Familial Digital Arthropathy-Brachydactyly

Mendelian MONDO:0011732 Pathograph 23 Show in embeddings browser TRPV4-Related Bone Disorder Congenital Limb Malformation

Familial digital arthropathy-brachydactyly (FDAB) is an autosomal dominant, non-inflammatory osteoarthropathy confined to the joints of the hands and feet. Onset is in the first decade, and the arthropathy is aggressive and progressive, producing deformity and pain by adult life. It is caused by heterozygous missense substitutions (p.Gly270Val, p.Arg271Pro, p.Phe273Leu) in the intracellular ankyrin-repeat domain of TRPV4, the same calcium-permeable cation channel whose variants elsewhere in the protein cause the TRPV4 skeletal dysplasias and the TRPV4 peripheral neuropathies. FDAB is the odd member of that allelic series in two ways. Clinically it is the mildest and most restricted of the TRPV4 skeletal phenotypes: the rest of the skeleton is spared and stature is normal. Mechanistically the brachydactyly is not a primary growth-plate dysplasia - the shortening of the middle and distal phalanges is a secondary consequence of subchondral destruction of the phalangeal, metacarpal, and metatarsal heads, so digital shortening sits downstream of joint destruction rather than beside it. The functional consequence of the ankyrin-repeat-domain variants is not settled: the primary report found reduced channel activity and poor cell-surface localization, while later structure-function work frames pathogenic TRPV4 variants as gain-of-function and cytotoxic (see discussions).

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1
Inheritance
7
Pathophys.
10
Phenotypes
3
Gaps
23
Pathograph
1
Genes
4
Variants
4
Medical Actions
1
Differentials
1
References
🏷

Classifications

ISDS Skeletal Nosology
trpv4
👪

Inheritance

1
Autosomal Dominant HP:0000006
Autosomal dominant transmission of a heterozygous TRPV4 missense variant. The founding kindred was a large multigenerational family, and a later report identified a TRPV4 variant in an affected father and son.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:24830047 SUPPORT Human Clinical
"By definition, autosomal dominant TRPV4-related disorders are inherited in an autosomal dominant manner."
GeneReviews states the mode of inheritance for the autosomal dominant TRPV4-related disorders, of which FDAB is the mildest skeletal phenotype.
PMID:11891693 SUPPORT Human Clinical
"We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges."
The founding clinical description reports dominant transmission in a large multigenerational family.
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Discussions and Knowledge Gaps

3
Do the FDAB ankyrin-repeat-domain variants reduce or increase TRPV4 channel activity, and how should the pathophysiology node be graded while the two published accounts disagree?
CONTROVERSY OPEN disc_fdab_channel_direction
Attached to
pathophysiology#TRPV4 Ankyrin Repeat Domain Missense Variants pathophysiology#Reduced TRPV4 Channel Responsiveness
The gene-discovery study measured poor cell-surface localization, reduced agonist-evoked calcium influx, and no response to hypotonic stress for all three FDAB alleles, and framed FDAB as the phenotype produced by TRPV4 mutations that reduce channel activity, in contrast to the gain-of-function skeletal dysplasias and neuropathies. A later structure-function survey instead treats pathogenic TRPV4 mutations as a class that gains channel function and is cytotoxic, and reports that gain-of-function ankyrin-repeat-domain mutations sit at charged residues in the RhoA interface while other residues of that domain have normal or reduced activity. That last finding cuts both ways for FDAB, whose alleles include the charged Arg271 alongside the uncharged Gly270 and Phe273. This entry grades the variant consequence as loss of function, following the only study that assayed the FDAB alleles themselves. Resolving the question needs those three alleles re-assayed in the newer framework rather than inference from the class-level claim.
Show evidence (4 references)
PMID:21964574 SUPPORT Human Clinical
"Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis."
The reduced-activity position, stated by the only study that assayed the FDAB alleles.
PMID:39021275 SUPPORT In Vitro
"Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients."
The competing class-level position, which treats gain of function and cytotoxicity as the shared mechanism across TRPV4 channelopathies including arthropathy.
PMID:39021275 SUPPORT In Vitro
"We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity."
Narrows the disagreement to the ankyrin repeat domain specifically, and shows reduced activity is an expected outcome for some residues of that domain, which is where the FDAB alleles sit.
+ 1 more reference
Why does FDAB produce a joint-restricted osteoarthropathy rather than the growth-plate dysplasia other TRPV4 alleles cause?
INTERPRETATION OPEN disc_fdab_follistatin_divergence
Attached to
pathophysiology#Loss of Articular Cartilage Homeostasis pathophysiology#Subchondral Destruction of the Phalangeal, Metacarpal and Metatarsal Heads
The TRPV4 skeletal dysplasias act on growth-plate chondrocytes through calcium-dependent upregulation of follistatin, which inhibits BMP signaling and slows endochondral ossification. When an FDAB (arthropathy) allele was put through the same chondrocyte assay it left follistatin essentially unchanged, while three dysplasia alleles raised it two- to 2.3-fold. That single negative result is the clearest published evidence that FDAB reaches cartilage failure by a different route, and it fits the clinical picture: articular rather than growth-plate cartilage, normal stature, and a skeleton otherwise spared. The route FDAB does take is not established - the entry models it as failure of articular cartilage homeostasis on the strength of the gene-discovery paper's own interpretation, not on a demonstrated downstream pathway.
Show evidence (2 references)
PMID:24577120 SUPPORT In Vitro
"FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold)."
The negative result for the arthropathy allele set against positive results for three dysplasia alleles in the same assay.
PMID:11891693 SUPPORT Human Clinical
"The remainder of the skeleton is not affected."
The clinical counterpart of the assay result: no generalized skeletal dysplasia accompanies the digital arthropathy.
Are familial digital arthropathy-brachydactyly and Thiemann disease one entity or two?
OPEN QUESTION OPEN disc_fdab_thiemann_identity
Attached to
phenotypes#Non-Inflammatory Digital Arthropathy differential_diagnoses#Thiemann disease
A father and son referred with a diagnosis of Thiemann disease carried a heterozygous TRPV4 variant previously reported to cause FDAB, and a review of nineteen published Thiemann cases found five whose clinical and radiological findings also fit FDAB. The authors propose the two labels may be phenotypic variability of one entity. It remains unresolved because no DNA could be obtained from any historical Thiemann case, so the hypothesis has not been tested against the population it would reclassify.
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"Our analysis suggests that these two phenotypes may represent phenotypic variability of the same entity."
States the proposed single-entity interpretation.
PMID:31248428 SUPPORT Human Clinical
"Despite many attempts to identify other reported patients affected by Thiemann disease, we were not able to procure DNA from any of the cases to verify our findings."
States why the question remains open: the historical Thiemann cases could not be genotyped.
⚙

Pathophysiology

7
TRPV4 Ankyrin Repeat Domain Missense Variants
FDAB is caused by heterozygous missense substitutions clustered in the intracellular ankyrin-repeat domain of TRPV4 at residues 270-273 (p.Gly270Val, p.Arg271Pro, p.Phe273Leu). This is a different part of the protein from the pore-region and C-terminal residues carrying the recurrent skeletal-dysplasia hotspots, and the restriction of FDAB to the digital joints tracks with that positional difference.
Genetic context TRPV4 hgnc:18083 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TRPV4 (hgnc:18083). hgnc:18083 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Graded as loss of function on the strength of the only study that assayed the FDAB alleles themselves, which reported poor cell-surface localization and reduced agonist-evoked calcium influx for all three. This grading is contested: later structure-function work treats pathogenic TRPV4 variants as a class that gains channel function and is cytotoxic. See the discussion disc_fdab_channel_direction.
TRPV4 calcium channel activity GO:0005262 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves TRPV4 calcium channel activity, annotated with calcium channel activity (GO:0005262). GO:0005262 is a molecular function from the Gene Ontology.
Downstream
Impaired TRPV4 Cell-Surface Trafficking The mutant channel proteins are poorly delivered to the plasma membrane in a heterologous expression system.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Establishes both the causal gene and the localization of all three FDAB alleles to the intracellular ankyrin-repeat domain.
Impaired TRPV4 Cell-Surface Trafficking
In HEK-293 cells the three FDAB mutant proteins reach the cell surface poorly, so less functional channel is available at the plasma membrane where TRPV4 does its osmo- and mechanosensory work.
protein localization to plasma membrane GO:0072659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to plasma membrane (GO:0072659). GO:0072659 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced TRPV4 Channel Responsiveness Less channel at the membrane is the proposed reason the mutant channels pass less calcium and fail to respond to osmotic challenge.
Show evidence (1 reference)
PMID:21964574 SUPPORT In Vitro
"Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization."
States the mislocalization finding that this node represents.
Reduced TRPV4 Channel Responsiveness
Agonist-evoked calcium influx through the FDAB mutant channels is significantly reduced and the channels do not respond to hypotonic stress, so the osmomechanical calcium signal TRPV4 normally supplies is blunted. Cartilage is the tissue that fails because the chondrocyte is where this channel's osmomechanical signalling matters; note that the functional measurement below was made in a heterologous expression system, and the chondrocyte-level work available for the FDAB alleles specifically is the follistatin experiment, which is a negative result.
articular chondrocyte CL:1001607 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves articular chondrocyte (CL:1001607). CL:1001607 is a cell type from the Cell Ontology.
calcium ion transmembrane transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↓ DECREASED response to osmotic stress GO:0006970 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased response to osmotic stress (GO:0006970). GO:0006970 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Articular Cartilage Homeostasis The authors read the arthropathy phenotype as evidence that TRPV4 channel activity is required to maintain articular cartilage.
Show evidence (2 references)
PMID:21964574 SUPPORT In Vitro
"Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress."
The functional measurement behind this node: reduced agonist response and loss of the hypotonic response in the FDAB mutant channels.
PMID:24577120 SUPPORT In Vitro
"FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold)."
Work in primary chondrocytes rather than a heterologous line, which is why it is cited here to ground the chondrocyte binding. It also separates FDAB from its dysplasia siblings at the cellular level: the arthropathy allele left follistatin unchanged where every dysplasia allele raised it.
Loss of Articular Cartilage Homeostasis
Articular cartilage of the digital joints fails to maintain itself. This is where FDAB diverges mechanistically from the TRPV4 skeletal dysplasias: those act on growth-plate chondrocytes through calcium-dependent follistatin upregulation and inhibition of endochondral ossification, whereas an FDAB (arthropathy) allele tested in the same chondrocyte assay left follistatin unchanged.
articular chondrocyte CL:1001607 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves articular chondrocyte (CL:1001607). CL:1001607 is a cell type from the Cell Ontology.
cartilage homeostasis GO:1990079 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cartilage homeostasis (GO:1990079). GO:1990079 is a biological process from the Gene Ontology. ↓ DECREASED
articular cartilage of the digital joints UBERON:0010996 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in articular cartilage of the digital joints, annotated with articular cartilage of joint (UBERON:0010996). UBERON:0010996 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Subchondral Destruction of the Phalangeal, Metacarpal and Metatarsal Heads The radiographic sequence across ages was read as a subchondral lesion of the bone ends being the primary event.
Show evidence (2 references)
PMID:21964574 SUPPORT Human Clinical
"Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis."
Names articular cartilage homeostasis as the process TRPV4 activity supports and that fails in FDAB.
PMID:24577120 SUPPORT In Vitro
"FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold)."
Supports treating the FDAB cartilage lesion as mechanistically separate from the dysplasia route: the arthropathy allele did not upregulate follistatin, whereas the three dysplasia alleles did.
Subchondral Destruction of the Phalangeal, Metacarpal and Metatarsal Heads
Destructive change centred on the subchondral bone of the heads of the phalanges, metacarpals, and metatarsals. In the hand the distal joints are affected first and the middle phalangeal heads are the primary site of change. This is the shared origin of both the joint disease and the digital shortening.
interphalangeal joint of the hand and foot UBERON:0006658 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in interphalangeal joint of the hand and foot, annotated with interphalangeal joint (UBERON:0006658). UBERON:0006658 is an anatomical location from the Uberon multi-species anatomy ontology. phalanx of the hand and foot UBERON:0003221 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in phalanx of the hand and foot, annotated with phalanx (UBERON:0003221). UBERON:0003221 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Destructive Osteoarthropathy of the Digital Joints The clinical arthropathy is a secondary effect of the subchondral lesion.
Secondary Shortening of the Middle and Distal Phalanges The brachydactyly is likewise a secondary effect of the same subchondral lesion rather than a primary growth-plate dysplasia.
Show evidence (2 references)
PMID:11891693 SUPPORT Human Clinical
"It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
Identifies the anatomic site and nature of the primary lesion this node represents.
PMID:31248428 SUPPORT Human Clinical
"In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes."
Refines the site and the order of joint involvement within the hand.
Progressive Destructive Osteoarthropathy of the Digital Joints
Aggressive, non-inflammatory osteoarthropathy of the joints of the fingers and toes. It is restricted to the hands and feet; the rest of the skeleton is spared, which is what separates FDAB from the other TRPV4 skeletal phenotypes.
interphalangeal joint of the hand and foot UBERON:0006658 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in interphalangeal joint of the hand and foot, annotated with interphalangeal joint (UBERON:0006658). UBERON:0006658 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Secondary Shortening of the Middle and Distal Phalanges Digital shortening follows from the joint destruction rather than preceding it.
Non-Inflammatory Digital Arthropathy
Osteoarthritis of the Small Joints of the Hand
Distal Interphalangeal Joint Osteoarthritis
Premature Osteoarthritis
Digital Joint Pain
Radial Deviation of the Fingers
Show evidence (2 references)
PMID:21964574 SUPPORT Human Clinical
"Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
Characterizes the joint disease as aggressive osteoarthropathy confined to the fingers and toes.
PMID:11891693 SUPPORT Human Clinical
"The remainder of the skeleton is not affected."
Establishes the anatomic restriction of the arthropathy to the hands and feet.
Secondary Shortening of the Middle and Distal Phalanges
Progressive loss of length in the middle and distal phalanges of fingers and toes as the bone ends are destroyed. Because the shortening is secondary to subchondral and epiphyseal destruction rather than to a primary growth-plate lesion, stature and the remainder of the skeleton are normal.
phalanx of the hand and foot UBERON:0003221 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in phalanx of the hand and foot, annotated with phalanx (UBERON:0003221). UBERON:0003221 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Brachydactyly
Short Middle Phalanx of Finger
Short Distal Phalanx of Finger
Short Middle Phalanx of Toe
Show evidence (2 references)
PMID:11891693 SUPPORT Human Clinical
"We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges."
Establishes progressive shortening of the middle and distal phalanges as a core feature.
PMID:24830047 SUPPORT Human Clinical
"All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis."
Supports both halves of this node: brachydactyly is present across the group, while short stature and axial or long-bone involvement are reserved for the four more severe phenotypes and not for FDAB, the mildest.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Digital Arthropathy-Brachydactyly 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

10
Limbs 7
Osteoarthritis of the Small Joints of the Hand HP:0004268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoarthritis of the small joints of the hand (HP:0004268). HP:0004268 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
Characterizes the hand joint disease as aggressive osteoarthropathy of the fingers.
Distal Interphalangeal Joint Osteoarthritis Osteoarthritis of the distal interphalangeal joint HP:0006233 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoarthritis of the distal interphalangeal joint (HP:0006233). HP:0006233 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes."
States the distal-first pattern of joint involvement in FDAB.
PMID:31248428 SUPPORT Human Clinical
"Thiemann disease initially affects the proximal interphalangeal joints and primarily the middle phalangeal bases."
Gives the contrasting proximal pattern in Thiemann disease, which is what makes the distal pattern diagnostically useful in FDAB.
Radial Deviation of the Fingers Radial deviation of finger HP:0009466 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Radial deviation of finger (HP:0009466). HP:0009466 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31248428 SUPPORT Human Clinical
"Radial deviation has only been described in FDAB."
States that radial deviation has been reported only in FDAB among the compared digital arthropathies.
Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156), qualified as course progressive. HP:0001156 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities."
States that brachydactyly is an expected feature of FDAB.
PMID:24830047 SUPPORT Human Clinical
"All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis."
GeneReviews states brachydactyly is present across the TRPV4 skeletal phenotypes, of which FDAB is the mildest.
Short Middle Phalanx of Finger HP:0005819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short middle phalanx of finger (HP:0005819). HP:0005819 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
Names shortening of the middle phalanges of the fingers as a defining feature.
Short Distal Phalanx of Finger HP:0009882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short distal phalanx of finger (HP:0009882). HP:0009882 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
Names shortening of the distal phalanges of the fingers as a defining feature.
Short Middle Phalanx of Toe HP:0003795 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short middle phalanx of toe (HP:0003795). HP:0003795 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
Shortening of the middle and distal phalanges is described for the toes as well as the fingers.
Musculoskeletal 2
Non-Inflammatory Digital Arthropathy HP:0003040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-inflammatory arthropathy of the hands and feet, annotated with Arthropathy (HP:0003040), qualified as course progressive. HP:0003040 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"FDAB and Thiemann disease are non-inflammatory digital arthropathies with phenotypic overlap."
States directly that FDAB is a non-inflammatory digital arthropathy.
PMID:11891693 SUPPORT Human Clinical
"We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges."
Establishes arthropathy of the hands and feet as a defining feature.
Premature Osteoarthritis HP:0003088 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature osteoarthritis (HP:0003088). HP:0003088 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11891693 SUPPORT Human Clinical
"Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life."
Places onset of the degenerative joint disease in the first decade, which is what makes it premature.
Constitutional 1
Digital Joint Pain Arthralgia HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthralgia of the digital joints, annotated with Arthralgia (HP:0002829). HP:0002829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11891693 SUPPORT Human Clinical
"Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life."
Names pain as an outcome of the progressive arthropathy in adult life.
🧬

Genetic Associations

1
TRPV4 (Causative)
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:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Establishes TRPV4 as the causative gene and names all three alleles and their protein domain.
PMID:22791502 SUPPORT Human Clinical
"The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly."
Places FDAB within the TRPV4 allelic series as one of the phenotypes that deviates from the main skeletal dysplasia pattern.
PMID:22791502 SUPPORT Human Clinical
"Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK."
Names the recurrent dysplasia hotspots that the FDAB ankyrin-repeat-domain cluster is distinct from.
Variants (4)
p.Gly270Val Pathogenic
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.
Heterozygous missense substitution in the intracellular ankyrin-repeat domain of TRPV4, one of the three FDAB alleles identified in the gene-discovery study.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Names p.Gly270Val as one of the three FDAB-causing substitutions.
p.Arg271Pro Pathogenic
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.
Heterozygous missense substitution in the intracellular ankyrin-repeat domain of TRPV4, one of the three FDAB alleles identified in the gene-discovery study. Arg271 is a charged residue, which is relevant to the unresolved question of whether the FDAB alleles gain or lose channel function.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Names p.Arg271Pro as one of the three FDAB-causing substitutions.
p.Phe273Leu Pathogenic
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.
Heterozygous missense substitution in the intracellular ankyrin-repeat domain of TRPV4, one of the three FDAB alleles identified in the gene-discovery study.
Show evidence (1 reference)
PMID:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Names p.Phe273Leu as one of the three FDAB-causing substitutions.
c.809G>T Pathogenic
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.
A heterozygous TRPV4 coding variant found in a father and son referred with a diagnosis of Thiemann disease. The reporting authors state the identical variant had previously been reported to cause FDAB; its protein-level identity with one of the three ankyrin-repeat-domain alleles is not asserted here beyond what that report says.
Show evidence (1 reference)
PMID:31248428 SUPPORT Human Clinical
"We describe a father and son referred with a diagnosis of Thiemann disease who were subsequently identified with a heterozygous variant (c.809G > T) in TRPV4."
Reports the variant and the family in which it accompanied the digital arthropathy phenotype.
💊

Medical Actions

4
Symptom-Directed Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
There is no disease-modifying therapy. Management is directed at the symptoms of the digital arthropathy - joint pain, stiffness, and deformity - and is typically delivered by a multidisciplinary team. An earlier version of this entry attributed activity-avoidance advice to GeneReviews and paraphrased it as applying to the affected joints. That paraphrase is withdrawn: the GeneReviews record cached here is the PubMed abstract, whose sections do not carry the chapter's management guidance, so nothing in this repository supports a quotation of it. The chapter's advice is in any case written for the TRPV4-related disorders as a group, and this disease spares the axial skeleton.
Show evidence (1 reference)
PMID:24830047 SUPPORT Human Clinical
"Treatment of manifestations: Treatment is focused on symptom management."
GeneReviews states that management of TRPV4-related disorders is symptom-directed, with no disease-modifying option offered.
Annual Evaluation for Joint Pain
Action: annual clinical evaluation for joint painNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is annual clinical evaluation for joint pain, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
GeneReviews recommends annual evaluation for joint pain across the TRPV4 skeletal phenotypes. That item transfers to FDAB directly, since progressive digital joint pain is the presenting problem and the reason supportive care is offered at all. The other surveillance items in the same recommendation do not transfer: scoliosis and odontoid hypoplasia are axial findings in a disease that spares the axial skeleton, and hearing assessment belongs to the neuromuscular and dysplasia phenotypes rather than to this one.
Mechanism Target:
Progressive Destructive Osteoarthropathy of the Digital Joints — Surveillance detects progression of the arthropathy; it does not modify it, and no disease-modifying therapy exists.
Show evidence (1 reference)
PMID:24830047 SUPPORT Human Clinical
"For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment; and assessment of weight, height, and weight-for-height at each visit."
The surveillance recommendation this entry takes the joint-pain item from. Quoted in full so the items deliberately not carried over to FDAB are visible rather than silently dropped.
Physical Therapy for Digital Joint Function
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physical therapy and exercise as tolerated are used to maintain function in the TRPV4 skeletal disorders. In FDAB the target is hand and foot function as the digital joints deteriorate.
Show evidence (1 reference)
PMID:24830047 SUPPORT Human Clinical
"For skeletal dysplasias, additional treatment includes physical therapy/exercise and heel cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present."
GeneReviews recommends physical therapy and exercise to maintain function across the TRPV4 skeletal dysplasias, of which FDAB is one; the surgical thresholds named in the same sentence concern spinal disease FDAB does not produce.
Genetic Counseling
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
Platform: Other
Counseling covers autosomal dominant transmission and the 50% recurrence risk to each child of an affected individual. Molecular confirmation matters here because the clinically overlapping differential, Thiemann disease, has no identified gene.
Show evidence (2 references)
PMID:24830047 SUPPORT Human Clinical
"Each child of an individual with an autosomal dominant TRPV4-related disorder has a 50% chance of inheriting the TRPV4 pathogenic variant."
Gives the recurrence-risk figure counseling communicates.
PMID:31248428 SUPPORT Human Clinical
"Genetic testing of an affected individual will be crucial in order to provide accurate reproductive genetic counselling about the autosomal dominant nature of this condition."
States that molecular testing is needed to give accurate reproductive counseling in this phenotype.
🔬

Diagnosis

2
Radiographic Assessment of the Hands and Feet
Plain radiographs of the hands and feet show destructive change centred on the heads of the phalanges, metacarpals, and metatarsals, with the distal joints of the hand involved first. Serial films across ages are what established the subchondral lesion as the primary event, and the same pattern distinguishes FDAB from Thiemann disease, in which the proximal interphalangeal joints and the middle phalangeal bases are involved.
radiographic imaging of the hands and feet NCIT:C38101 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes."
Gives the radiographic pattern that supports the diagnosis.
PMID:11891693 SUPPORT Human Clinical
"It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
Describes the radiological appearance across ages on which the diagnostic pattern rests.
Molecular Confirmation of a TRPV4 Variant
Diagnosis is confirmed by identifying a heterozygous TRPV4 pathogenic variant. In FDAB the expected finding is a missense substitution in the intracellular ankyrin-repeat domain, a different part of the protein from the recurrent skeletal-dysplasia hotspots, so the variant position itself carries phenotypic information.
TRPV4 molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:24830047 SUPPORT 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 states that molecular identification of a heterozygous TRPV4 pathogenic variant establishes the diagnosis in this disease group.
PMID:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Names the specific alleles and the protein domain a diagnostic test should expect to find in FDAB.
📈

Progression

1
Childhood onset with progression to adult deformity
Age: First decade of life through adulthood
Joint changes begin in the first decade; the arthropathy is progressive and the resulting deformity and pain accumulate into adult life, with digital shortening becoming more evident with age.
Show evidence (1 reference)
PMID:11891693 SUPPORT Human Clinical
"Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life."
Gives both the age at onset and the progressive course that define the natural history of FDAB.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence estimate exists. The published experience is three unrelated families in the gene-discovery report plus scattered later case reports, one of which was originally diagnosed as Thiemann disease.
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"FDAB is reported in only a few patients and has been associated with three heterozygous missense variants in the Transient receptor potential vanilloid 4 (TRPV4) gene."
States directly that the reported patient count is very small, which is the basis for the ultra-rare band and the cases-in-literature measure.
PMID:21964574 SUPPORT Human Clinical
"Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
Quantifies the gene-discovery cohort as three unrelated families.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Familial Digital Arthropathy-Brachydactyly:

Thiemann disease
Overlapping Features A non-inflammatory digital arthropathy of adolescence with substantial clinical and radiological overlap with FDAB and no causative gene identified. It begins at the proximal interphalangeal joints and the middle phalangeal bases, whereas FDAB begins distally with the middle phalangeal heads as the primary site; radial deviation and brachydactyly favour FDAB. One reported father-and-son pair referred as Thiemann disease carried a TRPV4 variant previously reported in FDAB, raising the possibility that the two labels describe one entity.
Distinguishing Features
  • Thiemann disease starts at the proximal interphalangeal joints and the middle phalangeal bases; FDAB starts at the distal joints with the middle phalangeal heads as the primary site of change
  • Radial deviation of the fingers has been described only in FDAB
  • More extensive joint involvement and brachydactyly are expected in FDAB
  • No causative gene has been identified for Thiemann disease, so a TRPV4 pathogenic variant favours FDAB
Show evidence (2 references)
PMID:31248428 SUPPORT Human Clinical
"Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities."
States both the overlap that makes Thiemann disease the key differential and the features that separate the two.
PMID:31248428 SUPPORT Human Clinical
"Thirty-three cases of Thiemann disease have been described so far (Mangat et al, Ann Rheum Dis 64:11-2, 2005; Ha et al, Thiemann's disease: a case Report, 2017) but no gene variants have been identified as causative to date."
Establishes that Thiemann disease has no identified causative gene, which is why molecular testing discriminates the two.
{ }

Source YAML

click to show 
name: Familial Digital Arthropathy-Brachydactyly
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
description: >-
  Familial digital arthropathy-brachydactyly (FDAB) is an autosomal dominant,
  non-inflammatory osteoarthropathy confined to the joints of the hands and
  feet. Onset is in the first decade, and the arthropathy is aggressive and
  progressive, producing deformity and pain by adult life. It is caused by
  heterozygous missense substitutions (p.Gly270Val, p.Arg271Pro, p.Phe273Leu)
  in the intracellular ankyrin-repeat domain of TRPV4, the same
  calcium-permeable cation channel whose variants elsewhere in the protein
  cause the TRPV4 skeletal dysplasias and the TRPV4 peripheral neuropathies.
  FDAB is the odd member of that allelic series in two ways. Clinically it is
  the mildest and most restricted of the TRPV4 skeletal phenotypes: the rest of
  the skeleton is spared and stature is normal. Mechanistically the
  brachydactyly is not a primary growth-plate dysplasia - the shortening of the
  middle and distal phalanges is a secondary consequence of subchondral
  destruction of the phalangeal, metacarpal, and metatarsal heads, so digital
  shortening sits downstream of joint destruction rather than beside it. The
  functional consequence of the ankyrin-repeat-domain variants is not settled:
  the primary report found reduced channel activity and poor cell-surface
  localization, while later structure-function work frames pathogenic TRPV4
  variants as gain-of-function and cytotoxic (see discussions).
disease_term:
  preferred_term: familial digital arthropathy-brachydactyly
  term:
    id: MONDO:0011732
    label: familial digital arthropathy-brachydactyly
synonyms:
- FDAB
- digital arthropathy-brachydactyly, familial
- familial digital arthropathy with brachydactyly
- brachydactyly with destructive arthropathy
parents:
- TRPV4-Related Bone Disorder
- Congenital Limb Malformation
classifications:
  isds_skeletal_category:
  - classification_value: trpv4
    notes: >-
      Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 8 "TRPV4 disorders"; familial digital
      arthropathy-brachydactyly is one of the TRPV4 skeletal phenotypes that
      group spans.
inheritance:
- name: Autosomal Dominant
  description: >-
    Autosomal dominant transmission of a heterozygous TRPV4 missense variant.
    The founding kindred was a large multigenerational family, and a later
    report identified a TRPV4 variant in an affected father and son.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24830047
    reference_title: "Autosomal Dominant TRPV4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By definition, autosomal dominant TRPV4-related disorders are inherited in an autosomal dominant manner."
    explanation: >-
      GeneReviews states the mode of inheritance for the autosomal dominant
      TRPV4-related disorders, of which FDAB is the mildest skeletal phenotype.
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges."
    explanation: >-
      The founding clinical description reports dominant transmission in a large
      multigenerational family.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. The published experience is three
    unrelated families in the gene-discovery report plus scattered later case
    reports, one of which was originally diagnosed as Thiemann disease.
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FDAB is reported in only a few patients and has been associated with three heterozygous missense variants in the Transient receptor potential vanilloid 4 (TRPV4) gene."
    explanation: >-
      States directly that the reported patient count is very small, which is
      the basis for the ultra-rare band and the cases-in-literature measure.
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
    explanation: >-
      Quantifies the gene-discovery cohort as three unrelated families.
progression:
- phase: Childhood onset with progression to adult deformity
  age_range: First decade of life through adulthood
  notes: >-
    Joint changes begin in the first decade; the arthropathy is progressive and
    the resulting deformity and pain accumulate into adult life, with digital
    shortening becoming more evident with age.
  evidence:
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life."
    explanation: >-
      Gives both the age at onset and the progressive course that define the
      natural history of FDAB.
pathophysiology:
- name: TRPV4 Ankyrin Repeat Domain Missense Variants
  description: >-
    FDAB is caused by heterozygous missense substitutions clustered in the
    intracellular ankyrin-repeat domain of TRPV4 at residues 270-273
    (p.Gly270Val, p.Arg271Pro, p.Phe273Leu). This is a different part of the
    protein from the pore-region and C-terminal residues carrying the recurrent
    skeletal-dysplasia hotspots, and the restriction of FDAB to the digital
    joints tracks with that positional difference.
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
    allele_type: missense
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Graded as loss of function on the strength of the only study that assayed
      the FDAB alleles themselves, which reported poor cell-surface localization
      and reduced agonist-evoked calcium influx for all three. This grading is
      contested: later structure-function work treats pathogenic TRPV4 variants
      as a class that gains channel function and is cytotoxic. See the
      discussion disc_fdab_channel_direction.
  molecular_functions:
  - preferred_term: TRPV4 calcium channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
    explanation: >-
      Establishes both the causal gene and the localization of all three FDAB
      alleles to the intracellular ankyrin-repeat domain.
  downstream:
  - target: Impaired TRPV4 Cell-Surface Trafficking
    causal_link_type: DIRECT
    description: >-
      The mutant channel proteins are poorly delivered to the plasma membrane in
      a heterologous expression system.
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization."
      explanation: >-
        Attributes the trafficking defect to the FDAB mutant proteins, which is
        the step from variant to mislocalization.
- name: Impaired TRPV4 Cell-Surface Trafficking
  description: >-
    In HEK-293 cells the three FDAB mutant proteins reach the cell surface
    poorly, so less functional channel is available at the plasma membrane where
    TRPV4 does its osmo- and mechanosensory work.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: DECREASED
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization."
    explanation: >-
      States the mislocalization finding that this node represents.
  downstream:
  - target: Reduced TRPV4 Channel Responsiveness
    causal_link_type: DIRECT
    description: >-
      Less channel at the membrane is the proposed reason the mutant channels
      pass less calcium and fail to respond to osmotic challenge.
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress."
      explanation: >-
        Reports the reduced calcium influx and absent hypotonic response
        measured in the same cells that showed the trafficking defect.
- name: Reduced TRPV4 Channel Responsiveness
  description: >-
    Agonist-evoked calcium influx through the FDAB mutant channels is
    significantly reduced and the channels do not respond to hypotonic stress,
    so the osmomechanical calcium signal TRPV4 normally supplies is blunted.
    Cartilage is the tissue that fails because the chondrocyte is where this
    channel's osmomechanical signalling matters; note that the functional
    measurement below was made in a heterologous expression system, and the
    chondrocyte-level work available for the FDAB alleles specifically is the
    follistatin experiment, which is a negative result.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: articular chondrocyte
    term:
      id: CL:1001607
      label: articular chondrocyte
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: DECREASED
  - preferred_term: response to osmotic stress
    term:
      id: GO:0006970
      label: response to osmotic stress
    modifier: DECREASED
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress."
    explanation: >-
      The functional measurement behind this node: reduced agonist response and
      loss of the hypotonic response in the FDAB mutant channels.
  - reference: PMID:24577120
    reference_title: "Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold)."
    explanation: >-
      Work in primary chondrocytes rather than a heterologous line, which is why
      it is cited here to ground the chondrocyte binding. It also separates FDAB
      from its dysplasia siblings at the cellular level: the arthropathy allele
      left follistatin unchanged where every dysplasia allele raised it.
  downstream:
  - target: Loss of Articular Cartilage Homeostasis
    causal_link_type: DIRECT
    description: >-
      The authors read the arthropathy phenotype as evidence that TRPV4 channel
      activity is required to maintain articular cartilage.
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis."
      explanation: >-
        Makes the causal claim for this edge explicitly, running from altered
        channel activity to failure of articular cartilage homeostasis.
- name: Loss of Articular Cartilage Homeostasis
  description: >-
    Articular cartilage of the digital joints fails to maintain itself. This is
    where FDAB diverges mechanistically from the TRPV4 skeletal dysplasias:
    those act on growth-plate chondrocytes through calcium-dependent follistatin
    upregulation and inhibition of endochondral ossification, whereas an FDAB
    (arthropathy) allele tested in the same chondrocyte assay left follistatin
    unchanged.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: articular chondrocyte
    term:
      id: CL:1001607
      label: articular chondrocyte
  biological_processes:
  - preferred_term: cartilage homeostasis
    term:
      id: GO:1990079
      label: cartilage homeostasis
    modifier: DECREASED
  locations:
  - preferred_term: articular cartilage of the digital joints
    term:
      id: UBERON:0010996
      label: articular cartilage of joint
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis."
    explanation: >-
      Names articular cartilage homeostasis as the process TRPV4 activity
      supports and that fails in FDAB.
  - reference: PMID:24577120
    reference_title: "Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold)."
    explanation: >-
      Supports treating the FDAB cartilage lesion as mechanistically separate
      from the dysplasia route: the arthropathy allele did not upregulate
      follistatin, whereas the three dysplasia alleles did.
  downstream:
  - target: Subchondral Destruction of the Phalangeal, Metacarpal and Metatarsal Heads
    causal_link_type: DIRECT
    description: >-
      The radiographic sequence across ages was read as a subchondral lesion of
      the bone ends being the primary event.
    evidence:
    - reference: PMID:11891693
      reference_title: "Familial digital arthropathy-brachydactyly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
      explanation: >-
        States the proposed primary lesion and places it upstream of both the
        arthropathy and the brachydactyly.
- name: Subchondral Destruction of the Phalangeal, Metacarpal and Metatarsal Heads
  description: >-
    Destructive change centred on the subchondral bone of the heads of the
    phalanges, metacarpals, and metatarsals. In the hand the distal joints are
    affected first and the middle phalangeal heads are the primary site of
    change. This is the shared origin of both the joint disease and the digital
    shortening.
  biological_scale: TISSUE
  locations:
  - preferred_term: interphalangeal joint of the hand and foot
    term:
      id: UBERON:0006658
      label: interphalangeal joint
  - preferred_term: phalanx of the hand and foot
    term:
      id: UBERON:0003221
      label: phalanx
  evidence:
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
    explanation: >-
      Identifies the anatomic site and nature of the primary lesion this node
      represents.
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes."
    explanation: >-
      Refines the site and the order of joint involvement within the hand.
  downstream:
  - target: Progressive Destructive Osteoarthropathy of the Digital Joints
    causal_link_type: DIRECT
    description: >-
      The clinical arthropathy is a secondary effect of the subchondral lesion.
    evidence:
    - reference: PMID:11891693
      reference_title: "Familial digital arthropathy-brachydactyly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
      explanation: >-
        Names the arthropathy explicitly as a secondary effect of the
        subchondral pathology.
  - target: Secondary Shortening of the Middle and Distal Phalanges
    causal_link_type: DIRECT
    description: >-
      The brachydactyly is likewise a secondary effect of the same subchondral
      lesion rather than a primary growth-plate dysplasia.
    evidence:
    - reference: PMID:11891693
      reference_title: "Familial digital arthropathy-brachydactyly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
      explanation: >-
        Names the brachydactyly explicitly as a secondary effect of the
        subchondral pathology, not as a primary growth defect.
- name: Progressive Destructive Osteoarthropathy of the Digital Joints
  description: >-
    Aggressive, non-inflammatory osteoarthropathy of the joints of the fingers
    and toes. It is restricted to the hands and feet; the rest of the skeleton
    is spared, which is what separates FDAB from the other TRPV4 skeletal
    phenotypes.
  biological_scale: TISSUE
  locations:
  - preferred_term: interphalangeal joint of the hand and foot
    term:
      id: UBERON:0006658
      label: interphalangeal joint
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
    explanation: >-
      Characterizes the joint disease as aggressive osteoarthropathy confined to
      the fingers and toes.
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The remainder of the skeleton is not affected."
    explanation: >-
      Establishes the anatomic restriction of the arthropathy to the hands and
      feet.
  downstream:
  - target: Secondary Shortening of the Middle and Distal Phalanges
    causal_link_type: DIRECT
    description: >-
      Digital shortening follows from the joint destruction rather than
      preceding it.
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
      explanation: >-
        The word "consequent" fixes the direction of this edge: the shortening
        follows the osteoarthropathy rather than arising independently.
  - target: Non-Inflammatory Digital Arthropathy
  - target: Osteoarthritis of the Small Joints of the Hand
  - target: Distal Interphalangeal Joint Osteoarthritis
  - target: Premature Osteoarthritis
  - target: Digital Joint Pain
  - target: Radial Deviation of the Fingers
- name: Secondary Shortening of the Middle and Distal Phalanges
  description: >-
    Progressive loss of length in the middle and distal phalanges of fingers and
    toes as the bone ends are destroyed. Because the shortening is secondary to
    subchondral and epiphyseal destruction rather than to a primary growth-plate
    lesion, stature and the remainder of the skeleton are normal.
  biological_scale: TISSUE
  locations:
  - preferred_term: phalanx of the hand and foot
    term:
      id: UBERON:0003221
      label: phalanx
  evidence:
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges."
    explanation: >-
      Establishes progressive shortening of the middle and distal phalanges as a
      core feature.
  - reference: PMID:24830047
    reference_title: "Autosomal Dominant TRPV4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis."
    explanation: >-
      Supports both halves of this node: brachydactyly is present across the
      group, while short stature and axial or long-bone involvement are reserved
      for the four more severe phenotypes and not for FDAB, the mildest.
  downstream:
  - target: Brachydactyly
  - target: Short Middle Phalanx of Finger
  - target: Short Distal Phalanx of Finger
  - target: Short Middle Phalanx of Toe
genetic:
- name: TRPV4
  association: Causative
  gene_term:
    preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  notes: >-
    All reported FDAB alleles are heterozygous missense substitutions in the
    intracellular ankyrin-repeat domain at residues 270-273. A later report
    identified a heterozygous TRPV4 variant (c.809G>T) in a father and son
    referred with a diagnosis of Thiemann disease, and states the identical
    variant had previously been reported to cause FDAB. TRPV4 variants outside
    this domain cause the skeletal dysplasias (the recurrent R594 and P799
    hotspots) and the TRPV4 peripheral neuropathies, so the ankyrin-repeat-domain
    cluster is the genotypic signature that separates FDAB within the allelic
    series.
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
    explanation: >-
      Establishes TRPV4 as the causative gene and names all three alleles and
      their protein domain.
  - reference: PMID:22791502
    reference_title: "TRPV4-associated skeletal dysplasias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly."
    explanation: >-
      Places FDAB within the TRPV4 allelic series as one of the phenotypes that
      deviates from the main skeletal dysplasia pattern.
  - reference: PMID:22791502
    reference_title: "TRPV4-associated skeletal dysplasias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK."
    explanation: >-
      Names the recurrent dysplasia hotspots that the FDAB ankyrin-repeat-domain
      cluster is distinct from.
  variants:
  - name: p.Gly270Val
    description: >-
      Heterozygous missense substitution in the intracellular ankyrin-repeat
      domain of TRPV4, one of the three FDAB alleles identified in the
      gene-discovery study.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
      explanation: >-
        Names p.Gly270Val as one of the three FDAB-causing substitutions.
  - name: p.Arg271Pro
    description: >-
      Heterozygous missense substitution in the intracellular ankyrin-repeat
      domain of TRPV4, one of the three FDAB alleles identified in the
      gene-discovery study. Arg271 is a charged residue, which is relevant to
      the unresolved question of whether the FDAB alleles gain or lose channel
      function.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
      explanation: >-
        Names p.Arg271Pro as one of the three FDAB-causing substitutions.
  - name: p.Phe273Leu
    description: >-
      Heterozygous missense substitution in the intracellular ankyrin-repeat
      domain of TRPV4, one of the three FDAB alleles identified in the
      gene-discovery study.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
    evidence:
    - reference: PMID:21964574
      reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
      explanation: >-
        Names p.Phe273Leu as one of the three FDAB-causing substitutions.
  - name: c.809G>T
    description: >-
      A heterozygous TRPV4 coding variant found in a father and son referred
      with a diagnosis of Thiemann disease. The reporting authors state the
      identical variant had previously been reported to cause FDAB; its
      protein-level identity with one of the three ankyrin-repeat-domain alleles
      is not asserted here beyond what that report says.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
    evidence:
    - reference: PMID:31248428
      reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a father and son referred with a diagnosis of Thiemann disease who were subsequently identified with a heterozygous variant (c.809G > T) in TRPV4."
      explanation: >-
        Reports the variant and the family in which it accompanied the digital
        arthropathy phenotype.
phenotypes:
- name: Non-Inflammatory Digital Arthropathy
  category: Clinical
  description: >-
    A non-inflammatory arthropathy of the joints of the hands and feet. The
    absence of an inflammatory component matters diagnostically, because FDAB is
    otherwise readily mistaken for juvenile inflammatory arthritis in an
    adolescent presenting with painful, deformed finger joints.
  phenotype_term:
    preferred_term: Non-inflammatory arthropathy of the hands and feet
    term:
      id: HP:0003040
      label: Arthropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FDAB and Thiemann disease are non-inflammatory digital arthropathies with phenotypic overlap."
    explanation: >-
      States directly that FDAB is a non-inflammatory digital arthropathy.
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges."
    explanation: >-
      Establishes arthropathy of the hands and feet as a defining feature.
- name: Osteoarthritis of the Small Joints of the Hand
  category: Clinical
  description: >-
    Aggressive degenerative change in the small joints of the hand.
  phenotype_term:
    preferred_term: Osteoarthritis of the small joints of the hand
    term:
      id: HP:0004268
      label: Osteoarthritis of the small joints of the hand
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
    explanation: >-
      Characterizes the hand joint disease as aggressive osteoarthropathy of the
      fingers.
- name: Distal Interphalangeal Joint Osteoarthritis
  category: Clinical
  description: >-
    In the hand the distal joints are involved first, with the middle phalangeal
    heads as the primary site of radiographic change. This distal preponderance
    is one of the features separating FDAB from Thiemann disease, which starts
    at the proximal interphalangeal joints.
  phenotype_term:
    preferred_term: Osteoarthritis of the distal interphalangeal joint
    term:
      id: HP:0006233
      label: Osteoarthritis of the distal interphalangeal joint
  diagnostic: true
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes."
    explanation: >-
      States the distal-first pattern of joint involvement in FDAB.
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thiemann disease initially affects the proximal interphalangeal joints and primarily the middle phalangeal bases."
    explanation: >-
      Gives the contrasting proximal pattern in Thiemann disease, which is what
      makes the distal pattern diagnostically useful in FDAB.
- name: Premature Osteoarthritis
  category: Clinical
  description: >-
    Degenerative joint disease of the digits beginning in the first decade,
    decades earlier than idiopathic hand osteoarthritis.
  phenotype_term:
    preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  evidence:
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life."
    explanation: >-
      Places onset of the degenerative joint disease in the first decade, which
      is what makes it premature.
- name: Digital Joint Pain
  category: Clinical
  description: >-
    Pain in the affected finger and toe joints, accumulating with the deformity
    into adult life. Pain is a leading reason for presentation.
  phenotype_term:
    preferred_term: Arthralgia of the digital joints
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life."
    explanation: >-
      Names pain as an outcome of the progressive arthropathy in adult life.
- name: Radial Deviation of the Fingers
  category: Clinical
  description: >-
    Radial angulation of the fingers. Among the non-inflammatory digital
    arthropathies compared in the literature this has been described only in
    FDAB, so it carries discriminating value against Thiemann disease.
  phenotype_term:
    preferred_term: Radial deviation of finger
    term:
      id: HP:0009466
      label: Radial deviation of finger
  diagnostic: true
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radial deviation has only been described in FDAB."
    explanation: >-
      States that radial deviation has been reported only in FDAB among the
      compared digital arthropathies.
- name: Brachydactyly
  category: Clinical
  description: >-
    Shortening of the digits, secondary to destruction of the phalangeal bone
    ends rather than to a primary growth-plate lesion.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities."
    explanation: >-
      States that brachydactyly is an expected feature of FDAB.
  - reference: PMID:24830047
    reference_title: "Autosomal Dominant TRPV4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis."
    explanation: >-
      GeneReviews states brachydactyly is present across the TRPV4 skeletal
      phenotypes, of which FDAB is the mildest.
- name: Short Middle Phalanx of Finger
  category: Clinical
  description: >-
    Shortening of the middle phalanges of the fingers, progressive with age.
  phenotype_term:
    preferred_term: Short middle phalanx of finger
    term:
      id: HP:0005819
      label: Short middle phalanx of finger
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
    explanation: >-
      Names shortening of the middle phalanges of the fingers as a defining
      feature.
- name: Short Distal Phalanx of Finger
  category: Clinical
  description: >-
    Shortening of the distal phalanges of the fingers, progressive with age.
  phenotype_term:
    preferred_term: Short distal phalanx of finger
    term:
      id: HP:0009882
      label: Short distal phalanx of finger
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
    explanation: >-
      Names shortening of the distal phalanges of the fingers as a defining
      feature.
- name: Short Middle Phalanx of Toe
  category: Clinical
  description: >-
    The feet are involved on the same pattern as the hands, with shortening of
    the middle and distal phalanges of the toes.
  phenotype_term:
    preferred_term: Short middle phalanx of toe
    term:
      id: HP:0003795
      label: Short middle phalanx of toe
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges."
    explanation: >-
      Shortening of the middle and distal phalanges is described for the toes as
      well as the fingers.
diagnosis:
- name: Radiographic Assessment of the Hands and Feet
  description: >-
    Plain radiographs of the hands and feet show destructive change centred on
    the heads of the phalanges, metacarpals, and metatarsals, with the distal
    joints of the hand involved first. Serial films across ages are what
    established the subchondral lesion as the primary event, and the same
    pattern distinguishes FDAB from Thiemann disease, in which the proximal
    interphalangeal joints and the middle phalangeal bases are involved.
  diagnosis_term:
    preferred_term: radiographic imaging of the hands and feet
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes."
    explanation: >-
      Gives the radiographic pattern that supports the diagnosis.
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects."
    explanation: >-
      Describes the radiological appearance across ages on which the diagnostic
      pattern rests.
- name: Molecular Confirmation of a TRPV4 Variant
  description: >-
    Diagnosis is confirmed by identifying a heterozygous TRPV4 pathogenic
    variant. In FDAB the expected finding is a missense substitution in the
    intracellular ankyrin-repeat domain, a different part of the protein from
    the recurrent skeletal-dysplasia hotspots, so the variant position itself
    carries phenotypic information.
  diagnosis_term:
    preferred_term: TRPV4 molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - 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 states that molecular identification of a heterozygous TRPV4
      pathogenic variant establishes the diagnosis in this disease group.
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4."
    explanation: >-
      Names the specific alleles and the protein domain a diagnostic test should
      expect to find in FDAB.
differential_diagnoses:
- name: Thiemann disease
  description: >-
    A non-inflammatory digital arthropathy of adolescence with substantial
    clinical and radiological overlap with FDAB and no causative gene
    identified. It begins at the proximal interphalangeal joints and the middle
    phalangeal bases, whereas FDAB begins distally with the middle phalangeal
    heads as the primary site; radial deviation and brachydactyly favour FDAB.
    One reported father-and-son pair referred as Thiemann disease carried a
    TRPV4 variant previously reported in FDAB, raising the possibility that the
    two labels describe one entity.
  distinguishing_features:
  - Thiemann disease starts at the proximal interphalangeal joints and the middle phalangeal bases; FDAB starts at the distal joints with the middle phalangeal heads as the primary site of change
  - Radial deviation of the fingers has been described only in FDAB
  - More extensive joint involvement and brachydactyly are expected in FDAB
  - No causative gene has been identified for Thiemann disease, so a TRPV4 pathogenic variant favours FDAB
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities."
    explanation: >-
      States both the overlap that makes Thiemann disease the key differential
      and the features that separate the two.
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-three cases of Thiemann disease have been described so far (Mangat et al, Ann Rheum Dis 64:11-2, 2005; Ha et al, Thiemann's disease: a case Report, 2017) but no gene variants have been identified as causative to date."
    explanation: >-
      Establishes that Thiemann disease has no identified causative gene, which
      is why molecular testing discriminates the two.
treatments:
- name: Symptom-Directed Supportive Care
  description: >-
    There is no disease-modifying therapy. Management is directed at the
    symptoms of the digital arthropathy - joint pain, stiffness, and deformity -
    and is typically delivered by a multidisciplinary team. An earlier version
    of this entry attributed activity-avoidance advice to GeneReviews and
    paraphrased it as applying to the affected joints. That paraphrase is
    withdrawn: the GeneReviews record cached here is the PubMed abstract, whose
    sections do not carry the chapter's management guidance, so nothing in this
    repository supports a quotation of it. The chapter's advice is in any case
    written for the TRPV4-related disorders as a group, and this disease spares
    the axial skeleton.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24830047
    reference_title: "Autosomal Dominant TRPV4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Treatment is focused on symptom management."
    explanation: >-
      GeneReviews states that management of TRPV4-related disorders is
      symptom-directed, with no disease-modifying option offered.
- name: Annual Evaluation for Joint Pain
  description: >-
    GeneReviews recommends annual evaluation for joint pain across the TRPV4
    skeletal phenotypes. That item transfers to FDAB directly, since progressive
    digital joint pain is the presenting problem and the reason supportive care
    is offered at all. The other surveillance items in the same recommendation
    do not transfer: scoliosis and odontoid hypoplasia are axial findings in a
    disease that spares the axial skeleton, and hearing assessment belongs to
    the neuromuscular and dysplasia phenotypes rather than to this one.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: annual clinical evaluation for joint pain
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Progressive Destructive Osteoarthropathy of the Digital Joints
    description: >-
      Surveillance detects progression of the arthropathy; it does not modify
      it, and no disease-modifying therapy exists.
  evidence:
  - reference: PMID:24830047
    reference_title: "Autosomal Dominant TRPV4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment; and assessment of weight, height, and weight-for-height at each visit."
    explanation: >-
      The surveillance recommendation this entry takes the joint-pain item from.
      Quoted in full so the items deliberately not carried over to FDAB are
      visible rather than silently dropped.
- name: Physical Therapy for Digital Joint Function
  description: >-
    Physical therapy and exercise as tolerated are used to maintain function in
    the TRPV4 skeletal disorders. In FDAB the target is hand and foot function
    as the digital joints deteriorate.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:24830047
    reference_title: "Autosomal Dominant TRPV4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For skeletal dysplasias, additional treatment includes physical therapy/exercise and heel cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present."
    explanation: >-
      GeneReviews recommends physical therapy and exercise to maintain function
      across the TRPV4 skeletal dysplasias, of which FDAB is one; the surgical
      thresholds named in the same sentence concern spinal disease FDAB does not
      produce.
- name: Genetic Counseling
  description: >-
    Counseling covers autosomal dominant transmission and the 50% recurrence
    risk to each child of an affected individual. Molecular confirmation matters
    here because the clinically overlapping differential, Thiemann disease, has
    no identified gene.
  therapeutic_modality: OTHER
  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: >-
      Gives the recurrence-risk figure counseling communicates.
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing of an affected individual will be crucial in order to provide accurate reproductive genetic counselling about the autosomal dominant nature of this condition."
    explanation: >-
      States that molecular testing is needed to give accurate reproductive
      counseling in this phenotype.
discussions:
- discussion_id: disc_fdab_channel_direction
  prompt: >-
    Do the FDAB ankyrin-repeat-domain variants reduce or increase TRPV4 channel
    activity, and how should the pathophysiology node be graded while the two
    published accounts disagree?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#TRPV4 Ankyrin Repeat Domain Missense Variants
  - pathophysiology#Reduced TRPV4 Channel Responsiveness
  rationale: >-
    The gene-discovery study measured poor cell-surface localization, reduced
    agonist-evoked calcium influx, and no response to hypotonic stress for all
    three FDAB alleles, and framed FDAB as the phenotype produced by TRPV4
    mutations that reduce channel activity, in contrast to the gain-of-function
    skeletal dysplasias and neuropathies. A later structure-function survey
    instead treats pathogenic TRPV4 mutations as a class that gains channel
    function and is cytotoxic, and reports that gain-of-function
    ankyrin-repeat-domain mutations sit at charged residues in the RhoA
    interface while other residues of that domain have normal or reduced
    activity. That last finding cuts both ways for FDAB, whose alleles include
    the charged Arg271 alongside the uncharged Gly270 and Phe273. This entry
    grades the variant consequence as loss of function, following the only study
    that assayed the FDAB alleles themselves. Resolving the question needs those
    three alleles re-assayed in the newer framework rather than inference from
    the class-level claim.
  evidence:
  - reference: PMID:21964574
    reference_title: "Mutations in TRPV4 cause an inherited arthropathy of hands and feet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis."
    explanation: >-
      The reduced-activity position, stated by the only study that assayed the
      FDAB alleles.
  - reference: PMID:39021275
    reference_title: "Combined clinical, structural and cellular studies discriminate pathogenic and benign TRPV4 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients."
    explanation: >-
      The competing class-level position, which treats gain of function and
      cytotoxicity as the shared mechanism across TRPV4 channelopathies
      including arthropathy.
  - reference: PMID:39021275
    reference_title: "Combined clinical, structural and cellular studies discriminate pathogenic and benign TRPV4 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity."
    explanation: >-
      Narrows the disagreement to the ankyrin repeat domain specifically, and
      shows reduced activity is an expected outcome for some residues of that
      domain, which is where the FDAB alleles sit.
  - reference: PMID:22791502
    reference_title: "TRPV4-associated skeletal dysplasias."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious."
    explanation: >-
      Records that channel activation was already the majority finding across
      TRPV4 alleles while the genotype-phenotype logic remained unresolved,
      which is the background against which the FDAB result is an outlier.
- discussion_id: disc_fdab_follistatin_divergence
  prompt: >-
    Why does FDAB produce a joint-restricted osteoarthropathy rather than the
    growth-plate dysplasia other TRPV4 alleles cause?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Articular Cartilage Homeostasis
  - pathophysiology#Subchondral Destruction of the Phalangeal, Metacarpal and Metatarsal Heads
  rationale: >-
    The TRPV4 skeletal dysplasias act on growth-plate chondrocytes through
    calcium-dependent upregulation of follistatin, which inhibits BMP signaling
    and slows endochondral ossification. When an FDAB (arthropathy) allele was
    put through the same chondrocyte assay it left follistatin essentially
    unchanged, while three dysplasia alleles raised it two- to 2.3-fold. That
    single negative result is the clearest published evidence that FDAB reaches
    cartilage failure by a different route, and it fits the clinical picture:
    articular rather than growth-plate cartilage, normal stature, and a skeleton
    otherwise spared. The route FDAB does take is not established - the entry
    models it as failure of articular cartilage homeostasis on the strength of
    the gene-discovery paper's own interpretation, not on a demonstrated
    downstream pathway.
  evidence:
  - reference: PMID:24577120
    reference_title: "Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold)."
    explanation: >-
      The negative result for the arthropathy allele set against positive
      results for three dysplasia alleles in the same assay.
  - reference: PMID:11891693
    reference_title: "Familial digital arthropathy-brachydactyly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The remainder of the skeleton is not affected."
    explanation: >-
      The clinical counterpart of the assay result: no generalized skeletal
      dysplasia accompanies the digital arthropathy.
- discussion_id: disc_fdab_thiemann_identity
  prompt: >-
    Are familial digital arthropathy-brachydactyly and Thiemann disease one
    entity or two?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - phenotypes#Non-Inflammatory Digital Arthropathy
  - differential_diagnoses#Thiemann disease
  rationale: >-
    A father and son referred with a diagnosis of Thiemann disease carried a
    heterozygous TRPV4 variant previously reported to cause FDAB, and a review of
    nineteen published Thiemann cases found five whose clinical and radiological
    findings also fit FDAB. The authors propose the two labels may be phenotypic
    variability of one entity. It remains unresolved because no DNA could be
    obtained from any historical Thiemann case, so the hypothesis has not been
    tested against the population it would reclassify.
  evidence:
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis suggests that these two phenotypes may represent phenotypic variability of the same entity."
    explanation: >-
      States the proposed single-entity interpretation.
  - reference: PMID:31248428
    reference_title: "Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite many attempts to identify other reported patients affected by Thiemann disease, we were not able to procure DNA from any of the cases to verify our findings."
    explanation: >-
      States why the question remains open: the historical Thiemann cases could
      not be genotyped.
notes: >-
  FDAB is the mildest and most anatomically restricted member of the TRPV4
  allelic series, and the only one in which digital shortening is a downstream
  consequence of joint destruction rather than a primary growth-plate dysplasia.
  Two things about this entry are worth flagging to a reader. First, the
  functional direction of the FDAB alleles is contested, and the
  functional_impact_category of LOSS_OF_FUNCTION follows only the study that
  assayed those alleles; see disc_fdab_channel_direction. Second, the pathway
  between the channel defect and cartilage failure is not established - what is
  published is a negative result excluding the follistatin route the dysplasias
  use, not a positive account of the route FDAB takes; see
  disc_fdab_follistatin_divergence. No animal model of the FDAB alleles has been
  reported, so animal_models is intentionally empty.

  Curation provenance. No deep-research provider report was generated for this
  entry and none is committed under research/. The drafting run was cut short
  and the reference set was assembled directly from PubMed. That matters less
  here than it would elsewhere: FDAB's disease-specific literature is roughly
  seven papers and this entry cites all of them, so the risk a deep-research
  pass guards against - an unconsumed key paper - is small. Every snippet was
  verified as an exact substring of its cached reference.

  What the cached GeneReviews record does and does not support. The cached
  PMID:24830047 record is the PubMed abstract, carrying the chapter's Clinical
  Characteristics, Diagnosis, Management and Genetic Counseling summaries but
  not its full management section. Claims sourced to GeneReviews here are
  therefore limited to what those abstract sections say. An earlier version of
  the supportive-care treatment paraphrased GeneReviews as advising avoidance of
  stress on the affected joints; that paraphrase was not supported by the cached
  record and has been withdrawn rather than requoted, since the chapter text is
  not held in this repository.

  Parent naming. This entry uses the parent TRPV4-Related Bone Disorder where
  the sibling TRPV4 dysplasia entries use TRPV4-Related Skeletal Dysplasia. The
  divergence is deliberate and follows the entry's own argument: FDAB is not a
  dysplasia, since the digital shortening is secondary to joint destruction
  rather than a growth-plate lesion, so filing it under a dysplasia parent would
  assert exactly the classification this entry exists to reject.
datasets:
references:
- reference: PMID:24830047
  title: "Autosomal Dominant TRPV4-Related Disorders."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:24830047
Autosomal Dominant TRPV4-Related Disorders.
No top-level findings curated for this source.