform scaling, sclerosing palmoplantar keratoderma
  with constricting digital bands, and keratotic papules arranged in linear, cord-like bands in the flexures,
  especially the arm folds and wrists. Every genetically studied patient has been homozygous for the same single
  nucleotide deletion in the 5' untranslated region of POMP, which encodes the proteasome maturation chaperone. The
  deletion shifts POMP transcription toward long 5' UTR isoforms and reduces effective POMP in differentiating
  keratinocytes, producing proteasome insufficiency, endoplasmic reticulum stress and defective profilaggrin processing
  in the upper epidermis. Disease is confined to the skin; whether mild dermal inflammation reflects an
  autoinflammatory component is debated.
category: Mendelian
disease_term:
  preferred_term: KLICK syndrome
  term:
    id: MONDO:0011169
    label: keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome
synonyms:
- keratosis linearis with ichthyosis congenita and sclerosing keratoderma
- keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome
parents:
- Hereditary Palmoplantar Keratoderma
- Inherited Ichthyosis
notes: >-
  No GeneReviews chapter covers KLICK syndrome. Heterozygous truncating POMP variants in the penultimate exon cause
  a different disorder, proteasome-associated autoinflammatory syndrome 2 (PRAAS2), with immunodeficiency,
  neutrophilic dermatosis and autoimmunity; those features are not part of KLICK and the two are not lumped. The
  digital constriction bands (pseudoainhum) are left without an HPO binding: HP:0010491 Digital constriction ring is
  a subclass of HP:0009775 Amniotic constriction ring and would assert an amniotic origin. Several KLICK case
  reports (PMID:27503413, PMID:29315485, PMID:21571163, PMID:21275938) have no PubMed abstract and could not be
  quoted, so clinical claims rest on the abstracts and full texts that are available. One of them
  (PMID:21571163) reports aggressive cutaneous squamous cell carcinoma in a KLICK patient; a single case does not
  establish an increased cancer risk.
prevalence:
- population: France (capture-recapture study of inherited ichthyosis)
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.023
  rate_low: 0.019
  rate_high: 0.030
  notes: >-
    0.23 per million (95% CI 0.19-0.30), derived from two recorded KLICK patients in a national French survey. The
    estimate rests on two cases and should not be read as a precise or global figure.
  evidence:
  - reference: PMID:24393603
    reference_title: "Prevalence of inherited ichthyosis in France: a study using capture-recapture method."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| KLICK syndrome | 2 (1.7) | 0.23 [0.19 – 0.30] |"
    explanation: >-
      Table row from the French capture-recapture study: two KLICK patients, prevalence 0.23 per million with its
      confidence interval.
- population: Published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: Fourteen genetically characterized patients were described in the literature by 2020.
  evidence:
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion."
    explanation: Review count of reported patients; a literature count, not a population rate.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous for the POMP c.-95delC deletion; the first family was consanguineous and the
    later single case had no prior family history.
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling."
    explanation: States the recessive inheritance in the gene-identification study.
  - reference: PMID:2521286
    reference_title: "Congenital ichthyosiform dermatosis with linear keratotic flexural papules and sclerosing palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
    explanation: Affected relatives in a consanguineous family, consistent with recessive transmission.
pathophysiology:
- name: Homozygous POMP 5' UTR Deletion
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion is homozygosity for a single-nucleotide deletion at c.-95 in the 5' untranslated region of
    POMP. It lies in the long 5' UTR used by a subset of POMP transcript variants and does not alter the coding
    sequence.
  genes:
  - preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  genetic_context:
    genes:
    - preferred_term: POMP
      term:
        id: hgnc:20330
        label: POMP
    variant_type: deletion
    allele_type: single-nucleotide deletion in the 5' untranslated region
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands."
    explanation: Homozygous c.-95 deletion found in all eight European probands.
  downstream:
  - target: POMP Transcriptional Switch to Long 5' UTR Variants
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20226437
      reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients."
      explanation: Patient keratinocytes carrying the deletion show increased long-5' UTR transcripts.
- name: POMP Transcriptional Switch to Long 5' UTR Variants
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Keratinocytes from patients show a marked increase in POMP transcripts with long 5' UTRs. How this switch lowers
    the amount of functional POMP in differentiating epidermis has not been characterized at the level of
    translation or protein stability.
  genes:
  - preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients."
    explanation: Direct measurement in patient keratinocytes.
  downstream:
  - target: Reduced POMP in Differentiating Keratinocytes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The step from altered transcript isoforms to reduced POMP is inferred from patient immunostaining and from
      knockdown experiments that reproduce the patient pattern; the molecular intermediate is not shown.
    evidence:
    - reference: PMID:20226437
      reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin."
      explanation: The authors link the deletion to altered epidermal POMP distribution.
      directness: INDIRECT
- name: Reduced POMP in Differentiating Keratinocytes
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient epidermis shows altered POMP distribution. Silencing POMP in organotypic human epidermis by about half
    reproduced the patient staining pattern for POMP, proteasome subunits and filaggrin, supporting reduced POMP as
    the causal intermediate. POMP acts as a proteasome assembly chaperone by binding proteasome precursor subunits;
    GO has no molecular-function term for assembly-chaperone activity, so the binding activity is recorded with the
    general protein binding term, which is POMP's experimentally supported GO function.
  genes:
  - preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  molecular_functions:
  - preferred_term: proteasome precursor subunit binding (assembly chaperone)
    modifier: DECREASED
    term:
      id: GO:0005515
      label: protein binding
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP."
    explanation: Patient skin biopsies show altered POMP distribution.
  - reference: PMID:22235297
    reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunohistochemical analysis of the tissue constructs revealed aberrant staining of POMP, proteasome subunits and the skin differentiation marker filaggrin when compared to control tissue constructs."
    explanation: Knockdown in organotypic epidermis reproduces the patient staining pattern.
  downstream:
  - target: Epidermal Proteasome Insufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22235297
      reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The combined results indicate that KLICK is caused by reduced levels of POMP, leading to proteasome insufficiency in differentiating keratinocytes."
      explanation: Knockdown experiments establish reduced POMP as the cause of proteasome insufficiency.
- name: Epidermal Proteasome Insufficiency
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    POMP is the chaperone for proteasome assembly. Reducing it lowers the amount of the alpha 7 and beta 5 proteasome
    subunits, with compensatory up-regulation of their transcripts; the same subunits are weakly or patchily stained
    in KLICK epidermis.
  genes:
  - preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  biological_processes:
  - preferred_term: proteasome assembly
    modifier: DECREASED
    term:
      id: GO:0043248
      label: proteasome assembly
  cellular_components:
  - preferred_term: proteasome complex
    term:
      id: GO:0000502
      label: proteasome complex
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:22235297
    reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knock-down of POMP expression in regular cell cultures resulted in decreased amounts of proteasome subunits."
    explanation: Direct cell-culture result linking POMP loss to reduced proteasome subunits.
  - reference: PMID:22235297
    reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The effect of POMP knock-down on proteasome subunits explains the weaker expression of α7 and β5 in KLICK epidermis."
    explanation: Connects the cell-culture effect to the patient biopsy finding.
  downstream:
  - target: Keratinocyte ER Stress and Unfolded Protein Response
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22235297
      reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Prolonged silencing of POMP in cultured cells induced C/EBP homologous protein (CHOP) expression consistent with an activation of the unfolded protein response and increased endoplasmic reticulum (ER) stress."
      explanation: POMP silencing induces CHOP, a late unfolded-protein-response marker.
  - target: Defective Profilaggrin Processing
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22235297
      reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In combination, these findings indicate that the proteasome is involved in profilaggrin processing and that KLICK is associated with a disturbed epidermal expression of filaggrin."
      explanation: Proteasome insufficiency in organotypic epidermis disturbs profilaggrin processing.
- name: Keratinocyte ER Stress and Unfolded Protein Response
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    CHOP staining is increased in the differentiated layers of patient epidermis, and prolonged POMP silencing induces
    CHOP in HeLa and HaCaT cells, with a slight BiP increase in HaCaT keratinocytes only. ER stress is proposed as the
    route by which proteasome insufficiency disturbs terminal differentiation; its exact contribution relative to the
    profilaggrin defect is not resolved.
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:22235297
    reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Furthermore, differentiated epidermal layers of patient skin biopsies show increased staining of the unfolded protein response (UPR) protein CHOP, suggesting that ER stress is a pathophysiological mechanism in KLICK [4]."
    explanation: Restates the earlier patient-biopsy CHOP finding from the gene-identification study.
  - reference: PMID:22235297
    reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, POMP knock-down caused a slight increase in the ER chaperone BiP in keratinocyte derived HaCaT cells, but not in HeLa cells, supporting tissue specific sensitivity to ER stress, as suggested previously [18]."
    explanation: Keratinocyte-specific ER stress response to POMP loss.
  downstream:
  - target: Perturbed Terminal Epidermal Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22235297
      reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Proteasome insufficiency disturbs terminal epidermal differentiation, presumably by increased ER stress, and leads to perturbed processing of profilaggrin."
      explanation: The authors present ER stress as the presumed route to disturbed differentiation.
      directness: INDIRECT
  - target: ER Stress-Driven Cutaneous Autoinflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - klick_er_stress_autoinflammation
    description: >-
      Hypothesized link from keratinocyte ER stress to cutaneous autoinflammation; not tested in KLICK.
    evidence:
    - reference: PMID:32425927
      reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "the inflammation seen in KLICK syndrome could be considered to result from continuous abnormal ER stress in keratinocytes"
      explanation: Review proposal that keratinocyte ER stress drives the inflammation; a hypothesis, not a measurement.
      directness: INDIRECT
- name: Defective Profilaggrin Processing
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    KLICK epidermis shows patchy staining of the cornified layer with retained profilaggrin granules in the outermost
    cells. POMP-silenced tissue constructs show the same retention and altered profilaggrin cleavage products. The
    large keratohyaline granules seen by electron microscopy in the 1997 case fit this defect.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:22235297
    reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Similar to what was observed in skin from KLICK patients the POMP siRNA treated tissue constructs also showed a retention of profilaggrin granules in the cornified cell layer"
    explanation: Organotypic knockdown reproduces the patient profilaggrin retention.
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy disclosed numerous large keratohyaline granules in superficial keratinocytes."
    explanation: Ultrastructural keratohyaline abnormality in patient skin, consistent with disturbed profilaggrin handling.
    directness: INDIRECT
  downstream:
  - target: Perturbed Terminal Epidermal Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22235297
      reference_title: "siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our results are consistent with different possible mechanisms contributing to perturbed epidermal differentiation in KLICK genodermatosis: Firstly, the cleavage products of profilaggrin have been shown to be indispensable in the formation of the epidermal water barrier ... we show that the proteasome is essential for adequate profilaggrin processing."
      explanation: The authors propose impaired profilaggrin processing as one route to disturbed differentiation.
      directness: INDIRECT
- name: Perturbed Terminal Epidermal Differentiation
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The outermost epidermal layers form abnormally, giving marked acanthosis, hypergranulosis and hyperkeratosis on
    biopsy. This is the shared tissue-level basis of the scaling, keratoderma and linear keratoses. Why lesions
    concentrate in palms, soles and flexures is not explained.
  biological_processes:
  - preferred_term: keratinocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  locations:
  - preferred_term: epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis."
    explanation: Gene-identification study links the POMP defect to terminal epidermal differentiation.
    directness: INDIRECT
  downstream:
  - target: Ichthyosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20226437
      reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin."
      explanation: Perturbed formation of the outer epidermis is proposed as the basis of the cutaneous phenotype.
      directness: INDIRECT
  - target: Sclerosing palmoplantar keratoderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20226437
      reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin."
      explanation: Same proposed tissue mechanism; the site-specific distribution is not explained.
      directness: INDIRECT
  - target: Linear keratotic flexural papules
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20226437
      reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin."
      explanation: Same proposed tissue mechanism; the linear flexural pattern is not explained.
      directness: INDIRECT
  - target: Hyperkeratosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32425927
      reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis."
      explanation: The histological pattern is the direct tissue expression of the differentiation defect.
  - target: Hypergranulosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32425927
      reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers"
      explanation: Hyperplasia of the granular and spinous layers is the histological expression of the differentiation defect.
  - target: Epidermal acanthosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32425927
      reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers"
      explanation: Hyperplasia of the granular and spinous layers is the histological expression of the differentiation defect.
- name: ER Stress-Driven Cutaneous Autoinflammation
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Proposed: chronic keratinocyte ER stress triggers innate-immune or type 1 interferon activation, which would
    make KLICK an autoinflammatory keratinization disease and explain the mild upper dermal infiltrate seen on
    biopsy. No inflammatory pathway has been measured in KLICK patients, and the PRAAS2 discovery paper describes
    KLICK as non-inflammatory. The observed infiltrate itself is recorded under histopathology.
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  evidence:
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "As we have cited that prolonged ER stress is known to induce inflammation in numerous chronic inflammatory skin diseases (23), the inflammation seen in KLICK syndrome could be considered to result from continuous abnormal ER stress in keratinocytes."
    explanation: Hypothesis that keratinocyte ER stress drives the dermal inflammation.
    directness: INDIRECT
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although there are no reports of hyperactivation of innate immunity or of the induction of a type 1 interferon response in KLICK patients, the chronic ER stress present in the epidermis of KLICK patients may eventually trigger autoinflammation (16)."
    explanation: The same review states that innate-immune or interferon activation has not been shown in patients.
  - reference: PMID:29805043
    reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
    supports: REFUTE
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "AR deletions in the 5′ UTR of an alternative POMP transcript give rise to a longer-lived transcript that leads to a keratinization disorder of the skin ... with no inflammatory component."
    explanation: The PRAAS2 gene-discovery paper characterizes KLICK as non-inflammatory.
mechanistic_hypotheses:
- hypothesis_group_id: klick_er_stress_autoinflammation
  hypothesis_label: ER stress-driven autoinflammation in KLICK skin
  status: EMERGING
  description: >-
    Chronic ER stress in POMP-deficient keratinocytes may activate innate immunity and drive dermal inflammation,
    placing KLICK among autoinflammatory keratinization diseases. Contested: no inflammatory pathway has been
    measured in patients.
  evidence:
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome."
    explanation: States the autoinflammation hypothesis.
    directness: INDIRECT
phenotypes:
- name: Ichthyosis
  category: Dermatologic
  diagnostic: true
  description: >-
    Ichthyosiform scaling, generalized or variably mild, persisting through life. It is congenital in the original
    reports; one review places onset in early childhood, beginning with generalized erythema and fine scaling.
  phenotype_term:
    preferred_term: Congenital ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:2521286
    reference_title: "Congenital ichthyosiform dermatosis with linear keratotic flexural papules and sclerosing palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
    explanation: Congenital ichthyosiform dermatosis in the original family.
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 32-year-old man with an unusual combination of congenital ichthyosis, sclerosing palmoplantar keratoderma with pseudoainhum, and bizarre striate hyperkeratosis in the fixtures, but no systemic involvement."
    explanation: Congenital ichthyosis in the case that named the syndrome.
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling."
    explanation: Ichthyosiform scaling is a defining feature.
  - reference: PMID:32147745
    reference_title: "Diagnosis and Management of Inherited Palmoplantar Keratodermas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "presents in early childhood and similar to LK, starts with generalised erythema and fine scaling"
    explanation: Review describing onset in early childhood with erythema and fine scaling.
- name: Sclerosing palmoplantar keratoderma
  category: Dermatologic
  diagnostic: true
  description: >-
    Diffuse, smooth palmoplantar keratoderma with a sclerosing quality. Reviews classify it as a diffuse, mutilating
    keratoderma because constricting bands can form around the digits.
  phenotype_term:
    preferred_term: Sclerosing diffuse palmoplantar keratoderma
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:2521286
    reference_title: "Congenital ichthyosiform dermatosis with linear keratotic flexural papules and sclerosing palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
    explanation: Sclerosing palmoplantar keratoderma in the original family.
  - reference: PMID:31334055
    reference_title: "Hereditary Palmoplantar Keratoderma: A Practical Approach to the Diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "KLICK syndrome (keratosis linearis with ichthyosis) | AR | POMP (POMP) | Diffuse, mutilating PPK"
    explanation: Review table classifying the KLICK keratoderma as diffuse and mutilating.
  sequelae:
  - target: Constricting digital bands (pseudoainhum)
    description: >-
      The constricting digital bands occur within the sclerosing palmoplantar keratoderma; the tissue process that
      forms them has not been studied.
- name: Constricting digital bands (pseudoainhum)
  category: Dermatologic
  description: >-
    Circular constrictions around the fingers in sclerosing keratoderma. HPO's only constriction-ring terms describe
    amniotic bands, so no HPO term is bound; see the entry notes.
  evidence:
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 32-year-old man with an unusual combination of congenital ichthyosis, sclerosing palmoplantar keratoderma with pseudoainhum, and bizarre striate hyperkeratosis in the fixtures, but no systemic involvement."
    explanation: Pseudoainhum accompanying the sclerosing keratoderma.
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists."
    explanation: Review lists circular finger constrictions among the defining features.
- name: Linear keratotic flexural papules
  category: Dermatologic
  diagnostic: true
  description: >-
    Keratotic papules arranged in linear, cord-like bands in the flexures, especially the arm folds and wrists; a
    review also describes starfish keratoses over large joints.
  phenotype_term:
    preferred_term: Linear keratotic papules in flexural areas
    term:
      id: HP:0045059
      label: Hyperkeratotic papule
  evidence:
  - reference: PMID:2521286
    reference_title: "Congenital ichthyosiform dermatosis with linear keratotic flexural papules and sclerosing palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution."
    explanation: Linear, cord-like keratotic papules in the original family.
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists."
    explanation: Places the linear papules in the arm folds and on the wrists.
  - reference: PMID:32147745
    reference_title: "Diagnosis and Management of Inherited Palmoplantar Keratodermas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Flexural linear and starfish keratoses overlying large joints are distinctive"
    explanation: Review identifies the flexural linear keratoses as a distinctive sign.
- name: Hyperkeratosis
  category: Dermatologic
  description: >-
    Involved epidermis shows marked acanthosis, hypergranulosis and hyperkeratosis on light microscopy, with large
    keratohyaline granules on electron microscopy.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis."
    explanation: Lesional histology in the index case.
- name: Hypergranulosis
  category: Dermatologic
  phenotype_term:
    preferred_term: Hypergranulosis
    term:
      id: HP:0025114
      label: Hypergranulosis
  evidence:
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis."
    explanation: Hypergranulosis on lesional histology.
- name: Epidermal acanthosis
  category: Dermatologic
  phenotype_term:
    preferred_term: Epidermal acanthosis
    term:
      id: HP:0025092
      label: Epidermal acanthosis
  evidence:
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis."
    explanation: Acanthosis on lesional histology.
histopathology:
- name: Mild upper dermal inflammatory infiltrate
  description: >-
    Mild, sparse nonspecific or lymphohistiocytic inflammatory infiltrates in the upper dermis of lesional skin.
    Whether they reflect autoinflammation is unresolved; see the ER stress-driven autoinflammation hypothesis.
  notes: No specific finding term is assigned for this infiltrate.
  evidence:
  - reference: PMID:32425927
    reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In addition, mild, spare nonspecific/lymphohistiocytic infiltrates of inflammatory cells are seen in the upper dermis"
    explanation: Review summary of the biopsy findings in reported patients.
genetic:
- name: POMP
  gene_term:
    preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  relationship_type: CAUSATIVE
  notes: >-
    All genetically studied patients carry the same homozygous 5' UTR deletion. Heterozygous truncating POMP variants
    cause PRAAS2, a separate immune-dysregulatory disorder, and are not KLICK alleles.
  variants:
  - name: c.-95delC
    description: >-
      Single-nucleotide deletion at c.-95 in the 5' UTR present in the long-UTR POMP transcript variants; homozygous
      in every reported KLICK patient.
    variant_type: deletion
    evidence:
    - reference: PMID:20226437
      reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands."
      explanation: The variant was homozygous in all eight probands of the discovery study.
    - reference: PMID:32425927
      reference_title: "KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion."
      explanation: All reported patients share this one allele.
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q."
    explanation: Homozygosity mapping localized the gene before POMP sequencing.
diagnosis:
- name: POMP 5' UTR testing
  diagnosis_term:
    preferred_term: POMP 5' UTR sequencing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    Molecular confirmation is homozygosity for the recurrent POMP 5' UTR deletion. Because the variant is noncoding,
    the assay must cover the 5' UTR; an exon-only test can miss it.
  evidence:
  - reference: PMID:20226437
    reference_title: "A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands."
    explanation: The diagnostic variant lies at c.-95, in the 5' UTR.
treatments:
- name: Oral retinoids
  description: >-
    Systemic retinoids are the only reported symptomatic therapy with an observed effect. The index case improved on
    etretinate, and a keratoderma review recommends acitretin for both the ichthyosis and the keratoderma. Evidence is
    limited to case experience.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: oral retinoid therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: etretinate
      term:
        id: CHEBI:4913
        label: etretinate
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_phenotypes:
  - preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  - preferred_term: Diffuse palmoplantar keratoderma
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:9188877
    reference_title: "Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The condition, which improved on oral etretinate therapy, had not appeared previously in the family."
    explanation: Single-case report of improvement on etretinate.
  - reference: PMID:32147745
    reference_title: "Diagnosis and Management of Inherited Palmoplantar Keratodermas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Acitretin can be helpful for both the ichthyosis and keratoderma"
    explanation: Review-level recommendation of acitretin for KLICK.
discussions:
- discussion_id: gap_klick_autoinflammation
  prompt: >-
    Does chronic keratinocyte ER stress in KLICK drive innate-immune or type 1 interferon activation, or is the mild
    dermal infiltrate a nonspecific consequence of hyperkeratosis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#ER Stress-Driven Cutaneous Autoinflammation
  rationale: >-
    One review proposes KLICK as an autoinflammatory keratinization disease, while the PRAAS2 gene-discovery paper
    describes KLICK as non-inflammatory. No inflammatory pathway has been measured in KLICK patient skin, and the
    answer determines whether anti-inflammatory therapy is a rational option.
📚

References & Deep Research

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: KLICK_Syndrome · 2026-10-09T21:15:57Z · View source

New entry for KLICK syndrome (MONDO:0011169), curated from a Perplexity sonar-deep-research report (research/KLICK_Syndrome-deep-research-perplexity.md; 14/14 references resolved; preflight-dr WARN only because the report cites the POMP gene MIM 613386 rather than the disease MIM 601952, POMP mentioned 29 times). Built a seven-node chain from the homozygous POMP c.-95delC 5' UTR deletion through the long-UTR transcript switch, reduced POMP, proteasome insufficiency, ER stress and defective profilaggrin processing to perturbed terminal epidermal differentiation, with all seven phenotypes causally connected. The contested autoinflammatory interpretation is a HYPOTHETICAL node carrying both SUPPORT (Takeichi & Akiyama 2020 review) and REFUTE (PRAAS2 discovery paper, same review's own caveat) evidence, plus a KNOWLEDGE_GAP discussion. Pseudoainhum is left unbound because HP:0010491 is a subclass of Amniotic constriction ring. Four KLICK case reports have no PubMed abstract (cached as unavailable) and were not quoted. Acitretin claims from web-only sources in the report were replaced by a PubMed-indexed PPK review. No GeneReviews chapter (check-genereviews NO_CHAPTER). Validation: just validate, validate-terms, count-verified-snippets (48/48), check-entity-refs, check-causal-targets, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading, check-enum-values, check-duplicate-keys, and validate-disorders (48 snippets, 0 issues) all passed.

Perplexity ▸
KLICK syndrome: disease-characteristics research report
sonar-deep-research 53 citations 2026-10-09T20:59:09.671103

KLICK syndrome: disease-characteristics research report

KLICK syndrome is a lifelong, autosomal-recessive disorder of epidermal keratinization caused, in genetically confirmed reports, by a homozygous one-base deletion in the 5′ untranslated region of POMP, c.-95delC. Its defining combination is congenital ichthyosiform scaling, palmoplantar keratoderma, linear keratotic lesions—especially in flexures—and sclerosing constriction bands around digits (pseudoainhum). The strongest mechanistic evidence links reduced POMP activity in differentiating keratinocytes to defective proteasome maturation, disturbed epidermal differentiation, and endoplasmic-reticulum (ER) stress. Evidence for a further, disease-specific inflammatory signaling cascade remains preliminary. [121][122][146][80]

Evidence convention: “Human” denotes patients or their skin; “in vitro” denotes experimental cell or epidermal cultures; “computational” denotes pathway or drug-prediction analyses. Percentages derived from ontology aggregators are not treated as measured patient frequencies.

1. Disease information

Identifier or name KLICK syndrome entry or interpretation
MONDO MONDO:0011169. [300]
OMIM phenotype 601952; the causal POMP gene is OMIM 613386. [24][108]
Orphanet ORPHA:281201. [146]
ICD-11 EC20.0Y, as mapped by KEGG; this is a keratinization-disorder code, not a uniquely named KLICK code. [296]
ICD-10 No verified KLICK-specific code identified. Q80.8, “other congenital ichthyosis,” is a broader potential coding category, not an exact synonym. [330][339]
MeSH / MedGen MeSH supplementary concept C566600; MedGen concept C1866029. [296][300]
Other KEGG disease H00790; SNOMED CT 763775000. [296][1]
Names “Keratosis linearis with ichthyosis congenita and sclerosing keratoderma”; “keratosis linearis–ichthyosis congenita–sclerosing keratoderma syndrome”; KLICK syndrome. [146][300]
Evidence provenance This entry synthesizes published individuals and families, patient biopsies, experimental models, and aggregated disease resources. It is not an individual-patient EHR record. [121][122][146]

The original 1989 report described four affected members of a consanguineous family; the 1997 report introduced “KLICK” and described a 32-year-old man without systemic involvement. The discovery study examined DNA from eight European probands. [181][151][121]

2. Etiology: causal, risk, protective, and environmental factors

Established cause: biallelic germline POMP c.-95delC, a noncoding regulatory deletion, rather than a protein-truncating mutation. In the original series, 12 patients from eight European families were homozygous; six available parents were heterozygous, and five unaffected siblings tested were carriers or noncarriers. Several affected haplotypes support a recurrent variant, rather than one demonstrated founder chromosome. [121][125][135]

Risk factors: having two pathogenic alleles is the established genetic risk. A family history and consanguinity increase the chance of such a recessive genotype within a family, but consanguinity is not required: affected unrelated families and a later family with non-consanguineous parents have been reported. No validated KLICK susceptibility loci or severity-modifier genes have been established. A reported combination of KLICK and woolly hair/hypotrichosis was attributed to two separate recessive disorders, not proof that the hair-disorder gene modifies KLICK. [181][125][145][43]

Protective and gene–environment factors: no protective human allele, preventive diet, toxin exposure, infection, lifestyle determinant, or demonstrated gene–environment interaction has been established. Mechanical effects of established hyperkeratosis may contribute to digital constriction; this is a consequence of the skin disorder, not evidence that friction causes KLICK. [121][269]

3. Phenotypes

The table separates reported disease features from suggested HPO coding. Qualitative frequency is deliberately conservative: small case series do not justify patient-level percentages. A secondary phenotype aggregator labels ichthyosis and palmoplantar keratoderma “80–99%,” but supplies no corresponding observed-case denominator; those labels should not be entered as measured frequencies. [web:4nCoJaX02N7jbUnYFD4vhaVy][181][146]

Phenotype and type Onset, severity, course, and defensible frequency Functional or quality-of-life effect Suggested HPO term
Ichthyosiform scaling, clinical sign Often congenital; generalized or variably mild scaling; chronic. Characteristic, without a reliable percentage. [181][146][43] Visible scaling and continuing skin care may be burdensome; no KLICK-specific validated quality-of-life score was identified. [80] Ichthyosis HP:0008064; use more specific subtypes only when documented. [web:4nCoJaX02N7jbUnYFD4vhaVy]
Palmoplantar keratoderma, clinical sign Congenital or develops in early childhood; diffuse, sometimes sclerosing and functionally severe; persistent. Characteristic, unquantified. [181][192][151] Thick, stiff skin and associated deformity can impair hand and foot function. [80] Palmoplantar keratoderma HP:0000982; diffuse palmoplantar hyperkeratosis HP:0007447 when appropriate. [198][197]
Linear keratotic papules and plaques, clinical sign Typically symmetric, cord-like flexural lesions at wrists, antecubital or popliteal folds; plaques may affect other sites. Characteristic but not obligatory; one family report noted that typical flexural papules were not always present. [146][145] Visible lesions and thickened skin may affect comfort and daily care; effect has not been quantified separately. [146] Linear arrays of macular hyperkeratoses in flexural areas HP:0007490; hyperkeratotic papule HP:0045059 where applicable. [web:4nCoJaX02N7jbUnYFD4vhaVy][246]
Digital sclerosis, constriction bands, pseudoainhum, flexural deformity, physical manifestations Can become conspicuous in childhood or later; severity varies and may restrict movement. Characteristic, without a trustworthy frequency or KLICK-specific progression rate. [151][146][43] Hand use and mobility may be impaired; assess threatened digits clinically. [80] Flexion contracture of digit HP:0030044 if present. Describe pseudoainhum in free text: HPO HP:0009775 means amniotic constriction ring and should not automatically be used for keratoderma-related bands. [247][250][277]
Hyperkeratosis, acanthosis, hypergranulosis, sometimes parakeratosis and enlarged keratohyaline granules, biopsy signs Findings in lesional epidermis; prevalence across patients unknown. Sparse upper-dermal inflammatory infiltrates have also been described. [80][337] These are diagnostic tissue findings, not independently measured patient-reported outcomes. Hyperkeratosis HP:0000962; epidermal acanthosis HP:0025092; hypergranulosis HP:0025114; parakeratosis HP:0001036 when observed. [246][242][web:4nCoJaX02N7jbUnYFD4vhaVy]
Erythema or atypically placed plaques, variable clinical signs Reported in some individuals; a 2024 clinically diagnosed but genetically unconfirmed boy had symmetric extensor-foot plaques. These are not universal defining findings. [80][43] Not separately measured. Code the observed erythema or plaque morphology individually; do not generalize from one case.
Nail or dental abnormalities, occasional findings Described inconsistently; normal hair, nails, teeth, and hearing have also been documented. Their absence does not exclude KLICK. [80][43][337] Not established. Nail dystrophy HP:0008404 only if actually present. [web:4nCoJaX02N7jbUnYFD4vhaVy]

No characteristic behavioral or psychiatric phenotype, systemic laboratory abnormality, or electrophysiologic phenotype has been demonstrated for KLICK. The characteristic disorder is predominantly cutaneous; do not transfer immunodeficiency or systemic autoinflammation findings from other POMP-related diseases to KLICK. [80][296]

4. Genetic and molecular information

Field Knowledge-base annotation
Causal gene POMP, proteasome maturation protein; HGNC:20330, NCBI Gene 51371, Ensembl ENSG00000132963, OMIM 613386; chromosome 13q12.3. [106][46][108]
Established KLICK allele NM_015932.5:c.-95delC, rs112368783, ClinVar variation 116 / VCV000000116, OMIM allelic variant 613386.0001. ClinVar’s GRCh38 expression is NC_000013.11:g.28659090del. Specify transcript and genome build when recording coordinates. [web:6g8nEzSiusklPoXtMf9sE4Zs]
Classification and origin Pathogenic germline deletion. ClinVar’s KLICK-specific record RCV000000136 is pathogenic but its OMIM assertion has no assertion criteria provided; the overall variant-level record has additional concordant submissions. [web:6g8nEzSiusklPoXtMf9sE4Zs]
Population frequency The ClinVar page quotes approximately 0.01% in gnomAD and 0.013% of European non-Finnish alleles in a submitter comment. These are quoted submitter figures, not an independently verified current release-wide carrier-frequency estimate. The discovery report found no deletion in 280 Swedish control chromosomes. [web:6g8nEzSiusklPoXtMf9sE4Zs]
Functional consequence Shift toward longer POMP 5′-UTR transcripts in patient keratinocytes, with reduced effective POMP expression in differentiating epidermis and altered proteasome-subunit distribution: regulatory hypomorphic effect, not a coding frameshift. [121][122]
Important boundary Heterozygous truncating POMP variants are associated with a distinct immune-dysregulatory syndrome; other POMP variants appearing in disease aggregators must not automatically be annotated as KLICK-causing. [80][132][254]

No KLICK-specific pathogenic chromosomal rearrangement, somatic driver, modifier gene, disease-specific DNA-methylation signature, or histone-change signature has been established in the cited evidence. [121][80]

5. Environmental information

KLICK is not an infectious disease. No implicated pathogen, toxin, radiation exposure, occupation, smoking pattern, alcohol exposure, or diet has been identified as a cause or reproducible trigger. Skin care and physical stress can matter to symptom management, but they should not be recorded as proven etiologic exposures or gene–environment interactions. [121][146][43]

6. Mechanism and pathophysiology

Ordered causal chain

  1. Homozygous POMP c.-95delC leads to a shift toward longer 5′-UTR transcripts in patient keratinocytes; this upstream change was observed in human material. [121]
  2. The transcript shift leads to reduced effective POMP availability during terminal keratinocyte differentiation; altered patient-skin staining and knockdown experiments support this connection. [121][122]
  3. Reduced POMP leads to impaired maturation or availability of proteasomes, with altered epidermal α7 and β5 subunit distribution; patient staining and POMP-silenced cultures support this step. [121][122]
  4. Proteasome insufficiency leads to two overlapping downstream branches: (a) disturbed profilaggrin processing and epidermal differentiation; (b) increased ER stress and unfolded-protein-response markers, including CHOP. These branches are supported experimentally, although their exact causal order and contribution in each patient are not fully demonstrated. [122]
  5. Disordered differentiation leads to hyperkeratosis, scaling, thick palmoplantar skin, and keratotic flexural lesions; this clinicopathologic link is strongly supported, but the exact mechanism producing each lesion’s distribution remains inferred. [121][122][146]
  6. Thickening and sclerosis of acral skin lead to constricting digital bands and functional deformity; their clinical co-occurrence is established, while a complete tissue-level account of band formation remains inferred. [181][151][80]
  7. Possible inflammatory branch: chronic epidermal stress may lead to local inflammatory signaling and upper-dermal infiltrates. The infiltrates are observed; a causal, KLICK-specific type-I-interferon or innate-immune pathway has not been established. Single-patient 2023 transcriptomics subsequently implicated interferon and other inflammatory pathways, which remains hypothesis-generating. [80][web:Tf1ZaGLHBmtWAOFIPhrk7u7I]

Experimental detail. In 2012, POMP siRNA in human air–liquid-interface epidermal cultures reduced POMP transcripts by about 54% and produced abnormal POMP, α7, and filaggrin staining resembling patient biopsies. Cultures showed altered profilaggrin cleavage; prolonged knockdown induced CHOP in cultured cells. This is an in-vitro approximation, not a precise recreation of the human regulatory deletion. The authors concluded that reduced POMP causes “proteasome insufficiency in differentiating keratinocytes.” PMID 22235297. [122]

Recent molecular profiling. Two 2023–2024 conference abstracts describe analyses centered on a biopsy from a 32-year-old woman, not a large cohort. Immunostaining showed early involucrin/loricrin expression and retained corneal loricrin; RNA sequencing implicated differentiation, cornification, interferon-related, WNT, and EGFR pathways. The 2024 abstract additionally reports hyperkeratosis, hypergranulosis, delayed cellular flattening, and upregulated epidermal-development pathways. Pathway enrichment shows association, not that EGFR, WNT, PI3K, or interferon signaling is an initiating lesion. No KLICK-specific proteomic, metabolomic, lipidomic, single-cell, or spatial-transcriptomic signature was established in these reports. [web:Tf1ZaGLHBmtWAOFIPhrk7u7I][web:D3ONl5rWbzCOhp8RZ9J0LKCn]

Suggested annotations: POMP’s established biological role maps to proteasome assembly GO:0043248; downstream processes can be annotated as ER unfolded-protein response GO:0030968, keratinocyte differentiation GO:0030216, and epidermis development GO:0008544. The principal cell type is keratinocyte CL:0000312. KEGG proteasome pathway hsa03050 is relevant. These are term suggestions, not claims that every branch has been causally validated in KLICK. [219][311][315][212][web:OBwZDlDrUUCwK4OoTkS8VFYr]

7. Anatomical structures affected

The principal organ is skin: especially palmoplantar skin, finger and toe skin, wrists, and flexural skin around large joints. Lesions are often bilaterally symmetric, though severity and location can vary. The key tissue is stratified epidermal epithelium, particularly differentiating granular and cornified layers; sparse inflammatory cells may occur in the superficial dermis. There is no reproducibly established primary internal-organ lesion. [146][80][43]

Suggested anatomy codes are skin epidermis UBERON:0001003, stratum granulosum UBERON:0002069, and dermis UBERON:0002067; principal cell keratinocyte CL:0000312. The implicated subcellular machinery comprises proteasome precursors and ER-associated stress responses; proteasome component GO:0000502 can be considered for the complex. The clinical reports do not establish a primary mitochondrial or lysosomal defect. [213][217][212][108][122]

8. Temporal development

Scaling can begin at birth; keratoderma and distinctive plaques become recognizable during childhood, and digital changes can remain or become more consequential over time. The course is chronic, not episodic or relapsing-remitting; formal early/intermediate/end-stage criteria and a measured progression rate are unavailable. In one reported patient, acitretin improved skin disease during ages 8–18, symptoms worsened after withdrawal, and improvement followed restarting treatment—evidence for symptom recurrence, not cure or a defined remission pattern. No established critical intervention window or longitudinal natural-history cohort was found. [181][192][337][web:DbOxl2jVYciByL4D8NA19q5j]

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous parents, standard Mendelian counseling gives a 25% affected, 50% carrier, and 25% noncarrier probability per pregnancy. Penetrance is not reliably quantified; expressivity varies in lesion distribution and severity. No evidence establishes anticipation, germline mosaicism, or a population-specific founder effect. The discovery families came from Spain, Italy, the Netherlands, Sweden, and Norway; this is case ascertainment, not a geographic prevalence map or sex-ratio estimate. [121][125][145]

A 2014 French capture–recapture study recorded two KLICK patients and estimated 0.23 per million people—0.023 per 100,000—with a reported 95% CI of 0.19–0.30 per million. Its regional sampling and two observed cases make that estimate unsuitable as a precise current global prevalence. Incidence, carrier frequency, sex ratio, and population age distribution are unknown. PMID 24393603. [web:l8hwjUlxLNP95I2ckj2kB2E9][web:XLIpeecMmc7bsWpaMAssV2mA][166]

10. Diagnostics

Clinical approach: suspect KLICK when congenital scaling coexists with diffuse palmoplantar keratoderma, linear flexural keratoses, and digital sclerosis or pseudoainhum. Examine skin distribution, digital movement and constrictions, nails, hair, hearing, and family history; biopsy can show acanthosis, hypergranulosis, hyperkeratosis, abnormal keratohyaline granules, and sometimes parakeratosis. Histology supports but does not independently establish the molecular diagnosis. There are no validated KLICK-specific blood, urine, enzyme, circulating, imaging, electrophysiologic, or functional biomarkers. Imaging may be clinically useful for a severely affected digit, but is not a routine confirmatory KLICK test. [181][337][80][43]

Confirmatory genetic approach: test for biallelic POMP c.-95delC with explicit 5′-UTR coverage and deletion calling, followed by parental segregation testing where possible. Targeted variant testing is efficient for a classic presentation; a palmoplantar-keratoderma or ichthyosis panel that demonstrably covers this noncoding position is useful for broader differentials. WGS may help if the result is unresolved and covers the site; WES or an exon-only panel may miss it. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion assays are not first-line confirmatory tests for this one-base regulatory deletion. RNA sequencing is research-useful, not a validated clinical diagnostic requirement. Genomics England lists POMP on relevant panels and flags the noncoding allele. [web:6g8nEzSiusklPoXtMf9sE4Zs][web:hxtT0cGAbBRZFmp1k1sc18df][121]

Differential: other inherited ichthyoses and mutilating palmoplantar keratodermas, including loricrin/Vohwinkel-spectrum disease; evaluate genetic results and accompanying features rather than assuming that ichthyosis plus constriction bands identifies KLICK. Also distinguish recessive KLICK from the different, often systemic phenotype of heterozygous truncating POMP variants. No validated population newborn-screening program or KLICK-specific clinical diagnostic scoring criteria were identified. [203][80][192]

11. Outcome and prognosis

Cutaneous morbidity can be substantial, particularly where stiff keratoderma and digital constriction impair function. The 1997 case and later descriptions did not establish a characteristic systemic illness or reduced life expectancy. Survival, mortality, life expectancy, formal disability rates, prognostic biomarkers, and KLICK-specific EQ-5D/SF-36/PROMIS results are unavailable. A 2011 letter reported aggressive cutaneous squamous-cell carcinoma in one KLICK patient; this establishes an observed case, not a measured cancer incidence or proven elevated risk. Clinical attention to new or changing skin lesions is reasonable. [151][80][web:4MK80yHz0MUgrWJs1ZOMahEi]

12. Treatment

Treatment evidence consists chiefly of individual case reports, not comparative KLICK trials. Suggested NCIT labels below are intervention concepts to map and verify locally, not asserted numeric NCIT codes. [151][337][43]

Intervention and suggested NCIT concept Evidence, intended role, and limits
Emollients and humectants — topical emollient therapy Supportive management of scaling and dryness. A 2024 case used emollients alongside systemic treatment; their isolated KLICK response was not quantified. [43]
Topical urea or other keratolytics — topical keratolytic therapy; urea Used to reduce thick scale; 30% urea cream was reported in clinical care. No controlled response or adverse-event rate is available for KLICK. [43][36]
Oral acitretin — systemic retinoid therapy; acitretin Case experience reports improvement, including after re-initiation following worsening off treatment. A 2024 boy received 25 mg/day, but that report did not quantify his response and did not genetically confirm KLICK. Assess systemic-retinoid risks and contraindications individually; no KLICK-specific optimal dose or response rate is established. [web:DbOxl2jVYciByL4D8NA19q5j][43]
Oral etretinate — systemic retinoid therapy; etretinate The 1997 primary case abstract reports that disease “improved on oral etretinate therapy.” This is case evidence, not a comparative efficacy estimate. PMID 9188877. [151]
Digit assessment and functional support — dermatologic assessment; rehabilitative therapy Individualized clinical management of painful, function-threatening constrictions and impaired hand or foot function is reasonable. No validated KLICK-specific surgical algorithm, operation outcome, or rehabilitation trial was identified. [80][146]
Erlotinib / EGFR inhibition; PI3K inhibition — targeted therapy research candidates only A 2024 computational reverse-transcriptomics analysis shortlisted erlotinib; a 2023 abstract also proposed EGFR and PI3K inhibition. Neither abstract establishes treatment efficacy or safety in a KLICK patient. [web:D3ONl5rWbzCOhp8RZ9J0LKCn][web:Tf1ZaGLHBmtWAOFIPhrk7u7I]
Anti-cytokine treatment or proteostasis-directed therapy — investigational interventions only Discussed as hypotheses by experts, not demonstrated KLICK therapies. A registered study NCT04996485 concerns broader congenital ichthyosis; its listing is not evidence of KLICK-specific enrollment or benefit. [80][298]

No established KLICK gene therapy, cell therapy, RNA therapy, immunotherapy, genotype-specific pharmacogenomic rule, licensed targeted treatment, or comparative combination-treatment algorithm was identified. [80][web:D3ONl5rWbzCOhp8RZ9J0LKCn]

13. Prevention

Primary prevention of the mutation through lifestyle or vaccination is not applicable. Reproductive genetic counseling can explain recessive risk and discuss carrier testing of relatives and, where appropriate, prenatal or preimplantation testing for the known familial variant. Secondary prevention consists of timely clinical recognition and confirmatory testing in symptomatic relatives, with targeted family testing as appropriate; no population newborn-screening program is established. Tertiary prevention focuses on skin care, monitoring constricting digits and function, and assessment of concerning new lesions. No KLICK-specific vaccine, chemoprophylaxis, environmental intervention, or risk-prediction model has been established. [121][web:6g8nEzSiusklPoXtMf9sE4Zs][80][web:4MK80yHz0MUgrWJs1ZOMahEi]

14. Other species and naturally occurring disease

The genetically established natural disease described here is human (NCBI Taxon:9606). The mouse (NCBI Taxon:10090) has a Pomp ortholog, NCBI Gene:66537, but orthology is not evidence of naturally occurring veterinary KLICK. No confirmed companion-animal breed or VBO entry, spontaneous nonhuman KLICK disease, zoonotic potential, cross-species transmission, or comparative natural-disease prevalence was identified. Proteasome assembly is conserved, but the specific human clinical phenotype cannot be assigned to another species solely from that conservation. [116][112][122]

15. Model organisms and experimental systems

Model type and system Demonstrated recapitulation, use, and limitation
In-vitro human epidermal air–liquid culture with POMP siRNA Reproduced aspects of patient POMP/proteasome/filaggrin staining and disturbed profilaggrin processing. Useful for testing proteasome insufficiency and differentiation; knockdown is not the patient’s exact c.-95delC allele, and cultures cannot reproduce whole-person digital deformity. PMID 22235297. [122]
In-vitro HaCaT keratinocytes and HeLa comparison cultures with POMP knockdown Supported reduced proteasome-subunit abundance and CHOP induction with prolonged depletion; cell-line results cannot establish patient-level natural history or treatment response. PMID 22235297. [122]
CRISPR-edited HaCaT cells carrying the KLICK allele Reported as successfully generated in a 2024 conference abstract; a genotype-matched experimental platform, not yet evidence that a candidate drug works. [web:D3ONl5rWbzCOhp8RZ9J0LKCn]
Patient-derived induced pluripotent stem-cell line Reported generated in the same 2024 abstract for prospective disease modeling. No differentiated-organism phenotype or drug-response result was reported there. [web:D3ONl5rWbzCOhp8RZ9J0LKCn]
KLICK-specific mouse or other whole-animal knock-in model Not established in the retrieved KLICK studies. A mouse Pomp ortholog exists, but an ortholog or a model of another inflammatory disorder must not be represented as a KLICK phenocopy. MGI is an appropriate resource for checking future alleles. [80][112][161]

Primary-source anchors and exact abstract excerpts

Publication date PMID and URL Exact supporting abstract excerpt and evidence type
January 1989 2521286 — https://pubmed.ncbi.nlm.nih.gov/2521286/ “Four members of a consanguineous family showed a congenital disorder characterized by an ichthyosiform dermatosis, sclerosing palmoplantar keratoderma, and multiple keratotic papules arranged in bands with a linear, cordlike distribution.” Human clinical. [181]
May 1997 9188877 — https://pubmed.ncbi.nlm.nih.gov/9188877/ “The condition, which improved on oral etretinate therapy, had not appeared previously in the family.” Human clinical, single case. [151]
9 April 2010 20226437 — https://pubmed.ncbi.nlm.nih.gov/20226437/ “Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands.” Human genetic and biopsy research. [web:nnNpUmDlV0JUFMameO0eW531][134]
3 January 2012 22235297 — https://pmc.ncbi.nlm.nih.gov/articles/PMC3250448/ “The combined results indicate that KLICK is caused by reduced levels of POMP, leading to proteasome insufficiency in differentiating keratinocytes.” In vitro, compared with human biopsies. [122]
6 January 2014 24393603 — https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-9-1/tables/5 The study’s disease table records “KLICK syndrome | 2 (1.7) | 0.23 [0.19 – 0.30]”, with prevalence per million. Population study, based on two recorded KLICK cases. [web:l8hwjUlxLNP95I2ckj2kB2E9][166]
7 July 2023 No PMID verified — https://academic.oup.com/bjd/article/189/1/e21/7221241 “RNA sequencing revealed dysregulated pathways relating to keratinocyte differentiation, keratinization, cornification, and interferon signalling.” Single-patient biopsy and transcriptomics; conference abstract. [web:Tf1ZaGLHBmtWAOFIPhrk7u7I]
17 May 2024 No PMID verified — https://academic.oup.com/bjd/article/190/6/e78/7675832 “HaCaT keratinocytes were successfully edited using CRISPR-Cas9 to carry the KLICK patient POMP variant and a KLICK patient iPSC line was generated.” Cell-model and computational research; conference abstract. [web:D3ONl5rWbzCOhp8RZ9J0LKCn]

Knowledge-base caution: annotate POMP c.-95delC and the characteristic skin phenotype as established; annotate specific inflammatory cascades, repurposed EGFR inhibitors, long-term outcomes, and animal phenocopy claims as unproven or not available. [121][122][80][web:D3ONl5rWbzCOhp8RZ9J0LKCn]

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 14
On topic 7
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 27
Resolved 22
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 5

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, Taxon, Gene.

22 of 27 terms resolved to a current term; the rest could not be looked up either way.