Tall stature-scoliosis-macrodactyly of the great toes syndrome (epiphyseal chondrodysplasia, Miura type; ECDM) is a rare autosomal dominant skeletal overgrowth disorder caused by heterozygous activating variants in NPR2, which encodes the C-type natriuretic peptide (CNP) receptor NPR-B (guanylyl cyclase-B). Activating alleles raise ligand-independent and CNP-stimulated cGMP production, and in a chondrocyte-targeted transgenic mouse the excess cartilage cGMP widens the growth plate and lengthens the long bones, vertebrae and digits. Affected people have tall stature, long and broad great toes, arachnodactyly, scoliosis, coxa valga, valgus deformity of the lower limbs, slipped capital femoral epiphysis and pseudoepiphyses of the phalanges, with marked intrafamilial variability. It is the mirror image of NPR2 loss of function, which causes short stature and acromesomelic dysplasia, Maroteaux type.
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Conditions with similar clinical presentations that must be differentiated from Tall Stature-Scoliosis-Macrodactyly of the Great Toes Syndrome:
name: Tall Stature-Scoliosis-Macrodactyly of the Great Toes Syndrome
creation_date: "2026-10-09T12:00:00Z"
category: Mendelian
description: >-
Tall stature-scoliosis-macrodactyly of the great toes syndrome (epiphyseal
chondrodysplasia, Miura type; ECDM) is a rare autosomal dominant skeletal
overgrowth disorder caused by heterozygous activating variants in NPR2, which
encodes the C-type natriuretic peptide (CNP) receptor NPR-B (guanylyl
cyclase-B). Activating alleles raise ligand-independent and CNP-stimulated
cGMP production, and in a chondrocyte-targeted transgenic mouse the excess
cartilage cGMP widens the growth plate and lengthens the long bones,
vertebrae and digits. Affected people have tall stature, long and broad
great toes, arachnodactyly, scoliosis, coxa valga, valgus deformity of the
lower limbs, slipped capital femoral epiphysis and pseudoepiphyses of the
phalanges, with marked intrafamilial variability. It is the mirror image of
NPR2 loss of function, which causes short stature and acromesomelic
dysplasia, Maroteaux type.
disease_term:
preferred_term: Tall Stature-Scoliosis-Macrodactyly of the Great Toes Syndrome
term:
id: MONDO:0014401
label: tall stature-scoliosis-macrodactyly of the great toes syndrome
synonyms:
- epiphyseal chondrodysplasia, Miura type
- Miura type epiphyseal chondrodysplasia
- ECDM
- tall stature-scoliosis-macrodactyly of the halluces syndrome
parents:
- Skeletal Dysplasia
notes: >-
No disease-specific GeneReviews chapter exists for this disorder. MONDO:0014401
carries the OMIM 615923 cross-reference, whose OMIM title is "epiphyseal
chondrodysplasia, Miura type", and lists that name as a related synonym, so
the Miura-type name and the tall stature-scoliosis-macrodactyly name refer to
one NPR2-related entity and are lumped here. Orphanet ORPHA:329191 also
links the recessive NPR3-related tall stature disorder (Boudin-Mortier
syndrome, OMIM 619543), which is a separate disease with its own MONDO term
and is recorded here only as a differential diagnosis. The NPR2 p.Arg655Cys
allele was reported in a man with extreme tall stature without skeletal
deformities; it is listed as an activating NPR2 allele but that proband does
not show the toe and spinal features that define this syndrome.
prevalence:
- population: Published literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
A family-level count from a 2021 report, before which four families had
been published. It is not a population rate.
evidence:
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Epiphyseal chondrodysplasia, Miura type (ECDM) is a skeletal dysplasia
with tall stature and distinctive skeletal features caused by
heterozygous NPR2 pathogenic variants. Only four families have been
reported.
explanation: States that only four families had been reported when this fifth family was published.
progression:
- phase: Birth
age_range: Neonatal period
notes: >-
Enlarged great toes and increased birth length can already be present at
birth.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Long and wide great toes were already present at birth.
explanation: The original proband had enlarged great toes at birth.
- phase: Childhood growth
age_range: Early childhood through adolescence
notes: >-
Great-toe enlargement progresses during childhood, and valgus deformities
of the hips, knees and ankles can progress and lead to surgery.
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They were referred for clinical genetic evaluation at the age of 6 and 4
years, respectively, because of progressive macrodactyly of the great
toes.
explanation: Great-toe enlargement progressed during early childhood in both daughters.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive valgus deformities (at the hips, knees, and ankles) were the
main complaints and necessitated orthopedic investigations and surgery.
explanation: Progressive lower-limb valgus deformity was the main clinical problem during growth in this family.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
expressivity: VARIABLE
description: >-
A single heterozygous activating NPR2 allele causes the disorder and
segregates through two to four generations in the reported families.
Severity differs within families: a mildly affected mother had severely
affected children carrying the same allele.
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to
co-segregate with the phenotype in this family.
explanation: Co-segregation of a heterozygous NPR2 allele through a four-generation family.
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a three-generation family with tall stature, scoliosis and
macrodactyly of the great toes and a heterozygous p.Val883Met mutation in
Npr2
explanation: Vertical transmission of a heterozygous allele over three generations.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mother's phenotype was relatively mild: borderline tall stature and
elongated halluces operated during childhood. The children were
remarkably more severely affected
explanation: Variable expressivity of the same p.Val883Met allele between mother and children.
genetic:
- name: NPR2
gene_term:
preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >-
Heterozygous activating alleles cluster in the intracellular regions of
NPR-B: the submembrane segment (p.Ala488Pro, p.Met482_Leu483del), the
kinase homology domain (p.Arg655Cys) and the guanylyl cyclase domain
(p.Val883Met). Loss-of-function NPR2 alleles cause the opposite, short
stature phenotypes, so the direction of the variant's effect on receptor
activity has to be established before an NPR2 variant is assigned to this
disorder.
variants:
- name: p.Val883Met
description: >-
NM_003995 c.2647G>A, a missense variant in the conserved C-terminal
guanylyl cyclase domain. It segregated in a three-generation Japanese
family and was found again in a two-generation family with five affected
members. In transfected cells it produces cGMP without CNP and blocks
the normal desensitization of the receptor.
gene:
preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
variant_type: single nucleotide variant
functional_effects:
- function: guanylate cyclase activity
description: Ligand-independent cGMP production and loss of time-dependent receptor inactivation.
type: gain-of-function
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
When expressed in HEK293A cells, the mutant Npr2 cDNA generated
intracellular cGMP (cyclic guanosine monophosphate) in the absence of
CNP ligand.
explanation: Transfected-cell assay showing constitutive activity of the variant.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all affected individuals had a heterozygous c.2647G>A (p.Val883Met)
NPR2 variant in a highly conserved region in the carboxyl-terminal
guanylyl cyclase domain
explanation: Recurrence of the same allele in an independent family.
- name: p.Ala488Pro
description: >-
c.1462G>C, a missense variant in the intracellular submembrane region,
co-segregating in a four-generation Korean family. The mutant receptor is
overactive at baseline and with CNP; biochemically it lowers the EC50 for
CNP and the Km for GTP, and requires receptor phosphorylation for its
CNP-dependent activation.
gene:
preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
variant_type: single nucleotide variant
functional_effects:
- function: guanylate cyclase activity
description: Increased basal and CNP-stimulated receptor activity.
type: gain-of-function
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro transfection assay of the mutant NPR2 revealed overactivity of
the mutant receptor at baseline as well as with the ligand.
explanation: Functional evidence that the segregating allele is activating.
- reference: PMID:28450398
reference_title: Skeletal overgrowth-causing mutations mimic an allosterically activated conformation of guanylyl cyclase-B that is inhibited by 2,4,6,-trinitrophenyl ATP.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The A488P mutation decreased the EC50 5-fold, increased Vmax 2.6-fold,
and decreased the Km 13-fold
explanation: Enzyme kinetics of the mutant receptor in a heterologous expression system.
- name: p.Met482_Leu483del
description: >-
c.1444_1449delATGCTG, a six-base in-frame deletion removing two residues
of the intracellular submembrane region, found in a Dutch mother and her
two daughters. Patient fibroblasts and transfected HEK-293 cells show
raised basal and CNP-stimulated cGMP production.
gene:
preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
variant_type: deletion
functional_effects:
- function: guanylate cyclase activity
description: Increased ligand-independent and CNP-stimulated cGMP synthesis.
type: gain-of-function
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated
cGMP production were markedly increased compared with controls.
explanation: Patient-derived cells show the deletion is activating.
- name: p.Arg655Cys
description: >-
A missense variant in the kinase homology domain reported in a man with
extreme tall stature but without the skeletal deformities of this
syndrome. It increases CNP responsiveness and ATP-dependent allosteric
activation and forms stable heterodimers with wild-type NPR-B. It is an
activating NPR2 allele at the boundary of the clinical entity rather than
a typical cause of it.
gene:
preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
variant_type: single nucleotide variant
functional_effects:
- function: guanylate cyclase activity
description: Increased CNP-stimulated cGMP production in patient fibroblasts and transfected cells.
type: gain-of-function
evidence:
- reference: PMID:24057292
reference_title: An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
CNP-stimulated cGMP production by the mutant NPR2 was markedly
increased in patient skin fibroblasts and transfected human embryonic
kidney 293 cells.
explanation: Functional evidence that p.Arg655Cys is activating.
- reference: PMID:24057292
reference_title: An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we describe an extremely tall male without skeletal deformities,
with a novel NPR2 mutation (p.Arg655Cys) located in the kinase
homology domain.
explanation: Records the narrower clinical presentation of the p.Arg655Cys carrier.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a three-generation family with tall stature, scoliosis and
macrodactyly of the great toes and a heterozygous p.Val883Met mutation in
Npr2
explanation: Original identification of a heterozygous NPR2 variant in an affected family.
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to
co-segregate with the phenotype in this family.
explanation: Independent replication of NPR2 causation in a second family.
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Loss-of-function sequence variants in NPR-B (encoded by the NPR2 gene)
cause short stature (8-10), whereas gain-of-function variants lead to
tall stature (11-13).
explanation: States the opposite growth outcomes of NPR2 loss- and gain-of-function alleles, synthesizing earlier reports.
pathophysiology:
- name: Heterozygous Activating NPR2 Variant
description: >-
A germline heterozygous NPR2 allele with an intracellular missense change
or small in-frame deletion activates the NPR-B receptor. This is the
initiating lesion of the disorder.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
genetic_context:
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: GAIN_OF_FUNCTION
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These results indicate that p.Val883Met is a constitutive active
gain-of-function mutation
explanation: The original study classifies the causal allele as gain of function.
downstream:
- target: Constitutive and CNP-Hypersensitive NPR-B Guanylyl Cyclase Activity
causal_link_type: DIRECT
description: >-
The variant receptor is catalytically overactive without ligand and
responds more strongly to low CNP concentrations.
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Consistently, assays with transfected HEK-293 cells showed markedly
augmented baseline and ligand-dependent activity of mutant NPR-B.
explanation: The deletion variant directly increases basal and ligand-dependent receptor activity.
- name: Constitutive and CNP-Hypersensitive NPR-B Guanylyl Cyclase Activity
description: >-
Activating NPR2 alleles hold the receptor in a conformation that mimics the
allosterically (ATP-) activated state. Depending on the allele, basal
maximal velocity rises, the Km for GTP and EC50 for CNP fall, the
requirement for ATP or receptor phosphorylation changes, and normal
desensitization is lost. The guanylyl cyclase is therefore driven outside
its normal ligand and phosphorylation control, which is why the activity
is annotated as gain of function rather than a quantitative increase. The
ATP analogue TNP-ATP inhibits the mutant but not the wild-type receptor in
vitro, an experimental lead with no clinical data.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
molecular_functions:
- preferred_term: ligand-independent NPR-B guanylate cyclase activity
term:
id: GO:0004383
label: guanylate cyclase activity
modifier: GAIN_OF_FUNCTION
- preferred_term: CNP receptor activity
term:
id: GO:0016941
label: natriuretic peptide receptor activity
modifier: GAIN_OF_FUNCTION
biological_processes:
- preferred_term: receptor guanylyl cyclase signaling pathway
term:
id: GO:0007168
label: receptor guanylyl cyclase signaling pathway
modifier: INCREASED
evidence:
- reference: PMID:23827346
reference_title: A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We conclude that the V883M mutation increases maximal velocity in the
absence of CNP, eliminates the requirement for ATP in the CNP-dependent
Km reduction, and disrupts the normal inactivation process.
explanation: Enzyme kinetics show the receptor escapes ligand, ATP and desensitization control.
- reference: PMID:28450398
reference_title: Skeletal overgrowth-causing mutations mimic an allosterically activated conformation of guanylyl cyclase-B that is inhibited by 2,4,6,-trinitrophenyl ATP.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the A488P and R655C missense mutations result in a GC-B conformation that
mimics the allosterically activated conformation
explanation: A shared allosterically activated conformation across distinct activating alleles.
- reference: PMID:28450398
reference_title: Skeletal overgrowth-causing mutations mimic an allosterically activated conformation of guanylyl cyclase-B that is inhibited by 2,4,6,-trinitrophenyl ATP.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Finally, 1 mm 2,4,6,-trinitrophenyl ATP inhibited all three mutants by as
much as 80% but failed to inhibit WT-GC-B.
explanation: Mutant-selective pharmacological inhibition in vitro, without patient data.
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In the presence of CNP, cGMP production was greater in cells that had
been transfected with the mutant Npr2 cDNA compared to wild-type cDNA.
explanation: CNP-stimulated activity is also increased.
downstream:
- target: Increased cGMP in Growth-Plate Chondrocytes
causal_link_type: DIRECT
description: >-
The overactive receptor converts more GTP to cGMP in chondrocytes,
shown in transfected chondrocytic cells and in the cartilage of
transgenic mice.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Transgenic mice in which the mutant Npr2 was expressed in chondrocytes
driven by the promoter and intronic enhancer of the Col11a2 gene
exhibited an enhanced production of cGMP in cartilage
explanation: The mutant receptor raises cartilage cGMP in vivo.
- reference: PMID:23827346
reference_title: A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
overexpression of the GC-B-V883M mutant resulted in cGMP levels that
were more than four-fold higher than those observed in cells
transfected with the WT enzyme
explanation: Increased cGMP in ATDC5 chondrocytic cells expressing the mutant receptor.
- name: Increased cGMP in Growth-Plate Chondrocytes
description: >-
Excess cGMP accumulates in cartilage. Circulating cGMP is also raised in
patients carrying p.Val883Met, while NT-proCNP is not increased, which
places the excess at the receptor rather than at ligand supply.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: growth plate cartilage chondrocyte
term:
id: CL:1000217
label: growth plate cartilage chondrocyte
biological_processes:
- preferred_term: cGMP biosynthetic process
term:
id: GO:0006182
label: cGMP biosynthetic process
modifier: INCREASED
chemical_entities:
- preferred_term: cGMP
term:
id: CHEBI:16356
label: 3',5'-cyclic GMP
modifier: INCREASED
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Although the total amount of Npr2 was 5.1 times higher in Tg. 28 than Wt,
the cGMP concentration was 17.3 times higher, supporting the in vitro
data demonstrating the gain of function of the p.Val883Met mutant NPR2.
explanation: Cartilage cGMP rose more than receptor expression in the transgenic line.
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition, blood cGMP concentrations were elevated in the patients.
explanation: Raised circulating cGMP in affected family members.
downstream:
- target: CREB-Driven Continued Proliferation of Hypertrophic Chondrocytes
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- cGMP-dependent phosphorylation of CREB
- Cyclin D1 induction
description: >-
In mature chondrocytes, receptor activation and cell-permeable cGMP
increase CREB phosphorylation and cyclin D1, independently of the
cAMP/PKA pathway.
evidence:
- reference: PMID:30544148
reference_title: CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro cell studies revealed that NPRB activation increased the
phosphorylation of cyclic AMP-responsive element binding protein (CREB)
and expression of cyclin D1 in matured chondrocytes. Treatment with
cell-permeable cGMP also enhanced the CREB phosphorylation.
explanation: cGMP links receptor activation to CREB phosphorylation and cyclin D1 expression.
- name: CREB-Driven Continued Proliferation of Hypertrophic Chondrocytes
description: >-
In growth plates of NPRB p.V883M transgenic mice some hypertrophic
chondrocytes keep proliferating, whereas wild-type chondrocytes stop
dividing once they become hypertrophic; these cells stain for Ki67,
phosphorylated CREB and cyclin D1. Whether this cellular step operates
identically for every human allele has not been measured in patient
growth plates.
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: proliferation of hypertrophic chondrocytes
term:
id: GO:0035988
label: chondrocyte proliferation
modifier: INCREASED
evidence:
- reference: PMID:30544148
reference_title: CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
An in vivo BrdU-labeling assay suggested that some of the hypertrophic
chondrocytes in NPRB ... mice continued to proliferate, although
wild-type (WT) chondrocytes stopped proliferating after they became
hypertrophic.
explanation: In vivo labeling shows continued proliferation of hypertrophic chondrocytes.
downstream:
- target: Growth Plate Widening with Expanded Hypertrophic Zone
causal_link_type: DIRECT
description: >-
Continued division of hypertrophic chondrocytes enlarges the hypertrophic
zone and widens the growth plate.
evidence:
- reference: PMID:30544148
reference_title: CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results suggest that NPRB activation evokes its signal in
hypertrophic chondrocytes to induce CREB phosphorylation and make them
continue to proliferate, leading to the skeletal overgrowth in ECDM.
explanation: The authors' conclusion connecting hypertrophic-chondrocyte proliferation to overgrowth.
- name: Growth Plate Widening with Expanded Hypertrophic Zone
description: >-
Transgenic mice show wider growth plates, a thickened hypertrophic zone, a
disorganized chondrocyte arrangement and more hypertrophic chondrocytes.
biological_scale: TISSUE
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: growth plate cartilage development
term:
id: GO:0003417
label: growth plate cartilage development
modifier: DYSREGULATED
- preferred_term: chondrocyte hypertrophy
term:
id: GO:0003415
label: chondrocyte hypertrophy
modifier: INCREASED
locations:
- preferred_term: growth plate cartilage
term:
id: UBERON:0004129
label: growth plate cartilage
evidence:
- reference: PMID:30544148
reference_title: CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The hypertrophic zone of growth plate was thickened
explanation: Direct histological observation in the mouse model.
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
At higher magnification, a disorganized arrangement of chondrocytes with
increased number of hypertrophic chondrocytes was observed in Tg. 28
explanation: Increased hypertrophic chondrocyte number and disorganized columns.
downstream:
- target: Excessive Endochondral Longitudinal Bone Growth
causal_link_type: DIRECT
description: >-
The widened growth plate drives longitudinal overgrowth of endochondral
bones.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Histological examination confirmed that the skeletal overgrowth was
caused by the widening of the growth plates in the transgenic mice
expressing the mutant Npr2
explanation: Directly attributes the overgrowth to growth-plate widening.
- name: Excessive Endochondral Longitudinal Bone Growth
description: >-
Long bones, vertebrae, metatarsals and phalanges overgrow. In humans this
appears as tall stature and elongated digits, with the great toes most
affected; why the hallux is preferentially affected is not known.
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: endochondral bone growth
term:
id: GO:0003416
label: endochondral bone growth
modifier: INCREASED
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
All the metatarsal bones and distal phalanges were longer in Tg. 28 than
Wt
explanation: Digital overgrowth in the mouse model parallels the human toe phenotype.
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
naso-occipital length of the calvarium, femoral length, and tibial length
were significantly longer in Tg. 28 than Wt at 18 weeks
explanation: Long bone overgrowth in the transgenic line.
downstream:
- target: Tall stature
causal_link_type: DIRECT
description: Long bone and vertebral overgrowth produces tall stature.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Taken together, our data are compatible with the interpretation that
p.Val883Met mutant is constitutively active and causes skeletal
overgrowth by increasing the level of cGMP in chondrocytes.
explanation: The authors connect chondrocyte cGMP excess to the skeletal overgrowth seen in patients and mice.
- target: Macrodactyly of the great toes
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Digital overgrowth is the most consistent feature of activating NPR2
alleles, but why the great toe is preferentially enlarged is unknown.
A role for cGMP-mediated inhibition of PDE3A in digit formation has been
proposed and is untested.
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, why overactivation of CNP/NPR-B/cGMP signalling preferentially
affects the growth of the big toes is presently unknown.
explanation: Records that the receptor-to-hallux step has no identified intermediate.
- target: Broad hallux
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The enlarged great toe is wide as well as long; the intervening steps are not characterized.
- target: Arachnodactyly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Overgrowth of the phalanges lengthens the fingers and toes, as seen in
the mouse model; the human step is inferred.
- target: Pseudoepiphyses of the phalanges of the hand
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Extra phalangeal epiphyses accompany digital overgrowth; how excess
CNP/NPR-B signalling produces them is not established.
- target: Pseudoepiphyses of the toes
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
As for the hand, extra epiphyses of the toe phalanges accompany toe
overgrowth without a characterized intermediate.
- target: Scoliosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Vertebral overgrowth is shown in the mouse, which develops kyphosis; the
step from axial overgrowth to human scoliosis is inferred.
- target: Coxa valga
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Altered growth of the proximal femur and its epiphysis is inferred to
produce coxa valga; the tissue-level transition has not been studied.
- target: Genu valgum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Progressive valgus deformity of the knees is inferred to follow from
abnormal limb overgrowth; not directly studied.
- target: Slipped capital femoral epiphysis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Slippage through the overactive proximal femoral physis is inferred, not
studied.
phenotypes:
- name: Tall stature
category: Growth
diagnostic: true
description: >-
Increased length can be present at birth, and height is above +2 SD
through childhood and adulthood in most affected people. Some affected
relatives are only borderline tall, consistent with polygenic background
effects on height.
phenotype_term:
preferred_term: Tall stature
term:
id: HP:0000098
label: Tall stature
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At the age of 15, his height reached 191.2 cm (+3.89 SD)
explanation: Tall stature in the original proband.
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mother's height was +2.77 standard deviation scores (SDS). The heights of
her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of
age.
explanation: Tall stature in the mother, with daughters still near the upper normal range.
- name: Macrodactyly of the great toes
category: Skeletal
diagnostic: true
description: >-
Markedly long great toes, often bilateral and progressive during childhood,
which in several families were shortened surgically. This is the most
consistent feature across activating NPR2 alleles.
phenotype_term:
preferred_term: Macrodactyly of the great toes
term:
id: HP:0001847
label: Long hallux
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a four-generation family with an overgrowth syndrome
characterized by tall stature, macrodactyly of the great toes, scoliosis,
coxa valga and slipped capital femoral epiphysis
explanation: The defining toe phenotype in the Korean family.
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pronounced macrodactyly of the great toes is a striking feature shared by
almost all known gain-of-function NPR-B variants
explanation: Consistency of the feature across reported alleles.
- name: Broad hallux
category: Skeletal
description: The enlarged great toe is wide as well as long.
phenotype_term:
preferred_term: Broad hallux
term:
id: HP:0010055
label: Broad hallux
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Physical examination showed tall stature, scoliosis, and long hands and
feet with arachnodactyly of all the fingers and toes, the great toes
being markedly long and wide.
explanation: The proband's great toes were both long and wide.
- name: Arachnodactyly
category: Skeletal
description: >-
Long, slender fingers and toes, which together with tall stature can
prompt suspicion of Marfan syndrome.
phenotype_term:
preferred_term: Arachnodactyly
term:
id: HP:0001166
label: Arachnodactyly
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Physical examination showed tall stature, scoliosis, and long hands and
feet with arachnodactyly of all the fingers and toes, the great toes
being markedly long and wide.
explanation: Arachnodactyly of fingers and toes in the original proband.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The children were remarkably more severely affected with tall stature,
scoliosis, and elongated toes and fingers leading to suspicion of Marfan
syndrome.
explanation: Elongated digits in a second family.
- name: Scoliosis
category: Skeletal
description: >-
Mild to severe scoliosis is common but not obligatory; one mother carrying
an activating allele had none.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a three-generation family with tall stature, scoliosis and
macrodactyly of the great toes
explanation: Scoliosis in the original family.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographs showed coxa valga, scoliosis, multiple pseudoepiphyses of the
fingers and toes with uneven elongation of the digits and ankle valgus.
explanation: Radiographic scoliosis in a second family.
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: She has a minor ankle valgus, no scoliosis, and no joint hypermobility.
explanation: An adult carrier of an activating allele had no scoliosis, so the feature is not obligatory.
- name: Coxa valga
category: Skeletal
phenotype_term:
preferred_term: Coxa valga
term:
id: HP:0002673
label: Coxa valga
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a four-generation family with an overgrowth syndrome
characterized by tall stature, macrodactyly of the great toes, scoliosis,
coxa valga and slipped capital femoral epiphysis
explanation: Coxa valga in the Korean family.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographs showed coxa valga, scoliosis, multiple pseudoepiphyses of the
fingers and toes with uneven elongation of the digits and ankle valgus.
explanation: Coxa valga in a second family.
- name: Genu valgum
category: Skeletal
description: >-
Progressive valgus deformity at the knees, together with the hips and
ankles, required orthopedic surgery in one family.
phenotype_term:
preferred_term: Genu valgum
term:
id: HP:0002857
label: Genu valgum
evidence:
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive valgus deformities (at the hips, knees, and ankles) were the
main complaints and necessitated orthopedic investigations and surgery.
explanation: Knee valgus as part of the progressive lower-limb deformity.
- name: Slipped capital femoral epiphysis
category: Skeletal
description: >-
Slippage of the proximal femoral epiphysis was reported in the Korean
family; it is a hip complication to consider in a growing child with hip
or knee pain.
phenotype_term:
preferred_term: Slipped capital femoral epiphysis
term:
id: HP:0006461
label: Proximal femoral epiphysiolysis
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a four-generation family with an overgrowth syndrome
characterized by tall stature, macrodactyly of the great toes, scoliosis,
coxa valga and slipped capital femoral epiphysis
explanation: Slipped capital femoral epiphysis in the Korean family.
- name: Pseudoepiphyses of the phalanges of the hand
category: Skeletal
description: Extra epiphyses of the middle and proximal phalanges of the fingers on skeletal survey.
phenotype_term:
preferred_term: Pseudoepiphyses of the phalanges of the hand
term:
id: HP:0010235
label: Pseudoepiphyses of the phalanges of the hand
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Skeletal surveys of the girls showed pseudo-epiphyses of the mid- and
proximal phalanges of all fingers and both great toes
explanation: Pseudoepiphyses of the finger phalanges on skeletal survey.
- name: Pseudoepiphyses of the toes
category: Skeletal
description: Extra epiphyses of the toe phalanges, including the great toes.
phenotype_term:
preferred_term: Pseudoepiphyses of the toes
term:
id: HP:0010169
label: Pseudoepiphyses of the toes
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Skeletal surveys of the girls showed pseudo-epiphyses of the mid- and
proximal phalanges of all fingers and both great toes
explanation: Pseudoepiphyses of the great toes.
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographs showed coxa valga, scoliosis, multiple pseudoepiphyses of the
fingers and toes with uneven elongation of the digits and ankle valgus.
explanation: Multiple pseudoepiphyses of the toes in a second family.
- name: Clinodactyly of the 5th finger
category: Skeletal
phenotype_term:
preferred_term: Clinodactyly of the 5th finger
term:
id: HP:0004209
label: Clinodactyly of the 5th finger
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, the fifth distal phalanx of the hands exhibited minor
clinodactyly
explanation: Minor fifth-finger clinodactyly in the original proband.
- name: Reduced bone mineral density
category: Skeletal
description: >-
Low height-adjusted lumbar spine bone mineral density with raised bone
turnover markers in the original proband. It has not been reported as a
consistent feature across families.
phenotype_term:
preferred_term: Reduced bone mineral density
term:
id: HP:0004349
label: Reduced bone mineral density
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The bone mineral density (BMD) Z-score of the lumbar spine for L2–4,
determined with dual-energy x-ray absorptiometry (Discovery A, Hologic),
was −1.2, and −3.9 when corrected for his height.
explanation: Height-corrected lumbar BMD Z-score of -3.9.
- name: Vertebral compression fracture
category: Skeletal
description: >-
Lumbar vertebral compression fractures in an affected adult; the original
proband also had fractures at 11 and 12 years.
phenotype_term:
preferred_term: Vertebral compression fracture
term:
id: HP:0002953
label: Vertebral compression fracture
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The BMD of the lumbar spine for L2–4 could not be evaluated due to
compressed fractures of the lumbar vertebrae.
explanation: Lumbar compression fractures in the proband's mother.
- name: Elevated bone-specific alkaline phosphatase
category: Laboratory
description: Raised bone formation and resorption markers in the original proband.
phenotype_term:
preferred_term: Elevated bone-specific alkaline phosphatase
term:
id: HP:0010639
label: Elevated alkaline phosphatase of bone origin
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, bone formation and resorption markers were increased (serum
bone-specific alkaline phosphatase, 270 U/l
explanation: Bone-specific alkaline phosphatase was raised in the proband.
biochemical:
- name: Plasma cGMP
presence: INCREASED
biomarker_term:
preferred_term: plasma cyclic GMP
term:
id: NCIT:C534
label: Cyclic GMP
context: >-
Raised in three affected members of the original family and normal in an
unaffected relative. This is a research observation, not a validated
diagnostic cutoff.
readouts:
- target: Increased cGMP in Growth-Plate Chondrocytes
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Circulating cGMP is a systemic readout of the overactive receptor; how
much of it comes from cartilage is not established.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Plasma cGMP concentrations were elevated in III-1, II-5, and I-3; 20.0,
12.0, and 7.3 pmol/ml. Conversely, that in I-2 without the phenotype
was 3.6 pmol/ml, which was similar to the values in healthy adults.
explanation: Plasma cGMP separates affected from unaffected relatives in one family.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition, blood cGMP concentrations were elevated in the patients.
explanation: Elevated blood cGMP in affected family members.
- name: Serum amino-terminal proCNP
presence: NORMAL OR DECREASED
context: >-
NT-proCNP, a marker of tissue CNP production, is normal or low, which
distinguishes receptor activation from CNP overproduction.
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The serum level of amino-terminal proCNP was normal in the proband.
explanation: Normal NT-proCNP with an activating receptor allele.
- reference: PMID:24057292
reference_title: An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In accordance with augmented endogenous receptor activity, plasma
N-terminal pro-CNP (a marker of CNP production in tissues) was reduced in
the proband.
explanation: Reduced NT-proCNP in a carrier of another activating allele.
treatments:
- name: Great-toe epiphysiodesis
description: >-
Surgical arrest of growth at the great-toe epiphyses to limit progressive
hallux elongation, reported at 5 and 8 years of age in one family. The
reports describe individual use, not comparative outcomes.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: epiphysiodesis of the great toes
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
target_phenotypes:
- preferred_term: Long hallux
term:
id: HP:0001847
label: Long hallux
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At the age of 8 years, she was treated for the first time for markedly
long great toes by bilateral percutaneous epiphysiodesis.
explanation: Epiphysiodesis used for hallux overgrowth in the proband.
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: She underwent epiphysiodesis of both great toes when she was 5 years old.
explanation: Epiphysiodesis in the proband's older daughter.
- name: Corrective osteotomy and guided growth
description: >-
Osteotomies and guided growth were used to correct progressive axial
deformities of the lower limbs in one family.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: osteotomy and guided growth for valgus deformity
term:
id: NCIT:C51903
label: Osteotomy
target_phenotypes:
- preferred_term: Genu valgum
term:
id: HP:0002857
label: Genu valgum
- preferred_term: Coxa valga
term:
id: HP:0002673
label: Coxa valga
evidence:
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The two older brothers underwent osteotomies and guided growth for axial
deformities and arthrodesis for elongated halluces.
explanation: Osteotomy and guided growth for axial deformity.
- name: Hallux arthrodesis
description: Arthrodesis of the elongated great toes, reported in one family.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: arthrodesis of the great toe
term:
id: NCIT:C52007
label: Arthrodesis
target_phenotypes:
- preferred_term: Long hallux
term:
id: HP:0001847
label: Long hallux
evidence:
- reference: PMID:33073519
reference_title: A new family with epiphyseal chondrodysplasia type Miura.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The two older brothers underwent osteotomies and guided growth for axial
deformities and arthrodesis for elongated halluces.
explanation: Arthrodesis for elongated halluces.
- name: High-dose estrogen for adult height reduction
description: >-
One affected woman received supraphysiological ethinylestradiol with a
progestogen from 14 to 16 years to reduce predicted adult height. It had
little effect on her growth; this is a historical individual treatment,
not a recommended therapy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Estrogen Therapy
term:
id: NCIT:C15483
label: Estrogen Therapy
therapeutic_agent:
- preferred_term: ethinylestradiol
term:
id: CHEBI:4903
label: 17alpha-ethynylestradiol
target_phenotypes:
- preferred_term: Tall stature
term:
id: HP:0000098
label: Tall stature
evidence:
- reference: PMID:32282051
reference_title: An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: Treatment had little effect on her growth and was discontinued at the age of 16 years.
explanation: In the single reported use, high-dose estrogen did not meaningfully reduce growth.
animal_models:
- name: Col11a2-NPR2 p.Val883Met transgenic mouse
species: Mouse
genotype: Col11a2 promoter/enhancer-driven NPR2 p.Val883Met transgene
genes:
- preferred_term: NPR2
term:
id: hgnc:7944
label: NPR2
description: >-
Transgenic mice expressing the p.Val883Met receptor in chondrocytes have
raised cartilage cGMP, wider growth plates with an expanded hypertrophic
zone, and longer long bones, vertebrae, metatarsals and phalanges. Severity
differs between founders; the most severe founder had severe kyphosis and
died at seven weeks.
publication: PMID:22870295
modeled_mechanisms:
- target: Increased cGMP in Growth-Plate Chondrocytes
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: Cartilage cGMP is elevated in the transgenic line.
limitations: >-
The transgene is overexpressed (total Npr2 mRNA about five-fold wild
type) on top of the endogenous gene, so part of the effect may reflect
receptor dosage rather than the variant alone.
readouts:
- name: Costal cartilage cGMP concentration
target: Increased cGMP in Growth-Plate Chondrocytes
direction: INCREASED
interpretation: Direct tissue measurement of the node in the model.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Although the total amount of Npr2 was 5.1 times higher in Tg. 28 than
Wt, the cGMP concentration was 17.3 times higher
explanation: Cartilage cGMP was measured directly and raised.
- target: Excessive Endochondral Longitudinal Bone Growth
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: Long bones, vertebrae and digits are longer than in wild-type littermates.
limitations: >-
Mice develop kyphosis rather than scoliosis, and the human hallux
predominance has no clear murine counterpart.
evidence:
- reference: PMID:22870295
reference_title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Thus, the transgenic mice exhibited the skeletal overgrowth associated with the overproduction of cGMP in cartilage.
explanation: Skeletal overgrowth reproduced in the model.
evidence:
- reference: PMID:30544148
reference_title: CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The mutant mice ... exhibited postnatal skeletal overgrowth and increased
cGMP in cartilage.
explanation: Independent confirmation of the transgenic phenotype.
differential_diagnoses:
- name: Marfan syndrome
disease_term:
preferred_term: Marfan syndrome
term:
id: MONDO:0007947
label: Marfan syndrome
description: >-
Tall stature, arachnodactyly and scoliosis lead to suspicion of Marfan
syndrome.
distinguishing_features:
- Macrodactyly of the great toes and phalangeal pseudoepiphyses point to an activating NPR2 variant.
- An activating NPR2 allele with raised cGMP signalling confirms the diagnosis.
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This overgrowth syndrome caused by a gain-of-function mutation at NPR2
should be differentiated from Marfan or related syndromes
explanation: The authors name Marfan and related syndromes as the main differential.
- name: Boudin-Mortier syndrome
disease_term:
preferred_term: NPR3-related tall stature
term:
id: MONDO:0859194
label: Boudin-Mortier syndrome
description: >-
Recessive NPR3 loss of function produces a closely similar phenotype of
tall stature, long great toes and extra epiphyses.
distinguishing_features:
- Autosomal recessive inheritance with biallelic NPR3 variants rather than a dominant NPR2 allele.
evidence:
- reference: PMID:40171685
reference_title: Tall Stature and Scoliosis Associated With a Novel Homozygous Loss-of-Function Missense Variant in NPR3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
NPR3-related tall stature is characterized by tall stature, elongated big
toes, and additional epiphyses in hand and foot bones. The condition is
caused by biallelic loss-of-function variants affecting natriuretic
peptide receptor 3 (NPR3).
explanation: The overlapping phenotype and distinct recessive NPR3 genetic basis.
- name: CNP overproduction from chromosomal rearrangement
description: >-
Translocations increasing CNP production cause a similar overgrowth
phenotype through excess ligand rather than an activated receptor.
distinguishing_features:
- Activating NPR2 alleles occur with normal or low NT-proCNP, which argues against CNP overproduction.
evidence:
- reference: PMID:24259409
reference_title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
overproduction of CNP by chromosomal translocation and a gain-of-function
mutation at NPR2 have been reported to be responsible for an overgrowth
syndrome in three cases and one family, respectively.
explanation: Places CNP overproduction alongside NPR2 activation as causes of a similar overgrowth syndrome.
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.
Create: Tall_Stature-Scoliosis-Macrodactyly_of_the_Great_Toes_Syndrome · 2026-10-09T21:21:06Z · View source
Created from the required Perplexity deep-research report (preflight-dr PASS: NPR2 mentioned 41 times, OMIM 615923 matches MONDO). The report's 12 references all resolved; claims were taken only where a cached PubMed record could be quoted. Lump decision: MONDO:0014401 carries the OMIM 615923 xref (OMIM title epiphyseal chondrodysplasia, Miura type) and lists the Miura name as a related synonym, so both names are one NPR2 gain-of-function entity; Orphanet ORPHA:329191 also links recessive NPR3-related Boudin-Mortier syndrome (MONDO:0859194), kept separate as a differential. Added PubMed sources found from the report's leads: Hannema 2013 (PMID:24057292, p.Arg655Cys, extreme tall stature without skeletal deformity, recorded as a boundary allele), Robinson 2013 (PMID:23827346) and Dickey 2017 (PMID:28450398) receptor biochemistry. Not used: the 2023 nosology (PMID:36779427) because its cached full text does not contain the classification table; ClinVar classifications and Orphanet prevalence because no quotable cache exists (ORPHA bulk XML absent locally); Moffatt 2025 used only for the NPR3 differential. The causal chain runs variant -> constitutive/CNP-hypersensitive guanylyl cyclase (GAIN_OF_FUNCTION modifier, since mutants escape ligand, ATP and desensitization control) -> chondrocyte cGMP -> CREB-driven hypertrophic chondrocyte proliferation (mouse, PROVISIONAL) -> growth plate widening -> endochondral overgrowth -> phenotypes; edges from overgrowth to scoliosis, coxa valga, genu valgum, SCFE, pseudoepiphyses and broad hallux are INDIRECT_UNKNOWN_INTERMEDIATES and uncited because no source establishes the transition. No disease-specific GeneReviews chapter (check-genereviews NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets (73/73) and validate-disorders.
The best-defined molecular entity for this name is NPR2-related tall stature with long halluces, traditionally called Miura-type epiphyseal chondrodysplasia. It is an autosomal-dominant skeletal overgrowth disorder caused by heterozygous activating, or gain-of-function, NPR2 variants. Its distinguishing combination is excessive linear growth and disproportionately long or broad great toes, often accompanied by scoliosis and abnormalities of the hip and growth plates. The 2023 international skeletal-disorder nosology explicitly names it “tall stature with long halluces, NPR2-related” and separates it from the clinically similar recessive NPR3-related disorder. That separation is important when populating a knowledge base: Orphanet’s broader ORPHA:329191 entry currently links both disorders. [1][31][116]
Evidence scope. This report describes an aggregated disease-level entity, not an EHR cohort. Its clinical observations come from a small number of published families; experimental claims are identified below as human, mouse, cell-based, or computational evidence. In particular, percentages calculated within one family must not be entered as population-wide phenotype frequencies. [1][53][116]
| Identifier or name | Value | Interpretation |
|---|---|---|
| MONDO | MONDO:0014401 | Identifier associated with the requested disease name in ClinVar. [2] |
| OMIM phenotype | 615923 | NPR2-related Miura-type epiphyseal chondrodysplasia; autosomal dominant. [1] |
| OMIM causal gene | 108961 — NPR2 | Gene locus at 9p13.3. [1] |
| Orphanet | ORPHA:329191 | “Tall stature–long halluces–multiple extra-epiphyses syndrome”; its present listing also cross-references the distinct NPR3 disorder, OMIM 619543. [31] |
| ICD-10; ICD-11 | Q87.3; LD2C | Broad codes displayed by Orphanet, not disease-specific molecular identifiers. [31] |
| Other cross-reference | DOID:0070316 | Miura-type epiphyseal chondrodysplasia. [1] |
| Synonyms | Miura-type epiphyseal chondrodysplasia; ECDM; tall stature with long halluces, NPR2-related; tall stature–scoliosis–macrodactyly of the halluces syndrome | The gene-qualified name is preferable for distinguishing NPR2 from NPR3. [1][24][116] |
No disease-specific MeSH descriptor was established in the consulted records; the original report is indexed under broader headings including growth disorders and congenital limb deformities. [18]
Cause. Activating variants in one copy of NPR2 increase the activity of its product, natriuretic peptide receptor-B (NPR-B/guanylyl cyclase-B). The receptor then produces excessive cyclic GMP (cGMP), particularly in developing cartilage. Segregation in families, direct receptor assays, patient-cell studies, and chondrocyte-specific transgenic mice support this causal assignment. NPR2 loss-of-function variants instead belong to short-stature disorders; finding any rare NPR2 variant is therefore insufficient to diagnose this overgrowth syndrome. [18][20][71][75]
The established risk factor is inheriting a causative activating allele; an affected heterozygous parent has the usual 50% transmission probability for an autosomal-dominant allele per pregnancy, although severity cannot be predicted from that probability. Neither an environmental cause nor a reproducible dietary, occupational, infectious, or lifestyle risk or protective factor has been established for this Mendelian disorder. No protective allele, validated modifier gene, or disease-specific gene–environment interaction was identified in the cited families. Parental height was proposed as a possible influence on stature in one three-person family, not demonstrated as a modifier of the skeletal dysplasia. [1][28][53]
The table separates documented observations from suggested HPO annotations. “Reported” is not a frequency estimate. Signs commonly become apparent during growth, but a proband’s great-toe enlargement and height exceeding +3 SD were documented at birth; orthopedic deformities can progress during childhood. Impact statements are clinical implications or reported reasons for intervention, not measured EQ-5D, SF-36, or PROMIS outcomes. [1][54][53]
| Phenotype and type | Characteristics, onset, progression, and available frequency | Function or quality-of-life relevance | Suggested HPO term |
|---|---|---|---|
| Tall stature / proportional overgrowth — physical sign | Core feature; reported from birth in one proband and through childhood or adulthood in families. A 2020 family included a mother at +2.77 height SDS and daughters at +1.96 and +1.30 SDS when assessed. Severity varies. [1][71] | May prompt growth and endocrine assessment; no syndrome-specific QOL score is available. | Tall stature, HP:0000098. [91] |
| Long and/or broad great toes, often termed macrodactyly — physical sign | Core distinguishing finding, sometimes bilateral and progressive; childhood toe procedures are reported. Long hallux and broad hallux should be annotated separately when observed. [54][28][53] | Marked elongation has led to epiphysiodesis or arthrodesis; an individual-level functional effect should be recorded rather than assumed. [53][28] | Long hallux, HP:0001847; broad hallux, HP:0010055. [91][92] |
| Arachnodactyly / elongated fingers and toes — physical sign | Reported in the original and subsequent families; variable expression. [18][53] | Can lead initially to assessment for Marfan syndrome; functional impairment is unquantified. [53] | Arachnodactyly, HP:0001166. [91] |
| Scoliosis — spinal sign | Mild to severe in reported relatives; not obligatory—the mother in the 2020 deletion-variant family had none. [54][28] | Severe deformity warrants orthopedic assessment; a disease-specific disability rate is unavailable. | Scoliosis, HP:0002650. [91] |
| Coxa valga, femoral-head epiphyseal dysplasia, and leg or ankle valgus — orthopedic signs | All 11 affected relatives in the reported Korean family had coxa valga with capital-epiphyseal dysplasia; progressive hip, knee, and ankle valgus drove surgery in another family. The 11/11 observation applies only to that family. [1][53] | Progressive axial deformity can require investigation, guided growth, or osteotomy. [53] | Coxa valga, HP:0002673; abnormality of femoral-head epiphysis, HP:0010574. [144][191] |
| Slipped capital femoral epiphysis — complication/sign | 2 of 11 affected members of the Korean kindred were reported to have a slip; this is not an estimated syndrome-wide rate. [1] | A potential urgent cause of hip or referred knee pain, limp, and loss of hip function. [182][186] | Epiphysiolysis of the hip, HP:0006461. [182] |
| Extra or pseudoepiphyses of the hands and feet — radiographic sign | Reported on skeletal surveys and re-examination of family radiographs; ascertainment depends on imaging. [1][28][53] | Useful diagnostically; an independent QOL effect is unmeasured. | Pseudoepiphyses, HP:0010584, where radiographically appropriate. [192] |
| Low bone density and increased turnover — imaging/laboratory findings | The original proband had a height-adjusted spinal bone-density z score of −3.9 and raised bone-formation and resorption markers. Another activating-NPR2 patient had normal mineral density: neither finding is universal. [1] | May justify individual bone-health assessment; fracture risk has not been quantified for the disorder. | Osteopenia, HP:0000938; elevated bone-specific alkaline phosphatase, HP:0010639; increased urinary type-I-collagen N-terminal telopeptide, HP:0032208, only when measured. [91] |
Behavioral or neurodevelopmental abnormalities are not established defining features. Minor motor delay and speech therapy were mentioned for one child, but their causation by NPR2 was not established. [1]
NPR2 is at 9p13.3; identifiers include HGNC:7944, NCBI Gene:4882, OMIM:108961, and UniProtKB:P20594. Its receptor contains extracellular ligand-binding, transmembrane, intracellular regulatory, and guanylyl-cyclase catalytic regions. These reported activating alleles are germline, not tumor-derived somatic drivers. [1][61][372]
| Reported variant | Variant class and evidence | Classification or population-data qualification |
|---|---|---|
| NPR2 NM_003995.4:c.2647G>A, p.Val883Met | Missense variant in the catalytic region; segregated with disease in the original three-generation family and appeared again in a five-person family. Cell and mouse experiments establish increased signaling. [18][53][54] | ClinVar: pathogenic, literature-only submission for Miura-type disease, VCV000143053; absent from 214 Japanese control alleles in the original study. A numerical gnomAD frequency was not established from these sources. [120][54] |
| NPR2 c.1462G>C, p.Ala488Pro | Missense, intracellular juxtamembrane region; segregated in the four-generation Korean family and increased basal and ligand-stimulated receptor activity. [20][1] | Strong human segregation plus functional evidence; a current condition-specific ACMG/AMP ClinVar classification and numerical gnomAD frequency were not independently established here. [20] |
| NPR2 c.1444_1449delATGCTG, p.Met482_Leu483del | Six-base-pair in-frame deletion, not a frameshift; found in a mother and two daughters. Patient fibroblasts and transfected cells showed increased basal and CNP-stimulated cGMP. [71][28] | Functionally activating; numerical population frequency and an independently verified ClinVar ACMG/AMP classification unavailable here. [71] |
| NPR2 c.1963C>T, p.Arg655Cys | Activating missense allele in the kinase-homology region associated with extreme tall stature, but without the full characteristic toe/skeletal phenotype in its initial proband. [web:24057292][1] | Record as an NPR2 activating-overgrowth phenotype, not evidence that all carriers meet the narrower clinical presentation. The citation token [web:24057292] is not a tool source ID; supporting sources are [150][1]. |
Correction for knowledge-base use: the final row’s evidence is [150][1], not a claim of a separately verified variant classification. ClinVar entries that merely list this syndrome beside an NPR2 variant—including variants classified VUS—must not be promoted to causal gain-of-function alleles. The direction of receptor effect, segregation, and condition-specific interpretation matter. [81][86][120]
No syndrome-causing aneuploidy or large structural variant, established disease-specific DNA-methylation signature, modifier-gene association, or multi-omics signature was found. Chromosomal rearrangements increasing NPPC/CNP expression produce a related signaling phenotype but are not demonstrated NPR2-variant ECDM. The 2023 experimental paper on eight NPR2 missense variants investigated loss of function and short stature, rather than providing eight new ECDM alleles. [20][75][254]
There is no established toxin, radiation, pollution, diet, smoking exposure, infectious agent, or lifestyle behavior that initiates this inherited syndrome. This does not rule out ordinary clinical effects of growth, loading, or physical activity on an individual’s orthopedic symptoms; it means those exposures have not been demonstrated as disease causes or validated genotype–environment interactions in the available reports. [18][20][53]
Ordered causal chain — evidence type is stated at each step:
Here, [web:30544148] denotes the original mouse study accessible at [138] only as a cell-ontology result; the verified study source is [53] for clinical findings and [web:30544148] should not be used as a citation token. The direct experimental source is [138] for the cell term and [54] for the mouse model; the PubMed abstract was retrieved in this research and reports PMID 30544148.
At the protein level, activating alleles need not act identically. A biochemical comparison found increased basal intracellular cGMP of approximately 11-fold for p.Arg655Cys, 21-fold for p.Ala488Pro, and 28-fold for p.Val883Met in its transfected-cell system. The authors found allele-dependent phosphorylation requirements; the results support an allosterically activated receptor conformation, not increased gene dosage as a general explanation. A separate 2020 deletion-variant study measured approximately 9.9-fold higher basal cGMP in its own transfected-cell assay. These assay-specific fold changes are not patient severity scores. [305][225][28]
The principal cells are growth-plate chondrocytes, including hypertrophic chondrocytes; proposed ontology annotations are CL:0000138 and CL:0000743. Suggested functional terms are GO:0006182, cGMP biosynthetic process; GO:0060351, cartilage development involved in endochondral bone morphogenesis; and GO:0005886, plasma membrane for receptor localization. GO:0001958 is marked obsolete by QuickGO, so it should not be newly assigned without ontology-version review. The relevant small molecule is cGMP, CHEBI:57746 for its physiological anion. [136][138][139][388][401][257]
Mechanistic boundaries. CNP–NPR-B signaling can interact with the FGFR3/MAPK growth-control network, but the NPR2-ECDM experiments above directly establish excess receptor/cGMP signaling, not an ECDM-specific MAPK, immune, oxidative-damage, or epigenetic signature. No disease-specific single-cell atlas, spatial-transcriptomic map, proteomic, metabolomic, lipidomic, or CRISPR screen was established from the consulted studies. [176][18][web:30544148]
| Level | Documented structure or proposed ontology annotation | Qualification |
|---|---|---|
| Organ and system | Axial and appendicular skeleton—vertebral column, hips/femora, hands, feet, especially the hallux (UBERON:0003631); femur (UBERON:0000981). [1][298][285] | Primarily a skeletal growth disorder, not an established systemic inflammatory or infectious disorder. |
| Tissue | Epiphyseal growth-plate cartilage, UBERON:0008187 as an ontology suggestion; cartilage UBERON:0002418. [54][138][269] | Growth-plate involvement is directly supported in mutant mice; human radiographs support altered epiphyseal development. |
| Cells | Chondrocyte CL:0000138; hypertrophic chondrocyte CL:0000743. [136][138] | Directly examined in the mouse model. |
| Subcellular | Plasma membrane, GO:0005886, and the receptor’s intracellular catalytic region. [web:30544148][372] | Activating-receptor localization should not be conflated with ER retention described for loss-of-function, short-stature alleles. [75] |
| Lateralization | Both great toes were affected in the original family and the 2020 family. [54][28] | Bilaterality is reported, not proven universal; valgus and scoliosis can be asymmetric. |
Onset is developmental: overgrowth or enlarged toes can be evident at birth, while Orphanet lists childhood onset for the broader entry. Growth and toe enlargement can progress during childhood; progressive valgus deformity prompted surgery in one family. A femoral-head slip is particularly relevant around periods of active growth. After skeletal maturity, the inherited variant persists, but no formal early/intermediate/end-stage system, progression rate, remission pattern, or longitudinal natural-history curve exists for this specific disorder. [1][31][53][54]
Inheritance is autosomal dominant for molecularly defined NPR2-ECDM. An affected mother was much more mildly affected than her four children in one five-person family, establishing variable expressivity in that family; the limited reports do not establish complete penetrance, anticipation, germline-mosaicism frequency, a founder effect, carrier frequency, or a sex ratio. Published Japanese, Korean, Dutch, and other families are reports of ascertainment, not evidence of ancestry-specific risk. [1][28][53]
Orphanet gives prevalence <1 per 1,000,000 for its broader combined entry. A defensible NPR2-specific point prevalence, incidence per year, and geographic distribution cannot be calculated from the family reports. Orphanet’s simultaneous “autosomal dominant” and “autosomal recessive” labels reflect its inclusion of dominant NPR2 and recessive NPR3 entities; they should not be assigned together to OMIM:615923. [31][116]
Practical diagnostic sequence: recognize disproportionate hallux elongation plus tall stature; document family growth and skeletal history; examine the spine, limb axes, and hips; obtain appropriate hand/foot and targeted spine/pelvis radiographs; then pursue germline NPR2 sequencing with gain-of-function-aware interpretation. A targeted NPR2 test or skeletal-dysplasia/overgrowth panel is reasonable when the phenotype is characteristic; WES or WGS is useful when the presentation is uncertain or an initial test is unrevealing. Testing an affected and unaffected relative for segregation can strengthen interpretation. Commercial germline testing and skeletal-dysplasia panels include NPR2. [1][53][242][240]
Assess growth trajectory and orthopedic symptoms rather than relying on one stature measurement. Plain radiography documents hallux and finger epiphyses, coxa valga, spinal curvature, and possible hip slip. Bone-density and turnover measurements may be considered when clinically indicated but are not validated standalone diagnostic tests. Elevated plasma cGMP in three members of the first family is a research observation, not an established diagnostic cutoff; amino-terminal proCNP was normal in the proband of the Korean family. No routine biopsy, electrophysiologic test, liquid biopsy, omics classifier, or newborn biochemical screen is established. [1][20][54]
The critical differential includes Marfan and related connective-tissue disorders, recessive NPR3-related Boudin–Mortier syndrome (OMIM:619543), and CNP/NPPC-overexpression overgrowth. The combination of hallux and radiographic findings plus an activating NPR2 allele distinguishes the molecular diagnosis. In contrast to normal echocardiograms reported in the NPR2 families, aortic dilatation occurred in two of three NPR3-related families in the primary report; do not transfer that NPR3 statistic to NPR2-ECDM. Likewise, NPR2 loss-of-function alleles and their short-stature phenotype are not molecular confirmation of this disorder. [1][20][59][web:30032985][75]
Available observations chiefly establish skeletal morbidity: potentially progressive spinal or lower-limb deformity, toe procedures, and a documented risk of slipped capital femoral epiphysis. The five-person family report states: “Progressive valgus deformities (at the hips, knees, and ankles) were the main complaints and necessitated orthopedic investigations and surgery.” Adult affected individuals have been described, but there are no reliable syndrome-specific survival rates, life-expectancy estimates, mortality rates, disability prevalence, validated prognostic biomarker, or standardized quality-of-life scores. Severity within a family is not reliably predicted by identifying its allele alone. [53][1][28]
Management is individualized orthopedic and supportive care; no drug, gene therapy, RNA therapy, cell therapy, or molecularly targeted treatment has established clinical efficacy for NPR2 activating-overgrowth ECDM. These are reports of treatment in individuals, not comparative efficacy trials. [53][28][225]
| Intervention | Disease-specific use and evidence | Suggested NCIT clinical-intervention annotation |
|---|---|---|
| Orthopedic surveillance, imaging, and individualized rehabilitation | Follow symptomatic scoliosis, hip position, limb axes, and function during growth; supportive therapy may be tailored to impairment. No syndrome-specific response rate is reported. [1][53] | Use an appropriate verified orthopedic-assessment or physical-therapy term in the local NCIT release; specific code not verified here. |
| Great-toe epiphysiodesis | Reported at age 8 in the 2020 mother and age 5 in her older daughter; the original family also describes toe-shortening surgery. These observations do not establish an optimal age or success rate. [28][54] | Epiphysiodesis—term suggestion; specific NCIT code not verified. |
| Guided growth, osteotomy, or toe arthrodesis | In a five-person family, the two older brothers underwent osteotomies and guided growth for axial deformities and arthrodesis for elongated halluces. [53] | Osteotomy, NCIT:C51903; verify release-specific terms for guided growth and arthrodesis. [357] |
| Prompt assessment and stabilization of a suspected slipped capital femoral epiphysis | Hip or knee pain or limp merits prompt hip assessment. Stabilization is standard care for an actual slip; it has not been evaluated as a syndrome-specific preventive procedure. [1][186] | Surgical stabilization of slipped femoral epiphysis—term suggestion; specific NCIT code not verified. |
| High-dose estrogen/progestogen for predicted tall adult stature | Historical individual treatment, not a recommended syndrome regimen: one affected mother received it at 14–16 years; the report states that it had little effect on growth. [225] | Hormonal therapy—historical annotation only; specific NCIT code not verified. |
| Mutant-receptor inhibition with TNP-ATP | Experimental, cell-based only: an ATP analogue inhibited several activating mutant receptors in biochemical assays. No patient response or clinical safety data were reported. [305] | Experimental guanylyl-cyclase inhibition—no established disease intervention code. |
Avoid a direction-of-effect error: vosoritide is a CNP receptor agonist studied or used for conditions of inadequate growth, including achondroplasia or some NPR2 deficiency trials. Such studies are not ECDM treatment trials and do not establish an indication for a receptor that is already overactive. No ECDM-specific NCT efficacy trial was established from the consulted evidence. [176][241]
Primary prevention by lifestyle change, vaccination, environmental control, or prophylactic medication is not established for this inherited disorder. Once a familial causal allele is characterized, genetic counseling and targeted familial testing can support reproductive decisions and earlier recognition; prenatal or preimplantation testing is technically conditional on knowing the family’s variant and appropriate specialist counseling. Secondary and tertiary prevention means recognizing potentially progressive deformity and evaluating new hip/leg pain or limping promptly, then treating complications on their own clinical merits. No population newborn-screening program or validated asymptomatic-population risk score is established. [1][53][186][242]
The documented naturally affected species is human, Homo sapiens (NCBI Taxon:9606)*. The experimental ortholog is mouse Npr2 (*NCBI Gene:230103; MGI:97372) in Mus musculus (NCBI Taxon:10090). No naturally occurring companion-animal breed or wildlife syndrome equivalent, VBO breed identifier, veterinary prevalence, zoonotic transmission, or infectious cross-species susceptibility was established in the cited material. Similar skeletal responses in humans and engineered mice provide the relevant comparative biology, not evidence of animal-to-human transmission. [330][332][270][18]
| Model and evidence type | Phenotype recapitulated or finding | Principal limitation and application |
|---|---|---|
| Col11a2-directed p.Val883Met Npr2 transgenic mouse — engineered organism | Increased cartilage cGMP, elongated bones, digits, and vertebrae, enlarged growth plates, and kyphosis; severity differed among founders. [18][54] | Kyphosis in mice is not identical to human scoliosis. Useful for testing skeletal causality and growth-plate mechanisms, not a measured human treatment response. [54] |
| p.Val883Met mutant mouse growth-plate/chondrocyte experiments — organism plus cellular assays | Thickened hypertrophic zone, BrdU evidence that some hypertrophic cells kept proliferating, and increased CREB phosphorylation and cyclin-D1 expression in experimental cells. The primary study is PMID:30544148. [54][73] | Identifies a plausible downstream mechanism; its exact contribution in each human allele has not been directly measured in patient growth plates. |
| Patient skin fibroblasts — human ex-vivo model | The 2020 deletion variant showed raised basal and CNP-stimulated cGMP; p.Arg655Cys was also studied in patient fibroblasts. [71][web:24057292] | Fibroblasts can test native receptor function but are not growth-plate cartilage. |
| Transfected HEK-293/293T cells and receptor biochemistry — in-vitro model | Reproduced ligand-independent and ligand-stimulated activation, enabled variant comparisons, and supported allosteric-mechanism and inhibitor experiments. [18][20][71][305] | Expression and drug effects in a heterologous cell system do not establish clinical efficacy or safety. |
| Publication date | Source, URL, and PMID | Exact abstract excerpt or principal evidentiary contribution |
|---|---|---|
| 3 August 2012 | Miura et al., PLoS ONE. PMID:22870295; https://pubmed.ncbi.nlm.nih.gov/22870295/ | “elevated levels of cGMP in growth plates lead to the elongation of long bones.” Foundational family, cell, and mouse evidence. [18] |
| 20 November 2013 online; January 2014 issue | Miura et al., American Journal of Medical Genetics A. PMID:24259409; https://pubmed.ncbi.nlm.nih.gov/24259409/ | “A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to co-segregate with the phenotype”. [20] |
| 1 April 2019 | Yamamoto et al., Human Molecular Genetics. PMID:30544148; https://pubmed.ncbi.nlm.nih.gov/?term=CREB+activation+hypertrophic+chondrocytes+Miura+NPR2+Yamamoto | Mutant-mouse and cell study of hypertrophic-zone expansion and CREB/cyclin-D1 signaling. [73] |
| 1 July 2020 | Lauffer et al., Journal of Clinical Endocrinology & Metabolism. PMID:32282051; https://pubmed.ncbi.nlm.nih.gov/32282051/ | “basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls.” [71] |
| 19 October 2020 online; January 2021 issue | Kenis et al., American Journal of Medical Genetics A. PMID:33073519; https://pubmed.ncbi.nlm.nih.gov/33073519/ | Five affected relatives, substantial intrafamilial variability, and documented orthopedic operations. [53] |
| 13 February 2023 online; May 2023 issue | Unger et al., 2023 skeletal-disorder nosology, PMID:36779427; https://pubmed.ncbi.nlm.nih.gov/36779427/ | Classifies “Tall stature with long halluces, NPR2-related” separately from the NPR3-related condition. This is authoritative classification, not a new patient series. [116][201] |
| 23 November 2023 | Original functional research on NPR2 loss-of-function variants, DOI 10.3389/fcell.2023.1294748; https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1294748/full | Relevant to interpreting variant direction of effect, but not primary evidence for new activating ECDM variants. [75] |
Knowledge-base conclusion: curate monoallelic activating NPR2 → excessive receptor-generated cGMP → abnormal growth-plate activity → skeletal overgrowth* as the supported disease chain. Keep NPR3-related recessive tall stature, NPPC-overexpression phenocopies, and NPR2* loss-of-function short stature as separate molecular entities; leave unsupported frequencies, modifiers, molecular therapies, and prognosis fields explicitly unknown. [18][20][53][116][web:30032985]
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 12 |
| Resolved | 12 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 12 |
| On topic | 6 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 37 |
| Resolved | 26 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 11 |
| Terms whose name was checked | 2 |
| Terms named correctly | 0 |
| Terms named as a different term | 2 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0014401 (1 mention) - the report calls it "MONDO"; MONDO calls it tall stature-scoliosis-macrodactyly of the great toes syndromeDOID:0070316 (2 mentions) - the report calls it "Other cross-reference"; DOID calls it Miura type epiphyseal chondrodysplasiaTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Gene, OMIM, UniProtKB, Taxon, MGI.