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.

• 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.

All extracted references resolved successfully.

Term Validation

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

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.