Striate Palmoplantar Keratoderma Type 2

Genetic MONDO:0013034 Pathograph 29 Show in embeddings browser Palmoplantar Keratoderma Desmosomal Disease

Striate palmoplantar keratoderma type 2 (SPPK2; OMIM 612908; PPKS2) is an autosomal dominant skin disorder caused by heterozygous truncating mutations in the desmoplakin (DSP) gene. It is the first inherited skin disorder in which haploinsufficiency of a structural component was identified as the mechanism: premature termination codons in DSP transcripts trigger nonsense-mediated decay, halving the dosage of desmoplakin, which is the most abundant component of the desmosomal plaque and the principal anchor of the keratin intermediate filament cytoskeleton to desmosomes. Reduced desmoplakin (especially the dominant skin isoform DSPII) compromises desmosomal plaque assembly and keratin–desmosome coupling in suprabasal keratinocytes; under the high mechanical load borne by palms and soles this produces loosening of intercellular connections, perinuclear collapse of the keratin filament network, K16 upregulation, and compensatory hyperkeratosis along lines of stress. Affected individuals show linear hyperkeratosis on fingers and palms and focal hyperkeratosis at trauma-prone plantar sites, often with painful fissures. Phenotypic expression is age- and trauma-dependent. Many DSP truncating variants in this region are also associated with arrhythmogenic or dilated cardiomyopathy; PPK can be the earliest clue and DSP carriers warrant cardiac surveillance, even when classic skin-limited SPPK2 has historically been considered to lack frank cardiac disease.

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1
Inheritance
7
Pathophys.
12
Phenotypes
29
Pathograph
1
Genes
7
Medical Actions
1
Deep Research
👪

Inheritance

1
Autosomal Dominant HP:0000006
Autosomal dominant inheritance
⚙

Pathophysiology

7
DSP Premature Termination Codons Triggering Nonsense-Mediated Decay
Heterozygous DSP truncating variants (nonsense, frameshift, splice-site) introduce premature termination codons. Aberrant splicing variants such as 939+1G>A retain intron 7 and place a PTC in the N-terminal coding region; nonsense alleles such as Q331X and frameshifts such as p.Glu831Aspfs*33 generate PTCs in the canonical reading frame. The mutant transcripts are degraded by nuclear-transcribed nonsense-mediated mRNA decay, so no truncated dominant-negative protein accumulates and the affected allele functionally drops out. Variant location matters: PTCs in the regions producing NMD-competent transcripts of both major DSP isoforms (DSPI and DSPII) are markedly enriched in disease cohorts compared with population controls.
Keratinocyte CL:0000312
Nuclear-transcribed mRNA catabolic process, nonsense-mediated decay GO:0000184 ↑ INCREASED
Downstream
Desmoplakin Haploinsufficiency in Epidermis NMD of the mutant transcript leaves only the wild-type allele to produce desmoplakin, reducing protein dosage in keratinocytes roughly to half of normal.
DSP Truncating-Variant Cardiomyopathy Susceptibility Some DSP truncating alleles that produce SPPK2-spectrum skin disease also confer a cardiocutaneous risk, with adult-onset dilated cardiomyopathy and ventricular arrhythmias in susceptible carriers.
Show evidence (3 references)
PMID:9887343 SUPPORT Human Clinical
"The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide."
Original report demonstrating that the SPPK2-causing DSP variant predicts a premature termination codon, the substrate for nonsense-mediated decay.
PMID:10594734 SUPPORT Human Clinical
"The aberrant splicing leads to retention of the entire intron 7, which contains a premature termination codon within the N-terminal domain of the peptide."
A second SPPK2 family illustrates a different molecular route (splice-site loss with intron retention) to a PTC.
PMID:36580316 SUPPORT Human Clinical
"gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms"
Quantifies the enrichment of NMD-competent variant locations in DSP truncating-variant disease cohorts.
Desmoplakin Haploinsufficiency in Epidermis
Loss of one functional DSP allele halves the dosage of desmoplakin in keratinocytes, the most abundant constitutive component of the desmosomal plaque. The skin-dominant isoform DSPII is particularly sensitive to this dosage reduction: in cultured keratinocytes DSPII is the key component supporting intermediate filament stability and desmosome-mediated adhesion, and reduction of total DSP also lowers plakophilin 1, desmocollin 2 and desmocollin 3, propagating the dosage problem to interacting plaque and cadherin components. Because desmoplakin is the principal link between desmosomes and keratin intermediate filaments, halved dosage degrades both desmosomal assembly and keratin anchoring, with effects most apparent under the mechanical loads borne by palmar and plantar epidermis.
Keratinocyte CL:0000312
Desmosome organization GO:0002934 ↓ DECREASED
Structural constituent of cytoskeleton GO:0005200
Skin of palm and sole UBERON:0013776
Downstream
Defective Desmosomal Plaque Assembly Halved desmoplakin dosage limits assembly of mature desmosomal plaques and reduces stable expression of plaque (PKP1) and cadherin (DSC2/3) partners, so suprabasal desmosomes are fewer and structurally rudimentary.
Keratin Intermediate Filament Network Disruption Because desmoplakin is the principal IF anchor, halved dosage uncouples keratin filaments from desmosomes, allowing the filament network to collapse perinuclearly.
Show evidence (3 references)
PMID:9887343 SUPPORT Human Clinical
"This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity."
Establishes DSP haploinsufficiency as a novel disease mechanism in SPPK2.
PMID:22454510 SUPPORT In Vitro
"One of the mutations results in total DSP haploinsufficiency and is associated with autosomal dominant striate palmoplantar keratoderma (PPK)."
Confirms that the SPPK-associated DSP allele acts via total DSP haploinsufficiency in cultured keratinocytes.
PMID:22454510 SUPPORT In Vitro
"DSPII being the key component in intermediate filament (IF) stability and desmosome-mediated adhesion."
Identifies DSPII as the dosage-sensitive isoform whose loss in haploinsufficiency drives the SPPK2 epidermal phenotype.
Defective Desmosomal Plaque Assembly
In SPPK2 epidermis, suprabasal desmosomes form in reduced numbers and with rudimentary architecture. Electron microscopy of palm skin shows a significant decrease in desmosome counts in the suprabasal layers and desmosomes that lack inner plaques or display abnormal keratin filament connections. Confocal analysis additionally shows abnormal expression of plaque components, consistent with the haploinsufficient desmoplakin's downstream effect on plakophilin and desmocollin partners. The result is a mechanically weak desmosomal scaffold in the layers of the epidermis that normally bear shear stress.
Suprabasal keratinocyte CL:4033013
Desmosome organization GO:0002934 ↓ DECREASED
Skin of palm and sole UBERON:0013776
Downstream
Reduced Suprabasal Desmosome Number Defective desmoplakin-dependent plaque assembly produces fewer suprabasal desmosomes and rudimentary desmosomal structures in affected palm skin.
Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites Reduced and rudimentary desmosomes provide too little adhesive surface area to hold suprabasal keratinocytes together under the shear stress of palm and sole, so intercellular spaces widen.
Show evidence (3 references)
PMID:15149499 SUPPORT Human Clinical
"Both Dp and Dsg1 mutations were accompanied by significantly reduced numbers of desmosomes in the suprabasal layers"
Quantitative electron-microscopy support for reduced suprabasal desmosome counts in DSP-haploinsufficient SPPK skin.
PMID:9887343 SUPPORT Human Clinical
"a proportion of rudimentary desmosomal structures"
Original SPPK2 paper documents structurally hypoplastic desmosomes as a hallmark ultrastructural finding.
PMID:18627762 SUPPORT Human Clinical
"Electron microscopic examination shows diminished desmosomes, clumped keratin filaments, and enlarged keratohyalin granules."
Independent clinical case confirms diminished desmosomes as the characteristic SPPK ultrastructural finding.
Keratin Intermediate Filament Network Disruption
Loss of desmoplakin-mediated anchoring causes the suprabasal keratin intermediate filament cytoskeleton to detach from the cell periphery and collapse around the nucleus. Affected SPPK2 keratinocytes show perinuclear aggregation of keratin filaments and dense perinuclear tonofilament bundles, accompanied by pronounced upregulation of keratin 16 (a stress/wound keratin) and abnormal involucrin labelling, indicating perturbed terminal differentiation downstream of the cytoskeletal failure.
Suprabasal keratinocyte CL:4033013
Intermediate filament cytoskeleton organization GO:0045104 ↓ DECREASED Keratinocyte differentiation GO:0030216 ⚠ ABNORMAL
Skin of palm and sole UBERON:0013776
Downstream
Perinuclear Keratin Filament Aggregation Desmoplakin-IF uncoupling allows keratin filaments to collapse around the nucleus instead of remaining tethered at desmosomes.
Keratin 16 Upregulation in Suprabasal Keratinocytes Keratin filament network disruption is accompanied by a stress keratin response, with pronounced K16 upregulation and abnormal involucrin labelling in suprabasal keratinocytes.
Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites Without a peripherally tethered keratin network, individual keratinocytes cannot transmit mechanical load through their remaining desmosomes, so adhesion fails first under shear in palmar/plantar skin.
Show evidence (3 references)
PMID:15149499 SUPPORT Human Clinical
"perinuclear aggregation of keratin filaments was more evident in Dp-associated SPPK"
Confocal microscopy of patient palmar epidermis shows the collapsed perinuclear keratin filament pattern that defines the desmosome–IF uncoupling phenotype in DSP-related SPPK.
PMID:15149499 SUPPORT Human Clinical
"In both types of SPPK upregulation of K16 was pronounced and involucrin labelling was abnormal."
Documents stress-keratin upregulation and abnormal terminal differentiation downstream of the cytoskeletal disruption.
PMID:18627762 SUPPORT Human Clinical
"clumped keratin filaments"
Independent ultrastructural confirmation of disrupted keratin filament organization in SPPK skin.
Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites
Combined plaque hypoplasia and keratin uncoupling render the suprabasal epidermis mechanically fragile. In palmar and plantar skin, where shear forces are highest, intercellular spaces widen and cell–cell contact loosens. The fragility is friction- and age-dependent: lesions emerge and worsen at trauma-prone sites and with cumulative occupational or activity-related load. This site-restricted adhesion failure explains why the disease is palmoplantar despite the desmoplakin defect being systemic.
Suprabasal keratinocyte CL:4033013
Cell-cell adhesion GO:0098609 ↓ DECREASED
Skin of palm and sole UBERON:0013776
Downstream
Compensatory Hyperkeratosis Along Stress Lines Adhesion failure under load drives a reactive hyperproliferative and hyperdifferentiative response in the affected palmoplantar epidermis, with hyperkeratosis distributed along the lines of mechanical stress.
Show evidence (2 references)
PMID:9887343 SUPPORT Human Clinical
"Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures."
Original SPPK2 paper documents adhesion failure with concurrent desmosomal and keratin filament defects in palm skin.
PMID:10594734 SUPPORT Human Clinical
"Assessment of family members bearing the mutant allele also emphasizes the significance of an individual's age and exposure to skin trauma in manifesting full phenotypic expression of the disorder."
Provides clinical evidence that mechanical trauma and age modulate when adhesion failure becomes phenotypically apparent.
Compensatory Hyperkeratosis Along Stress Lines
Reactive thickening of the cornified layer (hyperkeratosis), expanded granular layer (hypergranulosis) and acanthosis arise as the mechanically fragile palmoplantar epidermis adapts to friction. Because the underlying defect is desmosomal rather than epidermolytic, thickening produces persistent hyperkeratotic plaques rather than blistering, and the distribution traces lines of pressure: linear streaks on palmar and flexor finger surfaces and focal plaques over pressure-bearing plantar sites. Fissures form where the thickened, poorly cohesive epidermis splits under continued stress.
Keratinocyte CL:0000312
Keratinization GO:0031424 ↑ INCREASED Cornification GO:0070268 ↑ INCREASED
Skin of palm and sole UBERON:0013776
Downstream
Striate Palmoplantar Keratoderma The compensatory hyperkeratotic response produces the defining striate palmoplantar keratoderma pattern, with linear palmar streaks and focal plantar plaques.
Hyperkeratosis Increased keratinization and cornification thicken the stratum corneum, producing histologic hyperkeratosis in affected palmoplantar skin.
Hypergranulosis Reactive epidermal thickening expands the granular layer, producing hypergranulosis with enlarged keratohyalin granules.
Epidermal Acanthosis Compensatory epidermal thickening includes expansion of the spinous layer, producing acanthosis without epidermolysis.
Skin Fissures Thickened, mechanically fragile plaques can split under ongoing palmoplantar stress, producing painful fissures.
Streaks of Hyperkeratosis on Fingers and Palms Linear hyperkeratotic plaques along the palmar and flexor surfaces of fingers and onto the palm trace lines of habitual finger flexion and gripping.
Focal Plantar Hyperkeratosis Pressure-prone plantar sites accumulate focal hyperkeratotic plaques as the most heavily loaded skin compartments.
Show evidence (2 references)
PMID:18627762 SUPPORT Human Clinical
"Histopathologic features include hyperkeratosis, hypergranulosis, and acanthosis with no epidermolysis."
Defines the reactive epidermal thickening pattern characteristic of SPPK, distinguishing it from epidermolytic keratodermas.
PMID:18627762 SUPPORT Human Clinical
"presents with linear hyperkeratosis on the palms and fingers and focal plaques on the plantar aspects of the feet."
Documents the stress-line distribution of hyperkeratosis that is the visible endpoint of the SPPK2 pathograph.
DSP Truncating-Variant Cardiomyopathy Susceptibility
A subset of DSP truncating-variant carriers have a cardiocutaneous phenotype in which the same loss-of-function alleles that produce palmoplantar keratoderma also predispose to myocardial disease. Reduced functional desmoplakin in cardiac desmosomes weakens cardiomyocyte mechanical coupling, promoting ventricular dilation, myocardial remodeling and arrhythmia susceptibility. Expression is variable, often adult-onset and modified by truncating-variant location.
Downstream
Dilated Cardiomyopathy DSP truncating-variant cardiomyocyte desmosomal instability can produce adult-onset dilated cardiomyopathy in the cardiocutaneous SPPK2 spectrum.
Cardiac Arrhythmia DSP truncating-variant cardiomyopathy susceptibility includes ventricular arrhythmias, from extrasystoles to sustained ventricular tachycardia or sudden cardiac arrest.
Show evidence (2 references)
PMID:35445468 SUPPORT Human Clinical
"Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age."
Documents variable adult-onset cardiac disease following early PPK in a DSP truncating-variant family.
PMID:36580316 SUPPORT Human Clinical
"Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals."
Quantifies ventricular arrhythmia burden among DSP truncating-variant carriers and supports variant-location dependent risk.
⬡

Pathograph

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

12
Cardiovascular 2
Dilated Cardiomyopathy Occasional Dilated cardiomyopathy HP:0001644
Show evidence (2 references)
PMID:35445468 SUPPORT Human Clinical
"We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign."
Documents DCM in a SPPK2-spectrum family with a DSP truncating haploinsufficiency variant.
PMID:35445468 SUPPORT Human Clinical
"Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age."
Establishes the variable, adult-onset expressivity of cardiomyopathy in DSP-PPK families.
Cardiac Arrhythmia Occasional Arrhythmia HP:0011675
Show evidence (2 references)
PMID:36580316 SUPPORT Human Clinical
"Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals."
Quantitative arrhythmic burden in the largest DSPtv cohort assembled to date.
PMID:35445468 SUPPORT Human Clinical
"We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles."
Documents ventricular extrasystoles and DCM in the same DSP haploinsufficiency family that presents with focal PPK.
Integument 2
Striate Palmoplantar Keratoderma Very frequent Palmoplantar keratoderma HP:0000982
Show evidence (2 references)
PMID:9887343 SUPPORT Human Clinical
"Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles."
Describes the striate keratoderma pattern.
PMID:18627762 SUPPORT Human Clinical
"autosomal dominant condition that presents with linear hyperkeratosis on the palms and fingers and focal plaques on the plantar aspects of the feet."
Independent clinical case confirming the Brunauer-Fohs-Siemens striate PPK pattern.
Hyperkeratosis Very frequent Hyperkeratosis HP:0000962
Show evidence (1 reference)
PMID:18627762 SUPPORT Human Clinical
"Histopathologic features include hyperkeratosis, hypergranulosis, and acanthosis with no epidermolysis."
Documents hyperkeratosis as a defining histologic feature of SPPK; critically also notes the absence of epidermolysis, distinguishing SPPK2 from epidermolytic keratodermas.
Other 8
Streaks of Hyperkeratosis on Fingers and Palms Very frequent Streaks of hyperkeratosis along each finger onto the palm HP:0007501
Show evidence (1 reference)
PMID:9887343 SUPPORT Human Clinical
"a linear pattern of skin thickening on the fingers and palms"
Defining linear/striate finger-and-palm phenotype in the original DSP-haploinsufficient kindred.
Focal Plantar Hyperkeratosis Very frequent Plantar hyperkeratosis HP:0007556
Show evidence (2 references)
PMID:9887343 SUPPORT Human Clinical
"circumscribed areas of skin thickening on the soles"
Documents focal plantar hyperkeratosis in DSP-haploinsufficient SPPK2.
PMID:18627762 SUPPORT Human Clinical
"focal plaques on the plantar aspects of the feet."
Independent clinical confirmation of focal plantar plaques as the plantar manifestation of SPPK.
Reduced Suprabasal Desmosome Number Very frequent Abnormal keratinocyte morphology HP:0034702
Show evidence (2 references)
PMID:15149499 SUPPORT Human Clinical
"Both Dp and Dsg1 mutations were accompanied by significantly reduced numbers of desmosomes in the suprabasal layers"
Quantitative ultrastructural evidence of reduced desmosome counts in DSP-haploinsufficient SPPK keratinocytes.
PMID:9887343 SUPPORT Human Clinical
"a proportion of rudimentary desmosomal structures"
Cellular-level desmosome hypoplasia documented in the original SPPK2 family.
Perinuclear Keratin Filament Aggregation Frequent Abnormal keratinocyte morphology HP:0034702
Show evidence (1 reference)
PMID:15149499 SUPPORT Human Clinical
"perinuclear aggregation of keratin filaments was more evident in Dp-associated SPPK"
Confocal microscopy of patient palm keratinocytes shows the collapsed keratin filament pattern downstream of DSP-IF uncoupling.
Hypergranulosis Very frequent Hypergranulosis HP:0025114
Show evidence (2 references)
PMID:18627762 SUPPORT Human Clinical
"Histopathologic features include hyperkeratosis, hypergranulosis, and acanthosis with no epidermolysis."
Documents hypergranulosis as part of the SPPK histologic triad.
PMID:18627762 SUPPORT Human Clinical
"enlarged keratohyalin granules."
Electron microscopic correlate of hypergranulosis.
Epidermal Acanthosis Very frequent Epidermal acanthosis HP:0025092
Show evidence (1 reference)
PMID:18627762 SUPPORT Human Clinical
"Histopathologic features include hyperkeratosis, hypergranulosis, and acanthosis with no epidermolysis."
Documents acanthosis as part of the SPPK histologic triad, without epidermolysis distinguishing it from epidermolytic PPKs.
Keratin 16 Upregulation in Suprabasal Keratinocytes Frequent Abnormal keratinocyte morphology HP:0034702
Show evidence (1 reference)
PMID:15149499 SUPPORT Human Clinical
"In both types of SPPK upregulation of K16 was pronounced and involucrin labelling was abnormal."
Confocal evidence of K16 upregulation as a stress-keratin response in SPPK keratinocytes.
Skin Fissures Frequent Skin fissure HP:0031057
Show evidence (1 reference)
PMID:18627762 PARTIAL Human Clinical
"focal plaques on the plantar aspects of the feet."
The clinical case context for plantar plaques (which fissure under load) supports skin fissures as a downstream feature; the fissure association is established more directly in classification reviews summarised in the SPPK2 falcon deep-research output.
🧬

Genetic Associations

1
DSP Heterozygous Truncating Variants Causing Haploinsufficiency (Pathogenic Variants)
Gene: DSP hgnc:3052
Autosomal Dominant
Show evidence (5 references)
PMID:9887343 SUPPORT Human Clinical
"The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67."
Linkage mapping confirming DSP locus on 6p21 for striate PPK.
PMID:10594734 SUPPORT Human Clinical
"This study demonstrates the relevance of haploinsufficiency for desmoplakin in the pathogenesis of this genodermatosis."
Establishes haploinsufficiency as the unifying mechanism across DSP truncating variants causing SPPK2.
PMID:25227139 SUPPORT Human Clinical
"Today, more than 120 dominant and recessive desmoplakin (DSP) gene mutations have been reported to be associated with skin, hair and/or heart defects."
Captures the breadth of pathogenic DSP allelic heterogeneity relevant to SPPK2 and the broader DSP cardiocutaneous spectrum.
+ 2 more references
💊

Medical Actions

7
Topical Emollients
Action: application of emollient to skin MAXO:0000996
Regular application of bland topical emollients (white soft paraffin, urea-free moisturisers) maintains stratum corneum hydration, reduces scaling and fissuring, and is the foundational first-line management combined with keratolytics. Supportive rather than disease-modifying.
Mechanism Target:
MODULATES Compensatory Hyperkeratosis Along Stress Lines — Emollients soften and partially reduce the cornified mass produced by the compensatory hyperkeratosis branch.
Target Phenotypes: Skin fissure HP:0031057
Topical Keratolytics
Action: Keratolytic therapy Ontology label: Pharmacotherapy NCIT:C15986
Topical keratolytic agents (urea, salicylic acid, lactic acid) reduce hyperkeratosis and limit fissure formation. First-line and ongoing symptomatic care, usually combined with emollients.
Mechanism Target:
MODULATES Compensatory Hyperkeratosis Along Stress Lines — Keratolytics thin the stratum corneum, partially reversing the downstream compensatory thickening but not the upstream desmoplakin defect.
Target Phenotypes: Palmoplantar keratoderma HP:0000982
Show evidence (1 reference)
PMID:18627762 SUPPORT Human Clinical
"Treatment may include keratolytics, oral retinoids, and surgical debridement."
Documents keratolytics as part of standard SPPK management.
Mechanical Debridement / Paring
Action: Mechanical debridement Ontology label: Surgical Procedure NCIT:C15329
Manual or podiatric paring of hyperkeratotic plaques reduces callus bulk, relieves pressure-related pain, and limits fissure formation; often combined with footwear modification for plantar lesions.
Mechanism Target:
MODULATES Compensatory Hyperkeratosis Along Stress Lines — Physically reduces the cornified mass produced by the compensatory hyperkeratosis branch.
Show evidence (1 reference)
PMID:18627762 SUPPORT Human Clinical
"Treatment may include keratolytics, oral retinoids, and surgical debridement."
Documents surgical/mechanical debridement as recognised SPPK management.
Oral Retinoid Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: acitretin CHEBI:50172
Systemic retinoids (acitretin, isotretinoin) are the principal systemic option for severe SPPK2; they reduce hyperkeratosis but may worsen pain or erythema in some patients, and benefit is variable. Histopathologic subtype matters because epidermolytic PPKs can worsen with retinoids; SPPK2 lacks epidermolysis.
Mechanism Target:
MODULATES Compensatory Hyperkeratosis Along Stress Lines — Retinoids modulate keratinocyte differentiation and reduce cornification, dampening the reactive hyperkeratosis branch.
Target Phenotypes: Palmoplantar keratoderma HP:0000982
Show evidence (1 reference)
PMID:18627762 SUPPORT Human Clinical
"Treatment may include keratolytics, oral retinoids, and surgical debridement."
Documents oral retinoids as part of standard SPPK management.
Footwear Modification and Pressure Off-loading
Action: Orthotic support Ontology label: Supportive Care NCIT:C15747
Custom insoles, padded footwear and activity modification reduce the mechanical loading that triggers and sustains plantar lesions in SPPK2.
Mechanism Target:
MODULATES Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites — Off-loading reduces the mechanical-stress trigger that precipitates suprabasal adhesion failure in SPPK2 plantar skin.
Cardiac Surveillance for DSP Truncating-Variant Carriers
Action: Serial echocardiographic and electrocardiographic cardiac surveillance Ontology label: echocardiography MAXO:0010203
Because DSP truncating variants extend across a cardiocutaneous spectrum, baseline and serial cardiology evaluation - including echocardiography, ECG, ambulatory Holter monitoring, and cardiac MRI - is recommended for SPPK2 patients with confirmed pathogenic DSP alleles and for at-risk relatives. Skin findings can precede cardiac symptoms by years.
Target Phenotypes: Dilated cardiomyopathy HP:0001644 Arrhythmia HP:0011675
Show evidence (3 references)
PMID:35445468 SUPPORT Human Clinical
"PPK should trigger genetic testing to reveal mutations with possible related cardiac disease."
Recommends genetic testing in PPK patients to enable cardiac surveillance for DSP carriers.
PMID:35445468 SUPPORT Human Clinical
"Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age."
Justifies surveillance: skin findings precede cardiomyopathy/ arrhythmias, so SPPK2 patients with DSP truncating alleles need early cardiac evaluation.
PMID:25227139 SUPPORT Human Clinical
"Early diagnosis is crucial and cardiac examinations have to be performed on a regular basis."
Review evidence supporting routine cardiac assessment in DSP variant carriers.
Genetic Counseling
Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling for autosomal dominant inheritance with 50% recurrence risk per pregnancy. Counseling should include cascade testing of relatives, the variable expressivity of cutaneous severity (age- and trauma-dependent), and the cardiocutaneous risk that justifies cardiology referral when DSP truncating variants are identified.
{ }

Source YAML

click to show 
name: Striate Palmoplantar Keratoderma Type 2
creation_date: "2026-04-04T00:00:00Z"
updated_date: "2026-05-02T00:00:00Z"
description: >-
  Striate palmoplantar keratoderma type 2 (SPPK2; OMIM 612908; PPKS2) is an
  autosomal dominant skin disorder caused by heterozygous truncating mutations
  in the desmoplakin (DSP) gene. It is the first inherited skin disorder in
  which haploinsufficiency of a structural component was identified as the
  mechanism: premature termination codons in DSP transcripts trigger
  nonsense-mediated decay, halving the dosage of desmoplakin, which is the most
  abundant component of the desmosomal plaque and the principal anchor of the
  keratin intermediate filament cytoskeleton to desmosomes. Reduced desmoplakin
  (especially the dominant skin isoform DSPII) compromises desmosomal plaque
  assembly and keratin–desmosome coupling in suprabasal keratinocytes; under
  the high mechanical load borne by palms and soles this produces loosening of
  intercellular connections, perinuclear collapse of the keratin filament
  network, K16 upregulation, and compensatory hyperkeratosis along lines of
  stress. Affected individuals show linear hyperkeratosis on fingers and palms
  and focal hyperkeratosis at trauma-prone plantar sites, often with painful
  fissures. Phenotypic expression is age- and trauma-dependent. Many DSP
  truncating variants in this region are also associated with arrhythmogenic
  or dilated cardiomyopathy; PPK can be the earliest clue and DSP carriers
  warrant cardiac surveillance, even when classic skin-limited SPPK2 has
  historically been considered to lack frank cardiac disease.
category: Genetic
parents:
- Palmoplantar Keratoderma
- Desmosomal Disease
disease_term:
  preferred_term: keratosis palmoplantaris striata 2
  term:
    id: MONDO:0013034
    label: keratosis palmoplantaris striata 2
prevalence:
- population: Global
  prevalence_class: RARE
  percentage: Rare
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
pathophysiology:
- name: DSP Premature Termination Codons Triggering Nonsense-Mediated Decay
  description: >-
    Heterozygous DSP truncating variants (nonsense, frameshift, splice-site)
    introduce premature termination codons. Aberrant splicing variants such
    as 939+1G>A retain intron 7 and place a PTC in the N-terminal coding
    region; nonsense alleles such as Q331X and frameshifts such as
    p.Glu831Aspfs*33 generate PTCs in the canonical reading frame. The
    mutant transcripts are degraded by nuclear-transcribed nonsense-mediated
    mRNA decay, so no truncated dominant-negative protein accumulates and
    the affected allele functionally drops out. Variant location matters:
    PTCs in the regions producing NMD-competent transcripts of both major
    DSP isoforms (DSPI and DSPII) are markedly enriched in disease cohorts
    compared with population controls.
  biological_processes:
  - preferred_term: Nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation was a heterozygous C-->T transition in exon 4 of the
      desmoplakin gene and predicted a premature termination codon in the
      N-terminal region of the peptide.
    explanation: >-
      Original report demonstrating that the SPPK2-causing DSP variant
      predicts a premature termination codon, the substrate for
      nonsense-mediated decay.
  - reference: PMID:10594734
    reference_title: "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aberrant splicing leads to retention of the entire intron 7,
      which contains a premature termination codon within the N-terminal
      domain of the peptide.
    explanation: >-
      A second SPPK2 family illustrates a different molecular route
      (splice-site loss with intron retention) to a PTC.
  - reference: PMID:36580316
    reference_title: "Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gene region was important with variants in cases (cohort n=98;
      Clinvar n=167) more likely to occur in the regions resulting in
      nonsense mediated decay of both major DSP isoforms
    explanation: >-
      Quantifies the enrichment of NMD-competent variant locations in
      DSP truncating-variant disease cohorts.
  downstream:
  - target: Desmoplakin Haploinsufficiency in Epidermis
    causal_link_type: DIRECT
    description: >-
      NMD of the mutant transcript leaves only the wild-type allele to
      produce desmoplakin, reducing protein dosage in keratinocytes
      roughly to half of normal.
    evidence:
    - reference: PMID:10594734
      reference_title: "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This study demonstrates the relevance of haploinsufficiency for
        desmoplakin in the pathogenesis of this genodermatosis.
      explanation: >-
        Establishes that the molecular consequence of the NMD-prone
        variant is haploinsufficiency of desmoplakin protein.
  - target: DSP Truncating-Variant Cardiomyopathy Susceptibility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - NMD-competent DSP truncating variants reduce functional desmoplakin dosage in cardiac desmosomes.
    - Variant location modifies cardiomyopathy and ventricular arrhythmia risk among DSP truncating-variant carriers.
    description: >-
      Some DSP truncating alleles that produce SPPK2-spectrum skin
      disease also confer a cardiocutaneous risk, with adult-onset
      dilated cardiomyopathy and ventricular arrhythmias in susceptible
      carriers.
    evidence:
    - reference: PMID:36580316
      reference_title: "Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DSPtv location and proband status were independent risk
        factors for ventricular arrhythmia.
      explanation: >-
        Establishes that DSP truncating-variant location modifies
        arrhythmic cardiomyopathy risk.
    - reference: PMID:35445468
      reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a novel autosomal dominant truncating DSP
        c.2493delA p.(Glu831Aspfs*33) mutation associated with
        dilated cardiomyopathy (DCM) with arrhythmia susceptibility
        and focal PPK as an early cutaneous sign.
      explanation: >-
        Links a DSP truncating haploinsufficiency allele to the
        cardiocutaneous phenotype in which PPK precedes cardiac
        disease.
- name: Desmoplakin Haploinsufficiency in Epidermis
  description: >-
    Loss of one functional DSP allele halves the dosage of desmoplakin in
    keratinocytes, the most abundant constitutive component of the
    desmosomal plaque. The skin-dominant isoform DSPII is particularly
    sensitive to this dosage reduction: in cultured keratinocytes DSPII
    is the key component supporting intermediate filament stability and
    desmosome-mediated adhesion, and reduction of total DSP also lowers
    plakophilin 1, desmocollin 2 and desmocollin 3, propagating the
    dosage problem to interacting plaque and cadherin components. Because
    desmoplakin is the principal link between desmosomes and keratin
    intermediate filaments, halved dosage degrades both desmosomal
    assembly and keratin anchoring, with effects most apparent under the
    mechanical loads borne by palmar and plantar epidermis.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: Structural constituent of cytoskeleton
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  biological_processes:
  - preferred_term: Desmosome organization
    term:
      id: GO:0002934
      label: desmosome organization
    modifier: DECREASED
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first reported mutation of desmo-plakin and also the
      first inherited skin disorder in which haploinsufficiency of a
      structural component has been implicated. It identifies dosage of
      desmoplakin as critical in maintaining epidermal integrity.
    explanation: >-
      Establishes DSP haploinsufficiency as a novel disease mechanism
      in SPPK2.
  - reference: PMID:22454510
    reference_title: "The DSPII splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      One of the mutations results in total DSP haploinsufficiency and is
      associated with autosomal dominant striate palmoplantar keratoderma
      (PPK).
    explanation: >-
      Confirms that the SPPK-associated DSP allele acts via total DSP
      haploinsufficiency in cultured keratinocytes.
  - reference: PMID:22454510
    reference_title: "The DSPII splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DSPII being the key component in intermediate filament (IF)
      stability and desmosome-mediated adhesion.
    explanation: >-
      Identifies DSPII as the dosage-sensitive isoform whose loss in
      haploinsufficiency drives the SPPK2 epidermal phenotype.
  downstream:
  - target: Defective Desmosomal Plaque Assembly
    causal_link_type: DIRECT
    description: >-
      Halved desmoplakin dosage limits assembly of mature desmosomal
      plaques and reduces stable expression of plaque (PKP1) and
      cadherin (DSC2/3) partners, so suprabasal desmosomes are fewer
      and structurally rudimentary.
    evidence:
    - reference: PMID:22454510
      reference_title: "The DSPII splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        reduction in DSP expression reduced the amount of plakophilin
        1, desmocollin (DSC) 2 and DSC3
      explanation: >-
        Mechanism for how DSP haploinsufficiency depletes other
        plaque/cadherin components and yields hypoplastic desmosomes.
  - target: Keratin Intermediate Filament Network Disruption
    causal_link_type: DIRECT
    description: >-
      Because desmoplakin is the principal IF anchor, halved dosage
      uncouples keratin filaments from desmosomes, allowing the
      filament network to collapse perinuclearly.
    evidence:
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        disruption of desmosome-keratin intermediate filament
        interactions
      explanation: >-
        Original SPPK2 paper directly links DSP haploinsufficiency to
        keratin filament uncoupling.
- name: Defective Desmosomal Plaque Assembly
  description: >-
    In SPPK2 epidermis, suprabasal desmosomes form in reduced numbers and
    with rudimentary architecture. Electron microscopy of palm skin shows
    a significant decrease in desmosome counts in the suprabasal layers
    and desmosomes that lack inner plaques or display abnormal keratin
    filament connections. Confocal analysis additionally shows abnormal
    expression of plaque components, consistent with the haploinsufficient
    desmoplakin's downstream effect on plakophilin and desmocollin
    partners. The result is a mechanically weak desmosomal scaffold in
    the layers of the epidermis that normally bear shear stress.
  cell_types:
  - preferred_term: Suprabasal keratinocyte
    term:
      id: CL:4033013
      label: suprabasal keratinocyte
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  biological_processes:
  - preferred_term: Desmosome organization
    term:
      id: GO:0002934
      label: desmosome organization
    modifier: DECREASED
  evidence:
  - reference: PMID:15149499
    reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both Dp and Dsg1 mutations were accompanied by significantly
      reduced numbers of desmosomes in the suprabasal layers
    explanation: >-
      Quantitative electron-microscopy support for reduced suprabasal
      desmosome counts in DSP-haploinsufficient SPPK skin.
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a proportion of rudimentary desmosomal structures
    explanation: >-
      Original SPPK2 paper documents structurally hypoplastic
      desmosomes as a hallmark ultrastructural finding.
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopic examination shows diminished desmosomes,
      clumped keratin filaments, and enlarged keratohyalin granules.
    explanation: >-
      Independent clinical case confirms diminished desmosomes as the
      characteristic SPPK ultrastructural finding.
  downstream:
  - target: Reduced Suprabasal Desmosome Number
    causal_link_type: DIRECT
    description: >-
      Defective desmoplakin-dependent plaque assembly produces fewer
      suprabasal desmosomes and rudimentary desmosomal structures in
      affected palm skin.
    evidence:
    - reference: PMID:15149499
      reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both Dp and Dsg1 mutations were accompanied by significantly
        reduced numbers of desmosomes in the suprabasal layers
      explanation: >-
        Quantitative ultrastructural evidence links defective
        desmosomal assembly to reduced suprabasal desmosome number.
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a proportion of rudimentary desmosomal structures
      explanation: >-
        Original DSP-haploinsufficient SPPK2 family documents
        rudimentary desmosomes in affected skin.
  - target: Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites
    causal_link_type: DIRECT
    description: >-
      Reduced and rudimentary desmosomes provide too little adhesive
      surface area to hold suprabasal keratinocytes together under the
      shear stress of palm and sole, so intercellular spaces widen.
    evidence:
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        loosening of intercellular connections
      explanation: >-
        Direct observation that desmosomal hypoplasia produces
        loosened intercellular adhesion in affected palmar skin.
- name: Keratin Intermediate Filament Network Disruption
  description: >-
    Loss of desmoplakin-mediated anchoring causes the suprabasal keratin
    intermediate filament cytoskeleton to detach from the cell periphery
    and collapse around the nucleus. Affected SPPK2 keratinocytes show
    perinuclear aggregation of keratin filaments and dense perinuclear
    tonofilament bundles, accompanied by pronounced upregulation of
    keratin 16 (a stress/wound keratin) and abnormal involucrin
    labelling, indicating perturbed terminal differentiation downstream
    of the cytoskeletal failure.
  cell_types:
  - preferred_term: Suprabasal keratinocyte
    term:
      id: CL:4033013
      label: suprabasal keratinocyte
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  biological_processes:
  - preferred_term: Intermediate filament cytoskeleton organization
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: DECREASED
  - preferred_term: Keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15149499
    reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      perinuclear aggregation of keratin filaments was more evident in
      Dp-associated SPPK
    explanation: >-
      Confocal microscopy of patient palmar epidermis shows the
      collapsed perinuclear keratin filament pattern that defines
      the desmosome–IF uncoupling phenotype in DSP-related SPPK.
  - reference: PMID:15149499
    reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both types of SPPK upregulation of K16 was pronounced and
      involucrin labelling was abnormal.
    explanation: >-
      Documents stress-keratin upregulation and abnormal terminal
      differentiation downstream of the cytoskeletal disruption.
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clumped keratin filaments
    explanation: >-
      Independent ultrastructural confirmation of disrupted keratin
      filament organization in SPPK skin.
  downstream:
  - target: Perinuclear Keratin Filament Aggregation
    causal_link_type: DIRECT
    description: >-
      Desmoplakin-IF uncoupling allows keratin filaments to collapse
      around the nucleus instead of remaining tethered at desmosomes.
    evidence:
    - reference: PMID:15149499
      reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        perinuclear aggregation of keratin filaments was more evident
        in Dp-associated SPPK
      explanation: >-
        Confocal microscopy directly links DSP-associated SPPK to
        perinuclear keratin filament aggregation.
  - target: Keratin 16 Upregulation in Suprabasal Keratinocytes
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cytoskeletal scaffold disruption.
    - Wound/stress keratinocyte differentiation response.
    description: >-
      Keratin filament network disruption is accompanied by a stress
      keratin response, with pronounced K16 upregulation and abnormal
      involucrin labelling in suprabasal keratinocytes.
    evidence:
    - reference: PMID:15149499
      reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In both types of SPPK upregulation of K16 was pronounced and
        involucrin labelling was abnormal.
      explanation: >-
        Patient epidermis shows K16 upregulation as part of the
        disrupted keratinocyte scaffold and differentiation response.
  - target: Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites
    causal_link_type: DIRECT
    description: >-
      Without a peripherally tethered keratin network, individual
      keratinocytes cannot transmit mechanical load through their
      remaining desmosomes, so adhesion fails first under shear in
      palmar/plantar skin.
    evidence:
    - reference: PMID:15149499
      reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations in Dp and Dsg1 genes causing SPPK may be associated
        with perturbations in epidermal differentiation accompanied by
        a marked disruption of several components of the epidermal
        scaffold including desmosomes and the KIF network.
      explanation: >-
        Concludes that combined desmosome and keratin filament
        disruption is the integrated mechanism producing SPPK's
        epidermal scaffold failure.
- name: Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites
  description: >-
    Combined plaque hypoplasia and keratin uncoupling render the
    suprabasal epidermis mechanically fragile. In palmar and plantar skin,
    where shear forces are highest, intercellular spaces widen and
    cell–cell contact loosens. The fragility is friction- and
    age-dependent: lesions emerge and worsen at trauma-prone sites and
    with cumulative occupational or activity-related load. This
    site-restricted adhesion failure explains why the disease is
    palmoplantar despite the desmoplakin defect being systemic.
  cell_types:
  - preferred_term: Suprabasal keratinocyte
    term:
      id: CL:4033013
      label: suprabasal keratinocyte
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  biological_processes:
  - preferred_term: Cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: DECREASED
  triggers:
  - preferred_term: Mechanical friction
  - preferred_term: Repetitive mechanical trauma
  - preferred_term: Weight-bearing activity
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected skin demonstrated loosening of intercellular connections,
      disruption of desmosome-keratin intermediate filament interactions
      and a proportion of rudimentary desmosomal structures.
    explanation: >-
      Original SPPK2 paper documents adhesion failure with concurrent
      desmosomal and keratin filament defects in palm skin.
  - reference: PMID:10594734
    reference_title: "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assessment of family members bearing the mutant allele also
      emphasizes the significance of an individual's age and exposure
      to skin trauma in manifesting full phenotypic expression of the
      disorder.
    explanation: >-
      Provides clinical evidence that mechanical trauma and age modulate
      when adhesion failure becomes phenotypically apparent.
  downstream:
  - target: Compensatory Hyperkeratosis Along Stress Lines
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Sub-clinical micro-separation of suprabasal keratinocytes activates a wound-like keratinocyte response, including K16 upregulation and altered terminal differentiation, which biases the epidermis toward thickening rather than blistering.
    description: >-
      Adhesion failure under load drives a reactive hyperproliferative
      and hyperdifferentiative response in the affected palmoplantar
      epidermis, with hyperkeratosis distributed along the lines of
      mechanical stress.
    evidence:
    - reference: PMID:18627762
      reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathologic features include hyperkeratosis,
        hypergranulosis, and acanthosis with no epidermolysis.
      explanation: >-
        Confirms a hyperproliferative/hyperkeratotic response without
        frank blister formation as the histological signature of
        SPPK.
- name: Compensatory Hyperkeratosis Along Stress Lines
  description: >-
    Reactive thickening of the cornified layer (hyperkeratosis), expanded
    granular layer (hypergranulosis) and acanthosis arise as the
    mechanically fragile palmoplantar epidermis adapts to friction.
    Because the underlying defect is desmosomal rather than epidermolytic,
    thickening produces persistent hyperkeratotic plaques rather than
    blistering, and the distribution traces lines of pressure: linear
    streaks on palmar and flexor finger surfaces and focal plaques over
    pressure-bearing plantar sites. Fissures form where the thickened,
    poorly cohesive epidermis splits under continued stress.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  biological_processes:
  - preferred_term: Keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: INCREASED
  - preferred_term: Cornification
    term:
      id: GO:0070268
      label: cornification
    modifier: INCREASED
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologic features include hyperkeratosis, hypergranulosis,
      and acanthosis with no epidermolysis.
    explanation: >-
      Defines the reactive epidermal thickening pattern characteristic
      of SPPK, distinguishing it from epidermolytic keratodermas.
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presents with linear hyperkeratosis on the palms and fingers and
      focal plaques on the plantar aspects of the feet.
    explanation: >-
      Documents the stress-line distribution of hyperkeratosis that is
      the visible endpoint of the SPPK2 pathograph.
  downstream:
  - target: Striate Palmoplantar Keratoderma
    causal_link_type: DIRECT
    description: >-
      The compensatory hyperkeratotic response produces the defining
      striate palmoplantar keratoderma pattern, with linear palmar
      streaks and focal plantar plaques.
    evidence:
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected individuals had a linear pattern of skin thickening
        on the fingers and palms and circumscribed areas of skin
        thickening on the soles.
      explanation: >-
        Connects the hyperkeratotic stress-line mechanism to the
        defining SPPK2 clinical phenotype.
    - reference: PMID:18627762
      reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        presents with linear hyperkeratosis on the palms and fingers
        and focal plaques on the plantar aspects of the feet.
      explanation: >-
        Independent clinical report confirms the linear palmar and
        focal plantar distribution of the SPPK phenotype.
  - target: Hyperkeratosis
    causal_link_type: DIRECT
    description: >-
      Increased keratinization and cornification thicken the stratum
      corneum, producing histologic hyperkeratosis in affected
      palmoplantar skin.
    evidence:
    - reference: PMID:18627762
      reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathologic features include hyperkeratosis,
        hypergranulosis, and acanthosis with no epidermolysis.
      explanation: >-
        Documents hyperkeratosis as a histologic endpoint of the
        compensatory palmoplantar epidermal thickening.
  - target: Hypergranulosis
    causal_link_type: DIRECT
    description: >-
      Reactive epidermal thickening expands the granular layer, producing
      hypergranulosis with enlarged keratohyalin granules.
    evidence:
    - reference: PMID:18627762
      reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathologic features include hyperkeratosis,
        hypergranulosis, and acanthosis with no epidermolysis.
      explanation: >-
        Documents hypergranulosis as part of the SPPK histologic
        thickening pattern.
  - target: Epidermal Acanthosis
    causal_link_type: DIRECT
    description: >-
      Compensatory epidermal thickening includes expansion of the
      spinous layer, producing acanthosis without epidermolysis.
    evidence:
    - reference: PMID:18627762
      reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathologic features include hyperkeratosis,
        hypergranulosis, and acanthosis with no epidermolysis.
      explanation: >-
        Documents acanthosis as a non-epidermolytic histologic
        feature of SPPK.
  - target: Skin Fissures
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Brittle hyperkeratotic plaques.
    - Continued mechanical loading at palmoplantar stress sites.
    description: >-
      Thickened, mechanically fragile plaques can split under ongoing
      palmoplantar stress, producing painful fissures.
    evidence:
    - reference: PMID:18627762
      reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        focal plaques on the plantar aspects of the feet.
      explanation: >-
        The case directly supports focal plantar plaques; fissuring is
        modeled as a downstream mechanical consequence of thickened,
        poorly cohesive plaques rather than as a directly quoted
        phenotype from this abstract.
  - target: Streaks of Hyperkeratosis on Fingers and Palms
    description: >-
      Linear hyperkeratotic plaques along the palmar and flexor surfaces
      of fingers and onto the palm trace lines of habitual finger
      flexion and gripping.
    evidence:
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected individuals had a linear pattern of skin thickening
        on the fingers and palms
      explanation: >-
        Connects the compensatory hyperkeratosis mechanism to the
        characteristic linear/striate finger-and-palm phenotype.
  - target: Focal Plantar Hyperkeratosis
    description: >-
      Pressure-prone plantar sites accumulate focal hyperkeratotic
      plaques as the most heavily loaded skin compartments.
    evidence:
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        circumscribed areas of skin thickening on the soles
      explanation: >-
        Connects compensatory hyperkeratosis to focal plantar
        hyperkeratosis.
- name: DSP Truncating-Variant Cardiomyopathy Susceptibility
  description: >-
    A subset of DSP truncating-variant carriers have a cardiocutaneous
    phenotype in which the same loss-of-function alleles that produce
    palmoplantar keratoderma also predispose to myocardial disease. Reduced
    functional desmoplakin in cardiac desmosomes weakens cardiomyocyte
    mechanical coupling, promoting ventricular dilation, myocardial
    remodeling and arrhythmia susceptibility. Expression is variable,
    often adult-onset and modified by truncating-variant location.
  evidence:
  - reference: PMID:35445468
    reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Onset of dermatological findings preceded cardiac symptoms which
      were variable and occurred at adult age.
    explanation: >-
      Documents variable adult-onset cardiac disease following early
      PPK in a DSP truncating-variant family.
  - reference: PMID:36580316
    reference_title: "Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ventricular arrhythmia (sudden cardiac arrest, sustained
      ventricular tachycardia, appropriate implantable cardioverter
      defibrillator therapy) occurred in 56 (33%) individuals.
    explanation: >-
      Quantifies ventricular arrhythmia burden among DSP
      truncating-variant carriers and supports variant-location
      dependent risk.
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cardiomyocyte desmosomal instability.
    - Ventricular remodeling and dilation.
    description: >-
      DSP truncating-variant cardiomyocyte desmosomal instability can
      produce adult-onset dilated cardiomyopathy in the cardiocutaneous
      SPPK2 spectrum.
    evidence:
    - reference: PMID:35445468
      reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a novel autosomal dominant truncating DSP
        c.2493delA p.(Glu831Aspfs*33) mutation associated with
        dilated cardiomyopathy (DCM) with arrhythmia susceptibility
        and focal PPK as an early cutaneous sign.
      explanation: >-
        Directly documents dilated cardiomyopathy in a DSP
        truncating-variant PPK family.
  - target: Cardiac Arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - DSP truncating-variant myocardial disease susceptibility.
    - Ventricular electrical instability.
    description: >-
      DSP truncating-variant cardiomyopathy susceptibility includes
      ventricular arrhythmias, from extrasystoles to sustained
      ventricular tachycardia or sudden cardiac arrest.
    evidence:
    - reference: PMID:36580316
      reference_title: "Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ventricular arrhythmia (sudden cardiac arrest, sustained
        ventricular tachycardia, appropriate implantable cardioverter
        defibrillator therapy) occurred in 56 (33%) individuals.
      explanation: >-
        Establishes ventricular arrhythmia as a common clinical
        outcome in DSP truncating-variant cardiomyopathy cohorts.
    - reference: PMID:35445468
      reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        focal PPK with varying severity and left ventricular
        dilatation and ventricular extrasystoles.
      explanation: >-
        Links arrhythmia susceptibility to the same DSP truncating
        variant family with early palmoplantar keratoderma.
phenotypes:
- category: Dermatologic
  name: Striate Palmoplantar Keratoderma
  frequency: Very frequent
  description: >-
    The defining clinical phenotype: linear hyperkeratotic streaks on
    fingers and palms combined with circumscribed plantar hyperkeratosis,
    classified as the type 2 (DSP-related) form of striate PPK
    (PPKS2/SPPK2; OMIM 612908). The pattern is recognised as
    Brunauer–Fohs–Siemens phenotype.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals had a linear pattern of skin thickening on
      the fingers and palms and circumscribed areas of skin thickening
      on the soles.
    explanation: >-
      Describes the striate keratoderma pattern.
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autosomal dominant condition that presents with linear
      hyperkeratosis on the palms and fingers and focal plaques on the
      plantar aspects of the feet.
    explanation: >-
      Independent clinical case confirming the Brunauer-Fohs-Siemens
      striate PPK pattern.
- category: Dermatologic
  name: Streaks of Hyperkeratosis on Fingers and Palms
  frequency: Very frequent
  description: >-
    Linear hyperkeratotic streaks running along the palmar/flexor surfaces
    of the fingers and onto the palms, tracing lines of habitual
    gripping/flexion. This stress-line distribution is the most specific
    cutaneous sign of SPPK2.
  phenotype_term:
    preferred_term: Streaks of hyperkeratosis along each finger onto the palm
    term:
      id: HP:0007501
      label: Streaks of hyperkeratosis along each finger onto the palm
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a linear pattern of skin thickening on the fingers and palms
    explanation: >-
      Defining linear/striate finger-and-palm phenotype in the original
      DSP-haploinsufficient kindred.
- category: Dermatologic
  name: Focal Plantar Hyperkeratosis
  frequency: Very frequent
  description: >-
    Circumscribed hyperkeratotic plaques over pressure-bearing plantar
    sites (heel, forefoot, great toe), distributed where mechanical load
    is highest.
  phenotype_term:
    preferred_term: Plantar hyperkeratosis
    term:
      id: HP:0007556
      label: Plantar hyperkeratosis
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      circumscribed areas of skin thickening on the soles
    explanation: >-
      Documents focal plantar hyperkeratosis in DSP-haploinsufficient
      SPPK2.
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      focal plaques on the plantar aspects of the feet.
    explanation: >-
      Independent clinical confirmation of focal plantar plaques as the
      plantar manifestation of SPPK.
- category: Cellular
  name: Reduced Suprabasal Desmosome Number
  frequency: Very frequent
  description: >-
    Cellular phenotype: electron microscopy of palm skin shows a
    significant reduction in the number of desmosomes in the suprabasal
    layers of SPPK2 epidermis, with rudimentary desmosomal structures.
  phenotype_term:
    preferred_term: Hypoplastic suprabasal desmosomes
    term:
      id: HP:0034702
      label: Abnormal keratinocyte morphology
  evidence:
  - reference: PMID:15149499
    reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both Dp and Dsg1 mutations were accompanied by significantly
      reduced numbers of desmosomes in the suprabasal layers
    explanation: >-
      Quantitative ultrastructural evidence of reduced desmosome counts
      in DSP-haploinsufficient SPPK keratinocytes.
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a proportion of rudimentary desmosomal structures
    explanation: >-
      Cellular-level desmosome hypoplasia documented in the original
      SPPK2 family.
- category: Cellular
  name: Perinuclear Keratin Filament Aggregation
  frequency: Frequent
  description: >-
    Cellular phenotype: keratin intermediate filaments collapse around
    the nucleus in suprabasal keratinocytes from DSP-haploinsufficient
    SPPK2 palm skin, instead of extending peripherally to desmosomes.
  phenotype_term:
    preferred_term: Perinuclear keratin filament aggregation
    term:
      id: HP:0034702
      label: Abnormal keratinocyte morphology
  evidence:
  - reference: PMID:15149499
    reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      perinuclear aggregation of keratin filaments was more evident in
      Dp-associated SPPK
    explanation: >-
      Confocal microscopy of patient palm keratinocytes shows the
      collapsed keratin filament pattern downstream of DSP-IF
      uncoupling.
- category: Histopathologic
  name: Hyperkeratosis
  frequency: Very frequent
  description: >-
    Marked thickening of the cornified layer (stratum corneum) on light
    microscopy of palmoplantar skin biopsies, correlating with the
    clinical hyperkeratotic plaques.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologic features include hyperkeratosis, hypergranulosis,
      and acanthosis with no epidermolysis.
    explanation: >-
      Documents hyperkeratosis as a defining histologic feature of
      SPPK; critically also notes the absence of epidermolysis,
      distinguishing SPPK2 from epidermolytic keratodermas.
- category: Histopathologic
  name: Hypergranulosis
  frequency: Very frequent
  description: >-
    Increased thickness of the granular layer with enlarged keratohyalin
    granules on light/electron microscopy of SPPK palm skin.
  phenotype_term:
    preferred_term: Hypergranulosis
    term:
      id: HP:0025114
      label: Hypergranulosis
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologic features include hyperkeratosis, hypergranulosis,
      and acanthosis with no epidermolysis.
    explanation: >-
      Documents hypergranulosis as part of the SPPK histologic triad.
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      enlarged keratohyalin granules.
    explanation: >-
      Electron microscopic correlate of hypergranulosis.
- category: Histopathologic
  name: Epidermal Acanthosis
  frequency: Very frequent
  description: >-
    Thickening of the spinous (prickle) layer (acanthosis) without
    epidermolysis or acantholytic clefting in SPPK2 palm skin.
  phenotype_term:
    preferred_term: Epidermal acanthosis
    term:
      id: HP:0025092
      label: Epidermal acanthosis
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologic features include hyperkeratosis, hypergranulosis,
      and acanthosis with no epidermolysis.
    explanation: >-
      Documents acanthosis as part of the SPPK histologic triad,
      without epidermolysis distinguishing it from epidermolytic PPKs.
- category: Cellular
  name: Keratin 16 Upregulation in Suprabasal Keratinocytes
  frequency: Frequent
  description: >-
    Pronounced upregulation of keratin 16 (a stress/wound-associated
    keratin) and abnormal involucrin expression in SPPK2 palmar
    epidermis, indicating perturbed terminal differentiation downstream
    of cytoskeletal disruption.
  phenotype_term:
    preferred_term: Abnormal keratinocyte differentiation
    term:
      id: HP:0034702
      label: Abnormal keratinocyte morphology
  evidence:
  - reference: PMID:15149499
    reference_title: "Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both types of SPPK upregulation of K16 was pronounced and
      involucrin labelling was abnormal.
    explanation: >-
      Confocal evidence of K16 upregulation as a stress-keratin
      response in SPPK keratinocytes.
- category: Dermatologic
  name: Skin Fissures
  frequency: Frequent
  description: >-
    Painful fissures form within thickened, poorly cohesive plantar
    and palmar plaques as the brittle hyperkeratotic epidermis splits
    under continued mechanical load. Fissures are a major contributor
    to SPPK2 morbidity.
  phenotype_term:
    preferred_term: Skin fissure
    term:
      id: HP:0031057
      label: Skin fissure
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      focal plaques on the plantar aspects of the feet.
    explanation: >-
      The clinical case context for plantar plaques (which fissure
      under load) supports skin fissures as a downstream feature; the
      fissure association is established more directly in classification
      reviews summarised in the SPPK2 falcon deep-research output.
- category: Cardiac
  name: Dilated Cardiomyopathy
  frequency: Occasional
  description: >-
    Dilated cardiomyopathy is reported in a subset of SPPK2 families
    with DSP truncating variants whose location yields NMD-competent
    transcripts of both major DSP isoforms. Expression is variable and
    often adult-onset, with dermatologic findings preceding cardiac
    symptoms by years. The Karvonen 2022 multigenerational pedigree
    with DSP c.2493delA p.Glu831Aspfs*33 is the prototype.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:35445468
    reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel autosomal dominant truncating DSP
      c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated
      cardiomyopathy (DCM) with arrhythmia susceptibility and focal
      PPK as an early cutaneous sign.
    explanation: >-
      Documents DCM in a SPPK2-spectrum family with a DSP truncating
      haploinsufficiency variant.
  - reference: PMID:35445468
    reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Onset of dermatological findings preceded cardiac symptoms
      which were variable and occurred at adult age.
    explanation: >-
      Establishes the variable, adult-onset expressivity of
      cardiomyopathy in DSP-PPK families.
- category: Cardiac
  name: Cardiac Arrhythmia
  frequency: Occasional
  description: >-
    Ventricular arrhythmia (sustained ventricular tachycardia, sudden
    cardiac arrest, or appropriate ICD therapy) and lesser arrhythmias
    including ventricular extrasystoles are reported in DSP truncating-
    variant carriers. In a large multicenter DSPtv cohort, ventricular
    arrhythmia occurred in 33% of clinically affected individuals; risk
    depends on variant location within DSP and proband status.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:36580316
    reference_title: "Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ventricular arrhythmia (sudden cardiac arrest, sustained
      ventricular tachycardia, appropriate implantable cardioverter
      defibrillator therapy) occurred in 56 (33%) individuals.
    explanation: >-
      Quantitative arrhythmic burden in the largest DSPtv cohort
      assembled to date.
  - reference: PMID:35445468
    reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel truncating DSP mutation causing focal PPK
      with varying severity and left ventricular dilatation and
      ventricular extrasystoles.
    explanation: >-
      Documents ventricular extrasystoles and DCM in the same DSP
      haploinsufficiency family that presents with focal PPK.
genetic:
- name: DSP Heterozygous Truncating Variants Causing Haploinsufficiency
  association: Pathogenic Variants
  gene_term:
    preferred_term: DSP
    term:
      id: hgnc:3052
      label: DSP
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Heterozygous loss-of-function variants in DSP (chromosome 6p21:
    24-exon, ~45 kb gene). Pathogenic alleles include nonsense (e.g.
    Q331X), frameshift (e.g. p.Glu831Aspfs*33) and splice-site (e.g.
    939+1G>A) variants whose mutant transcripts undergo
    nonsense-mediated decay, producing 50% reduction in DSP protein
    dosage. Variant location matters: PTCs in regions yielding
    NMD-competent transcripts of both major DSP isoforms (DSPI and
    DSPII) carry additional risk for arrhythmogenic cardiomyopathy.
    Cohort series (e.g. Gram et al. 2025) report further DSP truncating
    alleles in PPK patients (variant nomenclature in source paper body)
    that confer the same cardiomyopathy risk.
  variants:
  - name: DSP c.991C>T p.Gln331Ter (Q331X)
    description: >-
      Heterozygous nonsense variant in exon 4 of DSP, in the original
      Northern Irish kindred linked to chromosome 6p21. Predicts a
      PTC in the N-terminal region; mutant transcript is undetectable,
      consistent with NMD and haploinsufficiency.
    gene:
      preferred_term: DSP
      term:
        id: hgnc:3052
        label: DSP
    clinical_significance: PATHOGENIC
    type: nonsense variant
    evidence:
    - reference: PMID:9887343
      reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mutation was a heterozygous C-->T transition in exon 4
        of the desmoplakin gene and predicted a premature
        termination codon in the N-terminal region of the peptide.
      explanation: >-
        Defines the canonical Q331X nonsense allele underlying
        SPPK2 in the Armstrong et al. 1999 family.
  - name: DSP 939+1G>A intron 7 splice donor variant
    description: >-
      Heterozygous splice-donor variant at intron 7 of DSP. Aberrant
      splicing retains the entire intron 7, introducing an in-frame
      PTC within the N-terminal coding region. Provides a second,
      independent example that DSP haploinsufficiency causes SPPK2.
    gene:
      preferred_term: DSP
      term:
        id: hgnc:3052
        label: DSP
    clinical_significance: PATHOGENIC
    type: splice site variant
    evidence:
    - reference: PMID:10594734
      reference_title: "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mutation was a heterozygous G > A transition at the
        donor + 1 site of intron 7 of the desmoplakin gene (939 + 1
        G > A; Genbank M77830).
      explanation: >-
        Defines the second SPPK2 family demonstrating
        haploinsufficiency via splicing disruption.
  - name: DSP c.2493delA p.Glu831Aspfs*33
    description: >-
      Heterozygous frameshift variant identified in a multigenerational
      Finnish family with focal/striate-spectrum PPK (often the
      earliest sign) plus dilated cardiomyopathy and arrhythmias in
      adult carriers. Illustrates that DSPtv haploinsufficiency
      alleles can extend beyond skin-limited SPPK2 to a
      cardiocutaneous phenotype.
    gene:
      preferred_term: DSP
      term:
        id: hgnc:3052
        label: DSP
    clinical_significance: PATHOGENIC
    type: frameshift truncating variant
    evidence:
    - reference: PMID:35445468
      reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a novel autosomal dominant truncating DSP
        c.2493delA p.(Glu831Aspfs*33) mutation associated with
        dilated cardiomyopathy (DCM) with arrhythmia susceptibility
        and focal PPK as an early cutaneous sign.
      explanation: >-
        Documents the variant and its cardiocutaneous phenotype in
        a large multigenerational pedigree.
  evidence:
  - reference: PMID:9887343
    reference_title: "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disorder mapped to chromosome 6p21 with a maximum lod score
      of 10.67.
    explanation: >-
      Linkage mapping confirming DSP locus on 6p21 for striate PPK.
  - reference: PMID:10594734
    reference_title: "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study demonstrates the relevance of haploinsufficiency for
      desmoplakin in the pathogenesis of this genodermatosis.
    explanation: >-
      Establishes haploinsufficiency as the unifying mechanism across
      DSP truncating variants causing SPPK2.
  - reference: PMID:25227139
    reference_title: "Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Today, more than 120 dominant and recessive desmoplakin (DSP)
      gene mutations have been reported to be associated with skin,
      hair and/or heart defects.
    explanation: >-
      Captures the breadth of pathogenic DSP allelic heterogeneity
      relevant to SPPK2 and the broader DSP cardiocutaneous spectrum.
  - reference: PMID:36580316
    reference_title: "Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DSPtv location and proband status were independent risk factors
      for ventricular arrhythmia.
    explanation: >-
      Genotype-phenotype data showing variant location within DSP
      modulates cardiac arrhythmia risk among DSP truncating-variant
      carriers, a key counselling point for SPPK2 patients with these
      alleles.
  - reference: PMID:39630431
    reference_title: "Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with palmoplantar keratoderma due to DSP variants
      were found, which is important to identify because of an
      associated risk of cardiomyopathy.
    explanation: >-
      Recent prospective Danish PPK cohort independently confirms
      DSP-PPK as a clinically important diagnosis specifically because
      of cardiomyopathy risk; supports the case for cardiac
      surveillance in SPPK2 patients with DSP truncating variants.
treatments:
- name: Topical Emollients
  description: >-
    Regular application of bland topical emollients (white soft
    paraffin, urea-free moisturisers) maintains stratum corneum
    hydration, reduces scaling and fissuring, and is the foundational
    first-line management combined with keratolytics. Supportive
    rather than disease-modifying.
  treatment_term:
    preferred_term: application of emollient to skin
    term:
      id: MAXO:0000996
      label: application of emollient to skin
  target_mechanisms:
  - target: Compensatory Hyperkeratosis Along Stress Lines
    treatment_effect: MODULATES
    description: >-
      Emollients soften and partially reduce the cornified mass
      produced by the compensatory hyperkeratosis branch.
  target_phenotypes:
  - preferred_term: Skin fissure
    term:
      id: HP:0031057
      label: Skin fissure
- name: Topical Keratolytics
  description: >-
    Topical keratolytic agents (urea, salicylic acid, lactic acid)
    reduce hyperkeratosis and limit fissure formation. First-line and
    ongoing symptomatic care, usually combined with emollients.
  treatment_term:
    preferred_term: Keratolytic therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Compensatory Hyperkeratosis Along Stress Lines
    treatment_effect: MODULATES
    description: >-
      Keratolytics thin the stratum corneum, partially reversing the
      downstream compensatory thickening but not the upstream
      desmoplakin defect.
  target_phenotypes:
  - preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment may include keratolytics, oral retinoids, and surgical
      debridement.
    explanation: >-
      Documents keratolytics as part of standard SPPK management.
- name: Mechanical Debridement / Paring
  description: >-
    Manual or podiatric paring of hyperkeratotic plaques reduces callus
    bulk, relieves pressure-related pain, and limits fissure formation;
    often combined with footwear modification for plantar lesions.
  treatment_term:
    preferred_term: Mechanical debridement
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Compensatory Hyperkeratosis Along Stress Lines
    treatment_effect: MODULATES
    description: >-
      Physically reduces the cornified mass produced by the
      compensatory hyperkeratosis branch.
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment may include keratolytics, oral retinoids, and surgical
      debridement.
    explanation: >-
      Documents surgical/mechanical debridement as recognised SPPK
      management.
- name: Oral Retinoid Therapy
  description: >-
    Systemic retinoids (acitretin, isotretinoin) are the principal
    systemic option for severe SPPK2; they reduce hyperkeratosis but may
    worsen pain or erythema in some patients, and benefit is variable.
    Histopathologic subtype matters because epidermolytic PPKs can
    worsen with retinoids; SPPK2 lacks epidermolysis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_mechanisms:
  - target: Compensatory Hyperkeratosis Along Stress Lines
    treatment_effect: MODULATES
    description: >-
      Retinoids modulate keratinocyte differentiation and reduce
      cornification, dampening the reactive hyperkeratosis branch.
  target_phenotypes:
  - preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:18627762
    reference_title: "Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment may include keratolytics, oral retinoids, and surgical
      debridement.
    explanation: >-
      Documents oral retinoids as part of standard SPPK management.
- name: Footwear Modification and Pressure Off-loading
  description: >-
    Custom insoles, padded footwear and activity modification reduce the
    mechanical loading that triggers and sustains plantar lesions in
    SPPK2.
  treatment_term:
    preferred_term: Orthotic support
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Suprabasal Keratinocyte Adhesion Failure in Mechanical Stress Sites
    treatment_effect: MODULATES
    description: >-
      Off-loading reduces the mechanical-stress trigger that
      precipitates suprabasal adhesion failure in SPPK2 plantar skin.
- name: Cardiac Surveillance for DSP Truncating-Variant Carriers
  description: >-
    Because DSP truncating variants extend across a cardiocutaneous
    spectrum, baseline and serial cardiology evaluation - including
    echocardiography, ECG, ambulatory Holter monitoring, and cardiac
    MRI - is recommended for SPPK2 patients with confirmed pathogenic
    DSP alleles and for at-risk relatives. Skin findings can precede
    cardiac symptoms by years.
  treatment_term:
    preferred_term: Serial echocardiographic and electrocardiographic cardiac surveillance
    term:
      id: MAXO:0010203
      label: echocardiography
  target_phenotypes:
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  - preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:35445468
    reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PPK should trigger genetic testing to reveal mutations with
      possible related cardiac disease.
    explanation: >-
      Recommends genetic testing in PPK patients to enable cardiac
      surveillance for DSP carriers.
  - reference: PMID:35445468
    reference_title: "A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Onset of dermatological findings preceded cardiac symptoms which
      were variable and occurred at adult age.
    explanation: >-
      Justifies surveillance: skin findings precede cardiomyopathy/
      arrhythmias, so SPPK2 patients with DSP truncating alleles need
      early cardiac evaluation.
  - reference: PMID:25227139
    reference_title: "Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early diagnosis is crucial and cardiac examinations have to be
      performed on a regular basis.
    explanation: >-
      Review evidence supporting routine cardiac assessment in DSP
      variant carriers.
- name: Genetic Counseling
  description: >-
    Genetic counseling for autosomal dominant inheritance with 50%
    recurrence risk per pregnancy. Counseling should include cascade
    testing of relatives, the variable expressivity of cutaneous
    severity (age- and trauma-dependent), and the cardiocutaneous risk
    that justifies cardiology referral when DSP truncating variants are
    identified.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
datasets:
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 55 citations 2026-04-30T20:58:02.025209

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Striate Palmoplantar Keratoderma Type 2
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Striate Palmoplantar Keratoderma Type 2 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: Striate Palmoplantar Keratoderma Type 2 (SPPK2; DSP-related)

Executive summary

Striate palmoplantar keratoderma type 2 (SPPK2) is a hereditary palmoplantar keratoderma characterized by linear ("striate") hyperkeratosis on palms/fingers and focal hyperkeratosis at trauma/pressure sites on the soles, caused by pathogenic variants in DSP (desmoplakin), classically via haploinsufficiency. While many individuals have a skin-limited phenotype, DSP variants can also present within a cardiocutaneous spectrum (hair abnormalities and dilated/arrhythmogenic cardiomyopathy), requiring integrated dermatology–cardiology care. (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, petrof2012desmosomalgenodermatoses pages 2-4, karvonen2022anoveldesmoplakin pages 1-1)

Artifact: identifiers and normalization

Disease name Synonyms / alternative names Key identifier(s) Causal gene Inheritance Typical onset Core clinical features Key references
Striate palmoplantar keratoderma type II SPPK2; Striate PPK type II; striate palmoplantar keratoderma; striate PPK; SPPK; PPKS2; desmoplakin-related striate palmoplantar keratoderma OMIM 612908 DSP (desmoplakin) Autosomal dominant Childhood to early adulthood; first or early second decade reported in classic kindreds Linear hyperkeratosis on palms and palmar/flexor aspects of fingers; focal hyperkeratosis at trauma/pressure-prone plantar sites (heel, forefoot, great toe); fissuring may occur; phenotype often skin-limited but DSP-related disease can overlap with woolly/curly hair and cardiomyopathy in some families (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, guerra2018hereditarypalmoplantarkeratodermas. pages 40-43, armstrong1999haploinsufficiencyofdesmoplakin pages 1-2, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3) Guerra et al., 2018, JEADV, DOI: 10.1111/jdv.14902, https://doi.org/10.1111/jdv.14902 (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, guerra2018hereditarypalmoplantarkeratodermas. pages 40-43); Petrof et al., 2012, Br J Dermatol, DOI: 10.1111/j.1365-2133.2011.10640.x, https://doi.org/10.1111/j.1365-2133.2011.10640.x (petrof2012desmosomalgenodermatoses pages 2-4, petrof2012desmosomalgenodermatoses pages 1-2); Armstrong et al., 1999, Hum Mol Genet, DOI: 10.1093/hmg/8.1.143, https://doi.org/10.1093/hmg/8.1.143 (armstrong1999haploinsufficiencyofdesmoplakin pages 1-2, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3)

Table: This table summarizes the canonical naming, OMIM identifier, gene, inheritance, onset, and defining clinical features of DSP-related striate palmoplantar keratoderma type II. It is useful as a compact normalization artifact for disease knowledge base mapping and curation.

1. Disease information

1.1 What is the disease?

SPPK2 is an inherited disorder of keratinization with persistent palmoplantar hyperkeratosis, classically presenting as linear hyperkeratosis on the palms/palmar aspects of fingers and focal hyperkeratosis at trauma-prone plantar sites, often with fissures and a progressive course (“progrediens”). (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

1.2 Key identifiers (from retrieved literature)

  • OMIM: 612908 (explicitly listed for Striate PPK type II and also referred to as PPKS2 in OMIM-oriented reviews). (petrof2012desmosomalgenodermatoses pages 2-4, guerra2018hereditarypalmoplantarkeratodermas. pages 37-40)
  • Gene: DSP (desmoplakin). (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

Not found in the retrieved sources: Orphanet ID, ICD-10/ICD-11, MeSH, MONDO ID. The retrieved full texts did not include these mappings; they would require direct database lookup outside the present evidence set. (petrof2012desmosomalgenodermatoses pages 2-4, guerra2018hereditarypalmoplantarkeratodermas. pages 37-40)

1.3 Synonyms / alternative names

  • Striate PPK type II (DSP-related) (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)
  • Striate palmoplantar keratoderma (SPPK); striate PPK (petrof2012desmosomalgenodermatoses pages 2-4, petrof2012desmosomalgenodermatoses pages 1-2)
  • PPKS2 (OMIM label for DSP-related striate PPK) (petrof2012desmosomalgenodermatoses pages 2-4, petrof2012desmosomalgenodermatoses pages 1-2)

1.4 Evidence source type

The disease entity is defined in aggregated disease-level resources and reviews (clinicogenetic classifications) as well as family-based primary genetic studies identifying causal DSP variants. (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, petrof2012desmosomalgenodermatoses pages 2-4)

2. Etiology

2.1 Disease causal factors

Primary cause: Germline pathogenic variants in DSP (desmoplakin). SPPK2 is typically associated with heterozygous loss-of-function DSP variants causing haploinsufficiency. (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, guerra2018hereditarypalmoplantarkeratodermas. pages 8-12, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3)

2.2 Risk factors

Genetic risk factors

  • DSP truncating variants (nonsense/frameshift) are strongly implicated in striate/focal palmoplantar keratoderma and can also confer cardiomyopathy/arrhythmia risk depending on variant context. (karvonen2022anoveldesmoplakin pages 1-1, pigors2015desmoplakinmutationswith pages 1-2, gram2025clinicalandgenetic pages 5-6)

Environmental/physiologic modifiers

  • Lesions localize to mechanically stressed/pressure areas, implicating friction and repetitive trauma as phenotype modifiers. (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

2.3 Protective factors / gene–environment interactions

No protective genetic or environmental factors were identified in the retrieved evidence set for DSP-related striate PPK.

3. Phenotypes

3.1 Core cutaneous phenotype (SPPK2)

From a clinicogenetic classification table, DSP-related SPPK2 shows: (i) linear palmar hyperkeratosis affecting palms and palmar aspects of fingers; (ii) focal plantar hyperkeratosis at trauma-prone sites; (iii) fissures; (iv) progressive course (progrediens). Histology/EM correlates are summarized in the Mechanism section. (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

3.2 Expanded DSP phenotype spectrum (cardiocutaneous overlap)

A 2022 multigenerational family with heterozygous DSP frameshift c.2493delA (p.Glu831Aspfs*33) presented with: variable PPK (mainly focal; 8/9 carriers affected), aquagenic whitening (5/9), occasional hyperhidrosis (2/9), frequent wavy/curly hair (13 family members), and dilated cardiomyopathy (DCM) with mostly mild arrhythmias. PPK onset ranged 1–30 years, showing variable expressivity. (karvonen2022anoveldesmoplakin pages 4-4, karvonen2022anoveldesmoplakin pages 3-3)

3.3 Pain and quality-of-life impact

Hereditary PPKs commonly cause pain and functional limitation. A striate PPK case report described “longstanding pain” and activity-related worsening (sports, manual labor/farming), reflecting occupational impact. (fukaura2017striatepalmoplantarkeratoderma pages 1-2)

In broader inherited PPK management literature, plantar pain can have a neuropathic component and “can be severe enough to require ambulatory aids,” with disease exacerbated by weight-bearing and work demands. (thomas2020diagnosisandmanagement pages 5-6)

3.4 Suggested HPO terms (examples)

Cutaneous: * Palmoplantar keratoderma (HP:0000982) * Hyperkeratosis (HP:0000962) * Fissure (skin fissures) (HP:0100782) * Palmoplantar hyperhidrosis (HP:0007410) * Aquagenic wrinkling/whitening of palms (often mapped as aquagenic keratoderma; term availability varies)

Hair: * Woolly hair / abnormal hair texture (e.g., woolly/curly hair) (HP:0002222 for woolly hair; HP:0002283 for abnormal hair texture)

Cardiac: * Dilated cardiomyopathy (HP:0001644) * Cardiac arrhythmia (HP:0011675)

(Phenotype presence/attribution varies by variant and family; see Karvonen family frequencies above.) (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43, karvonen2022anoveldesmoplakin pages 4-4, thomas2020diagnosisandmanagement pages 5-6)

4. Genetic / molecular information

4.1 Causal gene

DSP (desmoplakin) is the causal gene for SPPK2 (OMIM 612908/PPKS2). (petrof2012desmosomalgenodermatoses pages 2-4, guerra2018hereditarypalmoplantarkeratodermas. pages 37-40)

4.2 Pathogenic variant classes and examples

Dominant SPPK2 is typically due to heterozygous truncating variants causing haploinsufficiency. * Classic family: DSP c.1323C>T, p.Gln331Ter (Q331X); mutant transcript absent (nonsense-mediated decay), consistent with haploinsufficiency. (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3) * Cardiocutaneous family: DSP c.2493delA, p.Glu831Aspfs*33, AD segregation with PPK and DCM/arrhythmias. (karvonen2022anoveldesmoplakin pages 1-1, karvonen2022anoveldesmoplakin pages 4-4) * PPK cohort (Denmark): truncating DSP variants c.2821C>T (p.Arg941Ter) (pathogenic) and c.175dupA (p.Thr59Asnfs*34) (likely pathogenic). (gram2025clinicalandgenetic pages 5-6)

4.3 Genotype–phenotype correlations

  • Skin-limited phenotype: reported for early DSP haploinsufficiency families (SPPK only). (petrof2012desmosomalgenodermatoses pages 1-2)
  • Cardiocutaneous phenotype: DSP variants can also produce woolly/curly hair and cardiomyopathy/arrhythmia (Carvajal/Naxos-related spectrum), with regular cardiac evaluation recommended. (pigors2015desmoplakinmutationswith pages 1-2, petrof2012desmosomalgenodermatoses pages 2-4)

4.4 Population genetics / recent quantitative data (cardiac risk)

In a 2023 multicenter cohort of individuals with DSP truncating variants (DSPtv) and any cardiac phenotype, ventricular arrhythmia occurred in 56 (33%); variant location and proband status were independent risk factors. Case variants were enriched in regions predicted to trigger nonsense-mediated decay of both major DSP isoforms versus gnomAD control truncations (83.6% vs 16.4%, P<0.0001). This provides a quantitative basis for risk-stratified cardiac management in DSPtv carriers, including those identified initially by skin findings. (hoorntje2023variantlocationis pages 1-2)

5. Environmental information

SPPK2 is primarily genetic. The most consistent non-genetic contributor evidenced here is mechanical stress (friction/pressure) as a modifier of lesion distribution and severity. (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

6. Mechanism / pathophysiology

6.1 Causal chain (genotype → tissue defect → phenotype)

DSP encodes desmoplakin, a key desmosomal plaque protein that links desmosomes to keratin intermediate filaments. Heterozygous truncating variants can yield haploinsufficiency (via NMD), weakening desmosome–keratin anchoring. Under high mechanical load in palms/soles, reduced adhesion resilience promotes epidermal micro-separation and compensatory hyperkeratosis, producing striate/focal keratoderma and fissuring. (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, armstrong1999haploinsufficiencyofdesmoplakin pages 3-5)

6.2 Histopathology / ultrastructure

In DSP haploinsufficiency striate PPK, reported findings include: * Histology: hyperkeratosis, acanthosis, widened intercellular spaces/loosening of cell–cell connections, and “abnormal bunching of the keratin.” (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3) * EM: desmosomes lacking inner plaques, abnormal keratin filament connections, and other desmosome–IF linkage abnormalities. (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, armstrong1999haploinsufficiencyofdesmoplakin pages 3-5)

A clinicogenetic classification of DSP striate PPK II lists: histology with “hyperkeratosis, widening of intercellular spaces and condensation of the keratin filament network” and EM with “markedly reduced desmosome number… dense perinuclear tonofilament bundles.” (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

6.3 Cardiocutaneous extension

DSP is also essential in the heart; recessive or certain truncating variants can cause syndromes with PPK + woolly hair + DCM (Carvajal spectrum). Mechanistically, truncations that ablate the tail domain essential for intermediate filament binding can disrupt desmosome anchoring in both epidermis and myocardium. (norgett2000recessivemutationin pages 1-2, lee2021mutationsingenes pages 6-6)

6.4 Suggested ontology terms

GO Biological Process (examples): * Cell–cell adhesion (GO:0098609) * Desmosome organization (GO:0031581) * Keratinocyte differentiation (GO:0030216)

GO Cellular Component (examples): * Desmosome (GO:0030057) * Intermediate filament (GO:0005882)

Cell Ontology (examples): * Keratinocyte (CL:0000312)

(These ontology terms are proposed as mechanistically relevant; the retrieved sources support desmosome–IF anchoring and keratinocyte adhesion defects.) (armstrong1999haploinsufficiencyofdesmoplakin pages 2-3, lee2021mutationsingenes pages 6-6)

7. Anatomical structures affected

Primary: * Palmar skin and plantar skin (palmoplantar epidermis). (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)

Secondary/possible extracutaneous (variant-dependent): * Hair shaft/hair follicles (woolly/curly hair). (karvonen2022anoveldesmoplakin pages 4-4, thomas2020diagnosisandmanagement pages 5-6) * Heart (dilated cardiomyopathy/arrhythmias). (karvonen2022anoveldesmoplakin pages 1-1, thomas2020diagnosisandmanagement pages 5-6)

Suggested UBERON terms (examples): palm skin; sole of foot; epidermis; heart left ventricle.

8. Temporal development

  • Onset: childhood to early adulthood for classic SPPK2; in a DSP frameshift family, onset ranged 1–30 years. (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, karvonen2022anoveldesmoplakin pages 4-4)
  • Course: progressive (“progrediens”) with fissuring. (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)
  • Cardiac manifestations: may occur later than skin findings; in the Karvonen family, dermatologic signs preceded adult-onset cardiac symptoms. (karvonen2022anoveldesmoplakin pages 1-1)

9. Inheritance and population

9.1 Inheritance

  • Autosomal dominant inheritance for striate PPK type II (DSP-related) in clinicogenetic classifications and classic DSP families. (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3)

9.2 Epidemiology

Robust population-based prevalence/incidence for hereditary PPK—and specifically striate PPK—was not found in the retrieved evidence set. * A 2021 cohort study states: “The exact incidence and prevalence of hereditary PPK is not known.” In that clinical series (n=64), striate PPK was not observed. (harjama2021hereditarypalmoplantarkeratoderma pages 1-4) * A 2004 report describes striated PPK as “very rare” but provides no numeric rate. (rubegni2004acralmalignantmelanoma pages 1-3)

10. Diagnostics

10.1 Clinical diagnosis

Diagnosis begins with pattern recognition (diffuse vs focal/striate vs punctate) and assessment of associated features (pain/blistering, sweating, infection, hair/nails/teeth, and systemic features). (thomas2020diagnosisandmanagement pages 1-2)

10.2 Histopathology

DSP/DSG1-related striate PPKs can show widening of intercellular spaces/acantholysis (disadhesion) in suprabasal layers and characteristic EM changes in desmosomes/tonofilaments. (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43, guerra2018hereditarypalmoplantarkeratodermas. pages 8-12)

10.3 Genetic testing

Next-generation sequencing panels spanning PPK genes (including DSP) with Sanger confirmation are used in practice and are recommended in reviews because of clinical overlap among PPK subtypes. (karvonen2022anoveldesmoplakin pages 1-1, karvonen2022anoveldesmoplakin pages 2-2)

10.4 Cardiac evaluation (critical in DSP-associated disease)

Because DSP mutations can underlie cardiocutaneous syndromes, PPK may be an early marker. One study emphasizes: PPK should trigger genetic testing to reveal mutations “with possible related cardiac disease,” with family evaluation by echocardiography, ECG, Holter, and cardiac MRI. (karvonen2022anoveldesmoplakin pages 1-1)

A management review states: patients with striate keratoderma/PPK and woolly hair should have cardiac investigations, and family members should be screened (recognizing both AR and AD patterns in related syndromes). (thomas2020diagnosisandmanagement pages 5-6)

10.5 Differential diagnosis (examples)

Differentials include other inherited PPKs (DSG1-, KRT1-, KRT9-related) and acquired palmoplantar hyperkeratoses (psoriasis/eczema), and histologic differentials for acantholysis (e.g., pemphigus) where clinical blistering patterns differ. (metze2026desmosomaltypeacantholysis—anew pages 18-19)

11. Outcomes / prognosis

SPPK2 is typically chronic and skin-limited, but prognosis changes substantially if DSP variants confer cardiomyopathy risk. * DSPtv cardiomyopathy cohorts show substantial arrhythmic burden (ventricular arrhythmia 33%), supporting the importance of surveillance. (hoorntje2023variantlocationis pages 1-2)

No survival estimates specific to SPPK2 skin-only disease were identified in the retrieved evidence set.

12. Treatment

12.1 Current applications (real-world management)

Management is largely symptomatic and focused on mechanical load reduction and hyperkeratosis control: * Emollients + keratolytics + mechanical debridement/paring are core measures. (thomas2020diagnosisandmanagement pages 2-2, has2016palmoplantarkeratodermasclinical pages 15-17) * Footwear modification/custom insoles to off-load pressure and reduce pain. (thomas2020diagnosisandmanagement pages 5-6) * Oral retinoids (e.g., acitretin/isotretinoin) used for hyperkeratosis, with variable benefit and potential worsening of pain/erythema; histopathologic subtype matters for retinoid tolerability. (has2016palmoplantarkeratodermasclinical pages 15-17, thomas2020diagnosisandmanagement pages 3-4) * Botulinum toxin may help when hyperhidrosis contributes to symptoms and can reduce pain in some patients. (thomas2020diagnosisandmanagement pages 5-6) * Treat secondary bacterial/fungal infections when present. (has2016palmoplantarkeratodermasclinical pages 15-17)

A practical, MAXO-mapped management summary is provided in artifact-02.

Domain Intervention / Recommendation Purpose / Notes MAXO term suggestion Evidence citation
Symptomatic skin care Emollients Regular topical emollients reduce scaling/thickness and help prevent painful fissures; supportive rather than curative. MAXO: topical skin barrier/emollient therapy (has2016palmoplantarkeratodermasclinical pages 13-15, has2016palmoplantarkeratodermasclinical pages 15-17)
Symptomatic skin care Topical keratolytics Routine keratolytics are standard symptomatic care to reduce hyperkeratosis; often combined with emollients. MAXO: keratolytic topical therapy (thomas2020diagnosisandmanagement pages 2-2, has2016palmoplantarkeratodermasclinical pages 13-15, has2016palmoplantarkeratodermasclinical pages 15-17)
Symptomatic skin care Mechanical debridement / paring / podiatry Mechanical reduction of callus burden is a core management measure; often performed by podiatry/professional foot care. MAXO: mechanical debridement procedure (thomas2020diagnosisandmanagement pages 2-2, thomas2020diagnosisandmanagement pages 5-6, has2016palmoplantarkeratodermasclinical pages 15-17)
Symptomatic skin care Footwear modification / customized insoles / pressure off-loading Reduces pressure-related pain and recurrent plantar thickening at trauma-prone sites. MAXO: orthotic support / pressure off-loading (thomas2020diagnosisandmanagement pages 5-6, has2016palmoplantarkeratodermasclinical pages 15-17)
Pharmacotherapy Oral retinoids (acitretin, isotretinoin; sometimes alitretinoin) Main systemic option for hyperkeratosis; benefit is variable and may worsen pain/erythema. Histopathologic subtype matters because epidermolytic PPK can worsen with retinoids. MAXO: systemic retinoid therapy (thomas2020diagnosisandmanagement pages 2-2, thomas2020diagnosisandmanagement pages 5-6, thomas2020diagnosisandmanagement pages 4-5, has2016palmoplantarkeratodermasclinical pages 15-17, thomas2020diagnosisandmanagement pages 3-4)
Pharmacotherapy Topical retinoids / calcipotriol Used in some inherited PPKs as adjunctive topical therapy; response variable. MAXO: topical retinoid therapy / topical vitamin D analog therapy (thomas2020diagnosisandmanagement pages 2-2)
Supportive treatment Botulinum toxin for hyperhidrosis / plantar pain Used when sweating contributes to maceration, pain, or worsening plantar symptoms. MAXO: botulinum toxin injection (thomas2020diagnosisandmanagement pages 2-2, thomas2020diagnosisandmanagement pages 5-6)
Infection management Treat bacterial or fungal superinfection Microbiologic assessment and targeted antibiotics/antifungals are recommended because infection commonly complicates fissured/scaly keratoderma. MAXO: antimicrobial therapy (thomas2020diagnosisandmanagement pages 2-2, has2016palmoplantarkeratodermasclinical pages 13-15, has2016palmoplantarkeratodermasclinical pages 15-17, thomas2020diagnosisandmanagement pages 3-4)
Procedural treatment Surgical or laser treatment for recalcitrant focal lesions Reserved for severe/refractory focal keratoderma; outcomes variable and case-dependent. MAXO: surgical excision / laser ablation (thomas2020diagnosisandmanagement pages 2-2, thomas2020diagnosisandmanagement pages 4-5, has2016palmoplantarkeratodermasclinical pages 15-17)
Genetic diagnostics Multigene NGS panel including DSP and other PPK genes, with Sanger confirmation Recommended for clinically suspected inherited PPK because subtype overlap is common; DSP testing is especially important when hair changes or cardiomyopathy risk is suspected. MAXO: multigene panel testing / confirmatory Sanger sequencing (karvonen2022anoveldesmoplakin pages 2-2, karvonen2022anoveldesmoplakin pages 1-1)
Genetic diagnostics Cascade family testing for relatives of a DSP-variant carrier Enables early identification of at-risk relatives for dermatologic and cardiac monitoring. MAXO: familial cascade genetic testing (karvonen2022anoveldesmoplakin pages 4-4, karvonen2022anoveldesmoplakin pages 1-1)
Cardiac risk assessment Baseline cardiology evaluation for DSP variant carriers DSP-associated PPK can precede cardiomyopathy/arrhythmia; baseline evaluation should not wait for cardiac symptoms. MAXO: cardiovascular system evaluation (pigors2015desmoplakinmutationswith pages 1-2, karvonen2022anoveldesmoplakin pages 1-1)
Cardiac surveillance ECG and ambulatory Holter monitoring Used to detect conduction disease, extrasystoles, and arrhythmias in DSP carriers. MAXO: electrocardiographic monitoring (karvonen2022anoveldesmoplakin pages 1-1, karvonen2022anoveldesmoplakin pages 2-2)
Cardiac surveillance Echocardiography Standard structural/functional surveillance for dilated or arrhythmogenic cardiomyopathy in DSP carriers. MAXO: echocardiography (karvonen2022anoveldesmoplakin pages 1-1, karvonen2022anoveldesmoplakin pages 2-2)
Cardiac surveillance Cardiac MRI (CMR) Useful for ventricular structure/function and arrhythmogenic/dilated cardiomyopathy characterization. MAXO: cardiac magnetic resonance imaging (karvonen2022anoveldesmoplakin pages 4-4, karvonen2022anoveldesmoplakin pages 1-1, karvonen2022anoveldesmoplakin pages 2-2)
Long-term management Ongoing/lifelong cardiac follow-up for DSP truncating-variant carriers Supported by cardiocutaneous case series and broader DSP truncating-variant data showing substantial ventricular arrhythmia burden. MAXO: longitudinal cardiac surveillance (lin2026aframeshiftvariation pages 4-6, hoorntje2023variantlocationis pages 1-2)
Counseling Genetic counseling regarding autosomal dominant transmission and cardiocutaneous risk Important for reproductive counseling, family screening, and explaining variable expressivity (skin, hair, heart). MAXO: genetic counseling (guerra2018hereditarypalmoplantarkeratodermas. pages 37-40, karvonen2022anoveldesmoplakin pages 1-1)

Table: This table summarizes practical diagnostic and management actions for DSP-related striate palmoplantar keratoderma, including skin-directed therapies, genetic testing, and cardiac surveillance. It is useful because DSP-associated disease can extend beyond the skin to arrhythmia and cardiomyopathy, so management must integrate dermatology and cardiology.

12.2 Recent developments / emerging therapies (evidence in retrieved set)

The 2020 review notes early promise for targeted approaches (e.g., rapamycin, siRNA in related keratin disorders), but these were not specific, established therapies for DSP-related SPPK2 in the retrieved passages and remain investigational. (thomas2020diagnosisandmanagement pages 5-6)

No DSP-specific gene therapy or RNA therapy trials for SPPK2 were identified in the retrieved clinical trial search results.

13. Prevention

No primary prevention is available for a dominantly inherited genodermatosis. Prevention focuses on: * Genetic counseling and cascade testing in families. (karvonen2022anoveldesmoplakin pages 1-1) * Tertiary prevention: prevention of fissures/pain via skin care and off-loading; prevention of sudden cardiac events via cardiology surveillance and management in at-risk DSP variant carriers. (hoorntje2023variantlocationis pages 1-2, has2016palmoplantarkeratodermasclinical pages 15-17)

14. Other species / natural disease

No naturally occurring veterinary DSP striate PPK analogs were identified in the retrieved evidence set.

15. Model organisms / experimental systems

Although DSP-specific keratoderma models were not directly retrieved as full texts here, multiple desmosome perturbation models support the mechanistic framework: * Epidermis-restricted plakoglobin (Jup) knockout mice “largely recapitulated” human palmoplantar keratoderma with overcornification/thickening and disrupted desmosomes. (li2012lackofplakoglobin pages 1-1) * Epidermis-specific iASPP deficiency causes palmoplantar abnormalities resembling keratoderma with incomplete penetrance and provides evidence linking desmosome stability pathways to keratoderma. (dedeic2018cellautonomousrole pages 2-4)

These models support the concept that impaired desmosome assembly/stability and keratinocyte adhesion is sufficient to drive keratoderma-like phenotypes.

Key recent/authoritative sources (with URLs and publication dates)

  • Guerra et al., JEADV (May 2018): classification of non-syndromic PPKs including Striate PPK type II with OMIM 612908 and DSP, plus histology/EM features. https://doi.org/10.1111/jdv.14902 (guerra2018hereditarypalmoplantarkeratodermas. pages 40-43)
  • Karvonen et al., JEADV (May 2022): DSP c.2493delA family; quantified cutaneous and cardiac features, onset range, and recommendation for genetic testing with cardiac evaluation. https://doi.org/10.1111/jdv.18164 (karvonen2022anoveldesmoplakin pages 4-4, karvonen2022anoveldesmoplakin pages 1-1)
  • Hoorntje et al., Circulation: Genomic and Precision Medicine (Feb 2023): DSP truncating variants cardiomyopathy cohort; ventricular arrhythmia 33%; variant location and NMD enrichment vs gnomAD controls. https://doi.org/10.1161/circgen.121.003672 (hoorntje2023variantlocationis pages 1-2)
  • Gram et al., JAMA Dermatology (Feb 2025; online 2024): large PPK cohort with DSP truncating variants and cardiocutaneous clues (woolly/curly hair) and symptom improvement statistic (3/5). https://doi.org/10.1001/jamadermatol.2024.4824 (gram2025clinicalandgenetic pages 5-6)

Limitations of this report

  • Orphanet/ICD/MeSH/MONDO identifiers were not present in the retrieved full-text sources and therefore cannot be provided with evidence-based citations here.
  • Some therapy and epidemiology elements for SPPK2 specifically remain based on broader inherited PPK management literature and small DSP family series; no RCT-level DSP-specific treatment evidence was found in the retrieved set.

Artifact: DSP variants & phenotype spectrum

Study (first author, year) PMID Variant (cDNA, protein) Zygosity Phenotype (PPK pattern, hair findings, cardiomyopathy/arrhythmia) Notable quantitative data URL/DOI
Armstrong, 1999 c.1323C>T, p.Gln331Ter (Q331X) Heterozygous Classic DSP-related striate palmoplantar keratoderma: linear hyperkeratosis on flexor fingers/palms, focal plantar hyperkeratosis at pressure sites; phenotype restricted to skin in reported kindred; no frank blistering Autosomal dominant pedigree; maximum LOD 10.67; onset in first or early second decade; mutant transcript not detected, supporting haploinsufficiency (armstrong1999haploinsufficiencyofdesmoplakin pages 1-2, armstrong1999haploinsufficiencyofdesmoplakin pages 2-3) https://doi.org/10.1093/hmg/8.1.143
Karvonen, 2022 c.2493delA, p.Glu831Aspfs*33 Heterozygous Focal/striate-spectrum PPK as early sign; curly/wavy hair in family; dilated cardiomyopathy and arrhythmias in carriers Variant in 9/21 tested relatives; PPK onset range 1-30 years; aquagenic whitening in 5/9; palmoplantar hyperhidrosis in 2/9; dermatologic signs preceded adult-onset cardiac symptoms (karvonen2022anoveldesmoplakin pages 4-4, karvonen2022anoveldesmoplakin pages 1-1) https://doi.org/10.1111/jdv.18164
Pigors, 2015 c.7566_7567delAAinsC, p.Arg2522Serfs*39 Palmoplantar keratoderma with woolly hair/hypotrichosis and cardiac manifestations in DSP cardiocutaneous spectrum Example case developed hypotrichosis and striate PPK from age 5; review notes >120 DSP mutations reported and emphasizes regular cardiac examinations (pigors2015desmoplakinmutationswith pages 1-2) https://doi.org/10.2340/00015555-1974
Pigors, 2015 c.7756C>T, p.Arg2586Ter Palmoplantar keratoderma with woolly hair/hypotrichosis and cardiomyopathy/arrhythmogenic overlap Cardiac disease may progress to severe left ventricular failure; genotype-phenotype correlation noted as complex (pigors2015desmoplakinmutationswith pages 1-2) https://doi.org/10.2340/00015555-1974
Pigors, 2015 c.2131_2132delAG plus c.1067C>A, p.Thr356Lys Compound / biallelic context reported Palmoplantar keratoderma with hair abnormalities and cardiac involvement in syndromic DSP disease Report highlights variable expression and need for early diagnosis with regular cardiac follow-up (pigors2015desmoplakinmutationswith pages 1-2) https://doi.org/10.2340/00015555-1974
Gram, 2025 c.2821C>T, p.Arg941Ter PPK with cardiocutaneous overlap; woolly/curly hair noted as diagnostic clue in DSP-variant families In Danish cohort, DSP-variant participants small in number; 3/5 (60%) reported symptom improvement; striate subtype represented by 3 cases overall (gram2025clinicalandgenetic pages 5-6) https://doi.org/10.1001/jamadermatol.2024.4824
Gram, 2025 c.175dupA, p.Thr59Asnfs*34 PPK with risk of associated disease, including cardiomyopathy overlap in DSP-related cases Same cohort context as above; supports DSP as a “PPK with risk of associated diseases” gene (gram2025clinicalandgenetic pages 5-6) https://doi.org/10.1001/jamadermatol.2024.4824
Hoorntje, 2023 Multiple DSP truncating variants (DSPtv), location-dependent risk Mostly heterozygous truncating DSP truncating variants associated with cardio-cutaneous spectrum including striate palmoplantar keratoderma; cardiac phenotype includes arrhythmogenic cardiomyopathy/ventricular arrhythmia Multicenter cohort: 98 probands + 72 family members; 146 clinically affected; ventricular arrhythmia in 56/170 (33% of all included individuals); case variants enriched in NMD-competent regions affecting both isoforms: 148/177 (83.6%) vs 29/124 gnomAD control variants (16.4%), P<0.0001 (hoorntje2023variantlocationis pages 1-2) https://doi.org/10.1161/CIRCGEN.121.003672
Pantou, 2023 c.8586delC, p.Ser2863Hisfs*20 Homozygous in proband Arrhythmogenic left ventricular cardiomyopathy without typical dermatologic signs; included here as DSP cardiocutaneous-spectrum comparator highlighting C-terminal functional importance Brother died suddenly at 18 during exercise; heterozygous mother had mild arrhythmic phenotype; no classic PPK in proband despite DSP C-terminal truncation (hoorntje2023variantlocationis pages 1-2) https://doi.org/10.1186/s12920-023-01527-6
Lin, 2026 c.6218_6219dup, p.Ala2074Ter Heterozygous Atypical epidermolytic/acantholytic PPK distinct from classic striate PPK; prior literature summary in same paper includes woolly hair, DCM, ACM in truncating DSP cases Variant absent from gnomAD; paper tabulates recent DSP-PPK cases including Karvonen 2022 family (9 cases) and recommends lifelong ECG/echocardiographic surveillance for DSP carriers (lin2026aframeshiftvariation pages 4-6) https://doi.org/10.3389/fmed.2025.1728762

Table: This table summarizes reported DSP variants relevant to striate palmoplantar keratoderma type II and the broader DSP cardiocutaneous spectrum, including cutaneous, hair, and cardiac findings. It highlights variant-specific phenotype patterns and recent quantitative risk data useful for diagnosis and surveillance.

References

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