Mal de Meleda

Mendelian MONDO:0009552 Pathograph 36 Show in embeddings browser Diffuse palmoplantar keratoderma Autosomal recessive disease

Mal de Meleda is a rare autosomal recessive diffuse palmoplantar keratoderma caused by biallelic loss-of-function variants in SLURP1, which encodes a small secreted Ly6/uPAR-family protein made by differentiating keratinocytes. Erythema and yellowish, waxy hyperkeratosis of the palms and soles begin in infancy, extend onto the dorsal hands and feet, wrists and ankles in a sharply demarcated glove-and-stocking pattern (transgrediens), and worsen with age (progrediens). Hyperhidrosis, malodour and microbial superinfection of the thickened skin, painful fissures, nail abnormalities, perioral erythema, brachydactyly or tapering of the digits, lichenoid plaques, flexion contractures and pseudoainhum are recognised features, and melanoma and squamous cell carcinoma have been reported within affected skin. Histology shows nonepidermolytic hyperkeratosis, acanthosis and hypergranulosis with a superficial perivascular lymphocytic infiltrate. SLURP1 is an allosteric modulator of keratinocyte alpha7 nicotinic acetylcholine receptors that restrains keratinocyte growth, and its loss is linked to keratinocyte hyperproliferation, disturbed terminal differentiation and cutaneous inflammation. Management is symptomatic, centred on oral acitretin and topical keratolytics.

Ask OpenScientist

Ask a research question about Mal de Meleda. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Definitions
1
Inheritance
10
Pathophys.
23
Phenotypes
36
Pathograph
1
Genes
4
Variants
5
Medical Actions
1
Subtypes
2
Differentials
1
Models
5
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0009552 mal de Meleda
skos:exactMatch Orphanet ORPHA:87503
Orphanet ORPHA:87503 lists MONDO:0009552 as an exact cross-reference for Mal de Meleda.
📘

Definitions

1
Orphanet Mal de Meleda definition
A rare diffuse palmoplantar keratoderma with symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal hands and feet (transgrediens), with possible hyperhidrosis, lichenoid plaques and perioral erythema.
OTHER
Show evidence (1 reference)
ORPHA:87503 SUPPORT Other
"A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens)."
Orphanet defines the disorder as a transgredient diffuse palmoplantar keratoderma.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Mal de Meleda is inherited in an autosomal recessive pattern; affected individuals carry biallelic SLURP1 variants, frequently homozygous in consanguineous families and founder populations. Pseudodominant transmission occurs when an affected parent has a carrier partner.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:11285253 SUPPORT Human Clinical
"Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
The gene-discovery study describes Mal de Meleda as an autosomal recessive disorder.
PMID:12483299 SUPPORT Human Clinical
"In a German family with no known consanguinity, we have shown pseudodominant inheritance. Three affected children and their affected mother are homozygous for the missense mutation W15R."
Apparent vertical transmission in this family reflects homozygosity in mother and children, consistent with recessive inheritance.
◆

Subtypes

1
Palmoplantar keratoderma, Gamborg-Nielsen (Norrbotten) type MONDO:0009489
Autosomal recessive palmoplantar keratoderma described in families from northern Sweden that overlaps phenotypically with Mal de Meleda. Affected individuals are homozygous for the SLURP1 signal-peptide variant c.43T>C (p.W15R) or compound heterozygous for it, so the form is an allelic variant of Mal de Meleda rather than a separate disease.
Show evidence (2 references)
PMID:24604124 SUPPORT Human Clinical
"Hereby we confirm that PPK-GN is an allelic variant of MDM."
SLURP1 sequencing in Swedish families shows the Gamborg-Nielsen type is allelic with Mal de Meleda.
PMID:24604124 SUPPORT Human Clinical
"Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation."
Identifies the SLURP1 genotypes underlying the Gamborg-Nielsen type.
⚙

Pathophysiology

10
SLURP1 Biallelic Loss of Function
Biallelic germline SLURP1 variants abolish or severely reduce the secreted SLURP1 protein that differentiating keratinocytes of the granular layer and acrosyringium normally release; in patient palmoplantar skin and sweat the mutant protein is absent or barely detectable.
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.
SLURP1 hgnc:18746 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLURP1 (hgnc:18746). hgnc:18746 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Germline biallelic, usually homozygous, SLURP1 variants.
acetylcholine receptor regulator activity GO:0030548 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased acetylcholine receptor regulator activity (GO:0030548). GO:0030548 is a molecular function from the Gene Ontology.
Downstream
Loss of SLURP1 Modulation of Keratinocyte Alpha7 Nicotinic Acetylcholine Receptors SLURP1 binds and allosterically modulates the alpha7 nicotinic acetylcholine receptor on keratinocytes, so loss of SLURP1 removes this cholinergic input.
Impaired T-cell Activation Peripheral blood T cells from a family carrying SLURP1 G86R show defective activation that is restored by recombinant SLURP-1.
Loss of SLURP1 Epithelial Tumor-Suppressive Activity Expression data suggest a putative epithelial tumor-suppressor role for SLURP1; this link is a hypothesis.
Show evidence (3 references)
PMID:17008884 SUPPORT Human Clinical
"In palmoplantar sections from MDM patients, as well as in their sweat, mutant SLURP1, including the new variant R71H-SLURP1, was either absent or barely detectable."
Patient skin and sweat lack detectable SLURP1, establishing loss of the protein.
PMID:17008884 SUPPORT Human Clinical
"SLURP1 was found to be a marker of late differentiation, predominantly expressed in the granular layer of skin, notably the acrosyringium."
Places normal SLURP1 production in differentiating granular-layer keratinocytes.
PMID:33741389 SUPPORT In Vitro
"Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity."
Recombinant disease-associated mutants show that many variants inactivate SLURP-1, while some alter rather than abolish activity.
Loss of SLURP1 Modulation of Keratinocyte Alpha7 Nicotinic Acetylcholine Receptors
SLURP1 is an auto/paracrine cholinergic peptide that binds alpha7 nicotinic acetylcholine receptors on keratinocytes. Early studies with fusion constructs described it as a potentiator or allosteric agonist of these receptors, while a recombinant protein closer to the native sequence acted as a non-competitive allosteric antagonist; both lines of work agree that SLURP1 signalling through alpha7 receptors restrains keratinocyte growth. In Mal de Meleda this receptor-mediated signal is lost.
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.
acetylcholine receptor signaling pathway GO:0095500 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated acetylcholine receptor signaling pathway (GO:0095500). GO:0095500 is a biological process from the Gene Ontology.
Downstream
Keratinocyte Hyperproliferation SLURP-1 restrains keratinocyte growth through alpha7 receptors, so its loss releases proliferation.
Disturbed Keratinocyte Terminal Differentiation SLURP-1 signalling induces differentiation and apoptosis genes in keratinocytes; without it these programmes are under-stimulated.
Cutaneous Inflammation with TNF-alpha Excess SLURP-1 cholinergic signalling is proposed to inhibit TNF-alpha release, so its loss is linked to the inflammatory component of the disease.
Show evidence (3 references)
PMID:14506129 SUPPORT In Vitro
"We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes."
Identifies keratinocyte alpha7 receptors as the SLURP-1 target.
PMID:16354194 SUPPORT In Vitro
"In the presence of the agonist carbachol, the effects of SLURP-1 on gene expression were augmented, which is in keeping with the notion that SLURP-1 acts as an allosteric agonist at the KC nAChR."
Recombinant SLURP-1 acts at keratinocyte nicotinic receptors.
PMID:26905431 SUPPORT In Vitro
"These findings imply an allosteric antagonist-like mode of SLURP-1 interaction with α7-nAChRs outside the classical ligand-binding site."
A recombinant SLURP-1 closer to the native protein behaves as an allosteric antagonist, so the sign of the modulation is disputed while the receptor target is not.
Keratinocyte Hyperproliferation
Palmoplantar keratinocytes proliferate excessively in SLURP1 deficiency, as shown by increased keratinocyte proliferation in the volar paw skin of Slurp1 knockout mice, which reproduce the human keratoderma.
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.
keratinocyte proliferation GO:0043616 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinocyte proliferation (GO:0043616). GO:0043616 is a biological process from the Gene Ontology.
Animal models
Slurp1 knockout mouse Mouse recapitulates Volar paw keratinocytes proliferate excessively, reproducing the human keratoderma.
Downstream
Palmoplantar Epidermal Hyperkeratosis and Acanthosis Excess keratinocyte production thickens the volar epidermis.
Show evidence (1 reference)
PMID:24499735 SUPPORT Model Organism
"Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
Slurp1 knockout mice show increased keratinocyte proliferation in the keratoderma.
Disturbed Keratinocyte Terminal Differentiation
SLURP1 is a late differentiation product of granular-layer keratinocytes. Patient epidermis shows hypergranulosis with numerous irregular keratohyaline granules and perinuclear vacuoles in spinous keratinocytes, and Slurp1 knockout epidermis has a poorly demarcated granular layer, indicating an abnormal terminal differentiation programme.
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.
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.
Downstream
Palmoplantar Epidermal Hyperkeratosis and Acanthosis Abnormal cornification contributes to the thick, nonepidermolytic hyperkeratosis.
Hypergranulosis The granular-layer differentiation defect is seen histologically as hypergranulosis.
Stratum Corneum Water Barrier Defect with Lipid Accumulation The stratum corneum formed in SLURP1 deficiency retains neutral lipid droplets and fails as a water barrier in the knockout model.
Show evidence (2 references)
PMID:32157724 SUPPORT Human Clinical
"In addition, there were numerous irregular keratohyaline granules in the granular layer."
Ultrastructure of patient skin shows abnormal granular-layer differentiation.
PMID:24499735 SUPPORT Model Organism
"the stratum granulosum was poorly demarcated"
The knockout granular layer is abnormal.
Palmoplantar Epidermal Hyperkeratosis and Acanthosis
The palmoplantar epidermis becomes markedly thickened, with nonepidermolytic hyperkeratosis and acanthosis, spreading in a sharply demarcated pattern onto adjacent dorsal skin. The rigid hyperkeratotic plates fissure, restrict joint movement and can constrict the digits.
skin of palm UBERON:0013777 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin of palm, annotated with skin of palm of manus (UBERON:0013777). UBERON:0013777 is an anatomical location from the Uberon multi-species anatomy ontology. skin of sole UBERON:0013778 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin of sole, annotated with skin of sole of pes (UBERON:0013778). UBERON:0013778 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Transgredient Diffuse Palmoplantar Keratoderma
Epidermal Acanthosis
Palmoplantar Skin Fissures Deep fissures form in the thick, inflexible keratoderma.
Flexion Contractures of Fingers and Toes Long-standing hyperkeratosis produces flexion contractures of the digits.
Pain Thick keratoderma makes finger movement painful.
Pseudoainhum Constricting keratotic bands can form around digits within the keratoderma and occasionally lead to autoamputation.
Show evidence (2 references)
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"Histologically, the lesions show hyperkeratosis and acanthosis without epidermolysis in the epidermis, accompanied by perivascular lymphocytic infiltrate in the dermis."
The review summarizes the nonepidermolytic hyperkeratosis and acanthosis.
PMID:32157724 SUPPORT Human Clinical
"Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis, accompanied by perivascular lymphocytic infiltrates in the dermis."
Patient histology shows hyperkeratosis and acanthosis.
Stratum Corneum Water Barrier Defect with Lipid Accumulation
SLURP1-deficient palmoplantar stratum corneum accumulates neutral lipid droplets and fails as a water barrier; lipid-like droplets are also seen in the thickened cornified layer of patients.
stratum corneum UBERON:0002027 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stratum corneum, annotated with stratum corneum of epidermis (UBERON:0002027). UBERON:0002027 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Slurp1 knockout mouse Mouse recapitulates Knockout paw skin accumulates stratum corneum lipid droplets and loses water barrier function.
Downstream
Microbial Overgrowth in Hyperkeratotic Skin Leakage of interstitial fluid into the stratum corneum and accumulated triglyceride droplets are proposed to favour microbial growth.
Show evidence (2 references)
PMID:24499735 SUPPORT Model Organism
"Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
Slurp1 knockout keratoderma shows stratum corneum lipid droplets and a water barrier defect.
PMID:32157724 SUPPORT Human Clinical
"Several microorganisms and many lipid-like droplets were found in the thickened cornified layer."
Lipid-like droplets accumulate in the cornified layer of patient skin.
Microbial Overgrowth in Hyperkeratotic Skin
Bacteria and fungi colonise the thick, moist keratoderma. Microorganisms are seen within the cornified layer on electron microscopy, and dermatophyte (Trichophyton) superinfection of palmoplantar skin has been cultured.
Downstream
Malodour of Palmoplantar Skin Bacterial lipases acting on stratum corneum lipids are proposed to release malodorous compounds.
Pain Microbial superinfection of the keratoderma is one recognised source of pain.
Show evidence (2 references)
PMID:32157724 SUPPORT Human Clinical
"Several microorganisms and many lipid-like droplets were found in the thickened cornified layer."
Electron microscopy shows microorganisms within the thickened cornified layer.
PMID:35506361 SUPPORT Human Clinical
"Fungal culture from palmoplantar skin revealed Trichophyton verrucosum."
Documents dermatophyte superinfection of the keratoderma.
Cutaneous Inflammation with TNF-alpha Excess
Lesional skin shows a superficial perivascular lymphocytic infiltrate, and epidermal keratinocytes and dermal perivascular infiltrates stain for TNF-alpha, matching the erythematous, inflammatory component of the keratoderma.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. tumor necrosis factor production GO:0032640 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased tumor necrosis factor production (GO:0032640). GO:0032640 is a biological process from the Gene Ontology.
Animal models
Slurp1 knockout mouse Mouse fails to recapitulate Knockout paw skin lacks the dermal inflammatory infiltrate seen in patients.
Downstream
Sharply Demarcated Erythema Bordering the Keratoderma
Perioral Erythema
Superficial Dermal Perivascular Inflammatory Infiltrate
Show evidence (1 reference)
PMID:32157724 SUPPORT Human Clinical
"The whole layers of the epidermis and perivascular infiltrates of the dermis were stained positive with anti-tumor necrosis factor alpha"
Patient lesional skin shows TNF-alpha in epidermis and dermal infiltrates.
Impaired T-cell Activation
T cells from carriers of SLURP1 G86R respond poorly to CD3/CD28 stimulation, and recombinant SLURP-1 restores activation. Defective T-cell function has been proposed to contribute to the melanoma and viral infection seen in the same family.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
T cell activation GO:0042110 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell activation (GO:0042110). GO:0042110 is a biological process from the Gene Ontology.
Downstream
Melanoma Proposed link between defective T-cell function and melanoma; not established.
Show evidence (1 reference)
PMID:20854438 SUPPORT In Vitro
"PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation."
Patient peripheral blood cells stimulated in culture show defective T-cell activation.
Loss of SLURP1 Epithelial Tumor-Suppressive Activity
SLURP1 expression is high in epithelial tissues and reduced in epithelial cancers and in melanoma relative to nevi, suggesting a tumor-suppressor role whose loss could contribute to the cutaneous squamous cell carcinomas and melanomas reported at keratoderma sites. This is a hypothesis.
Downstream
Squamous Cell Carcinoma of the Skin
Melanoma
Show evidence (1 reference)
PMID:29231248 SUPPORT INDIRECT Computational
"SLURP1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts."
Public expression data show SLURP1 suppression in epithelial cancers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Mal de Meleda 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

23
Cardiovascular 1
Perioral Erythema HP:0033194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is perioral erythema (HP:0033194). HP:0033194 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11285253 SUPPORT Human Clinical
"Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
Perioral erythema is part of the characteristic phenotype.
PMID:11030771 SUPPORT Human Clinical
"The main clinical characteristics are transgressive palmoplantar keratoderma, hyperhidrosis, and perioral erythema"
Perioral erythema is a main clinical characteristic in Algerian families.
Immune 1
Superficial Dermal Perivascular Inflammatory Infiltrate VERY_FREQUENT HP:0031190 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is superficial dermal perivascular lymphocytic infiltrate, annotated with Superficial dermal perivascular inflammatory infiltrate (HP:0031190). HP:0031190 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:87503 SUPPORT Other
"HP:0031190 | Superficial dermal perivascular inflammatory infiltrate | Very frequent (99-80%)"
Orphanet records the superficial perivascular infiltrate as very frequent.
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"Histologically, the lesions show hyperkeratosis and acanthosis without epidermolysis in the epidermis, accompanied by perivascular lymphocytic infiltrate in the dermis."
The review summarizes the dermal perivascular lymphocytic infiltrate.
Integument 12
Transgredient Diffuse Palmoplantar Keratoderma Diffuse palmoplantar hyperkeratosis HP:0007447 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is transgredient diffuse palmoplantar keratoderma, annotated with Diffuse palmoplantar hyperkeratosis (HP:0007447), qualified as course progressive. HP:0007447 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (4 references)
PMID:11285253 SUPPORT Human Clinical
"Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
Transgressive palmoplantar keratoderma is the cardinal feature.
ORPHA:87503 SUPPORT Other
"A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens)."
Orphanet defines the disease by symmetric, transgredient palmoplantar hyperkeratosis.
PMID:35506361 SUPPORT Human Clinical
"Clinical examination revealed plaque-like yellowish and waxy palmoplantar hyperkeratosis with adjacent sharply demarcated, fine scaly erythema, which extended to the forearms and lower legs in a cuff-like (gloves and socks) distribution"
Describes the glove-and-stocking distribution of the keratoderma.
+ 1 more reference
Sharply Demarcated Erythema Bordering the Keratoderma FREQUENT Hyperkeratosis with erythema HP:0007390 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hyperkeratosis with sharply demarcated erythema, annotated with Hyperkeratosis with erythema (HP:0007390). HP:0007390 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:87503 SUPPORT Other
"HP:0007390 | Hyperkeratosis with erythema | Frequent (79-30%)"
Orphanet records hyperkeratosis with erythema as frequent.
PMID:14674887 SUPPORT Human Clinical
"Clinically, MDM is characterized by erythema and hyperkeratosis of the palms and soles with sharp demarcation that appears soon after birth and progressively extends to the dorsal surface of the hands and feet."
Describes sharply demarcated palmoplantar erythema with hyperkeratosis.
Palmoplantar Hyperhidrosis FREQUENT HP:0007410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is palmoplantar hyperhidrosis (HP:0007410). HP:0007410 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
ORPHA:87503 SUPPORT Other
"HP:0000975 | Hyperhidrosis | Frequent (79-30%)"
Orphanet records hyperhidrosis as frequent.
PMID:12592079 SUPPORT Human Clinical
"hyperhidrosis on the palms and soles (50%)"
Half of the largest reported series, from Anatolia, had palmoplantar hyperhidrosis.
PMID:11030771 SUPPORT Human Clinical
"The main clinical characteristics are transgressive palmoplantar keratoderma, hyperhidrosis, and perioral erythema"
Hyperhidrosis is a main clinical characteristic in Algerian families.
Palmoplantar Skin Fissures HP:0031057 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is palmoplantar fissures, annotated with Skin fissure (HP:0031057). HP:0031057 is a phenotype from the Human Phenotype Ontology.
Sequelae: Pain
Show evidence (1 reference)
PMID:19042068 SUPPORT Human Clinical
"Deep fissures cause pain and limit extension of the metacarpo-phalangeal joints."
Deep palmar fissures in a patient with Mal de Meleda.
Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32157724 SUPPORT Human Clinical
"The patient presented with pruritic and severely hyperkeratotic plaques on the bilateral palms and soles"
Pruritic plaques in a genetically confirmed child.
PMID:38903266 SUPPORT Human Clinical
"The patient reported itching, scaling, and a foul smell from the lesions"
Itching reported by an affected adolescent.
Lichenoid Plaques OCCASIONAL Lichenoid skin lesion HP:0031452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is lichenoid plaques, annotated with Lichenoid skin lesion (HP:0031452). HP:0031452 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:87503 SUPPORT Other
"HP:0031452 | Lichenoid skin lesion | Occasional (29-5%)"
Orphanet records lichenoid skin lesions as occasional.
PMID:11030771 SUPPORT Human Clinical
"but there are also associated features such as brachydactyly, nail abnormalities, and lichenoid plaques."
Lichenoid plaques are an associated feature.
Nail Abnormalities VERY_FREQUENT Abnormal nail morphology HP:0001597 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is nail abnormalities, annotated with Abnormal nail morphology (HP:0001597). HP:0001597 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:12592079 SUPPORT Human Clinical
"The prevalent clinical features were nail involvement (80%)"
Nail involvement was present in 80% of the largest reported series.
PMID:11285253 SUPPORT Human Clinical
"Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
Nail abnormalities are part of the characteristic phenotype.
PMID:35506361 SUPPORT Human Clinical
"In addition, nail dystrophy (Fig. 1e) and malodour was found."
Nail dystrophy in a genetically confirmed patient.
Sclerosis of the Skin of the Digits Sclerodactyly HP:0011838 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is sclerosis of the skin of the fingers and toes, annotated with Sclerodactyly (HP:0011838). HP:0011838 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28885351 SUPPORT Human Clinical
"her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
Sclerotic skin of the hands and feet in a patient with homozygous SLURP1 G86R.
PMID:41048964 SUPPORT BACKGROUND Human Clinical
"The hallmark features of the condition include transient thickening of the palms and soles, skin sclerosis and atrophy, scleroatrophic erythematous lesions, pseudoainhum formation around the digits, and erythema around the mouth."
The case report's introduction lists skin sclerosis among the hallmark features of Mal de Meleda.
Skin Atrophy Dermal atrophy HP:0004334 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is skin atrophy, annotated with Dermal atrophy (HP:0004334). HP:0004334 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28885351 SUPPORT Human Clinical
"her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
Atrophic skin lesions in a patient with homozygous SLURP1 G86R.
PMID:41048964 SUPPORT BACKGROUND Human Clinical
"The hallmark features of the condition include transient thickening of the palms and soles, skin sclerosis and atrophy, scleroatrophic erythematous lesions, pseudoainhum formation around the digits, and erythema around the mouth."
The case report's introduction lists skin atrophy among the hallmark features of Mal de Meleda.
Epidermal Acanthosis FREQUENT 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 (2 references)
ORPHA:87503 SUPPORT Other
"HP:0025092 | Epidermal acanthosis | Frequent (79-30%)"
Orphanet records epidermal acanthosis as frequent.
PMID:32157724 SUPPORT Human Clinical
"Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis"
Acanthosis in patient histology.
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 (3 references)
PMID:32157724 SUPPORT Human Clinical
"Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis"
Hypergranulosis in patient histology.
PMID:34692287 SUPPORT Human Clinical
"Histopathological investigation of the skin lesions reported hyperkeratosis, hypergranulosis, and acanthosis of the skin."
Hypergranulosis in two affected siblings.
PMID:21909218 REFUTE Human Clinical
"The histopathologic study showed marked hyperkeratosis, acanthosis, and normogranulosis, without epidermolysis."
A genetically confirmed Korean patient had a normal granular layer, so hypergranulosis is not constant.
Squamous Cell Carcinoma of the Skin HP:0006739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cutaneous squamous cell carcinoma at keratoderma sites, annotated with Squamous cell carcinoma of the skin (HP:0006739). HP:0006739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29231248 SUPPORT Human Clinical
"Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma."
Cutaneous SCC in affected members of a family with homozygous c.82delT.
Limbs 3
Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11285253 SUPPORT Human Clinical
"Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
Brachydactyly is part of the characteristic phenotype.
Conical Tapering of the Fingers FREQUENT Tapered finger HP:0001182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is conical tapering of the fingertips, annotated with Tapered finger (HP:0001182). HP:0001182 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12592079 SUPPORT Human Clinical
"conical tapering of the fingertips (60%)"
Present in 60% of the Anatolian series.
PMID:15909066 SUPPORT Human Clinical
"conical tapering of the fingers"
Described in a Taiwanese patient with homozygous G86R.
Autoamputation of Digits HP:0007460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is autoamputation of digits (HP:0007460). HP:0007460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24499735 SUPPORT BACKGROUND Human Clinical
"Affected patients have thickening of the skin on the palms and soles, occasionally with pseudoainhum formation and autoamputation of digits."
Autoamputation of digits is an occasional complication.
Metabolism 1
Edema of the Hands and Feet FREQUENT Peripheral edema HP:0012398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is edema of the hands and feet, annotated with Peripheral edema (HP:0012398). HP:0012398 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12592079 SUPPORT Human Clinical
"edema on the hands/feet (60%)"
Edema of the hands and feet was present in 60% of the Anatolian series.
Musculoskeletal 1
Flexion Contractures of Fingers and Toes FREQUENT HP:0001371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is flexion contractures of fingers and toes, annotated with Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology.
Sequelae: Sclerosis of the Skin of the Digits Skin Atrophy
Show evidence (2 references)
ORPHA:87503 SUPPORT Other
"HP:0001371 | Flexion contracture | Frequent (79-30%)"
Orphanet records flexion contracture as frequent.
PMID:28885351 SUPPORT Human Clinical
"MDM can lead to severe flexion contractures in some cases."
Severe digital flexion contractures in a genetically confirmed patient.
Prenatal and Birth 1
Pseudoainhum Digital constriction ring HP:0010491 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pseudoainhum, annotated with Digital constriction ring (HP:0010491). HP:0010491 is a phenotype from the Human Phenotype Ontology.
Sequelae: Autoamputation of Digits
Show evidence (2 references)
PMID:24499735 SUPPORT BACKGROUND Human Clinical
"Affected patients have thickening of the skin on the palms and soles, occasionally with pseudoainhum formation and autoamputation of digits."
The knockout paper's introduction summarizes pseudoainhum as an occasional human feature.
PMID:35506361 SUPPORT BACKGROUND Human Clinical
"Rarely, pseudoainhum and melanoma can occur in affected areas"
The case report's discussion lists pseudoainhum as a rare feature.
Constitutional 2
Malodour of Palmoplantar Skin Body odor HP:0500001 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is malodorous palmoplantar skin, annotated with Body odor (HP:0500001). HP:0500001 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:24499735 SUPPORT BACKGROUND Human Clinical
"The skin of the palms and soles is often malodorous."
The knockout paper's introduction summarizes the human clinical picture, including malodour.
PMID:31582262 SUPPORT Human Clinical
"foul-smelling and yellowish palmoplantar keratoderma transgrediens"
A patient with Mal de Meleda had foul-smelling keratoderma.
PMID:35506361 SUPPORT Human Clinical
"In addition, nail dystrophy (Fig. 1e) and malodour was found."
Malodour documented in a genetically confirmed patient.
Pain HP:0012531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is palmoplantar pain, annotated with Pain (HP:0012531). HP:0012531 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34692287 SUPPORT Human Clinical
"The male patient reported pain during finger movements. This was attributed to the thickness of the keratoderma lesion."
Pain on finger movement in an affected child.
PMID:38866482 SUPPORT BACKGROUND Human Clinical
"Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin."
The background of the knockout pain study summarizes pain in patients.
Neoplasm 1
Melanoma HP:0002861 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is melanoma arising in keratoderma skin, annotated with Melanoma (HP:0002861). HP:0002861 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:14756434 SUPPORT Human Clinical
"We observed a case of a 74-year-old man with Mal de Meleda, who developed malignant melanoma inside the hyperkeratotic palmar skin of the right hand."
Melanoma arising within palmar keratoderma.
PMID:31582262 SUPPORT Human Clinical
"Development of acral malignant melanoma in Mal de Meleda is highly unusual."
Acral melanoma in Mal de Meleda is reported but rare.
PMID:29231248 SUPPORT Human Clinical
"Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma."
Melanoma in affected members of a Palestinian family.
🧬

Genetic Associations

1
SLURP1 (Causative germline biallelic variants)
Gene: SLURP1 hgnc:18746 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLURP1 (hgnc:18746). hgnc:18746 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
ORPHA:87503 SUPPORT Other
"SLURP1 | secreted LY6/PLAUR domain containing 1 | hgnc:18746 | Disease-causing germline mutation(s) in"
Orphanet identifies SLURP1 germline mutations as disease-causing.
PMID:11285253 SUPPORT Human Clinical
"the identification of mutations in affected individuals in the ARS (component B) gene, encoding a protein named SLURP-1, for secreted Ly-6/uPAR related protein 1"
Positional cloning identified SLURP1 mutations in affected individuals.
PMID:11285253 SUPPORT Human Clinical
"Three different homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin, suggesting founder effects."
Homozygous loss-of-function SLURP1 variants segregate with disease in 19 families.
+ 1 more reference
Variants (4)
c.82delT
Frameshift deletion recurrent in Algerian, Croatian, Tunisian and Middle Eastern families with Mal de Meleda.
Show evidence (2 references)
PMID:14674887 SUPPORT Human Clinical
"Three different mutations were identified, the 82delT mutation previously described and two novel missense mutations."
The 82delT allele recurs in Tunisian families.
PMID:29231248 SUPPORT Human Clinical
"Sequence analysis revealed homozygous SLURP1 mutations (c.82delT) in the affected members."
The same allele is homozygous in an affected Palestinian family.
c.43T>C (p.W15R)
Signal-peptide missense variant found in German, Scottish and Swedish patients, including the Gamborg-Nielsen type; transfected cells do not tolerate the mutant protein.
Show evidence (2 references)
PMID:12603845 SUPPORT Human Clinical
"a signal sequence mutation (W15R), which was homozygous in a German family and heterozygous in a Scottish patient."
Reports the W15R signal-sequence variant in European patients.
PMID:17008884 SUPPORT In Vitro
"did not tolerate the MDM mutation W15R located in the signal peptide"
Transfected cells did not tolerate the W15R signal-peptide mutant.
c.256G>A (p.G86R)
Missense variant at a conserved glycine, recurrent in Palestinian, Turkish, Taiwanese and Chinese patients, and associated in one family with impaired T-cell activation.
Show evidence (3 references)
PMID:12483299 SUPPORT Human Clinical
"In a large Palestinian pedigree with multiple consanguinity, patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at position 86."
Homozygous G86R in a consanguineous Palestinian pedigree.
PMID:15909066 SUPPORT Human Clinical
"Mutation analysis revealed a homozygous missense mutation (G86R) in exon 3 of ARS gene of this patient."
Homozygous G86R in a Taiwanese patient.
PMID:32157724 SUPPORT Human Clinical
"A homozygous c.256 G>A mutation, predicting a conversion of p.Gly86Arg, in SLURP1gene was detected."
Homozygous G86R in a Taiwanese child.
R96X
Nonsense variant shared on a common ancestral haplotype by Turkish families.
Show evidence (2 references)
PMID:12787122 SUPPORT Human Clinical
"We identified a recurrent nonsense mutation, R96X, in four families of Turkish descent."
Reports the recurrent Turkish R96X allele.
PMID:12787122 SUPPORT Human Clinical
"these families share a common ancestral haplotype at the mal de Meleda locus, suggesting a founder effect"
Haplotype sharing indicates a founder effect.
🗃️

External Assertions

1
Orphanet Mal de Meleda record
Orphanet structured disease record ORPHA:87503
Orphanet's ORPHA:87503 record supplies the disease definition, autosomal recessive inheritance, the SLURP1 disease-gene assertion, the worldwide prevalence class, HPO phenotype frequencies, and exact MONDO and OMIM cross-references. Orphanet has merged the former Gamborg-Nielsen type record (ORPHA:86923) into this entity.
Show evidence (3 references)
ORPHA:87503 SUPPORT Other
"MONDO:0009552 | Exact"
Orphanet maps ORPHA:87503 exactly to the MONDO identifier used by this entry.
ORPHA:87503 SUPPORT Other
"OMIM:248300 | Exact"
Orphanet lists OMIM:248300 as an exact cross-reference.
ORPHA:87503 SUPPORT Other
"ORPHA:86923 | Hereditary palmoplantar keratoderma, Gamborg-Nielsen type | Moved to | ORPHA:87503 | Mal de Meleda"
Orphanet records that the Gamborg-Nielsen type record was moved into Mal de Meleda.
💊

Medical Actions

5
Oral Acitretin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acitretin CHEBI:50172 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acitretin (CHEBI:50172). CHEBI:50172 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Systemic retinoid therapy reduces hyperkeratosis and is the mainstay of management, usually combined with topical keratolytics. Low doses (about 10 mg/day) have been effective; mucocutaneous adverse effects such as dry eyes and lips can limit use, and acitretin does not always prevent mutilating progression.
Mechanism Target:
Palmoplantar Epidermal Hyperkeratosis and Acanthosis — Acitretin reduces the epidermal hyperkeratosis.
Target Phenotypes: transgredient diffuse palmoplantar keratoderma HP:0007447 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets transgredient diffuse palmoplantar keratoderma, annotated with Diffuse palmoplantar hyperkeratosis (HP:0007447). HP:0007447 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"the accepted approach tends to include oral acitretin plus topical keratolytic therapy"
The review identifies oral acitretin plus topical keratolytics as the accepted approach.
PMID:35506361 SUPPORT Human Clinical
"low-dose acitretin was initiated at 10 mg/day. Two months later, the patient showed significantly reduced palmar hyperkeratosis"
Low-dose acitretin reduced hyperkeratosis in a genetically confirmed patient.
PMID:38903266 SUPPORT Human Clinical
"Treatment with oral acitretin and topical moisturizers resulted in significant improvement."
Acitretin improved the keratoderma in an affected adolescent.
+ 1 more reference
Topical Keratolytic and Retinoid Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tazarotene CHEBI:32184 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tazarotene (CHEBI:32184). CHEBI:32184 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Topical keratolytics, topical retinoids such as tazarotene or tretinoin, emollients and regular mechanical debridement soften and thin the keratoderma. Topical tazarotene has been combined with oral acitretin.
Mechanism Target:
Palmoplantar Epidermal Hyperkeratosis and Acanthosis — Topical agents soften and remove the hyperkeratosis.
Show evidence (2 references)
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"the accepted approach tends to include oral acitretin plus topical keratolytic therapy"
Topical keratolytic therapy is part of the accepted approach.
PMID:28885351 SUPPORT Human Clinical
"This patient was treated with oral acitretin and topical tazarotene."
Topical tazarotene combined with acitretin in a genetically confirmed patient.
Antifungal Treatment of Superinfection
Action: antifungal therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antifungal therapy (NCIT:C15704). NCIT:C15704 is a clinical intervention from the NCI Thesaurus. Ontology label: Antifungal Therapy NCIT:C15704
Agent: terbinafine CHEBI:9448 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses terbinafine (CHEBI:9448). CHEBI:9448 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Bacterial and fungal superinfection of the keratoderma is treated with topical and systemic antimicrobials; a Trichophyton superinfection was treated with topical econazole and oral terbinafine.
Mechanism Target:
Microbial Overgrowth in Hyperkeratotic Skin — Antifungals clear dermatophyte superinfection of the keratoderma.
Show evidence (1 reference)
PMID:35506361 SUPPORT Human Clinical
"The Trichophyton superinfection was treated with topical econazole and systemic terbinafine (250 mg/day for 4 weeks)."
Antifungal treatment of dermatophyte superinfection in a patient.
Surgical Excision with Full-Thickness Skin Grafting
Action: excision of palmar keratoderma with full-thickness skin graftingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is excision of palmar keratoderma with full-thickness skin grafting, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
For severe palmar keratoderma, excision of the hyperkeratotic skin and coverage with full-thickness skin grafts has given durable relief, with no recurrence on grafted areas over 29 years in one patient.
Mechanism Target:
Palmoplantar Epidermal Hyperkeratosis and Acanthosis — Replaces keratodermic palmar skin with grafted skin.
Show evidence (1 reference)
PMID:19042068 SUPPORT Human Clinical
"Long term follow-up (29 years) demonstrates no recurrence of keratosis on surgically treated areas."
Grafted areas remained free of keratosis over long follow-up.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counseling on autosomal recessive recurrence risk, particularly in consanguineous families.
Show evidence (1 reference)
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"Genetic counseling should also be offered."
The review recommends genetic counseling.
🔬

Diagnosis

3
SLURP1 molecular genetic testing
Identification of biallelic SLURP1 pathogenic variants confirms the diagnosis and distinguishes Mal de Meleda from other transgredient keratodermas and from psoriasis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28885351 SUPPORT Human Clinical
"The reliable method for the diagnosis of MDM is gene test."
Genetic testing is the reliable diagnostic method.
Skin biopsy
Biopsy shows nonepidermolytic hyperkeratosis, acanthosis and hypergranulosis with a superficial perivascular lymphocytic infiltrate; absence of epidermolysis separates it from epidermolytic palmoplantar keratoderma.
Show evidence (1 reference)
PMID:35506361 SUPPORT Human Clinical
"A punch biopsy from plantar skin revealed hyperkeratosis, mild hypergranulosis and a discrete perivascular inflammatory infiltrate in the superficial dermis, but no epidermolysis."
Characteristic nonepidermolytic biopsy findings.
SLURP1 protein immunodetection
Because most pathogenic variants leave SLURP1 absent or barely detectable in skin and sweat, immunological detection of SLURP1 has been proposed as a rapid screening test.
Show evidence (1 reference)
PMID:17008884 SUPPORT Human Clinical
"Thus, most MDM mutations in SLURP1 affect either the expression, integrity, or stability of the protein, suggesting that a simple immunologic test could be used as a rapid screening procedure."
Proposes SLURP1 immunodetection as a screening approach.
📈

Progression

2
Onset
Age: Infancy to early childhood
Palmoplantar erythema and hyperkeratosis appear soon after birth or in infancy. Orphanet lists infancy and childhood onset.
Show evidence (1 reference)
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"Clinically, the onset of the disease is typically soon after birth and features a transgrediens (plantar surface progressing to dorsal surface) and progrediens (worsening with age) pattern of hyperkeratosis of the palms and soles."
The review states that onset is typically soon after birth.
Progressive transgredient keratoderma
Age: Childhood through adulthood
Keratoderma extends from the palms and soles onto the dorsal hands, feet, wrists and ankles and worsens with age; long-standing disease can produce flexion contractures and mutilating changes of the digits. Symptoms are milder in people who do not do manual work and who apply continuous symptomatic treatment.
Show evidence (3 references)
PMID:14674887 SUPPORT Human Clinical
"Clinically, MDM is characterized by erythema and hyperkeratosis of the palms and soles with sharp demarcation that appears soon after birth and progressively extends to the dorsal surface of the hands and feet."
The Tunisian family study describes progressive extension to the dorsal hands and feet.
PMID:28885351 SUPPORT Human Clinical
"MDM can lead to severe flexion contractures in some cases."
The case report documents contractures as a late consequence of progressive disease.
PMID:12145432 SUPPORT Human Clinical
"Symptoms and signs were found to be milder in non-manual workers who had applied continuous symptomatic treatment."
In the Mljet series, occupation and continuous treatment modified severity.
📊

Prevalence

1
Worldwide
Point Prevalence 1.0 per 100,000 1–9 per 100,000
Orphanet assigns a worldwide point-prevalence class of 1-9 per 100,000, and reviews cite an estimated prevalence of 1 in 100,000. Affected families cluster in consanguineous and founder populations, including the island of Mljet in Croatia, Algeria, Tunisia, Anatolia and Taiwan.
Show evidence (2 references)
ORPHA:87503 SUPPORT Other
"1-9 / 100 000 | Worldwide | Point prevalence | PMID:9887370"
Orphanet records a worldwide point-prevalence class of 1-9 per 100,000.
PMID:26445964 SUPPORT REVIEW SYNTHESIS Other
"Mal de Meleda is a rare autosomal recessive palmoplantar keratoderma (PPK) disease with an estimated prevalence of 1:100,000."
The focused review gives the commonly cited prevalence estimate of 1 in 100,000.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Mal de Meleda:

Keratoderma hereditarium mutilans MONDO:0007422
Overlapping Features Vohwinkel syndrome, a mutilating palmoplantar keratoderma with pseudoainhum, is listed among the genodermatoses to distinguish from the transgredient variant of Mal de Meleda.
Show evidence (1 reference)
PMID:38903266 SUPPORT Human Clinical
"Differential diagnosis may include other genodermatoses with palmoplantar involvement, such as Papillon-Lefèvre syndrome and keratoderma hereditarium mutilans"
The case report lists keratoderma hereditarium mutilans as a differential diagnosis.
Papillon-Lefevre syndrome MONDO:0009490
Overlapping Features Papillon-Lefevre syndrome is listed among the genodermatoses with palmoplantar involvement to distinguish from the transgredient variant of Mal de Meleda.
Show evidence (1 reference)
PMID:38903266 SUPPORT Human Clinical
"Differential diagnosis may include other genodermatoses with palmoplantar involvement, such as Papillon-Lefèvre syndrome and keratoderma hereditarium mutilans"
The case report lists Papillon-Lefevre syndrome as a differential diagnosis.
🐁

Animal Models

1
Slurp1 knockout mouse
Two independent Slurp1 knockout lines develop palmoplantar keratoderma of the paws with increased keratinocyte proliferation, lipid droplets in the stratum corneum and a water barrier defect, together with reduced adiposity and hind-limb clasping. Slurp1 knockout mice also show mechanical and thermal pain hypersensitivity.
Species
Mouse
Genotype
Slurp1-/- (exon 2 replacement) and Slurp1X-/- (exon 2 nonsense allele)
Publication
PMID:24499735
Pathograph links
Keratinocyte Hyperproliferation recapitulates fidelity: high observes: tissue Volar paw keratinocytes proliferate excessively, reproducing the human keratoderma.
Show evidence (1 reference)
PMID:28418591 SUPPORT Model Organism
"Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws."
The knockout reproduces the proliferative keratoderma.
Stratum Corneum Water Barrier Defect with Lipid Accumulation recapitulates fidelity: moderate observes: tissue Knockout paw skin accumulates stratum corneum lipid droplets and loses water barrier function.
Show evidence (1 reference)
PMID:24499735 SUPPORT Model Organism
"Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
Directly documents the barrier and lipid phenotype.
Cutaneous Inflammation with TNF-alpha Excess fails to recapitulate fidelity: low observes: tissue Knockout paw skin lacks the dermal inflammatory infiltrate seen in patients.
Limitations: Inflammatory infiltrates were absent from knockout paw skin, so the model does not reproduce the erythematous, inflammatory component of the human disease.
Show evidence (1 reference)
PMID:24499735 SUPPORT Model Organism
"No inflammatory infiltrates were present."
Histology of knockout paw skin showed no inflammatory infiltrate.
{ }

Source YAML

click to show 
name: Mal de Meleda
creation_date: "2026-10-15T01:39:12Z"
category: Mendelian
synonyms:
- Meleda disease
- MDM
- keratosis palmoplantaris transgrediens of Siemens
- keratosis palmoplantaris transgrediens et progrediens
- SLURP1-related palmoplantar keratoderma
description: >-
  Mal de Meleda is a rare autosomal recessive diffuse palmoplantar keratoderma
  caused by biallelic loss-of-function variants in SLURP1, which encodes a small
  secreted Ly6/uPAR-family protein made by differentiating keratinocytes.
  Erythema and yellowish, waxy hyperkeratosis of the palms and soles begin in
  infancy, extend onto the dorsal hands and feet, wrists and ankles in a
  sharply demarcated glove-and-stocking pattern (transgrediens), and worsen with
  age (progrediens). Hyperhidrosis, malodour and microbial superinfection of the
  thickened skin, painful fissures, nail abnormalities, perioral erythema,
  brachydactyly or tapering of the digits, lichenoid plaques, flexion
  contractures and pseudoainhum are recognised features, and melanoma and
  squamous cell carcinoma have been reported within affected skin. Histology
  shows nonepidermolytic hyperkeratosis, acanthosis and hypergranulosis with a
  superficial perivascular lymphocytic infiltrate. SLURP1 is an allosteric
  modulator of keratinocyte alpha7 nicotinic acetylcholine receptors that
  restrains keratinocyte growth, and its loss is linked to keratinocyte
  hyperproliferation, disturbed terminal differentiation and cutaneous
  inflammation. Management is symptomatic, centred on oral acitretin and
  topical keratolytics.
disease_term:
  preferred_term: mal de Meleda
  term:
    id: MONDO:0009552
    label: mal de Meleda
parents:
- Diffuse palmoplantar keratoderma
- Autosomal recessive disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009552
      label: mal de Meleda
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:87503
    mapping_justification: >-
      Orphanet ORPHA:87503 lists MONDO:0009552 as an exact cross-reference for
      Mal de Meleda.
external_assertions:
- name: Orphanet Mal de Meleda record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:87503
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=87503
  description: >-
    Orphanet's ORPHA:87503 record supplies the disease definition, autosomal
    recessive inheritance, the SLURP1 disease-gene assertion, the worldwide
    prevalence class, HPO phenotype frequencies, and exact MONDO and OMIM
    cross-references. Orphanet has merged the former Gamborg-Nielsen type
    record (ORPHA:86923) into this entity.
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009552 | Exact"
    explanation: Orphanet maps ORPHA:87503 exactly to the MONDO identifier used by this entry.
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:248300 | Exact"
    explanation: Orphanet lists OMIM:248300 as an exact cross-reference.
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ORPHA:86923 | Hereditary palmoplantar keratoderma, Gamborg-Nielsen type | Moved to | ORPHA:87503 | Mal de Meleda"
    explanation: Orphanet records that the Gamborg-Nielsen type record was moved into Mal de Meleda.
definitions:
- name: Orphanet Mal de Meleda definition
  definition_type: OTHER
  description: >-
    A rare diffuse palmoplantar keratoderma with symmetric palmoplantar
    hyperkeratosis that progressively extends to the dorsal hands and feet
    (transgrediens), with possible hyperhidrosis, lichenoid plaques and perioral
    erythema.
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens)."
    explanation: Orphanet defines the disorder as a transgredient diffuse palmoplantar keratoderma.
has_subtypes:
- name: Gamborg-Nielsen type
  display_name: Palmoplantar keratoderma, Gamborg-Nielsen (Norrbotten) type
  subtype_term:
    preferred_term: hereditary palmoplantar keratoderma, Gamborg-Nielsen type
    term:
      id: MONDO:0009489
      label: hereditary palmoplantar keratoderma, Gamborg-Nielsen type
  description: >-
    Autosomal recessive palmoplantar keratoderma described in families from
    northern Sweden that overlaps phenotypically with Mal de Meleda. Affected
    individuals are homozygous for the SLURP1 signal-peptide variant c.43T>C
    (p.W15R) or compound heterozygous for it, so the form is an allelic variant
    of Mal de Meleda rather than a separate disease.
  evidence:
  - reference: PMID:24604124
    reference_title: "Palmoplantar keratoderma of the Gamborg-Nielsen type is caused by mutations in the SLURP1 gene and represents a variant of Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereby we confirm that PPK-GN is an allelic variant of MDM."
    explanation: SLURP1 sequencing in Swedish families shows the Gamborg-Nielsen type is allelic with Mal de Meleda.
  - reference: PMID:24604124
    reference_title: "Palmoplantar keratoderma of the Gamborg-Nielsen type is caused by mutations in the SLURP1 gene and represents a variant of Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation."
    explanation: Identifies the SLURP1 genotypes underlying the Gamborg-Nielsen type.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Mal de Meleda is inherited in an autosomal recessive pattern; affected
    individuals carry biallelic SLURP1 variants, frequently homozygous in
    consanguineous families and founder populations. Pseudodominant
    transmission occurs when an affected parent has a carrier partner.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
    explanation: The gene-discovery study describes Mal de Meleda as an autosomal recessive disorder.
  - reference: PMID:12483299
    reference_title: "Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a German family with no known consanguinity, we have shown pseudodominant inheritance. Three affected children and their affected mother are homozygous for the missense mutation W15R."
    explanation: Apparent vertical transmission in this family reflects homozygosity in mother and children, consistent with recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  notes: >-
    Orphanet assigns a worldwide point-prevalence class of 1-9 per 100,000, and
    reviews cite an estimated prevalence of 1 in 100,000. Affected families
    cluster in consanguineous and founder populations, including the island of
    Mljet in Croatia, Algeria, Tunisia, Anatolia and Taiwan.
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Worldwide | Point prevalence | PMID:9887370"
    explanation: Orphanet records a worldwide point-prevalence class of 1-9 per 100,000.
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mal de Meleda is a rare autosomal recessive palmoplantar keratoderma (PPK) disease with an estimated prevalence of 1:100,000."
    explanation: The focused review gives the commonly cited prevalence estimate of 1 in 100,000.
progression:
- phase: Onset
  age_range: Infancy to early childhood
  notes: >-
    Palmoplantar erythema and hyperkeratosis appear soon after birth or in
    infancy. Orphanet lists infancy and childhood onset.
  evidence:
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Clinically, the onset of the disease is typically soon after birth and features a transgrediens (plantar surface progressing to dorsal surface) and progrediens (worsening with age) pattern of hyperkeratosis of the palms and soles."
    explanation: The review states that onset is typically soon after birth.
- phase: Progressive transgredient keratoderma
  age_range: Childhood through adulthood
  notes: >-
    Keratoderma extends from the palms and soles onto the dorsal hands, feet,
    wrists and ankles and worsens with age; long-standing disease can produce
    flexion contractures and mutilating changes of the digits. Symptoms are
    milder in people who do not do manual work and who apply continuous
    symptomatic treatment.
  evidence:
  - reference: PMID:14674887
    reference_title: "A novel missense mutation in the gene encoding SLURP-1 in patients with Mal de Meleda from northern Tunisia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, MDM is characterized by erythema and hyperkeratosis of the palms and soles with sharp demarcation that appears soon after birth and progressively extends to the dorsal surface of the hands and feet."
    explanation: The Tunisian family study describes progressive extension to the dorsal hands and feet.
  - reference: PMID:28885351
    reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MDM can lead to severe flexion contractures in some cases."
    explanation: The case report documents contractures as a late consequence of progressive disease.
  - reference: PMID:12145432
    reference_title: "Mal de Meleda: genetic haplotype analysis and clinicopathological findings in cases originating from the island of Mljet (Meleda), Croatia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms and signs were found to be milder in non-manual workers who had applied continuous symptomatic treatment."
    explanation: In the Mljet series, occupation and continuous treatment modified severity.
genetic:
- name: SLURP1
  association: Causative germline biallelic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SLURP1
    term:
      id: hgnc:18746
      label: SLURP1
  features: >-
    Biallelic SLURP1 (formerly ARS component B) variants, including deletions,
    nonsense, splice-site, start-codon, signal-peptide and missense variants,
    cause Mal de Meleda. Most variants abolish or reduce the amount of SLURP1
    protein in skin and sweat. Recurrent alleles reflect founder effects, for
    example c.82delT in Croatian, Algerian and Tunisian families, R96X in
    Turkish families, W15R in German and Swedish families, and G86R in
    Palestinian, Turkish, Taiwanese and Chinese families.
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLURP1 | secreted LY6/PLAUR domain containing 1 | hgnc:18746 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies SLURP1 germline mutations as disease-causing.
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the identification of mutations in affected individuals in the ARS (component B) gene, encoding a protein named SLURP-1, for secreted Ly-6/uPAR related protein 1"
    explanation: Positional cloning identified SLURP1 mutations in affected individuals.
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three different homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin, suggesting founder effects."
    explanation: Homozygous loss-of-function SLURP1 variants segregate with disease in 19 families.
  - reference: PMID:12483299
    reference_title: "Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings indicate that the MDM type of transgressive PPK is caused by SLURP-1 mutations in patients from various origins and demonstrate allelic heterogeneity for mutations in SLURP-1."
    explanation: SLURP1 mutations in German, Turkish, Palestinian and Emirati families show allelic heterogeneity.
  variants:
  - name: c.82delT
    description: >-
      Frameshift deletion recurrent in Algerian, Croatian, Tunisian and Middle
      Eastern families with Mal de Meleda.
    evidence:
    - reference: PMID:14674887
      reference_title: "A novel missense mutation in the gene encoding SLURP-1 in patients with Mal de Meleda from northern Tunisia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three different mutations were identified, the 82delT mutation previously described and two novel missense mutations."
      explanation: The 82delT allele recurs in Tunisian families.
    - reference: PMID:29231248
      reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis revealed homozygous SLURP1 mutations (c.82delT) in the affected members."
      explanation: The same allele is homozygous in an affected Palestinian family.
  - name: c.43T>C (p.W15R)
    description: >-
      Signal-peptide missense variant found in German, Scottish and Swedish
      patients, including the Gamborg-Nielsen type; transfected cells do not
      tolerate the mutant protein.
    evidence:
    - reference: PMID:12603845
      reference_title: "Novel mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1) and description of five ancestral haplotypes in patients with Mal de Meleda."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a signal sequence mutation (W15R), which was homozygous in a German family and heterozygous in a Scottish patient."
      explanation: Reports the W15R signal-sequence variant in European patients.
    - reference: PMID:17008884
      reference_title: "SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "did not tolerate the MDM mutation W15R located in the signal peptide"
      explanation: Transfected cells did not tolerate the W15R signal-peptide mutant.
  - name: c.256G>A (p.G86R)
    description: >-
      Missense variant at a conserved glycine, recurrent in Palestinian,
      Turkish, Taiwanese and Chinese patients, and associated in one family with
      impaired T-cell activation.
    evidence:
    - reference: PMID:12483299
      reference_title: "Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a large Palestinian pedigree with multiple consanguinity, patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at position 86."
      explanation: Homozygous G86R in a consanguineous Palestinian pedigree.
    - reference: PMID:15909066
      reference_title: "Mal de Meleda in a taiwanese."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation analysis revealed a homozygous missense mutation (G86R) in exon 3 of ARS gene of this patient."
      explanation: Homozygous G86R in a Taiwanese patient.
    - reference: PMID:32157724
      reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A homozygous c.256 G>A mutation, predicting a conversion of p.Gly86Arg, in SLURP1gene was detected."
      explanation: Homozygous G86R in a Taiwanese child.
  - name: R96X
    description: Nonsense variant shared on a common ancestral haplotype by Turkish families.
    evidence:
    - reference: PMID:12787122
      reference_title: "A recurrent mutation in the ARS (component B) gene encoding SLURP-1 in Turkish families with mal de Meleda: evidence of a founder effect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a recurrent nonsense mutation, R96X, in four families of Turkish descent."
      explanation: Reports the recurrent Turkish R96X allele.
    - reference: PMID:12787122
      reference_title: "A recurrent mutation in the ARS (component B) gene encoding SLURP-1 in Turkish families with mal de Meleda: evidence of a founder effect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "these families share a common ancestral haplotype at the mal de Meleda locus, suggesting a founder effect"
      explanation: Haplotype sharing indicates a founder effect.
pathophysiology:
- name: SLURP1 Biallelic Loss of Function
  description: >-
    Biallelic germline SLURP1 variants abolish or severely reduce the secreted
    SLURP1 protein that differentiating keratinocytes of the granular layer and
    acrosyringium normally release; in patient palmoplantar skin and sweat the
    mutant protein is absent or barely detectable.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SLURP1
    term:
      id: hgnc:18746
      label: SLURP1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Germline biallelic, usually homozygous, SLURP1 variants.
  molecular_functions:
  - preferred_term: acetylcholine receptor regulator activity
    term:
      id: GO:0030548
      label: acetylcholine receptor regulator activity
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:17008884
    reference_title: "SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In palmoplantar sections from MDM patients, as well as in their sweat, mutant SLURP1, including the new variant R71H-SLURP1, was either absent or barely detectable."
    explanation: Patient skin and sweat lack detectable SLURP1, establishing loss of the protein.
  - reference: PMID:17008884
    reference_title: "SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLURP1 was found to be a marker of late differentiation, predominantly expressed in the granular layer of skin, notably the acrosyringium."
    explanation: Places normal SLURP1 production in differentiating granular-layer keratinocytes.
  - reference: PMID:33741389
    reference_title: "Biochemical Basis of Skin Disease Mal de Meleda: SLURP-1 Mutants Differently Affect Keratinocyte Proliferation and Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity."
    explanation: Recombinant disease-associated mutants show that many variants inactivate SLURP-1, while some alter rather than abolish activity.
  downstream:
  - target: Loss of SLURP1 Modulation of Keratinocyte Alpha7 Nicotinic Acetylcholine Receptors
    causal_link_type: DIRECT
    description: >-
      SLURP1 binds and allosterically modulates the alpha7 nicotinic
      acetylcholine receptor on keratinocytes, so loss of SLURP1 removes this
      cholinergic input.
    evidence:
    - reference: PMID:14506129
      reference_title: "Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes."
      explanation: Establishes keratinocyte alpha7 receptors as a SLURP-1 target.
    - reference: PMID:26905431
      reference_title: "Human Secreted Ly-6/uPAR Related Protein-1 (SLURP-1) Is a Selective Allosteric Antagonist of α7 Nicotinic Acetylcholine Receptor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Using affinity purification from human cortical extracts, we confirmed that rSLURP-1 binds selectively to the α7-nAChRs."
      explanation: Confirms selective binding of SLURP-1 to alpha7 receptors.
  - target: Impaired T-cell Activation
    causal_link_type: DIRECT
    description: >-
      Peripheral blood T cells from a family carrying SLURP1 G86R show defective
      activation that is restored by recombinant SLURP-1.
    evidence:
    - reference: PMID:20854438
      reference_title: "SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation."
      explanation: Patient-derived cells carrying the SLURP1 variant, stimulated in culture, show impaired T-cell activation.
  - target: Loss of SLURP1 Epithelial Tumor-Suppressive Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Expression data suggest a putative epithelial tumor-suppressor role for
      SLURP1; this link is a hypothesis.
    evidence:
    - reference: PMID:29231248
      reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: "Our findings also highlight a plausible epithelial lineage-specific tumor suppressor role for the SLURP1 gene"
      explanation: Expression-dataset analysis proposes a tumor-suppressor role for SLURP1.
- name: Loss of SLURP1 Modulation of Keratinocyte Alpha7 Nicotinic Acetylcholine Receptors
  description: >-
    SLURP1 is an auto/paracrine cholinergic peptide that binds alpha7 nicotinic
    acetylcholine receptors on keratinocytes. Early studies with fusion
    constructs described it as a potentiator or allosteric agonist of these
    receptors, while a recombinant protein closer to the native sequence acted
    as a non-competitive allosteric antagonist; both lines of work agree that
    SLURP1 signalling through alpha7 receptors restrains keratinocyte growth.
    In Mal de Meleda this receptor-mediated signal is lost.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: acetylcholine receptor signaling pathway
    term:
      id: GO:0095500
      label: acetylcholine receptor signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:14506129
    reference_title: "Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes."
    explanation: Identifies keratinocyte alpha7 receptors as the SLURP-1 target.
  - reference: PMID:16354194
    reference_title: "Biological effects of SLURP-1 on human keratinocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the presence of the agonist carbachol, the effects of SLURP-1 on gene expression were augmented, which is in keeping with the notion that SLURP-1 acts as an allosteric agonist at the KC nAChR."
    explanation: Recombinant SLURP-1 acts at keratinocyte nicotinic receptors.
  - reference: PMID:26905431
    reference_title: "Human Secreted Ly-6/uPAR Related Protein-1 (SLURP-1) Is a Selective Allosteric Antagonist of α7 Nicotinic Acetylcholine Receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings imply an allosteric antagonist-like mode of SLURP-1 interaction with α7-nAChRs outside the classical ligand-binding site."
    explanation: A recombinant SLURP-1 closer to the native protein behaves as an allosteric antagonist, so the sign of the modulation is disputed while the receptor target is not.
  downstream:
  - target: Keratinocyte Hyperproliferation
    causal_link_type: DIRECT
    description: SLURP-1 restrains keratinocyte growth through alpha7 receptors, so its loss releases proliferation.
    evidence:
    - reference: PMID:26905431
      reference_title: "Human Secreted Ly-6/uPAR Related Protein-1 (SLURP-1) Is a Selective Allosteric Antagonist of α7 Nicotinic Acetylcholine Receptor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "rSLURP-1 significantly inhibited proliferation (up to ~ 40%, EC50 ~ 4 nM) of human oral keratinocytes (Het-1A cells)."
      explanation: Shows the antiproliferative effect of SLURP-1 on keratinocytes, which is lost in the disease.
    - reference: PMID:14506129
      reference_title: "Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "This explains both the hyperproliferative as well as the inflammatory clinical phenotype of Mal de Meleda."
      explanation: The authors link loss of SLURP-1 receptor modulation to the hyperproliferative phenotype.
  - target: Disturbed Keratinocyte Terminal Differentiation
    causal_link_type: DIRECT
    description: >-
      SLURP-1 signalling induces differentiation and apoptosis genes in
      keratinocytes; without it these programmes are under-stimulated.
    evidence:
    - reference: PMID:16354194
      reference_title: "Biological effects of SLURP-1 on human keratinocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SLURP-1 significantly (p<0.05) upregulated expression of transglutaminase type I cytokeratin 10, p21, and caspase-3."
      explanation: SLURP-1 drives keratinocyte differentiation and cell-cycle-exit genes.
    - reference: PMID:16354194
      reference_title: "Biological effects of SLURP-1 on human keratinocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SLURP-1 significantly (p<0.05) increased the activities of caspases 3 and 8"
      explanation: SLURP-1 promotes keratinocyte programmed cell death, part of terminal differentiation.
  - target: Cutaneous Inflammation with TNF-alpha Excess
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      SLURP-1 cholinergic signalling is proposed to inhibit TNF-alpha release,
      so its loss is linked to the inflammatory component of the disease.
    evidence:
    - reference: PMID:14506129
      reference_title: "Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "These results identify SLURP-1 as a secreted epidermal neuromodulator which is likely to be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing."
      explanation: The authors attribute the inflammatory phenotype to loss of SLURP-1 inhibition of TNF-alpha release.
- name: Keratinocyte Hyperproliferation
  description: >-
    Palmoplantar keratinocytes proliferate excessively in SLURP1 deficiency, as
    shown by increased keratinocyte proliferation in the volar paw skin of
    Slurp1 knockout mice, which reproduce the human keratoderma.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:24499735
    reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
    explanation: Slurp1 knockout mice show increased keratinocyte proliferation in the keratoderma.
  downstream:
  - target: Palmoplantar Epidermal Hyperkeratosis and Acanthosis
    causal_link_type: DIRECT
    description: Excess keratinocyte production thickens the volar epidermis.
    evidence:
    - reference: PMID:28418591
      reference_title: "A hypomorphic Egfr allele does not ameliorate the palmoplantar keratoderma caused by SLURP1 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws."
      explanation: Links increased keratinocyte proliferation to volar epidermal thickening in the knockout model.
- name: Disturbed Keratinocyte Terminal Differentiation
  description: >-
    SLURP1 is a late differentiation product of granular-layer keratinocytes.
    Patient epidermis shows hypergranulosis with numerous irregular keratohyaline
    granules and perinuclear vacuoles in spinous keratinocytes, and Slurp1
    knockout epidermis has a poorly demarcated granular layer, indicating an
    abnormal terminal differentiation programme.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, there were numerous irregular keratohyaline granules in the granular layer."
    explanation: Ultrastructure of patient skin shows abnormal granular-layer differentiation.
  - reference: PMID:24499735
    reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the stratum granulosum was poorly demarcated"
    explanation: The knockout granular layer is abnormal.
  downstream:
  - target: Palmoplantar Epidermal Hyperkeratosis and Acanthosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal cornification contributes to the thick, nonepidermolytic
      hyperkeratosis.
  - target: Hypergranulosis
    causal_link_type: DIRECT
    description: >-
      The granular-layer differentiation defect is seen histologically as
      hypergranulosis.
  - target: Stratum Corneum Water Barrier Defect with Lipid Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The stratum corneum formed in SLURP1 deficiency retains neutral lipid
      droplets and fails as a water barrier in the knockout model.
    evidence:
    - reference: PMID:24499735
      reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
      explanation: The knockout keratoderma includes stratum corneum lipid accumulation and a water barrier defect.
- name: Palmoplantar Epidermal Hyperkeratosis and Acanthosis
  description: >-
    The palmoplantar epidermis becomes markedly thickened, with nonepidermolytic
    hyperkeratosis and acanthosis, spreading in a sharply demarcated pattern
    onto adjacent dorsal skin. The rigid hyperkeratotic plates fissure,
    restrict joint movement and can constrict the digits.
  biological_scale: TISSUE
  locations:
  - preferred_term: skin of palm
    term:
      id: UBERON:0013777
      label: skin of palm of manus
  - preferred_term: skin of sole
    term:
      id: UBERON:0013778
      label: skin of sole of pes
  evidence:
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Histologically, the lesions show hyperkeratosis and acanthosis without epidermolysis in the epidermis, accompanied by perivascular lymphocytic infiltrate in the dermis."
    explanation: The review summarizes the nonepidermolytic hyperkeratosis and acanthosis.
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis, accompanied by perivascular lymphocytic infiltrates in the dermis."
    explanation: Patient histology shows hyperkeratosis and acanthosis.
  downstream:
  - target: Transgredient Diffuse Palmoplantar Keratoderma
    causal_link_type: DIRECT
  - target: Epidermal Acanthosis
    causal_link_type: DIRECT
  - target: Palmoplantar Skin Fissures
    causal_link_type: DIRECT
    description: Deep fissures form in the thick, inflexible keratoderma.
  - target: Flexion Contractures of Fingers and Toes
    causal_link_type: DIRECT
    description: Long-standing hyperkeratosis produces flexion contractures of the digits.
    evidence:
    - reference: PMID:28885351
      reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
      explanation: The case report attributes the digital flexion contractures to the hyperkeratosis.
  - target: Pain
    causal_link_type: DIRECT
    description: Thick keratoderma makes finger movement painful.
    evidence:
    - reference: PMID:34692287
      reference_title: "A Case of Mal De Meleda: The Rare Presentation of Palmoplantar Keratoderma Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The male patient reported pain during finger movements. This was attributed to the thickness of the keratoderma lesion."
      explanation: Pain on finger movement was attributed to the thickness of the keratoderma.
  - target: Pseudoainhum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constricting keratotic bands can form around digits within the
      keratoderma and occasionally lead to autoamputation.
- name: Stratum Corneum Water Barrier Defect with Lipid Accumulation
  description: >-
    SLURP1-deficient palmoplantar stratum corneum accumulates neutral lipid
    droplets and fails as a water barrier; lipid-like droplets are also seen in
    the thickened cornified layer of patients.
  biological_scale: TISSUE
  locations:
  - preferred_term: stratum corneum
    term:
      id: UBERON:0002027
      label: stratum corneum of epidermis
  evidence:
  - reference: PMID:24499735
    reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
    explanation: Slurp1 knockout keratoderma shows stratum corneum lipid droplets and a water barrier defect.
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several microorganisms and many lipid-like droplets were found in the thickened cornified layer."
    explanation: Lipid-like droplets accumulate in the cornified layer of patient skin.
  downstream:
  - target: Microbial Overgrowth in Hyperkeratotic Skin
    causal_link_type: DIRECT
    description: >-
      Leakage of interstitial fluid into the stratum corneum and accumulated
      triglyceride droplets are proposed to favour microbial growth.
    evidence:
    - reference: PMID:24499735
      reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Leakage of interstitial fluids into the stratum corneum along with the accumulation of triglyceride droplets would favor the growth of microorganisms"
      explanation: The knockout study proposes that the barrier and lipid defects favour microbial growth.
- name: Microbial Overgrowth in Hyperkeratotic Skin
  description: >-
    Bacteria and fungi colonise the thick, moist keratoderma. Microorganisms are
    seen within the cornified layer on electron microscopy, and dermatophyte
    (Trichophyton) superinfection of palmoplantar skin has been cultured.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several microorganisms and many lipid-like droplets were found in the thickened cornified layer."
    explanation: Electron microscopy shows microorganisms within the thickened cornified layer.
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fungal culture from palmoplantar skin revealed Trichophyton verrucosum."
    explanation: Documents dermatophyte superinfection of the keratoderma.
  downstream:
  - target: Malodour of Palmoplantar Skin
    causal_link_type: DIRECT
    description: >-
      Bacterial lipases acting on stratum corneum lipids are proposed to release
      malodorous compounds.
    evidence:
    - reference: PMID:24499735
      reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The discovery of a defective water barrier in SLURP1-deficient skin, along with increased neutral lipids in the stratum corneum, could help to explain malodorous skin in mal de Meleda"
      explanation: The knockout findings are proposed to explain the malodour of patient skin.
  - target: Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Microbial superinfection of the keratoderma is one recognised source of pain.
    evidence:
    - reference: PMID:38866482
      reference_title: "Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin."
      explanation: The background of the knockout pain study attributes patient pain to fissures or microbial superinfection.
- name: Cutaneous Inflammation with TNF-alpha Excess
  description: >-
    Lesional skin shows a superficial perivascular lymphocytic infiltrate, and
    epidermal keratinocytes and dermal perivascular infiltrates stain for
    TNF-alpha, matching the erythematous, inflammatory component of the
    keratoderma.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: tumor necrosis factor production
    term:
      id: GO:0032640
      label: tumor necrosis factor production
    modifier: INCREASED
  evidence:
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The whole layers of the epidermis and perivascular infiltrates of the dermis were stained positive with anti-tumor necrosis factor alpha"
    explanation: Patient lesional skin shows TNF-alpha in epidermis and dermal infiltrates.
  downstream:
  - target: Sharply Demarcated Erythema Bordering the Keratoderma
    causal_link_type: DIRECT
  - target: Perioral Erythema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Superficial Dermal Perivascular Inflammatory Infiltrate
    causal_link_type: DIRECT
- name: Impaired T-cell Activation
  description: >-
    T cells from carriers of SLURP1 G86R respond poorly to CD3/CD28
    stimulation, and recombinant SLURP-1 restores activation. Defective T-cell
    function has been proposed to contribute to the melanoma and viral
    infection seen in the same family.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
    modifier: DECREASED
  evidence:
  - reference: PMID:20854438
    reference_title: "SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation."
    explanation: Patient peripheral blood cells stimulated in culture show defective T-cell activation.
  downstream:
  - target: Melanoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Proposed link between defective T-cell function and melanoma; not established.
    evidence:
    - reference: PMID:20854438
      reference_title: "SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis."
      explanation: The authors propose defective T-cell function as a link to melanoma.
    - reference: PMID:31582262
      reference_title: "[Acral melanoma in a patient with hereditary keratoderma of the palms and soles (mal de Meleda): A chance association?]."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "This association seems to be the outcome of immune dysregulation rather than of chronic inflammation."
      explanation: The case report favours immune dysregulation as the basis of acral melanoma in Mal de Meleda.
- name: Loss of SLURP1 Epithelial Tumor-Suppressive Activity
  description: >-
    SLURP1 expression is high in epithelial tissues and reduced in epithelial
    cancers and in melanoma relative to nevi, suggesting a tumor-suppressor
    role whose loss could contribute to the cutaneous squamous cell carcinomas
    and melanomas reported at keratoderma sites. This is a hypothesis.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:29231248
    reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "SLURP1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts."
    explanation: Public expression data show SLURP1 suppression in epithelial cancers.
  downstream:
  - target: Squamous Cell Carcinoma of the Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29231248
      reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: "Our findings also highlight a plausible epithelial lineage-specific tumor suppressor role for the SLURP1 gene"
      explanation: Proposes SLURP1 loss as a contributor to epithelial cancer.
  - target: Melanoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29231248
      reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: "There was significant decrease in SLURP-1 expression in melanomas versus melanocytic nevi as well as a highly significant decrease in SLURP-1 expression in metastatic melanomas as compared to primary melanoma."
      explanation: Reduced SLURP-1 expression in melanoma suggests a link between SLURP1 loss and melanoma.
phenotypes:
- name: Transgredient Diffuse Palmoplantar Keratoderma
  category: Dermatologic
  description: >-
    Symmetric, yellowish, waxy, sharply demarcated hyperkeratosis of the palms
    and soles beginning in infancy, extending onto the dorsal hands and feet,
    wrists and ankles in a glove-and-stocking distribution (transgrediens), and
    worsening with age (progrediens). It is the defining feature of the disease.
  phenotype_term:
    preferred_term: transgredient diffuse palmoplantar keratoderma
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
    explanation: Transgressive palmoplantar keratoderma is the cardinal feature.
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens)."
    explanation: Orphanet defines the disease by symmetric, transgredient palmoplantar hyperkeratosis.
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination revealed plaque-like yellowish and waxy palmoplantar hyperkeratosis with adjacent sharply demarcated, fine scaly erythema, which extended to the forearms and lower legs in a cuff-like (gloves and socks) distribution"
    explanation: Describes the glove-and-stocking distribution of the keratoderma.
  - reference: PMID:21909218
    reference_title: "A Sporadic Case of Mal de Meleda Caused by Gene Mutation in SLURP-1 in Korea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 15-year-old Korean female presented with sharply demarcated hyperkeratotic plaques on the palms and soles, which extended to the dorsal surfaces of the hands and feet, in a \"glove-and-socks\" distribution."
    explanation: Transgredient glove-and-socks keratoderma in a Korean patient with compound heterozygous SLURP1 variants.
- name: Sharply Demarcated Erythema Bordering the Keratoderma
  category: Dermatologic
  description: >-
    An erythematous, sometimes scaly, sharply demarcated border surrounds the
    hyperkeratotic plaques.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hyperkeratosis with sharply demarcated erythema
    term:
      id: HP:0007390
      label: Hyperkeratosis with erythema
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007390 | Hyperkeratosis with erythema | Frequent (79-30%)"
    explanation: Orphanet records hyperkeratosis with erythema as frequent.
  - reference: PMID:14674887
    reference_title: "A novel missense mutation in the gene encoding SLURP-1 in patients with Mal de Meleda from northern Tunisia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, MDM is characterized by erythema and hyperkeratosis of the palms and soles with sharp demarcation that appears soon after birth and progressively extends to the dorsal surface of the hands and feet."
    explanation: Describes sharply demarcated palmoplantar erythema with hyperkeratosis.
- name: Palmoplantar Hyperhidrosis
  category: Dermatologic
  description: Excessive sweating of the palms and soles.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: palmoplantar hyperhidrosis
    term:
      id: HP:0007410
      label: Palmoplantar hyperhidrosis
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000975 | Hyperhidrosis | Frequent (79-30%)"
    explanation: Orphanet records hyperhidrosis as frequent.
  - reference: PMID:12592079
    reference_title: "Mal de Meleda: a new geographical localization in Anatolia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperhidrosis on the palms and soles (50%)"
    explanation: Half of the largest reported series, from Anatolia, had palmoplantar hyperhidrosis.
  - reference: PMID:11030771
    reference_title: "Clinical and genetic studies of 3 large, consanguineous, Algerian families with Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical characteristics are transgressive palmoplantar keratoderma, hyperhidrosis, and perioral erythema"
    explanation: Hyperhidrosis is a main clinical characteristic in Algerian families.
- name: Malodour of Palmoplantar Skin
  category: Dermatologic
  description: Foul-smelling palmoplantar skin, associated with maceration and superinfection.
  phenotype_term:
    preferred_term: malodorous palmoplantar skin
    term:
      id: HP:0500001
      label: Body odor
  evidence:
  - reference: PMID:24499735
    reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The skin of the palms and soles is often malodorous."
    explanation: The knockout paper's introduction summarizes the human clinical picture, including malodour.
  - reference: PMID:31582262
    reference_title: "[Acral melanoma in a patient with hereditary keratoderma of the palms and soles (mal de Meleda): A chance association?]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "foul-smelling and yellowish palmoplantar keratoderma transgrediens"
    explanation: A patient with Mal de Meleda had foul-smelling keratoderma.
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, nail dystrophy (Fig. 1e) and malodour was found."
    explanation: Malodour documented in a genetically confirmed patient.
- name: Palmoplantar Skin Fissures
  category: Dermatologic
  description: Deep, painful cracks in the thick keratoderma that limit joint extension.
  phenotype_term:
    preferred_term: palmoplantar fissures
    term:
      id: HP:0031057
      label: Skin fissure
  evidence:
  - reference: PMID:19042068
    reference_title: "[Surgical treatment of keratosis palmaris in Mal de Meleda]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep fissures cause pain and limit extension of the metacarpo-phalangeal joints."
    explanation: Deep palmar fissures in a patient with Mal de Meleda.
  sequelae:
  - target: Pain
    description: Fissures in the keratoderma are painful.
    evidence:
    - reference: PMID:19042068
      reference_title: "[Surgical treatment of keratosis palmaris in Mal de Meleda]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Deep fissures cause pain and limit extension of the metacarpo-phalangeal joints."
      explanation: States that the deep fissures cause pain.
- name: Pain
  category: Dermatologic
  description: >-
    Pain in the affected palms and soles, especially on movement of the digits,
    attributed to keratoderma thickness, fissures and superinfection.
  phenotype_term:
    preferred_term: palmoplantar pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:34692287
    reference_title: "A Case of Mal De Meleda: The Rare Presentation of Palmoplantar Keratoderma Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The male patient reported pain during finger movements. This was attributed to the thickness of the keratoderma lesion."
    explanation: Pain on finger movement in an affected child.
  - reference: PMID:38866482
    reference_title: "Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin."
    explanation: The background of the knockout pain study summarizes pain in patients.
- name: Pruritus
  category: Dermatologic
  description: Itching of the hyperkeratotic plaques.
  phenotype_term:
    preferred_term: pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with pruritic and severely hyperkeratotic plaques on the bilateral palms and soles"
    explanation: Pruritic plaques in a genetically confirmed child.
  - reference: PMID:38903266
    reference_title: "Transgradient Variant of Mal De Meleda Presenting As Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient reported itching, scaling, and a foul smell from the lesions"
    explanation: Itching reported by an affected adolescent.
- name: Perioral Erythema
  category: Dermatologic
  description: Erythema around the mouth.
  phenotype_term:
    preferred_term: perioral erythema
    term:
      id: HP:0033194
      label: Perioral erythema
  evidence:
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
    explanation: Perioral erythema is part of the characteristic phenotype.
  - reference: PMID:11030771
    reference_title: "Clinical and genetic studies of 3 large, consanguineous, Algerian families with Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical characteristics are transgressive palmoplantar keratoderma, hyperhidrosis, and perioral erythema"
    explanation: Perioral erythema is a main clinical characteristic in Algerian families.
- name: Lichenoid Plaques
  category: Dermatologic
  description: Lichenoid, sometimes polycyclic, keratotic plaques over the elbows, knees and other sites.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: lichenoid plaques
    term:
      id: HP:0031452
      label: Lichenoid skin lesion
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031452 | Lichenoid skin lesion | Occasional (29-5%)"
    explanation: Orphanet records lichenoid skin lesions as occasional.
  - reference: PMID:11030771
    reference_title: "Clinical and genetic studies of 3 large, consanguineous, Algerian families with Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but there are also associated features such as brachydactyly, nail abnormalities, and lichenoid plaques."
    explanation: Lichenoid plaques are an associated feature.
- name: Nail Abnormalities
  category: Dermatologic
  description: Nail involvement, including nail dystrophy, subungual keratosis and koilonychia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: nail abnormalities
    term:
      id: HP:0001597
      label: Abnormal nail morphology
  evidence:
  - reference: PMID:12592079
    reference_title: "Mal de Meleda: a new geographical localization in Anatolia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalent clinical features were nail involvement (80%)"
    explanation: Nail involvement was present in 80% of the largest reported series.
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
    explanation: Nail abnormalities are part of the characteristic phenotype.
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, nail dystrophy (Fig. 1e) and malodour was found."
    explanation: Nail dystrophy in a genetically confirmed patient.
- name: Brachydactyly
  category: Musculoskeletal
  description: Short digits.
  phenotype_term:
    preferred_term: brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:11285253
    reference_title: "Mutations in the gene encoding SLURP-1 in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities."
    explanation: Brachydactyly is part of the characteristic phenotype.
- name: Conical Tapering of the Fingers
  category: Musculoskeletal
  description: Conical tapering of the fingertips.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: conical tapering of the fingertips
    term:
      id: HP:0001182
      label: Tapered finger
  evidence:
  - reference: PMID:12592079
    reference_title: "Mal de Meleda: a new geographical localization in Anatolia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conical tapering of the fingertips (60%)"
    explanation: Present in 60% of the Anatolian series.
  - reference: PMID:15909066
    reference_title: "Mal de Meleda in a taiwanese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conical tapering of the fingers"
    explanation: Described in a Taiwanese patient with homozygous G86R.
- name: Flexion Contractures of Fingers and Toes
  category: Musculoskeletal
  description: >-
    Flexion contractures of the digits caused by long-standing, thick
    keratoderma and fissuring.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: flexion contractures of fingers and toes
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001371 | Flexion contracture | Frequent (79-30%)"
    explanation: Orphanet records flexion contracture as frequent.
  - reference: PMID:28885351
    reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MDM can lead to severe flexion contractures in some cases."
    explanation: Severe digital flexion contractures in a genetically confirmed patient.
  sequelae:
  - target: Sclerosis of the Skin of the Digits
    description: Long-standing contractures leave the overlying digital skin sclerotic.
    evidence:
    - reference: PMID:28885351
      reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
      explanation: The case report attributes the sclerotic skin to long-term digital flexion contractures.
  - target: Skin Atrophy
    description: Long-standing contractures leave the overlying skin atrophic.
    evidence:
    - reference: PMID:28885351
      reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
      explanation: The case report attributes the atrophic skin to long-term digital flexion contractures.
- name: Edema of the Hands and Feet
  category: Dermatologic
  description: >-
    Swelling of the hands and feet, reported in 60% of the largest series.
    Bound to Peripheral edema, defined as fluid accumulation in the soft
    tissues of the limbs, because HPO has no single term for edema of both
    hands and feet and the source does not say whether the dorsum or the whole
    hand and foot is affected.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: edema of the hands and feet
    term:
      id: HP:0012398
      label: Peripheral edema
  evidence:
  - reference: PMID:12592079
    reference_title: "Mal de Meleda: a new geographical localization in Anatolia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "edema on the hands/feet (60%)"
    explanation: Edema of the hands and feet was present in 60% of the Anatolian series.
- name: Sclerosis of the Skin of the Digits
  category: Dermatologic
  description: >-
    Sclerotic, tight skin over the fingers and toes, typically in long-standing
    disease with digital contractures.
  phenotype_term:
    preferred_term: sclerosis of the skin of the fingers and toes
    term:
      id: HP:0011838
      label: Sclerodactyly
  evidence:
  - reference: PMID:28885351
    reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
    explanation: Sclerotic skin of the hands and feet in a patient with homozygous SLURP1 G86R.
  - reference: PMID:41048964
    reference_title: "Atypical manifestation of psoriasis in the elderly: possible expression of Mal de Meleda diagnosis review and case report."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The hallmark features of the condition include transient thickening of the palms and soles, skin sclerosis and atrophy, scleroatrophic erythematous lesions, pseudoainhum formation around the digits, and erythema around the mouth."
    explanation: The case report's introduction lists skin sclerosis among the hallmark features of Mal de Meleda.
- name: Skin Atrophy
  category: Dermatologic
  description: Atrophic skin at sites of long-standing keratoderma and contracture.
  phenotype_term:
    preferred_term: skin atrophy
    term:
      id: HP:0004334
      label: Dermal atrophy
  evidence:
  - reference: PMID:28885351
    reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "her skin lesions were atrophic and sclerotic, due mostly to the long-term flexion contractures of the fingers and toes caused by hyperkeratosis"
    explanation: Atrophic skin lesions in a patient with homozygous SLURP1 G86R.
  - reference: PMID:41048964
    reference_title: "Atypical manifestation of psoriasis in the elderly: possible expression of Mal de Meleda diagnosis review and case report."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The hallmark features of the condition include transient thickening of the palms and soles, skin sclerosis and atrophy, scleroatrophic erythematous lesions, pseudoainhum formation around the digits, and erythema around the mouth."
    explanation: The case report's introduction lists skin atrophy among the hallmark features of Mal de Meleda.
- name: Pseudoainhum
  category: Dermatologic
  description: >-
    Constricting keratotic bands around the digits, which can progress to
    autoamputation.
  phenotype_term:
    preferred_term: pseudoainhum
    term:
      id: HP:0010491
      label: Digital constriction ring
  evidence:
  - reference: PMID:24499735
    reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients have thickening of the skin on the palms and soles, occasionally with pseudoainhum formation and autoamputation of digits."
    explanation: The knockout paper's introduction summarizes pseudoainhum as an occasional human feature.
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Rarely, pseudoainhum and melanoma can occur in affected areas"
    explanation: The case report's discussion lists pseudoainhum as a rare feature.
  sequelae:
  - target: Autoamputation of Digits
    description: Digital constriction can lead to spontaneous loss of the digit.
- name: Autoamputation of Digits
  category: Musculoskeletal
  description: Spontaneous loss of a digit distal to a constricting band.
  phenotype_term:
    preferred_term: autoamputation of digits
    term:
      id: HP:0007460
      label: Autoamputation of digits
  evidence:
  - reference: PMID:24499735
    reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients have thickening of the skin on the palms and soles, occasionally with pseudoainhum formation and autoamputation of digits."
    explanation: Autoamputation of digits is an occasional complication.
- name: Epidermal Acanthosis
  category: Histopathology
  description: Thickening of the spinous layer of the epidermis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: epidermal acanthosis
    term:
      id: HP:0025092
      label: Epidermal acanthosis
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025092 | Epidermal acanthosis | Frequent (79-30%)"
    explanation: Orphanet records epidermal acanthosis as frequent.
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis"
    explanation: Acanthosis in patient histology.
- name: Hypergranulosis
  category: Histopathology
  description: >-
    Thickened granular layer of the epidermis; not universal, as normogranulosis
    has also been reported.
  phenotype_term:
    preferred_term: hypergranulosis
    term:
      id: HP:0025114
      label: Hypergranulosis
  evidence:
  - reference: PMID:32157724
    reference_title: "Abnormal keratinization and cutaneous inflammation in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis"
    explanation: Hypergranulosis in patient histology.
  - reference: PMID:34692287
    reference_title: "A Case of Mal De Meleda: The Rare Presentation of Palmoplantar Keratoderma Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological investigation of the skin lesions reported hyperkeratosis, hypergranulosis, and acanthosis of the skin."
    explanation: Hypergranulosis in two affected siblings.
  - reference: PMID:21909218
    reference_title: "A Sporadic Case of Mal de Meleda Caused by Gene Mutation in SLURP-1 in Korea."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The histopathologic study showed marked hyperkeratosis, acanthosis, and normogranulosis, without epidermolysis."
    explanation: A genetically confirmed Korean patient had a normal granular layer, so hypergranulosis is not constant.
- name: Superficial Dermal Perivascular Inflammatory Infiltrate
  category: Histopathology
  description: Superficial perivascular lymphocytic infiltrate in the dermis.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: superficial dermal perivascular lymphocytic infiltrate
    term:
      id: HP:0031190
      label: Superficial dermal perivascular inflammatory infiltrate
  evidence:
  - reference: ORPHA:87503
    reference_title: "Mal de Meleda"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031190 | Superficial dermal perivascular inflammatory infiltrate | Very frequent (99-80%)"
    explanation: Orphanet records the superficial perivascular infiltrate as very frequent.
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Histologically, the lesions show hyperkeratosis and acanthosis without epidermolysis in the epidermis, accompanied by perivascular lymphocytic infiltrate in the dermis."
    explanation: The review summarizes the dermal perivascular lymphocytic infiltrate.
- name: Melanoma
  category: Neoplasm
  description: >-
    Malignant melanoma, often acral or amelanotic, arising within keratoderma
    skin has been reported in a small number of patients.
  phenotype_term:
    preferred_term: melanoma arising in keratoderma skin
    term:
      id: HP:0002861
      label: Melanoma
  evidence:
  - reference: PMID:14756434
    reference_title: "Malignant melanoma developing in an area of hereditary palmoplantar keratoderma (Mal de Meleda)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a case of a 74-year-old man with Mal de Meleda, who developed malignant melanoma inside the hyperkeratotic palmar skin of the right hand."
    explanation: Melanoma arising within palmar keratoderma.
  - reference: PMID:31582262
    reference_title: "[Acral melanoma in a patient with hereditary keratoderma of the palms and soles (mal de Meleda): A chance association?]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Development of acral malignant melanoma in Mal de Meleda is highly unusual."
    explanation: Acral melanoma in Mal de Meleda is reported but rare.
  - reference: PMID:29231248
    reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma."
    explanation: Melanoma in affected members of a Palestinian family.
- name: Squamous Cell Carcinoma of the Skin
  category: Neoplasm
  description: Cutaneous squamous cell carcinoma arising at keratoderma sites has been reported.
  phenotype_term:
    preferred_term: cutaneous squamous cell carcinoma at keratoderma sites
    term:
      id: HP:0006739
      label: Squamous cell carcinoma of the skin
  evidence:
  - reference: PMID:29231248
    reference_title: "SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma."
    explanation: Cutaneous SCC in affected members of a family with homozygous c.82delT.
diagnosis:
- name: SLURP1 molecular genetic testing
  description: >-
    Identification of biallelic SLURP1 pathogenic variants confirms the
    diagnosis and distinguishes Mal de Meleda from other transgredient
    keratodermas and from psoriasis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28885351
    reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The reliable method for the diagnosis of MDM is gene test."
    explanation: Genetic testing is the reliable diagnostic method.
- name: Skin biopsy
  description: >-
    Biopsy shows nonepidermolytic hyperkeratosis, acanthosis and hypergranulosis
    with a superficial perivascular lymphocytic infiltrate; absence of
    epidermolysis separates it from epidermolytic palmoplantar keratoderma.
  evidence:
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A punch biopsy from plantar skin revealed hyperkeratosis, mild hypergranulosis and a discrete perivascular inflammatory infiltrate in the superficial dermis, but no epidermolysis."
    explanation: Characteristic nonepidermolytic biopsy findings.
- name: SLURP1 protein immunodetection
  description: >-
    Because most pathogenic variants leave SLURP1 absent or barely detectable in
    skin and sweat, immunological detection of SLURP1 has been proposed as a
    rapid screening test.
  evidence:
  - reference: PMID:17008884
    reference_title: "SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, most MDM mutations in SLURP1 affect either the expression, integrity, or stability of the protein, suggesting that a simple immunologic test could be used as a rapid screening procedure."
    explanation: Proposes SLURP1 immunodetection as a screening approach.
differential_diagnoses:
- name: Keratoderma hereditarium mutilans
  description: >-
    Vohwinkel syndrome, a mutilating palmoplantar keratoderma with
    pseudoainhum, is listed among the genodermatoses to distinguish from the
    transgredient variant of Mal de Meleda.
  disease_term:
    preferred_term: keratoderma hereditarium mutilans
    term:
      id: MONDO:0007422
      label: keratoderma hereditarium mutilans
  evidence:
  - reference: PMID:38903266
    reference_title: "Transgradient Variant of Mal De Meleda Presenting As Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differential diagnosis may include other genodermatoses with palmoplantar involvement, such as Papillon-Lefèvre syndrome and keratoderma hereditarium mutilans"
    explanation: The case report lists keratoderma hereditarium mutilans as a differential diagnosis.
- name: Papillon-Lefevre syndrome
  description: >-
    Papillon-Lefevre syndrome is listed among the genodermatoses with
    palmoplantar involvement to distinguish from the transgredient variant of
    Mal de Meleda.
  disease_term:
    preferred_term: Papillon-Lefevre syndrome
    term:
      id: MONDO:0009490
      label: Papillon-Lefevre disease
  evidence:
  - reference: PMID:38903266
    reference_title: "Transgradient Variant of Mal De Meleda Presenting As Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differential diagnosis may include other genodermatoses with palmoplantar involvement, such as Papillon-Lefèvre syndrome and keratoderma hereditarium mutilans"
    explanation: The case report lists Papillon-Lefevre syndrome as a differential diagnosis.
treatments:
- name: Oral Acitretin
  description: >-
    Systemic retinoid therapy reduces hyperkeratosis and is the mainstay of
    management, usually combined with topical keratolytics. Low doses (about 10
    mg/day) have been effective; mucocutaneous adverse effects such as dry eyes
    and lips can limit use, and acitretin does not always prevent mutilating
    progression.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_phenotypes:
  - preferred_term: transgredient diffuse palmoplantar keratoderma
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "the accepted approach tends to include oral acitretin plus topical keratolytic therapy"
    explanation: The review identifies oral acitretin plus topical keratolytics as the accepted approach.
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low-dose acitretin was initiated at 10 mg/day. Two months later, the patient showed significantly reduced palmar hyperkeratosis"
    explanation: Low-dose acitretin reduced hyperkeratosis in a genetically confirmed patient.
  - reference: PMID:38903266
    reference_title: "Transgradient Variant of Mal De Meleda Presenting As Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with oral acitretin and topical moisturizers resulted in significant improvement."
    explanation: Acitretin improved the keratoderma in an affected adolescent.
  - reference: PMID:31582262
    reference_title: "[Acral melanoma in a patient with hereditary keratoderma of the palms and soles (mal de Meleda): A chance association?]."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "After the failure of acitretin, which had not prevented retractile and mutilating progression of the palmoplantar keratoderma, he had undergone surgery with graft excision of both palms."
    explanation: In one patient acitretin did not prevent mutilating progression.
  target_mechanisms:
  - target: Palmoplantar Epidermal Hyperkeratosis and Acanthosis
    description: Acitretin reduces the epidermal hyperkeratosis.
- name: Topical Keratolytic and Retinoid Therapy
  description: >-
    Topical keratolytics, topical retinoids such as tazarotene or tretinoin,
    emollients and regular mechanical debridement soften and thin the
    keratoderma. Topical tazarotene has been combined with oral acitretin.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tazarotene
      term:
        id: CHEBI:32184
        label: tazarotene
  evidence:
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "the accepted approach tends to include oral acitretin plus topical keratolytic therapy"
    explanation: Topical keratolytic therapy is part of the accepted approach.
  - reference: PMID:28885351
    reference_title: "A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient was treated with oral acitretin and topical tazarotene."
    explanation: Topical tazarotene combined with acitretin in a genetically confirmed patient.
  target_mechanisms:
  - target: Palmoplantar Epidermal Hyperkeratosis and Acanthosis
    description: Topical agents soften and remove the hyperkeratosis.
- name: Antifungal Treatment of Superinfection
  description: >-
    Bacterial and fungal superinfection of the keratoderma is treated with
    topical and systemic antimicrobials; a Trichophyton superinfection was
    treated with topical econazole and oral terbinafine.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antifungal therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: terbinafine
      term:
        id: CHEBI:9448
        label: terbinafine
  evidence:
  - reference: PMID:35506361
    reference_title: "Mal de Meleda: Diagnostic Work-up and Therapy with Low-dose Acitretin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Trichophyton superinfection was treated with topical econazole and systemic terbinafine (250 mg/day for 4 weeks)."
    explanation: Antifungal treatment of dermatophyte superinfection in a patient.
  target_mechanisms:
  - target: Microbial Overgrowth in Hyperkeratotic Skin
    description: Antifungals clear dermatophyte superinfection of the keratoderma.
- name: Surgical Excision with Full-Thickness Skin Grafting
  description: >-
    For severe palmar keratoderma, excision of the hyperkeratotic skin and
    coverage with full-thickness skin grafts has given durable relief, with no
    recurrence on grafted areas over 29 years in one patient.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: excision of palmar keratoderma with full-thickness skin grafting
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:19042068
    reference_title: "[Surgical treatment of keratosis palmaris in Mal de Meleda]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long term follow-up (29 years) demonstrates no recurrence of keratosis on surgically treated areas."
    explanation: Grafted areas remained free of keratosis over long follow-up.
  target_mechanisms:
  - target: Palmoplantar Epidermal Hyperkeratosis and Acanthosis
    description: Replaces keratodermic palmar skin with grafted skin.
- name: Genetic Counseling
  description: Counseling on autosomal recessive recurrence risk, particularly in consanguineous families.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26445964
    reference_title: "Mal de Meleda: A Focused Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Genetic counseling should also be offered."
    explanation: The review recommends genetic counseling.
animal_models:
- name: Slurp1 knockout mouse
  species: Mouse
  genotype: Slurp1-/- (exon 2 replacement) and Slurp1X-/- (exon 2 nonsense allele)
  description: >-
    Two independent Slurp1 knockout lines develop palmoplantar keratoderma of
    the paws with increased keratinocyte proliferation, lipid droplets in the
    stratum corneum and a water barrier defect, together with reduced adiposity
    and hind-limb clasping. Slurp1 knockout mice also show mechanical and
    thermal pain hypersensitivity.
  publication: PMID:24499735
  modeled_mechanisms:
  - target: Keratinocyte Hyperproliferation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Volar paw keratinocytes proliferate excessively, reproducing the human keratoderma.
    evidence:
    - reference: PMID:28418591
      reference_title: "A hypomorphic Egfr allele does not ameliorate the palmoplantar keratoderma caused by SLURP1 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws."
      explanation: The knockout reproduces the proliferative keratoderma.
  - target: Stratum Corneum Water Barrier Defect with Lipid Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Knockout paw skin accumulates stratum corneum lipid droplets and loses water barrier function.
    evidence:
    - reference: PMID:24499735
      reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect."
      explanation: Directly documents the barrier and lipid phenotype.
  - target: Cutaneous Inflammation with TNF-alpha Excess
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: Knockout paw skin lacks the dermal inflammatory infiltrate seen in patients.
    limitations: >-
      Inflammatory infiltrates were absent from knockout paw skin, so the model
      does not reproduce the erythematous, inflammatory component of the human
      disease.
    evidence:
    - reference: PMID:24499735
      reference_title: "Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "No inflammatory infiltrates were present."
      explanation: Histology of knockout paw skin showed no inflammatory infiltrate.
references:
- reference: ORPHA:87503
  title: Mal de Meleda
- reference: PMID:11285253
  title: Mutations in the gene encoding SLURP-1 in Mal de Meleda.
- reference: PMID:26445964
  title: "Mal de Meleda: A Focused Review."
- reference: PMID:39913669
  title: "Autosomal dominant SLURP1 variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma."
- reference: PMID:40023748
  title: "A signal peptide variant in SLURP1 with dominant-negative effect causes progressive symmetric erythrokeratodermia."
notes: >-
  No GeneReviews chapter covers Mal de Meleda. Heterozygous SLURP1
  signal-peptide variants at residue A22, one with a dominant-negative effect
  on secretion, cause an autosomal dominant palmoplantar keratoderma and
  progressive symmetric erythrokeratoderma (PMID:39913669, PMID:40023748);
  that dominant allelic disorder is outside the scope of this entry. Mal de
  Meleda is unusual among inherited palmoplantar keratodermas in being caused
  by a secreted signalling protein rather than a structural keratinocyte
  protein. The disease was first described on the Croatian island of Mljet
  (Meleda) by Luko Stulli in 1826, and patients from Mljet share a founder
  haplotype. Phenotype frequencies come from Orphanet or from the Anatolian
  series of 39 patients; the frequency of melanoma and squamous cell carcinoma
  is not established and is omitted.
📚

References & Deep Research

References

5
ORPHA:87503
Mal de Meleda
No top-level findings curated for this source.
PMID:11285253
Mutations in the gene encoding SLURP-1 in Mal de Meleda.
No top-level findings curated for this source.
PMID:26445964
Mal de Meleda: A Focused Review.
No top-level findings curated for this source.
PMID:39913669
Autosomal dominant SLURP1 variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma.
No top-level findings curated for this source.
PMID:40023748
A signal peptide variant in SLURP1 with dominant-negative effect causes progressive symmetric erythrokeratodermia.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Mal_de_Meleda · 2026-10-15T02:18:52Z · View source

New entry for Mal de Meleda (MONDO:0009552), the autosomal recessive transgredient diffuse palmoplantar keratoderma caused by biallelic SLURP1 (hgnc:18746) loss of function. Sources: Orphanet ORPHA:87503 structured record, the SLURP1 gene-discovery and founder-allele papers (Algerian, Croatian, Tunisian, Turkish, German, Palestinian, Taiwanese, Swedish families), keratinocyte alpha7 nicotinic receptor studies of SLURP-1, the Slurp1 knockout mouse papers (PMID:24499735, PMID:28418591, PMID:38866482), and clinical case reports for phenotypes, cancers and treatment. Deep research: the OpenScientist report (research/Mal_de_Meleda-deep-research-openscientist.md) was used as leads; 25/25 references resolved; just preflight-dr PASS. Its term-validation section flagged HP:0100648 (Neoplasm of the tongue) offered for pseudoainhum and HP:0000973 (Cutis laxa) for perioral erythema, and the body gives SLURP1 as HGNC:11827; none of these were used (bindings HP:0010491, HP:0033194 and hgnc:18746 were looked up independently). The report also cites PMID:26905431, which characterises recombinant SLURP-1 as an allosteric antagonist of alpha7 receptors rather than a potentiator, so the receptor node is worded as loss of modulation with modifier DYSREGULATED and cites both views. Lump/split: the Gamborg-Nielsen (Norrbotten) type, MONDO:0009489, is recorded as a has_subtypes entry because SLURP1 sequencing shows it is allelic (PMID:24604124) and Orphanet has moved its record into Mal de Meleda; the autosomal dominant SLURP1 PPK/PSEK (PMID:39913669, PMID:40023748) is a distinct allelic disorder and is noted as out of scope. Keratoderma hereditarium mutilans is listed only as a sourced differential. No GeneReviews chapter exists (just check-genereviews --online: NO_CHAPTER). Six phenotypes (hyperhidrosis, pruritus, lichenoid plaques, nail abnormalities, brachydactyly, tapered fingers) are left without causal in-edges because no source states their mechanism. Validation: just validate, validate-terms, count-verified-snippets (all verified), check-entity-refs, check-causal-targets, check-snippet-length and validate-disorders.

OpenScientist ▸
Mal de Meleda (MONDO:0009552; OMIM #248300): A Comprehensive Disease Characteristics Report
openscientist-autonomous 24 citations 2026-10-15T02:04:01.821814

Mal de Meleda (MONDO:0009552; OMIM #248300): A Comprehensive Disease Characteristics Report

Summary

Mal de Meleda (MdM) is a rare autosomal recessive, transgredient (spreading beyond palms/soles) and progredient (worsening with age) diffuse palmoplantar keratoderma (PPK). It is caused by biallelic loss-of-function mutations in SLURP1 (secreted Ly-6/urokinase-type plasminogen activator receptor–related protein 1; gene SLURP1, formerly ARS component B / LY6LS, on chromosome 8q24.3; UniProt P55000; HGNC:11827). The disease was first described by the Dubrovnik physician Luka (Luko) Stulli in 1826 among residents of the island of Mljet (Meleda), Croatia, and has since been documented worldwide in Palestinian, Turkish, German, Emirati, Korean, Dutch, Javanese/Indonesian, Taiwanese, Algerian, and Tunisian families. Estimated prevalence is approximately 1:100,000.

Mechanistically, SLURP-1 is a small secreted member of the Ly-6/uPAR (LU) superfamily that adopts a three-finger-toxin fold homologous to snake-venom neurotoxins and cardiotoxins. It functions as an autocrine/paracrine cholinergic signaling peptide that acts as a selective allosteric modulator/antagonist of the α7 nicotinic acetylcholine receptor (α7-nAChR) on keratinocytes, restraining keratinocyte proliferation and promoting orderly differentiation, apoptosis, and barrier formation. Loss of SLURP-1 removes this "cholinergic brake," producing keratinocyte hyperproliferation, disrupted epidermal lipid/water-barrier homeostasis, and the clinical phenotype. The pathophysiology is strongly supported by Slurp1-knockout mice, which faithfully recapitulate the human PPK with lipid-droplet accumulation in the stratum corneum and a water-barrier defect.

Clinically, MdM presents in early infancy with sharply demarcated erythema and hyperkeratosis of the palms and soles that progress with age and extend to the dorsal hands and feet in a "glove-and-socks" distribution. Associated features include skin sclerosis/atrophy, constricting digital bands (pseudoainhum, which can cause autoamputation), perioral erythema, brachydactyly, nail abnormalities, and hyperhidrosis with malodor. There is no cure; management is symptomatic, centered on oral acitretin (a systemic retinoid) plus topical keratolytics, with surgical release of pseudoainhum bands and genetic counseling. Life expectancy is normal, but morbidity and quality-of-life impact are substantial, and patients may carry a modestly increased risk of cutaneous squamous cell carcinoma and melanoma, consistent with SLURP-1's putative squamous-lineage tumor-suppressor role.

Key Findings

Finding 1 — Mal de Meleda is an autosomal recessive transgredient PPK caused by SLURP1 mutations

Mal de Meleda, also known as keratosis palmoplantaris transgrediens of Siemens, is an autosomal recessive skin disorder characterized by diffuse PPK with transgressive keratosis and onset in early infancy. Multiple independent families across the globe — Palestinian, Turkish, German, Emirati, Korean, Dutch, Javanese/Indonesian, and Taiwanese — carry homozygous or compound heterozygous loss-of-function mutations in SLURP1 on chromosome 8q24.3. Documented pathogenic variants span a broad allelic spectrum, including the recurrent missense G86R (c.256G>A) substituting arginine for a conserved glycine, the W15R missense, a start-codon loss, nonsense/frameshift c.82delT, splice-site mutations, and the in-frame deletion c.271_273delTCT. The disorder is cataloged as OMIM #248300 with an estimated prevalence of ~1:100,000.

As stated in the primary genetic report: "Mal de Meleda (MDM) or keratosis palmoplantaris transgrediens of Siemens is an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma (PPK) and transgressive keratosis with an onset in early infancy" and "patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at position 86" (PMID: 12483299). The prevalence and inheritance are confirmed by a focused review: "Mal de Meleda is a rare autosomal recessive palmoplantar keratoderma (PPK) disease with an estimated prevalence of 1:100,000" (PMID: 26445964).

Finding 2 — SLURP-1 is a secreted Ly-6/uPAR protein that allosterically modulates keratinocyte α7-nAChRs

SLURP-1 is an autocrine/paracrine cholinergic peptide that regulates keratinocyte growth and differentiation. Recombinant SLURP-1 inhibits proliferation of human keratinocytes (~40%, EC50 ~4 nM) via the α7-nAChR; it binds selectively to α7-nAChR and non-competitively (allosterically) inhibits acetylcholine responses (IC50 ~1 μM) in oocyte electrophysiology. Downstream, SLURP-1 signaling through α7-nAChR upregulates NF-κB via Ca²⁺ influx and activation of MEK1, Jak2, CaMKII, and PKC. Functionally, SLURP-1 regulates keratinocyte proliferation, apoptosis/differentiation, and wound re-epithelialization.

Key supporting quotes: "Point mutations in the slurp-1 gene cause the autosomal inflammation skin disease Mal de Meleda. SLURP-1 is considered an autocrine/paracrine hormone that regulates growth and differentiation of keratinocytes" and "revealed α7 type nAChRs as an rSLURP-1 target in keratinocytes" (PMID: 26905431). The NF-κB signaling cascade is detailed in PMID: 20660165, and the wound-epithelialization role in PMID: 22168155.

Finding 3 — Slurp1-deficient mice recapitulate MdM PPK with lipid-droplet accumulation and barrier defect

Slurp1(-/-) mice, and an independent Slurp1X(-/-) (nonsense) line, develop severe PPK with increased keratinocyte proliferation, lipid-droplet accumulation in the stratum corneum, and an epidermal water-barrier defect. These mice also exhibit reduced adiposity, protection from diet-induced obesity, low plasma lipids, and hind-limb clasping (a neuromuscular sign). Importantly, reducing EGFR signaling via a hypomorphic Egfr allele did not ameliorate the PPK, indicating SLURP1 acts independently of (or downstream of) EGFR signaling.

Supporting quotes: "Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect" (PMID: 24499735), and "Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws" (PMID: 28418591).

Finding 4 — Clinical phenotype: transgredient/progredient PPK with sclerosis, pseudoainhum, perioral erythema, and nail changes

The hallmark features are sharply demarcated erythema and hyperkeratosis of palms and soles with onset soon after birth, progressing with age (progrediens) and extending to the dorsal hands and feet in a glove-and-socks distribution (transgrediens). Associated features include skin sclerosis/atrophy, scleroatrophic erythematous lesions, constricting digital bands (pseudoainhum) that can cause autoamputation, perioral erythema, brachydactyly, nail abnormalities (koilonychia, subungual hyperkeratosis), hyperhidrosis with malodor, and keratotic plaques over knees and elbows. Histopathology shows hyperkeratosis and acanthosis without epidermolysis, accompanied by a perivascular lymphocytic dermal infiltrate.

Supporting quotes: "The hallmark features of the condition include transient thickening of the palms and soles, skin sclerosis and atrophy, scleroatrophic erythematous lesions, pseudoainhum formation around the digits, and erythema around the mouth" (PMID: 41048964); "characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities" (PMID: 11285253); and "The histopathologic study showed marked hyperkeratosis, acanthosis, and normogranulosis, without epidermolysis" (PMID: 21909218).

Finding 5 — Founder origin on Mljet Island, Croatia, with founder haplotypes and consanguinity

MdM was first described by Luka Stulli in 1826 on Mljet (Meleda) Island, Croatia. Haplotype analysis of island cases revealed a shared haplotype near marker D8S1751 on 8qter in all affected individuals but none of 17 controls, with genealogies consistent with common ancestry. Founder effects have been documented in Mediterranean/Adriatic and North African (Algerian) populations, and the same mutation is shared between Mljet and families located along medieval Dubrovnik trade routes (Middle East, North Africa), implying spread by migration. Croatian island populations are characterized by genetic isolation, consanguinity, and inbreeding.

Supporting quotes: "These confirmed a shared haplotype in all cases, but in none of 17 unaffected control individuals, near the marker D8S1751 on chromosome 8" (PMID: 12145432); "The disease was first described on the island of Mljet, Croatia, by Luko Stulli in 1826" (PMID: 25102791); and "These populations are characterized by high degree of genetic isolation, consanguinity, and inbreeding" (PMID: 16909451).

Finding 6 — SLURP1 as a putative squamous-lineage tumor suppressor; impaired T-cell activation

In a Palestinian MdM family homozygous for c.82delT, affected members developed squamous cell carcinomas and melanoma at PPK sites. SLURP1 mRNA is markedly elevated in epithelial tissues and significantly suppressed in epithelial malignancies relative to normal or premalignant counterparts. Recombinant SLURP-1 reduces nitrosamine-induced tumorigenic transformation of keratinocytes in vitro and in nude mice. Peripheral blood mononuclear cells (PBMCs) from G86R homozygotes/heterozygotes show defective anti-CD3/CD28 T-cell activation that is rescued by recombinant SLURP-1, and homozygous patients are reported to be prone to melanoma and viral infection.

Supporting quotes: "SLURP1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts" (PMID: 29231248); and "PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation" (PMID: 20854438). Anti-tumorigenic activity of SLURP-1/-2 against tobacco nitrosamines is documented in PMID: 17643396 and PMID: 17280689.

Finding 7 — Management is symptomatic: oral acitretin plus topical keratolytics

Because MdM is rare, there are no formal guidelines. The accepted approach is oral acitretin (a systemic retinoid; ATC D05BB02) combined with topical keratolytic therapy (salicylic acid, urea, emollients), plus genetic counseling. Systemic retinoids reduce hyperkeratosis in related PPKs at ~0.3–0.5 mg/kg/day but relapse on cessation and carry dose-related toxicity (teratogenicity, mucocutaneous dryness, hepatic and lipid effects). Surgical excision with Z-plasty is used for constricting pseudoainhum bands, though recurrence is common. No gene/cell/RNA-targeted therapy is approved.

Supporting quotes: "there are no set guidelines for management, but the accepted approach tends to include oral acitretin plus topical keratolytic therapy. Genetic counseling should also be offered" (PMID: 26445964); and "Surgical excision is the only treatment of pseudoainhum; however, it is fraught with recurrence" (PMID: 39509536).

Finding 8 — SLURP-1 is a single-domain three-finger-toxin-fold protein; MdM mutations cause loss of function

SLURP-1 (UniProt P55000; HGNC:11827; gene SLURP1 on 8q24.3) is a small secreted member of the Ly-6/uPAR (LU) superfamily whose amino-acid composition is homologous to three-finger toxins such as frog cytotoxin and snake-venom neurotoxins/cardiotoxins, stabilized by a conserved disulfide-bonded β-sheet "three-finger" fold. It is expressed in suprabasal/granular keratinocytes of squamous epithelia. MdM pathogenic variants (missense G86R, W15R; nonsense/frameshift c.82delT; splice-site; start-codon loss; in-frame c.271_273delTCT) disrupt the fold or abolish the protein, producing loss of function.

Supporting quotes: "The amino acid composition of SLURP-1 is homologous to that of toxins such as frog cytotoxin and snake venom neurotoxins and cardiotoxins" and "Three different homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin" (PMID: 11285253).

Report by Research Section

1. Disease Information

Overview. Mal de Meleda is a rare monogenic, autosomal recessive diffuse transgredient palmoplantar keratoderma with onset in early infancy. It is "aggregated disease-level" knowledge derived predominantly from case reports, family studies, and small case series, rather than large EHR cohorts.

Key identifiers: - MONDO: MONDO:0009552 - OMIM: #248300 - Gene (OMIM): SLURP1 / ARS component B, OMIM 606119 - Orphanet: ORPHA:87503 (Mal de Meleda) - ICD-10: Q82.8 (other specified congenital malformations of skin); ICD-11: EC20.0 / LA90 range (hereditary PPK) - MeSH: "Keratoderma, Palmoplantar" (and "Mal de Meleda" as entry term) - HGNC: HGNC:11827 (SLURP1); UniProt:* P55000

Synonyms / alternative names: Meleda disease; keratosis palmoplantaris transgrediens of Siemens; keratoderma palmoplantare transgrediens; mal de Meleda; acroerythrokeratoderma; Mljet disease.

Evidence source: Aggregated disease-level resources (OMIM, Orphanet, UniProt, HGNC) plus primary literature. Not derived from individual EHR data.

2. Etiology

Causal factor: Monogenic — biallelic loss-of-function mutations in SLURP1 (Findings 1, 8). The disease is fully genetic; there is no established infectious or primary environmental cause.

Genetic risk factors: Causal variants are in SLURP1 only (no genetic heterogeneity confirmed for classic MdM, though clinically overlapping PPKs involve other genes — see Differential Diagnosis). Consanguinity and founder effects substantially increase risk in isolated/endemic populations (Mljet, Adriatic, Algerian, Middle Eastern) (Finding 5). Being the offspring of two carriers (each contributing a loss-of-function allele) is the key determinant.

Environmental risk factors: No proven environmental cause. Mechanical stress, friction, pressure, heat, and secondary bacterial/fungal colonization (contributing to malodor and maceration) may aggravate established lesions but do not cause disease.

Protective factors: None established genetically beyond simply not carrying biallelic loss-of-function alleles. No dietary/lifestyle protective factors are documented.

Gene–environment interactions: Minimal/none definitively established. The mouse data (reduced adiposity, protection from diet-induced obesity in Slurp1−/−) hint at a SLURP1–lipid-metabolism interaction, but this is a model-organism observation, not a demonstrated human GxE effect (Finding 3).

3. Phenotypes

Phenotype Type Onset Severity / Course Frequency Suggested HPO
Diffuse palmoplantar keratoderma Physical manifestation Early infancy / neonatal Severe, progressive Universal (~100%) HP:0007592 (transgressive PPK); HP:0000982 (PPK)
Transgredient spread to dorsa (glove-and-socks) Physical sign Childhood Progressive Characteristic / majority HP:0007556
Pseudoainhum (constricting digital bands) Clinical sign Childhood–adult Severe; can cause autoamputation Subset HP:0100648
Perioral erythema Clinical sign Childhood Variable Common HP:0000973 (approx.)
Brachydactyly Physical sign Congenital/childhood Variable Subset HP:0001156
Nail abnormalities (koilonychia, subungual hyperkeratosis) Physical sign Childhood Variable Common HP:0001598 / HP:0008392
Hyperhidrosis with malodor Symptom/sign Childhood Chronic Common HP:0000975
Skin sclerosis/atrophy Physical sign Progressive Variable Common HP:0100679 / HP:0000964
Keratotic plaques (knees/elbows) Physical sign Childhood Stable/progressive Subset HP:0000962 (hyperkeratosis)

Quality-of-life impact: Substantial. Painful hyperkeratosis and pseudoainhum impair ambulation and manual dexterity; malodor and visible disfigurement impose significant psychosocial burden and stigma, especially in close-knit island communities (Finding 4; qualitative data PMID: 31178100). Formal EQ-5D/SF-36 scores are not available for MdM specifically.

4. Genetic / Molecular Information

  • Causal gene: SLURP1 (ARS component B / LY6LS), 8q24.3; OMIM *606119; HGNC:11827; UniProt P55000.
  • Variant spectrum (all germline, loss-of-function): missense G86R (c.256G>A) at a conserved glycine (recurrent, pseudodominant transmission reported — PMID: 17184264); W15R; c.82delT frameshift; nonsense; splice-site; start-codon loss; in-frame c.271_273delTCT (Javanese — PMID: 29023701); c.154A>G reported in a Chinese cohort (PMID: 42384829).
  • Variant classification (ACMG/AMP): Pathogenic / likely pathogenic for the recurrent and null alleles.
  • Variant types: missense, frameshift, nonsense, splice-site, in-frame deletion, start-loss.
  • Allele frequency: Very rare in gnomAD; enriched locally by founder effects.
  • Somatic vs germline: Germline.
  • Functional consequence: Loss of function (protein absence or misfolded, non-functional three-finger domain) (Finding 8).
  • Modifier genes: None definitively established in humans. Mouse work shows Egfr reduction does not modify PPK (Finding 3), arguing against EGFR as a dominant modifier.
  • Epigenetic / chromosomal abnormalities: None reported; MdM is a single-gene disorder with no aneuploidy or structural chromosomal involvement.

5. Environmental Information

No environmental toxin, radiation, lifestyle, or infectious agent causes MdM. Secondary microbial colonization contributes to malodor and maceration. Mechanical/frictional stress may worsen hyperkeratosis locally. Not applicable as a primary etiologic category.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic loss-of-function mutation in SLURP1 (missense disrupting the three-finger fold, or null allele) leads to absence or non-functional secreted SLURP-1 protein in suprabasal/granular keratinocytes. (Demonstrated — Findings 1, 8.)
  2. Loss of secreted SLURP-1 results in loss of allosteric modulation of α7-nicotinic acetylcholine receptors (α7-nAChR) on keratinocytes. (Demonstrated in vitro/oocyte — Finding 2.)
  3. Absent α7-nAChR cholinergic signaling removes the physiological brake on keratinocyte proliferation and dysregulates the proliferation–differentiation–apoptosis balance (branch A) and disrupts downstream NF-κB/Ca²⁺/MEK1/Jak2/CaMKII/PKC signaling (branch B). (Demonstrated — Findings 2, 3; signaling detail [PMID: 20660165].)
  4. Branch A — Epidermal hyperproliferation leads to marked hyperkeratosis and acanthosis (without epidermolysis). (Demonstrated in human histology and mouse — Findings 3, 4.)
  5. Branch B — Disrupted epidermal lipid/barrier homeostasis results in lipid-droplet accumulation in the stratum corneum and a water-barrier defect. (Demonstrated in mouse; inferred in human — Finding 3.)
  6. Hyperkeratosis + barrier defect + chronic low-grade dermal inflammation (perivascular lymphocytic infiltrate) produce the clinical diffuse transgredient PPK, sclerosis, and erythema. (Demonstrated — Finding 4.)
  7. Progressive sclerosis around digits leads to constricting bands (pseudoainhum) and, in severe cases, autoamputation. (Demonstrated — Finding 4.)
  8. Parallel branch — Loss of SLURP-1 tumor-suppressor/immune function leads to impaired T-cell activation and reduced protection against malignant transformation, contributing to increased cutaneous SCC/melanoma risk. (Demonstrated/inferred — Finding 6.)

Molecular pathways: Non-neuronal cholinergic signaling via α7-nAChR; downstream Raf-1/MEK1/ERK1/2, Jak2, Ca²⁺/CaMKII/PKC, and NF-κB. GO terms: GO:0007271 (synaptic transmission, cholinergic — approximate), GO:0008284 (positive regulation of cell proliferation; here dysregulated), GO:0030216 (keratinocyte differentiation), GO:0031424 (keratinization), GO:0008544 (epidermis development), GO:0043066 (negative regulation of apoptosis). Cellular processes: keratinocyte proliferation, differentiation, apoptosis, wound re-epithelialization, inflammation. CL terms: CL:0000312 (keratinocyte), CL:0000362 (epidermal cell). Protein dysfunction: loss of function of a three-finger-toxin-fold modulator. Metabolic changes: epidermal lipid dysregulation (stratum corneum lipid droplets). Immune involvement: defective T-cell activation; chronic perivascular lymphocytic dermal infiltrate. CHEBI: acetylcholine (CHEBI:15355); nicotine (CHEBI:17688); acitretin (CHEBI:50172).

7. Anatomical Structures Affected

  • Primary organ: Skin (UBERON:0002097), specifically palmoplantar epidermis (UBERON:0006956, skin of palm; UBERON:0001513, skin of sole).
  • Secondary involvement: Dorsal hands/feet (transgrediens), perioral skin, nails (UBERON:0001705), knees/elbows; digits (pseudoainhum → autoamputation).
  • Body system: Integumentary. Mild neuromuscular signs reported in mouse model only.
  • Tissue/cell level: Stratified squamous epithelium; keratinocytes (CL:0000312), predominantly suprabasal/granular layer where SLURP-1 is expressed.
  • Subcellular: Secreted extracellular protein (GO:0005615, extracellular space); stratum corneum lipid droplets (GO:0005811).
  • Localization/laterality: Bilateral, symmetric.

8. Temporal Development

  • Onset: Congenital/early infancy (soon after birth).
  • Onset pattern: Insidious, chronic.
  • Progression: Progredient — worsens with age; transgredient spread over childhood. Disease course is chronic and lifelong, slowly progressive.
  • Stages: Early (infantile palmoplantar erythema/hyperkeratosis) → intermediate (transgredient spread, sclerosis) → advanced (pseudoainhum, digital constriction, possible autoamputation).
  • Remission: No spontaneous remission; partial, reversible improvement with retinoid therapy (relapses on cessation).
  • Critical periods: Early intervention with keratolytics/retinoids and vigilance for pseudoainhum are the main windows to reduce morbidity.

9. Inheritance and Population

  • Epidemiology: Prevalence ~1:100,000 (PMID: 26445964); higher in founder populations. Incidence not separately quantified.
  • Inheritance: Autosomal recessive (OMIM #248300). Pseudodominant transmission with G86R reported in highly consanguineous pedigrees (PMID: 17184264).
  • Penetrance: Complete for biallelic loss-of-function genotypes.
  • Expressivity: Variable (severity of pseudoainhum, transgrediens extent).
  • Anticipation: Not applicable (no repeat expansion).
  • Germline mosaicism: Not reported.
  • Founder effects: Well documented (Mljet/Adriatic, Algerian, Middle Eastern trade-route populations) (Finding 5).
  • Consanguinity: Major contributor in endemic/isolated populations.
  • Carrier frequency: Elevated in founder populations; low globally.
  • Geographic distribution: Worldwide but historically clustered along medieval Dubrovnik trade routes; cases from Croatia, Algeria, Germany, Turkey, Palestine, UAE, Korea, Netherlands, Indonesia (Java), Taiwan, China.
  • Sex ratio: ~1:1 (autosomal). Age distribution: All ages; lifelong.

10. Diagnostics

  • Clinical diagnosis: Based on characteristic diffuse transgredient PPK with onset in infancy, sclerosis, pseudoainhum, perioral erythema, and family history/consanguinity.
  • Histopathology (biopsy): Marked hyperkeratosis, acanthosis, normogranulosis, without epidermolysis; perivascular lymphocytic dermal infiltrate (PMID: 21909218). Distinguishes MdM from epidermolytic PPKs.
  • Genetic testing (confirmatory, gold standard): Single-gene SLURP1 sequencing; gene panels for hereditary PPK; whole-exome sequencing (WES) when the panel is negative or phenotype overlaps. WGS rarely needed. CMA, karyotyping, FISH, mitochondrial and repeat-expansion testing are not applicable.
  • Biomarkers: Reduced/absent SLURP-1; no routine circulating biomarker.
  • Imaging: Not diagnostic; radiographs may document acro-osteolysis/autoamputation.
  • Differential diagnosis: Other diffuse PPKs and mutilating keratodermas — Vohwinkel syndrome (GJB2/LOR), Olmsted syndrome (TRPV3), Papillon–Lefèvre syndrome (CTSC), Nagashima-type PPK (SERPINB7), Bothnia-type (AQP5), Greither/epidermolytic (KRT1/KRT10), loricrin keratoderma, progressive symmetric erythrokeratoderma. Distinguishing features: MdM lacks periodontitis (vs PLS), lacks deafness (vs KID/Vohwinkel classic), lacks epidermolysis histologically, and shows transgrediens with pseudoainhum and perioral erythema. MdM is "a great imitator" (PMID: 31178100).
  • Screening: Carrier/cascade screening in affected families and founder populations; prenatal/preimplantation testing possible once the familial variant is known.

11. Outcome / Prognosis

  • Survival/mortality: Normal life expectancy; MdM is not directly fatal.
  • Morbidity/function: High — chronic pain, impaired ambulation and hand function, malodor, psychosocial burden; pseudoainhum can cause digital autoamputation.
  • Disease course: Chronic, lifelong, slowly progressive; partial response to therapy with relapse on cessation.
  • Complications: Secondary bacterial/fungal infection, maceration, flexion contractures, autoamputation; increased risk of cutaneous squamous cell carcinoma and melanoma at PPK sites (Finding 6); reported susceptibility to viral infection.
  • Recovery potential: No cure; symptomatic control only.
  • Prognostic factors: Severity of pseudoainhum and transgrediens extent; adherence to keratolytic/retinoid therapy; timely surgical release of constricting bands.

12. Treatment

Pharmacotherapy (symptomatic): - Oral acitretin (systemic retinoid; ATC D05BB02; NCIT: Acitretin) — first-line, ~0.3–0.5 mg/kg/day; reduces hyperkeratosis; relapses on cessation; dose-related toxicity (teratogenicity, mucocutaneous dryness, hepatic/lipid effects) (PMID: 26445964; analogous PPK evidence PMID: 28008647, PMID: 29500825). Isotretinoin is an alternative retinoid. - Topical keratolytics: salicylic acid, urea, emollients, topical retinoids; often combined with low-dose systemic retinoid to limit toxicity (PMID: 29500825).

Surgical/interventional: Excision with Z-plasty for pseudoainhum constricting bands (recurrence common — PMID: 39509536); amputation in advanced digital involvement.

Supportive/rehabilitative: Skin hydration, debridement, antimicrobial management of secondary infection, foot/hand care, physiotherapy to preserve function; genetic counseling.

Advanced/targeted/experimental: No approved gene, cell, RNA-based, or SLURP-1-replacement therapy. Recombinant SLURP-1 is a conceptual mechanism-based candidate (restores the α7-nAChR brake in vitro), but no human trials exist. NCIT terms: Acitretin, Salicylic Acid, Surgical Procedure, Genetic Counseling.

Pharmacogenomics: None specific to MdM.

13. Prevention

  • Primary prevention: Not possible for a Mendelian disorder; genetic counseling, carrier screening in founder/consanguineous populations, and reproductive options (prenatal/preimplantation genetic testing) reduce new-case occurrence.
  • Secondary prevention: Early diagnosis and keratolytic/retinoid therapy; surveillance for pseudoainhum to prevent autoamputation.
  • Tertiary prevention: Prevent complications — skin-cancer surveillance (given SCC/melanoma risk), infection control, functional preservation.
  • Immunization / public health / environmental interventions: Not applicable.
  • Counseling: Genetic counseling is central, especially in consanguineous families.

14. Other Species / Natural Disease

  • Taxonomy: Human disease (Homo sapiens, NCBI:txid9606). Experimental models in Mus musculus (NCBI:txid10090).
  • Orthologous gene: Mouse Slurp1 (NCBI Gene).
  • Natural disease in other species: No well-characterized naturally occurring animal homolog of MdM documented in OMIA; disease knowledge in animals derives from engineered Slurp1-knockout mice (Finding 3), not natural disease.
  • Comparative biology: SLURP-1 and the cholinergic α7-nAChR axis are evolutionarily conserved; the mouse knockout recapitulates the human PPK, supporting mechanistic conservation.
  • Transmission: Not applicable (non-infectious genetic disease; no zoonotic potential).

15. Model Organisms

  • Mammalian model: Slurp1(-/-) knockout mouse and Slurp1X(-/-) nonsense-allele mouse (MGI). Genetic model types: knockout, nonsense knock-in.
  • Phenotype recapitulation: Faithful — severe PPK with increased keratinocyte proliferation, epidermal thickening on volar paw surfaces, stratum-corneum lipid-droplet accumulation, and water-barrier defect (Finding 3). Additional phenotypes: reduced adiposity, protection from diet-induced obesity, low plasma lipids, hind-limb clasping.
  • Model-based insight: EGFR reduction (hypomorphic Egfr) does not rescue the PPK, implicating SLURP1-independent/downstream mechanisms (Finding 3).
  • Cellular/in vitro models: Human epidermal and oral keratinocytes; immortalized Het-1A esophageal keratinocytes; recombinant SLURP-1 functional assays; Xenopus oocyte electrophysiology for α7-nAChR modulation (Finding 2).
  • Limitations: Mouse metabolic phenotypes (adiposity/lipid) are not prominent features of human MdM; models emphasize skin barrier/proliferation. Resources: MGI, IMPC.

Mechanistic Model / Interpretation

  SLURP1 biallelic LOF mutation (8q24.3)
 │ leads to
 ▼
  Absent / non-functional secreted SLURP-1
  (three-finger-toxin fold, Ly-6/uPAR family)
 │ results in
 ▼
  Loss of allosteric modulation of keratinocyte α7-nAChR
 │                                   │
   (Branch A) removes brake           (Branch B) disrupts
   on proliferation                    NF-κB/Ca²⁺/MEK1/Jak2
 │                                   │
 ▼                                   ▼
  Keratinocyte hyperproliferation     Epidermal lipid/barrier
  → hyperkeratosis + acanthosis       dysregulation → stratum
  (no epidermolysis)                  corneum lipid droplets,
 │                             water-barrier defect
 └──────────────┬──────────────┘
        ▼
      Diffuse transgredient/progredient PPK
      + sclerosis + perioral erythema + nail changes
        │ leads to
        ▼
  Pseudoainhum → digital autoamputation

  (Parallel) Loss of SLURP-1 tumor-suppressor/immune function
   → impaired T-cell activation + reduced protection from
     malignant transformation → ↑ cutaneous SCC / melanoma risk

The central, well-supported insight is that MdM is a non-neuronal cholinergic signaling disorder of the epidermis: SLURP-1 normally tunes keratinocyte behavior through α7-nAChR, and its loss simultaneously releases a proliferative brake and corrupts barrier lipid homeostasis. The convergence of human genetics (Findings 1, 8), biochemistry/pharmacology (Finding 2), and a faithful knockout mouse (Finding 3) makes this one of the better-validated causal chains among the inherited PPKs. The tumor-suppressor/immune arm (Finding 6) is biologically plausible and empirically supported but clinically secondary.

Evidence Base

PMID Role How it supports / challenges findings
12483299 Supports F1 Defines AR transgredient PPK; documents G86R across German/Turkish/Palestinian/UAE families
11285253 Supports F4, F8 First SLURP1 gene report; three-finger-toxin homology; LOF variant classes; clinical features
26445964 Supports F1, F4, F7 Focused review: prevalence 1:100,000, histology, acitretin + keratolytics
26905431 Supports F2 Identifies α7-nAChR as SLURP-1 target; selective allosteric antagonism
20660165 Supports F2 NF-κB upregulation via α7-nAChR, Ca²⁺/MEK1/Jak2/CaMKII/PKC
22168155 Supports F2 SLURP-1 regulates wound epithelialization via α7-nAChR
24499735 Supports F3 Slurp1−/− mice: PPK, lipid droplets, water-barrier defect
28418591 Supports F3 Faithful recapitulation; EGFR reduction does not rescue PPK
12145432 Supports F5 Founder haplotype near D8S1751 in Mljet cases
25102791 Supports F5 Historical origin, Stulli 1826, Mljet
16909451 Supports F5 Croatian island genetic isolation/consanguinity
29231248 Supports F6 SLURP1 tumor-suppressor; suppressed in epithelial malignancies; melanoma signal
20854438 Supports F6 Defective T-cell activation with G86R; rescued by recombinant SLURP-1
17643396, 17280689 Supports F6 SLURP-1 reduces nitrosamine-induced transformation (in vitro + nude mice)
39509536 Supports F7 Surgical excision for pseudoainhum; recurrence common
21909218 Supports F4 Histology: hyperkeratosis/acanthosis without epidermolysis
41048964 Supports F4 Enumerates hallmark features incl. pseudoainhum, perioral erythema
17184264 Supports F1/§9 Pseudodominant G86R inheritance in consanguineous pedigrees
29023701, 25557416 Supports F1/§9 Novel c.271_273delTCT; "ubiquitous" SLURP1 mutations (Indonesia)
42384829 Supports §10 Large Chinese PPK cohort; SLURP1 c.154A>G among diffuse PPK genes

Evidence source types: human clinical/genetic (family studies, case reports, cohorts), model organism (knockout mice), in vitro/biochemical (recombinant protein, oocyte electrophysiology, keratinocyte culture), and computational/structural (three-finger-fold homology).

Limitations and Knowledge Gaps

  1. No human omics data (transcriptomic/proteomic/metabolomic) on MdM lesional skin were identified; barrier-lipid mechanisms are inferred primarily from mouse.
  2. Quality-of-life metrics (EQ-5D/SF-36/PROMIS) are not formally quantified for MdM; QoL impact is described qualitatively.
  3. Cancer risk is based on small family observations plus mechanistic in vitro/model data; incidence of SCC/melanoma in MdM is not epidemiologically quantified.
  4. Genotype–phenotype correlations are incompletely defined; expressivity (pseudoainhum severity) varies even within genotype.
  5. No disease-modifying therapy; retinoid efficacy data are largely extrapolated from related PPKs rather than MdM-specific trials.
  6. Modifier genes and gene–environment interactions in humans remain essentially unknown.
  7. No natural animal disease model is catalogued; comparative/veterinary data are absent.

Proposed Follow-up Experiments / Actions

  1. Single-cell/spatial transcriptomics of MdM lesional vs. normal palmoplantar epidermis to map the keratinocyte proliferation–differentiation axis and barrier-lipid gene programs in humans (GEO/HCA).
  2. Lipidomics of MdM stratum corneum (LIPID MAPS/Metabolomics Workbench) to confirm the barrier-lipid defect observed in mice and identify targetable species.
  3. Recombinant SLURP-1 / α7-nAChR agonist topical replacement: preclinical testing in Slurp1−/− mice as a mechanism-based therapy, then early-phase human studies.
  4. Prospective registry to quantify prevalence, pseudoainhum incidence, SCC/melanoma risk, and validated QoL outcomes across founder and non-founder populations.
  5. Structural studies (AlphaFold/PDB) of G86R and W15R SLURP-1 to define how specific mutations destabilize the three-finger fold and inform variant interpretation.
  6. Carrier-screening programs in high-prevalence/consanguineous populations with genetic counseling and reproductive options.
  7. Gene/RNA-based therapy feasibility (e.g., AAV-delivered SLURP1 or mRNA) as a long-term curative strategy, given the small, secreted nature of the protein.

Report compiled from 8 confirmed findings and 64 reviewed papers over a 5-iteration autonomous investigation. Mal de Meleda is MONDO:0009552 / OMIM #248300, a SLURP1 loss-of-function autosomal recessive transgredient palmoplantar keratoderma.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 25
On topic 15
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 32
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 15
Terms named correctly 6
Terms named as a different term 5
Terms whose name is worth a second look 4

Terms the report names something else

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

  • HP:0007556 (1 mention) - the report calls it "Characteristic / majority"; HP calls it Plantar hyperkeratosis
  • HP:0100648 (1 mention) - the report calls it "Subset"; HP calls it Neoplasm of the tongue
  • HP:0000973 (1 mention) - the report calls it "approx"; HP calls it Cutis laxa
  • HP:0001156 (1 mention) - the report calls it "Subset"; HP calls it Brachydactyly
  • HP:0000975 (1 mention) - the report calls it "Common"; HP calls it Hyperhidrosis

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

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

  • GO:0007271 (1 mention) - the report calls it "synaptic transmission, cholinergic — approximate"; GO calls it synaptic transmission, cholinergic
  • GO:0008284 (1 mention) - the report calls it "positive regulation of cell proliferation; here dysregulated"; GO calls it positive regulation of cell population proliferation, and lists "positive regulation of cell proliferation" among its other names
  • GO:0043066 (1 mention) - the report calls it "negative regulation of apoptosis"; GO calls it negative regulation of apoptotic process, and lists "negative regulation of apoptosis" among its other names
  • UBERON:0002097 (1 mention) - the report calls it "Primary organ: Skin"; UBERON calls it skin of body**, and lists "skin organ" among its other names

Terms named inconsistently

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

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

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.