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Inheritance

1

Autosomal Dominant HP:0000006

Heterozygous NPR2 loss-of-function variants segregate with short stature in an autosomal dominant pattern. De novo variants also occur. Expressivity is variable, and some heterozygous family members have heights within or near the normal range.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:24001744 SUPPORT Human clinical

"These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7)."

Family segregation of three functionally deficient heterozygous NPR2 variants with short stature establishes dominant inheritance.

PMID:25703509 SUPPORT Human clinical

"We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant."

A case-control sequencing study found heterozygous NPR2 variants only in short patients, including one de novo variant.

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Discussions and Knowledge Gaps

1

Do dominant-negative missense alleles cause more severe growth failure than haploinsufficient alleles? Registry data show truncating alleles associated with shorter height than non-truncating alleles.

KNOWLEDGE GAP OPEN npr2_allele_class_and_severity

Attached to

pathophysiology#Reduced CNP-Stimulated NPR-B cGMP Production

In vitro, many missense alleles suppress wild-type receptor output, which predicts a larger loss than haploinsufficiency. The registry association runs the other way, so the in vitro assay may not reflect the dosage of NPR-B signalling in the growth plate.

Show evidence (1 reference)

PMID:40424589 SUPPORT Human clinical

"Patients with a truncating NPR2 variant had a shorter height compared to children with a non-truncating variant (-3.3 vs -2.5 SDS, P = .02)."

The genotype-severity association that motivates the question.

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Pathophysiology

4

Heterozygous NPR2 Loss-of-Function Variant

A single pathogenic NPR2 allele, germline and frequently inherited from a similarly short parent, initiates the disease. Allele classes include missense, splice-site and truncating variants spread across the ligand-binding, kinase-homology and guanylyl-cyclase domains.

NPR2 hgnc:7944

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Reduced CNP-Stimulated NPR-B cGMP Production Mutant receptors fail to generate cGMP in response to CNP and, for dominant-negative alleles, also suppress the wild-type receptor. This leaves heterozygotes with less than normal NPR-B output.

Show evidence (1 reference)

PMID:40424589 SUPPORT Human clinical

"Of these variants, 5 were truncating, 11 were non-truncating, and 2 were splice site. Most were located in the ligand binding domain or kinase homology domain (KHD)."

A national registry cohort documents the allelic spectrum and domain distribution of heterozygous NPR2 variants.

Reduced CNP-Stimulated NPR-B cGMP Production

NPR-B is a homodimeric receptor guanylyl cyclase. Heterozygous variants lower CNP-stimulated cGMP output by three routes: loss of one functional allele (haploinsufficiency); retention of misfolded receptor in the endoplasmic reticulum; or dominant-negative poisoning of wild-type subunits by catalytically dead mutant receptors that still reach the cell surface. The route varies by allele.

NPR2 hgnc:7944

receptor guanylyl cyclase signaling pathway GO:0007168 ↓ DECREASED cGMP biosynthetic process GO:0006182 ↓ DECREASED

guanylate cyclase activity GO:0004383 ↓ DECREASED natriuretic peptide receptor activity GO:0016941 ↓ DECREASED

Animal models

Npr2 cn/cn mouse Mouse partially recapitulates A catalytic-domain missense allele leaves chondrocytes unable to raise cGMP in response to CNP.

Npr2 (GC-B) knockout mouse Mouse partially recapitulates Null mice lack GC-B entirely, and the authors attribute the endochondral-ossification defect to loss of CNP-stimulated rather than basal GC-B activity, the quantity this node describes.

Downstream

Growth-Plate Chondrocyte Differentiation Deficit CNP/cGMP signalling normally restrains FGF-driven ERK activation in chondrocytes. Less NPR-B output weakens that brake, which reduces chondrocyte differentiation and hypertrophy.

Show evidence (4 references)

PMID:24001744 SUPPORT In vitro / ex vivo

"Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect."

Co-expression mimicking the heterozygous state shows mutant receptors suppress wild-type cGMP output.

PMID:24471569 SUPPORT In vitro / ex vivo

"R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression."

Two dominant-negative alleles reach the same outcome by different routes, one through ER retention and one at the cell surface.

PMID:26075495 SUPPORT In vitro / ex vivo

"Six were demonstrated to affect NPR-B cell trafficking and/or its ability to synthesize cyclic GMP (cGMP) under response to natriuretic peptide precursor C/brain natriuretic peptide stimulation."

Functional characterization of variants from disproportionate short stature referrals confirms trafficking and catalytic defects.

+ 1 more reference

Growth-Plate Chondrocyte Differentiation Deficit

In growth-plate chondrocytes, reduced NPR-B signalling impairs differentiation toward the hypertrophic state. Some misfolded mutant receptors also add endoplasmic-reticulum stress and chondrocyte apoptosis.

growth plate cartilage chondrocyte CL:1000217 hypertrophic chondrocyte CL:0000743

chondrocyte hypertrophy GO:0003415 ↓ DECREASED CNP-dependent restraint of the ERK1/2 cascade GO:0070373 ↓ DECREASED

growth plate cartilage UBERON:0004129

Animal models

Npr2 pwe/pwe mouse Mouse partially recapitulates Npr2 loss shrinks the proliferative and hypertrophic zones of the growth plate and raises activated ERK1/2 in the tibia, the chondrocyte deficit this node describes.

Downstream

Reduced Endochondral Longitudinal Bone Growth Fewer and less fully differentiated hypertrophic chondrocytes limit longitudinal elongation of endochondral bones.

Show evidence (2 references)

PMID:35455946 SUPPORT In vitro / ex vivo

"we found that ATDC5 cells with mutant NPR2 gene showed decreased differentiation, as evidenced by lower expression of ColII, ColX, and BMP4 and higher expression of Sox9."

Chondrogenic cells expressing patient NPR2 variants, including SNSK alleles, show impaired differentiation.

PMID:35455946 SUPPORT In vitro / ex vivo

"Moreover, the apoptosis rate was elevated in ATDC5 cells expressing the mutant NPR2 gene."

Mutant receptor expression also increases chondrocyte apoptosis.

Reduced Endochondral Longitudinal Bone Growth

Partial loss of NPR-B signalling reduces longitudinal bone growth less than biallelic loss does. The deficit accumulates through childhood and gives mild to moderate short stature, sometimes with mild limb disproportion and short hand bones.

endochondral bone growth GO:0003416 ↓ DECREASED endochondral ossification GO:0001958 ↓ DECREASED

growth plate cartilage UBERON:0004129

Animal models

Npr2 pwe/pwe mouse Mouse rescues MEK1/2 inhibitors restore growth of cultured fetal mutant tibiae, placing ERK disinhibition between Npr2 loss and the bone-growth deficit.

Npr2 cn/cn mouse Mouse partially recapitulates cn/cn mice have disproportionate dwarfism with short limbs and tail from disturbed chondrogenesis during endochondral ossification, the bone-growth outcome of the cGMP deficit this model also shows.

Npr2 (GC-B) knockout mouse Mouse partially recapitulates Loss of GC-B impairs endochondral ossification and longitudinal vertebral and limb-bone growth.

Downstream

Short Stature Reduced longitudinal bone growth directly lowers attained height.

Progressive Postnatal Height Deficit Because the growth deficit acts throughout childhood, the height SDS of heterozygous children falls as they grow.

Mild Disproportionate Short Stature Limb growth is affected somewhat more than trunk growth in some patients, giving mild disproportion.

Short Metacarpals Reduced growth of short tubular bones of the hand gives short metacarpals.

Clinodactyly Altered growth of the phalanges can give finger clinodactyly.

Small for Gestational Age Reduced prenatal longitudinal growth can show as small-for-gestational-age birth length in some heterozygotes.

Show evidence (2 references)

PMID:24471569 SUPPORT BACKGROUND Human clinical

"C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae."

States the role of CNP/NPR-B in endochondral longitudinal growth that heterozygous variants impair.

PMID:32720985 SUPPORT Human clinical

"Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature with by increasing loss of height potential with age."

A family carrying both genotypes shows a dosage relationship: heterozygous growth impairment is milder than biallelic.

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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.

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Phenotypes

8

Limbs 2

Short Metacarpals HP:0010049

Show evidence (1 reference)

PMID:35741827 SUPPORT Human clinical

"In three probands (P4, P5, and P7), we found additional skeletal findings, such as a shortened metacarpal bone of the fourth and fifth finger, a slightly shortened proximal part of the lower and upper extremities, clinodactyly and micrognathia"

Short fourth and fifth metacarpals were recorded in heterozygous probands.

Clinodactyly HP:0030084

Show evidence (1 reference)

PMID:35741827 SUPPORT Human clinical

"In three probands (P4, P5, and P7), we found additional skeletal findings, such as a shortened metacarpal bone of the fourth and fifth finger, a slightly shortened proximal part of the lower and upper extremities, clinodactyly and micrognathia"

Clinodactyly was recorded among the minor skeletal findings.

Musculoskeletal 1

Delayed Bone Age FREQUENT Delayed skeletal maturation HP:0002750

Show evidence (1 reference)

PMID:35741827 SUPPORT Human clinical

"In total, 9/12 probands had delayed bone age (range: -1.88 to -0.15 SDS), whereas in 3/12 (P2, P6, and P12), the probands bone age was advanced (range: +0.42 SDS to +1.44 SDS)."

Delayed bone age in 9 of 12 heterozygous probands, advanced in the remaining 3.

Growth 5

Short Stature VERY_FREQUENT HP:0004322

Show evidence (2 references)

PMID:24001744 SUPPORT Human clinical

"Affected patients have mild and variable degrees of short stature without a distinct phenotype."

The defining feature is mild, variable short stature without a recognizable syndrome.

PMID:40424589 SUPPORT Human clinical

"Median (IQR) baseline height SDS was -2.9 (-3.3 to -2.4)."

Quantifies the typical height deficit in a 27-child cohort.

Progressive Postnatal Height Deficit Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:32720985 SUPPORT Human clinical

"Height z-scores progressively and significantly decreased as NPR2-heterozygous children matured, while remaining constant in their wild-type siblings."

Longitudinal family data show the progressive loss of height SDS.

Mild Disproportionate Short Stature FREQUENT HP:0003498

Show evidence (4 references)

PMID:40424589 SUPPORT Human clinical

"Mild features suggestive of a skeletal dysplasia were found in 89%, most frequently mild disproportion and dysmorphic features of the hands."

Mild disproportion was the most frequent skeletal sign.

PMID:26075495 SUPPORT Human clinical

"All pathogenic mutations were detected in the suspected LWD referral group (∼3%)."

Pathogenic heterozygous NPR2 variants were found among patients referred for disproportionate, Leri-Weill-like short stature.

PMID:16384845 REFUTE Human clinical

"However, there was no difference in body proportion between carriers and noncarriers."

In the first family studied, carriers were short but not disproportionate, so disproportion is not a constant feature.

+ 1 more reference

Small for Gestational Age HP:0001518

Show evidence (2 references)

PMID:35741827 SUPPORT Human clinical

"8.8% participants born small for their gestational age (SGA) carried the NPR2 causal variant."

NPR2 variants were found among SGA-born children with short stature.

PMID:30602027 SUPPORT Human clinical

"Four of the genes are associated with growth plate development, IHH (n = 2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1)"

Two of 55 SGA children with isolated short stature carried NPR2 variants.

Increased Body Mass Index HP:0031418

Show evidence (1 reference)

PMID:35741827 SUPPORT Human clinical

"A clinically relevant increase in BMI (a mean gain in the BMI SDS of +1.41), a characteristic previously not reported in NPR2 individuals, was observed."

A single cohort reports a rise in BMI SDS in heterozygous NPR2 individuals.

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Genetic Associations

1

NPR2 (Causative)

Gene: NPR2 hgnc:7944 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:25703509 SUPPORT Human clinical

"With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature."

Case-control sequencing plus functional testing establishes heterozygous NPR2 loss of function as a cause of short stature.

PMID:16384845 SUPPORT Human clinical

"We have shown that heterozygous mutations in NPR2 are associated with short stature."

The first family-based study of heterozygous carriers of an AMDM allele showed reduced stature compared with non-carrier relatives.

PMID:35455946 SUPPORT BACKGROUND Human clinical

"Loss-of-function (LOF) mutations in NPR2 cause acromesomelic dysplasia, Maroteaux type (AMDM #602875), and short stature with nonspecific skeletal abnormalities (SNSK #616255)"

Places SNSK with AMDM as the two NPR2 loss-of-function disorders.

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Medical Actions

2

Somatropin Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: Somatropin NCIT:C837

Platform: Protein replacement

Recombinant human growth hormone is widely used, often under idiopathic or SGA short-stature indications. Early reports described little response. Larger cohorts report height gains, greater in prepubertal than in pubertal children, with variable individual response. No controlled trial in this disease has been reported.

Target Phenotypes: Short stature HP:0004322

Show evidence (4 references)

PMID:40424589 SUPPORT Human clinical

"After 2 years of GH treatment, median height gain SDS in prepubertal children was 1.2 (0.8 to 1.4) and in pubertal children 0.5 (0.3 to 0.9)."

Registry data show height gain on GH, uncontrolled.

PMID:31990356 SUPPORT Human clinical

"The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment."

Five children with familial short stature showed a sustained response.

PMID:24001744 REFUTE Human clinical

"All three of these patients were treated with recombinant human GH (33-50 μg/kg · d) without significant height SD score change during therapy."

An early series reported no meaningful response.

+ 1 more reference

Vosoritide (Investigational)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: vosoritide NCIT:C152918

Platform: Peptide

Vosoritide is a CNP analogue approved for achondroplasia. In a phase 2 open-label basket trial (NCT04219007) it increased annualized growth velocity in children with heterozygous NPR2 deficiency among other genetic short stature groups. It is investigational for this indication. Slipped capital femoral epiphysis and genu valgum were seen in the basket trial but not in the NPR2 subgroup.

Mechanism Target:

ACTIVATES Reduced CNP-Stimulated NPR-B cGMP Production — The CNP analogue stimulates the remaining functional NPR-B receptors and raises cGMP signalling in growth-plate chondrocytes.

Show evidence (1 reference)

PMID:41967490 SUPPORT BACKGROUND Human clinical

"Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia."

Identifies vosoritide as a CNP analogue. The pathway it inhibits is the MAPK cascade downstream of the receptor; acting as a CNP analogue, it stimulates NPR-B and raises cGMP, which is the ACTIVATES edge recorded here, and the MAPK inhibition is a consequence of that.

Target Phenotypes: Short stature HP:0004322

Show evidence (2 references)

PMID:41967490 SUPPORT Human clinical

"The increase in AGV was seen in all genetic subgroups."

Growth velocity rose in the NPR2 subgroup as in the other subgroups of the trial.

PMID:42678892 SUPPORT Human clinical

"In the basket trial, SCFE was observed in 2/12 participants with ACAN mutations, 1/11 with RASopathy but not in the 7 participants with NPR2 mutations or 24 with hypochondroplasia."

Safety signal context; no SCFE occurred in the NPR2 subgroup.

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Diagnosis

1

Gene Panel or Exome Sequencing in Idiopathic or Familial Short Stature

The phenotype is nonspecific, so the diagnosis is usually made by sequencing NPR2 in children first classified as idiopathic, familial, or SGA short stature, or SHOX-negative Leri-Weill-like short stature. Reported diagnostic yields are about 2-7% depending on the cohort.

Show evidence (5 references)

PMID:24001744 SUPPORT Human clinical

"We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS."

Yield in a Brazilian ISS cohort of 47 patients.

PMID:24471569 SUPPORT Human clinical

"We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature."

Yield in 101 Japanese patients with short stature.

PMID:31990356 SUPPORT Human clinical

"In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified"

Yield in a cohort with familial short stature.

+ 2 more references

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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Short Stature With Nonspecific Skeletal Abnormalities 1:

Acromesomelic Dysplasia, Maroteaux Type MONDO:0011275

Overlapping Features The allelic recessive disorder caused by biallelic NPR2 loss of function. It gives severe disproportionate acromesomelic short stature rather than the mild phenotype of heterozygotes.

Distinguishing Features

Biallelic rather than heterozygous NPR2 variants.
Severe short stature with acromesomelic limb shortening and marked brachydactyly.

Show evidence (1 reference)

PMID:32720985 SUPPORT Human clinical

"Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature with by increasing loss of height potential with age."

Contrasts the biallelic and heterozygous phenotypes within one family.

SHOX Deficiency (Leri-Weill Dyschondrosteosis)

Overlapping Features SHOX haploinsufficiency gives disproportionate short stature that heterozygous NPR2 variants can mimic. Madelung deformity favours SHOX deficiency.

Distinguishing Features

Madelung deformity has not been reported in heterozygous NPR2 patients.
SHOX or SHOX-enhancer defect on molecular testing.

Show evidence (1 reference)

PMID:26075495 SUPPORT Human clinical

"However, no patient has yet presented with Madelung deformity."

Absence of Madelung deformity separates NPR2 patients from classic LWD.

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Animal Models

3

Npr2 pwe/pwe mouse

A recessive loss-of-function Npr2 allele that models acromesomelic dysplasia, Maroteaux type. It shows the growth-plate consequence of losing NPR-B signalling and the ERK disinhibition behind it. Because it is biallelic, it bears on the mechanism of the heterozygous disease but not on its size.

Species

Mouse

Genotype

Npr2 pwe/pwe (L313X premature stop codon), homozygous

Publication

PMID:23065701

Pathograph links

Growth-Plate Chondrocyte Differentiation Deficit partially recapitulates fidelity: moderate observes: tissue Npr2 loss shrinks the proliferative and hypertrophic zones of the growth plate and raises activated ERK1/2 in the tibia, the chondrocyte deficit this node describes.

Limitations: Homozygous null rather than heterozygous, so the deficit is far larger than in patients with one variant allele; the model says nothing about the dominant-negative alleles some heterozygotes carry.

Divergences from the human mechanism

population mismatch qualifying

The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this entry describes. It shows the direction of the mechanism, not the size of the partial deficit that one remaining allele leaves.

species mismatch qualifying

Mouse long-bone growth plates do not fuse at sexual maturity as human ones do, and longitudinal growth runs over weeks rather than the years of human childhood, so the timing of the deficit and its effect on final height do not transfer directly to patients.

Readouts

Growth-plate proliferative and hypertrophic zone size

Direction: DECREASED

Interpretation: Histological correlate of the chondrocyte deficit.

Show evidence (1 reference)

PMID:23065701 SUPPORT Model organism

"We determined that the loss of Npr2 causes a reduction in the hypertrophic and proliferative zones of the growth plate, but mineralization of skeletal elements is normal."

Reports the growth-plate zone reduction in Npr2 pwe/pwe mice.

Activated ERK1/2 in tibia

Direction: INCREASED

Interpretation: Loss of the cGMP restraint on ERK that the upstream edge of this node describes.

Show evidence (1 reference)

PMID:23065701 SUPPORT Model organism

"Mutant tibiae have increased levels of the activated form of ERK1/2, consistent with the idea that natriuretic peptide receptor type 2 (NPR2) signaling inhibits the activation of the MEK/ERK mitogen activated protein kinase pathway."

Reports raised ERK1/2 activation in mutant tibiae.

Show evidence (1 reference)

PMID:23065701 SUPPORT Model organism

"We determined that the loss of Npr2 causes a reduction in the hypertrophic and proliferative zones of the growth plate, but mineralization of skeletal elements is normal."

Supports treating this model as informative for the chondrocyte node.

Reduced Endochondral Longitudinal Bone Growth rescues fidelity: low observes: tissue MEK1/2 inhibitors restore growth of cultured fetal mutant tibiae, placing ERK disinhibition between Npr2 loss and the bone-growth deficit.

Limitations: The rescue was shown in fetal tibia explants, not in living animals or postnatal bone, and in a homozygous null rather than a heterozygous model.

Divergences from the human mechanism

population mismatch qualifying

The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this entry describes. It shows the direction of the mechanism, not the size of the partial deficit that one remaining allele leaves.

species mismatch qualifying

Mouse long-bone growth plates do not fuse at sexual maturity as human ones do, and longitudinal growth runs over weeks rather than the years of human childhood, so the timing of the deficit and its effect on final height do not transfer directly to patients.

boundary omission qualifying

Explant culture removes the systemic and postnatal growth context, so the rescue shows a cell-autonomous growth-plate mechanism but not the childhood height deficit the node leads to.

Show evidence (1 reference)

PMID:23065701 SUPPORT In vitro / ex vivo

"Treatment of fetal tibiae explants with mitogen activated protein kinase 1 and 2 inhibitors U0126 and PD325901 rescues the Npr2(pwe/pwe) growth defect"

MEK inhibition reverses the bone-growth defect in mutant tibia explants.

Show evidence (1 reference)

PMID:23065701 SUPPORT Model organism

"The Npr2(pwe/pwe) mouse is a model for the human skeletal dysplasia acromesomelic dysplasia, Maroteaux type (AMDM)."

Establishes the model, and that it models the biallelic NPR2 disease rather than this one.

Npr2 cn/cn mouse

A spontaneous recessive achondroplastic mouse with disproportionate dwarfism, short limbs and tail. Its Npr2 missense allele abolishes CNP-stimulated cGMP production, the molecular step this entry's mechanism starts from.

Species

Mouse

Genotype

Npr2 cn/cn (Leu-to-Arg substitution in the guanylyl cyclase domain), homozygous

Publication

PMID:15722353

Pathograph links

Reduced CNP-Stimulated NPR-B cGMP Production partially recapitulates fidelity: moderate observes: cellular A catalytic-domain missense allele leaves chondrocytes unable to raise cGMP in response to CNP.

Limitations: Homozygous, so cGMP output is absent rather than reduced. The measurement was made in cultured chondrocytes from the mice and in transfected COS-7 cells, not in the growth plate in vivo.

Divergences from the human mechanism

population mismatch qualifying

The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this entry describes. It shows the direction of the mechanism, not the size of the partial deficit that one remaining allele leaves.

species mismatch immaterial

Mouse growth plates do not fuse at sexual maturity and mouse longitudinal growth runs over weeks, but this link claims only that NPR-B loss lowers CNP-stimulated cGMP output, which does not depend on growth-plate timing.

Readouts

CNP-stimulated intracellular cGMP in chondrocytes

Direction: ABOLISHED

Interpretation: Direct readout of NPR-B guanylyl cyclase output.

Show evidence (1 reference)

PMID:15722353 SUPPORT In vitro / ex vivo

"In cultured chondrocytes of cn/cn mice, stimulus with CNP did not significantly increase intracellular cGMP concentration, whereas it increased in +/+ mice."

CNP fails to raise cGMP in chondrocytes cultured from cn/cn mice.

Show evidence (1 reference)

PMID:15722353 SUPPORT Model organism

"We therefore concluded that the dwarf phenotype of cn/cn mouse is caused by a loss-of-function mutation of the Npr2 gene"

Ties the cn/cn dwarfism to loss of Npr2 function.

Reduced Endochondral Longitudinal Bone Growth partially recapitulates fidelity: moderate observes: tissue cn/cn mice have disproportionate dwarfism with short limbs and tail from disturbed chondrogenesis during endochondral ossification, the bone-growth outcome of the cGMP deficit this model also shows.

Limitations: Homozygous, so the growth failure is a dysplasia rather than the mild short stature of heterozygous patients.

Divergences from the human mechanism

population mismatch qualifying

The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this entry describes. It shows the direction of the mechanism, not the size of the partial deficit that one remaining allele leaves.

species mismatch qualifying

Mouse long-bone growth plates do not fuse at sexual maturity as human ones do, and longitudinal growth runs over weeks rather than the years of human childhood, so the timing of the deficit and its effect on final height do not transfer directly to patients.

Show evidence (1 reference)

PMID:15722353 SUPPORT Model organism

"The achondroplastic mouse is a spontaneous mutant characterized by disproportionate dwarfism with short limbs and tail due to disturbed chondrogenesis during endochondral ossification."

Reports short limbs and tail from disturbed endochondral ossification in cn/cn mice.

Show evidence (1 reference)

PMID:15722353 SUPPORT Model organism

"The achondroplastic mouse is a spontaneous mutant characterized by disproportionate dwarfism with short limbs and tail due to disturbed chondrogenesis during endochondral ossification."

Describes the cn/cn skeletal phenotype.

Npr2 (GC-B) knockout mouse

Gene-targeted GC-B null mice have impaired endochondral ossification and shortened vertebrae and limb bones, along with female infertility from failed reproductive-tract development.

Species

Mouse

Genotype

Npr2 null (gene-targeted guanylyl cyclase B deficiency), homozygous

Publication

PMID:15572448

Pathograph links

Reduced Endochondral Longitudinal Bone Growth partially recapitulates fidelity: moderate observes: tissue Loss of GC-B impairs endochondral ossification and longitudinal vertebral and limb-bone growth.

Limitations: Complete null, so growth failure is far more severe than in heterozygous patients; the female infertility of null mice has no counterpart in this entry.

Divergences from the human mechanism

population mismatch qualifying

The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this entry describes. It shows the direction of the mechanism, not the size of the partial deficit that one remaining allele leaves.

species mismatch qualifying

Mouse long-bone growth plates do not fuse at sexual maturity as human ones do, and longitudinal growth runs over weeks rather than the years of human childhood, so the timing of the deficit and its effect on final height do not transfer directly to patients.

Show evidence (1 reference)

PMID:15572448 SUPPORT Model organism

"A dramatic impairment of endochondral ossification and an attenuation of longitudinal vertebra or limb-bone growth were seen in null animals."

Shows reduced endochondral bone growth in GC-B null mice.

Reduced CNP-Stimulated NPR-B cGMP Production partially recapitulates fidelity: low observes: molecular Null mice lack GC-B entirely, and the authors attribute the endochondral-ossification defect to loss of CNP-stimulated rather than basal GC-B activity, the quantity this node describes.

Limitations: The abstract states that CNP-stimulated activity "appeared to be required"; it does not report a cGMP measurement in growth-plate chondrocytes, so this link rests on the authors' inference. A complete null removes the receptor rather than reducing its output, and cannot represent the dominant-negative alleles some heterozygous patients carry.

Divergences from the human mechanism

population mismatch qualifying

The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this entry describes. It shows the direction of the mechanism, not the size of the partial deficit that one remaining allele leaves.

species mismatch immaterial

Mouse growth plates do not fuse at sexual maturity and mouse longitudinal growth runs over weeks, but this link claims only that NPR-B loss lowers CNP-stimulated cGMP output, which does not depend on growth-plate timing.

Show evidence (1 reference)

PMID:15572448 SUPPORT INDIRECT Model organism

"C-type natriuretic peptide-dependent increases of guanylyl cyclase B activity, but not basal enzyme activity, appeared to be required for the progression of endochondral ossification."

Places the bone defect of null mice on loss of CNP-stimulated GC-B activity. This is an inference stated by the authors rather than a direct cGMP readout, hence INDIRECT.

Show evidence (1 reference)

PMID:15572448 SUPPORT Model organism

"C-type natriuretic peptide-dependent increases of guanylyl cyclase B activity, but not basal enzyme activity, appeared to be required for the progression of endochondral ossification."

Reports that the bone phenotype of null mice depends on loss of CNP-stimulated GC-B activity rather than basal activity.

{ }

Source YAML

click to show

name: Short Stature With Nonspecific Skeletal Abnormalities 1
creation_date: "2026-10-20T00:00:00Z"
category: Mendelian
description: >-
  Short stature with nonspecific skeletal abnormalities 1 (SNSK) is an autosomal
  dominant growth disorder caused by heterozygous loss-of-function variants in
  NPR2, which encodes natriuretic peptide receptor B (NPR-B), the guanylyl
  cyclase receptor for C-type natriuretic peptide (CNP). It is the heterozygous,
  allelic counterpart of acromesomelic dysplasia, Maroteaux type, which is caused
  by biallelic NPR2 loss of function. Reduced CNP-stimulated cGMP production,
  through haploinsufficiency or dominant-negative interference with the
  wild-type receptor, weakens the CNP/NPR-B restraint on MAPK signalling in
  growth-plate chondrocytes and limits endochondral longitudinal bone growth.
  Affected individuals have mild to moderate short stature, often first
  classified as idiopathic or familial short stature. The deficit can become
  more pronounced with age. Mild disproportion and minor hand findings such as
  short metacarpals or clinodactyly are common but not consistent.
synonyms:
- SNSK
- NPR2-related short stature
- heterozygous NPR2 deficiency
disease_term:
  preferred_term: short stature with nonspecific skeletal abnormalities 1
  term:
    id: MONDO:0014551
    label: short stature with nonspecific skeletal abnormalities 1
parents:
- Skeletal Dysplasia
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous NPR2 loss-of-function variants segregate with short stature in
    an autosomal dominant pattern. De novo variants also occur. Expressivity is
    variable, and some heterozygous family members have heights within or near
    the normal range.
  evidence:
  - reference: PMID:24001744
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These three mutations segregated with short stature phenotype in an
      autosomal dominant pattern (height SD score ranged from -4.5 to -1.7).
    explanation: >-
      Family segregation of three functionally deficient heterozygous NPR2
      variants with short stature establishes dominant inheritance.
  - reference: PMID:25703509
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We enrolled 192 unrelated patients with short stature and 192 controls of
      normal height and identified seven heterozygous NPR2 missense or splice
      site mutations all in the short stature patients, including one de novo
      splice site variant.
    explanation: >-
      A case-control sequencing study found heterozygous NPR2 variants only in
      short patients, including one de novo variant.
genetic:
- name: NPR2
  gene_term:
    preferred_term: NPR2
    term:
      id: hgnc:7944
      label: NPR2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Heterozygous missense, splice-site and truncating variants. Missense alleles
    act through ER retention, loss of catalytic activity, or dominant-negative
    interference with the wild-type subunit. Truncating alleles act by
    haploinsufficiency. Gain-of-function NPR2 variants cause the opposite
    phenotype (overgrowth; epiphyseal chondrodysplasia, Miura type).
  notes: >-
    No ClinGen gene-disease validity assertion for NPR2 and this disease was found
    in the local ClinGen cache, so gene_disease_validity is left unset.
  evidence:
  - reference: PMID:25703509
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With these data, we were able to rigorously verify that NPR2 functional
      haploinsufficiency contributes to short stature.
    explanation: >-
      Case-control sequencing plus functional testing establishes heterozygous
      NPR2 loss of function as a cause of short stature.
  - reference: PMID:16384845
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have shown that heterozygous mutations in NPR2 are associated with
      short stature.
    explanation: >-
      The first family-based study of heterozygous carriers of an AMDM allele
      showed reduced stature compared with non-carrier relatives.
  - reference: PMID:35455946
    reference_title: "Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function (LOF) mutations in NPR2 cause acromesomelic dysplasia, Maroteaux type (AMDM #602875), and short stature with nonspecific skeletal abnormalities (SNSK #616255)"
    explanation: >-
      Places SNSK with AMDM as the two NPR2 loss-of-function disorders.
pathophysiology:
- name: Heterozygous NPR2 Loss-of-Function Variant
  description: >-
    A single pathogenic NPR2 allele, germline and frequently inherited from a
    similarly short parent, initiates the disease. Allele classes include
    missense, splice-site and truncating variants spread across the
    ligand-binding, kinase-homology and guanylyl-cyclase domains.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NPR2
    term:
      id: hgnc:7944
      label: NPR2
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:40424589
    reference_title: "Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these variants, 5 were truncating, 11 were non-truncating, and 2 were
      splice site. Most were located in the ligand binding domain or kinase
      homology domain (KHD).
    explanation: >-
      A national registry cohort documents the allelic spectrum and domain
      distribution of heterozygous NPR2 variants.
  downstream:
  - target: Reduced CNP-Stimulated NPR-B cGMP Production
    causal_link_type: DIRECT
    description: >-
      Mutant receptors fail to generate cGMP in response to CNP and, for
      dominant-negative alleles, also suppress the wild-type receptor. This
      leaves heterozygotes with less than normal NPR-B output.
    evidence:
    - reference: PMID:24001744
      reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Cells transfected with the three mutants failed to produce cyclic GMP
        after treatment with C-type natriuretic peptide.
      explanation: Patient alleles directly abolish CNP-stimulated cGMP generation.
- name: Reduced CNP-Stimulated NPR-B cGMP Production
  description: >-
    NPR-B is a homodimeric receptor guanylyl cyclase. Heterozygous variants lower
    CNP-stimulated cGMP output by three routes: loss of one functional allele
    (haploinsufficiency); retention of misfolded receptor in the endoplasmic
    reticulum; or dominant-negative poisoning of wild-type subunits by
    catalytically dead mutant receptors that still reach the cell surface. The
    route varies by allele.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NPR2
    term:
      id: hgnc:7944
      label: NPR2
  molecular_functions:
  - preferred_term: guanylate cyclase activity
    term:
      id: GO:0004383
      label: guanylate cyclase activity
    modifier: DECREASED
  - preferred_term: natriuretic peptide receptor activity
    term:
      id: GO:0016941
      label: natriuretic peptide receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: receptor guanylyl cyclase signaling pathway
    term:
      id: GO:0007168
      label: receptor guanylyl cyclase signaling pathway
    modifier: DECREASED
  - preferred_term: cGMP biosynthetic process
    term:
      id: GO:0006182
      label: cGMP biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:24001744
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a
      significant decrease in cGMP levels after C-type natriuretic peptide
      stimulation in comparison with cells cotrasnfected with empty vector and
      wild type, suggesting a dominant-negative effect.
    explanation: >-
      Co-expression mimicking the heterozygous state shows mutant receptors
      suppress wild-type cGMP output.
  - reference: PMID:24471569
    reference_title: "Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R110C was defective in trafficking from the endoplasmic reticulum to the
      Golgi apparatus. In contrast, Q417E showed clear cell surface expression.
    explanation: >-
      Two dominant-negative alleles reach the same outcome by different routes,
      one through ER retention and one at the cell surface.
  - reference: PMID:26075495
    reference_title: "Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Six were demonstrated to affect NPR-B cell trafficking and/or its ability
      to synthesize cyclic GMP (cGMP) under response to natriuretic peptide
      precursor C/brain natriuretic peptide stimulation.
    explanation: >-
      Functional characterization of variants from disproportionate short
      stature referrals confirms trafficking and catalytic defects.
  - reference: PMID:17652215
    reference_title: "Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, L658F mutant impaired wild-type NPR-B-mediated cGMP
      production in a dose-dependent manner, suggesting that short stature
      found in L658F heterozygote can be caused by its dominant-negative effect.
    explanation: >-
      A kinase-homology-domain allele binds CNP normally but inhibits wild-type
      receptor output, explaining short stature in heterozygous parents.
  downstream:
  - target: Growth-Plate Chondrocyte Differentiation Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced cGMP-dependent restraint of FGF-induced ERK1/2 activation
    description: >-
      CNP/cGMP signalling normally restrains FGF-driven ERK activation in
      chondrocytes. Less NPR-B output weakens that brake, which reduces
      chondrocyte differentiation and hypertrophy.
    evidence:
    - reference: PMID:15869918
      reference_title: "Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        CNP and 8-bromo-cGMP strongly and dose-dependently inhibited the
        induction of ERK phosphorylation by FGF2 and FGF18 without changing the
        level of FGFR-3
      explanation: >-
        Establishes the cGMP-mediated restraint on FGF-induced ERK activation
        in chondrocytes that reduced NPR-B output weakens.
    - reference: PMID:23065701
      reference_title: "A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutant tibiae have increased levels of the activated form of ERK1/2,
        consistent with the idea that natriuretic peptide receptor type 2
        (NPR2) signaling inhibits the activation of the MEK/ERK mitogen
        activated protein kinase pathway.
      explanation: >-
        The homozygous Npr2 mutant mouse shows ERK disinhibition in growing
        bone. Heterozygosity is expected to have a partial effect, so this is
        indirect support.
- name: Growth-Plate Chondrocyte Differentiation Deficit
  description: >-
    In growth-plate chondrocytes, reduced NPR-B signalling impairs
    differentiation toward the hypertrophic state. Some misfolded mutant
    receptors also add endoplasmic-reticulum stress and chondrocyte apoptosis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: growth plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: chondrocyte hypertrophy
    term:
      id: GO:0003415
      label: chondrocyte hypertrophy
    modifier: DECREASED
  - preferred_term: CNP-dependent restraint of the ERK1/2 cascade
    term:
      id: GO:0070373
      label: negative regulation of ERK1 and ERK2 cascade
    modifier: DECREASED
  locations:
  - preferred_term: growth plate cartilage
    term:
      id: UBERON:0004129
      label: growth plate cartilage
  evidence:
  - reference: PMID:35455946
    reference_title: "Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we found that ATDC5 cells with mutant NPR2 gene showed decreased
      differentiation, as evidenced by lower expression of ColII, ColX, and
      BMP4 and higher expression of Sox9.
    explanation: >-
      Chondrogenic cells expressing patient NPR2 variants, including SNSK
      alleles, show impaired differentiation.
  - reference: PMID:35455946
    reference_title: "Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Moreover, the apoptosis rate was elevated in ATDC5 cells expressing the mutant NPR2 gene.
    explanation: Mutant receptor expression also increases chondrocyte apoptosis.
  downstream:
  - target: Reduced Endochondral Longitudinal Bone Growth
    causal_link_type: DIRECT
    description: >-
      Fewer and less fully differentiated hypertrophic chondrocytes limit
      longitudinal elongation of endochondral bones.
    evidence:
    - reference: PMID:15869918
      reference_title: "Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In the organ-cultured fetal mouse tibias, CNP and FGF18 counteracted on
        the longitudinal bone growth, and both the size and number of
        hypertrophic chondrocytes.
      explanation: >-
        In intact tibia, CNP signalling controls hypertrophic chondrocyte size
        and number together with longitudinal bone growth.
- name: Reduced Endochondral Longitudinal Bone Growth
  description: >-
    Partial loss of NPR-B signalling reduces longitudinal bone growth less than
    biallelic loss does. The deficit accumulates through childhood and gives
    mild to moderate short stature, sometimes with mild limb disproportion and
    short hand bones.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: endochondral bone growth
    term:
      id: GO:0003416
      label: endochondral bone growth
    modifier: DECREASED
  - preferred_term: endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  locations:
  - preferred_term: growth plate cartilage
    term:
      id: UBERON:0004129
      label: growth plate cartilage
  evidence:
  - reference: PMID:24471569
    reference_title: "Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B)
      signaling is critical for endochondral ossification, which is responsible
      for longitudinal growth in limbs and vertebrae.
    explanation: >-
      States the role of CNP/NPR-B in endochondral longitudinal growth that
      heterozygous variants impair.
  - reference: PMID:32720985
    reference_title: "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas
      heterozygous mutations lead to a subtler phenotype characterized by
      progressive short stature with by increasing loss of height potential
      with age.
    explanation: >-
      A family carrying both genotypes shows a dosage relationship: heterozygous
      growth impairment is milder than biallelic.
  downstream:
  - target: Short Stature
    causal_link_type: DIRECT
    description: Reduced longitudinal bone growth directly lowers attained height.
    evidence:
    - reference: PMID:16384845
      reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Height z-scores of these carriers were -1.8 +/- 1.1 (mean +/- sd), which
        was significantly less than the 23 noncarrier family members (-0.4 +/-
        0.8, P < 0.0005) and the general population (P < 0.0005).
      explanation: Heterozygous carriers are measurably shorter than non-carrier relatives.
  - target: Progressive Postnatal Height Deficit
    causal_link_type: DIRECT
    description: >-
      Because the growth deficit acts throughout childhood, the height SDS of
      heterozygous children falls as they grow.
    evidence:
    - reference: PMID:32720985
      reference_title: "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Height z-scores progressively and significantly decreased as
        NPR2-heterozygous children matured, while remaining constant in their
        wild-type siblings.
      explanation: Longitudinal family data show progressive loss of height SDS in heterozygotes.
  - target: Mild Disproportionate Short Stature
    causal_link_type: DIRECT
    description: >-
      Limb growth is affected somewhat more than trunk growth in some patients,
      giving mild disproportion.
    evidence:
    - reference: PMID:40424589
      reference_title: "Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mild features suggestive of a skeletal dysplasia were found in 89%,
        most frequently mild disproportion and dysmorphic features of the hands.
      explanation: Mild disproportion is the most common skeletal sign in a 27-child registry cohort.
  - target: Short Metacarpals
    causal_link_type: DIRECT
    description: Reduced growth of short tubular bones of the hand gives short metacarpals.
    evidence:
    - reference: PMID:35741827
      reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In three probands (P4, P5, and P7), we found additional skeletal
        findings, such as a shortened metacarpal bone of the fourth and fifth
        finger, a slightly shortened proximal part of the lower and upper
        extremities, clinodactyly and micrognathia
      explanation: Short fourth and fifth metacarpals were recorded in heterozygous probands.
  - target: Clinodactyly
    causal_link_type: DIRECT
    description: Altered growth of the phalanges can give finger clinodactyly.
    evidence:
    - reference: PMID:35741827
      reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In three probands (P4, P5, and P7), we found additional skeletal
        findings, such as a shortened metacarpal bone of the fourth and fifth
        finger, a slightly shortened proximal part of the lower and upper
        extremities, clinodactyly and micrognathia
      explanation: Clinodactyly was recorded among the minor skeletal findings in heterozygous probands.
  - target: Small for Gestational Age
    causal_link_type: DIRECT
    description: >-
      Reduced prenatal longitudinal growth can show as small-for-gestational-age
      birth length in some heterozygotes.
    evidence:
    - reference: PMID:30602027
      reference_title: "Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Four of the genes are associated with growth plate development, IHH (n =
        2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1)
      explanation: >-
        In a cohort of SGA children with isolated short stature, two carried
        NPR2 variants, linking the NPR2 growth-plate deficit to prenatal growth
        restriction.
phenotypes:
- category: Growth
  name: Short Stature
  frequency: VERY_FREQUENT
  description: >-
    Mild to moderate short stature, usually around -2 to -3 SDS and ranging to
    about -4.5 SDS. Patients are usually first classified as idiopathic or
    familial short stature.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24001744
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients have mild and variable degrees of short stature without
      a distinct phenotype.
    explanation: The defining feature is mild, variable short stature without a recognizable syndrome.
  - reference: PMID:40424589
    reference_title: "Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Median (IQR) baseline height SDS was -2.9 (-3.3 to -2.4).
    explanation: Quantifies the typical height deficit in a 27-child cohort.
- category: Growth
  name: Progressive Postnatal Height Deficit
  description: >-
    Height SDS declines as heterozygous children grow, so the deficit is often
    more marked at older ages than in early childhood.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:32720985
    reference_title: "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Height z-scores progressively and significantly decreased as
      NPR2-heterozygous children matured, while remaining constant in their
      wild-type siblings.
    explanation: Longitudinal family data show the progressive loss of height SDS.
- category: Skeletal
  name: Mild Disproportionate Short Stature
  frequency: FREQUENT
  description: >-
    Mild limb-trunk disproportion is common in clinic and registry cohorts. Some
    patients resemble Leri-Weill dyschondrosteosis without Madelung deformity.
    Family-based studies have also reported proportionate short stature, so
    disproportion is not required.
  phenotype_term:
    preferred_term: Disproportionate short stature
    term:
      id: HP:0003498
      label: Disproportionate short stature
  evidence:
  - reference: PMID:40424589
    reference_title: "Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild features suggestive of a skeletal dysplasia were found in 89%, most
      frequently mild disproportion and dysmorphic features of the hands.
    explanation: Mild disproportion was the most frequent skeletal sign.
  - reference: PMID:26075495
    reference_title: "Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All pathogenic mutations were detected in the suspected LWD referral
      group (∼3%).
    explanation: >-
      Pathogenic heterozygous NPR2 variants were found among patients referred
      for disproportionate, Leri-Weill-like short stature.
  - reference: PMID:16384845
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: However, there was no difference in body proportion between carriers and noncarriers.
    explanation: >-
      In the first family studied, carriers were short but not disproportionate,
      so disproportion is not a constant feature.
  - reference: PMID:32720985
    reference_title: "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous relatives had proportionate short stature (height z-scores
      -2.06 ± 0.97, median ± SD) compared with their wild-type siblings (-1.37
      ± 0.59).
    explanation: A second family reported proportionate short stature in heterozygotes.
- category: Skeletal
  name: Short Metacarpals
  description: Shortened fourth and fifth metacarpals are reported in a minority of patients.
  phenotype_term:
    preferred_term: Short metacarpal
    term:
      id: HP:0010049
      label: Short metacarpal
  evidence:
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In three probands (P4, P5, and P7), we found additional skeletal
      findings, such as a shortened metacarpal bone of the fourth and fifth
      finger, a slightly shortened proximal part of the lower and upper
      extremities, clinodactyly and micrognathia
    explanation: Short fourth and fifth metacarpals were recorded in heterozygous probands.
- category: Skeletal
  name: Clinodactyly
  description: Finger clinodactyly is reported as a minor hand finding.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In three probands (P4, P5, and P7), we found additional skeletal
      findings, such as a shortened metacarpal bone of the fourth and fifth
      finger, a slightly shortened proximal part of the lower and upper
      extremities, clinodactyly and micrognathia
    explanation: Clinodactyly was recorded among the minor skeletal findings.
- category: Growth
  name: Small for Gestational Age
  description: >-
    A subset of heterozygotes are born small for gestational age and present
    with short stature in childhood.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 8.8% participants born small for their gestational age (SGA) carried the NPR2 causal variant.
    explanation: NPR2 variants were found among SGA-born children with short stature.
  - reference: PMID:30602027
    reference_title: "Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of the genes are associated with growth plate development, IHH (n =
      2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1)
    explanation: Two of 55 SGA children with isolated short stature carried NPR2 variants.
- category: Skeletal
  name: Delayed Bone Age
  description: >-
    Bone age is delayed in most, but not all, heterozygous probands; a minority
    have advanced bone age.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed bone age
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 9/12 probands had delayed bone age (range: -1.88 to -0.15 SDS),
      whereas in 3/12 (P2, P6, and P12), the probands bone age was advanced
      (range: +0.42 SDS to +1.44 SDS).
    explanation: Delayed bone age in 9 of 12 heterozygous probands, advanced in the remaining 3.
- category: Growth
  name: Increased Body Mass Index
  description: >-
    Reported in one cohort, where BMI SDS rose during follow-up in heterozygous
    probands. Earlier reports found a normal BMI in NPR2 carriers, and the
    authors note that the rise may partly reflect height SDS staying flat
    while weight SDS increases.
  phenotype_term:
    preferred_term: Increasing body mass index during childhood
    term:
      id: HP:0031418
      label: Increased body mass index
  evidence:
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clinically relevant increase in BMI (a mean gain in the BMI SDS of
      +1.41), a characteristic previously not reported in NPR2 individuals, was
      observed.
    explanation: A single cohort reports a rise in BMI SDS in heterozygous NPR2 individuals.
diagnosis:
- name: Gene Panel or Exome Sequencing in Idiopathic or Familial Short Stature
  description: >-
    The phenotype is nonspecific, so the diagnosis is usually made by sequencing
    NPR2 in children first classified as idiopathic, familial, or SGA short
    stature, or SHOX-negative Leri-Weill-like short stature. Reported
    diagnostic yields are about 2-7% depending on the cohort.
  evidence:
  - reference: PMID:24001744
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified heterozygous NPR2 mutations in 6% of patients initially
      classified as ISS.
    explanation: Yield in a Brazilian ISS cohort of 47 patients.
  - reference: PMID:24471569
    reference_title: "Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature.
    explanation: Yield in 101 Japanese patients with short stature.
  - reference: PMID:31990356
    reference_title: "NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified
    explanation: Yield in a cohort with familial short stature.
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of ten heterozygous pathogenic/likely pathogenic NPR2 variants
      and two heterozygous NPR2 variants of uncertain significance were
      detected in twelve participants (frequency of causal variants: 10/150,
      6.7%).
    explanation: Yield in 150 children with idiopathic short stature.
  - reference: PMID:26075495
    reference_title: "Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Thus, NPR2 should be screened in the SHOX-negative LWD referrals.
    explanation: Supports NPR2 testing in SHOX-negative disproportionate short stature.
differential_diagnoses:
- name: Acromesomelic Dysplasia, Maroteaux Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Maroteaux type
    term:
      id: MONDO:0011275
      label: acromesomelic dysplasia 1, Maroteaux type
  description: >-
    The allelic recessive disorder caused by biallelic NPR2 loss of function.
    It gives severe disproportionate acromesomelic short stature rather than
    the mild phenotype of heterozygotes.
  distinguishing_features:
  - Biallelic rather than heterozygous NPR2 variants.
  - Severe short stature with acromesomelic limb shortening and marked brachydactyly.
  evidence:
  - reference: PMID:32720985
    reference_title: "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas
      heterozygous mutations lead to a subtler phenotype characterized by
      progressive short stature with by increasing loss of height potential
      with age.
    explanation: Contrasts the biallelic and heterozygous phenotypes within one family.
- name: SHOX Deficiency (Leri-Weill Dyschondrosteosis)
  description: >-
    SHOX haploinsufficiency gives disproportionate short stature that heterozygous
    NPR2 variants can mimic. Madelung deformity favours SHOX deficiency.
  distinguishing_features:
  - Madelung deformity has not been reported in heterozygous NPR2 patients.
  - SHOX or SHOX-enhancer defect on molecular testing.
  evidence:
  - reference: PMID:26075495
    reference_title: "Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, no patient has yet presented with Madelung deformity.
    explanation: Absence of Madelung deformity separates NPR2 patients from classic LWD.
- name: ACAN-Related Short Stature
  description: >-
    Heterozygous ACAN variants are another common growth-plate cause of
    idiopathic short stature, typically with advanced bone age and early growth
    cessation.
  distinguishing_features:
  - Advanced bone age and premature growth cessation point to ACAN; bone age is
    more often delayed in heterozygous NPR2 carriers (9 of 12 probands in one
    cohort).
  evidence:
  - reference: PMID:41967490
    reference_title: "A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with heterozygous mutations in ACAN present with short
      stature, often with advanced bone age and premature growth cessation (5).
    explanation: Describes the overlapping ACAN short-stature phenotype and its distinguishing bone-age pattern.
treatments:
- name: Somatropin Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Recombinant human growth hormone is widely used, often under idiopathic or
    SGA short-stature indications. Early reports described little response.
    Larger cohorts report height gains, greater in prepubertal than in pubertal
    children, with variable individual response. No controlled trial in this
    disease has been reported.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40424589
    reference_title: "Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 2 years of GH treatment, median height gain SDS in prepubertal
      children was 1.2 (0.8 to 1.4) and in pubertal children 0.5 (0.3 to 0.9).
    explanation: Registry data show height gain on GH, uncontrolled.
  - reference: PMID:31990356
    reference_title: "NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The growth velocity in the first year of GH treatment accelerated by 3.6
      to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of
      treatment.
    explanation: Five children with familial short stature showed a sustained response.
  - reference: PMID:24001744
    reference_title: "Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three of these patients were treated with recombinant human GH (33-50
      μg/kg · d) without significant height SD score change during therapy.
    explanation: An early series reported no meaningful response.
  - reference: PMID:35741827
    reference_title: "Heterozygous NPR2 Variants in Idiopathic Short Stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The response to GH treatment was variable (SDS height gain ranging from -0.01 to +0.74).
    explanation: Documents variable individual response.
- name: Vosoritide (Investigational)
  action_category: THERAPEUTIC
  therapeutic_modality: PEPTIDE
  description: >-
    Vosoritide is a CNP analogue approved for achondroplasia. In a phase 2
    open-label basket trial (NCT04219007) it increased annualized growth velocity
    in children with heterozygous NPR2 deficiency among other genetic short
    stature groups. It is investigational for this indication. Slipped capital
    femoral epiphysis and genu valgum were seen in the basket trial but not in
    the NPR2 subgroup.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vosoritide
      term:
        id: NCIT:C152918
        label: Vosoritide
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  target_mechanisms:
  - target: Reduced CNP-Stimulated NPR-B cGMP Production
    treatment_effect: ACTIVATES
    description: >-
      The CNP analogue stimulates the remaining functional NPR-B receptors and
      raises cGMP signalling in growth-plate chondrocytes.
    evidence:
    - reference: PMID:41967490
      reference_title: "A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Vosoritide, a C-type natriuretic peptide analog that inhibits this
        pathway, has been approved for use in achondroplasia.
      explanation: >-
        Identifies vosoritide as a CNP analogue. The pathway it inhibits is the
        MAPK cascade downstream of the receptor; acting as a CNP analogue, it
        stimulates NPR-B and raises cGMP, which is the ACTIVATES edge recorded
        here, and the MAPK inhibition is a consequence of that.
  evidence:
  - reference: PMID:41967490
    reference_title: "A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The increase in AGV was seen in all genetic subgroups.
    explanation: Growth velocity rose in the NPR2 subgroup as in the other subgroups of the trial.
  - reference: PMID:42678892
    reference_title: "Slipped Capital Femoral Epiphysis during Vosoritide Therapy for Short Stature: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the basket trial, SCFE was observed in 2/12 participants with ACAN
      mutations, 1/11 with RASopathy but not in the 7 participants with NPR2
      mutations or 24 with hypochondroplasia.
    explanation: Safety signal context; no SCFE occurred in the NPR2 subgroup.
animal_models:
- name: Npr2 pwe/pwe mouse
  species: Mouse
  genotype: Npr2 pwe/pwe (L313X premature stop codon), homozygous
  publication: PMID:23065701
  description: >-
    A recessive loss-of-function Npr2 allele that models acromesomelic dysplasia,
    Maroteaux type. It shows the growth-plate consequence of losing NPR-B signalling
    and the ERK disinhibition behind it. Because it is biallelic, it bears on the
    mechanism of the heterozygous disease but not on its size.
  modeled_mechanisms:
  - target: Growth-Plate Chondrocyte Differentiation Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Npr2 loss shrinks the proliferative and hypertrophic zones of the growth
      plate and raises activated ERK1/2 in the tibia, the chondrocyte deficit this
      node describes.
    limitations: >-
      Homozygous null rather than heterozygous, so the deficit is far larger than
      in patients with one variant allele; the model says nothing about the
      dominant-negative alleles some heterozygotes carry.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of
        acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this
        entry describes. It shows the direction of the mechanism, not the size of
        the partial deficit that one remaining allele leaves.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse long-bone growth plates do not fuse at sexual maturity as human ones
        do, and longitudinal growth runs over weeks rather than the years of human
        childhood, so the timing of the deficit and its effect on final height do
        not transfer directly to patients.
    readouts:
    - name: Growth-plate proliferative and hypertrophic zone size
      target: Growth-Plate Chondrocyte Differentiation Deficit
      direction: DECREASED
      interpretation: Histological correlate of the chondrocyte deficit.
      evidence:
      - reference: PMID:23065701
        reference_title: "A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We determined that the loss of Npr2 causes a reduction in the
          hypertrophic and proliferative zones of the growth plate, but
          mineralization of skeletal elements is normal.
        explanation: Reports the growth-plate zone reduction in Npr2 pwe/pwe mice.
    - name: Activated ERK1/2 in tibia
      target: Growth-Plate Chondrocyte Differentiation Deficit
      direction: INCREASED
      interpretation: >-
        Loss of the cGMP restraint on ERK that the upstream edge of this node
        describes.
      evidence:
      - reference: PMID:23065701
        reference_title: "A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Mutant tibiae have increased levels of the activated form of ERK1/2,
          consistent with the idea that natriuretic peptide receptor type 2
          (NPR2) signaling inhibits the activation of the MEK/ERK mitogen
          activated protein kinase pathway.
        explanation: Reports raised ERK1/2 activation in mutant tibiae.
    evidence:
    - reference: PMID:23065701
      reference_title: "A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We determined that the loss of Npr2 causes a reduction in the
        hypertrophic and proliferative zones of the growth plate, but
        mineralization of skeletal elements is normal.
      explanation: Supports treating this model as informative for the chondrocyte node.
  - target: Reduced Endochondral Longitudinal Bone Growth
    relationship: RESCUES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      MEK1/2 inhibitors restore growth of cultured fetal mutant tibiae, placing
      ERK disinhibition between Npr2 loss and the bone-growth deficit.
    limitations: >-
      The rescue was shown in fetal tibia explants, not in living animals or
      postnatal bone, and in a homozygous null rather than a heterozygous model.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of
        acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this
        entry describes. It shows the direction of the mechanism, not the size of
        the partial deficit that one remaining allele leaves.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse long-bone growth plates do not fuse at sexual maturity as human ones
        do, and longitudinal growth runs over weeks rather than the years of human
        childhood, so the timing of the deficit and its effect on final height do
        not transfer directly to patients.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Explant culture removes the systemic and postnatal growth context, so the
        rescue shows a cell-autonomous growth-plate mechanism but not the
        childhood height deficit the node leads to.
    evidence:
    - reference: PMID:23065701
      reference_title: "A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Treatment of fetal tibiae explants with mitogen activated protein kinase
        1 and 2 inhibitors U0126 and PD325901 rescues the Npr2(pwe/pwe) growth
        defect
      explanation: MEK inhibition reverses the bone-growth defect in mutant tibia explants.
  evidence:
  - reference: PMID:23065701
    reference_title: "A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The Npr2(pwe/pwe) mouse is a model for the human skeletal dysplasia
      acromesomelic dysplasia, Maroteaux type (AMDM).
    explanation: >-
      Establishes the model, and that it models the biallelic NPR2 disease rather
      than this one.
- name: Npr2 cn/cn mouse
  species: Mouse
  genotype: Npr2 cn/cn (Leu-to-Arg substitution in the guanylyl cyclase domain), homozygous
  publication: PMID:15722353
  description: >-
    A spontaneous recessive achondroplastic mouse with disproportionate dwarfism,
    short limbs and tail. Its Npr2 missense allele abolishes CNP-stimulated cGMP
    production, the molecular step this entry's mechanism starts from.
  modeled_mechanisms:
  - target: Reduced CNP-Stimulated NPR-B cGMP Production
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      A catalytic-domain missense allele leaves chondrocytes unable to raise cGMP
      in response to CNP.
    limitations: >-
      Homozygous, so cGMP output is absent rather than reduced. The measurement
      was made in cultured chondrocytes from the mice and in transfected COS-7
      cells, not in the growth plate in vivo.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of
        acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this
        entry describes. It shows the direction of the mechanism, not the size of
        the partial deficit that one remaining allele leaves.
    - divergence_type: SPECIES_MISMATCH
      materiality: IMMATERIAL
      description: >-
        Mouse growth plates do not fuse at sexual maturity and mouse longitudinal
        growth runs over weeks, but this link claims only that NPR-B loss lowers
        CNP-stimulated cGMP output, which does not depend on growth-plate timing.
    readouts:
    - name: CNP-stimulated intracellular cGMP in chondrocytes
      target: Reduced CNP-Stimulated NPR-B cGMP Production
      direction: ABOLISHED
      interpretation: Direct readout of NPR-B guanylyl cyclase output.
      evidence:
      - reference: PMID:15722353
        reference_title: "A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In cultured chondrocytes of cn/cn mice, stimulus with CNP did not
          significantly increase intracellular cGMP concentration, whereas it
          increased in +/+ mice.
        explanation: CNP fails to raise cGMP in chondrocytes cultured from cn/cn mice.
    evidence:
    - reference: PMID:15722353
      reference_title: "A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We therefore concluded that the dwarf phenotype of cn/cn mouse is caused
        by a loss-of-function mutation of the Npr2 gene
      explanation: Ties the cn/cn dwarfism to loss of Npr2 function.
  - target: Reduced Endochondral Longitudinal Bone Growth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      cn/cn mice have disproportionate dwarfism with short limbs and tail from
      disturbed chondrogenesis during endochondral ossification, the bone-growth
      outcome of the cGMP deficit this model also shows.
    limitations: >-
      Homozygous, so the growth failure is a dysplasia rather than the mild short
      stature of heterozygous patients.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of
        acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this
        entry describes. It shows the direction of the mechanism, not the size of
        the partial deficit that one remaining allele leaves.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse long-bone growth plates do not fuse at sexual maturity as human ones
        do, and longitudinal growth runs over weeks rather than the years of human
        childhood, so the timing of the deficit and its effect on final height do
        not transfer directly to patients.
    evidence:
    - reference: PMID:15722353
      reference_title: "A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The achondroplastic mouse is a spontaneous mutant characterized by
        disproportionate dwarfism with short limbs and tail due to disturbed
        chondrogenesis during endochondral ossification.
      explanation: Reports short limbs and tail from disturbed endochondral ossification in cn/cn mice.
  evidence:
  - reference: PMID:15722353
    reference_title: "A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The achondroplastic mouse is a spontaneous mutant characterized by
      disproportionate dwarfism with short limbs and tail due to disturbed
      chondrogenesis during endochondral ossification.
    explanation: Describes the cn/cn skeletal phenotype.
- name: Npr2 (GC-B) knockout mouse
  species: Mouse
  genotype: Npr2 null (gene-targeted guanylyl cyclase B deficiency), homozygous
  publication: PMID:15572448
  description: >-
    Gene-targeted GC-B null mice have impaired endochondral ossification and
    shortened vertebrae and limb bones, along with female infertility from failed
    reproductive-tract development.
  modeled_mechanisms:
  - target: Reduced Endochondral Longitudinal Bone Growth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Loss of GC-B impairs endochondral ossification and longitudinal vertebral
      and limb-bone growth.
    limitations: >-
      Complete null, so growth failure is far more severe than in heterozygous
      patients; the female infertility of null mice has no counterpart in this
      entry.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of
        acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this
        entry describes. It shows the direction of the mechanism, not the size of
        the partial deficit that one remaining allele leaves.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse long-bone growth plates do not fuse at sexual maturity as human ones
        do, and longitudinal growth runs over weeks rather than the years of human
        childhood, so the timing of the deficit and its effect on final height do
        not transfer directly to patients.
    evidence:
    - reference: PMID:15572448
      reference_title: "Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A dramatic impairment of endochondral ossification and an attenuation of
        longitudinal vertebra or limb-bone growth were seen in null animals.
      explanation: Shows reduced endochondral bone growth in GC-B null mice.
  - target: Reduced CNP-Stimulated NPR-B cGMP Production
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Null mice lack GC-B entirely, and the authors attribute the
      endochondral-ossification defect to loss of CNP-stimulated rather than
      basal GC-B activity, the quantity this node describes.
    limitations: >-
      The abstract states that CNP-stimulated activity "appeared to be required";
      it does not report a cGMP measurement in growth-plate chondrocytes, so this
      link rests on the authors' inference. A complete null removes the receptor
      rather than reducing its output, and cannot represent the dominant-negative
      alleles some heterozygous patients carry.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse is homozygous for a loss-of-function Npr2 allele, the genotype of
        acromesomelic dysplasia, Maroteaux type, not the heterozygous genotype this
        entry describes. It shows the direction of the mechanism, not the size of
        the partial deficit that one remaining allele leaves.
    - divergence_type: SPECIES_MISMATCH
      materiality: IMMATERIAL
      description: >-
        Mouse growth plates do not fuse at sexual maturity and mouse longitudinal
        growth runs over weeks, but this link claims only that NPR-B loss lowers
        CNP-stimulated cGMP output, which does not depend on growth-plate timing.
    evidence:
    - reference: PMID:15572448
      reference_title: "Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        C-type natriuretic peptide-dependent increases of guanylyl cyclase B
        activity, but not basal enzyme activity, appeared to be required for the
        progression of endochondral ossification.
      explanation: >-
        Places the bone defect of null mice on loss of CNP-stimulated GC-B
        activity. This is an inference stated by the authors rather than a
        direct cGMP readout, hence INDIRECT.
  evidence:
  - reference: PMID:15572448
    reference_title: "Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      C-type natriuretic peptide-dependent increases of guanylyl cyclase B
      activity, but not basal enzyme activity, appeared to be required for the
      progression of endochondral ossification.
    explanation: >-
      Reports that the bone phenotype of null mice depends on loss of
      CNP-stimulated GC-B activity rather than basal activity.
discussions:
- discussion_id: npr2_allele_class_and_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do dominant-negative missense alleles cause more severe growth failure than
    haploinsufficient alleles? Registry data show truncating alleles associated
    with shorter height than non-truncating alleles.
  rationale: >-
    In vitro, many missense alleles suppress wild-type receptor output, which
    predicts a larger loss than haploinsufficiency. The registry association runs
    the other way, so the in vitro assay may not reflect the dosage of
    NPR-B signalling in the growth plate.
  attaches_to:
  - pathophysiology#Reduced CNP-Stimulated NPR-B cGMP Production
  evidence:
  - reference: PMID:40424589
    reference_title: "Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with a truncating NPR2 variant had a shorter height compared to
      children with a non-truncating variant (-3.3 vs -2.5 SDS, P = .02).
    explanation: The genotype-severity association that motivates the question.
notes: >-
  The 1 in 30 idiopathic short stature figure in PMID:16384845 is derived from an
  assumed carrier frequency of 1 in 700, not measured, so no prevalence record
  is given. Measured diagnostic yields in short-stature cohorts are recorded
  under diagnosis. The vosoritide basket trial (NCT04219007) is cited through its
  publication because ClinicalTrials.gov could not be reached to cache the
  registry record.

📚

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)

Review round 1: reference titles, deep research, bone age and BMI · 2026-10-20T20:57:14Z · View source

Added reference_title to all 51 existing evidence items, copied from the references_cache title frontmatter by scripts/backfill_reference_titles.py. Committed a claude_code deep-research report; it ran two web searches and opened no primary papers, so it was used only as a theme cross-check. Its themes (short stature, disproportion, short metacarpals, delayed bone age, AMD1 and SNSK2 as separate entities, growth hormone, vosoritide) are covered by the entry, except delayed bone age, now added. Added two phenotypes from PMID:35741827: Delayed Bone Age (HP:0002750; 9 of 12 probands delayed, 3 advanced) and Increased Body Mass Index (HP:0031418; single-cohort report, with the authors' own caveat in the description). Noted the delayed bone age in the ACAN differential. In the SGA phenotype, dropped 'mainly for length', which PMID:30602027 reports for all eight diagnosed SGA patients across six genes rather than for NPR2 carriers. Replaced the SGA edge snippet with the NPR2-specific gene count from the same abstract. Expanded the vosoritide target_mechanisms explanation to say the MAPK inhibition follows from NPR-B activation, so the ACTIVATES edge does not read as a contradiction. Validated with just validate, validate-terms, count-verified-snippets (53/53) and check-reference-titles. preflight-dr could not run because the local MONDO build is absent.

Claude Code ▸

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

claude-haiku-5-5, claude-sonnet-5-5 6 citations 2026-10-20T20:43:32.609207

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:

Phenotype	Suggested HPO term (confirm with a lookup before binding)	Frequency
Short stature (below −2 SD, mild to variable)	Short stature (HP:0004322)	Defining feature
Increased arm span relative to height	Disproportionate short stature or similar; confirm the exact term	Reported, not quantified
Increased sitting height relative to total height	Confirm term	Reported, not quantified
Delayed bone age	Delayed skeletal maturation (HP:0002750)	"In some patients"
Shortened metacarpals	Short metacarpal (HP:0010049)	Reported, not quantified

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.

A heterozygous NPR2 variant reduces functional NPR2 protein, through lower expression or impaired function. The 2025 study supports reduced protein expression (PMC12315304).
This leads to reduced CNP-stimulated cGMP production in growth-plate chondrocytes. (Inferred from established receptor biology.)
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).
Reduced long-bone growth results in short stature, with disproportion (long arm span and relatively long trunk) and short metacarpals.
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

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	2
Resolved	1
Unresolved (possible confabulation)	0
Unverifiable	1
Quoted claims checked	0
Quoted claims found in source	0
Quoted claims not found in source	0
Quoted claims with nothing to check against	1
References weighed for topical relevance	1
On topic	1
Off topic	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.

Outcome	Count
Terms checked	6
Resolved	6
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	3
Terms named correctly	3
Terms named as a different term	0

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

Short Stature With Nonspecific Skeletal Abnormalities 1

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Deep Research

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

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Curation notes for the KB entry

Sources

Reference Validation

Quotes that could not be checked

Term Validation