👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals carry biallelic SERPINB7 variants. Because founder alleles are common in East Asia, an affected parent can have an affected child with a carrier partner, giving a pseudodominant pattern.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:24773080 SUPPORT Human clinical

"In all the families, the NPPK trait was inherited in an autosomal recessive manner; in one of the families, there was pseudodominant inheritance, which had not been described in NPPK."

Recessive inheritance in ten Japanese families, with one pseudodominant pedigree.

PMID:24207119 SUPPORT Human clinical

"We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily."

Biallelic variants in all 13 index patients.

?

Discussions and Knowledge Gaps

2

How does the SERPINB7-legumain barrier defect produce palmoplantar redness and hyperkeratosis, and what drives the plantar dysbiosis?

KNOWLEDGE GAP nppk_hyperkeratosis_erythema_mechanism

Attached to

phenotypes#Diffuse palmoplantar hyperkeratosis phenotypes#Palmoplantar erythema pathophysiology#Plantar Bacterial Dysbiosis

The barrier defect explains the water sign, but no study connects it to the redness and hyperkeratosis that define the disease, or to the odor and fungal susceptibility; a 2025 review states these mechanisms remain poorly understood (PMID:39749860). The legumain work is done on mouse body skin and cultured keratinocytes, so whether the same steps occur in palmoplantar epidermis is also open. Hyperhidrosis and the barrier defect are both candidate causes of the dysbiosis, and neither has been tested.

Proposed experiments

Legumain activity and O-GalNAc glycosylation in patient palmoplantar skin

nppk_lesional_legumain_and_glycosylation

Measure legumain activity, O-GalNAc glycosylation and tight junction proteins in lesional palmoplantar biopsies from NPPK patients and site-matched controls, before and after topical legumain inhibition where available.

Would support

pathophysiology#Legumain Overactivation pathophysiology#Impaired Keratinocyte Protein O-GalNAc Glycosylation

Supporting outcome

Lesional skin shows raised legumain activity and reduced O-GalNAc glycosylation compared with control palmoplantar skin.

Refuting outcome

Legumain activity and glycosylation are normal in lesional palmoplantar skin.

SERPINB7 loss reduces differentiation in a three-dimensional human epidermal model, yet patient skin shows no major differentiation defect. Is reduced differentiation part of NPPK in patients?

HUMAN MODEL MISMATCH nppk_differentiation_model_patient_conflict

Attached to

pathophysiology#Reduced Epidermal Differentiation

The model result (PMID:38909841) and the patient staining for loricrin, involucrin and filaggrin (PMID:24207119) disagree. If differentiation is intact in patients, the barrier defect arises through the legumain, glycosylation and cytoskeletal steps alone, and the differentiation node describes the culture system rather than the disease. The patient study examined three markers by immunostaining, so a subtle or region-specific defect is not excluded.

Proposed experiments

Quantitative differentiation profiling of lesional palmoplantar skin

nppk_lesional_differentiation_profiling

Measure late differentiation markers and cornified envelope proteins quantitatively (transcript and protein) in lesional palmoplantar skin from NPPK patients against site-matched controls.

Would support

pathophysiology#Reduced Epidermal Differentiation

Supporting outcome

Lesional skin shows reduced late differentiation markers compared with controls.

Refuting outcome

Differentiation markers are at control levels in lesional skin.

⚙

Pathophysiology

9

Biallelic SERPINB7 Loss-of-Function Variants

Nonsense, frameshift and splice variants, including the East Asian founder c.796C>T (p.Arg266*) and a Chinese deep intronic founder variant that inserts a pseudo-exon, all truncate SERPINB7 before its reactive site.

SERPINB7 hgnc:13902

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Downstream

Loss of SERPINB7 Protease Inhibitory Activity

Show evidence (2 references)

PMID:24207119 SUPPORT Human clinical

"We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations."

Identifies the founder nonsense variant.

PMID:40579253 SUPPORT Human clinical

"A deep intronic SERPINB7 variant was identified in six NPPK patients, leading to pseudo-exon inclusion and the production of a truncated, dysfunctional SERPINB7 protein."

A second class of truncating variant.

Loss of SERPINB7 Protease Inhibitory Activity

SERPINB7 is expressed in the cytoplasm of the stratum granulosum and stratum corneum. Despite its family name it behaves as a cysteine protease inhibitor, and its main target is legumain, which it binds and inhibits in a protease-substrate manner.

keratinocyte CL:0000312

SERPINB7 hgnc:13902

cysteine-type endopeptidase inhibitor activity GO:0004869 ↓ DECREASED

stratum granulosum of epidermis UBERON:0002069

Downstream

Legumain Overactivation

Reduced Epidermal Differentiation

Show evidence (2 references)

PMID:38909841 SUPPORT In vitro / ex vivo

"Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor and identified legumain as a key target protease of SERPINB7."

Establishes the inhibitory activity that patients lose and its target.

PMID:24207119 SUPPORT Human clinical

"SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis."

Locates SERPINB7 in the upper epidermis.

Legumain Overactivation

Legumain, an asparaginyl endopeptidase, is overactive in SERPINB7-deficient epidermis.

LGMN hgnc:9472

cysteine-type endopeptidase activity GO:0004197 ↑ INCREASED

Animal models

Serpinb7-null mouse Mouse recapitulates Legumain activity is increased in knockout skin.

Downstream

Impaired Keratinocyte Protein O-GalNAc Glycosylation

Weakened Keratinocyte Cytoskeletal Proteins

Show evidence (1 reference)

PMID:38909841 SUPPORT Model organism

"Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma."

Legumain is overactive when SERPINB7 is lost.

Impaired Keratinocyte Protein O-GalNAc Glycosylation

SERPINB7-deficient keratinocytes lose Golgi structure and O-GalNAc glycosyltransferases, so calcium-related and adhesion proteins are under-glycosylated.

keratinocyte CL:0000312

protein O-linked glycosylation via N-acetylgalactosamine GO:0016266 ↓ DECREASED Golgi organization GO:0007030 ⚠ ABNORMAL

Experimental models

SERPINB7-silenced human keratinocytes CELL LINE Knockdown reproduces the Golgi and glycosylation defect, rescued by legumain knockdown.

Downstream

Keratinocyte Tight Junction Disruption

Show evidence (1 reference)

PMID:41469525 SUPPORT In vitro / ex vivo

"SERPINB7 deficiency leads to reduced expression of O-GalNAc regulatory proteins and structural abnormalities in the Golgi apparatus, ultimately impairing protein O-GalNAc glycosylation."

SERPINB7 loss impairs O-GalNAc glycosylation in keratinocytes.

Keratinocyte Tight Junction Disruption

Tight junctions between keratinocytes are lost, with less occludin and weaker cell-cell and cell-matrix adhesion.

keratinocyte CL:0000312

tight junction organization GO:0120193 ↓ DECREASED

bicellular tight junction GO:0005923

Downstream

Epidermal Barrier Defect

Show evidence (1 reference)

PMID:41469525 SUPPORT In vitro / ex vivo

"We found that SERPINB7 deficiency disrupts tight junctions of keratinocytes in vitro, and specific knockout of Serpinb7 in keratinocytes impairs skin barrier function in vivo."

Tight junction loss in SERPINB7-deficient keratinocytes.

Weakened Keratinocyte Cytoskeletal Proteins

Cytoskeletal proteins are weakened in Serpinb7-null mouse skin.

keratinocyte CL:0000312

cytoskeleton organization GO:0007010 ⚠ ABNORMAL

Downstream

Epidermal Barrier Defect

Show evidence (1 reference)

PMID:38909841 SUPPORT Model organism

"The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins."

Direct observation in knockout mouse skin.

Reduced Epidermal Differentiation

SERPINB7 loss lowers keratinocyte differentiation in a three-dimensional human epidermal model.

keratinocyte CL:0000312

keratinocyte differentiation GO:0030216 ↓ DECREASED

Show evidence (2 references)

PMID:38909841 SUPPORT In vitro / ex vivo

"In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model."

Reduced differentiation in a human epidermal equivalent.

PMID:24207119 REFUTE Human clinical

"showed no major keratinocyte differentiation defect in NPPK skin (Figure 3E)."

Loricrin, involucrin and filaggrin staining in patient lesional skin showed no major differentiation defect, which contradicts the epidermal-model result.

Epidermal Barrier Defect

The stratum corneum lets water in and out too easily. In patients, water exposure turns lesional skin white and spongy within minutes; in knockout mice, the barrier is spontaneously disrupted.

establishment of skin barrier GO:0061436 ↓ DECREASED

stratum corneum of epidermis UBERON:0002027

Animal models

Serpinb7-null mouse Mouse recapitulates The knockout reproduces the barrier defect.

Keratinocyte-specific Serpinb7 knockout mouse Mouse recapitulates Shows the barrier defect is keratinocyte-intrinsic.

Downstream

Whitish spongy change after water exposure

Show evidence (2 references)

PMID:38909841 SUPPORT Model organism

"In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment."

Barrier disruption in the knockout mouse.

PMID:24207119 SUPPORT Human clinical

"Before water exposure, the mean TEWL values were higher in the lesional skin of NPPK individuals than in the nonlesional skin of NPPK individuals or the corresponding skin area of normal healthy controls (Figure 4B)"

Raised transepidermal water loss in patient lesional skin, measured in three patients and three controls.

Plantar Bacterial Dysbiosis

Sole skin carries a higher bacterial load and lower diversity than in healthy controls, dominated by Corynebacterium and Staphylococcus, especially between the toes. What causes the dysbiosis is not established.

skin of sole of pes UBERON:0013778

Downstream

Foot odor

Show evidence (1 reference)

PMID:41338335 SUPPORT Human clinical

"Compared with healthy controls, individuals with Nagashima-type palmoplantar keratosis exhibited significantly higher objective odor scores; increased bacterial load, especially in the intertoe area; and reduced microbial diversity."

Patient-control comparison of the plantar microbiome.

✶

Histopathology

3

Hyperorthokeratosis

Thick epidermis with orthokeratotic hyperkeratosis on palmar biopsy and electron microscopy. Reported in one well-documented case; frequency across patients is not known.

Show evidence (1 reference)

PMID:30581033 SUPPORT Human clinical

"Electron microscopy showed hyperorthokeratosis with hypergranulosis and loss of lamellar structure of the keratinosomes, as well as cleavage between corneocytes."

Ultrastructure of lesional skin in a SERPINB7 compound heterozygote.

Hypergranulosis

A thickened granular layer, the layer in which SERPINB7 is normally expressed.

Show evidence (1 reference)

PMID:30581033 SUPPORT Human clinical

"The epithelium displayed a thick granular layer."

Light-microscopy finding in the same case.

Loss of keratinosome lamellar structure and corneocyte cleavage

Lamellar bodies lose their lamellar structure and corneocytes separate. This was seen by electron microscopy in one case; the original patient series found no major ultrastructural defect, so the finding is not established as a feature of the disease.

Show evidence (2 references)

PMID:30581033 SUPPORT Human clinical

"Electron microscopy showed hyperorthokeratosis with hypergranulosis and loss of lamellar structure of the keratinosomes, as well as cleavage between corneocytes."

Electron microscopy of lesional skin.

PMID:24207119 REFUTE Human clinical

"Transmission electron microscopic studies of NPPK skin failed to show any major defect in the stratum granulosum or the SC (data not shown)."

The original series reports no major ultrastructural defect in the granular layer or stratum corneum, which conflicts with the single-case finding.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

6

Cardiovascular 1

Palmoplantar erythema OBLIGATE HP:0025493

Show evidence (1 reference)

PMID:24207119 SUPPORT Human clinical

""Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area."

Redness is part of the defining description.

Immune 1

Recurrent tinea pedis Recurrent plantar mycosis HP:0025472

Itch and eczema in NPPK are attributed to coexisting tinea pedis or atopic dermatitis rather than to NPPK itself (PMID:39749860), so they are not curated as NPPK phenotypes.

Show evidence (1 reference)

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"It is noteworthy that NPPK patients frequently experience recurrent tinea pedis, which bears resemblance to Mal de Meleda."

Recurrent tinea pedis is frequent.

Integument 3

Diffuse palmoplantar hyperkeratosis OBLIGATE HP:0007447

Severity: MILD

Show evidence (2 references)

PMID:24207119 SUPPORT Human clinical

""Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area."

Defines the distribution of the hyperkeratosis.

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"The redness extends to the dorsal surface of the toes, fingers, and the Achilles tendon areas (transgrediens), while the central dorsal area of the hands remains unaffected."

Describes the transgredient spread and its limit.

Whitish spongy change after water exposure OBLIGATE Maceration HP:0032007

Show evidence (2 references)

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"observed that the area of the skin exhibiting erythema and mild hyperkeratosis displayed a whitish change shortly after exposure to water and subsequently reverted to its original state upon drying in all 13 affected individuals."

Present in all 13 patients of the original series.

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"This phenomenon, which we term the “water sign,” is a diagnostic hallmark of NPPK (Figure 4) as it has been observed by the majority of parents of infant patients after exposure to water following bathing and swimming."

The water sign is used diagnostically.

Palmoplantar hyperhidrosis HP:0007410

Show evidence (2 references)

PMID:41338335 SUPPORT BACKGROUND Human clinical

"It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL."

Hyperhidrosis is a characteristic feature.

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"It is often complicated by hyperhidrosis of the palms and soles."

Hyperhidrosis is a frequent complication.

Constitutional 1

Foot odor Body odor HP:0500001

Show evidence (1 reference)

PMID:41338335 SUPPORT BACKGROUND Human clinical

"It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL."

Foot odor is a characteristic feature.

🧬

Genetic Associations

1

SERPINB7 (Causative)

Gene: SERPINB7 hgnc:13902 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:24207119 SUPPORT Human clinical

"We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily."

Identification of the causal gene.

PMID:42384829 SUPPORT Human clinical

"In 80% (304/380) patients, hotspot variants in SERPINB7 were identified, with c.796C>T (77%) and c.522_523insT (16%) being the most frequent."

SERPINB7 explains most hereditary palmoplantar keratoderma in a large Chinese cohort.

Variants (2)

SERPINB7 c.796C>T (p.Arg266*) Pathogenic

NONSENSE

East Asian founder variant, the most frequent NPPK allele in Japan and China.

Show evidence (1 reference)

PMID:24207119 SUPPORT Human clinical

"We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations."

Founder status of c.796C>T.

SERPINB7 c.522_523insT Pathogenic

FRAMESHIFT

Second most frequent hotspot variant in Chinese patients.

Show evidence (1 reference)

PMID:42384829 SUPPORT Human clinical

"In 80% (304/380) patients, hotspot variants in SERPINB7 were identified, with c.796C>T (77%) and c.522_523insT (16%) being the most frequent."

Frequency of c.522_523insT among hotspot carriers.

💊

Medical Actions

2

Topical gentamicin ointment

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: gentamicin CHEBI:759884

Platform: Small molecule

Aminoglycoside ointment applied to palms and soles, intended to make ribosomes read through premature stop codons such as p.Arg266* and restore full-length SERPINB7. In a double-blind, vehicle-controlled half-side study it improved hyperkeratosis, desquamation and quality of life but not erythema. In an open-label pediatric half-side study it also improved erythema and maceration, but not hyperhidrosis or odor.

Mechanism Target:

BYPASSES Biallelic SERPINB7 Loss-of-Function Variants — Readthrough of the premature stop codon is meant to bypass the nonsense allele and restore protein.

Show evidence (1 reference)

PMID:33554268 SUPPORT BACKGROUND Human clinical

"Nonsense suppression therapy has been studied for more than 20 years, and aims to suppress the termination of translation caused by premature termination codons (PTCs) and restore protein function (11)."

States the rationale for readthrough therapy; restoration of SERPINB7 in patient skin was not measured.

Target Phenotypes: Diffuse palmoplantar hyperkeratosis HP:0007447

Show evidence (3 references)

PMID:33554268 SUPPORT Human clinical

"Compared with the control vehicle, gentamicin ointment significantly improved hyperkeratosis, desquamation, and quality of life, based on VAS and DLQI scores."

Controlled evidence of benefit on hyperkeratosis.

PMID:33554268 REFUTE Human clinical

"No difference was found in the effect on erythema between gentamicin and vehicle."

No effect on erythema in the adult trial.

PMID:37736370 SUPPORT Human clinical

"Bilateral comparisons showed that gentamicin ointment significantly improved hyperkeratosis, erythema, maceration, and desquamation, but not hyperhidrosis and odor, indicating that gentamicin ointment is a promising therapeutic option for children with NPPK."

Benefit in children, without effect on hyperhidrosis or odor.

Topical benzoyl peroxide

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: benzoyl peroxide CHEBI:82405

Platform: Small molecule

Topical benzoyl peroxide to the feet reduces foot odor and bacterial load and restores microbial diversity.

Mechanism Target:

INHIBITS Plantar Bacterial Dysbiosis — Selectively reduces Corynebacterium, especially C. tuberculostearicum.

Show evidence (1 reference)

PMID:41338335 SUPPORT Human clinical

"The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum."

Benzoyl peroxide reverses the dysbiosis.

Target Phenotypes: Plantar foot odor HP:0500001

Show evidence (1 reference)

PMID:41338335 SUPPORT Human clinical

"The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum."

Benzoyl peroxide reduces odor.

🔬

Diagnosis

2

Clinical examination with the water sign

Mild transgredient palmoplantar redness and hyperkeratosis from infancy, with whitening of lesional skin after water exposure, suggests NPPK.

physical examination NCIT:C20989

Show evidence (1 reference)

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"This phenomenon, which we term the “water sign,” is a diagnostic hallmark of NPPK (Figure 4) as it has been observed by the majority of parents of infant patients after exposure to water following bathing and swimming."

The water sign is a diagnostic hallmark.

SERPINB7 hotspot testing and exome sequencing

In East Asian patients a panel targeting the founder variants confirms most cases; exome sequencing covers the rest and the other palmoplantar keratoderma genes.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:42384829 SUPPORT Human clinical

"Additionally, a diagnostic panel targeting ancestral SERPINB7 founder variants would markedly improve the molecular diagnostic yield in Chinese patients."

Supports founder-variant panels as a first-line test.

📈

Progression

2

Onset in infancy

Redness and mild hyperkeratosis are usually noticed by parents in the first year of life, at about three months on average in one series.

Show evidence (2 references)

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"The initial presentation of erythema and mild hyperkeratosis is typically observed by parents during the first year of the child's life."

Onset in the first year of life.

PMID:27666198 SUPPORT Human clinical

"The age of onset was ~3 months (Table I)."

Mean onset age in a Chinese series.

Stable lifelong course

The hyperkeratosis stays mild and does not progress, in contrast to mal de Meleda.

Show evidence (1 reference)

PMID:24207119 SUPPORT Human clinical

"Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda."

The course is nonprogressive.

📊

Prevalence

2

Japan

Point prevalence 12.0 per 100,000 1–9 per 10,000

1.2 per 10,000, an estimate derived from founder-allele carrier frequencies rather than a case count.

Show evidence (1 reference)

PMID:30581033 SUPPORT BACKGROUND Human clinical

"It is the most widespread form of PPK in Asia (with a prevalence of 1.2/10,000 in Japan and 3.1/10,000 in China)."

Gives the Japanese prevalence estimate, cited from the original genetic study.

China

Point prevalence 31.0 per 100,000 1–9 per 10,000

3.1 per 10,000, an estimate derived from founder-allele carrier frequencies rather than a case count.

Show evidence (1 reference)

PMID:30581033 SUPPORT BACKGROUND Human clinical

"It is the most widespread form of PPK in Asia (with a prevalence of 1.2/10,000 in Japan and 3.1/10,000 in China)."

Gives the Chinese prevalence estimate.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Palmoplantar Keratoderma Nagashima Type:

Mal de Meleda MONDO:0009552

Overlapping Features The SLURP1-related transgressive palmoplantar keratoderma, which shares the transgredient distribution and recurrent tinea pedis.

Distinguishing Features

NPPK hyperkeratosis is mild and nonprogressive; mal de Meleda is severe and progressive.
Mal de Meleda extends from the wrists to the forearms and from the feet to the ankles and can cause finger constriction.

Show evidence (2 references)

PMID:24207119 SUPPORT Human clinical

"Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda."

The main clinical distinction.

PMID:39749860 SUPPORT REVIEW SYNTHESIS Human clinical

"This disease is characterized by early childhood onset, severe and progressive keratinization, extension of the lesions from the wrists to the forearms and from the dorsal surfaces of the feet to the ankles, erythema of the elbows, knees, and mouth, and, occasionally, finger dissection (Figure 1)."

Describes mal de Meleda for comparison.

🔬

Clinical Trials

2

ChiCTR1800014771 NOT_APPLICABLE COMPLETED

Registration for the vehicle-controlled half-side study of topical gentamicin in genodermatoses caused by nonsense variants, reported for NPPK in PMID:33554268. The registry entry still lists recruiting; the study's results are published.

Show evidence (2 references)

ICTRP:ChiCTR1800014771 SUPPORT Other

"| Main ID | ChiCTR1800014771 |"

WHO ICTRP registration record establishing the trial's identity.

PMID:33554268 SUPPORT Human clinical

"Registration number: ChiCTR1800014771), and was conducted according to the principles of the Declaration of Helsinki, at the Department of Dermatology of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine."

Links the publication to the registration.

ChiCTR2300069011 NOT_APPLICABLE COMPLETED

Registration for the open-label half-side study of topical gentamicin in children with NPPK, reported in PMID:37736370. The registry entry still lists recruiting; the study's results are published.

Show evidence (2 references)

ICTRP:ChiCTR2300069011 SUPPORT Other

"| Main ID | ChiCTR2300069011 |"

WHO ICTRP registration record establishing the trial's identity.

PMID:37736370 SUPPORT Human clinical

"and was registered in the Chinese Clinical Trial Register System (registration number: ChiCTR2300069011)."

Links the publication to the registration.

🧫

Experimental Models

1

SERPINB7-silenced human keratinocytes CELL_LINE

HaCaT cells and primary neonatal human epidermal keratinocytes with SERPINB7 knocked down by siRNA.

Publication

PMID:41469525

Pathograph links

Impaired Keratinocyte Protein O-GalNAc Glycosylation recapitulates fidelity: moderate observes: cellular Knockdown reproduces the Golgi and glycosylation defect, rescued by legumain knockdown.

Limitations: Knockdown in submerged culture lacks a stratum corneum and palmoplantar identity.

Show evidence (1 reference)

PMID:41469525 SUPPORT In vitro / ex vivo

"Finally, we confirmed that silencing SERPINB7 downregulates the level of O-GalNAc glycosylation (Fig. 2F, G)."

The cell model shows reduced O-GalNAc glycosylation.

🐁

Animal Models

2

Serpinb7-null mouse

Global Serpinb7 knockout mice develop a disrupted skin barrier, worsened by acetone-ether-water challenge, with weakened cytoskeletal proteins and increased legumain activity.

Species

Mouse

Genotype

Serpinb7 homozygous knockout (Serpinb7-/-)

Publication

PMID:38909841

Pathograph links

Epidermal Barrier Defect recapitulates fidelity: moderate observes: tissue The knockout reproduces the barrier defect.

Limitations: The barrier defect is measured on furred body skin rather than on palmoplantar skin, and the source abstract does not report palmoplantar hyperkeratosis or erythema in the mouse.

Show evidence (1 reference)

PMID:38909841 SUPPORT Model organism

"In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment."

Barrier disruption in the knockout.

Legumain Overactivation recapitulates fidelity: moderate observes: molecular Legumain activity is increased in knockout skin.

Limitations: Legumain activity has not been measured in patient skin.

Show evidence (1 reference)

PMID:38909841 SUPPORT Model organism

"SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo."

Shows the in vivo relationship between SERPINB7 and legumain.

Keratinocyte-specific Serpinb7 knockout mouse

Mice lacking Serpinb7 in keratinocytes show cracks and fissures and raised transepidermal water loss in dorsal skin, reversed by a topical legumain inhibitor.

Species

Mouse

Genotype

Serpinb7 conditional knockout in keratinocytes

Publication

PMID:41469525

Pathograph links

Epidermal Barrier Defect recapitulates fidelity: moderate observes: tissue Shows the barrier defect is keratinocyte-intrinsic.

Limitations: Studied on dorsal skin, not palms or soles.

Show evidence (1 reference)

PMID:41469525 SUPPORT Model organism

"These mice exhibited cracks and fissures (Fig. 1H) and increased Trans Epidermal Water Loss (TEWL) (Fig. 1I) in the dorsal skin, which indicates impaired skin barrier."

Barrier impairment in the conditional knockout.

{ }

Source YAML

click to show

name: Palmoplantar Keratoderma Nagashima Type
creation_date: "2026-10-24T02:24:13Z"
category: Mendelian
description: >-
  Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive,
  non-syndromic, diffuse palmoplantar keratoderma caused by biallelic
  loss-of-function variants in SERPINB7, which encodes a cytoplasmic serpin of
  the upper epidermis. It is the most common hereditary palmoplantar
  keratoderma in East Asia, where founder variants such as c.796C>T
  (p.Arg266*) are frequent. From the first year of life, the palms and soles
  show well-demarcated redness with mild hyperkeratosis that extends onto the
  backs of the fingers, toes, hands and feet, the inner wrists and the
  Achilles tendon area (transgrediens). The lesions are not progressive, which
  separates NPPK from mal de Meleda. Lesional skin turns white and spongy
  within minutes of water exposure. Palmoplantar hyperhidrosis, a
  distinctive foot odor and recurrent tinea pedis are common. Loss of
  SERPINB7 releases its target protease legumain, which in keratinocyte and
  mouse studies impairs protein O-GalNAc glycosylation, tight junctions and
  cytoskeletal proteins and disrupts the epidermal barrier. How this barrier
  defect produces the erythema and hyperkeratosis is not known.
notes: >-
  The entry is anchored on MONDO:0014272 and SERPINB7 (hgnc:13902).

  The legumain and O-GalNAc steps of the pathophysiology come from Serpinb7
  knockout mice and SERPINB7-silenced human keratinocytes (PMID:38909841,
  PMID:41469525), not from patient skin. The water-sign barrier defect is
  observed in patients (PMID:24207119).

  Two treatments are curated, both topical: gentamicin ointment, aimed at
  nonsense-codon readthrough, and benzoyl peroxide for foot odor. Antisense
  correction of a deep intronic founder variant (PMID:40579253) and new
  readthrough compounds (PMID:42034525) have only been tested in cells and
  are not curated as treatments.

  No GeneReviews chapter covers this disease.
disease_term:
  preferred_term: palmoplantar keratoderma, Nagashima type
  term:
    id: MONDO:0014272
    label: palmoplantar keratoderma, Nagashima type
synonyms:
- Nagashima-type palmoplantar keratosis
- NPPK
- PPK, Nagashima type
- palmoplantar hyperkeratosis, Nagashima type
- SERPINB7-related palmoplantar epidermal differentiation disorder
parents:
- Diffuse Nonepidermolytic Palmoplantar Keratoderma
- Hereditary Palmoplantar Keratoderma
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry biallelic SERPINB7 variants. Because founder
    alleles are common in East Asia, an affected parent can have an affected
    child with a carrier partner, giving a pseudodominant pattern.
  evidence:
  - reference: PMID:24773080
    reference_title: "Highly prevalent SERPINB7 founder mutation causes pseudodominant inheritance pattern in Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all the families, the NPPK trait was inherited in an autosomal recessive manner; in one of the families, there was pseudodominant inheritance, which had not been described in NPPK."
    explanation: Recessive inheritance in ten Japanese families, with one pseudodominant pedigree.
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily."
    explanation: Biallelic variants in all 13 index patients.
prevalence:
- population: Japan
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 12.0
  notes: >-
    1.2 per 10,000, an estimate derived from founder-allele carrier
    frequencies rather than a case count.
  evidence:
  - reference: PMID:30581033
    reference_title: "[Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It is the most widespread form of PPK in Asia (with a prevalence of 1.2/10,000 in Japan and 3.1/10,000 in China)."
    explanation: Gives the Japanese prevalence estimate, cited from the original genetic study.
- population: China
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 31.0
  notes: >-
    3.1 per 10,000, an estimate derived from founder-allele carrier
    frequencies rather than a case count.
  evidence:
  - reference: PMID:30581033
    reference_title: "[Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It is the most widespread form of PPK in Asia (with a prevalence of 1.2/10,000 in Japan and 3.1/10,000 in China)."
    explanation: Gives the Chinese prevalence estimate.
progression:
- phase: Onset in infancy
  notes: Redness and mild hyperkeratosis are usually noticed by parents in the first year of life, at about three months on average in one series.
  evidence:
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The initial presentation of erythema and mild hyperkeratosis is typically observed by parents during the first year of the child's life."
    explanation: Onset in the first year of life.
  - reference: PMID:27666198
    reference_title: "Nagashima-type palmoplantar keratosis in a Chinese Han population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age of onset was ~3 months (Table I)."
    explanation: Mean onset age in a Chinese series.
- phase: Stable lifelong course
  notes: The hyperkeratosis stays mild and does not progress, in contrast to mal de Meleda.
  evidence:
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda."
    explanation: The course is nonprogressive.
pathophysiology:
- name: Biallelic SERPINB7 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Nonsense, frameshift and splice variants, including the East Asian founder
    c.796C>T (p.Arg266*) and a Chinese deep intronic founder variant that
    inserts a pseudo-exon, all truncate SERPINB7 before its reactive site.
  genes:
  - preferred_term: SERPINB7
    term:
      id: hgnc:13902
      label: SERPINB7
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations."
    explanation: Identifies the founder nonsense variant.
  - reference: PMID:40579253
    reference_title: "A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A deep intronic SERPINB7 variant was identified in six NPPK patients, leading to pseudo-exon inclusion and the production of a truncated, dysfunctional SERPINB7 protein."
    explanation: A second class of truncating variant.
  downstream:
  - target: Loss of SERPINB7 Protease Inhibitory Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24207119
      reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      directness: INDIRECT
      snippet: "All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin."
      explanation: The loss of inhibitory activity is inferred from where the variants truncate the protein, not measured.
- name: Loss of SERPINB7 Protease Inhibitory Activity
  biological_scale: MOLECULAR
  description: >-
    SERPINB7 is expressed in the cytoplasm of the stratum granulosum and
    stratum corneum. Despite its family name it behaves as a cysteine protease
    inhibitor, and its main target is legumain, which it binds and inhibits in
    a protease-substrate manner.
  genes:
  - preferred_term: SERPINB7
    term:
      id: hgnc:13902
      label: SERPINB7
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: stratum granulosum of epidermis
    term:
      id: UBERON:0002069
      label: stratum granulosum of epidermis
  molecular_functions:
  - preferred_term: cysteine-type endopeptidase inhibitor activity
    term:
      id: GO:0004869
      label: cysteine-type endopeptidase inhibitor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:38909841
    reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor and identified legumain as a key target protease of SERPINB7."
    explanation: Establishes the inhibitory activity that patients lose and its target.
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis."
    explanation: Locates SERPINB7 in the upper epidermis.
  downstream:
  - target: Legumain Overactivation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38909841
      reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo."
      explanation: Without SERPINB7, legumain is not inhibited.
  - target: Reduced Epidermal Differentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38909841
      reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model."
      explanation: SERPINB7 loss reduces differentiation in a human epidermal equivalent.
- name: Legumain Overactivation
  biological_scale: MOLECULAR
  description: Legumain, an asparaginyl endopeptidase, is overactive in SERPINB7-deficient epidermis.
  genes:
  - preferred_term: LGMN
    term:
      id: hgnc:9472
      label: LGMN
  molecular_functions:
  - preferred_term: cysteine-type endopeptidase activity
    term:
      id: GO:0004197
      label: cysteine-type endopeptidase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:38909841
    reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma."
    explanation: Legumain is overactive when SERPINB7 is lost.
  downstream:
  - target: Impaired Keratinocyte Protein O-GalNAc Glycosylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41469525
      reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our findings revealed that the knockdown of Legumain reversed the downregulation of Golgi structure and function-related proteins, including TRIP11, GCC2, and TMED5, as well as O-GalNAc glycosylation-associated proteins such as GALNT4, GALNT5, COSMC, and ST3GAL2, which were mediated by SERPINB7 deficiency (Fig. 3A)."
      explanation: Silencing legumain rescues the glycosylation defect, placing legumain upstream of it.
  - target: Weakened Keratinocyte Cytoskeletal Proteins
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38909841
      reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma."
      explanation: The authors propose, rather than show, that legumain disrupts cytoskeletal proteins.
- name: Impaired Keratinocyte Protein O-GalNAc Glycosylation
  biological_scale: CELLULAR
  description: >-
    SERPINB7-deficient keratinocytes lose Golgi structure and O-GalNAc
    glycosyltransferases, so calcium-related and adhesion proteins are
    under-glycosylated.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: protein O-linked glycosylation via N-acetylgalactosamine
    term:
      id: GO:0016266
      label: protein O-linked glycosylation via N-acetylgalactosamine
    modifier: DECREASED
  - preferred_term: Golgi organization
    term:
      id: GO:0007030
      label: Golgi organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:41469525
    reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SERPINB7 deficiency leads to reduced expression of O-GalNAc regulatory proteins and structural abnormalities in the Golgi apparatus, ultimately impairing protein O-GalNAc glycosylation."
    explanation: SERPINB7 loss impairs O-GalNAc glycosylation in keratinocytes.
  downstream:
  - target: Keratinocyte Tight Junction Disruption
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41469525
      reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "O-GalNAc inhibition exhibits biological effects analogous to those induced by SERPINB7 deficiency, leading to weakened tight junctions, reduced cell adhesion, and compromised skin barrier integrity in keratinocytes and mouse skin, respectively."
      explanation: Blocking O-GalNAc glycosylation alone weakens tight junctions.
- name: Keratinocyte Tight Junction Disruption
  biological_scale: CELLULAR
  description: Tight junctions between keratinocytes are lost, with less occludin and weaker cell-cell and cell-matrix adhesion.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  cellular_components:
  - preferred_term: bicellular tight junction
    term:
      id: GO:0005923
      label: bicellular tight junction
  biological_processes:
  - preferred_term: tight junction organization
    term:
      id: GO:0120193
      label: tight junction organization
    modifier: DECREASED
  evidence:
  - reference: PMID:41469525
    reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that SERPINB7 deficiency disrupts tight junctions of keratinocytes in vitro, and specific knockout of Serpinb7 in keratinocytes impairs skin barrier function in vivo."
    explanation: Tight junction loss in SERPINB7-deficient keratinocytes.
  downstream:
  - target: Epidermal Barrier Defect
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41469525
      reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Taken together, these results suggest that SERPINB7 deficiency impairs keratinocyte adhesion and disrupts tight junctions in vitro, while in vivo, it compromises skin barrier integrity in a keratinocyte-dependent manner."
      explanation: Connects the keratinocyte junction defect to barrier loss in mouse skin.
- name: Weakened Keratinocyte Cytoskeletal Proteins
  biological_scale: CELLULAR
  description: Cytoskeletal proteins are weakened in Serpinb7-null mouse skin.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cytoskeleton organization
    term:
      id: GO:0007010
      label: cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38909841
    reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins."
    explanation: Direct observation in knockout mouse skin.
  downstream:
  - target: Epidermal Barrier Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38909841
      reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma."
      explanation: The authors propose the cytoskeletal defect contributes to the barrier defect.
- name: Reduced Epidermal Differentiation
  biological_scale: CELLULAR
  description: SERPINB7 loss lowers keratinocyte differentiation in a three-dimensional human epidermal model.
  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: DECREASED
  evidence:
  - reference: PMID:38909841
    reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model."
    explanation: Reduced differentiation in a human epidermal equivalent.
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "showed no major keratinocyte differentiation defect in NPPK skin (Figure 3E)."
    explanation: >-
      Loricrin, involucrin and filaggrin staining in patient lesional skin
      showed no major differentiation defect, which contradicts the
      epidermal-model result.
  notes: >-
    The evidence conflicts: the three-dimensional model shows reduced
    differentiation, but patient skin stained for three differentiation
    markers does not. The node is kept without downstream edges, and the
    conflict is recorded as a human-model mismatch discussion.
- name: Epidermal Barrier Defect
  biological_scale: TISSUE
  description: >-
    The stratum corneum lets water in and out too easily. In patients, water
    exposure turns lesional skin white and spongy within minutes; in
    knockout mice, the barrier is spontaneously disrupted.
  locations:
  - preferred_term: stratum corneum of epidermis
    term:
      id: UBERON:0002027
      label: stratum corneum of epidermis
  biological_processes:
  - preferred_term: establishment of skin barrier
    term:
      id: GO:0061436
      label: establishment of skin barrier
    modifier: DECREASED
  evidence:
  - reference: PMID:38909841
    reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment."
    explanation: Barrier disruption in the knockout mouse.
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before water exposure, the mean TEWL values were higher in the lesional skin of NPPK individuals than in the nonlesional skin of NPPK individuals or the corresponding skin area of normal healthy controls (Figure 4B)"
    explanation: Raised transepidermal water loss in patient lesional skin, measured in three patients and three controls.
  downstream:
  - target: Whitish spongy change after water exposure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24207119
      reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure."
      explanation: The water sign is read as increased water permeation through a weakened stratum corneum.
- name: Plantar Bacterial Dysbiosis
  biological_scale: TISSUE
  description: >-
    Sole skin carries a higher bacterial load and lower diversity than in
    healthy controls, dominated by Corynebacterium and Staphylococcus,
    especially between the toes. What causes the dysbiosis is not
    established.
  locations:
  - preferred_term: skin of sole of pes
    term:
      id: UBERON:0013778
      label: skin of sole of pes
  evidence:
  - reference: PMID:41338335
    reference_title: "Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with healthy controls, individuals with Nagashima-type palmoplantar keratosis exhibited significantly higher objective odor scores; increased bacterial load, especially in the intertoe area; and reduced microbial diversity."
    explanation: Patient-control comparison of the plantar microbiome.
  downstream:
  - target: Foot odor
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41338335
      reference_title: "Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings suggest that microbial dysbiosis, especially the overgrowth of Corynebacterium species, is central to the pathogenesis of foot odor in Nagashima-type palmoplantar keratosis."
      explanation: Attributes the odor to the Corynebacterium overgrowth.
phenotypes:
- category: Dermatological
  name: Diffuse palmoplantar hyperkeratosis
  description: >-
    Mild, diffuse, well-demarcated hyperkeratosis of the palms and soles that
    extends onto the dorsal fingers and toes, the inner wrists, the Achilles
    tendon area, knees and elbows, while the central backs of the hands stay
    clear.
  phenotype_term:
    preferred_term: Diffuse transgressive palmoplantar hyperkeratosis
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
    severity: MILD
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "\"Nagashima-type\" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area."
    explanation: Defines the distribution of the hyperkeratosis.
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The redness extends to the dorsal surface of the toes, fingers, and the Achilles tendon areas (transgrediens), while the central dorsal area of the hands remains unaffected."
    explanation: Describes the transgredient spread and its limit.
- category: Dermatological
  name: Palmoplantar erythema
  description: Well-demarcated redness of the palms and soles accompanies the hyperkeratosis.
  phenotype_term:
    preferred_term: Palmoplantar erythema
    term:
      id: HP:0025493
      label: Palmoplantar erythema
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "\"Nagashima-type\" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area."
    explanation: Redness is part of the defining description.
- category: Dermatological
  name: Whitish spongy change after water exposure
  description: >-
    The "water sign": lesional skin turns white and spongy shortly after
    contact with water and returns to normal when dry. It was seen in all 13
    patients of the original series and is considered a diagnostic hallmark.
  phenotype_term:
    preferred_term: Whitish spongy maceration of lesional skin after water exposure
    term:
      id: HP:0032007
      label: Maceration
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "observed that the area of the skin exhibiting erythema and mild hyperkeratosis displayed a whitish change shortly after exposure to water and subsequently reverted to its original state upon drying in all 13 affected individuals."
    explanation: Present in all 13 patients of the original series.
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This phenomenon, which we term the “water sign,” is a diagnostic hallmark of NPPK (Figure 4) as it has been observed by the majority of parents of infant patients after exposure to water following bathing and swimming."
    explanation: The water sign is used diagnostically.
- category: Dermatological
  name: Palmoplantar hyperhidrosis
  phenotype_term:
    preferred_term: Palmoplantar hyperhidrosis
    term:
      id: HP:0007410
      label: Palmoplantar hyperhidrosis
  evidence:
  - reference: PMID:41338335
    reference_title: "Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL."
    explanation: Hyperhidrosis is a characteristic feature.
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is often complicated by hyperhidrosis of the palms and soles."
    explanation: Hyperhidrosis is a frequent complication.
- category: Dermatological
  name: Foot odor
  description: A distinctive plantar odor that impairs quality of life.
  phenotype_term:
    preferred_term: Plantar foot odor
    term:
      id: HP:0500001
      label: Body odor
  evidence:
  - reference: PMID:41338335
    reference_title: "Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL."
    explanation: Foot odor is a characteristic feature.
- category: Infectious
  name: Recurrent tinea pedis
  notes: >-
    Itch and eczema in NPPK are attributed to coexisting tinea pedis or atopic
    dermatitis rather than to NPPK itself (PMID:39749860), so they are not
    curated as NPPK phenotypes.
  phenotype_term:
    preferred_term: Recurrent tinea pedis
    term:
      id: HP:0025472
      label: Recurrent plantar mycosis
  evidence:
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is noteworthy that NPPK patients frequently experience recurrent tinea pedis, which bears resemblance to Mal de Meleda."
    explanation: Recurrent tinea pedis is frequent.
histopathology:
- name: Hyperorthokeratosis
  description: >-
    Thick epidermis with orthokeratotic hyperkeratosis on palmar biopsy and
    electron microscopy. Reported in one well-documented case; frequency
    across patients is not known.
  finding_term:
    preferred_term: hyperorthokeratosis
    term:
      id: NCIT:C35541
      label: Hyperkeratosis
  evidence:
  - reference: PMID:30581033
    reference_title: "[Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy showed hyperorthokeratosis with hypergranulosis and loss of lamellar structure of the keratinosomes, as well as cleavage between corneocytes."
    explanation: Ultrastructure of lesional skin in a SERPINB7 compound heterozygote.
- name: Hypergranulosis
  description: A thickened granular layer, the layer in which SERPINB7 is normally expressed.
  evidence:
  - reference: PMID:30581033
    reference_title: "[Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The epithelium displayed a thick granular layer."
    explanation: Light-microscopy finding in the same case.
  notes: >-
    Left unbound. An OLS search of NCIT for "hypergranulosis" returned no
    term, and HP:0025114 Hypergranulosis is outside the
    HistopathologyFindingTerm enum.
- name: Loss of keratinosome lamellar structure and corneocyte cleavage
  description: >-
    Lamellar bodies lose their lamellar structure and corneocytes separate.
    This was seen by electron microscopy in one case; the original patient
    series found no major ultrastructural defect, so the finding is not
    established as a feature of the disease.
  evidence:
  - reference: PMID:30581033
    reference_title: "[Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy showed hyperorthokeratosis with hypergranulosis and loss of lamellar structure of the keratinosomes, as well as cleavage between corneocytes."
    explanation: Electron microscopy of lesional skin.
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopic studies of NPPK skin failed to show any major defect in the stratum granulosum or the SC (data not shown)."
    explanation: >-
      The original series reports no major ultrastructural defect in the
      granular layer or stratum corneum, which conflicts with the single-case
      finding.
  notes: >-
    Left unbound. An OLS search of NCIT for "lamellar body" returns
    NCIT:C32913 Lamellar Body, an anatomical structure rather than a
    histopathology finding, and a search for "keratinosome" returns nothing.
genetic:
- name: SERPINB7
  gene_term:
    preferred_term: SERPINB7
    term:
      id: hgnc:13902
      label: SERPINB7
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    SERPINB7 (18q21.33) encodes megsin, a clade B intracellular serpin. Several
    founder alleles circulate in East Asia; in a Chinese cohort of 380 tested
    patients with palmoplantar keratoderma, 80% carried a SERPINB7 hotspot
    variant.
  evidence:
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily."
    explanation: Identification of the causal gene.
  - reference: PMID:42384829
    reference_title: "Large-Scale Cohort Study on the Genetic and Phenotypic Findings of Palmoplantar Keratodermas in the Chinese Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 80% (304/380) patients, hotspot variants in SERPINB7 were identified, with c.796C>T (77%) and c.522_523insT (16%) being the most frequent."
    explanation: SERPINB7 explains most hereditary palmoplantar keratoderma in a large Chinese cohort.
  variants:
  - name: SERPINB7 c.796C>T (p.Arg266*)
    type: NONSENSE
    clinical_significance: PATHOGENIC
    description: East Asian founder variant, the most frequent NPPK allele in Japan and China.
    evidence:
    - reference: PMID:24207119
      reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations."
      explanation: Founder status of c.796C>T.
  - name: SERPINB7 c.522_523insT
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    description: Second most frequent hotspot variant in Chinese patients.
    evidence:
    - reference: PMID:42384829
      reference_title: "Large-Scale Cohort Study on the Genetic and Phenotypic Findings of Palmoplantar Keratodermas in the Chinese Population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 80% (304/380) patients, hotspot variants in SERPINB7 were identified, with c.796C>T (77%) and c.522_523insT (16%) being the most frequent."
      explanation: Frequency of c.522_523insT among hotspot carriers.
treatments:
- name: Topical gentamicin ointment
  description: >-
    Aminoglycoside ointment applied to palms and soles, intended to make
    ribosomes read through premature stop codons such as p.Arg266* and
    restore full-length SERPINB7. In a double-blind, vehicle-controlled
    half-side study it improved hyperkeratosis, desquamation and quality of
    life but not erythema. In an open-label pediatric half-side study it also
    improved erythema and maceration, but not hyperhidrosis or odor.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gentamicin
      term:
        id: CHEBI:759884
        label: gentamicin
  target_phenotypes:
  - preferred_term: Diffuse palmoplantar hyperkeratosis
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  target_mechanisms:
  - target: Biallelic SERPINB7 Loss-of-Function Variants
    treatment_effect: BYPASSES
    description: Readthrough of the premature stop codon is meant to bypass the nonsense allele and restore protein.
    evidence:
    - reference: PMID:33554268
      reference_title: "Effect of Gentamicin Ointment in Patients with Nagashima-type Palmoplantar Keratosis: A Double-blind Vehicle-controlled Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Nonsense suppression therapy has been studied for more than 20 years, and aims to suppress the termination of translation caused by premature termination codons (PTCs) and restore protein function (11)."
      explanation: States the rationale for readthrough therapy; restoration of SERPINB7 in patient skin was not measured.
  evidence:
  - reference: PMID:33554268
    reference_title: "Effect of Gentamicin Ointment in Patients with Nagashima-type Palmoplantar Keratosis: A Double-blind Vehicle-controlled Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with the control vehicle, gentamicin ointment significantly improved hyperkeratosis, desquamation, and quality of life, based on VAS and DLQI scores."
    explanation: Controlled evidence of benefit on hyperkeratosis.
  - reference: PMID:33554268
    reference_title: "Effect of Gentamicin Ointment in Patients with Nagashima-type Palmoplantar Keratosis: A Double-blind Vehicle-controlled Study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No difference was found in the effect on erythema between gentamicin and vehicle."
    explanation: No effect on erythema in the adult trial.
  - reference: PMID:37736370
    reference_title: "Application of topical gentamicin ointment in the treatment of Nagashima-type palmoplantar keratosis in children with a nonsense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral comparisons showed that gentamicin ointment significantly improved hyperkeratosis, erythema, maceration, and desquamation, but not hyperhidrosis and odor, indicating that gentamicin ointment is a promising therapeutic option for children with NPPK."
    explanation: Benefit in children, without effect on hyperhidrosis or odor.
- name: Topical benzoyl peroxide
  description: Topical benzoyl peroxide to the feet reduces foot odor and bacterial load and restores microbial diversity.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: benzoyl peroxide
      term:
        id: CHEBI:82405
        label: Benzoyl peroxide
  target_phenotypes:
  - preferred_term: Plantar foot odor
    term:
      id: HP:0500001
      label: Body odor
  target_mechanisms:
  - target: Plantar Bacterial Dysbiosis
    treatment_effect: INHIBITS
    description: Selectively reduces Corynebacterium, especially C. tuberculostearicum.
    evidence:
    - reference: PMID:41338335
      reference_title: "Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum."
      explanation: Benzoyl peroxide reverses the dysbiosis.
  evidence:
  - reference: PMID:41338335
    reference_title: "Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum."
    explanation: Benzoyl peroxide reduces odor.
clinical_trials:
- name: ChiCTR1800014771
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Registration for the vehicle-controlled half-side study of topical
    gentamicin in genodermatoses caused by nonsense variants, reported for
    NPPK in PMID:33554268. The registry entry still lists recruiting; the
    study's results are published.
  evidence:
  - reference: ICTRP:ChiCTR1800014771
    reference_title: "The Exploratory Research of Gentamicin Topical Treatment of Genodermatosis Caused by Nonsense Mutations"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Main ID | ChiCTR1800014771 |"
    explanation: WHO ICTRP registration record establishing the trial's identity.
  - reference: PMID:33554268
    reference_title: "Effect of Gentamicin Ointment in Patients with Nagashima-type Palmoplantar Keratosis: A Double-blind Vehicle-controlled Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Registration number: ChiCTR1800014771), and was conducted according to the principles of the Declaration of Helsinki, at the Department of Dermatology of Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine."
    explanation: Links the publication to the registration.
- name: ChiCTR2300069011
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Registration for the open-label half-side study of topical gentamicin in
    children with NPPK, reported in PMID:37736370. The registry entry still
    lists recruiting; the study's results are published.
  evidence:
  - reference: ICTRP:ChiCTR2300069011
    reference_title: "The research and development of gentamicin topical preparation and the study on the readthrough effect in children with genodermatosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Main ID | ChiCTR2300069011 |"
    explanation: WHO ICTRP registration record establishing the trial's identity.
  - reference: PMID:37736370
    reference_title: "Application of topical gentamicin ointment in the treatment of Nagashima-type palmoplantar keratosis in children with a nonsense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and was registered in the Chinese Clinical Trial Register System (registration number: ChiCTR2300069011)."
    explanation: Links the publication to the registration.
diagnosis:
- name: Clinical examination with the water sign
  description: >-
    Mild transgredient palmoplantar redness and hyperkeratosis from infancy,
    with whitening of lesional skin after water exposure, suggests NPPK.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This phenomenon, which we term the “water sign,” is a diagnostic hallmark of NPPK (Figure 4) as it has been observed by the majority of parents of infant patients after exposure to water following bathing and swimming."
    explanation: The water sign is a diagnostic hallmark.
- name: SERPINB7 hotspot testing and exome sequencing
  description: >-
    In East Asian patients a panel targeting the founder variants confirms
    most cases; exome sequencing covers the rest and the other
    palmoplantar keratoderma genes.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42384829
    reference_title: "Large-Scale Cohort Study on the Genetic and Phenotypic Findings of Palmoplantar Keratodermas in the Chinese Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, a diagnostic panel targeting ancestral SERPINB7 founder variants would markedly improve the molecular diagnostic yield in Chinese patients."
    explanation: Supports founder-variant panels as a first-line test.
differential_diagnoses:
- name: Mal de Meleda
  disease_term:
    preferred_term: mal de Meleda
    term:
      id: MONDO:0009552
      label: mal de Meleda
  description: >-
    The SLURP1-related transgressive palmoplantar keratoderma, which shares
    the transgredient distribution and recurrent tinea pedis.
  distinguishing_features:
  - NPPK hyperkeratosis is mild and nonprogressive; mal de Meleda is severe and progressive.
  - Mal de Meleda extends from the wrists to the forearms and from the feet to the ankles and can cause finger constriction.
  evidence:
  - reference: PMID:24207119
    reference_title: "Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda."
    explanation: The main clinical distinction.
  - reference: PMID:39749860
    reference_title: "History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This disease is characterized by early childhood onset, severe and progressive keratinization, extension of the lesions from the wrists to the forearms and from the dorsal surfaces of the feet to the ankles, erythema of the elbows, knees, and mouth, and, occasionally, finger dissection (Figure 1)."
    explanation: Describes mal de Meleda for comparison.
animal_models:
- name: Serpinb7-null mouse
  species: Mouse
  genotype: Serpinb7 homozygous knockout (Serpinb7-/-)
  publication: PMID:38909841
  description: >-
    Global Serpinb7 knockout mice develop a disrupted skin barrier,
    worsened by acetone-ether-water challenge, with weakened cytoskeletal
    proteins and increased legumain activity.
  modeled_mechanisms:
  - target: Epidermal Barrier Defect
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The knockout reproduces the barrier defect.
    limitations: >-
      The barrier defect is measured on furred body skin rather than on
      palmoplantar skin, and the source abstract does not report palmoplantar
      hyperkeratosis or erythema in the mouse.
    evidence:
    - reference: PMID:38909841
      reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment."
      explanation: Barrier disruption in the knockout.
  - target: Legumain Overactivation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Legumain activity is increased in knockout skin.
    limitations: Legumain activity has not been measured in patient skin.
    evidence:
    - reference: PMID:38909841
      reference_title: "SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo."
      explanation: Shows the in vivo relationship between SERPINB7 and legumain.
- name: Keratinocyte-specific Serpinb7 knockout mouse
  species: Mouse
  genotype: Serpinb7 conditional knockout in keratinocytes
  publication: PMID:41469525
  description: >-
    Mice lacking Serpinb7 in keratinocytes show cracks and fissures and raised
    transepidermal water loss in dorsal skin, reversed by a topical legumain
    inhibitor.
  modeled_mechanisms:
  - target: Epidermal Barrier Defect
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Shows the barrier defect is keratinocyte-intrinsic.
    limitations: Studied on dorsal skin, not palms or soles.
    evidence:
    - reference: PMID:41469525
      reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice exhibited cracks and fissures (Fig. 1H) and increased Trans Epidermal Water Loss (TEWL) (Fig. 1I) in the dorsal skin, which indicates impaired skin barrier."
      explanation: Barrier impairment in the conditional knockout.
experimental_models:
- name: SERPINB7-silenced human keratinocytes
  experimental_model_type: CELL_LINE
  description: HaCaT cells and primary neonatal human epidermal keratinocytes with SERPINB7 knocked down by siRNA.
  publication: PMID:41469525
  modeled_mechanisms:
  - target: Impaired Keratinocyte Protein O-GalNAc Glycosylation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Knockdown reproduces the Golgi and glycosylation defect, rescued by legumain knockdown.
    limitations: Knockdown in submerged culture lacks a stratum corneum and palmoplantar identity.
    evidence:
    - reference: PMID:41469525
      reference_title: "SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Finally, we confirmed that silencing SERPINB7 downregulates the level of O-GalNAc glycosylation (Fig. 2F, G)."
      explanation: The cell model shows reduced O-GalNAc glycosylation.
discussions:
- discussion_id: nppk_hyperkeratosis_erythema_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Diffuse palmoplantar hyperkeratosis
  - phenotypes#Palmoplantar erythema
  - pathophysiology#Plantar Bacterial Dysbiosis
  prompt: >-
    How does the SERPINB7-legumain barrier defect produce palmoplantar redness
    and hyperkeratosis, and what drives the plantar dysbiosis?
  rationale: >-
    The barrier defect explains the water sign, but no study connects it to
    the redness and hyperkeratosis that define the disease, or to the odor and
    fungal susceptibility; a 2025 review states these mechanisms remain
    poorly understood (PMID:39749860). The legumain work is done on mouse
    body skin and cultured keratinocytes, so whether the same steps occur in
    palmoplantar epidermis is also open. Hyperhidrosis and the barrier defect
    are both candidate causes of the dysbiosis, and neither has been tested.
  proposed_experiments:
  - experiment_id: nppk_lesional_legumain_and_glycosylation
    name: Legumain activity and O-GalNAc glycosylation in patient palmoplantar skin
    description: >-
      Measure legumain activity, O-GalNAc glycosylation and tight junction
      proteins in lesional palmoplantar biopsies from NPPK patients and
      site-matched controls, before and after topical legumain inhibition
      where available.
    would_support:
    - pathophysiology#Legumain Overactivation
    - pathophysiology#Impaired Keratinocyte Protein O-GalNAc Glycosylation
    supporting_outcome:
    - Lesional skin shows raised legumain activity and reduced O-GalNAc glycosylation compared with control palmoplantar skin.
    refuting_outcome:
    - Legumain activity and glycosylation are normal in lesional palmoplantar skin.
- discussion_id: nppk_differentiation_model_patient_conflict
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Reduced Epidermal Differentiation
  prompt: >-
    SERPINB7 loss reduces differentiation in a three-dimensional human
    epidermal model, yet patient skin shows no major differentiation defect.
    Is reduced differentiation part of NPPK in patients?
  rationale: >-
    The model result (PMID:38909841) and the patient staining for loricrin,
    involucrin and filaggrin (PMID:24207119) disagree. If differentiation is
    intact in patients, the barrier defect arises through the legumain,
    glycosylation and cytoskeletal steps alone, and the differentiation node
    describes the culture system rather than the disease. The patient study
    examined three markers by immunostaining, so a subtle or region-specific
    defect is not excluded.
  proposed_experiments:
  - experiment_id: nppk_lesional_differentiation_profiling
    name: Quantitative differentiation profiling of lesional palmoplantar skin
    description: >-
      Measure late differentiation markers and cornified envelope proteins
      quantitatively (transcript and protein) in lesional palmoplantar skin
      from NPPK patients against site-matched controls.
    would_support:
    - pathophysiology#Reduced Epidermal Differentiation
    supporting_outcome:
    - Lesional skin shows reduced late differentiation markers compared with controls.
    refuting_outcome:
    - Differentiation markers are at control levels in lesional skin.

📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Palmoplantar Keratoderma Nagashima Type · 2026-10-24T03:07:04Z · View source

New entry for SERPINB7-related Nagashima-type palmoplantar keratosis (MONDO:0014272). Deep research ran with the claude_code provider (research/Palmoplantar_Keratoderma_Nagashima_Type-deep-research-claude_code.md); it rested on one full-text read and listed several sources without PMIDs. A PubMed search on SERPINB7 found the mechanistic papers the report lacked: legumain as the SERPINB7 target in Serpinb7-null mice (PMID:38909841) and the legumain to O-GalNAc glycosylation to tight junction route in keratinocytes and keratinocyte-specific knockout mice (PMID:41469525), plus the plantar dysbiosis and benzoyl peroxide study (PMID:41338335), the two gentamicin ointment studies and their ChiCTR registrations (fetched as ICTRP records), a 380-patient Chinese genetic cohort (PMID:42384829), and a 2025 review (PMID:39749860). The pathophysiology is an atomic chain from SERPINB7 truncation to loss of inhibitory activity, legumain overactivation, two branches (glycosylation then tight junctions; cytoskeletal weakening) converging on the epidermal barrier defect and the water sign, with reduced differentiation and plantar dysbiosis as separate nodes. Hyperkeratosis and erythema are deliberately left without an incoming edge because no source links the barrier defect to them; this is recorded as a knowledge-gap discussion. The DOI-only Acta Derm Venereol 2016 case report the report cited was not used because its content is unavailable in the cache. Validated with just validate-disorders (0 issues) and the offline whole-repo gates.

Claude Code ▸

Nagashima-type palmoplantar keratosis (NPPK): research report

claude-haiku-5-5, claude-sonnet-5-5 9 citations 2026-10-24T02:25:06.063922

Nagashima-type palmoplantar keratosis (NPPK): research report

Causal gene (first paragraph, as requested): NPPK is caused by biallelic loss-of-function variants in SERPINB7. SERPINB7 is a clade-B intracellular serine protease inhibitor, with the HGNC ID hgnc:13902 (not retrieved in this session; look it up before binding). The identifiers below were confirmed from a GARD/NIH record found by search, but I did not open that record: MONDO:0014272, OMIM:615598, ORPHA:140966, DOID:0070555 (GARD record; KEGG H02264). The disease is autosomal recessive.

Scope and limits. This report rests on one full-text read (Kubo 2013) and on search-result abstracts and snippets for the rest. I could not read the full text of the 2016 Acta Dermato-Venereologica paper. Anything I could not source is marked "not retrieved". Every CURIE below is a lead to be looked up before binding, per the repo's rules.

1. Disease information

NPPK is an isolated, diffuse, non-epidermolytic palmoplantar keratoderma (PPK) with transgrediens (spread beyond the palms and soles). It is the most common PPK in East Asia and very rare elsewhere (Acta Derm Venereol 2016). The characteristic picture is well-demarcated erythema with mild-to-moderate hyperkeratosis. It can extend to the backs of the hands and feet and the Achilles tendon area. Lesional skin turns whitish and spongy after water exposure.
Identifiers: see above. Synonyms: palmoplantar keratosis/keratoderma, Nagashima type; "PPK Nagashima type"; "Nagashima-type palmoplantar keratosis with SERPINB7 mutation".
All data are aggregated from patient case series and disease-level resources, not EHR.

2. Etiology

Causal factors. The cause is genetic. Kubo et al. found "biallelic putative loss-of-function mutations in SERPINB7" in 13 unrelated Japanese patients (PMID:24207119; PMC3824127). Six were homozygous and seven compound heterozygous.

Risk and protective factors. No genetic modifiers, protective variants or gene-environment interactions are established (not retrieved). Water and mechanical friction visibly worsen the whitish, spongy change in lesional skin, but I found no formal exposure studies.

3. Phenotypes

Based on the clinical summaries above. Frequencies are not retrieved and should come from a case series or Orphanet.

Phenotype	Suggested HPO lead (verify)
Palmoplantar keratoderma, diffuse	HP:0000982
Palmoplantar erythema, well-demarcated	HP:0010783 (erythema)
Transgrediens to the dorsal hands/feet and Achilles area	no specific term (leave as a note)
Whitish, spongy change after water exposure (maceration)	no specific term

Onset and course: Onset is in infancy or early childhood (typical for NPPK; not confirmed from a retrieved source). Severity is mild to moderate, and the course is stable or slowly progressive.
Atypical presentation: Extensive erythema and hyperkeratosis of the extremities and lumbar area has been reported (Acta Derm Venereol 2016).
Quality of life: Not retrieved.

4. Genetic/molecular information

Gene: SERPINB7 (chromosome 18q21.3). The OMIM entry for the disease is 615598.
Variants (Kubo 2013):
The founder variant c.796C>T (p.Arg266*).
c.218_219del2ins12 (p.Gln73Leufs*17).
c.455-1G>A (p.Gly152Valfs*21).
c.309delT (p.Phe103Leufs*33).
c.336+2T>G.
Later reports:
c.650_653delCTGT, in compound heterozygosity with c.796C>T in two brothers.
A homozygous c.522dupT (p.Val175Cysfs*46) in a Thai patient.
Novel c.530T>C and c.643A>G, from a 2022 Chinese series of eight patients that reviewed 15 pathogenic variants (PMC9303684).
Consequence: Loss of function. The reactive-site loop (residues 331–352) is predicted to be lost in all the truncating mutant proteins (PMID:24207119).
Population frequency:
1000 Genomes: c.796C>T was heterozygous in 2 of 89 Japanese individuals (about 0.4% allele frequency; PMID:24207119).
gnomAD, per ClinVar submissions: about 0.7–0.8% in East Asians (347/44,860 alleles in v4.0). I did not check gnomAD directly. The variant is 18-61471522-C-T (ClinVar Miner).
Digenic or modifier genes, epigenetics, chromosomal abnormalities: None reported (not retrieved).

5. Environmental information

No environmental or infectious causes were found. Water exposure is a clinical sign, not a cause: whitening and sponginess appeared within 10 minutes in lesional skin only (PMID:24207119).

6. Mechanism / pathophysiology

Causal chain 1. Biallelic loss-of-function SERPINB7 variants (nonsense, frameshift and splice-site) lead to loss of SERPINB7 protein. The reactive-site loop is lost, and protein signal is markedly reduced in patient skin (demonstrated; PMID:24207119). 2. This results in a complete loss of protease-inhibitory activity in the epidermis. The authors wrote of "a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin" (inferred from the predicted protein structure). 3. The proposed next step is overactive, unrestrained proteases in the stratum corneum, which weaken its structure. This is an inference and was not tested, and the target proteases are not identified (PMID:24207119). 4. Impaired barrier function follows. Transepidermal water loss was higher in lesional skin before and after water exposure (3 patients vs 3 controls; demonstrated, small sample). 5. The clinical result is erythema and hyperkeratosis of the palms and soles. These are likely reactive, because loricrin, involucrin and filaggrin staining and electron microscopy showed no major differentiation or ultrastructural defect.

Details - Localization: SERPINB7 sits in the cytoplasm of the stratum granulosum and upper stratum corneum, with mild apical concentration. Staining was also seen in facial and abdominal epidermis. SERPINB7 was first described in kidney mesangial cells (as MEGSIN), but NPPK patients have no renal disease. - Cell types: keratinocyte (CL:0000312) and granular-layer keratinocyte (verify the CURIE). - GO leads (verify): serine-type endopeptidase inhibitor activity (GO:0004867); epidermis development (GO:0008544). - Open question: A 2023 report suggests c.796C>T may alter SERPINB7's subcellular localization (Lyu et al., Exp Dermatol 32(6):766-776; I saw only the abstract). - Molecular profiling, single-cell and CRISPR data: not retrieved.

7. Anatomical structures affected

Palmar and plantar skin (UBERON:0001045 skin of hand; UBERON:0001046 skin of foot; verify). The disease extends onto the dorsa of the hands and feet and the Achilles area.
Tissue and cell level: the epidermis, mainly the stratum granulosum and stratum corneum (UBERON:0000483 epithelium; UBERON:0002027 stratum corneum, verify).
Subcellular level: the cytoplasm (GO:0005737).
The disease is bilateral and symmetric.

8. Temporal development

Onset is in early life; the course is chronic and lifelong. Remission is not described. This section is mostly unsourced beyond the clinical summaries above.

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007). Pseudodominant inheritance, from a high carrier frequency, has been reported in one Japanese family (Fujita Health University).
Prevalence (estimated by Kubo; PMID:24207119): about 1.2 per 10,000 in Japanese, 3.1 per 10,000 in Chinese, and about 0.5 per 100,000,000 in non-Asian populations.
Founder effect: c.796C>T is a founder variant in Japanese and Chinese populations. In a Chinese Han cohort of nine patients, five were homozygous for it and four were compound heterozygous (Spandidos).
Geography: Cases outside East Asia have been reported in France, Finland and Thailand (PMC9303684).
Not retrieved: sex ratio, penetrance and expressivity, and consanguinity role.

10. Diagnostics

Clinical: the typical distribution, plus the whitening after water exposure.
Genetic: SERPINB7 sequencing or a gene panel. Targeting c.796C>T first is efficient in East Asian patients.
Histology: hyperkeratosis without a major differentiation defect.
Differential diagnosis: other PPKs such as Unna-Thost and Mal de Meleda, and tinea. I did not source the distinguishing features.
Screening: none established.

11. Outcome/prognosis

The disease is benign and non-syndromic, with no extracutaneous or renal involvement (PMID:24207119). Complications such as secondary infection and quality-of-life data are not retrieved.

12. Treatment

No curative or approved disease-specific treatment was found. Standard care is topical keratolytics (urea, salicylic acid) and emollients, plus management of any superimposed infection. I did not source these, and the repo rules require a retrievable citation before any claim is curated.
The 2023 Exp Dermatol report describes one homozygous patient who showed moderate improvement in keratinization on ixekizumab (an anti-IL-17A antibody). This is a single case and not evidence of efficacy.
NCIT leads: Pharmacotherapy (NCIT:C15986) for any topical or systemic agent; Supportive Care (NCIT:C15747).
Clinical trials: none found.

13. Prevention

Genetic counseling (NCIT:C15240) is appropriate. With a carrier rate near 0.7–0.8% in East Asians, a pseudodominant pattern in a family is possible. Other prevention items: not applicable.

14. Other species / natural disease

No naturally occurring analogue was found. Zebrafish homologs (serpinb1l1 and serpinb1l3) are expressed in the larval digestive tract (ZFIN). Mouse and other orthologs: not retrieved.

15. Model organisms

No mouse or other genetic model of NPPK was found. The zebrafish expression work above is descriptive only, not a disease model.

Key references

Kubo A, et al. Am J Hum Genet 2013;93:945–956. PMID:24207119.
Acta Derm Venereol 2016 (DOI 10.2340/00015555-2391): PMID not retrieved.
Lyu et al., Exp Dermatol 2023;32(6):766-776: PMID not retrieved.
Chinese Han cohort; 2022 Chinese series; Fujita Health University pseudodominant report.

Sources: - Kubo 2013 (PMC3824127) - GARD record - KEGG H02264 - ClinVar Miner - ZFIN

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	4
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	18
Resolved	16
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	6
Terms named correctly	2
Terms named as a different term	1
Terms whose name is worth a second look	3

Terms the report names something else

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

GO:0005737 (1 mention) - the report calls it "Subcellular level: the cytoplasm"; GO calls it cytoplasm

Terms whose name is worth a second look

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

HP:0000982 (1 mention) - the report calls it "Palmoplantar keratoderma, diffuse"; HP calls it Palmoplantar keratoderma
CL:0000312 (1 mention) - the report calls it "Cell types: keratinocyte"; CL calls it keratinocyte**
NCIT:C15986 (1 mention) - the report calls it "NCIT leads: Pharmacotherapy"; NCIT calls it Pharmacotherapy

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, ORPHA.

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

Deep Research

Nagashima-type palmoplantar keratosis (NPPK): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic/molecular information

5. Environmental information

6. Mechanism / pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome/prognosis

12. Treatment

13. Prevention

14. Other species / natural disease

15. Model organisms

Key references

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver