Punctate Palmoplantar Keratoderma

1. Disease Information

1.1 Overview and definition (current understanding)

Punctate palmoplantar keratoderma (punctate PPK; PPPK/PPKP) is a rare disorder of keratinization characterized by multiple discrete hyperkeratotic papules/lesions on the palms and soles, often progressive with age and prone to coalescence at pressure-bearing sites. A classic description for type 1 notes “progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin.” (matsuzawa2013heterozygousmutationsin pages 1-2)

1.2 Key identifiers and subtype taxonomy

In the landmark genetics literature, OMIM recognizes three inherited punctate PPK types: - PPKP1 (Buschke–Fischer–Brauer): OMIM #148600 - PPKP2 (porokeratotic type / porokeratosis punctata palmaris et plantaris): OMIM #175860 - PPKP3 (acrokeratoelastoidosis): OMIM #101850 (pohler2012haploinsufficiencyforaagab pages 1-2)

The 2021 Japanese Dermatological Association guidelines further subdivide punctate type 1 into: - Punctate PPK type 1A: AAGAB - Punctate PPK type 1B: COL14A1 (yoneda2021japaneseguidelinesfor pages 4-5)

Orphanet / ICD-10 / ICD-11 / MeSH / MONDO: these identifiers were not explicitly provided in the retrieved excerpts; therefore, they cannot be reliably populated from this evidence set.

1.3 Common synonyms and alternative names

• Punctate palmoplantar keratoderma (PPPK)
• Punctate PPK / PPKP
• Buschke–Fischer–Brauer disease (type 1) (gram2023ispunctatepalmoplantar pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)
• Porokeratosis punctata palmaris et plantaris (type 2) (gram2023ispunctatepalmoplantar pages 1-2)
• Acrokeratoelastoidosis (type 3) (gram2023ispunctatepalmoplantar pages 1-2)

1.4 Evidence sources (individual vs aggregated)

The evidence base is dominated by families and case reports/series rather than large epidemiologic cohorts. A 2023 systematic review identified 45 included studies, where most were single-family or multi-family reports; it counted 280 index cases and 817 total affected individuals across the literature. The review emphasized limitations of study quality and concluded it could not confirm a malignancy association. (gram2023ispunctatepalmoplantar pages 1-2)

2. Etiology

2.1 Disease causal factors (genetic and mechanistic)

PPPK type 1 (PPKP1/Buschke–Fischer–Brauer) is most strongly associated with heterozygous loss-of-function variants in AAGAB, consistent with haploinsufficiency. (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2014newandrecurrent pages 1-2)

A less frequent genetic association reported for punctate PPK type 1 includes COL14A1, emphasized in guidelines as punctate type 1B and referenced as occurring in Chinese pedigrees. (yoneda2021japaneseguidelinesfor pages 4-5, thomas2020diagnosisandmanagement pages 5-6)

2.2 Risk factors

Genetic risk: - AAGAB heterozygous truncating/splice variants (nonsense/frameshift/splice) are repeatedly observed in pedigrees and case series. Recurrent variants include AAGAB c.370C>T (p.Arg124Ter). (pohler2014newandrecurrent pages 2-3, pohler2014newandrecurrent pages 1-2)

Environmental/occupational modifiers: - Lesions may worsen with water exposure and at pressure/friction sites (knowles2023punctatepalmoplantarkeratoderma pages 4-5, elhaji2020aagabmutationsin pages 1-2). - Lesions can be worse in manual labourers (trauma/friction exposure). (thomas2020diagnosisandmanagement pages 5-6)

Acquired punctate PPK phenocopies: - The 2023 systematic review notes PPK can be hereditary or acquired due to exposures/conditions such as “arsenic exposure, menopause, and paraneoplastic syndromes.” (gram2023ispunctatepalmoplantar pages 1-2)

2.3 Protective factors

No genetic or environmental protective factors were identified in the retrieved sources.

2.4 Gene–environment interaction

Direct GxE interaction studies were not identified in this evidence set; however, multiple sources consistently indicate that mechanical stress/pressure and water exposure can modulate severity in genetically affected individuals (suggesting an interaction between inherited predisposition and local environmental triggers). (thomas2020diagnosisandmanagement pages 5-6, elhaji2020aagabmutationsin pages 1-2)

3. Phenotypes

3.1 Core clinical phenotypes

Morphology: multiple punctate hyperkeratotic papules/lesions on palms and soles, which may coalesce into plaques at pressure-bearing areas. (matsuzawa2013heterozygousmutationsin pages 1-2, pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)

Pain and functional impact: plantar pain can be prominent; a case series highlights plantar pain with functional impact on walking/standing and notes that manual paring and analgesia can help. (zamiri2019painfulpunctatepalmoplantar pages 5-6)

Progression: a large Danish cohort reported progression in 31/42 punctate probands (74%), stability in 8/42 (19%), and improvement in 1/42 (2%). (gram2025clinicalandgenetic pages 3-4)

Distribution: in the Danish cohort, punctate probands had palms and soles involvement in 40/42 (95%). (gram2025clinicalandgenetic pages 3-4)

3.2 Age of onset

• Often begins in adolescence/early adulthood, but range is broad. Median onset for punctate PPK in the Danish cohort was 19.0 years (range 5–47). (gram2025clinicalandgenetic pages 3-4)
• A pain-focused series reports onsets spanning childhood through later adulthood (e.g., ~8 to 50s). (zamiri2019painfulpunctatepalmoplantar pages 5-6)

3.3 Histopathology

A characteristic lesion histology described in genetic studies includes a central epidermal depression with hypergranulosis and an overlying orthokeratotic layer; immunostaining suggests a hyperproliferative basal compartment. (pohler2012haploinsufficiencyforaagab pages 1-2)

3.4 Suggested HPO terms (examples)

(IDs not provided in evidence; listed as term labels for mapping) - Punctate palmoplantar keratoderma - Palmoplantar hyperkeratosis - Hyperkeratosis - Plantar pain - Progressive skin disease - Verrucous skin lesion / Hyperkeratotic papule

4. Genetic / Molecular Information

4.1 Causal genes

• AAGAB (major gene for PPKP1/PPPK1 type 1A) (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)
• COL14A1 (reported; emphasized as type 1B in guidelines; rare compared to AAGAB) (yoneda2021japaneseguidelinesfor pages 4-5, thomas2020diagnosisandmanagement pages 5-6)

4.2 Pathogenic variant classes and functional consequences

AAGAB variants reported across studies are predominantly truncating/splice variants consistent with loss of function and haploinsufficiency (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2014newandrecurrent pages 1-2). A 2014 multi-family report noted “27 distinct loss-of-function mutations reported in AAGAB,” illustrating substantial allelic heterogeneity. (pohler2014newandrecurrent pages 2-3)

A large 2019 series lists many AAGAB truncating/splice variants across families and includes both familial and sporadic cases, supporting dominant inheritance and recurrent mutational spectra. (zamiri2019painfulpunctatepalmoplantar pages 5-6)

Founder variant example (recent development): A 2024 Clinical Genetics study demonstrates AAGAB c.370C>T (p.Arg124Ter) is a founder variant in Southern Denmark: shared haplotype 3.0 Mb and an estimated most recent common ancestor 12.1 generations (~339 years; CI 137–568); it recommends initial screening for this variant in the region and potentially all Danish punctate PPK patients. (gram2024identificationofa pages 1-2)

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No validated modifier genes, epigenetic drivers, or chromosomal abnormalities specific to PPPK were identified in the retrieved sources.

5. Environmental Information

5.1 Environmental and lifestyle contributors

• Mechanical stress/friction: worse in manual labourers; pressure points are common sites of coalescence. (thomas2020diagnosisandmanagement pages 5-6, pohler2012haploinsufficiencyforaagab pages 1-2)
• Water exposure: reported to worsen papules in several reports. (knowles2023punctatepalmoplantarkeratoderma pages 4-5, elhaji2020aagabmutationsin pages 1-2)

5.2 Infectious agents

No infectious triggers were identified as causal in the retrieved evidence.

6. Mechanism / Pathophysiology

6.1 Mechanistic causal chain (AAGAB/PPKP1)

AAGAB encodes p34 (α- and γ-adaptin–binding protein), linked to clathrin adaptor complexes and membrane trafficking. Functional work supports the causal chain: 1) AAGAB loss-of-function → p34 deficiency (haploinsufficiency) (pohler2012haploinsufficiencyforaagab pages 1-2, giehl2012nonsensemutationsin pages 1-2) 2) Disrupted vesicle trafficking/endocytic recycling, with ultrastructural abnormalities in intracellular vesicle biology in lesional epidermis (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2012haploinsufficiencyforaagab pages 4-5) 3) Increased EGFR protein and activation: keratinocyte knockdown leads to markedly increased EGFR protein and phosphorylation, consistent with impaired receptor turnover (pohler2012haploinsufficiencyforaagab pages 4-5) 4) Keratinocyte hyperproliferation: increased cell division in vitro and hyperproliferative lesions in vivo (pohler2012haploinsufficiencyforaagab pages 1-2) 5) Clinical manifestation as focal hyperproliferative hyperkeratosis (punctate lesions) (pohler2012haploinsufficiencyforaagab pages 1-2)

A complementary mechanistic discussion highlights that impaired RTK endocytosis (EGFR/Axl) could sustain growth-factor signaling and drive hyperkeratosis. (matsuzawa2013heterozygousmutationsin pages 4-4)

6.2 Suggested GO biological process / cellular component terms (labels)

• Endocytosis; clathrin-mediated endocytosis (pohler2012haploinsufficiencyforaagab pages 4-5)
• Vesicle-mediated transport; endosomal recycling (pohler2012haploinsufficiencyforaagab pages 1-2)
• EGFR signaling pathway / receptor tyrosine kinase signaling (pohler2012haploinsufficiencyforaagab pages 4-5)
• Regulation of keratinocyte proliferation (pohler2012haploinsufficiencyforaagab pages 1-2)

6.3 Suggested CL (cell types)

• Keratinocyte; basal keratinocyte (pohler2012haploinsufficiencyforaagab pages 4-5)

6.4 Molecular profiling (transcriptomics/proteomics/metabolomics)

No disease-specific omics profiling studies were identified in the retrieved sources.

7. Anatomical Structures Affected

7.1 Organ/tissue level

• Primary sites: palmar and plantar skin (thick glabrous epidermis), frequently both. (gram2025clinicalandgenetic pages 3-4)

7.2 Suggested UBERON terms (labels)

• Skin of palm; skin of sole; epidermis

7.3 Subcellular/cellular compartments

Mechanistic evidence implicates vesicular/endocytic compartments (clathrin adaptor-related trafficking and receptor turnover). (pohler2012haploinsufficiencyforaagab pages 4-5)

8. Temporal Development

8.1 Onset

Typically after childhood/adolescence, with broad variability by family and cohort; Danish cohort median 19 years. (gram2025clinicalandgenetic pages 3-4)

8.2 Course

Often chronic and progressive; lesions increase in number and can coalesce over time. (pohler2012haploinsufficiencyforaagab pages 1-2, gram2025clinicalandgenetic pages 3-4)

9. Inheritance and Population

9.1 Inheritance

Type 1 punctate PPK is classically autosomal dominant with variable expressivity; AAGAB variants segregate in pedigrees with multiple affected generations. (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2014newandrecurrent pages 1-2)

9.2 Epidemiology and statistics

• Prevalence estimates in a review of inherited PPK: “1 in 100,000” with AD inheritance. (thomas2020diagnosisandmanagement pages 5-6)
• A case report cites an estimated prevalence of 1.17 per 100,000. (knowles2023punctatepalmoplantarkeratoderma pages 4-5)

9.3 Founder effects and population distribution (recent)

A 2024 founder study in Southern Denmark supports a founder origin for AAGAB c.370C>T (p.Arg124Ter) with a 3.0 Mb shared haplotype and estimated origin ~339 years; it recommends first-tier screening for this variant in Denmark. (gram2024identificationofa pages 1-2)

10. Diagnostics

10.1 Clinical diagnosis

Key features include punctate hyperkeratotic lesions on palms/soles; guidelines emphasize excluding look-alikes such as callus/clavus and viral warts when diagnosing PPK. (yoneda2021japaneseguidelinesfor pages 9-10)

10.2 Histopathology

Characteristic lesions may show central epidermal depression with orthokeratosis and hypergranulosis, consistent with hyperproliferation. (pohler2012haploinsufficiencyforaagab pages 1-2)

10.3 Genetic testing strategy (expert consensus / implementation)

• Guidelines recommend genetic counseling and consent in hereditary PPK (yoneda2021japaneseguidelinesfor pages 10-12).
• In Denmark, initial testing for founder AAGAB c.370C>T (p.Arg124Ter) is recommended for regional patients and potentially all Danish punctate PPK patients. (gram2024identificationofa pages 1-2)

10.4 Differential diagnosis

The punctate phenotype should prompt consideration of punctate PPK types 1A/1B/2/3 and related entities (including Cole disease), and recognition that PPK can be acquired (e.g., arsenic exposure or paraneoplastic syndromes). (yoneda2021japaneseguidelinesfor pages 10-12, gram2023ispunctatepalmoplantar pages 1-2)

11. Outcome / Prognosis

PPPK is primarily a chronic morbidity condition with variable severity; pain can be significant and impair ambulation in some patients (zamiri2019painfulpunctatepalmoplantar pages 5-6). No survival/mortality impact was identified in the retrieved sources.

Malignancy association (expert analysis; 2023 systematic review)

A 2023 Orphanet Journal of Rare Diseases systematic review states: “we could not confirm an association between PPPK1 and malignancy” and highlights “a lack of well-designed studies” to conclude cancer risk; it questions whether surveillance should be offered on the basis of existing literature. (gram2023ispunctatepalmoplantar pages 1-2)

12. Treatment

12.1 Standard management (real-world implementation)

Evidence and guidelines emphasize symptomatic management: - Topical keratolytics/emollients: urea and salicylic acid preparations are repeatedly listed. (yoneda2021japaneseguidelinesfor pages 8-9, knowles2023punctatepalmoplantarkeratoderma pages 4-5) - Mechanical debridement/paring/dermabrasion: cone cutters/razors/punches/scissors, and patient self-care. (yoneda2021japaneseguidelinesfor pages 8-9, yoneda2021japaneseguidelinesfor pages 9-10) - Systemic retinoids: guideline synthesis reports acitretin use with reported benefit in case-based evidence (see below). (yoneda2021japaneseguidelinesfor pages 10-12) - Practical measures: comfortable footwear and reducing trauma/friction. (thomas2020diagnosisandmanagement pages 5-6)

12.2 Retinoids (evidence and statistics)

The Japanese guidelines summarize case-based evidence and state that oral retinoids are useful for PPK; they report acitretin was used in 12 cases, with 10/12 showing therapeutic effect, and isotretinoin in 6 cases with variable outcomes and discontinuation for side effects in some cases. (yoneda2021japaneseguidelinesfor pages 10-12)

12.3 Emerging/experimental therapies (2022–2024 developments)

Two completed interventional trials evaluate KM-001 topical 1% cream, described as “a potent and selective TRPV3 antagonist,” in PPPK1 or pachyonychia congenita: - NCT05435638 (ClinicalTrials.gov record dated 2022; Phase 1; COMPLETED; enrollment 14): topical KM-001 1% twice daily for 12 or 16 weeks. (NCT05435638 chunk 1) - NCT05956314 (ClinicalTrials.gov record dated 2023; Phase 1b; COMPLETED; enrollment 18; primary completion Nov 2024; last update Jan 15, 2025): topical KM-001 1% twice daily for 12 or 16 weeks, with pain and clinician/patient global outcomes. (NCT05956314 chunk 1, NCT05956314 chunk 2)

No efficacy results were available in the retrieved trial record excerpts (status only).

12.4 Suggested MAXO terms (labels)

• Topical keratolytic therapy (salicylic acid; urea)
• Mechanical debridement/paring
• Systemic retinoid therapy (acitretin; isotretinoin)
• Genetic counseling
• Genetic testing
• Topical TRPV3 antagonist therapy (KM-001; investigational)

13. Prevention

No disease-specific primary prevention is established for hereditary PPPK. Secondary/tertiary prevention focuses on symptom control and prevention of fissures/pain via keratolytics, debridement, and minimizing mechanical stress. (yoneda2021japaneseguidelinesfor pages 8-9, thomas2020diagnosisandmanagement pages 5-6)

Genetic counseling and cascade testing can be considered for at-risk relatives in hereditary families. (yoneda2021japaneseguidelinesfor pages 10-12)

14. Other Species / Natural Disease

No naturally occurring animal disease analogs were identified in the retrieved sources.

15. Model Organisms

No whole-animal model systems were identified in the retrieved sources. However, mechanistic evidence includes in vitro keratinocyte knockdown experiments (e.g., HaCaT keratinocytes) showing increased proliferation and altered EGFR protein/phosphorylation, supporting cell-based modeling of AAGAB haploinsufficiency. (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2012haploinsufficiencyforaagab pages 4-5)

Subtype summary table

Table: This table summarizes the punctate palmoplantar keratoderma subtype framework used in the retrieved sources, including OMIM identifiers, clinical patterns, inheritance, and the distinction between type 1A (AAGAB) and type 1B (COL14A1). It is useful for quickly aligning historical subtype names with current gene-based understanding.

Visual evidence (figures)

• Pedigrees/clinical images/histology and an AAGAB mutation schematic (including the panel describing mutation locations relative to functional domains) were retrieved from a multi-family PPPK1 mutation report. (pohler2014newandrecurrent media e8a4666c, pohler2014newandrecurrent media f62067ed, pohler2014newandrecurrent media 7e640702)

Notes on gaps and limitations

1) This run’s retrieved excerpts did not explicitly contain Orphanet/ICD/MeSH/MONDO identifiers; these should be added by querying OMIM/Orphanet/MONDO directly if required for KB completeness. 2) Some gene claims (e.g., COL14A1 as type 1B) are supported here through guideline and review-level evidence but not by direct full-text extraction of the original COL14A1 pedigree paper in this run. 3) ClinicalTrials.gov entries show completed studies of KM-001, but trial results were not present in the retrieved record chunks.

References

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17. (yoneda2021japaneseguidelinesfor pages 10-12): Kozo Yoneda, Akiharu Kubo, Toshifumi Nomura, Akemi Ishida‐Yamamoto, Yasushi Suga, Masashi Akiyama, Nobuo Kanazawa, and Takashi Hashimoto. Japanese guidelines for the management of palmoplantar keratoderma. The Journal of Dermatology, Jun 2021. URL: https://doi.org/10.1111/1346-8138.15850, doi:10.1111/1346-8138.15850. This article has 10 citations.

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19. (NCT05435638 chunk 1): Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases. Kamari Pharma Ltd. 2022. ClinicalTrials.gov Identifier: NCT05435638

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22. (pohler2014newandrecurrent media e8a4666c): Elizabeth Pohler, M. Huber, S. E. Boonen, M. Zamiri, M. Zamiri, P. A. Gregersen, Mette Sommerlund, Mette Ramsing, Daniel Hohl, W. McLean, and F. Smith. New and recurrent aagab mutations in punctate palmoplantar keratoderma. The British Journal of Dermatology, 171:433-436, Aug 2014. URL: https://doi.org/10.1111/bjd.12927, doi:10.1111/bjd.12927. This article has 10 citations.

23. (pohler2014newandrecurrent media f62067ed): Elizabeth Pohler, M. Huber, S. E. Boonen, M. Zamiri, M. Zamiri, P. A. Gregersen, Mette Sommerlund, Mette Ramsing, Daniel Hohl, W. McLean, and F. Smith. New and recurrent aagab mutations in punctate palmoplantar keratoderma. The British Journal of Dermatology, 171:433-436, Aug 2014. URL: https://doi.org/10.1111/bjd.12927, doi:10.1111/bjd.12927. This article has 10 citations.

24. (pohler2014newandrecurrent media 7e640702): Elizabeth Pohler, M. Huber, S. E. Boonen, M. Zamiri, M. Zamiri, P. A. Gregersen, Mette Sommerlund, Mette Ramsing, Daniel Hohl, W. McLean, and F. Smith. New and recurrent aagab mutations in punctate palmoplantar keratoderma. The British Journal of Dermatology, 171:433-436, Aug 2014. URL: https://doi.org/10.1111/bjd.12927, doi:10.1111/bjd.12927. This article has 10 citations.