Pachyonychia Congenita

🏷

Classifications

Harrison's Part

Mechanistic Nosology

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

PC is inherited in an autosomal dominant manner. Roughly 70% of patients have an affected parent and about 30% represent de novo variants; a single case of germline mosaicism has been reported.

Autosomal dominant inheritance De novo rate: Approximately 30% of cases arise from a de novo pathogenic variant.

Show evidence (2 references)

PMID:20301457 SUPPORT Human Clinical

"Pachyonychia congenita is inherited in an autosomal dominant manner. Approximately 30% of cases appear to be caused by a de novo pathogenic variant."

GeneReviews states the mode of inheritance and the de novo rate.

PMID:21326300 SUPPORT Human Clinical

"PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17."

Confirms the heterozygous (dominant) state of the causal variants in a cohort of 90 families. Predates the addition of KRT6C to the gene set.

◆

Subtypes

5

PC-K6a (KRT6A; MONDO pachyonychia congenita 3) MONDO:0014324

KRT6A hgnc:6443

PC caused by heterozygous KRT6A variants. The most common subtype in most reported cohorts. Characterised by widespread nail dystrophy with the earliest age of onset and the highest number of involved nails, prominent oral leukokeratosis, hoarseness (laryngeal leukokeratosis), and the greatest likelihood of requiring walking aids. First-bite syndrome is reported predominantly in this subtype.

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids."

The IPCRR case-cohort study of 815 genetically confirmed patients defines the KRT6A genotype-phenotype correlation used for this subtype.

PMID:22264670 SUPPORT Human Clinical

"We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation."

An independent registry cohort replicates the KRT6A-oral leukokeratosis association.

PC-K6b (KRT6B; MONDO pachyonychia congenita 4) MONDO:0014325

KRT6B hgnc:6444

PC caused by heterozygous KRT6B variants. The least common of the four MONDO-recognised numbered subtypes, accounting for roughly 3% of families in a large mutational study. Plantar keratoderma, plantar pain and toenail dystrophy are near-universal, while fingernail involvement and oral leukokeratosis are less frequent than in PC-K6a.

Show evidence (1 reference)

PMID:21326300 SUPPORT Human Clinical

"Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B."

Establishes KRT6B as a confirmed but uncommon causal gene in a cohort of 90 genetically characterised PC families.

PC-K6c (KRT6C; no MONDO term available)

KRT6C hgnc:20406

PC caused by heterozygous KRT6C variants, most often in-frame deletions. Originally delineated in families presenting with focal palmoplantar keratoderma and minimal or absent nail change, and correspondingly a milder and probably underdiagnosed subtype; plantar keratoderma and plantar pain are nonetheless near-universal, while fingernail involvement is rare. KRT6C is expressed in plantar epidermis, consistent with the tissue restriction of the phenotype.

Show evidence (3 references)

PMID:19609311 SUPPORT Human Clinical

"mutational analysis of the recently identified KRT6C gene, encoding keratin K6c, showed heterozygous in-frame deletion mutations in all three kindreds"

The report that established KRT6C as the fifth PC/focal-PPK keratin gene, by in-frame deletion in three unrelated kindreds.

PMID:19609311 SUPPORT Human Clinical

"Here, we report three unrelated families who presented with familial FPPK with minor or absent nail changes."

Documents the nail-sparing, keratoderma-predominant presentation that distinguishes the KRT6C subtype.

PMID:31823354 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17)."

Confirms KRT6C as one of the five accepted causal genes, so the subtype is real despite lacking a MONDO identifier.

PC-K16 (KRT16; MONDO pachyonychia congenita 1) MONDO:0008173

KRT16 hgnc:6423

PC caused by heterozygous KRT16 variants; the second most common subtype in most cohorts and the most common in the Israeli population, where a founder p.R127H allele predominates. Plantar keratoderma and plantar pain are near-universal; oral leukokeratosis, cysts and natal teeth are less frequent than in PC-K6a/PC-K17. KRT16 variants can also cause focal non-epidermolytic PPK without other PC features.

Show evidence (2 references)

PMID:33190296 SUPPORT Human Clinical

"In contrast to the high prevalence of KRT6A mutations in other populations, we found that KRT16 mutations were the most common type among Israeli patients with PC (56%)."

Documents population-specific enrichment of the KRT16 subtype.

PMID:33190296 SUPPORT Human Clinical

"Most (77%) of the Israeli patients with PC with KRT16 mutation carried the same variant (c.380G>A; p.R127H) and shared the same haplotype around the KRT16 locus, suggestive of a founder effect."

Identifies a founder KRT16 allele underlying the subtype's local over-representation.

PC-K17 (KRT17; MONDO pachyonychia congenita 2) MONDO:0008174

KRT17 hgnc:6427

PC caused by heterozygous KRT17 variants. Distinguished by the strong clustering of pilosebaceous cysts (including steatocystomas and vellus hair cysts) and of natal or prenatal teeth; follicular hyperkeratosis is also common. Plantar keratoderma and plantar pain, while still the dominant burden, are somewhat less universal than in the KRT6A/KRT16 subtypes. The same heterozygous KRT17 variant can present as steatocystoma multiplex in other family members.

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"KRT17 mutations were most commonly associated with cysts and natal teeth."

The IPCRR case-cohort study of 815 patients establishes the defining KRT17 genotype-phenotype correlation.

PMID:22264670 SUPPORT Human Clinical

"We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation."

An independent registry cohort replicates the KRT17-cysts/natal-teeth association.

?

Discussions and Knowledge Gaps

3

What determines plantar pain severity in pachyonychia congenita, given that it is not proportional to the extent of hyperkeratosis?

KNOWLEDGE GAP OPEN pc_pain_not_proportional_to_keratoderma

Attached to

pathophysiology#Plantar Nociceptive and Neuropathic Pain

Plantar pain is the dominant disability in PC and dictates treatment goals, yet its severity tracks poorly with callus extent. Candidate contributors include subepidermal blistering beneath the callus, nociceptive input from tissue damage, neuropathic change in cutaneous sensory afferents, neurovascular structures within the callus, and TRPV3/EGFR-driven sensitisation. Quantitative sensory testing supports a neuropathic component but does not identify its cause, and the sensory phenotype does not differ by causal gene. Until this is resolved, dismech deliberately keeps pain as its own mechanism node rather than as a severity qualifier on the keratoderma node, since a therapy that thins the callus is not thereby predicted to relieve the pain.

Proposed experiments

Intraepidermal nerve fibre quantification in PC lesional vs non-lesional plantar skin

pc_ienfd_lesional_vs_nonlesional

Skin biopsy with PGP9.5 immunostaining to test whether small-fibre density or morphology in lesional plantar skin correlates with pain scores independently of callus thickness.

Correlation of neurovascular structure burden with quantitative sensory testing

pc_neurovascular_structures_vs_qst

Prospective study relating the number and distribution of intracallus neurovascular structures to mechanical hyperalgesia thresholds and DN4 scores.

Show evidence (2 references)

PMID:29210461 SUPPORT Human Clinical

"Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC."

Frames the open question: skin thickening explains part of the sensory phenotype but not the hyperalgesia and allodynia.

PMID:36116508 SUPPORT Human Clinical

"Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive."

A 2023 primary study states the gap explicitly.

Does the recessively inherited Krt16-null mouse model the same disease mechanism as dominant-negative keratin variants in human pachyonychia congenita?

HUMAN MODEL MISMATCH OPEN pc_krt16_null_mouse_dominant_negative_mismatch

Attached to

pathophysiology#Loss of Keratinocyte Mechanical Resilience pathophysiology#Keratin Intermediate Filament Network Disruption

Nearly all mechanistic insight into PC keratoderma — the pre-lesional differentiation defect, the KRT9 loss, the NRF2/oxidative-stress axis and the sulforaphane rescue — comes from mice lacking Krt16 entirely, a recessive loss-of-function state. Human PC is caused by heterozygous, dominant-negative alleles in which a mutant subunit is present and poisons the network. The model's own authors note that their findings call into question a purely gain-of-function view of PC keratoderma and emphasise the role of genetic modifiers. Whether the differentiation/redox cascade is equally engaged when a poisoned filament network is present, rather than no K16 at all, is unresolved, and it matters directly for whether NRF2-directed therapy will translate. Partial reassurance exists — hypophosphorylated NRF2 was confirmed in human PC lesional skin — but the rescue arm remains mouse-only.

Proposed experiments

Knock-in mouse carrying a human dominant-negative Krt16 allele

pc_krt16_dominant_negative_knockin_mouse

Generate a heterozygous knock-in of a recurrent human KRT16 PC allele and test whether the pre-lesional KRT9 loss and NRF2 hypoactivity of the null model are reproduced.

KRT9 and NRF2 pathway readouts in genotyped human PC plantar biopsies

pc_krt9_nrf2_readouts_human_biopsies

Compare KRT9 expression and NRF2 phosphorylation state across PC-K6a, PC-K16 and PC-K17 lesional skin to test whether the mouse cascade is genotype-independent in humans.

Show evidence (2 references)

PMID:22336941 SUPPORT Model Organism

"Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms."

The model's authors state the mechanistic mismatch between the recessive null mouse and the dominant human disease.

PMID:27183391 SUPPORT Human Clinical

"Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue."

Partially closes the mismatch for the NRF2 node by confirming it in human tissue; the therapeutic rescue arm remains mouse-only.

Should pachyonychia congenita be subtyped by the eponymous PC-1 (Jadassohn-Lewandowsky) / PC-2 (Jackson-Lawler) split or by causal keratin gene?

OPEN QUESTION RESOLVED pc_nosology_genotypic_supersedes_eponymous

Registry data showed that most keratin subgroups express a mixed constellation of the findings historically assigned to PC-1 and PC-2, so the eponymous categories cut across the causal genes and mislead on prognosis. Both large genotyped cohorts (n = 254 and n = 815) concluded in favour of a genotypic classification, and dismech follows that: has_subtypes is organised as PC-K6a/PC-K6b/PC-K6c/PC-K16/PC-K17. The eponyms are retained only as synonyms on the disease entry.

Resolution: Resolved in favour of the genotypic classification. Note that MONDO's numbered children still attach "Jadassohn-Lewandowsky" to the KRT16 class (MONDO:0008173) alone, which is a simplification of the historical usage (PC-1 spanned KRT6A and KRT16; PC-2 spanned KRT6B and KRT17). The MONDO terms are bound on their single-gene definitions, not on the eponyms.

Show evidence (3 references)

PMID:22264670 SUPPORT Human Clinical

"Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2."

The empirical basis for abandoning the eponymous split.

PMID:22264670 SUPPORT Human Clinical

"We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development."

The explicit proposal of the genotypic nosology adopted here.

PMID:31823354 SUPPORT Human Clinical

"The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features."

Confirms the registry-derived, gene-based classification as the accepted scheme.

⚙

Pathophysiology

9

Dominant-Negative Keratin Variant

A heterozygous variant — usually a missense change or a small in-frame insertion/deletion within one of the helix boundary (helix initiation or helix termination) motifs — in KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These motifs are the regions of the keratin polypeptide most critical for filament assembly, so the mutant protein acts in a dominant-negative fashion on the network built by the wild-type allele. The five genes encode the wound- and stress-inducible keratins whose expression domain (palmar and plantar epidermis, nail bed, oral mucosa, pilosebaceous unit) predicts the tissue distribution of disease.

KRT6A hgnc:6443 KRT6B hgnc:6444 KRT6C hgnc:20406 KRT16 hgnc:6423 KRT17 hgnc:6427

Downstream

Keratin Intermediate Filament Network Disruption Mutant keratin is co-expressed with wild-type keratin and incorporated into the same filament population, poisoning assembly.

Show evidence (2 references)

PMID:21326300 SUPPORT Human Clinical

"Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide."

Establishes the mutation class and its clustering in the assembly-critical helix boundary motifs across 90 PC families.

PMID:19609311 SUPPORT Human Clinical

"Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16, or KRT17, cause pachyonychia congenita (PC), characterized by hypertrophic nail dystrophy and other ectodermal features."

States the dominant-negative mechanism explicitly for the PC keratin genes.

Keratin Intermediate Filament Network Disruption

Keratin intermediate filaments are obligate heteropolymers of one type I and one type II keratin (K16/K17 with K6a/K6b/K6c in PC-relevant tissues). Mutant subunits assemble into aggregates instead of an extended filament network. This has been reproduced directly for the recurrent KRT6A N171K substitution and the N171del in-frame deletion in transfected cells, where fluorescent keratin reporters form aggregates rather than normal filaments.

keratinocyte CL:0000312

keratin intermediate filament assembly GO:0045109 ⚠ ABNORMAL intermediate filament cytoskeleton organization GO:0045104 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Experimental models

Dominant-negative K6a cell culture model CELL LINE Reproduces the defining molecular lesion — mutant-allele-dependent failure of keratin filament assembly — and shows it is reversible by removing the mutant transcript.

Organotypic PC epidermal equivalent ORGANOID Used to perturb the mutant keratin transcript pool with self-delivery siRNA and measure allele-selective knockdown in a stratified epidermal context.

Downstream

Loss of Keratinocyte Mechanical Resilience A defective keratin filament network leaves the palmoplantar keratinocyte unable to bear the mechanical load of weight-bearing skin.

Defective Terminal Differentiation of Volar Keratinocytes Beyond its structural role, K16 is required for the normal terminal differentiation programme of volar keratinocytes; its loss or disruption derails that programme ahead of any lesion.

Show evidence (2 references)

PMID:17145926 SUPPORT In Vitro

"Similar constructs containing a single nucleotide change (N171K) or a three-nucleotide deletion (N171del) showed keratin aggregate formation."

Directly demonstrates that PC-causing KRT6A alleles produce keratin aggregates rather than a normal filament network.

PMID:17145926 SUPPORT In Vitro

"Transfection experiments of a fusion gene consisting of K6a and a yellow fluorescent reporter (YFP) resulted in normal keratin filament formation in transfected cells as assayed by fluorescence microscopy."

Provides the wild-type control against which the mutant aggregation phenotype is read.

Loss of Keratinocyte Mechanical Resilience

Palmoplantar keratinocytes carrying a disrupted keratin network tolerate friction, pressure and shear poorly, so lesions form precisely at weight-bearing pressure points. Importantly, and unlike the KRT1/KRT10 and KRT9 keratinopathies, PC-associated keratoderma is non-epidermolytic: frank cytolysis of the differentiating epidermis is not the histological hallmark, and the mechanism is better described as reduced mechanical resilience plus derailed stress signalling than as simple cell lysis. Blistering can occur beneath the callus but is not the defining lesion.

keratinocyte CL:0000312

skin of sole of pes UBERON:0013778 nail bed UBERON:0005273

Animal models

Krt16-null mouse Mouse partially recapitulates Loss of the K16 filament subunit produces weight-bearing-site callus and compromised ambulation, mirroring the human lesion distribution.

Downstream

Compensatory Epidermal Hyperproliferation and Barrier Dysregulation Chronic mechanical stress at pressure points drives a compensatory hyperproliferative and barrier-repair response.

Plantar Nociceptive and Neuropathic Pain Tissue-level injury at weight-bearing sites is one hypothesised contributor to plantar pain, but the pain is not proportional to callus extent, so the intermediates are not established.

Show evidence (2 references)

PMID:37766547 SUPPORT Human Clinical

"PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17."

Supports the genetic basis of the keratinocyte defect; the review does not quantify mechanical resilience directly, hence PARTIAL.

PMID:22336941 SUPPORT Model Organism

"the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk"

Shows that loss of the K16 filament subunit alone is sufficient to produce weight-bearing-site callus and impaired ambulation in vivo.

Defective Terminal Differentiation of Volar Keratinocytes

Ahead of any visible lesion, palmoplantar keratinocytes show pleiotropic defects in terminal differentiation, most conspicuously loss of KRT9 — the keratin most robustly expressed in differentiating volar keratinocytes. This is an early driver of the keratoderma rather than a consequence of it, and is the basis for proposing restoration of KRT9 expression as a therapeutic target.

keratinocyte CL:0000312

keratinocyte differentiation GO:0030216 ⚠ ABNORMAL keratinization GO:0031424 ⚠ ABNORMAL

Animal models

Krt16-null mouse Mouse recapitulates Pre-lesional loss of Krt9 and pleiotropic terminal differentiation defects in footpad keratinocytes, mirrored in published human PC PPK expression data.

Downstream

Oxidative Stress and Hypoactive Keap1-NRF2 Signalling In the Krt16-null model, differentiation failure precedes and is followed by oxidative stress at the time of lesion onset.

Show evidence (2 references)

PMID:31220272 SUPPORT Model Organism

"Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation."

Establishes defective terminal differentiation with KRT9 loss as an early, pre-lesional event in the leading PC model.

PMID:31021398 SUPPORT Model Organism

"Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression."

A review of the Krt16-null model places differentiation failure first in the three-stage progression of PC-like keratoderma.

Oxidative Stress and Hypoactive Keap1-NRF2 Signalling

At the time of keratoderma onset, palmoplantar keratinocytes show elevated oxidative stress with an inability to sustain NRF2-dependent synthesis of glutathione. High levels of hypophosphorylated (hypoactive) NRF2 have been confirmed in lesional plantar skin biopsies from people with PC, not just in the mouse model. Genetic ablation of Nrf2 accelerates keratoderma in Krt16-null mice, and topical NRF2 activation prevents it — making this a causal node rather than a correlate.

keratinocyte CL:0000312

response to oxidative stress GO:0006979 ⚠ ABNORMAL

Animal models

Krt16-null mouse Mouse recapitulates Oxidative stress and failure of NRF2-dependent glutathione synthesis precede lesion onset; Nrf2 ablation accelerates and topical NRF2 activation prevents the keratoderma, and hypophosphorylated NRF2 is confirmed in human PC lesional skin.

Downstream

Compensatory Epidermal Hyperproliferation and Barrier Dysregulation Redox imbalance in volar keratinocytes drives the lesional hyperproliferative and barrier-alarmin response.

Show evidence (2 references)

PMID:27183391 SUPPORT Model Organism

"Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH)."

Establishes oxidative stress and failed NRF2-dependent glutathione synthesis as preceding lesion onset in the model.

PMID:27183391 SUPPORT Human Clinical

"Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue."

Confirms the NRF2 abnormality in human PC lesional skin, so the node is not mouse-only.

Compensatory Epidermal Hyperproliferation and Barrier Dysregulation

The lesional response to the preceding cellular defects: marked keratinocyte hyperproliferation and epidermal thickening, gross upregulation of danger-associated molecular patterns (alarmins) and skin-barrier regulators, and a profound loss of the epidermis's ability to return to homeostasis. In PC lesional skin this includes overactive EGFR signalling (epiregulin, TGF-alpha, HER1-EGFR and HER2 in the upper spinous layers) with downstream MAPK/ERK and mTOR activation, and increased TRPV3 — the rationale for the EGFR-inhibitor and mTOR-inhibitor treatment strategies.

keratinocyte CL:0000312

keratinocyte proliferation GO:0043616 ↑ INCREASED epidermis development GO:0008544 ⚠ ABNORMAL

skin of sole of pes UBERON:0013778

Downstream

Focal Palmoplantar Keratoderma Hyperproliferation and abnormal cornification at pressure points produce the focal callus.

Hypertrophic Nail Dystrophy The same process in the nail bed produces distal subungual hyperkeratosis and nail thickening.

Plantar Nociceptive and Neuropathic Pain Lesional signalling changes (TRPV3, EGFR ligands) plausibly sensitise cutaneous sensory afferents; EGFR inhibition reduces neuropathic pain.

Show evidence (3 references)

PMID:27183391 SUPPORT Human Clinical

"Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators."

Characterises the PC lesion by alarmin and barrier-gene upregulation.

PMID:36116508 SUPPORT Human Clinical

"In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling."

Demonstrates overactive EGFR-MAPK/mTOR signalling in human PC lesional epidermis.

PMID:31021398 SUPPORT Model Organism

"During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis."

Describes the failure of epidermal homeostasis that sustains the established lesion.

Plantar Nociceptive and Neuropathic Pain

Chronic, moderate-to-severe plantar pain, throbbing and stabbing in quality, worst on weight bearing, and the single most disabling feature of PC. It is modelled here as its own mechanism node rather than as a severity qualifier on the keratoderma for two reasons. First, its magnitude is not proportional to the extent of hyperkeratosis. Second, quantitative sensory testing in 62 patients versus 45 controls shows a signature that hyperkeratosis alone does not explain: mechanical hyperalgesia and static allodynia in painful regions, DN4 scores in the neuropathic range in the majority, and impaired conditioned pain modulation — i.e. a neuropathic component alongside the nociceptive one. Notably the sensory phenotype did not differ by causal gene, so pain is a shared final common pathway across subtypes rather than a subtype feature.

sensory perception of pain GO:0019233 ⚠ ABNORMAL

skin of sole of pes UBERON:0013778

Downstream

Plantar Pain The mechanism node surfaces clinically as the reported plantar pain phenotype and its mobility consequences.

Show evidence (4 references)

PMID:29210461 SUPPORT Human Clinical

"A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing."

Quantifies the prevalence and character of plantar pain in a controlled sensory-testing study.

PMID:29210461 SUPPORT Human Clinical

"Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC."

The authors explicitly separate what thickened skin can explain from what it cannot, supporting a neuropathic component distinct from the callus.

PMID:29210461 SUPPORT Human Clinical

"The specific gene and nature of the causative mutation did not affect any of these features."

Supports treating pain as a shared mechanism across all five genotypic subtypes rather than a subtype-specific feature.

+ 1 more reference

Focal Palmoplantar Keratoderma

Focal, non-epidermolytic hyperkeratotic calluses at plantar (and often palmar) pressure points, with marked hyperkeratosis and epidermal thickening. Distribution follows mechanical loading rather than being diffuse, which distinguishes PC keratoderma from the diffuse epidermolytic keratodermas.

keratinization GO:0031424 ↑ INCREASED

skin of sole of pes UBERON:0013778

Downstream

Focal Palmoplantar Keratoderma Phenotype The tissue lesion presenting as the clinical keratoderma.

Show evidence (1 reference)

PMID:19609311 SUPPORT Human Clinical

"In PC, focal PPK (FPPK) is the most painful and debilitating phenotypic feature."

Establishes the focal (not diffuse) character of PC keratoderma and its clinical primacy.

Hypertrophic Nail Dystrophy

Hyperkeratosis of the nail bed producing thickened, discoloured nails that either grow to full length with an upward distal slant or terminate in a sloping wedge of subungual hyperkeratosis with an exposed distal fingertip. Usually the first recognised sign of PC, appearing in the first months to first year of life.

nail bed UBERON:0005273 nail UBERON:0001705

Downstream

Hypertrophic Nail Dystrophy Phenotype The tissue lesion presenting as the clinical nail phenotype.

Show evidence (1 reference)

PMID:21326300 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma."

Confirms nail dystrophy as a cardinal, defining feature.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

10

Integument 1

Hypertrophic Nail Dystrophy Phenotype HP:0008404

Show evidence (2 references)

PMID:37766547 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy."

Establishes hypertrophic nail dystrophy as one of the three defining features.

PMID:20301457 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities."

The GeneReviews clinical characteristics statement lists hypertrophic nail dystrophy first among PC features.

Voice 1

Hoarseness Hoarse voice HP:0001609

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids."

Establishes hoarseness as a KRT6A-associated feature.

PMID:31823354 SUPPORT Human Clinical

"Hoarseness was correlated with an increased number of involved fingernails."

Places hoarseness within the correlated cluster of severe-disease features.

Other 8

Focal Palmoplantar Keratoderma Phenotype Nonepidermolytic palmoplantar hyperkeratosis HP:0007404

Show evidence (2 references)

PMID:37766547 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy."

Establishes focal palmoplantar keratoderma as one of the three defining features.

PMID:33190296 SUPPORT Human Clinical

"The most common clinical findings were painful focal plantar keratoderma (94%) accompanied by nail dystrophy (81%), pilosebaceous cysts (31%) and prenatal/natal teeth (13%)."

Quantifies focal plantar keratoderma as the most frequent finding in an independent molecularly confirmed cohort.

Plantar Pain Foot pain HP:0025238

Show evidence (3 references)

PMID:31823354 SUPPORT Human Clinical

"Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function."

Identifies plantar pain as the principal patient-reported burden in the largest genetically confirmed PC cohort.

PMID:29210461 SUPPORT Human Clinical

"In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet."

Quantifies the neuropathic sensory features accompanying the pain.

PMID:38805703 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma and hypertrophic nail dystrophy."

A dedicated review of PC pain places chronic severe plantar pain in the defining triad, alongside — not subordinate to — the keratoderma.

Thickened Nails Onychauxis HP:0012542

Show evidence (1 reference)

PMID:22264670 SUPPORT Human Clinical

"a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years"

Explicitly reports toenail thickening (rather than dystrophy in general) as part of the diagnostic triad.

Oral Leukokeratosis Oral leukoplakia HP:0002745

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts."

Lists oral leukokeratosis among the main clinical features of PC.

PMID:22264670 SUPPORT Human Clinical

"We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations"

Supports the subtype gradient, with KRT6A carriers most affected.

Pilosebaceous Cysts Steatocystoma multiplex HP:0012035

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"KRT17 mutations were most commonly associated with cysts and natal teeth."

Establishes cyst clustering with the KRT17 genotype.

PMID:20301457 SUPPORT Human Clinical

"pilosebaceous cysts (including steatocystoma and vellus hair cysts)"

GeneReviews specifies the cyst types seen in PC.

Natal Teeth Natal tooth HP:0000695

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation."

Establishes natal teeth as a prognostic marker within PC as well as a KRT17-associated feature.

PMID:22264670 SUPPORT Human Clinical

"a strong association of natal teeth and cysts in carriers of a KRT17 mutation"

Replicates the KRT17-natal teeth association in an independent cohort.

Follicular Hyperkeratosis HP:0007502

Show evidence (2 references)

PMID:20301457 SUPPORT Human Clinical

"follicular keratoses on the trunk and extremities"

GeneReviews lists follicular keratoses of trunk and extremities among the clinical characteristics.

PMID:37766547 SUPPORT Human Clinical

"Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures."

A recent review enumerates follicular hyperkeratosis among the additional PC features.

Palmoplantar Hyperhidrosis HP:0007410

Show evidence (1 reference)

PMID:20301457 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities."

GeneReviews lists palmoplantar hyperhidrosis among the defining clinical characteristics of PC. The quoted sentence preserves the source's spelling ("hyperhydrosis").

🧬

Genetic Associations

5

KRT6A (Causative)

Gene: KRT6A hgnc:6443 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (2 references)

PMID:31823354 SUPPORT Human Clinical

"Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17)."

Confirms KRT6A as one of the five causal genes.

PMID:17914454 SUPPORT In Vitro

"Targeting the single-nucleotide keratin 6a (K6a) N171K mutation responsible for the rare monogenic skin disorder pachyonychia congenita (PC), we demonstrate that small interfering RNAs (siRNAs) can potently and selectively block expression of mutant K6a."

Names the recurrent KRT6A N171K allele and confirms its causal role.

KRT6B (Causative)

Gene: KRT6B hgnc:6444 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:21326300 SUPPORT Human Clinical

"Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis."

Confirms KRT6B as a causal gene in molecularly confirmed families.

KRT6C (Causative)

Gene: KRT6C hgnc:20406 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (2 references)

PMID:19609311 SUPPORT Human Clinical

"Affected members of Families 1 and 2 carried the same mutation, p.Asn172del. In Family 3, the mutation p.Ile462-Glu470del co-segregated with the disease."

Reports the specific KRT6C alleles and their co-segregation with disease.

PMID:19609311 SUPPORT Human Clinical

"KRT6C was shown to be expressed in the plantar epidermis using reverse transcription-PCR, consistent with the phenotype observed in this tissue."

Links the gene's expression domain to the tissue restriction of the phenotype.

KRT16 (Causative)

Gene: KRT16 hgnc:6423 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:31220272 SUPPORT Human Clinical

"Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin."

Confirms KRT16 causality and its allelic relationship to isolated focal non-epidermolytic PPK.

KRT17 (Causative)

Gene: KRT17 hgnc:6427 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:31823354 SUPPORT Human Clinical

"KRT17 mutations were most commonly associated with cysts and natal teeth."

Establishes the KRT17 genotype-phenotype correlation.

💊

Medical Actions

11

Mechanical Callus Debridement and Friction Reduction

Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

The mainstay of care: paring, filing, grinding or clipping the plantar callus, together with lifestyle measures that reduce friction and trauma (comfortable footwear and orthotics, wicking socks and ventilated footwear, limiting standing and walking, maintaining ideal body weight, walking aids when needed). Benefit is variable and over-trimming can paradoxically worsen plantar pain, so paring frequency is set by patient preference.

Mechanism Target:

INHIBITS Focal Palmoplantar Keratoderma — Physical removal of hyperkeratotic material and reduction of the mechanical stimulus that drives it.

Show evidence (1 reference)

PMID:20301457 SUPPORT Human Clinical

"Foot care includes paring down of hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics)."

GeneReviews specifies debridement of the hyperkeratosis.

Show evidence (2 references)

PMID:20301457 SUPPORT Human Clinical

"Pain from the palmoplantar keratoderma may be reduced somewhat by limiting friction and trauma to the feet by minimizing walking or standing, reducing hydration of the stratum corneum by using wicking socks and ventilated footwear, selecting comfortable shoes, and maintaining ideal body weight."

GeneReviews describes the friction- and trauma-reduction strategy and is explicit that the benefit is only partial.

PMID:37766547 SUPPORT Human Clinical

"There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection."

Establishes that conservative and mechanical measures remain the standard of care, and that no disease-specific therapy is approved.

Topical Keratolytics and Emollients

Action: Pharmacotherapy NCIT:C15986

Agent: urea CHEBI:16199

Emollients with keratolytic agents (urea 40%, salicylic acid 10-20%, lactic acid) applied to the callus to soften and thin hyperkeratotic skin. Symptomatic only, with variable benefit.

Mechanism Target:

INHIBITS Focal Palmoplantar Keratoderma — Keratolysis of the accumulated stratum corneum.

Show evidence (1 reference)

PMID:20301457 SUPPORT Human Clinical

"Foot care includes paring down of hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics)."

GeneReviews recommends keratolytic-containing topical therapy as part of routine foot care.

Systemic Retinoids

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

Oral retinoids (acitretin, isotretinoin) thin the hyperkeratosis but frequently increase blistering and plantar pain, leading many patients to discontinue. Acitretin is highly teratogenic with a three-year washout, so it is often inappropriate for women of childbearing potential. Benefit is limited to a small subgroup.

Mechanism Target:

INHIBITS Compensatory Epidermal Hyperproliferation and Barrier Dysregulation — Retinoid modulation of keratinocyte proliferation and differentiation reduces hyperkeratosis, at the cost of increased fragility.

Show evidence (1 reference)

PMID:38805703 SUPPORT Human Clinical

"Current therapeutic options for pain in PC are limited to lifestyle adjustment and mechanical techniques, with a small subgroup of patients benefiting from oral retinoids."

Supports a real but narrow role for oral retinoids; PARTIAL because the review explicitly restricts the benefit to a small subgroup.

Neuropathic Pain Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Simple analgesia plus neuropathic agents (amitriptyline, gabapentin, pregabalin) used by some patients, with specialist pain input in severe cases. The rationale is the demonstrated neuropathic component of PC plantar pain rather than any effect on the keratoderma — which is precisely why plantar pain is modelled as its own mechanism node here.

Mechanism Target:

INHIBITS Plantar Nociceptive and Neuropathic Pain — Targets the neuropathic component of the pain directly, independently of callus thickness.

Show evidence (1 reference)

PMID:29210461 SUPPORT Human Clinical

"The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC."

The sensory-testing study's own therapeutic inference: neuropathic pain medication is indicated by the neuropathic phenotype.

Show evidence (1 reference)

PMID:29210461 SUPPORT Human Clinical

"Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy."

Supports the rationale; PARTIAL because no controlled trial of neuropathic agents in PC is cited.

TD101 Mutation-Specific siRNA

Action: Pharmacotherapy NCIT:C15986

TD101 (K6a_513a.12) is an allele-specific small interfering RNA designed to silence the KRT6A N171K mutant transcript while sparing wild-type K6a mRNA — the therapeutic embodiment of the dominant-negative mechanism. It was tested by intradermal injection into plantar calluses in a 17-week, prospective, double-blind, split-body (opposite feet), vehicle-controlled, dose-escalation phase Ib trial. IMPORTANT EVIDENCE CAVEAT: that trial enrolled a SINGLE PATIENT (n = 1). Callus regression was reported on the siRNA-treated foot only and no adverse events occurred, and the study is historically notable as the first clinical use of siRNA in human skin and the first targeting a dominant-negative mutant allele — but it is an n-of-1 observation and must not be read as established efficacy. The authors themselves framed the result as warranting further study. Development did not proceed to a larger trial, in part because intradermal needle administration to PC lesions is intensely painful.

Mechanism Target:

INHIBITS Keratin Intermediate Filament Network Disruption — Selective degradation of the mutant K6a transcript removes the dominant-negative subunit from the filament pool, permitting normal keratin filament formation from the wild-type allele. Demonstrated in cell culture; the human evidence is a single-patient trial.

Show evidence (2 references)

PMID:17914454 SUPPORT In Vitro

"Addition of mutant-specific siRNAs allowed normal filament formation, suggesting selective inhibition of mutant K6a."

Directly demonstrates that the siRNA acts on this mechanism node by restoring filament assembly in a dominant-negative cell model.

PMID:19935778 SUPPORT Human Clinical

"This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA."

Establishes the allele-selective target of the agent in the clinical formulation.

Show evidence (4 references)

PMID:19935778 SUPPORT Human Clinical

"The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial."

The design statement itself is the caveat: n = 1. Recorded as PARTIAL because a single-patient split-body observation cannot establish efficacy, however well controlled within that patient.

PMID:19935778 SUPPORT Human Clinical

"Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot."

Reports the observed effect, in the single treated patient, with the contralateral vehicle-treated foot as the internal control.

PMID:19935778 SUPPORT Human Clinical

"This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin."

Supports the historical significance claim, which is separable from — and does not imply — a claim about efficacy.

+ 1 more reference

Topical Rapamycin (Sirolimus)

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Topical mTOR inhibition, rationalised by the demonstrated EGFR-MAPK/ERK-mTOR overactivity in PC lesional epidermis and by reports that sirolimus selectively reduces KRT6A expression. Oral sirolimus improved keratoderma in an off-label series but had intolerable systemic effects, motivating the topical route. A multicentre phase 3 vehicle-controlled trial of QTORIN 3.9% rapamycin anhydrous gel is under way; efficacy is not yet established.

Mechanism Target:

INHIBITS Compensatory Epidermal Hyperproliferation and Barrier Dysregulation — mTOR inhibition downstream of the overactive EGFR-MAPK/ERK axis in lesional epidermis.

Show evidence (1 reference)

PMID:36116508 SUPPORT Human Clinical

"EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling."

Establishes mTOR activation in PC lesions as the target rationale; PARTIAL because this study tested EGFR inhibition, not rapamycin.

Show evidence (1 reference)

clinicaltrials:NCT05180708 SUPPORT Human Clinical

"This study evaluates the safety and efficacy of QTORIN 3.9% rapamycin anhydrous gel in the treatment of adults with Pachyonychia Congenita."

A registered phase 3 trial establishes that topical rapamycin is under formal evaluation in PC; PARTIAL because the registry record reports the design, not a result.

Oral EGFR Inhibition (Erlotinib)

Action: Pharmacotherapy NCIT:C15986

Oral erlotinib, given for 6-8 months to three patients with PC on the basis of demonstrated EGFR pathway overactivity in lesional skin, was well tolerated and produced an early, marked and sustained reduction in neuropathic pain with major quality-of-life improvement. This is a three-patient open series, not a controlled trial, but it is mechanistically important because it targets the pain node through the epidermal signalling node rather than through callus removal.

Mechanism Target:

INHIBITS Compensatory Epidermal Hyperproliferation and Barrier Dysregulation — Pharmacological inhibition of the overactive HER1-EGFR signalling demonstrated in the upper spinous layers of PC lesions.

Show evidence (1 reference)

PMID:36116508 SUPPORT Human Clinical

"Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC."

The authors' own statement that EGFR is the actionable target node.

INHIBITS Plantar Nociceptive and Neuropathic Pain — Reduction of neuropathic plantar pain reported in the treated patients.

Show evidence (1 reference)

PMID:36116508 SUPPORT Human Clinical

"To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL."

Reports the pain benefit; PARTIAL because n = 3 in an uncontrolled open series.

Oral Statin Therapy

Action: Pharmacotherapy NCIT:C15986

Off-label oral statins, proposed to downregulate KRT6A expression via STAT1. Case reports suggested benefit in KRT6A-associated disease, but a subsequent series of six adults with KRT16 or KRT17 variants found no significant improvement in plantar calluses or pain, and all patients discontinued for insufficient efficacy. Recorded here as a genotype-limited strategy with negative evidence outside KRT6A. No `target_mechanisms` link is asserted: the only quotable clinical evidence is negative, and the TreatmentEffectEnum has no value for "no effect", so claiming an INHIBITS edge would overstate the case.

Show evidence (2 references)

PMID:41100406 REFUTE Human Clinical

"Although the treatment was well tolerated in most cases, no significant clinical improvement in plantar calluses or pain was observed. All patients discontinued therapy due to insufficient efficacy."

A negative result for oral statins in the KRT16 and KRT17 subtypes.

PMID:41100406 SUPPORT Human Clinical

"Our findings indicate that oral statin therapy may offer limited benefit in KRT16/KRT17-pEDD-PC and suggest the potential importance of early intervention and genotype-specific therapeutic strategies."

The authors' conclusion, supporting a genotype-specific rather than universal role for statins in PC.

Management of Oral Leukokeratosis and Laryngeal Involvement

Action: Supportive Care NCIT:C15747

Gentle brushing with a soft toothbrush and good oral hygiene improve the oral plaques; most resolve without intervention. Infants with leukokeratosis may need a soft, enlarged-opening bottle nipple. Laryngeal thickening requires ENT review, since rare infantile airway obstruction may need emergency surgery — but surgery to the larynx can paradoxically worsen the condition.

Mechanism Target:

MODULATES Oral Leukokeratosis — Mechanical and hygiene measures for the oral mucosal plaques.

Show evidence (2 references)

PMID:20301457 SUPPORT Human Clinical

"Good oral hygiene and brushing gently with a soft toothbrush can improve thick, white patches on the tongue and oral mucosa."

GeneReviews management recommendation for oral leukokeratosis.

PMID:20301457 SUPPORT Human Clinical

"Rarely, young children with laryngeal thickening/growths need emergency surgery to reestablish the airway; however, surgery may exacerbate the condition."

Records both the airway risk and the explicit caution that surgery can make it worse.

Infection Prevention and Treatment

Action: Supportive Care NCIT:C15747

Secondary bacterial and fungal infection of dystrophic nails and macerated callus is common and a frequent reason for pain flares. Swabs and clippings should be taken and infections treated; a dilute bleach-bath regimen and pre/post-grooming hygiene are recommended for prevention. Infected or painful cysts can be incised and drained.

Mechanism Target:

MODULATES Hypertrophic Nail Dystrophy — Treating superimposed infection removes a common aggravator of nail disease and pain, without altering the underlying keratin defect.

Show evidence (1 reference)

PMID:20301457 SUPPORT Human Clinical

"Secondary fungal and bacterial infections that require treatment are common; cysts usually do not require treatment but can be incised and drained if infected or painful."

GeneReviews management recommendation for secondary infection and cysts.

Genetic Counselling

Action: Genetic Counseling NCIT:C15240

Autosomal dominant inheritance with a 50% recurrence risk for offspring and a roughly 30% de novo rate. Prenatal testing is possible once the familial variant is known; in vitro fertilisation with preimplantation genetic diagnosis is available but is generally reserved for severe disease.

Show evidence (1 reference)

PMID:20301457 SUPPORT Human Clinical

"The offspring of an affected individual have a 50% chance of inheriting the disorder. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible."

GeneReviews genetic counselling statement.

🔬

Diagnosis

1

Keratin gene molecular genetic testing

Identification of a heterozygous pathogenic variant in one of the five PC keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17) confirms the diagnosis and assigns the genotypic subtype. This is what makes the five-gene axis, rather than the older PC-1/PC-2 eponyms, the operative nosology for this entry.

genetic testing NCIT:C15709

Results: A heterozygous pathogenic variant in KRT6A, KRT6B, KRT6C, KRT16, or KRT17 establishes the diagnosis and the corresponding PC-K subtype.

Show evidence (1 reference)

PMID:20301457 SUPPORT Human Clinical

"PC is diagnosed by clinical findings and/or by the identification of a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17."

GeneReviews DIAGNOSIS/TESTING statement, establishing both the clinical and the molecular route to diagnosis and naming the five causal genes.

📈

Progression

3

Onset

Age: First months to first years of life

Hypertrophic nail dystrophy is typically the first recognised feature, usually in the first year; plantar keratoderma follows once the child begins to walk.

Show evidence (1 reference)

PMID:31823354 SUPPORT Human Clinical

"The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years."

Establishes nail dystrophy and keratoderma as the earliest manifestations and preschool age as the usual point of diagnosis.

Established disease

Age: By age 10 years

The diagnostic triad of toenail thickening, plantar keratoderma and plantar pain is present in nearly all patients by the end of the first decade.

Show evidence (1 reference)

PMID:22264670 SUPPORT Human Clinical

"a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years"

Quantifies completion of the diagnostic triad within the first decade.

Chronic

Age: Adolescence to adulthood

Lifelong disease without effect on lifespan. Chronic plantar pain becomes the dominant disability, frequently requiring walking aids and imposing occupational and psychosocial costs.

Show evidence (1 reference)

PMID:31021398 SUPPORT Human Clinical

"PC dramatically impacts quality of life although it does not affect lifespan."

Characterises the chronic, non-lethal but highly disabling natural history.

📊

Prevalence

1

Worldwide

Point Prevalence Ultra Rare

No numeric population-based prevalence estimate could be verified from a quotable abstract; contemporary reviews describe PC as rare and note that the true prevalence is probably underestimated because milder subtypes (particularly PC-K6c) go undiagnosed. rate_per_100000 is deliberately omitted rather than derived from a figure that could not be quoted.

Show evidence (1 reference)

PMID:37766547 SUPPORT Human Clinical

"Although classed as rare, the prevalence of PC is likely to be underestimated."

Supports the rare classification while flagging that ascertainment is incomplete; it does not supply a numeric rate, hence PARTIAL.

🔬

Clinical Trials

3

NCT05180708 PHASE_III UNKNOWN

Multicentre, randomised, double-blind, vehicle-controlled phase 3 study of QTORIN 3.9% rapamycin anhydrous gel in adults with pachyonychia congenita, with a 6-month treatment period.

Target Phenotypes: Focal nonepidermolytic palmoplantar keratoderma HP:0007404 Plantar pain HP:0025238

Show evidence (1 reference)

clinicaltrials:NCT05180708 SUPPORT Human Clinical

"This study evaluates the safety and efficacy of QTORIN 3.9% rapamycin anhydrous gel in the treatment of adults with Pachyonychia Congenita."

The registry record establishes a phase 3 evaluation of topical rapamycin specifically in PC.

NCT05435638 PHASE_I COMPLETED

Phase I open-label study of topical KM-001 1% in type I punctate palmoplantar keratoderma or pachyonychia congenita, with lesion clearance and VAS pain assessments. The same trial is recorded on Punctate_Palmoplantar_Keratoderma.yaml; it is duplicated here because pachyonychia congenita was an eligible enrolling condition in its own right.

Target Phenotypes: Focal nonepidermolytic palmoplantar keratoderma HP:0007404 Plantar pain HP:0025238

Show evidence (1 reference)

clinicaltrials:NCT05435638 SUPPORT Human Clinical

"In this phase 1 open label study for patients with type I punctate palmoplantar keratoderma or pachyonychia congenital, 2 arms will be recruited to be treated twice daily, with 1% topical KM-001."

The registry record confirms pachyonychia congenita as a co-enrolled condition for topical KM-001.

NCT05956314 PHASE_I COMPLETED

Phase Ib open-label study of topical KM-001 1% in type I punctate palmoplantar keratoderma or pachyonychia congenita, assessing safety, tolerability, efficacy, pharmacokinetics and patient-reported outcomes.

Target Phenotypes: Focal nonepidermolytic palmoplantar keratoderma HP:0007404 Plantar pain HP:0025238

Show evidence (1 reference)

clinicaltrials:NCT05956314 SUPPORT Human Clinical

"This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases."

The registry record confirms a second open-label KM-001 study enrolling pachyonychia congenita.

🧫

Experimental Models

2

Dominant-negative K6a cell culture model CELL_LINE

Cultured cells co-expressing wild-type and mutant (N171K) K6a, used to reproduce the dominant-negative filament defect in vitro and to test allele-selective siRNA. Simultaneous expression of both alleles yields defective filament formation; mutant-specific siRNA restores normal filaments.

Organism

human NCBITaxon:9606

Publication

PMID:17914454

Pathograph links

Keratin Intermediate Filament Network Disruption recapitulates fidelity: moderate Reproduces the defining molecular lesion — mutant-allele-dependent failure of keratin filament assembly — and shows it is reversible by removing the mutant transcript.

Limitations: A transfected, over-expression cell system rather than differentiated volar epidermis; it captures filament assembly but not the tissue-level hyperproliferation, differentiation and pain phenotypes.

Show evidence (1 reference)

PMID:17914454 SUPPORT In Vitro

"To test whether lead siRNAs could discriminate mutant mRNA in the presence of both wild-type and mutant forms, a dominant-negative PC cell culture model was developed."

Describes the construction of the model and its purpose, supporting its use as an informative system for this mechanism node.

Show evidence (1 reference)

PMID:17145926 SUPPORT In Vitro

"Similar constructs containing a single nucleotide change (N171K) or a three-nucleotide deletion (N171del) showed keratin aggregate formation."

The companion transfection study establishing the aggregate readout used in this model class.

Organotypic PC epidermal equivalent ORGANOID

An organotypic (raft) epidermal model built from PC keratinocytes, used to assay keratinocyte uptake of chemically modified self-delivery siRNA and allele-selective knockdown of mutant K6a mRNA. Developed specifically because intradermal needle delivery to PC plantar lesions is too painful to be viable.

Organism

human NCBITaxon:9606

Publication

PMID:21248764

Pathograph links

Keratin Intermediate Filament Network Disruption perturbs fidelity: moderate Used to perturb the mutant keratin transcript pool with self-delivery siRNA and measure allele-selective knockdown in a stratified epidermal context.

Limitations: An in vitro epidermal equivalent lacking innervation, mechanical loading and immune components, so it cannot report the pain or callus phenotypes that dominate the human disease.

Show evidence (1 reference)

PMID:21248764 SUPPORT In Vitro

"treatment of PC epidermal equivalents with self-delivery "TD101" siRNA resulted in marked reduction of mutant keratin 6a mRNA with little or no effect on wild-type expression."

Demonstrates allele-selective knockdown in the organotypic model, grounding its link to the filament-disruption node.

Show evidence (1 reference)

PMID:21191405 SUPPORT In Vitro

"demonstrate that repeated siRNA treatment results in sustained inhibition of mutant K6a mRNA in patient-derived keratinocyte cultures"

Companion work establishing quantitative molecular endpoints for this model system and for trials using it.

🐁

Animal Models

1

Krt16-null mouse

The principal animal model of PC-associated palmoplantar keratoderma. Mice null for Krt16 spontaneously develop oral lesions and PPK-like hyperkeratotic calluses on fore and hind paws that impair walking, and reproduce the sequence of pre-lesional differentiation failure, oxidative stress with hypoactive Keap1-Nrf2 signalling, and lesional loss of epidermal homeostasis.

Species

Mouse

Genotype

Krt16-/- (null)

Background

C57BL/6; also transferred to FVB/N

Genes

KRT16 hgnc:6423

Publication

PMID:22336941

Pathograph links

Loss of Keratinocyte Mechanical Resilience partially recapitulates fidelity: moderate Loss of the K16 filament subunit produces weight-bearing-site callus and compromised ambulation, mirroring the human lesion distribution.

Limitations: The mouse phenotype arises from complete loss of function inherited recessively, whereas human PC is a dominant-negative disease in heterozygotes — so the model tests the consequence of losing functional K16 filaments, not the consequence of a poisoned filament network.

Show evidence (1 reference)

PMID:22336941 SUPPORT Model Organism

"the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk"

Establishes the model's core palmoplantar phenotype and functional consequence.

Defective Terminal Differentiation of Volar Keratinocytes recapitulates fidelity: moderate Pre-lesional loss of Krt9 and pleiotropic terminal differentiation defects in footpad keratinocytes, mirrored in published human PC PPK expression data.

Limitations: Demonstrated in the null background; whether human dominant-negative alleles produce the same magnitude of KRT9 loss is not established.

Show evidence (1 reference)

PMID:31220272 SUPPORT Model Organism

"These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy."

States the model's central differentiation finding and its proposed translational read.

Oxidative Stress and Hypoactive Keap1-NRF2 Signalling recapitulates fidelity: high Oxidative stress and failure of NRF2-dependent glutathione synthesis precede lesion onset; Nrf2 ablation accelerates and topical NRF2 activation prevents the keratoderma, and hypophosphorylated NRF2 is confirmed in human PC lesional skin.

Limitations: The preventive effect of sulforaphane is shown in mice only; it has not been shown to prevent or reverse keratoderma in people with PC.

Show evidence (1 reference)

PMID:27183391 SUPPORT Model Organism

"Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools."

Demonstrates causal, rescuable involvement of the NRF2 node in the model.

Show evidence (1 reference)

PMID:31021398 SUPPORT Model Organism

"We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK."

Establishes the Krt16-null mouse as the reference model for PC-associated keratoderma, while wording the claim as mimicking several aspects only.

{ }

Source YAML

click to show

name: Pachyonychia Congenita
creation_date: "2026-08-18T11:45:00Z"
category: Mendelian
description: >-
  Pachyonychia congenita (PC) is a rare autosomal dominant disorder of
  keratinization caused by heterozygous, predominantly dominant-negative
  variants in one of five keratin genes — KRT6A, KRT6B, KRT6C, KRT16 or
  KRT17 — whose products are the wound- and stress-inducible keratins of
  palmoplantar epidermis and ectodermal appendages. The defining clinical
  triad is focal (non-epidermolytic) palmoplantar keratoderma, severe chronic
  plantar pain, and hypertrophic nail dystrophy; additional features include
  oral leukokeratosis, pilosebaceous cysts, follicular hyperkeratosis,
  palmoplantar hyperhidrosis, hoarseness and natal teeth. Mutant keratin
  incorporated into type I/type II heterodimers disrupts assembly of the
  keratin intermediate filament network; downstream, palmoplantar
  keratinocytes show defective terminal differentiation with loss of KRT9,
  oxidative stress with hypoactive Keap1-NRF2 signalling, barrier and
  alarmin dysregulation, and compensatory hyperproliferation, producing the
  focal callus. Plantar pain is the dominant patient-reported burden, is not
  proportional to the extent of keratoderma, and carries quantitative
  sensory-testing evidence of a neuropathic component; it is therefore
  modelled here as a mechanism and phenotype in its own right rather than as
  a severity qualifier on the keratoderma. Modern nosology is genotypic
  (PC-K6a, PC-K6b, PC-K6c, PC-K16, PC-K17) and supersedes the older
  eponymous PC-1 (Jadassohn-Lewandowsky) / PC-2 (Jackson-Lawler) split, which
  cuts across the causal genes.
disease_term:
  preferred_term: pachyonychia congenita
  term:
    id: MONDO:0016471
    label: pachyonychia congenita
parents:
- palmoplantar keratoderma
- genodermatosis
- keratinizing disorder
synonyms:
- PC
- pachyonychia congenita, Jadassohn-Lewandowsky type
- pachyonychia congenita, Jackson-Lawler type
- palmoplantar epidermal differentiation disorder associated with pachyonychia congenita
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    evidence:
    - reference: PMID:37766547
      reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy."
      explanation: >-
        A recent review characterises PC as a disorder of keratinization
        presenting with skin and nail disease, supporting placement in
        Harrison's dermatology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:20301457
      reference_title: "Pachyonychia Congenita."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pachyonychia congenita is inherited in an autosomal dominant manner."
      explanation: >-
        GeneReviews establishes PC as a Mendelian autosomal dominant disorder,
        supporting a second placement under Harrison's genetics Part.
  mechanistic_category:
  - classification_value: intermediate filament disease
    notes: >-
      PC arises from variants in five keratin genes whose products are type I
      and type II intermediate filament proteins of palmoplantar epidermis and
      ectodermal appendages; the proximal lesion is disruption of keratin
      intermediate filament assembly.
    evidence:
    - reference: PMID:22336941
      reference_title: "Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis upon wounding and other stressors."
      explanation: >-
        Identifies the PC-associated keratins as intermediate filament proteins,
        supporting the mechanistic nosology assignment.
references:
- reference: PMID:20301457
  title: "Pachyonychia Congenita."
  tags:
  - GeneReviews
has_subtypes:
- name: PC-K6a
  display_name: PC-K6a (KRT6A; MONDO pachyonychia congenita 3)
  subtype_term:
    preferred_term: PC-K6a
    term:
      id: MONDO:0014324
      label: pachyonychia congenita 3
  description: >-
    PC caused by heterozygous KRT6A variants. The most common subtype in most
    reported cohorts. Characterised by widespread nail dystrophy with the
    earliest age of onset and the highest number of involved nails, prominent
    oral leukokeratosis, hoarseness (laryngeal leukokeratosis), and the greatest
    likelihood of requiring walking aids. First-bite syndrome is reported
    predominantly in this subtype.
  genes:
  - preferred_term: KRT6A
    term:
      id: hgnc:6443
      label: KRT6A
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids."
    explanation: >-
      The IPCRR case-cohort study of 815 genetically confirmed patients defines
      the KRT6A genotype-phenotype correlation used for this subtype.
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation."
    explanation: >-
      An independent registry cohort replicates the KRT6A-oral leukokeratosis
      association.
- name: PC-K6b
  display_name: PC-K6b (KRT6B; MONDO pachyonychia congenita 4)
  subtype_term:
    preferred_term: PC-K6b
    term:
      id: MONDO:0014325
      label: pachyonychia congenita 4
  description: >-
    PC caused by heterozygous KRT6B variants. The least common of the four
    MONDO-recognised numbered subtypes, accounting for roughly 3% of families
    in a large mutational study. Plantar keratoderma, plantar pain and toenail
    dystrophy are near-universal, while fingernail involvement and oral
    leukokeratosis are less frequent than in PC-K6a.
  genes:
  - preferred_term: KRT6B
    term:
      id: hgnc:6444
      label: KRT6B
  evidence:
  - reference: PMID:21326300
    reference_title: "A large mutational study in pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B."
    explanation: >-
      Establishes KRT6B as a confirmed but uncommon causal gene in a cohort of
      90 genetically characterised PC families.
- name: PC-K6c
  display_name: PC-K6c (KRT6C; no MONDO term available)
  description: >-
    PC caused by heterozygous KRT6C variants, most often in-frame deletions.
    Originally delineated in families presenting with focal palmoplantar
    keratoderma and minimal or absent nail change, and correspondingly a
    milder and probably underdiagnosed subtype; plantar keratoderma and plantar
    pain are nonetheless near-universal, while fingernail involvement is rare.
    KRT6C is expressed in plantar epidermis, consistent with the tissue
    restriction of the phenotype.
  genes:
  - preferred_term: KRT6C
    term:
      id: hgnc:20406
      label: KRT6C
  review_notes: >-
    ONTOLOGY GAP: MONDO has no term for the KRT6C-caused subtype. The four
    numbered MONDO children of MONDO:0016471 cover KRT16 (MONDO:0008173),
    KRT17 (MONDO:0008174), KRT6A (MONDO:0014324) and KRT6B (MONDO:0014325)
    only, so subtype_term is deliberately left unbound here rather than forced
    onto a near-miss term. Note also that two obsolete MONDO classes exist in
    this area — MONDO:0000325 (obsolete pachyonychia congenita) and
    MONDO:0009827 (obsolete pachyonychia congenita, autosomal recessive) — and
    must never be used.
  evidence:
  - reference: PMID:19609311
    reference_title: "Keratin K6c mutations cause focal palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutational analysis of the recently identified KRT6C gene, encoding keratin K6c, showed heterozygous in-frame deletion mutations in all three kindreds"
    explanation: >-
      The report that established KRT6C as the fifth PC/focal-PPK keratin gene,
      by in-frame deletion in three unrelated kindreds.
  - reference: PMID:19609311
    reference_title: "Keratin K6c mutations cause focal palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report three unrelated families who presented with familial FPPK with minor or absent nail changes."
    explanation: >-
      Documents the nail-sparing, keratoderma-predominant presentation that
      distinguishes the KRT6C subtype.
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17)."
    explanation: >-
      Confirms KRT6C as one of the five accepted causal genes, so the subtype
      is real despite lacking a MONDO identifier.
- name: PC-K16
  display_name: PC-K16 (KRT16; MONDO pachyonychia congenita 1)
  subtype_term:
    preferred_term: PC-K16
    term:
      id: MONDO:0008173
      label: pachyonychia congenita 1
  description: >-
    PC caused by heterozygous KRT16 variants; the second most common subtype
    in most cohorts and the most common in the Israeli population, where a
    founder p.R127H allele predominates. Plantar keratoderma and plantar pain
    are near-universal; oral leukokeratosis, cysts and natal teeth are less
    frequent than in PC-K6a/PC-K17. KRT16 variants can also cause focal
    non-epidermolytic PPK without other PC features.
  genes:
  - preferred_term: KRT16
    term:
      id: hgnc:6423
      label: KRT16
  review_notes: >-
    MONDO labels this class "pachyonychia congenita 1" and attaches the
    Jadassohn-Lewandowsky eponym to it. That is a simplification: historically
    PC-1 spanned KRT6A and KRT16 (and PC-2 spanned KRT6B and KRT17), so the
    eponymous split cuts across the genotypic subtypes used here. The MONDO
    term is bound because its definition is the single-gene (KRT16) criterion,
    not because the eponym is endorsed.
  evidence:
  - reference: PMID:33190296
    reference_title: "Molecular epidemiology of pachyonychia congenita in the Israeli population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to the high prevalence of KRT6A mutations in other populations, we found that KRT16 mutations were the most common type among Israeli patients with PC (56%)."
    explanation: >-
      Documents population-specific enrichment of the KRT16 subtype.
  - reference: PMID:33190296
    reference_title: "Molecular epidemiology of pachyonychia congenita in the Israeli population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (77%) of the Israeli patients with PC with KRT16 mutation carried the same variant (c.380G>A; p.R127H) and shared the same haplotype around the KRT16 locus, suggestive of a founder effect."
    explanation: >-
      Identifies a founder KRT16 allele underlying the subtype's local
      over-representation.
- name: PC-K17
  display_name: PC-K17 (KRT17; MONDO pachyonychia congenita 2)
  subtype_term:
    preferred_term: PC-K17
    term:
      id: MONDO:0008174
      label: pachyonychia congenita 2
  description: >-
    PC caused by heterozygous KRT17 variants. Distinguished by the strong
    clustering of pilosebaceous cysts (including steatocystomas and vellus hair
    cysts) and of natal or prenatal teeth; follicular hyperkeratosis is also
    common. Plantar keratoderma and plantar pain, while still the dominant
    burden, are somewhat less universal than in the KRT6A/KRT16 subtypes. The
    same heterozygous KRT17 variant can present as steatocystoma multiplex in
    other family members.
  genes:
  - preferred_term: KRT17
    term:
      id: hgnc:6427
      label: KRT17
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRT17 mutations were most commonly associated with cysts and natal teeth."
    explanation: >-
      The IPCRR case-cohort study of 815 patients establishes the defining
      KRT17 genotype-phenotype correlation.
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation."
    explanation: >-
      An independent registry cohort replicates the KRT17-cysts/natal-teeth
      association.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: Approximately 30% of cases arise from a de novo pathogenic variant.
  description: >-
    PC is inherited in an autosomal dominant manner. Roughly 70% of patients
    have an affected parent and about 30% represent de novo variants; a single
    case of germline mosaicism has been reported.
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita is inherited in an autosomal dominant manner. Approximately 30% of cases appear to be caused by a de novo pathogenic variant."
    explanation: >-
      GeneReviews states the mode of inheritance and the de novo rate.
  - reference: PMID:21326300
    reference_title: "A large mutational study in pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17."
    explanation: >-
      Confirms the heterozygous (dominant) state of the causal variants in a
      cohort of 90 families. Predates the addition of KRT6C to the gene set.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ULTRA_RARE
  notes: >-
    No numeric population-based prevalence estimate could be verified from a
    quotable abstract; contemporary reviews describe PC as rare and note that
    the true prevalence is probably underestimated because milder subtypes
    (particularly PC-K6c) go undiagnosed. rate_per_100000 is deliberately
    omitted rather than derived from a figure that could not be quoted.
  evidence:
  - reference: PMID:37766547
    reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although classed as rare, the prevalence of PC is likely to be underestimated."
    explanation: >-
      Supports the rare classification while flagging that ascertainment is
      incomplete; it does not supply a numeric rate, hence PARTIAL.
progression:
- phase: Onset
  age_range: First months to first years of life
  notes: >-
    Hypertrophic nail dystrophy is typically the first recognised feature,
    usually in the first year; plantar keratoderma follows once the child
    begins to walk.
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years."
    explanation: >-
      Establishes nail dystrophy and keratoderma as the earliest manifestations
      and preschool age as the usual point of diagnosis.
- phase: Established disease
  age_range: By age 10 years
  notes: >-
    The diagnostic triad of toenail thickening, plantar keratoderma and plantar
    pain is present in nearly all patients by the end of the first decade.
  evidence:
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years"
    explanation: >-
      Quantifies completion of the diagnostic triad within the first decade.
- phase: Chronic
  age_range: Adolescence to adulthood
  notes: >-
    Lifelong disease without effect on lifespan. Chronic plantar pain becomes
    the dominant disability, frequently requiring walking aids and imposing
    occupational and psychosocial costs.
  evidence:
  - reference: PMID:31021398
    reference_title: "Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PC dramatically impacts quality of life although it does not affect lifespan."
    explanation: >-
      Characterises the chronic, non-lethal but highly disabling natural
      history.
pathophysiology:
- name: Dominant-Negative Keratin Variant
  conforms_to: "keratin_intermediate_filament_fragility#Dominant-Negative Keratin Variant in a Filament Assembly Domain"
  biological_scale: MOLECULAR
  description: >-
    A heterozygous variant — usually a missense change or a small in-frame
    insertion/deletion within one of the helix boundary (helix initiation or
    helix termination) motifs — in KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These
    motifs are the regions of the keratin polypeptide most critical for
    filament assembly, so the mutant protein acts in a dominant-negative
    fashion on the network built by the wild-type allele. The five genes encode
    the wound- and stress-inducible keratins whose expression domain (palmar
    and plantar epidermis, nail bed, oral mucosa, pilosebaceous unit) predicts
    the tissue distribution of disease.
  genes:
  - preferred_term: KRT6A
    term:
      id: hgnc:6443
      label: KRT6A
  - preferred_term: KRT6B
    term:
      id: hgnc:6444
      label: KRT6B
  - preferred_term: KRT6C
    term:
      id: hgnc:20406
      label: KRT6C
  - preferred_term: KRT16
    term:
      id: hgnc:6423
      label: KRT16
  - preferred_term: KRT17
    term:
      id: hgnc:6427
      label: KRT17
  evidence:
  - reference: PMID:21326300
    reference_title: "A large mutational study in pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide."
    explanation: >-
      Establishes the mutation class and its clustering in the assembly-critical
      helix boundary motifs across 90 PC families.
  - reference: PMID:19609311
    reference_title: "Keratin K6c mutations cause focal palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16, or KRT17, cause pachyonychia congenita (PC), characterized by hypertrophic nail dystrophy and other ectodermal features."
    explanation: >-
      States the dominant-negative mechanism explicitly for the PC keratin
      genes.
  downstream:
  - target: Keratin Intermediate Filament Network Disruption
    causal_link_type: DIRECT
    description: >-
      Mutant keratin is co-expressed with wild-type keratin and incorporated
      into the same filament population, poisoning assembly.
    evidence:
    - reference: PMID:17914454
      reference_title: "Single-nucleotide-specific siRNA targeting in a dominant-negative skin model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "As predicted for a dominant-negative disease, simultaneous expression of both wild-type and mutant K6a resulted in defective keratin filament formation. Addition of mutant-specific siRNAs allowed normal filament formation, suggesting selective inhibition of mutant K6a."
      explanation: >-
        Directly demonstrates that co-expression of mutant and wild-type K6a is
        what defeats filament formation, and that removing the mutant transcript
        restores it — the definition of a dominant-negative edge.
- name: Keratin Intermediate Filament Network Disruption
  conforms_to: "keratin_intermediate_filament_fragility#Keratin Filament Network Collapse and Aggregation"
  biological_scale: MOLECULAR
  description: >-
    Keratin intermediate filaments are obligate heteropolymers of one type I
    and one type II keratin (K16/K17 with K6a/K6b/K6c in PC-relevant tissues).
    Mutant subunits assemble into aggregates instead of an extended filament
    network. This has been reproduced directly for the recurrent KRT6A N171K
    substitution and the N171del in-frame deletion in transfected cells, where
    fluorescent keratin reporters form aggregates rather than normal filaments.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratin intermediate filament assembly
    term:
      id: GO:0045109
      label: intermediate filament organization
    modifier: ABNORMAL
  - preferred_term: intermediate filament cytoskeleton organization
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:17145926
    reference_title: "SiRNA-mediated selective inhibition of mutant keratin mRNAs responsible for the skin disorder pachyonychia congenita."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Similar constructs containing a single nucleotide change (N171K) or a three-nucleotide deletion (N171del) showed keratin aggregate formation."
    explanation: >-
      Directly demonstrates that PC-causing KRT6A alleles produce keratin
      aggregates rather than a normal filament network.
  - reference: PMID:17145926
    reference_title: "SiRNA-mediated selective inhibition of mutant keratin mRNAs responsible for the skin disorder pachyonychia congenita."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection experiments of a fusion gene consisting of K6a and a yellow fluorescent reporter (YFP) resulted in normal keratin filament formation in transfected cells as assayed by fluorescence microscopy."
    explanation: >-
      Provides the wild-type control against which the mutant aggregation
      phenotype is read.
  downstream:
  - target: Loss of Keratinocyte Mechanical Resilience
    causal_link_type: DIRECT
    description: >-
      A defective keratin filament network leaves the palmoplantar keratinocyte
      unable to bear the mechanical load of weight-bearing skin.
  - target: Defective Terminal Differentiation of Volar Keratinocytes
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of K16-dependent regulation of the volar keratinocyte differentiation
      programme, with downregulation of KRT9.
    description: >-
      Beyond its structural role, K16 is required for the normal terminal
      differentiation programme of volar keratinocytes; its loss or disruption
      derails that programme ahead of any lesion.
- name: Loss of Keratinocyte Mechanical Resilience
  conforms_to: "keratin_intermediate_filament_fragility#Loss of Keratinocyte Mechanical Resilience"
  biological_scale: CELLULAR
  description: >-
    Palmoplantar keratinocytes carrying a disrupted keratin network tolerate
    friction, pressure and shear poorly, so lesions form precisely at
    weight-bearing pressure points. Importantly, and unlike the KRT1/KRT10 and
    KRT9 keratinopathies, PC-associated keratoderma is non-epidermolytic:
    frank cytolysis of the differentiating epidermis is not the histological
    hallmark, and the mechanism is better described as reduced mechanical
    resilience plus derailed stress signalling than as simple cell lysis.
    Blistering can occur beneath the callus but is not the defining lesion.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: skin of sole of pes
    term:
      id: UBERON:0013778
      label: skin of sole of pes
  - preferred_term: nail bed
    term:
      id: UBERON:0005273
      label: nail bed
  mechanism_confidence: PROVISIONAL
  notes: >-
    The non-epidermolytic character of PC keratoderma is why this node is kept
    distinct from the downstream hyperproliferation/barrier node, following the
    node structure used in KRT1_Keratinopathies.yaml and the point raised in
    dismech#3401 that keratin network collapse and downstream hyperproliferation
    are separate mechanistic claims.
  evidence:
  - reference: PMID:37766547
    reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17."
    explanation: >-
      Supports the genetic basis of the keratinocyte defect; the review does not
      quantify mechanical resilience directly, hence PARTIAL.
  - reference: PMID:22336941
    reference_title: "Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk"
    explanation: >-
      Shows that loss of the K16 filament subunit alone is sufficient to
      produce weight-bearing-site callus and impaired ambulation in vivo.
  downstream:
  - target: Compensatory Epidermal Hyperproliferation and Barrier Dysregulation
    causal_link_type: DIRECT
    description: >-
      Chronic mechanical stress at pressure points drives a compensatory
      hyperproliferative and barrier-repair response.
  - target: Plantar Nociceptive and Neuropathic Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Tissue-level injury at weight-bearing sites is one hypothesised
      contributor to plantar pain, but the pain is not proportional to callus
      extent, so the intermediates are not established.
- name: Defective Terminal Differentiation of Volar Keratinocytes
  biological_scale: CELLULAR
  description: >-
    Ahead of any visible lesion, palmoplantar keratinocytes show pleiotropic
    defects in terminal differentiation, most conspicuously loss of KRT9 — the
    keratin most robustly expressed in differentiating volar keratinocytes.
    This is an early driver of the keratoderma rather than a consequence of it,
    and is the basis for proposing restoration of KRT9 expression as a
    therapeutic target.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31220272
    reference_title: "Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation."
    explanation: >-
      Establishes defective terminal differentiation with KRT9 loss as an early,
      pre-lesional event in the leading PC model.
  - reference: PMID:31021398
    reference_title: "Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression."
    explanation: >-
      A review of the Krt16-null model places differentiation failure first in
      the three-stage progression of PC-like keratoderma.
  downstream:
  - target: Oxidative Stress and Hypoactive Keap1-NRF2 Signalling
    causal_link_type: DIRECT
    description: >-
      In the Krt16-null model, differentiation failure precedes and is followed
      by oxidative stress at the time of lesion onset.
- name: Oxidative Stress and Hypoactive Keap1-NRF2 Signalling
  biological_scale: CELLULAR
  description: >-
    At the time of keratoderma onset, palmoplantar keratinocytes show elevated
    oxidative stress with an inability to sustain NRF2-dependent synthesis of
    glutathione. High levels of hypophosphorylated (hypoactive) NRF2 have been
    confirmed in lesional plantar skin biopsies from people with PC, not just
    in the mouse model. Genetic ablation of Nrf2 accelerates keratoderma in
    Krt16-null mice, and topical NRF2 activation prevents it — making this a
    causal node rather than a correlate.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27183391
    reference_title: "Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH)."
    explanation: >-
      Establishes oxidative stress and failed NRF2-dependent glutathione
      synthesis as preceding lesion onset in the model.
  - reference: PMID:27183391
    reference_title: "Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue."
    explanation: >-
      Confirms the NRF2 abnormality in human PC lesional skin, so the node is
      not mouse-only.
  downstream:
  - target: Compensatory Epidermal Hyperproliferation and Barrier Dysregulation
    causal_link_type: DIRECT
    description: >-
      Redox imbalance in volar keratinocytes drives the lesional
      hyperproliferative and barrier-alarmin response.
- name: Compensatory Epidermal Hyperproliferation and Barrier Dysregulation
  conforms_to: "epidermal_cornification_failure#Compensatory Epidermal Hyperproliferation and Retention Hyperkeratosis"
  biological_scale: TISSUE
  description: >-
    The lesional response to the preceding cellular defects: marked keratinocyte
    hyperproliferation and epidermal thickening, gross upregulation of
    danger-associated molecular patterns (alarmins) and skin-barrier regulators,
    and a profound loss of the epidermis's ability to return to homeostasis.
    In PC lesional skin this includes overactive EGFR signalling (epiregulin,
    TGF-alpha, HER1-EGFR and HER2 in the upper spinous layers) with downstream
    MAPK/ERK and mTOR activation, and increased TRPV3 — the rationale for the
    EGFR-inhibitor and mTOR-inhibitor treatment strategies.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  - preferred_term: epidermis development
    term:
      id: GO:0008544
      label: epidermis development
    modifier: ABNORMAL
  locations:
  - preferred_term: skin of sole of pes
    term:
      id: UBERON:0013778
      label: skin of sole of pes
  evidence:
  - reference: PMID:27183391
    reference_title: "Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators."
    explanation: >-
      Characterises the PC lesion by alarmin and barrier-gene upregulation.
  - reference: PMID:36116508
    reference_title: "EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling."
    explanation: >-
      Demonstrates overactive EGFR-MAPK/mTOR signalling in human PC lesional
      epidermis.
  - reference: PMID:31021398
    reference_title: "Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis."
    explanation: >-
      Describes the failure of epidermal homeostasis that sustains the
      established lesion.
  downstream:
  - target: Focal Palmoplantar Keratoderma
    causal_link_type: DIRECT
    description: >-
      Hyperproliferation and abnormal cornification at pressure points produce
      the focal callus.
  - target: Hypertrophic Nail Dystrophy
    causal_link_type: DIRECT
    description: >-
      The same process in the nail bed produces distal subungual hyperkeratosis
      and nail thickening.
  - target: Plantar Nociceptive and Neuropathic Pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased TRPV3 and EGFR-ligand signalling in lesional epidermis, coupled
      to sensory nerve endings.
    description: >-
      Lesional signalling changes (TRPV3, EGFR ligands) plausibly sensitise
      cutaneous sensory afferents; EGFR inhibition reduces neuropathic pain.
    evidence:
    - reference: PMID:36116508
      reference_title: "EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition, the calcium ion permeable channel TRPV3 was significantly increased in PC-lesional skin, suggesting a predominant role of the TRPV3/EGFR signaling complex in PC."
      explanation: >-
        Links a lesional epidermal signalling change to the pain phenotype;
        PARTIAL because the causal chain from TRPV3/EGFR to nociception is
        inferred, not demonstrated, in this study.
- name: Plantar Nociceptive and Neuropathic Pain
  biological_scale: ORGANISM
  description: >-
    Chronic, moderate-to-severe plantar pain, throbbing and stabbing in
    quality, worst on weight bearing, and the single most disabling feature of
    PC. It is modelled here as its own mechanism node rather than as a severity
    qualifier on the keratoderma for two reasons. First, its magnitude is not
    proportional to the extent of hyperkeratosis. Second, quantitative sensory
    testing in 62 patients versus 45 controls shows a signature that
    hyperkeratosis alone does not explain: mechanical hyperalgesia and static
    allodynia in painful regions, DN4 scores in the neuropathic range in the
    majority, and impaired conditioned pain modulation — i.e. a neuropathic
    component alongside the nociceptive one. Notably the sensory phenotype did
    not differ by causal gene, so pain is a shared final common pathway across
    subtypes rather than a subtype feature.
  biological_processes:
  - preferred_term: sensory perception of pain
    term:
      id: GO:0019233
      label: sensory perception of pain
    modifier: ABNORMAL
  locations:
  - preferred_term: skin of sole of pes
    term:
      id: UBERON:0013778
      label: skin of sole of pes
  evidence:
  - reference: PMID:29210461
    reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing."
    explanation: >-
      Quantifies the prevalence and character of plantar pain in a controlled
      sensory-testing study.
  - reference: PMID:29210461
    reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC."
    explanation: >-
      The authors explicitly separate what thickened skin can explain from what
      it cannot, supporting a neuropathic component distinct from the callus.
  - reference: PMID:29210461
    reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The specific gene and nature of the causative mutation did not affect any of these features."
    explanation: >-
      Supports treating pain as a shared mechanism across all five genotypic
      subtypes rather than a subtype-specific feature.
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function."
    explanation: >-
      Establishes plantar pain as the dominant patient-reported burden in the
      largest PC cohort described.
  downstream:
  - target: Plantar Pain
    causal_link_type: DIRECT
    description: >-
      The mechanism node surfaces clinically as the reported plantar pain
      phenotype and its mobility consequences.
- name: Focal Palmoplantar Keratoderma
  biological_scale: TISSUE
  description: >-
    Focal, non-epidermolytic hyperkeratotic calluses at plantar (and often
    palmar) pressure points, with marked hyperkeratosis and epidermal
    thickening. Distribution follows mechanical loading rather than being
    diffuse, which distinguishes PC keratoderma from the diffuse epidermolytic
    keratodermas.
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: INCREASED
  locations:
  - preferred_term: skin of sole of pes
    term:
      id: UBERON:0013778
      label: skin of sole of pes
  evidence:
  - reference: PMID:19609311
    reference_title: "Keratin K6c mutations cause focal palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In PC, focal PPK (FPPK) is the most painful and debilitating phenotypic feature."
    explanation: >-
      Establishes the focal (not diffuse) character of PC keratoderma and its
      clinical primacy.
  downstream:
  - target: Focal Palmoplantar Keratoderma Phenotype
    causal_link_type: DIRECT
    description: The tissue lesion presenting as the clinical keratoderma.
- name: Hypertrophic Nail Dystrophy
  biological_scale: TISSUE
  description: >-
    Hyperkeratosis of the nail bed producing thickened, discoloured nails that
    either grow to full length with an upward distal slant or terminate in a
    sloping wedge of subungual hyperkeratosis with an exposed distal fingertip.
    Usually the first recognised sign of PC, appearing in the first months to
    first year of life.
  locations:
  - preferred_term: nail bed
    term:
      id: UBERON:0005273
      label: nail bed
  - preferred_term: nail
    term:
      id: UBERON:0001705
      label: nail
  evidence:
  - reference: PMID:21326300
    reference_title: "A large mutational study in pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma."
    explanation: >-
      Confirms nail dystrophy as a cardinal, defining feature.
  downstream:
  - target: Hypertrophic Nail Dystrophy Phenotype
    causal_link_type: DIRECT
    description: The tissue lesion presenting as the clinical nail phenotype.
phenotypes:
- category: Dermatologic
  name: Focal Palmoplantar Keratoderma Phenotype
  description: >-
    Focal, non-epidermolytic palmoplantar keratoderma with calluses at
    weight-bearing pressure points. Present in nearly all patients; plantar
    involvement exceeds palmar involvement in every subtype.
  phenotype_term:
    preferred_term: Focal nonepidermolytic palmoplantar keratoderma
    term:
      id: HP:0007404
      label: Nonepidermolytic palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:37766547
    reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy."
    explanation: >-
      Establishes focal palmoplantar keratoderma as one of the three defining
      features.
  - reference: PMID:33190296
    reference_title: "Molecular epidemiology of pachyonychia congenita in the Israeli population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common clinical findings were painful focal plantar keratoderma (94%) accompanied by nail dystrophy (81%), pilosebaceous cysts (31%) and prenatal/natal teeth (13%)."
    explanation: >-
      Quantifies focal plantar keratoderma as the most frequent finding in an
      independent molecularly confirmed cohort.
- category: Neurologic
  name: Plantar Pain
  description: >-
    Chronic, severe plantar pain, worst on weight bearing, frequently requiring
    walking aids and often carrying neuropathic features (allodynia, tingling,
    mechanical hyperalgesia). The dominant determinant of quality of life in
    PC, and — importantly for modelling — not proportional to the extent of
    keratoderma.
  phenotype_term:
    preferred_term: Plantar pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function."
    explanation: >-
      Identifies plantar pain as the principal patient-reported burden in the
      largest genetically confirmed PC cohort.
  - reference: PMID:29210461
    reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet."
    explanation: >-
      Quantifies the neuropathic sensory features accompanying the pain.
  - reference: PMID:38805703
    reference_title: "Pachyonychia congenita: pathogenesis of pain and approaches to treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma and hypertrophic nail dystrophy."
    explanation: >-
      A dedicated review of PC pain places chronic severe plantar pain in the
      defining triad, alongside — not subordinate to — the keratoderma.
- category: Dermatologic
  name: Hypertrophic Nail Dystrophy Phenotype
  description: >-
    Thickened, dystrophic nails with distal subungual hyperkeratosis, usually
    the earliest recognised feature. Toenail involvement is near-universal
    across subtypes; fingernail involvement is far more frequent in PC-K6a and
    PC-K17 than in PC-K6c.
  phenotype_term:
    preferred_term: Hypertrophic nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:37766547
    reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy."
    explanation: >-
      Establishes hypertrophic nail dystrophy as one of the three defining
      features.
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities."
    explanation: >-
      The GeneReviews clinical characteristics statement lists hypertrophic nail
      dystrophy first among PC features.
- category: Dermatologic
  name: Thickened Nails
  description: >-
    Onychauxis — gross thickening of the nail plate — as the visible expression
    of nail bed hyperkeratosis. Recorded separately from the broader nail
    dystrophy phenotype because thickening rather than deformity is what gives
    the disease its name.
  phenotype_term:
    preferred_term: Onychauxis
    term:
      id: HP:0012542
      label: Onychauxis
  evidence:
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years"
    explanation: >-
      Explicitly reports toenail thickening (rather than dystrophy in general)
      as part of the diagnostic triad.
- category: Oral
  name: Oral Leukokeratosis
  description: >-
    Thickened white plaques on the tongue and buccal mucosa. Most prominent in
    PC-K6a, where it may extend to the laryngeal surfaces and cause hoarseness
    or, rarely, infantile airway obstruction. Frequently misdiagnosed as oral
    candidiasis in infants and may interfere with feeding.
  phenotype_term:
    preferred_term: Oral leukokeratosis
    term:
      id: HP:0002745
      label: Oral leukoplakia
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts."
    explanation: >-
      Lists oral leukokeratosis among the main clinical features of PC.
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations"
    explanation: >-
      Supports the subtype gradient, with KRT6A carriers most affected.
- category: Dermatologic
  name: Pilosebaceous Cysts
  description: >-
    Vellus hair cysts and steatocystomas, seen in all subtypes but strongly
    clustered in PC-K17, where they are near-universal. The same heterozygous
    KRT17 variant can present as steatocystoma multiplex in relatives with
    little or no keratoderma.
  subtype: PC-K17
  phenotype_term:
    preferred_term: Steatocystoma multiplex
    term:
      id: HP:0012035
      label: Steatocystoma multiplex
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRT17 mutations were most commonly associated with cysts and natal teeth."
    explanation: >-
      Establishes cyst clustering with the KRT17 genotype.
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pilosebaceous cysts (including steatocystoma and vellus hair cysts)"
    explanation: >-
      GeneReviews specifies the cyst types seen in PC.
- category: Dental
  name: Natal Teeth
  description: >-
    Teeth present at or shortly after birth, strongly associated with KRT17
    variants. Subsequent primary and secondary dentition is normal. Natal teeth
    predict earlier toenail involvement, walking difficulties and cyst
    formation.
  subtype: PC-K17
  phenotype_term:
    preferred_term: Natal tooth
    term:
      id: HP:0000695
      label: Natal tooth
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation."
    explanation: >-
      Establishes natal teeth as a prognostic marker within PC as well as a
      KRT17-associated feature.
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a strong association of natal teeth and cysts in carriers of a KRT17 mutation"
    explanation: >-
      Replicates the KRT17-natal teeth association in an independent cohort.
- category: Dermatologic
  name: Follicular Hyperkeratosis
  description: >-
    Keratotic follicular papules, most often on the elbows, knees and trunk;
    worst in childhood and adolescence and tending to improve in adulthood.
  phenotype_term:
    preferred_term: Follicular hyperkeratosis
    term:
      id: HP:0007502
      label: Follicular hyperkeratosis
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "follicular keratoses on the trunk and extremities"
    explanation: >-
      GeneReviews lists follicular keratoses of trunk and extremities among the
      clinical characteristics.
  - reference: PMID:37766547
    reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures."
    explanation: >-
      A recent review enumerates follicular hyperkeratosis among the additional
      PC features.
- category: Dermatologic
  name: Palmoplantar Hyperhidrosis
  description: >-
    Excessive palmoplantar sweating, which accompanies the keratoderma and is
    thought to contribute to maceration, blistering under the callus and pain
    — the rationale for the botulinum toxin and wicking-sock strategies.
  phenotype_term:
    preferred_term: Palmoplantar hyperhidrosis
    term:
      id: HP:0007410
      label: Palmoplantar hyperhidrosis
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities."
    explanation: >-
      GeneReviews lists palmoplantar hyperhidrosis among the defining clinical
      characteristics of PC. The quoted sentence preserves the source's
      spelling ("hyperhydrosis").
- category: Respiratory
  name: Hoarseness
  description: >-
    Hoarse voice from laryngeal leukokeratosis, most often in PC-K6a. Large
    laryngeal lesions can rarely cause life-threatening airway obstruction in
    infants, and laryngeal surgery may paradoxically worsen the condition.
  subtype: PC-K6a
  phenotype_term:
    preferred_term: Hoarseness
    term:
      id: HP:0001609
      label: Hoarse voice
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids."
    explanation: >-
      Establishes hoarseness as a KRT6A-associated feature.
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hoarseness was correlated with an increased number of involved fingernails."
    explanation: >-
      Places hoarseness within the correlated cluster of severe-disease
      features.
genetic:
- name: KRT6A
  gene_term:
    preferred_term: KRT6A
    term:
      id: hgnc:6443
      label: KRT6A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: PC-K6a
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Type II keratin. Heterozygous missense and small in-frame indel variants,
    predominantly in the helix boundary motifs; the recurrent N171K substitution
    and N171del deletion in the helix initiation motif are the alleles used in
    the mutant-specific siRNA (TD101) work. The most common PC gene in most
    cohorts.
  case_fractions:
  - population: 90 PC kindreds ascertained for a large mutational study
    case_fraction_percent: 52.0
    cohort_size: 90
    notes: Proportion of kindreds with a KRT6A variant.
    evidence:
    - reference: PMID:21326300
      reference_title: "A large mutational study in pachyonychia congenita."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B."
      explanation: Reports the KRT6A share of families in this cohort.
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17)."
    explanation: Confirms KRT6A as one of the five causal genes.
  - reference: PMID:17914454
    reference_title: "Single-nucleotide-specific siRNA targeting in a dominant-negative skin model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Targeting the single-nucleotide keratin 6a (K6a) N171K mutation responsible for the rare monogenic skin disorder pachyonychia congenita (PC), we demonstrate that small interfering RNAs (siRNAs) can potently and selectively block expression of mutant K6a."
    explanation: >-
      Names the recurrent KRT6A N171K allele and confirms its causal role.
- name: KRT6B
  gene_term:
    preferred_term: KRT6B
    term:
      id: hgnc:6444
      label: KRT6B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: PC-K6b
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Type II keratin, paralogous to KRT6A. The least frequently implicated of
    the four originally identified PC keratin genes.
  case_fractions:
  - population: 90 PC kindreds ascertained for a large mutational study
    case_fraction_percent: 3.0
    cohort_size: 90
    notes: Proportion of kindreds with a KRT6B variant.
    evidence:
    - reference: PMID:21326300
      reference_title: "A large mutational study in pachyonychia congenita."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "3% of families had mutations in KRT6B"
      explanation: Reports the KRT6B share of families in this cohort.
  evidence:
  - reference: PMID:21326300
    reference_title: "A large mutational study in pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis."
    explanation: Confirms KRT6B as a causal gene in molecularly confirmed families.
- name: KRT6C
  gene_term:
    preferred_term: KRT6C
    term:
      id: hgnc:20406
      label: KRT6C
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: PC-K6c
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Type II keratin, the last of the five PC genes to be identified. Reported
    variants are heterozygous in-frame deletions (p.Asn172del,
    p.Ile462-Glu470del). Expressed in plantar epidermis, consistent with a
    keratoderma-predominant, nail-sparing presentation.
  evidence:
  - reference: PMID:19609311
    reference_title: "Keratin K6c mutations cause focal palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected members of Families 1 and 2 carried the same mutation, p.Asn172del. In Family 3, the mutation p.Ile462-Glu470del co-segregated with the disease."
    explanation: >-
      Reports the specific KRT6C alleles and their co-segregation with disease.
  - reference: PMID:19609311
    reference_title: "Keratin K6c mutations cause focal palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRT6C was shown to be expressed in the plantar epidermis using reverse transcription-PCR, consistent with the phenotype observed in this tissue."
    explanation: >-
      Links the gene's expression domain to the tissue restriction of the
      phenotype.
- name: KRT16
  gene_term:
    preferred_term: KRT16
    term:
      id: hgnc:6423
      label: KRT16
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: PC-K16
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Type I keratin, the obligate partner of K6a/K6b/K6c. Constitutively
    expressed in ectoderm-derived appendages and palmar/plantar epidermis and
    robustly induced by chemical, mechanical or environmental stress. Allelic
    with focal non-epidermolytic PPK. A founder p.R127H allele accounts for
    most Israeli PC-K16 cases.
  case_fractions:
  - population: 90 PC kindreds ascertained for a large mutational study
    case_fraction_percent: 28.0
    cohort_size: 90
    notes: Proportion of kindreds with a KRT16 variant.
    evidence:
    - reference: PMID:21326300
      reference_title: "A large mutational study in pachyonychia congenita."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "28% had mutations in KRT16"
      explanation: Reports the KRT16 share of families in this cohort.
  - population: Israeli PC families
    case_fraction_percent: 56.0
    cohort_size: 16
    notes: >-
      Population-specific enrichment relative to other cohorts, attributed to a
      founder p.R127H allele.
    evidence:
    - reference: PMID:33190296
      reference_title: "Molecular epidemiology of pachyonychia congenita in the Israeli population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we found that KRT16 mutations were the most common type among Israeli patients with PC (56%)"
      explanation: Reports the KRT16 share of cases in the Israeli cohort.
  evidence:
  - reference: PMID:31220272
    reference_title: "Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin."
    explanation: >-
      Confirms KRT16 causality and its allelic relationship to isolated focal
      non-epidermolytic PPK.
- name: KRT17
  gene_term:
    preferred_term: KRT17
    term:
      id: hgnc:6427
      label: KRT17
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: PC-K17
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Type I keratin, highly expressed in sebaceous glands and hair follicles as
    well as nail bed — the basis for the cyst-predominant PC-K17 phenotype.
    Allelic with steatocystoma multiplex, which can occur in relatives carrying
    the same variant.
  case_fractions:
  - population: 90 PC kindreds ascertained for a large mutational study
    case_fraction_percent: 17.0
    cohort_size: 90
    notes: Proportion of kindreds with a KRT17 variant.
    evidence:
    - reference: PMID:21326300
      reference_title: "A large mutational study in pachyonychia congenita."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B."
      explanation: >-
        Reports the KRT17 share of families in this cohort (17%) alongside the
        other keratin genes, which is what fixes the denominator.
  evidence:
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRT17 mutations were most commonly associated with cysts and natal teeth."
    explanation: >-
      Establishes the KRT17 genotype-phenotype correlation.
treatments:
- name: Mechanical Callus Debridement and Friction Reduction
  description: >-
    The mainstay of care: paring, filing, grinding or clipping the plantar
    callus, together with lifestyle measures that reduce friction and trauma
    (comfortable footwear and orthotics, wicking socks and ventilated footwear,
    limiting standing and walking, maintaining ideal body weight, walking aids
    when needed). Benefit is variable and over-trimming can paradoxically
    worsen plantar pain, so paring frequency is set by patient preference.
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Focal Palmoplantar Keratoderma
    treatment_effect: INHIBITS
    description: >-
      Physical removal of hyperkeratotic material and reduction of the
      mechanical stimulus that drives it.
    evidence:
    - reference: PMID:20301457
      reference_title: "Pachyonychia Congenita."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Foot care includes paring down of hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics)."
      explanation: GeneReviews specifies debridement of the hyperkeratosis.
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pain from the palmoplantar keratoderma may be reduced somewhat by limiting friction and trauma to the feet by minimizing walking or standing, reducing hydration of the stratum corneum by using wicking socks and ventilated footwear, selecting comfortable shoes, and maintaining ideal body weight."
    explanation: >-
      GeneReviews describes the friction- and trauma-reduction strategy and is
      explicit that the benefit is only partial.
  - reference: PMID:37766547
    reference_title: "Pachyonychia Congenita: Clinical Features and Future Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection."
    explanation: >-
      Establishes that conservative and mechanical measures remain the standard
      of care, and that no disease-specific therapy is approved.
- name: Topical Keratolytics and Emollients
  description: >-
    Emollients with keratolytic agents (urea 40%, salicylic acid 10-20%, lactic
    acid) applied to the callus to soften and thin hyperkeratotic skin.
    Symptomatic only, with variable benefit.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: urea
      term:
        id: CHEBI:16199
        label: urea
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Focal Palmoplantar Keratoderma
    treatment_effect: INHIBITS
    description: Keratolysis of the accumulated stratum corneum.
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foot care includes paring down of hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics)."
    explanation: >-
      GeneReviews recommends keratolytic-containing topical therapy as part of
      routine foot care.
- name: Systemic Retinoids
  description: >-
    Oral retinoids (acitretin, isotretinoin) thin the hyperkeratosis but
    frequently increase blistering and plantar pain, leading many patients to
    discontinue. Acitretin is highly teratogenic with a three-year washout, so
    it is often inappropriate for women of childbearing potential. Benefit is
    limited to a small subgroup.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Compensatory Epidermal Hyperproliferation and Barrier Dysregulation
    treatment_effect: INHIBITS
    description: >-
      Retinoid modulation of keratinocyte proliferation and differentiation
      reduces hyperkeratosis, at the cost of increased fragility.
  evidence:
  - reference: PMID:38805703
    reference_title: "Pachyonychia congenita: pathogenesis of pain and approaches to treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current therapeutic options for pain in PC are limited to lifestyle adjustment and mechanical techniques, with a small subgroup of patients benefiting from oral retinoids."
    explanation: >-
      Supports a real but narrow role for oral retinoids; PARTIAL because the
      review explicitly restricts the benefit to a small subgroup.
- name: Neuropathic Pain Pharmacotherapy
  description: >-
    Simple analgesia plus neuropathic agents (amitriptyline, gabapentin,
    pregabalin) used by some patients, with specialist pain input in severe
    cases. The rationale is the demonstrated neuropathic component of PC
    plantar pain rather than any effect on the keratoderma — which is precisely
    why plantar pain is modelled as its own mechanism node here.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Plantar Nociceptive and Neuropathic Pain
    treatment_effect: INHIBITS
    description: >-
      Targets the neuropathic component of the pain directly, independently of
      callus thickness.
    evidence:
    - reference: PMID:29210461
      reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC."
      explanation: >-
        The sensory-testing study's own therapeutic inference: neuropathic pain
        medication is indicated by the neuropathic phenotype.
  evidence:
  - reference: PMID:29210461
    reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy."
    explanation: >-
      Supports the rationale; PARTIAL because no controlled trial of neuropathic
      agents in PC is cited.
- name: TD101 Mutation-Specific siRNA
  description: >-
    TD101 (K6a_513a.12) is an allele-specific small interfering RNA designed to
    silence the KRT6A N171K mutant transcript while sparing wild-type K6a
    mRNA — the therapeutic embodiment of the dominant-negative mechanism. It
    was tested by intradermal injection into plantar calluses in a 17-week,
    prospective, double-blind, split-body (opposite feet), vehicle-controlled,
    dose-escalation phase Ib trial. IMPORTANT EVIDENCE CAVEAT: that trial
    enrolled a SINGLE PATIENT (n = 1). Callus regression was reported on the
    siRNA-treated foot only and no adverse events occurred, and the study is
    historically notable as the first clinical use of siRNA in human skin and
    the first targeting a dominant-negative mutant allele — but it is an n-of-1
    observation and must not be read as established efficacy. The authors
    themselves framed the result as warranting further study. Development did
    not proceed to a larger trial, in part because intradermal needle
    administration to PC lesions is intensely painful.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SIRNA
  target_mechanisms:
  - target: Keratin Intermediate Filament Network Disruption
    treatment_effect: INHIBITS
    description: >-
      Selective degradation of the mutant K6a transcript removes the
      dominant-negative subunit from the filament pool, permitting normal
      keratin filament formation from the wild-type allele. Demonstrated in
      cell culture; the human evidence is a single-patient trial.
    evidence:
    - reference: PMID:17914454
      reference_title: "Single-nucleotide-specific siRNA targeting in a dominant-negative skin model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Addition of mutant-specific siRNAs allowed normal filament formation, suggesting selective inhibition of mutant K6a."
      explanation: >-
        Directly demonstrates that the siRNA acts on this mechanism node by
        restoring filament assembly in a dominant-negative cell model.
    - reference: PMID:19935778
      reference_title: "First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA."
      explanation: >-
        Establishes the allele-selective target of the agent in the clinical
        formulation.
  evidence:
  - reference: PMID:19935778
    reference_title: "First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial."
    explanation: >-
      The design statement itself is the caveat: n = 1. Recorded as PARTIAL
      because a single-patient split-body observation cannot establish efficacy,
      however well controlled within that patient.
  - reference: PMID:19935778
    reference_title: "First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot."
    explanation: >-
      Reports the observed effect, in the single treated patient, with the
      contralateral vehicle-treated foot as the internal control.
  - reference: PMID:19935778
    reference_title: "First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin."
    explanation: >-
      Supports the historical significance claim, which is separable from — and
      does not imply — a claim about efficacy.
  - reference: PMID:21248764
    reference_title: "Use of self-delivery siRNAs to inhibit gene expression in an organotypic pachyonychia congenita model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Unfortunately, the intense pain associated with hypodermic needle administration to PC lesions precludes this as a viable delivery option for this disorder."
    explanation: >-
      Documents the delivery barrier that stopped intradermal TD101 from
      progressing, and motivated self-delivery siRNA chemistry.
  notes: >-
    TD101 is the canonical dismech example of an allele-specific silencing
    therapy anchored to a dominant-negative mechanism node. Its evidence base is
    deliberately recorded as PARTIAL: the human data are a single-patient trial
    (PMID:19935778), supported by IN_VITRO allele-selectivity data
    (PMID:17914454, PMID:17145926, PMID:21248764) and by molecular endpoint
    development (PMID:21191405).
- name: Topical Rapamycin (Sirolimus)
  description: >-
    Topical mTOR inhibition, rationalised by the demonstrated
    EGFR-MAPK/ERK-mTOR overactivity in PC lesional epidermis and by reports
    that sirolimus selectively reduces KRT6A expression. Oral sirolimus
    improved keratoderma in an off-label series but had intolerable systemic
    effects, motivating the topical route. A multicentre phase 3
    vehicle-controlled trial of QTORIN 3.9% rapamycin anhydrous gel is under
    way; efficacy is not yet established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Compensatory Epidermal Hyperproliferation and Barrier Dysregulation
    treatment_effect: INHIBITS
    description: >-
      mTOR inhibition downstream of the overactive EGFR-MAPK/ERK axis in
      lesional epidermis.
    evidence:
    - reference: PMID:36116508
      reference_title: "EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling."
      explanation: >-
        Establishes mTOR activation in PC lesions as the target rationale;
        PARTIAL because this study tested EGFR inhibition, not rapamycin.
  evidence:
  - reference: clinicaltrials:NCT05180708
    reference_title: "A Multicenter, Phase 3 Randomized, Double-Blind, Vehicle-controlled Study Evaluating the Safety and Efficacy of QTORIN 3.9% Rapamycin Anhydrous Gel in the Treatment of Pachyonychia Congenita"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study evaluates the safety and efficacy of QTORIN 3.9% rapamycin anhydrous gel in the treatment of adults with Pachyonychia Congenita."
    explanation: >-
      A registered phase 3 trial establishes that topical rapamycin is under
      formal evaluation in PC; PARTIAL because the registry record reports the
      design, not a result.
- name: Oral EGFR Inhibition (Erlotinib)
  description: >-
    Oral erlotinib, given for 6-8 months to three patients with PC on the basis
    of demonstrated EGFR pathway overactivity in lesional skin, was well
    tolerated and produced an early, marked and sustained reduction in
    neuropathic pain with major quality-of-life improvement. This is a
    three-patient open series, not a controlled trial, but it is mechanistically
    important because it targets the pain node through the epidermal signalling
    node rather than through callus removal.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Compensatory Epidermal Hyperproliferation and Barrier Dysregulation
    treatment_effect: INHIBITS
    description: >-
      Pharmacological inhibition of the overactive HER1-EGFR signalling
      demonstrated in the upper spinous layers of PC lesions.
    evidence:
    - reference: PMID:36116508
      reference_title: "EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC."
      explanation: >-
        The authors' own statement that EGFR is the actionable target node.
  - target: Plantar Nociceptive and Neuropathic Pain
    treatment_effect: INHIBITS
    description: >-
      Reduction of neuropathic plantar pain reported in the treated patients.
    evidence:
    - reference: PMID:36116508
      reference_title: "EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL."
      explanation: >-
        Reports the pain benefit; PARTIAL because n = 3 in an uncontrolled open
        series.
- name: Oral Statin Therapy
  description: >-
    Off-label oral statins, proposed to downregulate KRT6A expression via
    STAT1. Case reports suggested benefit in KRT6A-associated disease, but a
    subsequent series of six adults with KRT16 or KRT17 variants found no
    significant improvement in plantar calluses or pain, and all patients
    discontinued for insufficient efficacy. Recorded here as a genotype-limited
    strategy with negative evidence outside KRT6A. No `target_mechanisms` link
    is asserted: the only quotable clinical evidence is negative, and the
    TreatmentEffectEnum has no value for "no effect", so claiming an INHIBITS
    edge would overstate the case.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:41100406
    reference_title: "Oral Statin Therapy in KRT16- and KRT17-Associated Palmoplantar Epidermal Differentiation Disorder (Pachyonychia Congenita)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the treatment was well tolerated in most cases, no significant clinical improvement in plantar calluses or pain was observed. All patients discontinued therapy due to insufficient efficacy."
    explanation: >-
      A negative result for oral statins in the KRT16 and KRT17 subtypes.
  - reference: PMID:41100406
    reference_title: "Oral Statin Therapy in KRT16- and KRT17-Associated Palmoplantar Epidermal Differentiation Disorder (Pachyonychia Congenita)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings indicate that oral statin therapy may offer limited benefit in KRT16/KRT17-pEDD-PC and suggest the potential importance of early intervention and genotype-specific therapeutic strategies."
    explanation: >-
      The authors' conclusion, supporting a genotype-specific rather than
      universal role for statins in PC.
- name: Management of Oral Leukokeratosis and Laryngeal Involvement
  description: >-
    Gentle brushing with a soft toothbrush and good oral hygiene improve the
    oral plaques; most resolve without intervention. Infants with leukokeratosis
    may need a soft, enlarged-opening bottle nipple. Laryngeal thickening
    requires ENT review, since rare infantile airway obstruction may need
    emergency surgery — but surgery to the larynx can paradoxically worsen the
    condition.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Oral Leukokeratosis
    treatment_effect: MODULATES
    description: Mechanical and hygiene measures for the oral mucosal plaques.
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Good oral hygiene and brushing gently with a soft toothbrush can improve thick, white patches on the tongue and oral mucosa."
    explanation: GeneReviews management recommendation for oral leukokeratosis.
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rarely, young children with laryngeal thickening/growths need emergency surgery to reestablish the airway; however, surgery may exacerbate the condition."
    explanation: >-
      Records both the airway risk and the explicit caution that surgery can
      make it worse.
- name: Infection Prevention and Treatment
  description: >-
    Secondary bacterial and fungal infection of dystrophic nails and macerated
    callus is common and a frequent reason for pain flares. Swabs and clippings
    should be taken and infections treated; a dilute bleach-bath regimen and
    pre/post-grooming hygiene are recommended for prevention. Infected or
    painful cysts can be incised and drained.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Hypertrophic Nail Dystrophy
    treatment_effect: MODULATES
    description: >-
      Treating superimposed infection removes a common aggravator of nail
      disease and pain, without altering the underlying keratin defect.
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary fungal and bacterial infections that require treatment are common; cysts usually do not require treatment but can be incised and drained if infected or painful."
    explanation: GeneReviews management recommendation for secondary infection and cysts.
  notes: >-
    GeneReviews also lists an "Agents/circumstances to avoid" item relevant to
    everyday management: "High temperatures and high humidity may worsen the
    condition."
- name: Genetic Counselling
  description: >-
    Autosomal dominant inheritance with a 50% recurrence risk for offspring and
    a roughly 30% de novo rate. Prenatal testing is possible once the familial
    variant is known; in vitro fertilisation with preimplantation genetic
    diagnosis is available but is generally reserved for severe disease.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The offspring of an affected individual have a 50% chance of inheriting the disorder. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible."
    explanation: GeneReviews genetic counselling statement.
diagnosis:
- name: Keratin gene molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Identification of a heterozygous pathogenic variant in one of the five PC
    keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17) confirms the diagnosis and
    assigns the genotypic subtype. This is what makes the five-gene axis, rather
    than the older PC-1/PC-2 eponyms, the operative nosology for this entry.
  results: >-
    A heterozygous pathogenic variant in KRT6A, KRT6B, KRT6C, KRT16, or KRT17
    establishes the diagnosis and the corresponding PC-K subtype.
  evidence:
  - reference: PMID:20301457
    reference_title: "Pachyonychia Congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PC is diagnosed by clinical findings and/or by the identification of a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17."
    explanation: >-
      GeneReviews DIAGNOSIS/TESTING statement, establishing both the clinical
      and the molecular route to diagnosis and naming the five causal genes.
clinical_trials:
- name: NCT05180708
  phase: PHASE_III
  status: UNKNOWN
  description: >-
    Multicentre, randomised, double-blind, vehicle-controlled phase 3 study of
    QTORIN 3.9% rapamycin anhydrous gel in adults with pachyonychia congenita,
    with a 6-month treatment period.
  target_phenotypes:
  - preferred_term: Focal nonepidermolytic palmoplantar keratoderma
    term:
      id: HP:0007404
      label: Nonepidermolytic palmoplantar hyperkeratosis
  - preferred_term: Plantar pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: clinicaltrials:NCT05180708
    reference_title: "A Multicenter, Phase 3 Randomized, Double-Blind, Vehicle-controlled Study Evaluating the Safety and Efficacy of QTORIN 3.9% Rapamycin Anhydrous Gel in the Treatment of Pachyonychia Congenita"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study evaluates the safety and efficacy of QTORIN 3.9% rapamycin anhydrous gel in the treatment of adults with Pachyonychia Congenita."
    explanation: >-
      The registry record establishes a phase 3 evaluation of topical rapamycin
      specifically in PC.
- name: NCT05435638
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase I open-label study of topical KM-001 1% in type I punctate
    palmoplantar keratoderma or pachyonychia congenita, with lesion clearance
    and VAS pain assessments. The same trial is recorded on
    Punctate_Palmoplantar_Keratoderma.yaml; it is duplicated here because
    pachyonychia congenita was an eligible enrolling condition in its own right.
  target_phenotypes:
  - preferred_term: Focal nonepidermolytic palmoplantar keratoderma
    term:
      id: HP:0007404
      label: Nonepidermolytic palmoplantar hyperkeratosis
  - preferred_term: Plantar pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: clinicaltrials:NCT05435638
    reference_title: "Phase I, Open Label Study Designed to Evaluate the Safety and Efficacy of a 1% Topical Formulation of KM-001 in the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenital Diseases"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this phase 1 open label study for patients with type I punctate palmoplantar keratoderma or pachyonychia congenital, 2 arms will be recruited to be treated twice daily, with 1% topical KM-001."
    explanation: >-
      The registry record confirms pachyonychia congenita as a co-enrolled
      condition for topical KM-001.
- name: NCT05956314
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase Ib open-label study of topical KM-001 1% in type I punctate
    palmoplantar keratoderma or pachyonychia congenita, assessing safety,
    tolerability, efficacy, pharmacokinetics and patient-reported outcomes.
  target_phenotypes:
  - preferred_term: Focal nonepidermolytic palmoplantar keratoderma
    term:
      id: HP:0007404
      label: Nonepidermolytic palmoplantar hyperkeratosis
  - preferred_term: Plantar pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: clinicaltrials:NCT05956314
    reference_title: "Phase 1b, Open Label Study to Evaluate the Safety, Tolerability, and Efficacy of a 1% Topical Formulation of KM-001 for the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenita"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases."
    explanation: >-
      The registry record confirms a second open-label KM-001 study enrolling
      pachyonychia congenita.
experimental_models:
- name: Dominant-negative K6a cell culture model
  description: >-
    Cultured cells co-expressing wild-type and mutant (N171K) K6a, used to
    reproduce the dominant-negative filament defect in vitro and to test
    allele-selective siRNA. Simultaneous expression of both alleles yields
    defective filament formation; mutant-specific siRNA restores normal
    filaments.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:17914454
  modeled_mechanisms:
  - target: Keratin Intermediate Filament Network Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the defining molecular lesion — mutant-allele-dependent failure
      of keratin filament assembly — and shows it is reversible by removing the
      mutant transcript.
    limitations: >-
      A transfected, over-expression cell system rather than differentiated
      volar epidermis; it captures filament assembly but not the tissue-level
      hyperproliferation, differentiation and pain phenotypes.
    evidence:
    - reference: PMID:17914454
      reference_title: "Single-nucleotide-specific siRNA targeting in a dominant-negative skin model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "To test whether lead siRNAs could discriminate mutant mRNA in the presence of both wild-type and mutant forms, a dominant-negative PC cell culture model was developed."
      explanation: >-
        Describes the construction of the model and its purpose, supporting its
        use as an informative system for this mechanism node.
  evidence:
  - reference: PMID:17145926
    reference_title: "SiRNA-mediated selective inhibition of mutant keratin mRNAs responsible for the skin disorder pachyonychia congenita."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Similar constructs containing a single nucleotide change (N171K) or a three-nucleotide deletion (N171del) showed keratin aggregate formation."
    explanation: >-
      The companion transfection study establishing the aggregate readout used
      in this model class.
- name: Organotypic PC epidermal equivalent
  description: >-
    An organotypic (raft) epidermal model built from PC keratinocytes, used to
    assay keratinocyte uptake of chemically modified self-delivery siRNA and
    allele-selective knockdown of mutant K6a mRNA. Developed specifically
    because intradermal needle delivery to PC plantar lesions is too painful to
    be viable.
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:21248764
  modeled_mechanisms:
  - target: Keratin Intermediate Filament Network Disruption
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Used to perturb the mutant keratin transcript pool with self-delivery
      siRNA and measure allele-selective knockdown in a stratified epidermal
      context.
    limitations: >-
      An in vitro epidermal equivalent lacking innervation, mechanical loading
      and immune components, so it cannot report the pain or callus phenotypes
      that dominate the human disease.
    evidence:
    - reference: PMID:21248764
      reference_title: "Use of self-delivery siRNAs to inhibit gene expression in an organotypic pachyonychia congenita model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "treatment of PC epidermal equivalents with self-delivery \"TD101\" siRNA resulted in marked reduction of mutant keratin 6a mRNA with little or no effect on wild-type expression."
      explanation: >-
        Demonstrates allele-selective knockdown in the organotypic model,
        grounding its link to the filament-disruption node.
  evidence:
  - reference: PMID:21191405
    reference_title: "Development of quantitative molecular clinical end points for siRNA clinical trials."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "demonstrate that repeated siRNA treatment results in sustained inhibition of mutant K6a mRNA in patient-derived keratinocyte cultures"
    explanation: >-
      Companion work establishing quantitative molecular endpoints for this
      model system and for trials using it.
animal_models:
- name: Krt16-null mouse
  species: Mouse
  genotype: Krt16-/- (null)
  background: C57BL/6; also transferred to FVB/N
  genes:
  - preferred_term: KRT16
    term:
      id: hgnc:6423
      label: KRT16
  publication: PMID:22336941
  description: >-
    The principal animal model of PC-associated palmoplantar keratoderma. Mice
    null for Krt16 spontaneously develop oral lesions and PPK-like
    hyperkeratotic calluses on fore and hind paws that impair walking, and
    reproduce the sequence of pre-lesional differentiation failure, oxidative
    stress with hypoactive Keap1-Nrf2 signalling, and lesional loss of epidermal
    homeostasis.
  modeled_mechanisms:
  - target: Loss of Keratinocyte Mechanical Resilience
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of the K16 filament subunit produces weight-bearing-site callus and
      compromised ambulation, mirroring the human lesion distribution.
    limitations: >-
      The mouse phenotype arises from complete loss of function inherited
      recessively, whereas human PC is a dominant-negative disease in
      heterozygotes — so the model tests the consequence of losing functional
      K16 filaments, not the consequence of a poisoned filament network.
    evidence:
    - reference: PMID:22336941
      reference_title: "Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk"
      explanation: >-
        Establishes the model's core palmoplantar phenotype and functional
        consequence.
  - target: Defective Terminal Differentiation of Volar Keratinocytes
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Pre-lesional loss of Krt9 and pleiotropic terminal differentiation defects
      in footpad keratinocytes, mirrored in published human PC PPK expression
      data.
    limitations: >-
      Demonstrated in the null background; whether human dominant-negative
      alleles produce the same magnitude of KRT9 loss is not established.
    evidence:
    - reference: PMID:31220272
      reference_title: "Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy."
      explanation: >-
        States the model's central differentiation finding and its proposed
        translational read.
  - target: Oxidative Stress and Hypoactive Keap1-NRF2 Signalling
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Oxidative stress and failure of NRF2-dependent glutathione synthesis
      precede lesion onset; Nrf2 ablation accelerates and topical NRF2
      activation prevents the keratoderma, and hypophosphorylated NRF2 is
      confirmed in human PC lesional skin.
    limitations: >-
      The preventive effect of sulforaphane is shown in mice only; it has not
      been shown to prevent or reverse keratoderma in people with PC.
    evidence:
    - reference: PMID:27183391
      reference_title: "Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools."
      explanation: >-
        Demonstrates causal, rescuable involvement of the NRF2 node in the model.
  evidence:
  - reference: PMID:31021398
    reference_title: "Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK."
    explanation: >-
      Establishes the Krt16-null mouse as the reference model for PC-associated
      keratoderma, while wording the claim as mimicking several aspects only.
discussions:
- discussion_id: pc_pain_not_proportional_to_keratoderma
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines plantar pain severity in pachyonychia congenita, given that
    it is not proportional to the extent of hyperkeratosis?
  attaches_to:
  - pathophysiology#Plantar Nociceptive and Neuropathic Pain
  rationale: >-
    Plantar pain is the dominant disability in PC and dictates treatment goals,
    yet its severity tracks poorly with callus extent. Candidate contributors
    include subepidermal blistering beneath the callus, nociceptive input from
    tissue damage, neuropathic change in cutaneous sensory afferents,
    neurovascular structures within the callus, and TRPV3/EGFR-driven
    sensitisation. Quantitative sensory testing supports a neuropathic
    component but does not identify its cause, and the sensory phenotype does
    not differ by causal gene. Until this is resolved, dismech deliberately
    keeps pain as its own mechanism node rather than as a severity qualifier on
    the keratoderma node, since a therapy that thins the callus is not thereby
    predicted to relieve the pain.
  proposed_experiments:
  - experiment_id: pc_ienfd_lesional_vs_nonlesional
    name: Intraepidermal nerve fibre quantification in PC lesional vs non-lesional plantar skin
    description: >-
      Skin biopsy with PGP9.5 immunostaining to test whether small-fibre density
      or morphology in lesional plantar skin correlates with pain scores
      independently of callus thickness.
  - experiment_id: pc_neurovascular_structures_vs_qst
    name: Correlation of neurovascular structure burden with quantitative sensory testing
    description: >-
      Prospective study relating the number and distribution of intracallus
      neurovascular structures to mechanical hyperalgesia thresholds and DN4
      scores.
  evidence:
  - reference: PMID:29210461
    reference_title: "Chronic pain in pachyonychia congenita: evidence for neuropathic origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC."
    explanation: >-
      Frames the open question: skin thickening explains part of the sensory
      phenotype but not the hyperalgesia and allodynia.
  - reference: PMID:36116508
    reference_title: "EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive."
    explanation: >-
      A 2023 primary study states the gap explicitly.
- discussion_id: pc_krt16_null_mouse_dominant_negative_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the recessively inherited Krt16-null mouse model the same disease
    mechanism as dominant-negative keratin variants in human pachyonychia
    congenita?
  attaches_to:
  - pathophysiology#Loss of Keratinocyte Mechanical Resilience
  - pathophysiology#Keratin Intermediate Filament Network Disruption
  rationale: >-
    Nearly all mechanistic insight into PC keratoderma — the pre-lesional
    differentiation defect, the KRT9 loss, the NRF2/oxidative-stress axis and
    the sulforaphane rescue — comes from mice lacking Krt16 entirely, a
    recessive loss-of-function state. Human PC is caused by heterozygous,
    dominant-negative alleles in which a mutant subunit is present and poisons
    the network. The model's own authors note that their findings call into
    question a purely gain-of-function view of PC keratoderma and emphasise the
    role of genetic modifiers. Whether the differentiation/redox cascade is
    equally engaged when a poisoned filament network is present, rather than no
    K16 at all, is unresolved, and it matters directly for whether NRF2-directed
    therapy will translate. Partial reassurance exists — hypophosphorylated NRF2
    was confirmed in human PC lesional skin — but the rescue arm remains
    mouse-only.
  proposed_experiments:
  - experiment_id: pc_krt16_dominant_negative_knockin_mouse
    name: Knock-in mouse carrying a human dominant-negative Krt16 allele
    description: >-
      Generate a heterozygous knock-in of a recurrent human KRT16 PC allele and
      test whether the pre-lesional KRT9 loss and NRF2 hypoactivity of the null
      model are reproduced.
  - experiment_id: pc_krt9_nrf2_readouts_human_biopsies
    name: KRT9 and NRF2 pathway readouts in genotyped human PC plantar biopsies
    description: >-
      Compare KRT9 expression and NRF2 phosphorylation state across PC-K6a,
      PC-K16 and PC-K17 lesional skin to test whether the mouse cascade is
      genotype-independent in humans.
  evidence:
  - reference: PMID:22336941
    reference_title: "Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms."
    explanation: >-
      The model's authors state the mechanistic mismatch between the recessive
      null mouse and the dominant human disease.
  - reference: PMID:27183391
    reference_title: "Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue."
    explanation: >-
      Partially closes the mismatch for the NRF2 node by confirming it in human
      tissue; the therapeutic rescue arm remains mouse-only.
- discussion_id: pc_nosology_genotypic_supersedes_eponymous
  kind: OPEN_QUESTION
  status: RESOLVED
  prompt: >-
    Should pachyonychia congenita be subtyped by the eponymous PC-1
    (Jadassohn-Lewandowsky) / PC-2 (Jackson-Lawler) split or by causal keratin
    gene?
  rationale: >-
    Registry data showed that most keratin subgroups express a mixed
    constellation of the findings historically assigned to PC-1 and PC-2, so the
    eponymous categories cut across the causal genes and mislead on prognosis.
    Both large genotyped cohorts (n = 254 and n = 815) concluded in favour of a
    genotypic classification, and dismech follows that: has_subtypes is
    organised as PC-K6a/PC-K6b/PC-K6c/PC-K16/PC-K17. The eponyms are retained
    only as synonyms on the disease entry.
  resolution_note: >-
    Resolved in favour of the genotypic classification. Note that MONDO's
    numbered children still attach "Jadassohn-Lewandowsky" to the KRT16 class
    (MONDO:0008173) alone, which is a simplification of the historical usage
    (PC-1 spanned KRT6A and KRT16; PC-2 spanned KRT6B and KRT17). The MONDO
    terms are bound on their single-gene definitions, not on the eponyms.
  evidence:
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2."
    explanation: >-
      The empirical basis for abandoning the eponymous split.
  - reference: PMID:22264670
    reference_title: "A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development."
    explanation: >-
      The explicit proposal of the genotypic nosology adopted here.
  - reference: PMID:31823354
    reference_title: "Revisiting pachyonychia congenita: a case-cohort study of 815 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features."
    explanation: >-
      Confirms the registry-derived, gene-based classification as the accepted
      scheme.
notes: >-
  NOSOLOGY. This entry uses the genotypic subtype axis (PC-K6a, PC-K6b, PC-K6c,
  PC-K16, PC-K17), which supersedes the older eponymous split into PC-1
  (Jadassohn-Lewandowsky) and PC-2 (Jackson-Lawler). The eponymous categories
  cut across the causal genes and are no longer the preferred nosology; they are
  retained here only as synonyms. MONDO's four numbered children of
  MONDO:0016471 are themselves defined genotypically, so they map cleanly onto
  four of the five subtypes: KRT16 to MONDO:0008173 ("pachyonychia congenita
  1"), KRT17 to MONDO:0008174 ("pachyonychia congenita 2"), KRT6A to
  MONDO:0014324 ("pachyonychia congenita 3"), KRT6B to MONDO:0014325
  ("pachyonychia congenita 4"). Note that MONDO's PC1 term folds the
  Jadassohn-Lewandowsky eponym onto KRT16 alone, which is itself a
  simplification: historically PC-1 spanned KRT6A and KRT16, and PC-2 spanned
  KRT6B and KRT17.

  ONTOLOGY GAP. There is no MONDO term for the KRT6C-caused subtype, so PC-K6c
  is curated with genes and evidence but with subtype_term deliberately left
  unbound rather than forced onto a near-miss term. Two obsolete MONDO classes
  exist in this area and must never be used: MONDO:0000325 (obsolete
  pachyonychia congenita) and MONDO:0009827 (obsolete pachyonychia congenita,
  autosomal recessive).

  MODELLING CHOICES. Two structural decisions follow the curation issue and the
  review of KRT1_Keratinopathies.yaml in dismech#3401. First, plantar pain is
  modelled as its own mechanism node ("Plantar Nociceptive and Neuropathic
  Pain") and its own phenotype ("Plantar Pain") rather than as a severity
  qualifier on the keratoderma, because its magnitude is not proportional to the
  extent of hyperkeratosis and quantitative sensory testing shows a neuropathic
  component that thickened skin does not explain. Second, keratin network
  collapse ("Keratin Intermediate Filament Network Disruption" and "Loss of
  Keratinocyte Mechanical Resilience") is kept separate from downstream
  hyperproliferation and barrier failure ("Compensatory Epidermal
  Hyperproliferation and Barrier Dysregulation"), with the differentiation and
  redox nodes between them, so that a therapy acting on one arm is not
  implicitly credited with acting on the other.

  RELATED ENTRIES. Punctate_Palmoplantar_Keratoderma.yaml (shares the KM-001
  trials, which co-enrolled PC),
  Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma.yaml, and
  KRT1_Keratinopathies.yaml (the epidermolytic keratin disorders, from which PC
  is distinguished by its non-epidermolytic histology). Named-entity caution for
  future curators: pachyonychia congenita is not dyskeratosis congenita (a
  telomere biology disorder that shares nail dystrophy and oral leukoplakia but
  adds bone marrow failure and lacks plantar pain), not Olmsted syndrome
  (TRPV3), not Clouston syndrome (GJB6), and not punctate or diffuse
  epidermolytic PPK.

📚

References & Deep Research

References

1

PMID:20301457

Pachyonychia Congenita.

No top-level findings curated for this source.

Pachyonychia Congenita

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References