Short Stature With Nonspecific Skeletal Abnormalities 1 (SNSK1): research report

Scope and verification. I ran two web searches, both returned only search snippets, and I opened no primary papers. The identifiers below are confirmed by those searches, and the source for each is linked. Where I recall a fact but did not confirm it, I mark it (unverified recall). The numeric PMIDs for the recalled papers are unverified too, so run just fetch-reference PMID:… and check the snippets before using them as evidence. Sections of your template that the sources did not cover are marked "not retrieved". I have not guessed at content for them.

1. Disease information

• Overview. SNSK1 is an autosomal dominant condition caused by heterozygous variants in NPR2. It is "characterized by short stature defined as a height less than 2 SD below normal, with no endocrine abnormalities" (MalaCards; MedGen via mirror). Affected people are much shorter than unaffected relatives.
• Identifiers.
• MONDO:0014551.
• OMIM #616255.
• MedGen C4225399.
• Gene: NPR2, 9p13.3.
• KEGG entry H02681.
• The searches did not return Orphanet, ICD or MeSH identifiers. This is not retrieved.
• Synonyms. SNSK1; short stature with nonspecific skeletal abnormalities (the heterozygous NPR2 form). Heterozygous NPR2 short stature is also discussed under idiopathic short stature (see below).
• Genetic heterogeneity and the numbering. SNSK2 is a separate OMIM entity caused by heterozygous IHH variants (2q35). It is the same locus as brachydactyly type A1 (BDA1, OMIM 112500) (MedGen mirror). Do not merge SNSK1 and SNSK2 in the KB.
• Related entity. Biallelic NPR2 variants cause acromesomelic dysplasia 1, Maroteaux type (AMD1/AMDM, OMIM 602875). That is a severe skeletal dysplasia and a different disease.
• Data source. The information is disease-level and aggregated, from OMIM and MedGen. It is not derived from EHR data.

2. Etiology

• Cause. Heterozygous loss-of-function or dominant-negative variants in NPR2. The sources I retrieved do not say which mechanism applies to which variant. A 2025 study found that NPR2 mutants (p.R318W, p.I908T, p.R976H) had significantly reduced protein expression, and that JAK2, p-JAK2 and p-STAT5 were reduced (PMC12315304).
• Contribution to idiopathic short stature. Heterozygous NPR2 variants may account for about 2–6% of idiopathic short stature (ISS) (search summary of the literature). The number is from the search summary and I did not confirm it in the paper.
• Environmental risk factors, protective factors and gene–environment interactions. None were retrieved. A monogenic skeletal-growth disorder is not expected to have established environmental risk factors, but I found no source saying so.

3. Phenotypes

The retrieved sources report:

All HPO IDs above come from my recall. Look each one up before use, as the KB rules require.

• Not retrieved. Onset age, progression, per-phenotype frequencies and quality-of-life data were not retrieved.
• Distinctness. Heterozygous patients have "mild and variable degrees of short stature without a distinct phenotype" (search summary).

4. Genetic and molecular information

• Gene. NPR2 (natriuretic peptide receptor 2, also called guanylyl cyclase B, GC-B) encodes the receptor for C-type natriuretic peptide (CNP, encoded by NPPC). The HGNC ID needs a lookup. The KB uses lowercase hgnc:.
• Inheritance, current classification.
• OMIM lists autosomal dominant inheritance.
• A Genomics England PanelApp panel (reviewed June 2026) lists NPR2 as both monoallelic and biallelic (PanelApp). This is a recent reclassification and may not yet be in OMIM.
• Variants. Variant lists, ACMG classifications and allele frequencies were not retrieved. Search ClinVar and gnomAD for these.
• Foundational literature (unverified recall):
• Vasques et al. 2013, J Clin Endocrinol Metab, reported heterozygous NPR2 variants in idiopathic short stature (the search surfaced PMID 24001744 on a related page, MedChemExpress; confirm that it is this paper).
• Hisado-Oliva et al. 2018 and others describe additional variants.
• Modifier genes, epigenetics and chromosomal abnormalities. Not retrieved.

5. Environmental information

Not retrieved. No source I found describes environmental, lifestyle or infectious contributors.

6. Mechanism and pathophysiology

An ordered causal chain follows. Steps 1–3 are well established from CNP–NPR2 biology. They are my recall and were not verified in a retrieved paper.

1. A heterozygous NPR2 variant reduces functional NPR2 protein, through lower expression or impaired function. The 2025 study supports reduced protein expression (PMC12315304).
2. This leads to reduced CNP-stimulated cGMP production in growth-plate chondrocytes. (Inferred from established receptor biology.)
3. Reduced cGMP signaling impairs chondrocyte proliferation and differentiation in the growth plate, which reduces endochondral bone growth. The 2025 paper links NPR2 variants to altered chondrocyte differentiation through JAK2–STAT5 (PMC12315304).
4. Reduced long-bone growth results in short stature, with disproportion (long arm span and relatively long trunk) and short metacarpals.
5. Because only one allele is affected, the effect is milder than in biallelic AMD1. This is an inferred dosage relationship.

Suggested ontology terms, each needing a lookup: - GO: receptor guanylyl cyclase signaling pathway; cGMP biosynthetic process; chondrocyte differentiation. - CL: chondrocyte. - UBERON: epiphyseal growth plate.

Omics, single-cell and functional-screen data were not retrieved.

7. Anatomical structures affected

• Organs and tissues. The long bones and the hand skeleton, specifically the metacarpals. The growth plate cartilage is the likely primary site.
• Cells. Growth-plate chondrocytes.
• Subcellular. NPR2 is a plasma-membrane receptor (GO cellular component: plasma membrane).
• Lateralization. Not retrieved. A genetic skeletal growth disorder is presumably bilateral, but I found no source stating this.

8. Temporal development

Not retrieved. A MedGen description describes progressive short stature in heterozygotes, but I did not confirm this against a primary source.

9. Inheritance and population

• Inheritance. Autosomal dominant (OMIM); see the PanelApp caveat above.
• Prevalence. No SNSK1 prevalence was found. The 2–6% figure for ISS is the only quantitative population estimate retrieved.
• Penetrance, expressivity and founder effects. Expressivity is variable, from the "mild and variable" description above. Penetrance, founder effects, carrier frequency, sex ratio and geography were not retrieved.

10. Diagnostics

• Clinical. Measure height, arm span and sitting height. Take a bone-age radiograph and a hand radiograph for metacarpal length.
• Endocrine workup. Normal endocrine function is part of the definition ("no endocrine abnormalities").
• Genetic. NPR2 is on skeletal-dysplasia and short-stature gene panels (PanelApp). Exome or panel testing is the practical route.
• Differential.
• SNSK2 (IHH) and BDA1.
• SHOX-related short stature.
• Biallelic AMD1.
• ISS from other causes.
• Not retrieved. GeneReviews coverage (run just check-genereviews on the entry), newborn screening, and omics-based diagnostics.

11. Outcome and prognosis

Not retrieved. No survival or morbidity data were found. The sources describe a skeletal phenotype without non-skeletal complications. Note this as an absence in the sources, not as a finding.

12. Treatment

• Established therapy. Nothing retrieved. In practice, recombinant growth hormone has been used in ISS and NPR2-variant short stature. I did not verify response data (unverified recall).
• Related advanced therapy. A CNP analog (vosoritide) is approved for achondroplasia. Its use in heterozygous NPR2 short stature was not verified. Search ClinicalTrials.gov before stating anything.
• NCIT terms to consider. Pharmacotherapy (NCIT:C15986), with a specific agent bound through therapeutic_agent. Look the IDs up.

13. Prevention

Genetic counseling for autosomal dominant inheritance (NCIT:C15240). Nothing else was retrieved.

14. Other species and natural disease

Not retrieved. Check OMIA for naturally occurring Npr2 variants.

15. Model organisms

Not retrieved from these searches. Known mouse models of Npr2 loss (for example cn/cn, "cn" for "chondrodysplasia") exist (unverified recall). Check MGI and the Alliance of Genome Resources before curating.

Curation notes for the KB entry

• Bind disease_term to MONDO:0014551. Record SNSK2 (IHH) as a sibling and not a subtype. Record AMD1 as the biallelic counterpart.
• The inheritance conflict (OMIM autosomal dominant versus PanelApp mono-/biallelic) is worth a note in the entry.
• Fetch and read the primary papers before writing any evidence snippet. I have none verified.
• If this entry is curated, claim the disease through the claim issue process and delete its stub in stubs/ in the same PR.

Sources

• MalaCards: SNSK1
• KEGG H02681
• MedGen C4225399 (mirror)
• PMC12315304: NPR2 variants and chondrocyte differentiation via JAK2–STAT5
• PanelApp: NPR2 (panel 1471)
• MedChemExpress page referencing PMID 24001744

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

• PMC:PMC12315304: "mild and variable degrees of short stature without a distinct phenotype"
• The PMC ID service was unreachable, so the quote was not checked

1 of 2 references resolved; the rest could not be looked up either way.

Term Validation

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

Every term resolved, and every label the report gave matched.