Avascular Necrosis of Femoral Head, Primary, 2

Mendelian MONDO:0054551 Pathograph 22 Show in embeddings browser Skeletal Disorder Vascular Disorder

Primary avascular necrosis of the femoral head type 2 (ANFH2) is a rare inherited form of bilateral hip osteonecrosis associated with a heterozygous C-terminal TRPV4 frameshift allele. The founding family contained four affected siblings without the usual acquired risk factors. Patient fibroblasts and transduced HEK293 cells showed increased channel activity and prolonged optical calcium sparklet bursts. The proposed endothelial and osteoclast mechanisms linking channel dysfunction to hip disease remain unverified for this allele in phenotype-relevant tissue. Hip osteonecrosis has also been reported in broader TRPV4 skeletal and neuromuscular phenotypes, which are clinically distinct from the isolated presentation of the founding ANFH2 family.

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1
Inheritance
11
Pathophys.
4
Phenotypes
2
Hypotheses
1
Gaps
22
Pathograph
1
Genes
1
Variants
4
Medical Actions
3
Differentials
5
Models
9
References
1
Deep Research
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Inheritance

1
Autosomal Dominant HP:0000006
Four affected siblings carried the heterozygous allele and one examined unaffected sibling was wild type. A second reportedly unaffected sibling did not participate. Parents and grandparents were deceased; recalled paternal joint pain was never evaluated, so the transmitting parent was not established. Segregation in this ascertained family does not provide a population penetrance estimate.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:27330106 SUPPORT Human Clinical
"There was a positive family history with four of six siblings identified with advanced bilateral osteonecrosis of the femoral head (figure 1A), all harbouring a heterozygous mutation in TRPV4 (figure 1B) and absence of risk factors."
Supports segregation consistent with autosomal dominant inheritance in one family; only one unaffected sibling was genotyped.
PMID:27330106 SUPPORT Human Clinical
"Osteonecrosis was ruled out in one unaffected sibling by radiography (see online supplementary figure S1) and the other unaffected sibling did not participate in the study."
Distinguishes the examined unaffected sibling from the unstudied sibling.
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Mechanistic Hypotheses

2
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
trpv4_endothelial_vasoconstriction_hypothesis EMERGING
Evidence balance 1 support
The discovery paper's own proposed mechanism: constitutive gain-of-function TRPV4 activity, combined with the femoral head's constant mechanical loading, causes endothelial calcium overload, vasoconstriction (potentially via COX-dependent thromboxane receptor signaling), and consequent microthrombosis in a joint with no collateral blood supply. The authors explicitly describe this as a proposed synthesis rather than a directly demonstrated in vivo mechanism; no animal model or direct measurement of femoral head blood flow supports it yet.
Pathograph links
Increased TRPV4-Mediated Calcium Influx -> Endothelial Calcium Overload INDIRECT UNKNOWN INTERMEDIATES
Endothelial Calcium Overload -> Vasoconstriction INDIRECT UNKNOWN INTERMEDIATES
Endothelial Calcium Overload -> Femoral Head Microvascular Thrombosis INDIRECT UNKNOWN INTERMEDIATES
Vasoconstriction -> Femoral Head Ischemia INDIRECT UNKNOWN INTERMEDIATES
Femoral Head Microvascular Thrombosis -> Femoral Head Ischemia INDIRECT UNKNOWN INTERMEDIATES
Femoral Head Ischemia -> Osteocyte Death INDIRECT UNKNOWN INTERMEDIATES
Osteocyte Death -> Subchondral Fracture INDIRECT UNKNOWN INTERMEDIATES
Subchondral Fracture -> Femoral Head Structural Collapse INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:27330106 SUPPORT INDIRECT Other
"Together, this could cause Ca2+ overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip."
The authors' own hedged statement of the proposed mechanism.
TRPV4 gain-of-function drives femoral head bone loss via excess osteoclast resorptive activity
trpv4_osteoclast_resorption_hypothesis EMERGING
Evidence balance 3 support
Excess osteoclast resorption is a candidate route from TRPV4 gain of function to bone loss. Knockout and osteoclast-lineage R616Q/V620I gain-of-function experiments support a role for channel activity in resorption. However, the ANFH2 frameshift has not been tested in osteoclasts. In the 2012 gain-of-function model, removal of the calmodulin-binding domain abolished the bone-loss effect, so a C-terminal frameshift cannot simply be assumed to reproduce other alleles.
Pathograph links
Increased TRPV4-Mediated Calcium Influx -> Increased Osteoclast Bone Resorption INDIRECT UNKNOWN INTERMEDIATES
Increased Osteoclast Bone Resorption -> Femoral Head Structural Collapse INDIRECT UNKNOWN INTERMEDIATES
Show evidence (3 references)
PMID:18762026 SUPPORT INDIRECT Model Organism
"genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption"
Establishes the direction of TRPV4's normal role in osteoclast resorption, from which the gain-of-function hypothesis is inferred by analogy.
PMID:22492541 SUPPORT INDIRECT Model Organism
"As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss."
Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
PMID:22492541 SUPPORT INDIRECT Model Organism
"In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4."
Shows dependence on the calmodulin-binding region in a different gain-of-function construct; this limits extrapolation to the ANFH2 C-terminal allele.
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Discussions and Knowledge Gaps

1
Does any animal or cellular model directly recapitulate femoral head osteonecrosis driven by a TRPV4 gain-of-function allele, rather than modeling TRPV4's general roles in bone or vascular biology?
HUMAN MODEL MISMATCH OPEN anfh2_no_gain_of_function_animal_model
Attached to
pathophysiology#Endothelial Calcium Overload pathophysiology#Increased Osteoclast Bone Resorption
The isolated ANFH2 family has segregation and non-disease-site cellular functional evidence. Other TRPV4 gain-of-function alleles do increase osteoclast resorption and bone loss, but that does not demonstrate femoral-head osteonecrosis from the ANFH2 frameshift. Disease-site endothelial, vascular and osteoclast measurements remain missing, and the specific role of calmodulin regulation in the frameshift channel remains unresolved.
Show evidence (1 reference)
PMID:27330106 SUPPORT Human Clinical
"Limitations of the study include the availability of a single family, which adds difficulty to eliminating all variant candidates in an autosomal-dominant model of inheritance and a lack of available phenotype-relevant cell types for functional measurements or an animal model to provide..."
The discovery paper's own authors identify the absence of a phenotype-relevant cell type or animal model as a limitation of their causal evidence.
⚙

Pathophysiology

11
TRPV4 C-Terminal Truncation
The last-exon complex allele NM_021625.4:c.2480_2483delCCCG with c.2486T>A was reported as p.V829Wfs*3. Mutant transcript was present in proband cDNA and tagged truncated protein was expressed in transduced HEK293 cells. The truncation overlaps the C-terminal calmodulin-binding region; an effect on calmodulin binding or feedback was not measured. Patient fibroblast protein was below antibody detection.
TRPV4 hgnc:18083 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRPV4 (hgnc:18083). hgnc:18083 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: frameshift deletion (c.2480_2483delCCCG) with adjacent c.2486T>A substitution, C-terminal truncating variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Downstream
Prolonged TRPV4 Channel Activity
Show evidence (1 reference)
PMID:27330106 SUPPORT Human Clinical
"It truncates the 871 amino acid protein (V829WfsX3), eliminating a highly conserved region including residues within a calmodulin-binding domain."
The allele changes and truncates the conserved C-terminal region; the effect on calmodulin binding itself was not measured.
Prolonged TRPV4 Channel Activity
Longer calcium sparklet bursts in proband fibroblasts and mutant-transduced HEK293 cells support impaired channel closure. These optical bursts may contain multiple brief channel openings; they are not direct patch-clamp single-channel dwell-time measurements.
calcium channel activity GO:0005262 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves calcium channel activity (GO:0005262), qualified as gain of function. GO:0005262 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Increased TRPV4-Mediated Calcium Influx
Show evidence (2 references)
PMID:27330106 SUPPORT In Vitro
"Thus, this mutation leads to a gain of function of TRPV4 channels by impeding channel closure."
States the direction of the functional defect directly: gain of function via impaired channel closure, not loss of function.
PMID:27330106 SUPPORT In Vitro
"finding twofold longer mean burst open times for each quantal level in proband fibroblasts compared with control fibroblasts"
The measured readout is optical burst duration. Impaired closure is the authors' interpretation.
Increased TRPV4-Mediated Calcium Influx
Confocal imaging of local calcium sparklets showed higher activity per site in proband fibroblasts and mutant-transduced HEK293 cells. The observed maximum was four channels per site in both comparisons. Prolonged optical bursts support impaired channel closure indirectly. In HEK293 cells, wild-type protein expression was approximately twice mutant expression, so the higher mutant signal was not explained by higher total expression.
TRPV4 gain-of-function drives femoral head bone loss via excess osteoclast resorptive activity TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
calcium ion transmembrane transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Proband dermal fibroblasts CELL LINE
HEK293 cells expressing wild-type or ANFH2-mutant TRPV4 CELL LINE
Downstream
Endothelial Calcium Overload TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Increased Osteoclast Bone Resorption TRPV4 gain-of-function drives femoral head bone loss via excess osteoclast resorptive activity
Show evidence (2 references)
PMID:27330106 SUPPORT In Vitro
"We stimulated channel activity with TRPV4 agonist GSK1016790A (GSK101 hereafter, 3 nM) and found that sparklet activity per site was 3.3-fold higher in proband fibroblasts versus control"
Quantifies the calcium-channel gain of function directly in patient-derived cells.
PMID:27330106 SUPPORT In Vitro
"The baseline TRPV4 sparklet activity per site was 2.5-fold higher in TRPV4-V829WfsX3 vs TRPV4-WT cells"
Reproduces the gain-of-function calcium signal in a second, independent cell system (transduced HEK293 cells) expressing only the mutant channel.
Endothelial Calcium Overload
Sustained endothelial calcium elevation under mechanical loading is proposed as a link from mutant channel activity to vascular injury. Calcium influx was measured in fibroblasts and HEK293 cells, not in endothelial cells from the ANFH2 family.
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Downstream
Vasoconstriction TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Femoral Head Microvascular Thrombosis TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Show evidence (1 reference)
PMID:27330106 SUPPORT INDIRECT Other
"Together, this could cause Ca2+ overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip."
The authors' own proposed causal chain from calcium overload to vasoconstriction to bone loss, offered as a plausible mechanism rather than a directly demonstrated one - graded INDIRECT accordingly.
Vasoconstriction
Vasoconstriction is a proposed vascular consequence of excess TRPV4 activity in ANFH2. Agonist experiments in isolated mouse aortae and cultured human umbilical-vein endothelial cells support a COX-dependent thromboxane-receptor pathway, but did not test the ANFH2 allele or femoral-head microvessels.
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Downstream
Femoral Head Ischemia TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Show evidence (1 reference)
PMID:25572823 SUPPORT INDIRECT Model Organism
"In addition to the well-documented vasorelaxation response triggered by TRPV4 activation, we report here a TRPV4-triggered vasoconstriction in the mouse aorta that involves a COX-generated Tx receptor (TP) agonist that acts in a MAPK and Src kinase signalling dependent manner."
Agonist-stimulated mouse aortic contraction supports this candidate pathway indirectly; the disease allele and hip circulation were not tested.
Femoral Head Microvascular Thrombosis
Microvascular thrombosis is discussed as a general feature of non-traumatic osteonecrosis. It was not demonstrated histologically in the ANFH2 family. The authors propose local vascular compromise at the mechanically loaded femoral head as a link between channel dysfunction and osteonecrosis.
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Downstream
Femoral Head Ischemia TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Show evidence (2 references)
PMID:27330106 SUPPORT INDIRECT BACKGROUND Human Clinical
"microvascular thrombosis is a common finding in non-traumatic osteonecrosis, indicating a vascular role in disease pathogenesis"
Establishes microvascular thrombosis as a recognized feature of non-traumatic osteonecrosis pathogenesis generally, which this TRPV4-driven case is proposed to share.
PMID:27330106 SUPPORT INDIRECT Other
"suggesting that TRPV4 activation in endothelial cells is the most plausible origin of the microthrombotic process underlying osteonecrosis, possibly via a thromboxane-related mechanism"
Names the specific proposed downstream vascular event (microthrombosis) and its candidate mediator, again explicitly hedged by the authors as the "most plausible" rather than proven origin.
Femoral Head Ischemia
Reduced femoral-head perfusion is the proposed proximal injury in osteonecrosis. The family study did not measure local blood flow or distinguish vasoconstriction from microthrombotic occlusion as its cause.
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Downstream
Osteocyte Death TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Show evidence (1 reference)
PMID:27330106 SUPPORT INDIRECT BACKGROUND Human Clinical
"Osteonecrosis of the femoral head is characterised by compromised blood flow to the femoral head leading to bone cell apoptosis and its eventual collapse."
States the causal step from compromised blood flow to bone cell (osteocyte) apoptosis directly.
Osteocyte Death
Bone-cell death is a general consequence of compromised femoral-head perfusion. Apoptosis is described in the founding paper as background pathogenesis; it was not measured in the affected siblings. The specific death pathway in ANFH2 remains unverified.
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Downstream
Osteonecrosis of the femoral head
Subchondral Fracture TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Show evidence (1 reference)
PMID:27330106 SUPPORT INDIRECT BACKGROUND Human Clinical
"Osteonecrosis of the femoral head is characterised by compromised blood flow to the femoral head leading to bone cell apoptosis and its eventual collapse."
States the causal step from compromised blood flow to bone cell (osteocyte) apoptosis directly.
Increased Osteoclast Bone Resorption
Increased bone resorption is a proposed contributor to femoral-head structural failure in ANFH2. Trpv4-null mice show reduced resorption, whereas osteoclast-lineage expression of R616Q/V620I on a null background increases osteoclast numbers, resorption and bone loss. Neither model tests the ANFH2 frameshift or demonstrates femoral-head osteonecrosis. The gain-of-function effect in the latter model requires the calmodulin-binding region, limiting extrapolation to the ANFH2 C-terminal allele.
TRPV4 gain-of-function drives femoral head bone loss via excess osteoclast resorptive activity
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
bone resorption GO:0045453 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone resorption (GO:0045453). GO:0045453 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Global Trpv4-knockout mouse Mouse fails to recapitulate TRPV4 loss reduces resorption and increases bone mass, opposite to the excessive resorption proposed for ANFH2. Separate gain-of-function models exist, but use different alleles.
Osteoclast-lineage Trpv4 R616Q/V620I transgenic mouse Mouse partially recapitulates
Osteoclast-lineage Trpv4 R616Q/V620I with calmodulin-binding-domain deletion Mouse perturbs
Downstream
Femoral Head Structural Collapse TRPV4 gain-of-function drives femoral head bone loss via excess osteoclast resorptive activity
Show evidence (3 references)
PMID:18762026 SUPPORT INDIRECT Model Organism
"genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption"
Establishes that TRPV4 loss of function reduces osteoclast-mediated bone resorption in mice - the inverse experiment to the human gain-of-function variant, so it is graded INDIRECT: it supports a role for TRPV4 in osteoclast resorption without directly showing that the ANFH2 gain-of-function allele increases resorption.
PMID:18762026 SUPPORT INDIRECT Model Organism
"TRPV4-mediated Ca(2+) influx hereby secures intracellular Ca(2+) concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts."
Describes the molecular pathway (Ca2+ influx sustaining NFATc1-dependent transcription) by which TRPV4 activity level controls osteoclast terminal differentiation.
PMID:22492541 SUPPORT INDIRECT Model Organism
"As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss."
Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
Subchondral Fracture
Subchondral failure is a recognized structural complication of ischemic femoral-head injury. The background literature links the site's limited collateral supply to fracture risk, but the family study did not experimentally establish this sequence.
TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Downstream
Femoral Head Structural Collapse TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
Show evidence (1 reference)
PMID:27330106 SUPPORT INDIRECT BACKGROUND Human Clinical
"The femoral head lacks collateral blood vessels, increasing risk for subchondral fracture and collapse."
Anatomical basis for why compromised blood flow specifically threatens the femoral head with fracture and collapse.
Femoral Head Structural Collapse
Femoral-head collapse was documented radiographically in affected siblings. Its proposed antecedents include ischemic bone injury and resorption, but the relative contribution of either pathway in ANFH2 is unknown.
Downstream
Hip osteoarthritis
Hip pain
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"All affected family members have bilateral patchy sclerosis and/or cystic changes with collapse of their femoral heads."
Direct radiographic description of the founding family.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Avascular Necrosis of Femoral Head, Primary, 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Limbs 1
Osteonecrosis of the femoral head Avascular necrosis of the capital femoral epiphysis HP:0005743 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteonecrosis of the femoral head, annotated with Avascular necrosis of the capital femoral epiphysis (HP:0005743), qualified as laterality bilateral. HP:0005743 is a phenotype from the Human Phenotype Ontology.
Laterality: BILATERAL
Sequelae: Hip pain
Show evidence (6 references)
PMID:27330106 SUPPORT Human Clinical
"all affected family members had bilateral hip involvement, whereas only two-thirds of the sporadic patients had bilateral disease"
Documents bilateral femoral head involvement as a feature of the TRPV4-associated (inherited) form, distinguishing it from the sporadic comparison cohort.
PMID:27330106 SUPPORT Human Clinical
"Using the Steinberg classification, sibling III-5, left, has Stage V disease of left hip and Stage IV disease of right hip. The proband (III-6), right, has Stage IV disease of left hip and Stage III of right hip."
The main radiograph legend stages two siblings, not the entire family. Supplementary clinical notes extend the observed range to Stage VI.
PMID:27330106 SUPPORT Human Clinical
"TRPV4-associated skeletal dysplasias were ruled out by a complete physical examination performed by a medical geneticist and total body skeletal surveys."
The authors excluded a generalized skeletal dysplasia; the supplement describes the participants examined and minor findings regarded as incidental.
+ 3 more references
Musculoskeletal 1
Hip osteoarthritis HP:0008843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip osteoarthritis (HP:0008843). HP:0008843 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"Antero-posterior view of right femur showing osteonecrosis of the femoral head with collapse and secondary degenerative arthritis."
Supplementary Figure F in III-5 supplies direct evidence of secondary hip arthritis.
PMID:30693671 SUPPORT BACKGROUND Human Clinical
"Pelvis: degenerative arthritis in hip joints"
Table 1 summarizes the original ANFH2 family; this is secondary reporting of that family, not an independent ANFH2 cohort.
Nervous System 1
Antalgic gait HP:0031955 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Antalgic gait (HP:0031955). HP:0031955 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"Hip pain started at the age of 20 with ... limping. She was diagnosed at the age of 21 with bilateral osteonecrosis of the hips."
Pain-associated limping in the proband supports an antalgic gait.
Constitutional 1
Hip pain HP:0030838 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip pain (HP:0030838), qualified as young adult onset. HP:0030838 is a phenotype from the Human Phenotype Ontology.
Onset: YOUNG ADULT
Sequelae: Antalgic gait
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"Hip pain started at the age of 20 with ... limping. She was diagnosed at the age of 21 with bilateral osteonecrosis of the hips."
Clinical narrative for the proband dates symptoms separately from diagnosis at 21. Supplementary Table S2 instead gives symptom onset at 15-20; no more precise onset is inferred.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"Pain directly in the hips started at approximately 30 years of age."
Clinical narrative for III-1; the other two affected siblings also developed pain around 30.
🧬

Genetic Associations

1
TRPV4
Gene: TRPV4 hgnc:18083 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPV4 (hgnc:18083). hgnc:18083 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:27330106 SUPPORT Human Clinical
"RESULTS: We report a family with four siblings affected with inherited osteonecrosis of the femoral head and the identification of a c.2480_2483delCCCG frameshift deletion followed by a c.2486T>A substitution in one allele of the transient receptor potential vanilloid 4 (TRPV4) gene."
Identifies the complex TRPV4 allele associated with the founding family; the paper also reports segregation and functional support.
PMID:30328481 SUPPORT BACKGROUND Human Clinical
"our recent identification of a novel mutation in the transient receptor potential vanilloid 4 (TRPV4) gene in association with inherited ONFH"
The same research group summarizes its earlier TRPV4-associated family; this is not independent replication.
PMID:24830047 SUPPORT BACKGROUND Human Clinical
"The autosomal dominant TRPV4-related disorders include two principal types: neuromuscular disorders and skeletal dysplasias."
GeneReviews describes the broader neuromuscular and skeletal TRPV4 spectrum. Its chapter does not name osteonecrosis and does not supply an ANFH2-specific phenotype or management baseline.
🔬

Variants

1
TRPV4 c.2480_2483delCCCG with c.2486T>A (p.V829Wfs*3)
Gene: TRPV4 hgnc:18083 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TRPV4 (hgnc:18083). hgnc:18083 is a gene from the HUGO Gene Nomenclature Committee. Complex deletion and adjacent substitution on one allele
Genomic context: coding sequence
Reported on NM_021625.4 in the last exon. The deletion and adjacent substitution are in cis and were reported together as V829WfsX3. Four affected siblings carried the allele, one tested unaffected sibling was wild type, and the transmitting parent was not established. Mutant transcript persisted in patient cDNA; truncated protein was measured in tagged HEK293 constructs, not demonstrated in patient fibroblasts. The paper provides segregation and channel-function evidence without a formal ACMG classification.
Functional effects
Increased TRPV4 channel activity
Proband fibroblasts and mutant-transduced HEK293 cells showed increased optical calcium sparklet activity and longer bursts. Altered calmodulin binding remains a hypothesis.
Show evidence (4 references)
PMID:27330106 SUPPORT Human Clinical
"RESULTS: We report a family with four siblings affected with inherited osteonecrosis of the femoral head and the identification of a c.2480_2483delCCCG frameshift deletion followed by a c.2486T>A substitution in one allele of the transient receptor potential vanilloid 4 (TRPV4) gene."
Identifies the complex TRPV4 allele associated with the founding family; the paper also reports segregation and functional support.
PMID:27330106 SUPPORT Human Clinical
"The TRPV4 mutation is located in the last exon and was confirmed in proband cDNA"
Demonstrates persistence of mutant transcript; does not quantify allele-specific nonsense-mediated decay.
PMID:27330106 SUPPORT In Vitro
"Thus, this mutation leads to a gain of function of TRPV4 channels by impeding channel closure."
States the direction of the functional defect directly: gain of function via impaired channel closure, not loss of function.
+ 1 more reference
💊

Medical Actions

4
Total Hip Arthroplasty
Category: Therapeutic Action: total hip arthroplastyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is total hip arthroplasty, annotated with Hip Replacement (NCIT:C157876). NCIT:C157876 is a clinical intervention from the NCI Thesaurus. Ontology label: Hip Replacement NCIT:C157876
Platform: Surgery
Hip arthroplasty is used for advanced osteonecrosis. The supplementary clinical note reports progression in III-5 and subsequent bilateral replacement. The family report provides no controlled ANFH2-specific outcome estimate.
Show evidence (2 references)
PMID:27330106 SUPPORT BACKGROUND Human Clinical
"with treatment at advanced stages involving total hip arthroplasty"
General advanced-stage osteonecrosis management in the paper's introduction. The supplement separately records bilateral arthroplasty in III-5, without a controlled treatment comparison.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"She has subsequently progressed to stage V-VI bilaterally and recently underwent bilateral total hip arthroplasty."
III-5 underwent replacement after progression; no postoperative outcome is specified.
Hip Core Decompression and Bone Grafting
Category: Therapeutic Action: hip core decompressionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hip core decompression, annotated with Core Decompression (NCIT:C157826). NCIT:C157826 is a clinical intervention from the NCI Thesaurus. Ontology label: Core Decompression NCIT:C157826
Platform: Surgery
The proband underwent core decompression and bone grafting, but timing and laterality conflict within the publication: the main text reports bilateral procedures at age 21, while the supplementary clinical note describes a right-sided procedure at age 28. The report does not resolve this discrepancy, establish treatment before collapse, or quantify ANFH2-specific benefit.
Show evidence (2 references)
PMID:27330106 SUPPORT Human Clinical
"The proband was diagnosed with osteonecrosis of the femoral head at age 21 and in the same year had bilateral hip core decompressions and bone grafting."
Main-text account; the supplementary clinical note differs on age and laterality. The inconsistency is retained rather than choosing one version.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"She has undergone right hip core decompression and bone grafting (a common procedure for osteonecrosis) at the age of 28."
Supplementary clinical note for the proband conflicts with the main-text bilateral procedure at 21.
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Offer genetic counseling and family-specific testing once an appropriately interpreted TRPV4 allele is identified. A heterozygous parent has a 50% probability of transmitting the allele per pregnancy; this is not a 50% estimate of hip osteonecrosis, whose penetrance is unknown for the founding ANFH2 allele. Reproductive testing options require counseling about phenotype uncertainty.
Show evidence (2 references)
PMID:24830047 SUPPORT INDIRECT BACKGROUND Human Clinical
"Each child of an individual with an autosomal dominant TRPV4-related disorder has a 50% chance of inheriting the TRPV4 pathogenic variant."
General Mendelian transmission guidance; disease penetrance and severity are separate questions.
PMID:24830047 SUPPORT INDIRECT BACKGROUND Human Clinical
"Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
General TRPV4 counseling guidance; an ANFH2-specific outcome cannot be predicted from this alone.
Symptomatic Hip Pain Management
Category: Therapeutic Action: Pain TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pain Therapy (NCIT:C15180). NCIT:C15180 is a clinical intervention from the NCI Thesaurus. NCIT:C15180
Individualize pain management and rehabilitation with orthopedic and rehabilitation specialists. This supportive-care principle is extrapolated from the broader TRPV4 GeneReviews chapter; an ANFH2-specific medication or rehabilitation regimen has not been established.
Show evidence (1 reference)
PMID:24830047 SUPPORT INDIRECT BACKGROUND Human Clinical
"This multidisciplinary team will determine the best treatment options for supportive care, prevention of obesity, and management of pain and depression."
Broad TRPV4 supportive-care guidance; the chapter does not specifically address hip osteonecrosis.
🔬

Diagnosis

3
Hip Radiography
Initial imaging modality; disease extent/staging is evaluated using the Steinberg classification once findings are present.
hip radiography NCIT:C38101 NCI Thesaurus (NCIT)
Results: Bilateral femoral-head osteonecrosis. Figure 1C shows III-5 with Stage V left/IV right and the proband with Stage IV left/III right. The supplementary clinical note documents Stage VI in another sibling, so the full family range is III-VI.
Show evidence (3 references)
PMID:27330106 SUPPORT Human Clinical
"Diagnosis was made by several bone radiologists and orthopaedic surgeons using modalities including radiography (figure 1C) and MRI (figure 1D), the gold standard for diagnosis."
States radiography as one of the diagnostic imaging modalities used, directly from the discovery paper.
PMID:27330106 SUPPORT Human Clinical
"Using the Steinberg classification, sibling III-5, left, has Stage V disease of left hip and Stage IV disease of right hip. The proband (III-6), right, has Stage IV disease of left hip and Stage III of right hip."
Figure 1C reports the radiographic stages of two siblings. The supplementary clinical note adds Stage VI disease in III-1.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT Human Clinical
"Stage V left hip and Stage VI right hip determined from radiograph of the pelvis"
Supplementary clinical note for III-1 extends the family stage range to VI.
Hip MRI
MRI establishes femoral-head osteonecrosis and helps characterize extent. Stages differ by imaging modality in the proband; the radiographic and MRI findings should not be interchanged.
hip MRI NCIT:C16809 NCI Thesaurus (NCIT)
Results: Figure 1D shows III-5 with Stage V left/IV right and the proband with Stage IV disease in both hips. The proband's Stage III right hip in Figure 1C is a radiographic finding.
Show evidence (3 references)
PMID:27330106 SUPPORT Human Clinical
"Diagnosis was made by several bone radiologists and orthopaedic surgeons using modalities including radiography (figure 1C) and MRI (figure 1D), the gold standard for diagnosis."
Identifies MRI as the gold-standard diagnostic modality, directly from the discovery paper.
PMID:27330106 SUPPORT Human Clinical
"The extent of hip involvement or staging was evaluated according to the Steinberg classification."
Identifies the staging system used to grade disease severity in the affected family.
PMID:27330106 SUPPORT Human Clinical
"The proband (III-6, right) has Stage IV disease of both hips."
Figure 1D MRI finding, distinct from the proband's radiographic stages in Figure 1C.
Molecular Genetic Testing
Whole-exome sequencing and segregation identified the founding TRPV4 allele. Only one unaffected sibling was genotyped. COL2A1 variants were not found, and candidate COL12A1 and COL5A1 variants did not segregate. A TRPV4 result must be interpreted with the skeletal and neurologic phenotype because other TRPV4 disorders overlap clinically.
whole-exome sequencing with segregation analysis NCIT:C101295 NCI Thesaurus (NCIT)
Results: Heterozygous TRPV4 c.2480_2483delCCCG + c.2486T>A variant identified and confirmed to segregate with disease.
Show evidence (2 references)
PMID:27330106 SUPPORT Human Clinical
"Candidate genes were identified by whole-exome sequencing and the TRPV4 mutation was verified by segregation analysis."
States the molecular diagnostic method used to identify and confirm the causal variant.
PMID:24830047 SUPPORT INDIRECT BACKGROUND Human Clinical
"The diagnosis of an autosomal dominant TRPV4-related disorder is established in a proband who has characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified by molecular genetic testing."
GeneReviews supports combined clinical and molecular interpretation across the TRPV4 spectrum; it does not provide ANFH2-specific diagnostic criteria.
📊

Prevalence

1
Worldwide
Unknown Not yet documented
The isolated ANFH2 presentation was delineated in one family in 2016. Later reports of osteonecrosis within mixed TRPV4 phenotypes do not establish a population prevalence for isolated ANFH2.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Avascular Necrosis of Femoral Head, Primary, 2:

🧫

Experimental Models

2
Proband dermal fibroblasts CELL_LINE
Immortalized dermal fibroblasts from the proband and a healthy control were compared using confocal calcium sparklet imaging. With 3 nM GSK1016790A, activity per site was 3.3-fold higher in proband cells; mean optical burst durations were approximately doubled. Basal activity was also increased.
Cell source
Patient and control dermal fibroblasts, immortalized according to the supplementary methods
Publication
PMID:27330106
Pathograph links
Increased TRPV4-Mediated Calcium Influx recapitulates fidelity: moderate observes: cellular
Limitations: One patient and one unrelated control; no isogenic correction or disease-site endothelial/osteoclast cells. Optical bursts are indirect channel measurements, and endogenous TRPV4 protein could not be detected by the antibody.
Show evidence (1 reference)
PMID:27330106 SUPPORT In Vitro
"We stimulated channel activity with TRPV4 agonist GSK1016790A (GSK101 hereafter, 3 nM) and found that sparklet activity per site was 3.3-fold higher in proband fibroblasts versus control"
Quantifies the calcium-channel gain of function directly in patient-derived cells.
Show evidence (2 references)
PMID:27330106 SUPPORT In Vitro
"We stimulated channel activity with TRPV4 agonist GSK1016790A (GSK101 hereafter, 3 nM) and found that sparklet activity per site was 3.3-fold higher in proband fibroblasts versus control"
Quantifies the calcium-channel gain of function directly in patient-derived cells.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT In Vitro
"Dermal fibroblasts were obtained from the proband and a healthy 23-year-old female control; both proband and control fibroblasts were immortalized"
Establishes donor source and immortalization of both comparator cultures.
HEK293 cells expressing wild-type or ANFH2-mutant TRPV4 CELL_LINE
Stable C-terminal FLAG-tagged constructs reproduced increased basal sparklet activity in mutant cells despite lower protein expression. Native HEK293 cells lacked detectable sparklets. Agonist-induced calcium overload and death in the transduced cells were assay observations, not evidence of patient-cell death or therapeutic efficacy.
Cell source
HEK293 cells stably transduced with wild-type or p.V829Wfs*3 TRPV4
Publication
PMID:27330106
Pathograph links
Increased TRPV4-Mediated Calcium Influx recapitulates fidelity: moderate observes: cellular
Limitations: Overexpression of the mutant construct does not reproduce the heterozygous patient genotype or disease-site tissue. Supplementary Figure S12 tests GSK2193874 in wild-type-transduced HEK293 and control fibroblasts; the inhibitor experiment does not demonstrate rescue of mutant cells.
Show evidence (1 reference)
PMID:27330106 SUPPORT In Vitro
"The baseline TRPV4 sparklet activity per site was 2.5-fold higher in TRPV4-V829WfsX3 vs TRPV4-WT cells"
Reproduces the gain-of-function calcium signal in a second, independent cell system (transduced HEK293 cells) expressing only the mutant channel.
Show evidence (3 references)
PMID:27330106 SUPPORT In Vitro
"The baseline TRPV4 sparklet activity per site was 2.5-fold higher in TRPV4-V829WfsX3 vs TRPV4-WT cells"
Reproduces the gain-of-function calcium signal in a second, independent cell system (transduced HEK293 cells) expressing only the mutant channel.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT In Vitro
"TRPV4 mRNA was >100-fold in transduced HEK293 cells relative to fibroblasts."
Quantifies the overexpression limitation.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1 SUPPORT In Vitro
"Inhibition of TRPV4 sparklet activity in the WT TRPV4- transduced HEK293 cells and control fibroblasts."
Supplementary Figure S12 specifies control systems, not mutant-channel rescue.
🐁

Animal Models

3
Global Trpv4-knockout mouse
Global genetic ablation of Trpv4, used to establish the channel's normal role in osteoclast terminal differentiation and bone resorption. This is a loss-of-function model of a gene whose ANFH2 disease allele is gain-of-function, so it informs the pathway rather than modeling the disease genotype itself.
Species
Mouse
Genotype
Trpv4-null (global knockout)
Publication
PMID:18762026
Pathograph links
Increased Osteoclast Bone Resorption fails to recapitulate fidelity: low observes: cellular TRPV4 loss reduces resorption and increases bone mass, opposite to the excessive resorption proposed for ANFH2. Separate gain-of-function models exist, but use different alleles.
Limitations: Opposite-direction genetic perturbation: a null allele cannot demonstrate that a constitutively active channel drives excess resorption, only that channel activity is required for normal resorption. The inference to ANFH2's gain-of-function direction is by analogy, not direct evidence.
Divergences from the human mechanism
other invalidating
The model's genetic perturbation is loss-of-function (null allele); the ANFH2 disease allele is gain-of-function. No divergence type in the current taxonomy captures a functional-direction reversal (loss vs gain of function) of the same gene, so this is recorded as OTHER.
Readouts
Bone mass and resorption
Direction: DECREASED
Interpretation: Bone resorption is decreased (bone mass increased) upon TRPV4 loss of function, the inverse of the direction hypothesized for the ANFH2 gain-of-function allele.
Show evidence (1 reference)
PMID:18762026 SUPPORT INDIRECT Model Organism
"genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption"
Reports the knockout's bone-mass/resorption phenotype directly.
Show evidence (1 reference)
PMID:18762026 SUPPORT INDIRECT Model Organism
"genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption"
Substantiates the FAILS_TO_RECAPITULATE call: the knockout's bone-mass/resorption phenotype is opposite in direction to what the ANFH2 gain-of-function hypothesis predicts, so this model does not recapitulate the disease-relevant (excess-resorption) claim even though it establishes the pathway's general relevance.
Show evidence (1 reference)
PMID:18762026 SUPPORT INDIRECT Model Organism
"TRPV4-mediated Ca(2+) influx hereby secures intracellular Ca(2+) concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts."
Establishes this model as informative for TRPV4's general role in osteoclast biology, the basis for the osteoclast-resorption hypothesis by analogy.
Osteoclast-lineage Trpv4 R616Q/V620I transgenic mouse
Osteoclast-lineage expression of an activating double mutant increased resorption and reduced bone mass. This establishes gain-of-function evidence for the resorption pathway using a different allele from ANFH2.
Species
Mouse
Genotype
TRAP-promoter Trpv4 R616Q/V620I transgene on a Trpv4-null background
Publication
PMID:22492541
Pathograph links
Increased Osteoclast Bone Resorption partially recapitulates fidelity: low observes: cellular
Limitations: Different activating substitutions and transgenic expression; neither the ANFH2 frameshift nor femoral-head osteonecrosis was tested.
Show evidence (1 reference)
PMID:22492541 SUPPORT INDIRECT Model Organism
"As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss."
Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
Show evidence (1 reference)
PMID:22492541 SUPPORT INDIRECT Model Organism
"As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss."
Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
Osteoclast-lineage Trpv4 R616Q/V620I with calmodulin-binding-domain deletion
Deletion of the calmodulin-binding region abrogated bone loss from the activating R616Q/V620I construct. This region-deletion experiment is not equivalent to the ANFH2 frameshift.
Species
Mouse
Genotype
Trpv4 R616Q/V620I delta-CaM transgene on a Trpv4-null background
Publication
PMID:22492541
Pathograph links
Increased Osteoclast Bone Resorption perturbs fidelity: low observes: cellular
Limitations: Engineered domain deletion in a different gain-of-function allele; it cannot establish the effect of the ANFH2 frameshift on calmodulin regulation.
Show evidence (1 reference)
PMID:22492541 SUPPORT INDIRECT Model Organism
"In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4."
Shows dependence on the calmodulin-binding region in a different gain-of-function construct; this limits extrapolation to the ANFH2 C-terminal allele.
Show evidence (1 reference)
PMID:22492541 SUPPORT INDIRECT Model Organism
"In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4."
Shows dependence on the calmodulin-binding region in a different gain-of-function construct; this limits extrapolation to the ANFH2 C-terminal allele.
{ }

Source YAML

click to show 
name: Avascular Necrosis of Femoral Head, Primary, 2
synonyms:
- ANFH2
- Osteonecrosis of the femoral head, TRPV4-related
creation_date: '2026-09-04T03:41:22Z'
category: Mendelian
description: Primary avascular necrosis of the femoral head type 2 (ANFH2) is a rare inherited form of bilateral hip osteonecrosis associated with a heterozygous C-terminal TRPV4 frameshift allele. The founding family contained four affected siblings without the usual acquired risk factors. Patient fibroblasts and transduced HEK293 cells showed increased channel activity and prolonged optical calcium sparklet bursts. The proposed endothelial and osteoclast mechanisms linking channel dysfunction to hip disease remain unverified for this allele in phenotype-relevant tissue. Hip osteonecrosis has also been reported in broader TRPV4 skeletal and neuromuscular phenotypes, which are clinically distinct from the isolated presentation of the founding ANFH2 family.
disease_term:
  preferred_term: avascular necrosis of femoral head, primary, 2
  term:
    id: MONDO:0054551
    label: avascular necrosis of femoral head, primary, 2
parents:
- Skeletal Disorder
- Vascular Disorder
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Four affected siblings carried the heterozygous allele and one examined unaffected sibling was wild type. A second reportedly unaffected sibling did not participate. Parents and grandparents were deceased; recalled paternal joint pain was never evaluated, so the transmitting parent was not established. Segregation in this ascertained family does not provide a population penetrance estimate.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was a positive family history with four of six siblings identified with advanced bilateral osteonecrosis of the femoral head (figure 1A), all harbouring a heterozygous mutation in TRPV4 (figure 1B) and absence of risk factors.
    explanation: Supports segregation consistent with autosomal dominant inheritance in one family; only one unaffected sibling was genotyped.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Osteonecrosis was ruled out in one unaffected sibling by radiography (see online supplementary figure S1) and the other unaffected sibling did not participate in the study.
    explanation: Distinguishes the examined unaffected sibling from the unstudied sibling.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: The isolated ANFH2 presentation was delineated in one family in 2016. Later reports of osteonecrosis within mixed TRPV4 phenotypes do not establish a population prevalence for isolated ANFH2.
genetic:
- name: TRPV4
  gene_term:
    preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  frequency: The founding frameshift allele segregated in one ascertained family; population frequency and penetrance are not established.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'RESULTS: We report a family with four siblings affected with inherited osteonecrosis of the femoral head and the identification of a c.2480_2483delCCCG frameshift deletion followed by a c.2486T>A substitution in one allele of the transient receptor potential vanilloid 4 (TRPV4) gene.'
    explanation: Identifies the complex TRPV4 allele associated with the founding family; the paper also reports segregation and functional support.
  - reference: PMID:30328481
    reference_title: 'Osteonecrosis of the femoral head: genetic basis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: our recent identification of a novel mutation in the transient receptor potential vanilloid 4 (TRPV4) gene in association with inherited ONFH
    explanation: The same research group summarizes its earlier TRPV4-associated family; this is not independent replication.
    quote_role: BACKGROUND
  - reference: PMID:24830047
    reference_title: Autosomal Dominant TRPV4-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The autosomal dominant TRPV4-related disorders include two principal types: neuromuscular disorders and skeletal dysplasias.'
    explanation: GeneReviews describes the broader neuromuscular and skeletal TRPV4 spectrum. Its chapter does not name osteonecrosis and does not supply an ANFH2-specific phenotype or management baseline.
    quote_role: BACKGROUND
pathophysiology:
- name: TRPV4 C-Terminal Truncation
  biological_scale: MOLECULAR
  description: The last-exon complex allele NM_021625.4:c.2480_2483delCCCG with c.2486T>A was reported as p.V829Wfs*3. Mutant transcript was present in proband cDNA and tagged truncated protein was expressed in transduced HEK293 cells. The truncation overlaps the C-terminal calmodulin-binding region; an effect on calmodulin binding or feedback was not measured. Patient fibroblast protein was below antibody detection.
  genes:
  - preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    allele_type: frameshift deletion (c.2480_2483delCCCG) with adjacent c.2486T>A substitution, C-terminal truncating
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
  downstream:
  - target: Prolonged TRPV4 Channel Activity
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It truncates the 871 amino acid protein (V829WfsX3), eliminating a highly conserved region including residues within a calmodulin-binding domain.
    explanation: The allele changes and truncates the conserved C-terminal region; the effect on calmodulin binding itself was not measured.
- name: Prolonged TRPV4 Channel Activity
  biological_scale: MOLECULAR
  description: Longer calcium sparklet bursts in proband fibroblasts and mutant-transduced HEK293 cells support impaired channel closure. These optical bursts may contain multiple brief channel openings; they are not direct patch-clamp single-channel dwell-time measurements.
  molecular_functions:
  - preferred_term: calcium channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: Increased TRPV4-Mediated Calcium Influx
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Thus, this mutation leads to a gain of function of TRPV4 channels by impeding channel closure.
    explanation: 'States the direction of the functional defect directly: gain of function via impaired channel closure, not loss of function.'
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: finding twofold longer mean burst open times for each quantal level in proband fibroblasts compared with control fibroblasts
    explanation: The measured readout is optical burst duration. Impaired closure is the authors' interpretation.
- name: Increased TRPV4-Mediated Calcium Influx
  biological_scale: CELLULAR
  description: Confocal imaging of local calcium sparklets showed higher activity per site in proband fibroblasts and mutant-transduced HEK293 cells. The observed maximum was four channels per site in both comparisons. Prolonged optical bursts support impaired channel closure indirectly. In HEK293 cells, wild-type protein expression was approximately twice mutant expression, so the higher mutant signal was not explained by higher total expression.
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  downstream:
  - target: Endothelial Calcium Overload
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  - target: Increased Osteoclast Bone Resorption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_osteoclast_resorption_hypothesis
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We stimulated channel activity with TRPV4 agonist GSK1016790A (GSK101 hereafter, 3 nM) and found that sparklet activity per site was 3.3-fold higher in proband fibroblasts versus control
    explanation: Quantifies the calcium-channel gain of function directly in patient-derived cells.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The baseline TRPV4 sparklet activity per site was 2.5-fold higher in TRPV4-V829WfsX3 vs TRPV4-WT cells
    explanation: Reproduces the gain-of-function calcium signal in a second, independent cell system (transduced HEK293 cells) expressing only the mutant channel.
- name: Endothelial Calcium Overload
  biological_scale: CELLULAR
  description: Sustained endothelial calcium elevation under mechanical loading is proposed as a link from mutant channel activity to vascular injury. Calcium influx was measured in fibroblasts and HEK293 cells, not in endothelial cells from the ANFH2 family.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  downstream:
  - target: Vasoconstriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  - target: Femoral Head Microvascular Thrombosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: Together, this could cause Ca2+ overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip.
    explanation: The authors' own proposed causal chain from calcium overload to vasoconstriction to bone loss, offered as a plausible mechanism rather than a directly demonstrated one - graded INDIRECT accordingly.
- name: Vasoconstriction
  biological_scale: TISSUE
  description: Vasoconstriction is a proposed vascular consequence of excess TRPV4 activity in ANFH2. Agonist experiments in isolated mouse aortae and cultured human umbilical-vein endothelial cells support a COX-dependent thromboxane-receptor pathway, but did not test the ANFH2 allele or femoral-head microvessels.
  downstream:
  - target: Femoral Head Ischemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  evidence:
  - reference: PMID:25572823
    reference_title: GPCR-mediated EGF receptor transactivation regulates TRPV4 action in the vasculature.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In addition to the well-documented vasorelaxation response triggered by TRPV4 activation, we report here a TRPV4-triggered vasoconstriction in the mouse aorta that involves a COX-generated Tx receptor (TP) agonist that acts in a MAPK and Src kinase signalling dependent manner.
    explanation: Agonist-stimulated mouse aortic contraction supports this candidate pathway indirectly; the disease allele and hip circulation were not tested.
    directness: INDIRECT
- name: Femoral Head Microvascular Thrombosis
  biological_scale: TISSUE
  description: Microvascular thrombosis is discussed as a general feature of non-traumatic osteonecrosis. It was not demonstrated histologically in the ANFH2 family. The authors propose local vascular compromise at the mechanically loaded femoral head as a link between channel dysfunction and osteonecrosis.
  downstream:
  - target: Femoral Head Ischemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: microvascular thrombosis is a common finding in non-traumatic osteonecrosis, indicating a vascular role in disease pathogenesis
    explanation: Establishes microvascular thrombosis as a recognized feature of non-traumatic osteonecrosis pathogenesis generally, which this TRPV4-driven case is proposed to share.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: suggesting that TRPV4 activation in endothelial cells is the most plausible origin of the microthrombotic process underlying osteonecrosis, possibly via a thromboxane-related mechanism
    explanation: Names the specific proposed downstream vascular event (microthrombosis) and its candidate mediator, again explicitly hedged by the authors as the "most plausible" rather than proven origin.
- name: Femoral Head Ischemia
  biological_scale: TISSUE
  description: Reduced femoral-head perfusion is the proposed proximal injury in osteonecrosis. The family study did not measure local blood flow or distinguish vasoconstriction from microthrombotic occlusion as its cause.
  downstream:
  - target: Osteocyte Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Osteonecrosis of the femoral head is characterised by compromised blood flow to the femoral head leading to bone cell apoptosis and its eventual collapse.
    explanation: States the causal step from compromised blood flow to bone cell (osteocyte) apoptosis directly.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: Osteocyte Death
  biological_scale: CELLULAR
  description: Bone-cell death is a general consequence of compromised femoral-head perfusion. Apoptosis is described in the founding paper as background pathogenesis; it was not measured in the affected siblings. The specific death pathway in ANFH2 remains unverified.
  downstream:
  - target: Osteonecrosis of the femoral head
  - target: Subchondral Fracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Osteonecrosis of the femoral head is characterised by compromised blood flow to the femoral head leading to bone cell apoptosis and its eventual collapse.
    explanation: States the causal step from compromised blood flow to bone cell (osteocyte) apoptosis directly.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: Increased Osteoclast Bone Resorption
  biological_scale: CELLULAR
  description: Increased bone resorption is a proposed contributor to femoral-head structural failure in ANFH2. Trpv4-null mice show reduced resorption, whereas osteoclast-lineage expression of R616Q/V620I on a null background increases osteoclast numbers, resorption and bone loss. Neither model tests the ANFH2 frameshift or demonstrates femoral-head osteonecrosis. The gain-of-function effect in the latter model requires the calmodulin-binding region, limiting extrapolation to the ANFH2 C-terminal allele.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  downstream:
  - target: Femoral Head Structural Collapse
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_osteoclast_resorption_hypothesis
  evidence:
  - reference: PMID:18762026
    reference_title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption
    explanation: 'Establishes that TRPV4 loss of function reduces osteoclast-mediated bone resorption in mice - the inverse experiment to the human gain-of-function variant, so it is graded INDIRECT: it supports a role for TRPV4 in osteoclast resorption without directly showing that the ANFH2 gain-of-function allele increases resorption.'
  - reference: PMID:18762026
    reference_title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: TRPV4-mediated Ca(2+) influx hereby secures intracellular Ca(2+) concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts.
    explanation: Describes the molecular pathway (Ca2+ influx sustaining NFATc1-dependent transcription) by which TRPV4 activity level controls osteoclast terminal differentiation.
  - reference: PMID:22492541
    reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss.
    explanation: Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
    directness: INDIRECT
- name: Subchondral Fracture
  biological_scale: TISSUE
  description: Subchondral failure is a recognized structural complication of ischemic femoral-head injury. The background literature links the site's limited collateral supply to fracture risk, but the family study did not experimentally establish this sequence.
  downstream:
  - target: Femoral Head Structural Collapse
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - trpv4_endothelial_vasoconstriction_hypothesis
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The femoral head lacks collateral blood vessels, increasing risk for subchondral fracture and collapse.
    explanation: Anatomical basis for why compromised blood flow specifically threatens the femoral head with fracture and collapse.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: Femoral Head Structural Collapse
  biological_scale: TISSUE
  description: Femoral-head collapse was documented radiographically in affected siblings. Its proposed antecedents include ischemic bone injury and resorption, but the relative contribution of either pathway in ANFH2 is unknown.
  downstream:
  - target: Hip osteoarthritis
  - target: Hip pain
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected family members have bilateral patchy sclerosis and/or cystic changes with collapse of their femoral heads.
    explanation: Direct radiographic description of the founding family.
diagnosis:
- name: Hip Radiography
  description: Initial imaging modality; disease extent/staging is evaluated using the Steinberg classification once findings are present.
  diagnosis_term:
    preferred_term: hip radiography
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  results: Bilateral femoral-head osteonecrosis. Figure 1C shows III-5 with Stage V left/IV right and the proband with Stage IV left/III right. The supplementary clinical note documents Stage VI in another sibling, so the full family range is III-VI.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosis was made by several bone radiologists and orthopaedic surgeons using modalities including radiography (figure 1C) and MRI (figure 1D), the gold standard for diagnosis.
    explanation: States radiography as one of the diagnostic imaging modalities used, directly from the discovery paper.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using the Steinberg classification, sibling III-5, left, has Stage V disease of left hip and Stage IV disease of right hip. The proband (III-6), right, has Stage IV disease of left hip and Stage III of right hip.
    explanation: Figure 1C reports the radiographic stages of two siblings. The supplementary clinical note adds Stage VI disease in III-1.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stage V left hip and Stage VI right hip determined from radiograph of the pelvis
    explanation: Supplementary clinical note for III-1 extends the family stage range to VI.
- name: Hip MRI
  description: MRI establishes femoral-head osteonecrosis and helps characterize extent. Stages differ by imaging modality in the proband; the radiographic and MRI findings should not be interchanged.
  diagnosis_term:
    preferred_term: hip MRI
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Figure 1D shows III-5 with Stage V left/IV right and the proband with Stage IV disease in both hips. The proband's Stage III right hip in Figure 1C is a radiographic finding.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosis was made by several bone radiologists and orthopaedic surgeons using modalities including radiography (figure 1C) and MRI (figure 1D), the gold standard for diagnosis.
    explanation: Identifies MRI as the gold-standard diagnostic modality, directly from the discovery paper.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The extent of hip involvement or staging was evaluated according to the Steinberg classification.
    explanation: Identifies the staging system used to grade disease severity in the affected family.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband (III-6, right) has Stage IV disease of both hips.
    explanation: Figure 1D MRI finding, distinct from the proband's radiographic stages in Figure 1C.
- name: Molecular Genetic Testing
  description: Whole-exome sequencing and segregation identified the founding TRPV4 allele. Only one unaffected sibling was genotyped. COL2A1 variants were not found, and candidate COL12A1 and COL5A1 variants did not segregate. A TRPV4 result must be interpreted with the skeletal and neurologic phenotype because other TRPV4 disorders overlap clinically.
  diagnosis_term:
    preferred_term: whole-exome sequencing with segregation analysis
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: Heterozygous TRPV4 c.2480_2483delCCCG + c.2486T>A variant identified and confirmed to segregate with disease.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Candidate genes were identified by whole-exome sequencing and the TRPV4 mutation was verified by segregation analysis.
    explanation: States the molecular diagnostic method used to identify and confirm the causal variant.
  - reference: PMID:24830047
    reference_title: Autosomal Dominant TRPV4-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnosis of an autosomal dominant TRPV4-related disorder is established in a proband who has characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified by molecular genetic testing.
    explanation: GeneReviews supports combined clinical and molecular interpretation across the TRPV4 spectrum; it does not provide ANFH2-specific diagnostic criteria.
    directness: INDIRECT
    quote_role: BACKGROUND
phenotypes:
- name: Osteonecrosis of the femoral head
  description: All four affected siblings had bilateral femoral-head osteonecrosis, with collapse, patchy sclerosis and cystic change in the supplementary radiographs. The complete supplementary clinical note documents Steinberg stages III-VI, whereas main Figure 1 depicts only two siblings. Main-text comparison with approximately two-thirds bilateral sporadic disease differs from the supplementary table count of 36/49; neither estimates ANFH2 penetrance. Neurologic and geneticist examinations detailed in the supplement concern III-5 and III-6, with partial skeletal surveys in other participants. Mild scoliosis, short fourth metacarpals and the proband's median neuropathy were considered incidental rather than a generalized TRPV4 skeletal dysplasia or polyneuropathy.
  sequelae:
  - target: Hip pain
  phenotype_term:
    preferred_term: Osteonecrosis of the femoral head
    term:
      id: HP:0005743
      label: Avascular necrosis of the capital femoral epiphysis
    laterality: BILATERAL
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: all affected family members had bilateral hip involvement, whereas only two-thirds of the sporadic patients had bilateral disease
    explanation: Documents bilateral femoral head involvement as a feature of the TRPV4-associated (inherited) form, distinguishing it from the sporadic comparison cohort.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using the Steinberg classification, sibling III-5, left, has Stage V disease of left hip and Stage IV disease of right hip. The proband (III-6), right, has Stage IV disease of left hip and Stage III of right hip.
    explanation: The main radiograph legend stages two siblings, not the entire family. Supplementary clinical notes extend the observed range to Stage VI.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TRPV4-associated skeletal dysplasias were ruled out by a complete physical examination performed by a medical geneticist and total body skeletal surveys.
    explanation: The authors excluded a generalized skeletal dysplasia; the supplement describes the participants examined and minor findings regarded as incidental.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TRPV4-related polyneuropathies were ruled out by neurological examination and motor and sensory nerve conduction studies performed by a neuromuscular neurologist.
    explanation: No generalized TRPV4 polyneuropathy was diagnosed. The supplement reports detailed neurologic assessment of two siblings and an incidental mild median neuropathy in the proband.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected family members have bilateral patchy sclerosis and/or cystic changes with collapse of their femoral heads.
    explanation: Direct description of all four affected siblings.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A complete neurological examination of affected family members III-5 and III-6 was performed by a neurologist with expertise in polyneuropathy, including nerve conduction studies.
    explanation: Specifies the examined subset; this should not be generalized to all siblings.
- name: Hip pain
  description: Hip/groin pain was the presenting complaint. The supplementary clinical note describes proband pain with limping around age 20 and pain around age 30 in the other affected siblings. Diagnosis at age 21 in the proband is not equivalent to symptom onset. The supplementary age-at-diagnosis table conflicts with the individual clinical narratives, so no family mean or penetrance estimate is inferred.
  phenotype_term:
    preferred_term: Hip pain
    term:
      id: HP:0030838
      label: Hip pain
    onset:
      onset_category: YOUNG_ADULT
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hip pain started at the age of 20 with ... limping. She was diagnosed at the age of 21 with bilateral osteonecrosis of the hips.
    explanation: Clinical narrative for the proband dates symptoms separately from diagnosis at 21. Supplementary Table S2 instead gives symptom onset at 15-20; no more precise onset is inferred.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pain directly in the hips started at approximately 30 years of age.
    explanation: Clinical narrative for III-1; the other two affected siblings also developed pain around 30.
  sequelae:
  - target: Antalgic gait
- name: Hip osteoarthritis
  description: Secondary degenerative hip-joint change accompanied advanced femoral-head osteonecrosis in the founding family. This is not evidence for generalized premature arthropathy across all TRPV4-related disorders.
  phenotype_term:
    preferred_term: Hip osteoarthritis
    term:
      id: HP:0008843
      label: Hip osteoarthritis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Antero-posterior view of right femur showing osteonecrosis of the femoral head with collapse and secondary degenerative arthritis.
    explanation: Supplementary Figure F in III-5 supplies direct evidence of secondary hip arthritis.
  - reference: PMID:30693671
    reference_title: Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Pelvis: degenerative arthritis in hip joints'
    explanation: Table 1 summarizes the original ANFH2 family; this is secondary reporting of that family, not an independent ANFH2 cohort.
    quote_role: BACKGROUND
- name: Antalgic gait
  description: The proband had limping accompanying hip pain in young adulthood. The report does not establish its frequency in other affected siblings.
  phenotype_term:
    preferred_term: Antalgic gait
    term:
      id: HP:0031955
      label: Antalgic gait
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hip pain started at the age of 20 with ... limping. She was diagnosed at the age of 21 with bilateral osteonecrosis of the hips.
    explanation: Pain-associated limping in the proband supports an antalgic gait.
treatments:
- name: Total Hip Arthroplasty
  description: Hip arthroplasty is used for advanced osteonecrosis. The supplementary clinical note reports progression in III-5 and subsequent bilateral replacement. The family report provides no controlled ANFH2-specific outcome estimate.
  treatment_term:
    preferred_term: total hip arthroplasty
    term:
      id: NCIT:C157876
      label: Hip Replacement
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with treatment at advanced stages involving total hip arthroplasty
    explanation: General advanced-stage osteonecrosis management in the paper's introduction. The supplement separately records bilateral arthroplasty in III-5, without a controlled treatment comparison.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has subsequently progressed to stage V-VI bilaterally and recently underwent bilateral total hip arthroplasty.
    explanation: III-5 underwent replacement after progression; no postoperative outcome is specified.
  action_category: THERAPEUTIC
- name: Hip Core Decompression and Bone Grafting
  description: 'The proband underwent core decompression and bone grafting, but timing and laterality conflict within the publication: the main text reports bilateral procedures at age 21, while the supplementary clinical note describes a right-sided procedure at age 28. The report does not resolve this discrepancy, establish treatment before collapse, or quantify ANFH2-specific benefit.'
  treatment_term:
    preferred_term: hip core decompression
    term:
      id: NCIT:C157826
      label: Core Decompression
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband was diagnosed with osteonecrosis of the femoral head at age 21 and in the same year had bilateral hip core decompressions and bone grafting.
    explanation: Main-text account; the supplementary clinical note differs on age and laterality. The inconsistency is retained rather than choosing one version.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has undergone right hip core decompression and bone grafting (a common procedure for osteonecrosis) at the age of 28.
    explanation: Supplementary clinical note for the proband conflicts with the main-text bilateral procedure at 21.
  action_category: THERAPEUTIC
- name: Genetic Counseling
  description: Offer genetic counseling and family-specific testing once an appropriately interpreted TRPV4 allele is identified. A heterozygous parent has a 50% probability of transmitting the allele per pregnancy; this is not a 50% estimate of hip osteonecrosis, whose penetrance is unknown for the founding ANFH2 allele. Reproductive testing options require counseling about phenotype uncertainty.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24830047
    reference_title: Autosomal Dominant TRPV4-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Each child of an individual with an autosomal dominant TRPV4-related disorder has a 50% chance of inheriting the TRPV4 pathogenic variant.
    explanation: General Mendelian transmission guidance; disease penetrance and severity are separate questions.
    directness: INDIRECT
    quote_role: BACKGROUND
  - reference: PMID:24830047
    reference_title: Autosomal Dominant TRPV4-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
    explanation: General TRPV4 counseling guidance; an ANFH2-specific outcome cannot be predicted from this alone.
    directness: INDIRECT
    quote_role: BACKGROUND
  action_category: COUNSELING_INFORMATIONAL
- name: Symptomatic Hip Pain Management
  description: Individualize pain management and rehabilitation with orthopedic and rehabilitation specialists. This supportive-care principle is extrapolated from the broader TRPV4 GeneReviews chapter; an ANFH2-specific medication or rehabilitation regimen has not been established.
  treatment_term:
    preferred_term: Pain Therapy
    term:
      id: NCIT:C15180
      label: Pain Therapy
  evidence:
  - reference: PMID:24830047
    reference_title: Autosomal Dominant TRPV4-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This multidisciplinary team will determine the best treatment options for supportive care, prevention of obesity, and management of pain and depression.
    explanation: Broad TRPV4 supportive-care guidance; the chapter does not specifically address hip osteonecrosis.
    directness: INDIRECT
    quote_role: BACKGROUND
  action_category: THERAPEUTIC
mechanistic_hypotheses:
- hypothesis_group_id: trpv4_endothelial_vasoconstriction_hypothesis
  hypothesis_label: TRPV4 gain-of-function drives osteonecrosis via endothelial calcium overload and vasoconstriction
  status: EMERGING
  description: 'The discovery paper''s own proposed mechanism: constitutive gain-of-function TRPV4 activity, combined with the femoral head''s constant mechanical loading, causes endothelial calcium overload, vasoconstriction (potentially via COX-dependent thromboxane receptor signaling), and consequent microthrombosis in a joint with no collateral blood supply. The authors explicitly describe this as a proposed synthesis rather than a directly demonstrated in vivo mechanism; no animal model or direct measurement of femoral head blood flow supports it yet.'
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: Together, this could cause Ca2+ overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip.
    explanation: The authors' own hedged statement of the proposed mechanism.
- hypothesis_group_id: trpv4_osteoclast_resorption_hypothesis
  hypothesis_label: TRPV4 gain-of-function drives femoral head bone loss via excess osteoclast resorptive activity
  status: EMERGING
  description: Excess osteoclast resorption is a candidate route from TRPV4 gain of function to bone loss. Knockout and osteoclast-lineage R616Q/V620I gain-of-function experiments support a role for channel activity in resorption. However, the ANFH2 frameshift has not been tested in osteoclasts. In the 2012 gain-of-function model, removal of the calmodulin-binding domain abolished the bone-loss effect, so a C-terminal frameshift cannot simply be assumed to reproduce other alleles.
  evidence:
  - reference: PMID:18762026
    reference_title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption
    explanation: Establishes the direction of TRPV4's normal role in osteoclast resorption, from which the gain-of-function hypothesis is inferred by analogy.
  - reference: PMID:22492541
    reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss.
    explanation: Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
    directness: INDIRECT
  - reference: PMID:22492541
    reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4.
    explanation: Shows dependence on the calmodulin-binding region in a different gain-of-function construct; this limits extrapolation to the ANFH2 C-terminal allele.
    directness: INDIRECT
animal_models:
- name: Global Trpv4-knockout mouse
  species: Mouse
  genotype: Trpv4-null (global knockout)
  publication: PMID:18762026
  description: Global genetic ablation of Trpv4, used to establish the channel's normal role in osteoclast terminal differentiation and bone resorption. This is a loss-of-function model of a gene whose ANFH2 disease allele is gain-of-function, so it informs the pathway rather than modeling the disease genotype itself.
  modeled_mechanisms:
  - target: Increased Osteoclast Bone Resorption
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: TRPV4 loss reduces resorption and increases bone mass, opposite to the excessive resorption proposed for ANFH2. Separate gain-of-function models exist, but use different alleles.
    limitations: 'Opposite-direction genetic perturbation: a null allele cannot demonstrate that a constitutively active channel drives excess resorption, only that channel activity is required for normal resorption. The inference to ANFH2''s gain-of-function direction is by analogy, not direct evidence.'
    divergences:
    - divergence_type: OTHER
      materiality: INVALIDATING
      description: The model's genetic perturbation is loss-of-function (null allele); the ANFH2 disease allele is gain-of-function. No divergence type in the current taxonomy captures a functional-direction reversal (loss vs gain of function) of the same gene, so this is recorded as OTHER.
    evidence:
    - reference: PMID:18762026
      reference_title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption
      explanation: 'Substantiates the FAILS_TO_RECAPITULATE call: the knockout''s bone-mass/resorption phenotype is opposite in direction to what the ANFH2 gain-of-function hypothesis predicts, so this model does not recapitulate the disease-relevant (excess-resorption) claim even though it establishes the pathway''s general relevance.'
    readouts:
    - name: Bone mass and resorption
      target: Increased Osteoclast Bone Resorption
      direction: DECREASED
      interpretation: Bone resorption is decreased (bone mass increased) upon TRPV4 loss of function, the inverse of the direction hypothesized for the ANFH2 gain-of-function allele.
      evidence:
      - reference: PMID:18762026
        reference_title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: MODEL_ORGANISM
        snippet: genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption
        explanation: Reports the knockout's bone-mass/resorption phenotype directly.
  evidence:
  - reference: PMID:18762026
    reference_title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: TRPV4-mediated Ca(2+) influx hereby secures intracellular Ca(2+) concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts.
    explanation: Establishes this model as informative for TRPV4's general role in osteoclast biology, the basis for the osteoclast-resorption hypothesis by analogy.
- name: Osteoclast-lineage Trpv4 R616Q/V620I transgenic mouse
  species: Mouse
  genotype: TRAP-promoter Trpv4 R616Q/V620I transgene on a Trpv4-null background
  publication: PMID:22492541
  description: Osteoclast-lineage expression of an activating double mutant increased resorption and reduced bone mass. This establishes gain-of-function evidence for the resorption pathway using a different allele from ANFH2.
  modeled_mechanisms:
  - target: Increased Osteoclast Bone Resorption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    limitations: Different activating substitutions and transgenic expression; neither the ANFH2 frameshift nor femoral-head osteonecrosis was tested.
    evidence:
    - reference: PMID:22492541
      reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss.
      explanation: Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
      directness: INDIRECT
  evidence:
  - reference: PMID:22492541
    reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss.
    explanation: Direct gain-of-function animal evidence for the osteoclast pathway using R616Q/V620I substitutions, not the ANFH2 frameshift allele.
    directness: INDIRECT
- name: Osteoclast-lineage Trpv4 R616Q/V620I with calmodulin-binding-domain deletion
  species: Mouse
  genotype: Trpv4 R616Q/V620I delta-CaM transgene on a Trpv4-null background
  publication: PMID:22492541
  description: Deletion of the calmodulin-binding region abrogated bone loss from the activating R616Q/V620I construct. This region-deletion experiment is not equivalent to the ANFH2 frameshift.
  modeled_mechanisms:
  - target: Increased Osteoclast Bone Resorption
    relationship: PERTURBS
    fidelity: LOW
    model_scale: CELLULAR
    limitations: Engineered domain deletion in a different gain-of-function allele; it cannot establish the effect of the ANFH2 frameshift on calmodulin regulation.
    evidence:
    - reference: PMID:22492541
      reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4.
      explanation: Shows dependence on the calmodulin-binding region in a different gain-of-function construct; this limits extrapolation to the ANFH2 C-terminal allele.
      directness: INDIRECT
  evidence:
  - reference: PMID:22492541
    reference_title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4.
    explanation: Shows dependence on the calmodulin-binding region in a different gain-of-function construct; this limits extrapolation to the ANFH2 C-terminal allele.
    directness: INDIRECT
discussions:
- discussion_id: anfh2_no_gain_of_function_animal_model
  prompt: Does any animal or cellular model directly recapitulate femoral head osteonecrosis driven by a TRPV4 gain-of-function allele, rather than modeling TRPV4's general roles in bone or vascular biology?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Endothelial Calcium Overload
  - pathophysiology#Increased Osteoclast Bone Resorption
  rationale: The isolated ANFH2 family has segregation and non-disease-site cellular functional evidence. Other TRPV4 gain-of-function alleles do increase osteoclast resorption and bone loss, but that does not demonstrate femoral-head osteonecrosis from the ANFH2 frameshift. Disease-site endothelial, vascular and osteoclast measurements remain missing, and the specific role of calmodulin regulation in the frameshift channel remains unresolved.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Limitations of the study include the availability of a single family, which adds difficulty to eliminating all variant candidates in an autosomal-dominant model of inheritance and a lack of available phenotype-relevant cell types for functional measurements or an animal model to provide additional evidence of causation.
    explanation: The discovery paper's own authors identify the absence of a phenotype-relevant cell type or animal model as a limitation of their causal evidence.
references:
- reference: PMID:27330106
  title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
- reference: PMID:30328481
  title: 'Osteonecrosis of the femoral head: genetic basis.'
- reference: PMID:18762026
  title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
- reference: PMID:24830047
  title: Autosomal Dominant TRPV4-Related Disorders.
  tags:
  - GeneReviews
- reference: PMID:22492541
  title: Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
- reference: PMID:25572823
  title: GPCR-mediated EGF receptor transactivation regulates TRPV4 action in the vasculature.
- reference: PMID:30693671
  title: Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.
- reference: PMID:33075594
  title: Novel TRPV4 mutation in a large Chinese family with congenital distal spinal muscular atrophy, skeletal dysplasia and scaly skin.
- reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
  title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
variants:
- name: TRPV4 c.2480_2483delCCCG with c.2486T>A (p.V829Wfs*3)
  gene:
    preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  type: Complex deletion and adjacent substitution on one allele
  genomic_contexts:
  - coding sequence
  description: Reported on NM_021625.4 in the last exon. The deletion and adjacent substitution are in cis and were reported together as V829WfsX3. Four affected siblings carried the allele, one tested unaffected sibling was wild type, and the transmitting parent was not established. Mutant transcript persisted in patient cDNA; truncated protein was measured in tagged HEK293 constructs, not demonstrated in patient fibroblasts. The paper provides segregation and channel-function evidence without a formal ACMG classification.
  functional_effects:
  - function: Increased TRPV4 channel activity
    description: Proband fibroblasts and mutant-transduced HEK293 cells showed increased optical calcium sparklet activity and longer bursts. Altered calmodulin binding remains a hypothesis.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'RESULTS: We report a family with four siblings affected with inherited osteonecrosis of the femoral head and the identification of a c.2480_2483delCCCG frameshift deletion followed by a c.2486T>A substitution in one allele of the transient receptor potential vanilloid 4 (TRPV4) gene.'
    explanation: Identifies the complex TRPV4 allele associated with the founding family; the paper also reports segregation and functional support.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The TRPV4 mutation is located in the last exon and was confirmed in proband cDNA
    explanation: Demonstrates persistence of mutant transcript; does not quantify allele-specific nonsense-mediated decay.
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Thus, this mutation leads to a gain of function of TRPV4 channels by impeding channel closure.
    explanation: 'States the direction of the functional defect directly: gain of function via impaired channel closure, not loss of function.'
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The assay did not distinguish between wild type and mutant TRPV4 mRNA.
    explanation: Supplementary Figure S7A describes total-transcript qPCR. Mutant cDNA detection supports transcript persistence but is not an allele-specific NMD quantification.
experimental_models:
- name: Proband dermal fibroblasts
  experimental_model_type: CELL_LINE
  cell_source: Patient and control dermal fibroblasts, immortalized according to the supplementary methods
  publication: PMID:27330106
  description: Immortalized dermal fibroblasts from the proband and a healthy control were compared using confocal calcium sparklet imaging. With 3 nM GSK1016790A, activity per site was 3.3-fold higher in proband cells; mean optical burst durations were approximately doubled. Basal activity was also increased.
  modeled_mechanisms:
  - target: Increased TRPV4-Mediated Calcium Influx
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: One patient and one unrelated control; no isogenic correction or disease-site endothelial/osteoclast cells. Optical bursts are indirect channel measurements, and endogenous TRPV4 protein could not be detected by the antibody.
    evidence:
    - reference: PMID:27330106
      reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We stimulated channel activity with TRPV4 agonist GSK1016790A (GSK101 hereafter, 3 nM) and found that sparklet activity per site was 3.3-fold higher in proband fibroblasts versus control
      explanation: Quantifies the calcium-channel gain of function directly in patient-derived cells.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We stimulated channel activity with TRPV4 agonist GSK1016790A (GSK101 hereafter, 3 nM) and found that sparklet activity per site was 3.3-fold higher in proband fibroblasts versus control
    explanation: Quantifies the calcium-channel gain of function directly in patient-derived cells.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Dermal fibroblasts were obtained from the proband and a healthy 23-year-old female control; both proband and control fibroblasts were immortalized
    explanation: Establishes donor source and immortalization of both comparator cultures.
- name: HEK293 cells expressing wild-type or ANFH2-mutant TRPV4
  experimental_model_type: CELL_LINE
  cell_source: HEK293 cells stably transduced with wild-type or p.V829Wfs*3 TRPV4
  publication: PMID:27330106
  description: Stable C-terminal FLAG-tagged constructs reproduced increased basal sparklet activity in mutant cells despite lower protein expression. Native HEK293 cells lacked detectable sparklets. Agonist-induced calcium overload and death in the transduced cells were assay observations, not evidence of patient-cell death or therapeutic efficacy.
  modeled_mechanisms:
  - target: Increased TRPV4-Mediated Calcium Influx
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: Overexpression of the mutant construct does not reproduce the heterozygous patient genotype or disease-site tissue. Supplementary Figure S12 tests GSK2193874 in wild-type-transduced HEK293 and control fibroblasts; the inhibitor experiment does not demonstrate rescue of mutant cells.
    evidence:
    - reference: PMID:27330106
      reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The baseline TRPV4 sparklet activity per site was 2.5-fold higher in TRPV4-V829WfsX3 vs TRPV4-WT cells
      explanation: Reproduces the gain-of-function calcium signal in a second, independent cell system (transduced HEK293 cells) expressing only the mutant channel.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The baseline TRPV4 sparklet activity per site was 2.5-fold higher in TRPV4-V829WfsX3 vs TRPV4-WT cells
    explanation: Reproduces the gain-of-function calcium signal in a second, independent cell system (transduced HEK293 cells) expressing only the mutant channel.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: TRPV4 mRNA was >100-fold in transduced HEK293 cells relative to fibroblasts.
    explanation: Quantifies the overexpression limitation.
  - reference: url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    reference_title: https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Inhibition of TRPV4 sparklet activity in the WT TRPV4- transduced HEK293 cells and control fibroblasts.
    explanation: Supplementary Figure S12 specifies control systems, not mutant-channel rescue.
differential_diagnoses:
- name: TRPV4-related skeletal dysplasia with osteonecrosis
  description: Hip osteonecrosis may occur within a broader skeletal phenotype. The 2019 p.K801E family had features spanning Kozlowski and Maroteaux phenotypes; computational modeling did not establish a measured channel-function direction.
  distinguishing_features:
  - Short stature, brachydactyly, vertebral and metaphyseal abnormalities favor a broader skeletal dysplasia rather than the isolated founding ANFH2 presentation.
  evidence:
  - reference: PMID:30693671
    reference_title: Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both disorders include brachydactyly, platyspondyly, and metaphyseal abnormalities in their phenotypes, signs that were all seen in the proband.
    explanation: Describes the wider skeletal phenotype of the p.K801E proband.
  - reference: PMID:30693671
    reference_title: Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Due to this conflict of symptoms, we cannot say with confidence whether this TRPV4 variant causes loss of function or gain of function in TRPV4 protein.
    explanation: The paper acknowledges uncertainty despite computational models and proposed mechanisms.
- name: TRPV4-related congenital distal spinal muscular atrophy with skeletal abnormalities
  description: A 2020 family carrying p.Trp785Cys included femoral-head osteonecrosis within a mixed neuromuscular, skeletal and skin phenotype. This expands the TRPV4 spectrum but does not replicate the isolated ANFH2 family or demonstrate gain of function for the new allele.
  distinguishing_features:
  - Congenital distal muscle atrophy and electrophysiologic abnormalities, together with skeletal changes and scaly skin, distinguish the mixed phenotype.
  evidence:
  - reference: PMID:33075594
    reference_title: Novel TRPV4 mutation in a large Chinese family with congenital distal spinal muscular atrophy, skeletal dysplasia and scaly skin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband and other four affected family members showed signs of congenital distal spinal muscular atrophy, skeletal abnormalities including osteonecrosis of the femoral head, and scaly skin.
    explanation: Five affected family members had a mixed phenotype; the abstract does not give a per-person osteonecrosis count.
- name: COL2A1-related inherited femoral-head osteonecrosis
  description: Another genetic cause of familial femoral-head osteonecrosis. The founding ANFH2 investigation found no COL2A1 mutation and used segregation to distinguish the TRPV4 allele from other collagen-gene candidates.
  distinguishing_features:
  - Molecular diagnosis identifies the implicated gene; hip imaging alone does not distinguish these inherited forms.
  evidence:
  - reference: PMID:27330106
    reference_title: Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No mutations in COL2A1 were present.
    explanation: COL2A1 was examined and excluded in the founding ANFH2 proband.
📚

References & Deep Research

References

9
PMID:27330106
Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.
No top-level findings curated for this source.
PMID:30328481
Osteonecrosis of the femoral head: genetic basis.
No top-level findings curated for this source.
PMID:18762026
TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
No top-level findings curated for this source.
PMID:24830047
Autosomal Dominant TRPV4-Related Disorders.
No top-level findings curated for this source.
PMID:22492541
Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass.
No top-level findings curated for this source.
PMID:25572823
GPCR-mediated EGF receptor transactivation regulates TRPV4 action in the vasculature.
No top-level findings curated for this source.
PMID:30693671
Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.
No top-level findings curated for this source.
PMID:33075594
Novel TRPV4 mutation in a large Chinese family with congenital distal spinal muscular atrophy, skeletal dysplasia and scaly skin.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
https://www.ncbi.nlm.nih.gov/research/bionlp/RESTful/supplmat.cgi/bioc_xml/PMC5035228/1
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Avascular Necrosis of Femoral Head, Primary, 2 · 2026-09-04T04:03:28Z · View source

De novo curation of ANFH2 (MONDO:0054551), an autosomal dominant, TRPV4-associated form of inherited osteonecrosis of the femoral head. Claimed via issue #10880. Deep research: attempted falcon (Edison) first per skill default, but Edison's API host (api.platform.edisonscientific.com) is blocked by this environment's outbound network policy (proxy returns 403 on CONNECT), not a bad key -- confirmed via /__agentproxy/status. The --fallback flag did not recover because the auth failure crashes before the client's internal retry/fallback chain engages. Switched explicitly to the claude_code provider (no external API key required; report at research/Avascular_Necrosis_Of_Femoral_Head_Primary_2-deep-research-claude_code.md), which completed with needs_review: true on both reference and term validation -- its term suggestions included several mislabelled CURIEs (e.g. HP:0010734 is actually 'Fibrous dysplasia of the bones', not femoral head osteonecrosis; HP:0100787 is 'Prostate neoplasm', not gait disturbance; the HGNC:12716 it and my own initial skeleton used for TRPV4 is actually TRPV1). None of these mislabelled report-suggested CURIEs were used; every ontology term in the entry (hgnc:18083 TRPV4, HP:0005743, HP:0030838, GO:0005262, GO:0070588, GO:0042310, CL:0000092, CL:0000115, GO:0030316) was independently verified via runoak against the live OAK adapters before binding. Core evidence is built from two primary PubMed sources found directly (not via the deep-research report): PMID:27330106 (Mah et al. 2016, J Med Genet, the discovery paper; full text was available via PMC and used for exact-quote snippets) establishing the causal TRPV4 c.2480_2483delCCCG+c.2486T>A gain-of-function frameshift/truncation variant and its calcium-sparklet electrophysiology, and PMID:30328481 (Wang et al. 2019 review) for genetic-basis context. Added a second pathophysiology branch (osteoclast calcium signaling / bone resorption) supported by PMID:18762026 (Masuyama et al. 2008, Cell Metab), graded directness: INDIRECT since it is opposite-direction (Trpv4-knockout) mouse evidence rather than direct GOF-variant data. Two mechanistic_hypotheses groups record the vascular-vasoconstriction and osteoclast-resorption branches as EMERGING, both explicitly hedged per the discovery paper's own limitations paragraph, which is also cited directly in a HUMAN_MODEL_MISMATCH discussion noting no animal or cellular model directly recapitulates the ANFH2 gain-of-function phenotype. No GeneReviews article exists for this disease (searched PubMed TI:GeneReviews, no hit) so no GeneReviews baseline was applicable. Validated: linkml-validate (Disease, no issues), linkml-term-validator (validate-data --labels, passed), reference_snippet_audit (20/20 snippets verified), full linkml-reference-validator (all checks pass), check-duplicate-keys / check-enum-values / check-entity-refs / check-causal-targets / check-qualifier-terms (all OK), whole-KB check-not4curation / check-folded-hyphens / check-snippet-length / check-title-snippets / check-snippet-grading (all OK, no new issues), term_cache_integrity (OK), and tests/test_data.py -k Avascular (2768 selected tests passed, no failures). linkml-data-qc weighted compliance 87.0%. Deleted stubs/Avascular_Necrosis_Of_Femoral_Head_Primary_2.yaml as part of this curation. Self-review round (before PR): ran a fresh-context adversarial review subagent against the entry, following dismech-pr-review, before opening a PR. It independently re-verified all evidence snippets by exact substring match against the cached references (found zero fabrication/misquoting) and checked ontology term/label pairs, pathophysiology chain integrity, mechanistic_hypotheses/discussions foreign keys, and evidence_source/directness classification. It confirmed the mislabelled-CURIE-avoidance claim above against the deep-research report's own term_validation frontmatter. It surfaced three real gaps, all fixed in this same session: (1) added a diagnosis: block (hip radiography + MRI + Steinberg staging, bound to NCIT:C18020 Diagnostic Procedure) quoting PMID:27330106's diagnostic-modality sentence, which had been omitted despite being in-scope, quotable, primary-source content; (2) reconciled the top-level references: block, which had PMID:18762026 missing (cited as evidence but absent from the list) and PMID:30328481 orphaned (listed but never cited) -- added 18762026 and added a genuine corroborating evidence item for 30328481 in the genetic: block (its own restatement of the TRPV4-ONFH finding); (3) re-graded three evidence items: the two instances of the authors' own hedged vasoconstriction-mechanism quote from HUMAN_CLINICAL to OTHER (it is interpretive synthesis prose, not a direct clinical observation), and the calmodulin-binding-domain truncation/localization quote from IN_VITRO to HUMAN_CLINICAL (it is a genomic/protein-sequence finding from patient DNA analysis, not a cell-based functional assay). Re-ran the full validation suite after each fix (schema, term, 23/23 snippets verified, snippet-grading, entity-refs, duplicate-keys, enum-values, causal-targets all clean). Final linkml-data-qc weighted compliance: 88.1%. Reviewer also flagged optional/non-blocking polish items (a note on the allelic ANFH1/COL2A1 differential, an IN_VITRO-vs-structural-finding quibble on one already-fixed snippet) which were judged not to warrant further changes.

Claude Code ▸
Avascular Necrosis of Femoral Head, Primary, 2 (ANFH2) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 29 citations 2026-09-04T03:48:52.501530

Avascular Necrosis of Femoral Head, Primary, 2 (ANFH2) — Comprehensive Research Report

1. Disease Information

Overview. Avascular Necrosis of Femoral Head, Primary, 2 (ANFH2) is a rare, monogenic, autosomal dominant form of osteonecrosis of the femoral head (ONFH) caused by a gain-of-function mutation in TRPV4 (transient receptor potential vanilloid 4), a calcium-permeable cation channel gene on chromosome 12q24.11. It was first delineated in 2016 by Mah et al., who identified the causal mutation in a Canadian family of Irish/Scottish descent in which four of six siblings developed severe, early-onset, bilateral osteonecrosis of the femoral head with no identifiable acquired risk factor (no corticosteroid use, alcohol abuse, trauma, or thrombophilia) (PMID:27330106). ANFH2 is genetically distinct from, but clinically overlapping with, ANFH1 (OMIM 608805), the COL2A1-associated form of familial ANFH first mapped and characterized by Liu et al. (2005).

More broadly, "avascular necrosis of the femoral head" (osteonecrosis of the femoral head, ONFH) refers to death of osteocytes and bone marrow elements in the femoral head secondary to interruption of its (already tenuous) blood supply, leading to subchondral collapse and secondary osteoarthritis. The great majority of ONFH cases are non-genetic/acquired ("secondary" — corticosteroid-, alcohol-, or trauma-associated) or idiopathic; ANFH1 and ANFH2 represent the rare familial/primary (Mendelian) subset in which a single-gene mutation is sufficient to cause the phenotype, typically with earlier onset, higher bilaterality, and a positive family history.

Key identifiers: - MONDO: MONDO:0054551 (Avascular Necrosis of Femoral Head, Primary, 2) - OMIM: #617383 (ANFH2, phenotype); 605427 (TRPV4, gene/locus) - Related/allelic locus (ANFH1): OMIM #608805 (phenotype); 120140 (COL2A1, gene) - Orphanet: the broader "familial avascular necrosis of femoral head" concept is cataloged by Orphanet/rarediseases.org under the TRPV4 and COL2A1 gene pages (Orphanet gene pages for TRPV4 and COL2A1) - Gene (ANFH2): TRPV4; HGNC:12716; NCBI Gene ID 59341; UniProt Q9HBA0 - Broader disease codes (osteonecrosis of femoral head, general): ICD-10 M87.0 (idiopathic aseptic necrosis of bone)/M87.8x; ICD-11 FA80.0/FA80.Z; MeSH D010020 ("Femur Head Necrosis") - Inheritance: Autosomal dominant

Synonyms/alternative names: ANFH2; Osteonecrosis of the femoral head, primary, 2; Familial avascular necrosis of the femoral head (TRPV4-related); Familial osteonecrosis of the femoral head, TRPV4-related. (Not to be confused with "avascular necrosis of the femoral head, primary 1," which is COL2A1-related, or with Legg-Calvé-Perthes disease, the pediatric form of ANFH which has also been linked to some COL2A1 variants.)

Evidence basis: Information for ANFH2 specifically derives from a single reported pedigree study (one Canadian family, 4 affected siblings; human clinical + in vitro electrophysiological functional data) (PMID:27330106), supplemented by OMIM curation (#617383) and by the broader TRPV4 channelopathy literature (skeletal dysplasias and peripheral neuropathies caused by other TRPV4 alleles), which is derived from many aggregated case reports/small cohorts rather than large-scale epidemiological data. This is not an EHR-derived or population-registry disease entity — data are case/pedigree-level.

2. Etiology

Disease Causal Factors

ANFH2 is caused by a heterozygous gain-of-function mutation in TRPV4, a mechanosensitive/osmosensitive Ca²⁺-permeable cation channel. The causal mechanism is genetic (single-gene, monogenic), not environmental/infectious — this distinguishes ANFH2 from the majority of ONFH cases, which are acquired (corticosteroid, alcohol, trauma).

Genetic Risk Factors

  • Causal variant (ANFH2 family): heterozygous TRPV4 c.2480_2483delCCCG frameshift deletion immediately followed by a c.2486T>A substitution (NM_021625.4), predicted to cause p.Val829TrpfsTer3 (V829Wfs3), a C-terminal frameshift/truncation. Functional testing showed this is a gain-of-function* allele (see Mechanism, below) (PMID:27330106). "All affected siblings with osteonecrosis of the femoral head harbored a heterozygous frameshift deletion in TRPV4" (per PMC5035228 summary of the paper); unaffected siblings were wild type — full segregation with disease in this family.
  • Allelic gene (ANFH1): heterozygous COL2A1 missense variants — e.g., c.2149G>A (p.Gly717Ser) in the original ANFH1 family (Liu et al., 2005) and a second independent family with c.3517G>A (p.Gly1173Ser) in exon 50 (Chinese family, PMID reported in PMC8178877) — establish genetic heterogeneity of primary/familial ANFH.
  • Susceptibility loci for sporadic (non-Mendelian) ONFH: SREBP-2 gene polymorphisms have been reported associated with AVN risk in a Korean population (PMC2600781); these are population susceptibility signals, distinct from the Mendelian ANFH1/ANFH2 causal alleles, and are not directly relevant to the ANFH2 KB entry's causal claim.

Environmental Risk Factors (relevant mainly to the broader ONFH phenotype, not specific to the TRPV4-driven form, but relevant for differential/modifier context)

  • Corticosteroid use — accounts for a large share of acquired (secondary) ONFH; risk estimates for corticosteroid-associated AVN range roughly 3–40% depending on dose/duration.
  • Alcohol use — dose-dependent risk: <400 mL/week alcohol confers ~3-fold risk; >400 mL/week confers ~11-fold risk versus non-drinkers.
  • Trauma (femoral neck fracture, hip dislocation).
  • Age/sex — AVN typically affects physically active adults 20–40 years old; a Japanese survey found idiopathic mechanisms accounted for 37.1% of cases, corticosteroids 34.7%, and alcohol 21.8%.
  • In the ANFH2 pedigree specifically, all of these acquired causes were explicitly excluded by the investigators ("no identifiable risk factors — alcohol, steroids, trauma, thrombophilia" per PMC5035228), supporting a purely genetic etiology in this family.

Protective Factors

No specific genetic or environmental protective factors have been established for TRPV4-related ANFH2. In the general ONFH literature, avoidance of high-dose/prolonged corticosteroids and heavy alcohol intake are the principal modifiable protective measures, but these pertain to the acquired form, not the Mendelian TRPV4 form.

Gene-Environment Interactions

No gene-environment interaction data have been reported specifically for TRPV4/ANFH2. It is biologically plausible (though undemonstrated) that mechanical loading of the femoral head — an already watershed, poorly collateralized vascular bed under constant mechanical stress — could interact with a constitutively gain-of-function TRPV4 channel (itself a mechanosensor) to potentiate localized vasoconstriction, but this remains inferential rather than experimentally established (see Mechanism section).

3. Phenotypes

Phenotype Type Onset Frequency in ANFH2 pedigree Suggested HPO term
Hip/groin pain Symptom 3rd–4th decade typically (proband diagnosed at age 21) Present in all 4 affected siblings HP:0030839 (Groin pain) / HP:0003326 (Myalgia) — best available is generic hip pain; consider HP:0030828 not applicable; use free text if no exact HP term
Avascular necrosis of the femoral head Clinical sign / imaging finding Onset 2nd–4th decade 4/4 affected, bilateral in all affected members HP:0010734 (Avascular necrosis of the capital femoral epiphysis)
Bilateral hip involvement Clinical sign Concurrent with above "All affected family members had bilateral hip involvement, whereas only two-thirds of the sporadic patients had bilateral disease" HP:0410030-type bilaterality qualifier, or a laterality: BILATERAL descriptor
Limping gait Sign Progressive Typical of advanced-stage disease HP:0100787 (Gait disturbance)
Limitation of hip range of motion Sign Progressive, later disease stages Typical HP:0002826 (Limited joint mobility)
Femoral head collapse / subchondral fracture (Steinberg stage III–V) Radiographic finding Progressive Affected siblings ranged Steinberg Stage III to Stage V HP:0003043 (relevant femoral abnormality terms are limited; consider HP:0011869 or free text "femoral head collapse")
Leg length discrepancy Sign (secondary to collapse) Late-stage Reported as part of the general ONFH clinical picture (per general ONFH literature) HP:0100559 (Asymmetric growth / limb length discrepancy)
Normal stature / no skeletal dysplasia Negative finding — differential N/A Explicitly documented negative (excludes TRPV4 skeletal-dysplasia allelic phenotype) —
Normal neurological exam / normal nerve conduction studies Negative finding — differential N/A Explicitly excludes TRPV4 peripheral-neuropathy allelic phenotype (CMT2C) —

Phenotype characteristics: - Age of onset: In the index family, the proband was diagnosed at age 21; OMIM notes onset of hip pain in reported ANFH2 families "typically occurs in the third to fourth decade of life." This is notably earlier than the acquired/idiopathic ONFH population (usually 20–40, similar range but with a genetic family showing earlier, more penetrant, and more severe presentation). - Severity/progression: Progressive — untreated disease advances through radiographic stages (Ficat/Arlet, Steinberg, or 2019 ARCO systems) toward subchondral collapse and secondary osteoarthritis. In the ANFH2 family, disease had already reached Steinberg Stage III–V at presentation in affected siblings, i.e., advanced/collapsed disease, consistent with a highly penetrant and aggressive natural history. - Bilaterality: A phenotypic hallmark distinguishing the familial/genetic form: 100% of affected ANFH2 family members had bilateral disease, versus roughly two-thirds of sporadic (acquired) ONFH patients — an important discriminating feature for entity classification. - Quality of life impact: Not separately quantified for ANFH2, but ONFH generally is "a severely disabling disease" causing progressive pain, gait disturbance, and eventual need for total hip arthroplasty, with substantial impact on mobility and work capacity in an otherwise young, active population.

4. Genetic/Molecular Information

Causal gene: TRPV4 (HGNC:12716; NCBI Gene ID 59341; OMIM *605427; chromosome 12q24.11; UniProt Q9HBA0). Encodes "transient receptor potential cation channel, subfamily V, member 4," a polymodal, calcium-permeable, non-selective cation channel activated by hypotonic cell swelling, moderate heat, mechanical stress/shear stress, low pH, and phorbol esters/endogenous lipid ligands.

Pathogenic variant (ANFH2 index family): - cDNA change: c.2480_2483delCCCG followed immediately by c.2486T>A (NM_021625.4/NM_021625.5) - Protein change: p.Val829TrpfsTer3 (V829Wfs3) — a frameshift causing premature truncation - Variant classification: Not formally reported to ClinVar under a standard ACMG tier in the sources retrieved here, but functionally characterized as pathogenic/gain-of-function by the original authors via electrophysiology. - Location/domain effect: The frameshift "eliminates a highly conserved region including residues within a calmodulin-binding domain" in the cytoplasmic C-terminus of TRPV4 — i.e., it removes part of the channel's autoinhibitory/regulatory machinery rather than ablating channel expression. - Origin: Germline, autosomal dominant, fully segregating with disease in the 4 affected/2 unaffected sibling pedigree. - Allele frequency: Not reported in population databases (gnomAD) for this specific ANFH2 frameshift variant in the sources retrieved; TRPV4 pathogenic missense alleles causing other TRPV4-opathies (e.g., p.Arg315Trp) are found only at extremely low frequency (e.g., 2/1,614,018 in gnomAD) or are entirely absent from population controls, consistent with strong purifying selection against gain-of-function TRPV4 alleles generally. - Functional consequence: Gain-of-function* — not loss-of-function. Disruption of the C-terminal calmodulin-binding region impairs normal Ca²⁺-calmodulin-dependent negative feedback/channel closure, producing sustained, excessive Ca²⁺ influx (see Mechanism, Section 6).

Allelic disease (ANFH1) causal gene: COL2A1 (HGNC:2200; OMIM *120140; chromosome 12q13.11), encoding the alpha-1 chain of type II collagen. Reported ANFH1 variants: c.2149G>A (p.Gly717Ser) in the original 2005 pedigree (Liu et al.), and c.3517G>A (p.Gly1173Ser) in a large Chinese kindred — both classic glycine-substitution collagen triple-helix mutations. COL2A1 variants are also implicated in Legg-Calvé-Perthes disease (LCPD, a pediatric ONFH phenotype), underscoring that COL2A1-collagenopathy mechanisms differ fundamentally (structural/matrix) from the TRPV4 vasoregulatory/ion-channel mechanism.

Modifier genes: None specifically established for ANFH2. For the general/sporadic ONFH phenotype, SREBP-2 polymorphisms have been proposed as population-level modifiers of risk (Korean cohort, PMC2600781), but this is not established as a modifier of TRPV4-driven ANFH2 specifically.

Epigenetic information: No epigenetic (DNA methylation/histone) data specific to ANFH2 or TRPV4-driven ONFH were identified in this search.

Chromosomal abnormalities: None reported; ANFH2 is caused by a small indel, not a chromosomal-scale rearrangement.

Suggested ontology bindings: - Gene: hgnc:12716 (TRPV4) - GO Molecular Function: GO:0005227 (calcium activated cation channel activity) / GO:0015643 — best available specific term is TRPV4's calcium channel activity, GO:0005262 (calcium channel activity) - GO Biological Process: GO:0070588 (calcium ion transmembrane transport); osmosensory/mechanosensory transduction — GO:0050982 (detection of mechanical stimulus) is plausible for TRPV4's mechanosensor role

5. Environmental Information

Environmental factors: Not causally implicated in the TRPV4-driven ANFH2 form itself (the index family was specifically screened and found negative for alcohol, steroid, trauma, and thrombophilia exposure). For the broader ONFH disease category (relevant as differential/comorbid triggers, and potentially as modifiers of expressivity in TRPV4 carriers, though this gene-environment interaction is not demonstrated): - Corticosteroid exposure (exogenous glucocorticoid therapy for any indication) — major driver of secondary ONFH. - Chronic heavy alcohol consumption — dose-dependent risk factor for secondary ONFH. - Case reports also describe ONFH following COVID-19 infection, independent of steroid use (PMC12337778), suggesting a possible inflammatory/coagulopathic environmental trigger pathway relevant to the broader disease category, though not tested in ANFH2 carriers specifically.

Lifestyle factors: Smoking and heavy alcohol use are generally cited modifiable lifestyle risk factors for ONFH broadly; no ANFH2-specific lifestyle-modifier data exist.

Infectious agents: No infectious etiology for ANFH2. (COVID-19 has been reported as an environmental trigger for sporadic ONFH cases generally, as above, but this is not established for the TRPV4-mutant form.)

6. Mechanism / Pathophysiology

Causal chain (ANFH2)

  1. A heterozygous germline frameshift mutation in TRPV4 (c.2480_2483delCCCG; c.2486T>A → p.Val829Trpfs3) removes/disrupts* a conserved C-terminal calmodulin-binding regulatory domain of the TRPV4 channel protein.
  2. This loss of the normal calmodulin-mediated negative feedback leads to a gain-of-function biophysical phenotype: patch-clamp/TIRF "sparklet" recordings in cells expressing the mutant channel show 2.5-fold higher baseline TRPV4 sparklet (single-channel Ca²⁺ influx event) activity and two-fold longer mean channel burst-open times at each conductance level compared to wild-type channel — i.e., the mutant channel opens more often and stays open longer (PMID:27330106).
  3. Prolonged/excessive channel opening results in sustained, pathologically elevated intracellular Ca²⁺ influx in cells expressing mutant TRPV4 (demonstrated experimentally, not merely inferred).
  4. Because TRPV4 is expressed in, and regulates, vascular endothelium/smooth muscle (vasoregulation) and osteoclasts (osteoclastic differentiation and bone resorption), this excess Ca²⁺ influx is proposed to cause two convergent downstream effects: (a) endothelial dysfunction and abnormal vascular tone/vasoconstriction in the vessels supplying the femoral head, and (b) altered osteoclast differentiation/bone-remodeling activity.
  5. The femoral head is anatomically a watershed vascular territory with minimal collateral circulation and is subject to constant mechanical loading — a physiologic niche in which TRPV4 (itself a mechanosensor) would be expected to be tonically engaged. The authors propose that this anatomic vulnerability amplifies the effect of chronic TRPV4 gain-of-function, producing localized "calcium overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip" (quoted mechanistic hypothesis from PMID:27330106) — this step (from cellular Ca²⁺ overload to clinically apparent ischemia at the hip specifically) is the authors' proposed integrative hypothesis rather than a step demonstrated in vivo in the family; it is inferred, not directly shown in patient bone/vascular tissue.
  6. Chronic interruption of blood supply to the femoral head leads to osteocyte death (necrosis) in the trabecular bone and marrow of the femoral head.
  7. Cumulative osteocyte death and unrepaired microdamage result in subchondral microfractures, which the femoral head — due to its high mechanical load-bearing role — cannot structurally tolerate, and this leads to progressive subchondral bone collapse (radiographically staged via Ficat/Steinberg/ARCO systems).
  8. Structural collapse of the femoral head causes the clinical manifestations: progressive groin/hip pain, limping gait, limitation of hip motion, leg-length discrepancy, and — ultimately — secondary degenerative osteoarthritis of the hip joint requiring total hip arthroplasty in advanced (uncollapsed-refractory) cases.

Branch — general (acquired) ONFH pathway, for contrast: in the far more common acquired/idiopathic form, the "final common pathway is interruption of blood flow to the bone," with intravascular coagulation (rather than a primary vasoregulatory ion-channel defect) proposed as the central inciting event, triggered by corticosteroid-induced lipid embolization/adipocyte hypertrophy or alcohol-induced fat emboli and hypercoagulability — a mechanistically distinct but convergent route to the same endpoint of osteocyte death, microfracture accumulation, and collapse.

Category detail

  • Molecular pathways: TRPV4-mediated Ca²⁺ signaling; downstream Ca²⁺/calmodulin signaling normally provides negative feedback on channel activity (disrupted in ANFH2); in TRPV4 skeletal-dysplasia alleles (a related but phenotypically distinct allelic series), gain-of-function Ca²⁺ signaling reprograms chondrocytes to increase follistatin production, which inhibits BMP signaling and impairs endochondral ossification — illustrating the pleiotropic, tissue-context-dependent downstream consequences of TRPV4 gain-of-function across the allelic series (skeletal dysplasia vs. ANFH vs. peripheral neuropathy).
  • Cellular processes: Osteocyte/osteoclast biology (TRPV4 regulates steady-state Ca²⁺ influx at the late stage of osteoclast differentiation, required for NFATc1-dependent transcription controlling osteoclast terminal differentiation and resorptive capacity — established in Trpv4-knockout mouse studies, which show the converse phenotype: reduced osteoclast number/activity and increased bone mass); vascular endothelial/smooth muscle tone regulation; mechanotransduction (TRPV4 mediates oscillatory fluid-shear-induced Ca²⁺ signaling in mesenchymal stem cells, partly via the primary cilium).
  • Protein dysfunction: Gain-of-function (not loss-of-function) via disruption of a C-terminal calmodulin-binding autoregulatory domain — a distinct molecular mechanism from the COL2A1 glycine-substitution mechanism in ANFH1 (structural collagen triple-helix disruption/dominant-negative matrix defect) and from TRPV4 loss-of-function.
  • Metabolic changes: Not specifically profiled for ANFH2.
  • Immune system involvement: Not implicated in the TRPV4-driven mechanism; in the general ONFH literature, intravascular coagulation/thromboembolic mechanisms (relevant to secondary ONFH) are more prominent than adaptive/innate immune mechanisms.
  • Tissue damage mechanisms: Ischemic necrosis (osteocyte death from vascular compromise) → microfracture accumulation → mechanical structural failure (subchondral collapse). This is fundamentally an ischemia/mechanical-failure mechanism rather than primary inflammatory or autoimmune tissue damage.
  • Biochemical abnormalities: Excess, prolonged Ca²⁺ influx through mutant TRPV4 channels (directly measured); downstream biochemical consequences (endothelial NO/vasoactive mediator dysregulation, osteoclast NFATc1 signaling) are inferred from the known biology of TRPV4 in vascular and bone tissue rather than measured directly in the ANFH2 family.
  • Molecular profiling: No transcriptomic, proteomic, metabolomic, or single-cell/spatial data specific to the ANFH2 family or its causal variant were identified in the literature retrieved.

Suggested ontology terms: - GO Biological Process: GO:0070588 (calcium ion transmembrane transport); GO:0030316 (osteoclast differentiation); vasoregulation — GO:0042311 (vasodilation) / GO:0042310 (vasoconstriction) - GO Molecular Function: GO:0005262 (calcium channel activity); GO:0005516 (calmodulin binding) - Cell types (CL): CL:0000092 (osteoclast); CL:0000115 (endothelial cell); CL:0002518 (kidney/vascular smooth muscle) — most relevant here is CL:0000359 (vascular associated smooth muscle cell) for the vasoregulatory arm, and CL:0001035 (bone cell) more generally for the osteoclast/osteocyte arm.

7. Anatomical Structures Affected

  • Organ level:
  • Primary: Femoral head (proximal epiphysis of the femur) — bilateral in ANFH2.
  • Secondary: Hip joint (acetabulum secondarily affected as osteoarthritis develops); overall lower-limb biomechanics (leg-length discrepancy, gait).
  • Body systems: Musculoskeletal system (primary); cardiovascular system (vascular supply to bone — the proposed mechanistic substrate).

  • UBERON: UBERON:0002378 (femur head / femoral head epiphysis — precise term is "head of femur," UBERON:0001417 is femur; the specific structure is the femoral head, UBERON:0001417's epiphyseal head — best available specific term: UBERON:0001417 femur, with the head specifically captured by HPO's HP:0010734 rather than a distinct UBERON term for "femoral head" alone in some ontology builds); Hip joint: UBERON:0001360.

  • Tissue and cell level:

  • Subchondral trabecular bone and bone marrow of the femoral head (site of osteocyte necrosis and microfracture).
  • Articular cartilage of the femoral head (secondarily affected once subchondral collapse occurs).
  • Osteoclasts (CL:0000092) — implicated via TRPV4's role in osteoclast differentiation.

  • Vascular endothelial cells (CL:0000115) and vascular smooth muscle (CL:0000359) of the retinacular/epiphyseal arteries supplying the femoral head — the anatomically limited, largely end-arterial blood supply of the femoral head (chiefly via the medial femoral circumflex artery) is the key anatomic vulnerability exploited by this mechanism.

  • Subcellular level:

  • Plasma membrane (site of TRPV4 channel activity) — GO:0005886 (plasma membrane) / GO:0034704 (calcium channel complex).

  • Primary cilium — implicated in TRPV4 mechanotransduction in mesenchymal/osteogenic cells generally (GO:0005929, cilium).

  • Localization: Bilateral in all reported ANFH2-affected individuals (100% bilaterality), in contrast to ~two-thirds bilaterality in sporadic/acquired ONFH — a notable, ontologically codable laterality distinction.

8. Temporal Development

  • Onset: Typically third to fourth decade of life for hip pain onset (per OMIM #617383); the index proband was formally diagnosed at age 21 with bilateral disease already present. Onset pattern is insidious (gradual, non-acute), with pain preceding radiographic collapse.
  • Progression: Progressive and, in the reported family, already advanced at diagnosis — affected siblings ranged from Steinberg Stage III to Stage V (i.e., subchondral collapse through end-stage secondary osteoarthritic change) at the time of clinical presentation, indicating a relatively aggressive, highly penetrant natural history in this pedigree. Using the general ONFH staging frameworks (Ficat/Arlet, University of Pennsylvania/Steinberg, 2019-revised ARCO), disease evolves from an asymptomatic pre-radiographic stage (Stage 0/I, MRI-only marrow signal change) through radiographically apparent sclerosis/cystic change (Stage II), subchondral fracture with head depression ≤2 mm (Stage IIIA) or >2 mm (Stage IIIB), to secondary osteoarthritis (Stage IV).
  • Patterns: No spontaneous remission is described for structurally collapsed disease; earlier-stage (pre-collapse) lesions can regress with intervention (e.g., core decompression halting/reversing Stage I disease in some general-ONFH series), but once subchondral collapse has occurred the process is essentially irreversible and progresses toward joint destruction. The critical window for joint-preserving intervention is pre-collapse (Ficat/ARCO Stage I–II); once Stage III (subchondral fracture/collapse) is reached, joint-preserving procedures are far less effective and total hip arthroplasty becomes the definitive treatment.

9. Inheritance and Population

  • Epidemiology (general ONFH, for context): ~10,000–20,000 new ONFH cases/year in the United States; a Japanese national survey estimated ~2,500–3,300 new hip ONFH cases/year, with idiopathic mechanisms accounting for 37.1%, corticosteroids 34.7%, and alcohol 21.8% of cases. ANFH2 (TRPV4-driven, Mendelian) is an ultra-rare subset of this broader idiopathic/familial category — only a single multiplex pedigree has been reported to date in the literature identified here, so no independent prevalence/incidence estimate exists for ANFH2 specifically; it should be classed as prevalence class: NOT_YET_DOCUMENTED / ultra-rare pending further case ascertainment.
  • Inheritance pattern: Autosomal dominant, fully penetrant in the reported pedigree (4/4 mutation carriers among tested siblings were affected; unaffected siblings were confirmed wild-type) — i.e., complete segregation, consistent with high penetrance, though formal penetrance/expressivity estimates across a larger population are not available (n=1 family).
  • Expressivity: Variable in severity/stage at presentation is plausible given the general ONFH literature but not separately quantified across ANFH2 carriers beyond the single reported family; bilaterality appears highly consistent (100% in this family).
  • Genetic anticipation: Not reported/assessed.
  • Germline mosaicism: Not reported/assessed; parents were deceased in the index family, so parental mutation status/de novo vs. inherited origin at the founder generation could not be determined from available records ("Parents and grandparents are deceased, but family members recalled paternal joint pain never formally evaluated" — consistent with, but not proof of, the mutation having been inherited from the paternal line).
  • Founder effects / consanguinity: No founder effect or consanguinity reported; this is a single, non-consanguineous Canadian (Irish/Scottish ancestry) pedigree.
  • Carrier frequency: Not established in population databases; the specific ANFH2 frameshift variant was not found reported in large population reference databases in the sources retrieved, consistent with its rarity and pathogenicity.
  • Population demographics: No broader ethnic/geographic prevalence data exist specific to TRPV4-driven ANFH2. General ONFH shows a male predominance in most series and predominantly affects adults 20–40 years old.
  • Sex ratio: Not separately reported for the ANFH2 pedigree (4 of 6 siblings affected; sex distribution among the 4 affected not specified in retrieved sources).

10. Diagnostics

  • Clinical tests / imaging:
  • Radiography (X-ray) — used for initial staging; normal in earliest disease (Ficat/ARCO Stage 0–I) and shows sclerosis, cystic change, subchondral lucency ("crescent sign"), and eventually head flattening/collapse in later stages.
  • MRI — the gold-standard imaging modality; the pathognomonic "double-line sign" (an outer low-signal-intensity rim adjacent to a second inner high-signal-intensity rim on T2/fluid-sensitive sequences, representing a fibrous/sclerotic reactive interface with an inner hyperemic granulation-tissue zone) is seen in ~80–85% of AVN cases and is considered highly specific for the diagnosis; MRI is sensitive to pre-radiographic (Stage I) marrow edema/signal change.
  • Staging systems: Ficat and Arlet classification (original, 3–6 stages); University of Pennsylvania (Steinberg) system (mild <15%, moderate 15–30%, severe >30% of articular surface/head involved); 2019-revised Association Research Circulation Osseous (ARCO) system (Stage I: normal X-ray, abnormal MRI; Stage II: abnormal X-ray and MRI, no collapse; Stage IIIA: subchondral fracture/collapse ≤2 mm; Stage IIIB: collapse >2 mm; Stage IV: secondary osteoarthritis).
  • In the ANFH2 family specifically, Steinberg classification was used, with affected siblings ranging from Stage III to Stage V.
  • Genetic testing:
  • Whole-exome sequencing was the discovery method used to identify the causal TRPV4 variant in the index family, followed by Sanger sequencing confirmation and segregation testing across siblings.
  • For clinical diagnostic purposes today, a targeted single-gene test (TRPV4) or a skeletal-dysplasia/osteonecrosis gene panel including TRPV4 and COL2A1 would be the appropriate approach in a patient with early-onset, bilateral, familial ONFH without acquired risk factors.
  • Differential genetic workup should also include COL2A1 (ANFH1) given genetic heterogeneity of the familial ONFH phenotype.
  • Exclusionary workup performed in the ANFH2 family (relevant "rule-out" diagnostics): skeletal survey (negative — excludes TRPV4 skeletal dysplasia allelic phenotype), neurological exam and nerve conduction studies (normal — excludes TRPV4 peripheral neuropathy/CMT2C allelic phenotype), thrombophilia panel (negative), and COL2A1 sequencing (negative, prior to TRPV4 discovery).
  • Clinical criteria / differential diagnosis: Differential diagnosis for early-onset bilateral hip osteonecrosis includes corticosteroid- or alcohol-associated secondary ONFH, sickle cell disease, Gaucher disease, hemoglobinopathies, thrombophilia/hypercoagulable states, systemic lupus erythematosus, decompression sickness ("caisson disease"), radiation-induced necrosis, and other primary/familial (COL2A1-associated) ANFH.
  • Screening: No population or newborn screening applicable given extreme rarity; cascade genetic testing/counseling of at-risk relatives in a known TRPV4-ANFH2 family would be the appropriate clinical screening strategy once a proband is identified.

11. Outcome/Prognosis

  • Survival/mortality: ANFH2 (and ONFH generally) is not directly life-threatening; it is a joint-destructive, disabling musculoskeletal condition rather than one associated with excess mortality.
  • Morbidity/function: Progressive pain, gait disturbance, and functional impairment of hip range of motion; untreated or advanced disease leads to secondary osteoarthritis and often requires total hip arthroplasty. In the ANFH2 family, disease had already advanced to Steinberg Stage III–V (subchondral collapse through secondary arthritic change) by the time of diagnosis/intervention, indicating a prognosis dominated by need for surgical joint preservation or replacement rather than medical management alone.
  • Disease course: Once subchondral collapse occurs, the process is essentially irreversible; pre-collapse (early-stage) disease has a better prognosis with joint-preserving intervention (e.g., core decompression).
  • Complications: Secondary osteoarthritis of the hip; leg-length discrepancy; long-term consequences of early hip arthroplasty in young patients (implant longevity/revision risk over a young patient's remaining lifespan is a significant prognostic concern given the young age of onset in ANFH2).
  • Recovery potential: With joint-preserving intervention (core decompression) at early (Ficat/ARCO Stage I) stage, some lesions have been reported to regress; more advanced disease (as seen in the ANFH2 family at presentation) gains little benefit from joint-preserving procedures, and total hip arthroplasty is the eventual outcome.
  • Prognostic factors: Stage at diagnosis/intervention is the dominant prognostic factor (pre-collapse vs. post-collapse); percentage of femoral head involvement (Steinberg mild/moderate/severe); bilaterality (100% in ANFH2, versus ~two-thirds in sporadic disease) worsens overall disease burden by requiring management of both hips.

12. Treatment

  • Pharmacotherapy (general ONFH management; not specifically trialed in ANFH2 patients in the literature retrieved):
  • Bisphosphonates / alendronate — reported effective against ischemic bone necrosis in some series, aiming to reduce bone resorption and preserve structural integrity during the reparative phase. NCIT: NCIT:C15986 (Pharmacotherapy); therapeutic agent class NCIT:C285 (Bisphosphonate, if available) or specific CHEBI term for alendronate.
  • Statins — proposed to reduce adipogenic differentiation of marrow stem cells and lower intraosseous pressure, improving perfusion.
  • Anticoagulants (e.g., enoxaparin) — used where hypercoagulability/thromboembolic mechanisms are implicated (more relevant to secondary/acquired ONFH than to the TRPV4 vasoregulatory mechanism, but occasionally used empirically).
  • No TRPV4-channel-targeted pharmacotherapy (e.g., a TRPV4 antagonist) has been reported as clinically trialed in ANFH2 patients, though this is a mechanistically rational future therapeutic direction given the established gain-of-function mechanism.
  • Non-pharmacologic/physical:
  • Hyperbaric oxygen therapy (HBOT) — reported to correct tissue ischemia/hypoxia, improve microcirculation, reduce blood viscosity, and promote angiogenesis; a controlled trial of 20 HBOT sessions reported sustained asymptomatic status at 7-year follow-up in treated patients (general ONFH literature).
  • Surgical/interventional:
  • Core decompression (± bone grafting) — the mainstay joint-preserving procedure for early-stage (pre-collapse) disease; reduces intraosseous pressure, disrupts the sclerotic barrier to healing, and stimulates local angiogenesis and new bone formation. In one series, all ARCO Stage I lesions regressed to Stage 0 at 12-month follow-up post-decompression. The ANFH2 proband underwent bilateral hip core decompression and bone grafting at age 21. NCIT: NCIT:C15329 (Surgical Procedure) or a more specific decompression/bone-grafting procedure term if available.
  • Free vascularized fibular grafting (FVFG) — indicated for smaller lesions (<300° of femoral head involvement) without preoperative collapse; provides both structural support and a new vascular supply to promote revascularization.
  • Total hip arthroplasty (THA) — definitive treatment for advanced/collapsed disease (Steinberg/ARCO Stage III–IV), as seen in the more severely affected ANFH2 siblings (Stage IV–V). NCIT: NCIT:C15329 or a specific hip-replacement procedure term (NCIT:C80355-type arthroplasty code if available).
  • Supportive/rehabilitative: Physical therapy, weight-bearing restriction/protected weight-bearing during the reparative phase, and pain management are standard adjuncts.
  • Experimental: No TRPV4-specific targeted or gene-based experimental therapy for ANFH2 was identified in the literature retrieved (no relevant ClinicalTrials.gov NCT identified for TRPV4-directed osteonecrosis therapy in this search).
  • Treatment strategy: Staging-driven treatment algorithm — pre-collapse (Ficat/ARCO 0–II): core decompression ± adjuncts (bone marrow aspirate/mesenchymal cell injection, bisphosphonates, HBOT); post-collapse, low-grade (IIIA, smaller lesion): FVFG or other joint-preserving osteotomy/grafting procedures; post-collapse, advanced (IIIB–IV): total hip arthroplasty. Because ANFH2 patients present with bilateral disease and often already at advanced stage, treatment planning must anticipate staged or combined bilateral intervention.

13. Prevention

  • Primary prevention: No TRPV4-channel-specific primary prevention exists. For carriers of a known familial TRPV4 (or COL2A1) mutation, there is no established pharmacologic prophylaxis to prevent osteonecrosis onset; avoidance of superimposed acquired risk factors (corticosteroids, heavy alcohol use, trauma) in a known mutation carrier would be a reasonable precautionary/behavioral recommendation, though not formally studied.
  • Secondary prevention (early detection): Given the young age of onset and high penetrance in the reported family, surveillance MRI of both hips in at-risk relatives of a confirmed ANFH2 proband would allow detection of pre-radiographic (Stage 0–I) disease, when joint-preserving core decompression is most effective — this is a reasonable extrapolated clinical strategy, not one formally validated in a screening trial.
  • Genetic screening/counseling: Cascade genetic testing of first-degree relatives of an identified TRPV4-ANFH2 proband is appropriate given autosomal dominant inheritance with apparently high penetrance; genetic counseling should address the ~50% transmission risk to offspring.
  • Behavioral interventions: Avoidance of corticosteroid overuse and heavy alcohol consumption remains generally advisable, though these were not implicated as contributing/modifying factors in the one reported ANFH2 pedigree.
  • Public health/prophylaxis: Not applicable at a population level given the extreme rarity of this Mendelian entity.

14. Other Species / Natural Disease

  • No naturally occurring TRPV4-associated osteonecrosis of the femoral head has been reported in non-human species in the literature retrieved by this search. TRPV4 orthologs are broadly conserved (mouse Trpv4, NCBI Gene ID 63873; also present in zebrafish and other vertebrates), and TRPV4 is functionally characterized across multiple species (e.g., zebrafish TRPV4 studies referenced in the ZFIN database), but a natural/spontaneous disease phenotype specifically analogous to ANFH2 has not been documented in veterinary or comparative-pathology literature retrieved here.
  • Comparative biology: The role of TRPV4 in vascular tone regulation and osteoclast differentiation is functionally conserved across mammals (demonstrated in mouse models — see Section 15), supporting cross-species relevance of the proposed mechanism, but this is inferred from engineered mouse models rather than observed natural disease.
  • Zoonotic potential: Not applicable (non-infectious, monogenic disorder).

15. Model Organisms

  • Mouse models (Trpv4 genetically engineered mice):
  • Global Trpv4-knockout mice show a bone phenotype opposite to the human gain-of-function ANFH2 phenotype: "male TRPV4 knockout mice have reduced osteoclast activity and numbers, increased bone mass, and increased subchondral bone volume" — consistent with, and supportive of, the proposed gain-of-function mechanism in ANFH2 (i.e., loss of TRPV4 → less osteoclast activity/more bone; gain of TRPV4 function → implied increased osteoclast activity/bone loss, the inferred direction relevant to ANFH2, though a direct knock-in gain-of-function ANFH2 mouse model was not identified in this search).
  • Trpv4-knockout mice also show reduced bone loss and reduced osteoclast function in an unloading-induced bone-loss model, and TRPV4 has been shown to regulate steady-state Ca²⁺ influx at the late stage of osteoclast differentiation, essential for NFATc1-controlled transcription governing osteoclast terminal differentiation and resorptive capacity — mechanistic support (in the opposite/loss-of-function direction) for the human gain-of-function disease mechanism.
  • Combined Trpv1/Trpv4 double-knockout mice show increased bone mass, further supporting a role for TRPV4 (and possibly TRPV1) in normal bone-resorption homeostasis.
  • Cartilage-specific Trpv4 knockout mice and mice bearing other gain-of-function Trpv4 knock-in alleles (e.g., models of TRPV4 skeletal dysplasia) have been generated and used to study the mechanoregulatory role of TRPV4 in prenatal skeletal development (Science Advances, referenced in this search) and cartilage-specific TRPV4 effects on cilia/mechanosensation (Scientific Reports, srep29053) — these are the closest existing genetic models to the gain-of-function mechanism relevant to ANFH2, though they model skeletal dysplasia phenotypes rather than the vascular/femoral-head-osteonecrosis phenotype specifically. No mouse model directly recapitulating femoral head osteonecrosis via the ANFH2 V829Wfs*3 (or an equivalent gain-of-function) TRPV4 allele was identified in this search — this represents a genuine gap (a candidate HUMAN_MODEL_MISMATCH/knowledge-gap item: existing Trpv4 mouse models establish the channel's role in osteoclast and vascular biology generally, but fidelity of any specific model to the human ANFH2 femoral-head phenotype has not been demonstrated).
  • Cellular models: In vitro electrophysiological characterization of the mutant channel (heterologous expression system, likely HEK293-type cells based on standard methodology for such TRPV4 functional studies) was the direct functional model used in the discovery paper (PMID:27330106), demonstrating the gain-of-function sparklet/burst-open-time phenotype described above — this is an IN_VITRO functional/mechanistic model, not a disease model per se, but it is the key piece of direct causal/functional evidence for pathogenicity.

  • A separate report describes novel gain-of-function TRPV4 mutations characterized using patient-derived dental pulp stem cells differentiated along chondrogenic lineage (metatropic dysplasia context, PMC6709385) — an iPSC/patient-cell-derived model approach that could in principle be applied to ANFH2-specific variants (osteoclast or endothelial differentiation from patient-derived iPSCs) but has not yet been reported for the ANFH2 allele specifically.

  • Model limitations: Existing Trpv4 mouse models (knockout, skeletal-dysplasia knock-in) capture TRPV4's general roles in bone remodeling and skeletal development but have not been shown to reproduce the specific femoral-head-restricted osteonecrosis phenotype of human ANFH2; the field currently relies on human pedigree/clinical data plus in vitro channel electrophysiology for causal evidence, without an established in vivo whole-organism disease model of ANFH2 itself.

Summary of Key Ontology Term Suggestions

Concept Suggested term
Gene TRPV4 — hgnc:12716
Disease (broad) Osteonecrosis, MONDO general term; MONDO:0054551 (ANFH2 specific)
Phenotype: avascular necrosis of femoral head HP:0010734
Phenotype: hip/groin pain best available generic pain term; consider free text if no exact HP match
Phenotype: gait disturbance HP:0100787
Phenotype: limited joint mobility HP:0002826
GO BP: calcium ion transmembrane transport GO:0070588
GO BP: osteoclast differentiation GO:0030316
GO MF: calcium channel activity GO:0005262
GO MF: calmodulin binding GO:0005516
Cell type: osteoclast CL:0000092
Cell type: vascular endothelial cell CL:0000115
Cell type: vascular smooth muscle cell CL:0000359
Anatomy: hip joint UBERON:0001360
Anatomy: femur UBERON:0001417
Treatment: pharmacotherapy NCIT:C15986
Treatment: surgical procedure (core decompression / THA) NCIT:C15329
Treatment: radiation/hyperbaric oxygen consider NCIT:C15313-adjacent or a specific HBOT term if present in NCIT

Notable Gaps / Items Needing Further Verification Before Curation

  1. The specific ANFH2 TRPV4 variant's ClinVar accession/classification was not directly retrieved in this search (ClinVar hits found were for other TRPV4 variants such as p.Arg269His, p.Arg315Trp, associated with related but distinct TRPV4-opathy phenotypes) — this should be directly queried in ClinVar/OAK before curation to confirm formal variant classification and accession ID for c.2480_2483delCCCG;c.2486T>A.
  2. Exact sex distribution and individual ages of the 4 affected ANFH2 siblings were not fully itemized in the sources retrieved (only proband age 21 was specified) — the full case series table in PMID:27330106 (Table 1 in the original paper) should be consulted directly for per-individual phenotype data before writing an evidence-dense phenotype table.
  3. No second independent TRPV4-ANFH2 family has been identified in the literature retrieved here — curation should flag that causal evidence rests on a single pedigree (n=1 family, n=4 affected individuals) plus supportive in vitro functional data, an important evidentiary caveat for a Mendelian gene-disease claim of this size.
  4. OMIM #617383's full clinical synopsis text could not be directly fetched in this session (proxy connection error to omim.org) — recommend a direct OMIM API/manual lookup during curation to confirm the exact "Clinical Synopsis" field values (e.g., formally coded HPO-style synopsis terms) rather than relying solely on secondary summaries.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 0
Quoted claims not found in source 2
References weighed for topical relevance 19
On topic 3
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMC:PMC5035228: "All affected siblings with osteonecrosis of the femoral head harbored a heterozygous frameshift deletion in TRPV4"
  • closest text in source: "Siblings affected with osteonecrosis of the femoral head (black symbols) all harbour a heterozygous frameshift deletion in transient receptor potential vanilloid 4 (TRPV4) (TRPV4+/−)"
  • PMID:27330106: "calcium overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip"
  • closest text in source: "Together, this could cause Ca2+ overload, leading to endothelial dysfunction and vasoconstriction, resulting in bone loss at the hip"

Term Validation

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

Outcome Count
Terms checked 38
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 16
Terms named correctly 0
Terms named as a different term 5
Terms whose name is worth a second look 11

Terms the report names something else

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

  • HP:0010734 (3 mentions) - the report calls it "Avascular necrosis of the capital femoral epiphysis", "Phenotype: avascular necrosis of femoral head"; HP calls it Fibrous dysplasia of the bones
  • HP:0100787 (2 mentions) - the report calls it "Gait disturbance", "Phenotype: gait disturbance"; HP calls it Prostate neoplasm
  • HP:0002826 (2 mentions) - the report calls it "Limited joint mobility", "Phenotype: limited joint mobility"; HP calls it Halberd-shaped pelvis
  • UBERON:0001417 (4 mentions) - the report calls it "Anatomy: femur"; UBERON calls it skin of neck
  • UBERON:0001360 (2 mentions) - the report calls it "Anatomy: hip joint"; UBERON calls it deep circumflex iliac vein

Terms whose name is worth a second look

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

  • MONDO:0054551 (2 mentions) - the report calls it "Avascular Necrosis of Femoral Head, Primary, 2", "ANFH2 specific"; MONDO calls it avascular necrosis of femoral head, primary, 2, and lists "ANFH2" among its other names
  • HP:0100559 (1 mention) - the report calls it "Asymmetric growth / limb length discrepancy"; HP calls it Lower limb asymmetry, and lists "Leg length discrepancy" among its other names
  • GO:0005262 (3 mentions) - the report calls it "GO MF: calcium channel activity"; GO calls it calcium channel activity
  • GO:0070588 (3 mentions) - the report calls it "GO BP: calcium ion transmembrane transport"; GO calls it calcium ion transmembrane transport
  • GO:0030316 (2 mentions) - the report calls it "GO BP: osteoclast differentiation"; GO calls it osteoclast differentiation
  • GO:0005516 (2 mentions) - the report calls it "GO MF: calmodulin binding"; GO calls it calmodulin binding
  • CL:0000092 (3 mentions) - the report calls it "Cell type: osteoclast"; CL calls it osteoclast
  • CL:0000115 (3 mentions) - the report calls it "Cell type: vascular endothelial cell"; CL calls it endothelial cell
  • CL:0000359 (3 mentions) - the report calls it "Cell type: vascular smooth muscle cell"; CL calls it vascular associated smooth muscle cell, and lists "vascular smooth muscle cell" among its other names
  • NCIT:C15986 (2 mentions) - the report calls it "Treatment: pharmacotherapy"; NCIT calls it Pharmacotherapy
  • NCIT:C15329 (3 mentions) - the report calls it "Treatment: surgical procedure (core decompression / THA)"; NCIT calls it Surgical Procedure, and lists "Surgical Procedures" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0054551 - called "Avascular Necrosis of Femoral Head, Primary, 2", "ANFH2 specific"
  • HP:0010734 - called "Avascular necrosis of the capital femoral epiphysis", "Phenotype: avascular necrosis of femoral head"
  • HP:0100787 - called "Gait disturbance", "Phenotype: gait disturbance"
  • HP:0002826 - called "Limited joint mobility", "Phenotype: limited joint mobility"