An X-linked dominant chondrodysplasia with severe platyspondyly, a distinctive metaphyseal cupping of the short tubular bones, hydrocephaly and microphthalmia, described in one four-generation family. It is mechanistically unusual in two ways. First, the causal lesion is not in a coding sequence: a single base change in the 3' untranslated region of HDAC6 destroys the seed-match for hsa-miR-433, so the microRNA can no longer repress the transcript and HDAC6 protein is over-produced. It is, as far as the reporting authors could establish, the first skeletal disease attributed to the loss of a microRNA-mediated regulatory interaction rather than to a change in a protein. Second, the direction of effect is a gain rather than a loss: the downstream biochemical consequence measured in affected tissue is a profound reduction in acetylated alpha-tubulin, which is what an excess of a tubulin deacetylase should do. The X-linked dominant pattern is expressed with striking sex difference. Affected males died perinatally or had their pregnancies terminated for skeletal abnormalities and hydrocephaly; carrier females had short stature, sometimes body asymmetry, and mild cognitive impairment. In one affected female the asymmetry was traced to X-inactivation: fibroblasts from the hypotrophic left arm expressed the mutant allele in about a third of cells and overexpressed HDAC6, while fibroblasts from the unaffected right arm did not express it at all.
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name: X-linked Dominant Chondrodysplasia Chassaing-Lacombe Type
creation_date: "2026-09-21T00:00:00Z"
description: >-
An X-linked dominant chondrodysplasia with severe platyspondyly, a distinctive
metaphyseal cupping of the short tubular bones, hydrocephaly and microphthalmia,
described in one four-generation family. It is mechanistically unusual in two
ways. First, the causal lesion is not in a coding sequence: a single base change
in the 3' untranslated region of HDAC6 destroys the seed-match for hsa-miR-433,
so the microRNA can no longer repress the transcript and HDAC6 protein is
over-produced. It is, as far as the reporting authors could establish, the first
skeletal disease attributed to the loss of a microRNA-mediated regulatory
interaction rather than to a change in a protein. Second, the direction of
effect is a gain rather than a loss: the downstream biochemical consequence
measured in affected tissue is a profound reduction in acetylated alpha-tubulin,
which is what an excess of a tubulin deacetylase should do.
The X-linked dominant pattern is expressed with striking sex difference. Affected
males died perinatally or had their pregnancies terminated for skeletal
abnormalities and hydrocephaly; carrier females had short stature, sometimes body
asymmetry, and mild cognitive impairment. In one affected female the asymmetry
was traced to X-inactivation: fibroblasts from the hypotrophic left arm expressed
the mutant allele in about a third of cells and overexpressed HDAC6, while
fibroblasts from the unaffected right arm did not express it at all.
category: Mendelian
parents:
- Chondrodysplasia
disease_term:
preferred_term: X-linked dominant chondrodysplasia, Chassaing-Lacombe type
term:
id: MONDO:0010463
label: X-linked dominant chondrodysplasia, Chassaing-Lacombe type
synonyms:
- CDPX-Chassaing-Lacombe
- X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly and microphthalmia
- HDAC6-related X-linked chondrodysplasia
notes: >-
Entry scope. Curated as a single DISEASE. The stub recorded no MONDO descendants
and one causal gene, hgnc:14064 HDAC6 (read from
stubs/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type.yaml). The entire
published literature on the disorder is two papers about one family - the
clinical description (PMID:16001442) and the molecular identification
(PMID:20181727) - so there is one pathograph and no basis for subtypes.
The evidence base is a single pedigree and the entry is written to make that
visible rather than to read like a characterised disease. Nothing here has been
replicated in a second family. The genotype-phenotype attribution rests on
segregation across four generations plus three lines of functional work in the
molecular paper, which is strong for an n-of-1 family but is not independent
replication.
The biggest gap is deliberately left open rather than papered over. There is a
measured molecular consequence (alpha-tubulin hypoacetylation in affected fetal
tissue) and a well-described skeletal phenotype, and no published work connects
them in this disease. No chondrocyte or growth-plate study of this variant
exists. The pathograph therefore stops at the biochemical node, and two
candidate bridges - HDAC6 stabilizing FGFR3, and HDAC6 driving primary-cilium
disassembly - are recorded as EMERGING entries in `mechanistic_hypotheses` and
as a knowledge gap with proposed experiments, not as causal edges.
An earlier draft of this note said flatly that no animal model of the mechanism
had been made and that every published manipulation removes or inhibits HDAC6.
That was wrong, and the correction is worth reading before the gap statement
above is taken at face value. PMID:41342396 (2026) reports a conditional
miR-433 tough-decoy mouse restricted to Prrx1-expressing skeletal progenitors,
which reduces miR-433 activity - the same regulatory interaction the human
variant destroys - raises Hdac6, and produces shortened, narrower femurs with
disorganized growth plates. It is curated in `animal_models` as
PARTIALLY_RECAPITULATES with typed divergences, because the decoy de-represses
the whole miR-433 target set rather than HDAC6 alone.
So the honest position is narrower than "nothing connects them": losing miR-433
activity in cartilage is now shown to be sufficient for a growth-plate
phenotype in a mammal, and what remains unshown is that the HDAC6 component of
that is what does it. The gap moved; it did not close.
Module conformance checked and left unset. `just list-modules` was read and
`kb/modules/` grepped for `chondro`, `cartilage`, `growth plate`, `endochondral`,
`microtubule`, `tubulin`, `cilia` and `deacetyl`. The ciliopathy module
(`ciliopathy_dysfunction`) is the nearest thematic neighbour and was rejected
on positive grounds: HDAC6 does act on ciliary disassembly, but nothing in either
paper about this disease examines cilia, and conforming on the strength of a
general HDAC6 property would assert a mechanism the disease's own literature
does not.
No GeneReviews chapter exists for this disorder. Checked offline with
`just check-genereviews kb/disorders/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type.yaml`
against the committed Bookshelf index; it reports NO_CHAPTER. The phenotype
baseline is the 2005 clinical description of the family.
Ontology note on the `Alpha-Tubulin Hypoacetylation` node, and two corrections
to earlier drafts of this note - the second of which is a negative-existence
claim that was false.
The binding is `GO:0071929 alpha-tubulin acetylation` with
`modifier: DECREASED`. Two earlier versions were wrong in different ways.
The first bound `GO:0006476 protein deacetylation`, over-broad for a node whose
claim is about tubulin. The second bound `GO:0090042 tubulin deacetylation`
with `modifier: INCREASED` and asserted that "GO has no alpha-tubulin-specific
process term". That assertion was made on the strength of a search for
`l~tubulin deacetylation` alone, and it is false:
`runoak -i ols:go search 'l~alpha-tubulin'` returns `GO:0071929 alpha-tubulin
acetylation` and `GO:0043014 alpha-tubulin binding`.
What is true, and is the narrower claim the earlier note should have made:
GO has no alpha-tubulin-specific *deacetylation* term. It has the
alpha-tubulin-specific acetylation process (`GO:0071929`) and the
tubulin-general deacetylation process (`GO:0090042`), and no term combining
both.
`GO:0071929` with `DECREASED` was chosen over `GO:0090042` with `INCREASED`
because it matches the measured quantity exactly. PMID:20181727 reports that
"the level of acetylated alpha-tubulin was found to be profoundly decreased" -
the measurement is alpha-tubulin acetylation, falling. The deacetylase
*activity* driving it is separately bound as `GO:0042903 tubulin deacetylase
activity` on the node above, so nothing about the enzymatic step is lost by
binding the state node to the state that was measured.
Searches run, so the next reader does not have to repeat them:
`l~tubulin deacetylation` (returns GO:0090042, GO:0090043, GO:0090044,
GO:1904428, GO:0042903), `l~alpha-tubulin` (GO:0071929, GO:0043014),
`l~tubulin acetyl` (GO:0019799, GO:0071929, GO:0120519).
Deep-research provenance.
`research/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type-deep-research-openscientist.md`
(provider openscientist, 14 citations, all 14 resolved, confabulation rate 0.0).
`just preflight-dr` returns PASS against MONDO:0010463, with HDAC6 mentioned 81
times and no rival gene above 9.
Reconciling it against this entry contributed two things and was declined on a
third. It supplied the Hdac6-knockout mouse (PMID:18180281), which sharpens the
dosage argument considerably and is curated in `animal_models`; and it supplied
the primary-cilium bridge (PMID:17604723), now carried alongside the FGFR3 one
as a second EMERGING hypothesis rather than instead of it. Its own causal chain
marks steps 4-6 [INFERRED] and states that the ciliary-Hedgehog mechanism is
"inferred, not directly demonstrated in patients", which is the same reading
this entry had already reached independently and is why `conforms_to
ciliopathy_dysfunction` stays unset.
What was NOT taken from it: its phenotype table lists intrauterine growth
retardation, macrocephaly, frontal bossing, low-set ears, thin ribs, eleven rib
pairs, iliac wing hypoplasia and poor skull mineralization, attributing them to
PMID:16001442 and the OMIM 300863 clinical synopsis. Those features are almost
certainly real, but none of them appears in the cached abstract of
PMID:16001442, which is the only text this repository can verify a snippet
against, and OMIM clinical synopses are not a citable quotable source here. They
are left out rather than curated against a quote that does not exist. The same
applies to its LOD score of 3.30 and its bone-histology description. This is a
genuine coverage cost of the exact-quote rule and it is recorded rather than
worked around.
It also reports a ClinVar missense candidate, NM_006044.4(HDAC6):c.2090C>T
(p.Thr697Ile), RCV001198391, annotated to this disease and not independently
validated. Not curated; recorded in `discussions`.
references:
- reference: PMID:16001442
title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
tags: []
findings:
- statement: >-
The clinical description: one family, four affected males and six affected
females over four generations, with severe platyspondyly and distinctive
metaphyseal cupping in males who died perinatally, and short stature with
body asymmetry in the less severely affected females.
- reference: PMID:20181727
title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
tags: []
findings:
- statement: >-
The molecular identification. A 3'-UTR variant in the hsa-miR-433 seed site
of HDAC6 segregating fully with the disease, reporter assays showing loss of
miR-433 repression, HDAC6 over-expression with profoundly reduced acetylated
alpha-tubulin in affected fetal thymus, and allele-specific expression in
fibroblasts from the two arms of an asymmetric female.
- reference: PMID:12024216
title: "HDAC6 is a microtubule-associated deacetylase."
tags: []
findings:
- statement: >-
Establishes the enzymatic identity this disease depends on: HDAC6 is the
tubulin deacetylase, and its overexpression causes global deacetylation of
alpha-tubulin.
- reference: PMID:27506979
title: "HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia."
tags: []
findings:
- statement: >-
Cited for the untested hypothesis only. Shows that FGFR3 accumulation depends
on HDAC6 and that deleting or inhibiting HDAC6 improves growth-plate bone
growth in a mouse chondrodysplasia model - the inverse manipulation to the one
this disease represents.
- reference: PMID:18180281
title: "Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally."
tags: []
findings:
- statement: >-
The dosage control. Mice with no HDAC6 at all are viable and fertile with
hyperacetylated tubulin in most tissues, and losing the gene produces only a
small increase in cancellous bone mineral density - which the authors read as
a minor role in bone biology. Losing HDAC6 is close to silent in the skeleton;
having too much of it is lethal in males.
- reference: PMID:17604723
title: "HEF1-dependent Aurora A activation induces disassembly of the primary cilium."
tags: []
findings:
- statement: >-
Cited for the second untested hypothesis only. Establishes that HDAC6 is the
effector of regulated ciliary resorption, activated at the basal body by an
Aurora A / HEF1 pathway that is necessary and sufficient for disassembly, and
that inhibiting HDAC6 stabilizes cilia.
- reference: PMID:41342396
title: "miR-433 targets BMP and Indian hedgehog signaling to coordinate murine postnatal growth plate dynamics."
tags: []
findings:
- statement: >-
The closest thing to an animal model of this disease. A conditional miR-433
tough-decoy mouse, restricted to Prrx1-expressing skeletal progenitors,
raises Hdac6 among other validated miR-433 targets and produces shortened,
narrower femurs with disorganized growth plates - reaching the skeleton
through the same regulatory route the human variant does, loss of miR-433
activity, rather than through HDAC6 directly.
- reference: PMID:29406621
title: "MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma."
tags: []
findings:
- statement: >-
Independent confirmation that loss of miR-433 specifically - not HDAC6
manipulation in general - raises HDAC6 and causes loss of primary cilia, and
that restoring the microRNA restores the cilia. Cited for the ciliary
hypothesis.
inheritance:
- name: X-linked dominant
inheritance_term:
preferred_term: X-linked dominant inheritance
term:
id: HP:0001423
label: X-linked dominant inheritance
description: >-
Transmitted through four generations with both sexes affected and a marked
sex difference in severity: affected males died in the perinatal period or had
pregnancies terminated, affected females survived with a milder phenotype. The
variant is in the 3' untranslated region and segregates completely with the
disease in the family.
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were affected through four generations."
explanation: "Establishes the inheritance pattern and the numbers of affected individuals of each sex."
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease."
explanation: "Complete segregation of the variant with the phenotype in the pedigree."
mechanistic_hypotheses:
- hypothesis_group_id: hdac6_fgfr3_stabilization
hypothesis_label: HDAC6 excess acts on the growth plate by stabilizing FGFR3
status: EMERGING
description: >-
Nothing published connects the measured tubulin hypoacetylation in this disease
to its skeletal phenotype. The most economical bridge is FGFR3. In a mouse model
of thanatophoric dysplasia, FGFR3 accumulation depends on HDAC6: cells lacking
HDAC6, or treated with an HDAC6 inhibitor, degrade FGFR3 through a
lysosome-dependent route, and deleting HDAC6 or giving tubacin reduces FGFR3 in
the growth plate and improves endochondral bone growth. That is the inverse of
the manipulation this disease represents, so an excess of HDAC6 would be
predicted to stabilize FGFR3 and push signalling in the direction that already
causes the FGFR3 chondrodysplasias - the group this disorder's radiographic
phenotype most resembles.
It is recorded as EMERGING and not as a causal edge because it is an inference
across two literatures. FGFR3 has never been measured in tissue from this
family, the growth plate has never been examined, and the direction of effect
has only ever been tested by removing HDAC6, not by over-expressing it in
chondrocytes. It is offered as the experiment worth doing, not as what is
happening.
evidence:
- reference: PMID:27506979
reference_title: "HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth."
explanation: "The whole basis of the hypothesis, and the reason it is INDIRECT: the manipulation is HDAC6 removal in a different disease model, and the inference to HDAC6 excess in this disease is the curator's, not the authors'."
- hypothesis_group_id: hdac6_ciliary_resorption
hypothesis_label: HDAC6 excess acts on the growth plate by destabilizing the primary cilium
status: EMERGING
description: >-
The second candidate bridge across the same gap, and the one an independent
deep-research pass proposed. HDAC6 is the effector of regulated primary-cilium
disassembly: at the ciliary basal body, HEF1/NEDD9 and Aurora A phosphorylate
and activate it, and that pathway is reported to be both necessary and
sufficient for ciliary resorption, with HDAC6 inhibitors stabilizing cilia.
Growth-plate chondrocytes depend on the primary cilium for Hedgehog signalling,
so constitutively elevated HDAC6 would be predicted to shorten or destabilize
chondrocyte cilia and attenuate that signal.
It is attractive because it explains the tubulin phenotype and the skeletal
phenotype with one mechanism, where the FGFR3 hypothesis explains the skeletal
phenotype through a route that does not obviously involve tubulin acetylation
at all. It is recorded as EMERGING for the same reason: no cilium has been
examined in any tissue from this family, the Aurora A/HEF1 work is in
tumour-derived cells rather than chondrocytes, and the inference is from
HDAC6's general biology rather than from anything measured in this disease.
The two hypotheses are not mutually exclusive, and are deliberately both
recorded rather than adjudicated. Neither has been tested.
evidence:
- reference: PMID:17604723
reference_title: "HEF1-dependent Aurora A activation induces disassembly of the primary cilium."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "we show that interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly"
explanation: "Establishes HDAC6 as the effector of ciliary disassembly, which is the whole basis of the hypothesis. INDIRECT: the inference to chondrocyte cilia in this disease is the curator's, not the authors'."
- reference: PMID:17604723
reference_title: "HEF1-dependent Aurora A activation induces disassembly of the primary cilium."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Moreover, we demonstrate that small molecule inhibitors of AurA and HDAC6 selectively stabilize cilia from regulated resorption cues, suggesting a novel mode of action for these clinical agents."
explanation: "Shows the relationship is pharmacologically reversible, which is what would make the hypothesis testable and, if true, actionable."
- reference: PMID:29406621
reference_title: "MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype."
explanation: "The strongest support for this hypothesis, and the reason it is not merely general HDAC6 biology: loss of miR-433 itself - the same regulatory interaction this disease destroys - raises HDAC6 and removes cilia, and restoring the microRNA restores them. INDIRECT because the cells are cholangiocarcinoma, not chondrocytes."
- reference: PMID:29406621
reference_title: "MicroRNA (miR)-433 and miR-22 dysregulations induce histone-deacetylase-6 overexpression and ciliary loss in cholangiocarcinoma."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6)."
explanation: "States the HDAC6-excess-to-ciliary-loss relationship in a tissue where it was measured rather than inferred."
pathophysiology:
- name: Loss of miR-433 Repression at the HDAC6 3' UTR
biological_scale: MOLECULAR
role: Initiating genetic lesion
description: >-
The single base substitution c.*281A>T falls inside the seed-match for
hsa-miR-433 in the HDAC6 3' untranslated region. In reporter assays miR-433
represses both endogenous HDAC6 and a construct carrying the wild-type 3' UTR,
and that repression is abolished when the construct carries the mutant 3' UTR.
The coding sequence is untouched: the protein that gets made is normal, there
is simply more of it.
genetic_context:
gene:
preferred_term: HDAC6
term:
id: hgnc:14064
label: HDAC6
variant_origin: GERMLINE
allele_type: SNV
zygosity: HEMIZYGOUS
functional_impact_category: HYPERMORPHIC
description: >-
A non-coding regulatory allele. HYPERMORPHIC rather than GAIN_OF_FUNCTION
because the protein's activity is unaltered - only its abundance increases.
Zygosity is recorded as hemizygous for the affected males; carrier females are
heterozygous and mosaic by X-inactivation, which is modelled as its own node.
genes:
- preferred_term: HDAC6
term:
id: hgnc:14064
label: HDAC6
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The variant is located in the seed sequence of hsa-miR-433."
explanation: "Places the variant precisely in the regulatory element whose loss this node asserts."
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3'-UTR."
explanation: "The reporter experiment demonstrating that the variant abolishes miR-433 repression, rather than merely sitting in a predicted binding site."
downstream:
- target: HDAC6 Overexpression
description: Derepression of the transcript raises HDAC6 protein levels.
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3'-UTR of HDAC6"
explanation: "Establishes that miR-433 normally holds HDAC6 down, so losing the site raises it."
- name: HDAC6 Overexpression
biological_scale: MOLECULAR
role: Primary molecular consequence
description: >-
HDAC6 protein is over-expressed in affected tissue. This was shown in two
independent materials from the family: thymus from an affected male fetus, and
fibroblasts cultured from the hypotrophic arm of an asymmetric affected female.
molecular_functions:
- preferred_term: HDAC6 tubulin deacetylase activity
term:
id: GO:0042903
label: tubulin deacetylase activity
modifier: INCREASED
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus."
explanation: "Direct measurement of the protein excess in tissue from an affected individual."
- reference: PMID:12024216
reference_title: "HDAC6 is a microtubule-associated deacetylase."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
snippet: "In vivo, the overexpression of HDAC6 leads to a global deacetylation of alpha-tubulin, whereas a decrease in HDAC6 increases alpha-tubulin acetylation."
explanation: "Independent cell-biology establishing that HDAC6 excess is sufficient to deacetylate alpha-tubulin globally. INDIRECT because it is not this disease's tissue."
downstream:
- target: Alpha-Tubulin Hypoacetylation
description: >-
An excess of the tubulin deacetylase strips the acetyl mark from alpha-tubulin.
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased."
explanation: "The acetylation change measured in the same affected tissue as the protein excess."
- name: Alpha-Tubulin Hypoacetylation
biological_scale: MOLECULAR
role: Terminal measured molecular abnormality
description: >-
Acetylated alpha-tubulin is profoundly reduced in affected fetal tissue while
total alpha-tubulin rises. Acetylation marks stable microtubule populations, so
this is a shift of the cytoskeleton toward a more dynamic, less stable state.
This is where the evidenced chain stops. No published work links this change to
cartilage, the growth plate, or any of the skeletal features, in this disease or
in any model of it. The node is curated as the last thing actually measured, and
the gap between it and the phenotype is recorded in `discussions` rather than
bridged with a plausible-sounding edge.
biological_processes:
- preferred_term: alpha-tubulin acetylation
term:
id: GO:0071929
label: alpha-tubulin acetylation
modifier: DECREASED
cellular_components:
- preferred_term: microtubule
term:
id: GO:0005874
label: microtubule
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "the level of acetylated alpha-tubulin was found to be profoundly decreased"
explanation: "The measurement itself, in tissue from an affected fetus."
- reference: PMID:12024216
reference_title: "HDAC6 is a microtubule-associated deacetylase."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Acetylated alpha-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts."
explanation: "Supplies the interpretation of the measurement - what losing the acetyl mark means for microtubule stability."
- name: Mosaic HDAC6 Overexpression by Random X-Inactivation
biological_scale: CELLULAR
role: Modifier of expressivity in females
description: >-
Carrier females are cellular mosaics for which X is active, so the proportion of
cells over-expressing HDAC6 varies between tissues and between body regions. In
the one female studied this produced measurable left-right asymmetry: fibroblasts
from the hypotrophic left arm expressed the mutant allele in 31% of cells and
over-expressed HDAC6, while fibroblasts from the normal right arm did not express
it at all. This is the mechanism of the milder and patchier female phenotype, and
it is directly evidenced rather than assumed.
biological_processes:
- preferred_term: random X-inactivation in carrier females
term:
id: GO:0060816
label: random inactivation of X chromosome
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm."
explanation: "Allele-specific expression measured separately in the affected and unaffected limb of the same patient - an internally controlled demonstration that the asymmetry tracks allelic expression."
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs."
explanation: "Establishes the clinical asymmetry that the allele-specific expression explains."
downstream:
- target: Lower limb asymmetry
description: Regional differences in the proportion of cells over-expressing HDAC6.
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Overexpression of HDAC6 was observed in left arm-derived fibroblasts."
explanation: "Links the regional overexpression to the hypotrophic side."
animal_models:
- name: Hdac6-knockout mouse
species: Mouse
genotype: Hdac6 global knockout (homologous recombination in ES cells)
publication: PMID:18180281
description: >-
The dosage control rather than a disease model, and it is curated because of
what it does not show. Mice with no HDAC6 at all are viable and fertile, with
hyperacetylated tubulin in most tissues - the exact mirror of the biochemical
state measured in affected fetal tissue in this disease. Losing the gene
produces only a small increase in cancellous bone mineral density, which the
authors describe as a minor role in bone biology.
Two things follow. The skeleton tolerates complete absence of HDAC6 almost
without comment, so the severe skeletal disease here cannot be a loss of
function and must be a consequence of excess - which is the argument for
`HYPERMORPHIC` on the lesion node. And no mouse exists that models the disease:
every published manipulation removes or inhibits HDAC6, none over-expresses it
in cartilage.
modeled_mechanisms:
- target: HDAC6 Overexpression
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
model_scale: ORGANISM
description: >-
The knockout is the opposite manipulation to the disease lesion. It is
informative about HDAC6 dosage and uninformative about this disorder's
pathogenesis.
limitations: >-
Removing HDAC6 cannot model over-expressing it, and the resulting tubulin
state is hyperacetylation rather than the hypoacetylation measured in
patients. The animal is normal where the disease is lethal, so the model has
no phenotype to compare. It is curated as a negative control on the direction
of effect, not as a model of the disease.
evidence:
- reference: PMID:18180281
reference_title: "Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: "HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues."
explanation: "A REFUTE item against any reading of this disease as HDAC6 loss of function: losing HDAC6 entirely produces a normal, fertile animal."
- reference: PMID:18180281
reference_title: "Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Furthermore, the lack of HDAC6 results in a small increase in cancellous bone mineral density, indicating that this deacetylase plays a minor role in bone biology."
explanation: "Quantifies how little the skeleton depends on HDAC6 being present, which is what makes the severity of the excess phenotype notable."
- name: miR-433 tough-decoy mouse (Prrx1-restricted)
species: Mouse
genotype: Conditional miR-433 tough-decoy competitive inhibitor, expressed in Prrx1-lineage skeletal progenitors
publication: PMID:41342396
description: >-
The closest existing model of this disease, and the reason the gap between
HDAC6 excess and the skeletal phenotype is now narrower than it looks from the
two disease papers alone. Rather than manipulating HDAC6, this model removes
miR-433 activity in skeletal progenitors - the same regulatory interaction the
human c.*281A>T variant destroys - and Hdac6 rises among the validated miR-433
targets. The animals have shortened, narrower femurs with disorganized growth
plates, fewer resting-zone cells, hypertrophic-like cells in the proliferative
zone and delayed secondary ossification.
It is not a model of the human variant. The decoy inhibits miR-433 globally in
that lineage, so Runx2 and Hif1a rise alongside Hdac6 and Bmpr1a and Ihh are
directly de-repressed. The skeletal phenotype is therefore produced by the
whole miR-433 target set, and the Hdac6 contribution to it is not separated
out. What it does establish is that losing miR-433 activity in cartilage is
sufficient for a growth-plate phenotype, which the human disease requires and
which nothing previously showed.
modeled_mechanisms:
- target: HDAC6 Overexpression
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Reproduces the regulatory lesion - loss of miR-433 activity raising Hdac6 -
in the right lineage, and reaches a growth-plate phenotype.
limitations: >-
Hdac6 is one of several miR-433 targets de-repressed here, so the model
cannot attribute the skeletal phenotype to HDAC6. It also inhibits the
microRNA rather than disrupting its binding site, which is the opposite end
of the same interaction, and it is a mouse growth plate rather than a human
one. The human disease's defining features - platyspondyly, metaphyseal
cupping, hydrocephaly, microphthalmia, male lethality - are not reported.
divergences:
- divergence_type: PROXY_QUANTITY
materiality: QUALIFYING
description: >-
The model's quantity is total miR-433 activity in the Prrx1 lineage. The
node's quantity is HDAC6 protein abundance. They move together here, but
the model changes several other targets by the same stroke, so its
skeletal readout is not a readout of HDAC6 dosage.
- divergence_type: BOUNDARY_OMISSION
materiality: QUALIFYING
description: >-
Vertebral body development, the cranial and ocular phenotypes, and the
sex-limited lethality are outside what this model reports. Femoral length
and growth-plate zonation are what it measures.
readouts:
- name: Hdac6 expression in miR-433-inhibited skeletal progenitors
target: HDAC6 Overexpression
direction: INCREASED
interpretation: >-
Confirms in a mammal that reducing miR-433 activity raises Hdac6, which is
the step the human 3' UTR variant achieves by destroying the binding site.
evidence:
- reference: PMID:41342396
reference_title: "miR-433 targets BMP and Indian hedgehog signaling to coordinate murine postnatal growth plate dynamics."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These defects were accompanied by elevated expression of Sox9, Ihh, PTHrP, Bmpr1a, as well as increased expression of validated miR-433 targets Runx2, Hdac6, and Hif1a."
explanation: "Records the Hdac6 increase, and in the same sentence the other targets that rise with it - which is why the link is PARTIALLY_RECAPITULATES."
evidence:
- reference: PMID:41342396
reference_title: "miR-433 targets BMP and Indian hedgehog signaling to coordinate murine postnatal growth plate dynamics."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Male and female mice expressing miR-433 TuD in Prrx1-expressing skeletal progenitors and their progeny exhibited shortened and narrower femurs, while a significantly decreased trabecular bone volume was only apparent in males."
explanation: "The skeletal phenotype produced by inhibiting miR-433 in skeletal progenitors, which is what makes this model informative for a disease caused by losing a miR-433 binding site."
- reference: PMID:41342396
reference_title: "miR-433 targets BMP and Indian hedgehog signaling to coordinate murine postnatal growth plate dynamics."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Male miR-433 decoy mice had disorganized growth plates with fewer resting zone cells, abnormal hypertrophic-like cells in the proliferative zone, and delayed secondary ossification center development."
explanation: "The growth-plate histology, which is the tissue-level phenotype this disease's own literature never examined."
phenotypes:
- name: Platyspondyly
category: Radiographic
description: >-
Severe flattening of the vertebral bodies, the dominant radiographic feature in
affected males.
diagnostic: true
phenotype_term:
preferred_term: Platyspondyly
term:
id: HP:0000926
label: Platyspondyly
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges."
explanation: "The radiographic finding in the four affected males."
- name: Metaphyseal cupping
category: Radiographic
description: >-
Cupping of the metaphyses of the metacarpals, metatarsals and phalanges. The
clinical report singles this out as distinctive, which makes it the
discriminating radiographic sign for this disorder among the chondrodysplasias.
diagnostic: true
phenotype_term:
preferred_term: Metaphyseal cupping
term:
id: HP:0003021
label: Metaphyseal cupping
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges."
explanation: "Names the bones involved and the authors' own description of it as distinctive."
- name: Brachydactyly
category: Clinical
description: >-
Short digits. The describing authors call this feature "distinctive
brachydactyly" and put it in their title, but the word itself appears only
there; what the abstract documents is the underlying radiographic finding -
metaphyseal cupping of the metacarpals, metatarsals and phalanges, which are
the bones of the digital rays. The evidence below quotes that finding rather
than the title, so the inference from bone involvement to the clinical sign is
marked INDIRECT and left visible.
phenotype_term:
preferred_term: Brachydactyly
term:
id: HP:0001156
label: Brachydactyly
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges."
explanation: "Documents abnormality of the metacarpals, metatarsals and phalanges - the bones whose shortening constitutes brachydactyly. INDIRECT because the quoted sentence reports the radiographic lesion, not the clinical sign."
- name: Hydrocephalus
category: Clinical
description: >-
Present in the affected male fetuses and one of the findings that prompted
termination of three pregnancies.
diagnostic: true
phenotype_term:
preferred_term: Hydrocephalus
term:
id: HP:0000238
label: Hydrocephalus
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies."
explanation: "Hydrocephaly detected antenatally in three affected males."
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia."
explanation: "Hydrocephaly in all four of the severely affected male patients."
- name: Microphthalmia
category: Clinical
description: Small globes, present in all four severely affected males.
phenotype_term:
preferred_term: Microphthalmia
term:
id: HP:0000568
label: Microphthalmia
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia."
explanation: "Microphthalmia in the four affected males."
- name: Abnormal facial shape
category: Clinical
description: >-
A recognisable facial appearance in affected males, described alongside the
microphthalmia but not itemised further in the source.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia."
explanation: "The source records distinctive facial features but does not enumerate them, which is why the binding stays at the generic term."
- name: Short stature
category: Clinical
description: >-
The principal feature in carrier females, who survive and are substantially less
severely affected than males. Recorded at disease level rather than against a
subtype: no `has_subtypes` rows are declared here, and the sex difference is
modelled mechanistically by the X-inactivation mosaicism node instead.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation."
explanation: "Small stature as the female phenotype."
- name: Lower limb asymmetry
category: Clinical
description: >-
Body asymmetry in affected females, with hypotrophy of the limbs on one side.
In the one female studied molecularly this tracked the proportion of cells
expressing the mutant allele, so the asymmetry is a direct readout of
X-inactivation mosaicism rather than an incidental finding.
phenotype_term:
preferred_term: Lower limb asymmetry
term:
id: HP:0100559
label: Lower limb asymmetry
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation."
explanation: "Body asymmetry recorded as a variable feature of affected females."
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs."
explanation: "The specific asymmetric limb hypotrophy in the female studied for allele-specific expression."
- name: Intellectual disability
category: Clinical
description: >-
Mild cognitive impairment in affected females. The source uses the older term
"mild mental retardation"; it is bound to the current HPO concept here.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
severity: MILD
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation."
explanation: "Records mild cognitive impairment as a variable feature in affected females."
genetic:
- name: HDAC6
gene_term:
preferred_term: HDAC6
term:
id: hgnc:14064
label: HDAC6
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: A 3' UTR variant (c.*281A>T) in the hsa-miR-433 seed site, causing HDAC6 over-expression
presence: Positive
inheritance:
- name: X-linked dominant
inheritance_term:
preferred_term: X-linked dominant inheritance
term:
id: HP:0001423
label: X-linked dominant inheritance
notes: >-
The gene-disease relationship rests on one family. It is recorded as CAUSATIVE
rather than hedged because the molecular paper supplies segregation plus three
converging functional results - reporter assays, protein and acetylation
measurement in affected tissue, and allele-specific expression correlating with
a clinical asymmetry within one patient. What it does not supply is a second
family, so the confidence is in the mechanism rather than in the epidemiology.
Note that this is a non-coding regulatory allele: a coding-region-only analysis
would not find it, which is worth knowing for anyone re-analysing an
unsolved chondrodysplasia.
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia."
explanation: "The authors' own attribution, stated with the hedge they chose."
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1."
explanation: "The prior linkage interval within which HDAC6 was found, establishing that the gene was located by mapping rather than picked as a candidate."
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
One family. Ten affected individuals across four generations - four males and
six females - and no second family has been reported since the 2010 molecular
paper. PubMed was searched for HDAC6 with chondrodysplasia, Chassaing and
platyspondyly on 2026-09-21 and returned only the two reports curated here plus
the unrelated FGFR3 mouse study. No rate is recorded because there is no
denominator.
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were affected through four generations."
explanation: "The entire case count for this disorder."
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This condition appears to be a previously unrecognized X-linked dominant chondrodysplasia."
explanation: "The authors' statement that the condition was new at the time of description, consistent with the ULTRA_RARE band."
clinical_burden:
burden_level: VARIABLE
rationale: >-
Sex splits the burden almost completely. In males the condition is lethal in the
perinatal period or before: three pregnancies were terminated after antenatal
detection of skeletal abnormalities and hydrocephaly, and the one male born
alive died at six days. In females it is a survivable condition of short
stature, sometimes asymmetry, and mild cognitive impairment. VARIABLE is the
honest level for a disorder whose burden is near-total in one sex and moderate
in the other; it should not be read as uncertainty about either.
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A fourth affected male died at 6 days of life."
explanation: "The outcome in the only affected male carried to term."
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation."
explanation: "The substantially lower burden in affected females."
diagnosis:
- name: Prenatal Ultrasonography
description: >-
In this family the disorder was detected antenatally in affected males by
ultrasound showing skeletal abnormalities together with hydrocephaly. Given the
perinatal lethality in males, imaging is how the condition presents rather than
how it is confirmed.
diagnosis_term:
preferred_term: prenatal ultrasonography
term:
id: NCIT:C17230
label: Ultrasound Imaging
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies."
explanation: "Antenatal detection of the combination that identifies an affected male."
- name: Skeletal Radiography
description: >-
Radiographs are what make the diagnosis specific: severe platyspondyly with
metaphyseal cupping of the metacarpals, metatarsals and phalanges is the
combination the describing authors treated as distinctive.
diagnosis_term:
preferred_term: skeletal survey radiography
term:
id: NCIT:C38101
label: X-Ray Imaging
evidence:
- reference: PMID:16001442
reference_title: "X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges."
explanation: "The radiographic pattern that distinguishes this chondrodysplasia."
- name: Targeted Sequencing of the HDAC6 3' Untranslated Region
description: >-
The causal allele is outside the coding sequence, in the 3' UTR. An exome that
does not extend into untranslated regions will not call it, and a filter that
drops non-coding variants will discard it if it is called. Confirmatory testing
in this family therefore requires the UTR to be sequenced and retained
deliberately.
diagnosis_term:
preferred_term: targeted sequencing of a non-coding regulatory region
term:
id: NCIT:C101293
label: Next Generation Sequencing
evidence:
- reference: PMID:20181727
reference_title: "A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease."
explanation: "Names the variant and its location outside the coding sequence, which is what makes targeted UTR sequencing necessary."
discussions:
- discussion_id: hdac6_tubulin_to_growth_plate_gap
status: OPEN
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Alpha-Tubulin Hypoacetylation
- phenotypes#Platyspondyly
prompt: >-
How does alpha-tubulin hypoacetylation, measured in fetal thymus, produce
platyspondyly and metaphyseal cupping? No published work examines cartilage,
the growth plate, or chondrocytes in this disorder.
rationale: >-
This is the load-bearing gap in the entry and the reason the pathograph has no
edge from the molecular node to any skeletal phenotype. Everything upstream is
measured: the variant, the loss of miR-433 repression, the protein excess, the
acetylation change. Everything downstream is described clinically. The join
between them is asserted nowhere in this disease, and the tissue in which the
biochemistry was measured - thymus, taken because it was what was available
from a terminated pregnancy - is not the tissue the disease is about.
The gap is narrower than it was. The miR-433 tough-decoy mouse
(PMID:41342396) shows that losing miR-433 activity in skeletal progenitors
raises Hdac6 and disorganizes the growth plate, so the regulatory lesion is
now known to be sufficient for a skeletal phenotype in a mammal. What it
cannot show is that HDAC6 is the target doing it: Runx2 and Hif1a rise in the
same animals, and Bmpr1a and Ihh are directly de-repressed. The question has
therefore moved from "does this route reach the growth plate" to "how much of
what happens there is HDAC6", which is a better question and a testable one.
It would still be easy to write an edge here from general knowledge about
microtubules in chondrocytes, and that edge would validate. It is left out
deliberately.
proposed_experiments:
- experiment_id: hdac6_chondrocyte_acetylation
name: Acetylated alpha-tubulin and HDAC6 levels in growth-plate cartilage from an affected fetus
description: >-
Repeat the measurement made in thymus on cartilage or growth plate from an
affected male, establishing whether the acetylation change occurs in the
tissue that is actually malformed. This is the minimum result that would
license a causal edge from the molecular node to the skeletal phenotypes.
readouts:
- name: Acetylated alpha-tubulin in growth-plate chondrocytes
target: pathophysiology#Alpha-Tubulin Hypoacetylation
direction: DECREASED
interpretation: >-
A reduction in cartilage comparable to that seen in thymus would extend the
evidenced chain into the affected tissue.
- experiment_id: hdac6_overexpression_chondrocyte
name: Chondrocyte-directed HDAC6 over-expression in a mouse, or Hdac6 rescue in the miR-433 decoy
description: >-
The disease-matched manipulation - raising HDAC6 in cartilage and nothing
else - has still not been done, and it is the experiment that would separate
the HDAC6 contribution from the rest of the miR-433 target set. Two routes.
Direct: over-express HDAC6 in chondrocytes and ask whether excess alone is
sufficient for the growth-plate phenotype. Subtractive, and cheaper now that
the decoy mouse exists: cross the miR-433 tough-decoy onto an Hdac6-null
background and ask how much of the femoral shortening and growth-plate
disorganization survives. Either would also let FGFR3 and ciliary length be
measured in the growth plate, testing both standing hypotheses in the same
animal.
readouts:
- name: Growth plate architecture and FGFR3 accumulation
target: pathophysiology#Alpha-Tubulin Hypoacetylation
direction: ALTERED
interpretation: >-
Shortened long bones with raised growth-plate FGFR3 would support the
FGFR3-stabilization hypothesis; a skeletal phenotype without an FGFR3
change would refute it while still confirming sufficiency.
- discussion_id: hdac6_single_family_replication
status: OPEN
kind: KNOWLEDGE_GAP
attaches_to:
- genetic#HDAC6
prompt: >-
Has any second family with this disorder, or any other pathogenic HDAC6 3' UTR
allele, been reported since 2010?
rationale: >-
The gene-disease relationship rests entirely on one pedigree. Sixteen years on,
a PubMed search for HDAC6 with chondrodysplasia, platyspondyly or Chassaing
(run 2026-09-21) returns no second family. That is expected for an ultra-rare
condition, but it also means the attribution has never been independently
tested, and that non-coding variants of this class are systematically invisible
to the coding-region analyses most diagnostic labs run - so absence of further
reports is weak evidence either way. Worth revisiting if a UTR-aware
reanalysis cohort is published.
- discussion_id: hdac6_clinvar_missense_candidate
status: OPEN
kind: OPEN_QUESTION
attaches_to:
- genetic#HDAC6
prompt: >-
ClinVar carries a missense candidate, NM_006044.4(HDAC6):c.2090C>T
(p.Thr697Ile), annotated to this disease. Is there allelic heterogeneity here
beyond the single 3' UTR variant?
rationale: >-
Surfaced by the deep-research pass for this entry, which reports it as
RCV001198391 and explicitly notes it was not independently validated there.
It is not curated in `genetic`, for two reasons. The ClinVar record was not
retrieved and read as part of this curation, so its assertion criteria,
submitter and classification are unknown here; and a coding missense allele
would be a mechanistically different lesion from a 3' UTR dosage variant -
it would change the protein rather than the amount of it - so adding it to
the same `genetic` row would assert an allelic series that has not been
argued.
Worth resolving, because it bears directly on the entry's framing. The whole
case for a hypermorphic dosage mechanism rests on the causal allele being
non-coding and the protein being normal. A validated pathogenic coding allele
would either widen the disease or indicate that the ClinVar annotation is
mis-assigned, and which of those it is changes how this entry should read.
Resolving it means reading the ClinVar record directly - submitter, review
status, evidence - not taking the count from a report.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Entry scope. Curated as a single DISEASE. The stub recorded no MONDO descendants and one causal gene, hgnc:14064 HDAC6 (read from stubs/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type.yaml). The entire published literature on the disorder is two papers about one family - the clinical description (PMID:16001442) and the molecular identification (PMID:20181727) - so there is one pathograph and no basis for subtypes. The evidence base is a single pedigree and the entry is written to make that visible rather than to read like a characterised disease. Nothing here has been replicated in a second family. The genotype-phenotype attribution rests on segregation across four generations plus three lines of functional work in the molecular paper, which is strong for an n-of-1 family but is not independent replication. The biggest gap is deliberately left open rather than papered over. There is a measured molecular consequence (alpha-tubulin hypoacetylation in affected fetal tissue) and a well-described skeletal phenotype, and no published work connects them in this disease. No chondrocyte or growth-plate study of this variant exists. The pathograph therefore stops at the biochemical node, and two candidate bridges - HDAC6 stabilizing FGFR3, and HDAC6 driving primary-cilium disassembly - are recorded as EMERGING entries in `mechanistic_hypotheses` and as a knowledge gap with proposed experiments, not as causal edges. An earlier draft of this note said flatly that no animal model of the mechanism had been made and that every published manipulation removes or inhibits HDAC6. That was wrong, and the correction is worth reading before the gap statement above is taken at face value. PMID:41342396 (2026) reports a conditional miR-433 tough-decoy mouse restricted to Prrx1-expressing skeletal progenitors, which reduces miR-433 activity - the same regulatory interaction the human variant destroys - raises Hdac6, and produces shortened, narrower femurs with disorganized growth plates. It is curated in `animal_models` as PARTIALLY_RECAPITULATES with typed divergences, because the decoy de-represses the whole miR-433 target set rather than HDAC6 alone. So the honest position is narrower than "nothing connects them": losing miR-433 activity in cartilage is now shown to be sufficient for a growth-plate phenotype in a mammal, and what remains unshown is that the HDAC6 component of that is what does it. The gap moved; it did not close. Module conformance checked and left unset. `just list-modules` was read and `kb/modules/` grepped for `chondro`, `cartilage`, `growth plate`, `endochondral`, `microtubule`, `tubulin`, `cilia` and `deacetyl`. The ciliopathy module (`ciliopathy_dysfunction`) is the nearest thematic neighbour and was rejected on positive grounds: HDAC6 does act on ciliary disassembly, but nothing in either paper about this disease examines cilia, and conforming on the strength of a general HDAC6 property would assert a mechanism the disease's own literature does not. No GeneReviews chapter exists for this disorder. Checked offline with `just check-genereviews kb/disorders/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type.yaml` against the committed Bookshelf index; it reports NO_CHAPTER. The phenotype baseline is the 2005 clinical description of the family. Ontology note on the `Alpha-Tubulin Hypoacetylation` node, and two corrections to earlier drafts of this note - the second of which is a negative-existence claim that was false. The binding is `GO:0071929 alpha-tubulin acetylation` with `modifier: DECREASED`. Two earlier versions were wrong in different ways. The first bound `GO:0006476 protein deacetylation`, over-broad for a node whose claim is about tubulin. The second bound `GO:0090042 tubulin deacetylation` with `modifier: INCREASED` and asserted that "GO has no alpha-tubulin-specific process term". That assertion was made on the strength of a search for `l~tubulin deacetylation` alone, and it is false: `runoak -i ols:go search 'l~alpha-tubulin'` returns `GO:0071929 alpha-tubulin acetylation` and `GO:0043014 alpha-tubulin binding`. What is true, and is the narrower claim the earlier note should have made: GO has no alpha-tubulin-specific *deacetylation* term. It has the alpha-tubulin-specific acetylation process (`GO:0071929`) and the tubulin-general deacetylation process (`GO:0090042`), and no term combining both. `GO:0071929` with `DECREASED` was chosen over `GO:0090042` with `INCREASED` because it matches the measured quantity exactly. PMID:20181727 reports that "the level of acetylated alpha-tubulin was found to be profoundly decreased" - the measurement is alpha-tubulin acetylation, falling. The deacetylase *activity* driving it is separately bound as `GO:0042903 tubulin deacetylase activity` on the node above, so nothing about the enzymatic step is lost by binding the state node to the state that was measured. Searches run, so the next reader does not have to repeat them: `l~tubulin deacetylation` (returns GO:0090042, GO:0090043, GO:0090044, GO:1904428, GO:0042903), `l~alpha-tubulin` (GO:0071929, GO:0043014), `l~tubulin acetyl` (GO:0019799, GO:0071929, GO:0120519). Deep-research provenance. `research/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type-deep-research-openscientist.md` (provider openscientist, 14 citations, all 14 resolved, confabulation rate 0.0). `just preflight-dr` returns PASS against MONDO:0010463, with HDAC6 mentioned 81 times and no rival gene above 9. Reconciling it against this entry contributed two things and was declined on a third. It supplied the Hdac6-knockout mouse (PMID:18180281), which sharpens the dosage argument considerably and is curated in `animal_models`; and it supplied the primary-cilium bridge (PMID:17604723), now carried alongside the FGFR3 one as a second EMERGING hypothesis rather than instead of it. Its own causal chain marks steps 4-6 [INFERRED] and states that the ciliary-Hedgehog mechanism is "inferred, not directly demonstrated in patients", which is the same reading this entry had already reached independently and is why `conforms_to ciliopathy_dysfunction` stays unset. What was NOT taken from it: its phenotype table lists intrauterine growth retardation, macrocephaly, frontal bossing, low-set ears, thin ribs, eleven rib pairs, iliac wing hypoplasia and poor skull mineralization, attributing them to PMID:16001442 and the OMIM 300863 clinical synopsis. Those features are almost certainly real, but none of them appears in the cached abstract of PMID:16001442, which is the only text this repository can verify a snippet against, and OMIM clinical synopses are not a citable quotable source here. They are left out rather than curated against a quote that does not exist. The same applies to its LOD score of 3.30 and its bone-histology description. This is a genuine coverage cost of the exact-quote rule and it is recorded rather than worked around. It also reports a ClinVar missense candidate, NM_006044.4(HDAC6):c.2090C>T (p.Thr697Ile), RCV001198391, annotated to this disease and not independently validated. Not curated; recorded in `discussions`.
Bind GO:0090042 tubulin deacetylation, replacing an over-broad GO:0006476 · 2026-09-21T05:35:24Z · View source
Review round on the approving review from ai4c-reviewer on PR #12402. The review found no CRITICAL or IMPORTANT issues and marked two SUGGESTIONS as optional. Optional findings do not start a push under the repository's review rules, and this round is a push anyway, for a reason worth recording. Suggestion 1 observed that the Alpha-Tubulin Hypoacetylation node binds GO:0006476 protein deacetylation while its preferred_term is 'alpha-tubulin deacetylation', and proposed - explicitly as optional - adding a one-line note recording that a tubulin-specific GO term had been searched for. Its stated reasoning was that the broad binding is the correct call under the term contract because manufacturing a narrower match would be worse. Running the search before writing that note showed the premise was false. runoak -i ols:go search 'l~tubulin deacetylation' returns GO:0090042 tubulin deacetylation, along with GO:0090043 regulation of tubulin deacetylation, GO:0090044 positive regulation, GO:1904428 negative regulation, and the molecular-function term GO:0042903 tubulin deacetylase activity already bound on the node above. A tubulin-specific biological-process term exists and the entry was not using it. So the binding was over-broad, not a justified compromise, and the Ontology Term Contract's instruction to bind the most specific term that accurately represents the claim was not being met. Changed to GO:0090042. The note added to the entry records the query and what it returned, and states positively that GO has no alpha-tubulin-specific process term so the alpha-tubulin specificity stays in preferred_term - rather than asserting an absence that was not checked. Had the suggested note been written as proposed, it would have been a false justification of exactly the kind the dismech-terms skill documents at step 3a: a sentence asserting a search was run, attached to an over-broad binding, telling the next reviewer to skip the one check that would catch it. That is the third instance of that failure shape in this five-entry batch and the first where the false note was proposed by a reviewer rather than by the curator. This push dismisses the approving review, which is a real cost and was weighed. A wrong ontology binding in a knowledge base whose value rests on correct bindings is not a cosmetic defect, and the approval was granted on a premise that turned out to be false. Suggestion 2 was not acted on and needs no change: it flags that the pathograph is deliberately not one connected component, and explicitly does not ask for the missing edge. That disconnection is the entry's central documented knowledge gap. Two mislabelled CURIEs the reviewer found in the deep-research report were independently re-checked here rather than taken on trust: HP:0005830 resolves to Flexion contracture of toe (the report calls it 'Poor skull mineralization') and HP:0001010 to Hypopigmentation of the skin (the report calls it 'Body/limb asymmetry'). Both confirmed via ols:hp, and grep confirms neither appears anywhere in the entry. No action needed; recorded because it is further evidence that a deep-research CURIE is a lead and not a binding. Validation after the round: just validate passes with 43/43 snippets verified; validate-terms, check-entity-refs, check-causal-targets and check-duplicate-keys all pass.
Create: X-linked Dominant Chondrodysplasia Chassaing-Lacombe Type (HDAC6) · 2026-09-21T05:10:31Z · View source
New DISEASE entry for MONDO:0010463, the HDAC6 3'-UTR chondrodysplasia described in one four-generation family. Why this entry stops where it does. There is a measured molecular consequence (alpha-tubulin hypoacetylation in affected fetal thymus) and a well-described skeletal phenotype, and nothing published connects them. No chondrocyte or growth-plate study of this variant exists and no animal model of it has been made. The pathograph therefore ends at the biochemical node, with no causal edge to any skeletal phenotype. It would have been easy to write that edge from general knowledge about microtubules in chondrocytes and it would have validated; it is left out deliberately and recorded as a KNOWLEDGE_GAP discussion with two proposed experiments. Two candidate bridges across that gap are carried as EMERGING mechanistic_hypotheses rather than as edges, and neither is adjudicated: - hdac6_fgfr3_stabilization: FGFR3 accumulation depends on HDAC6, and deleting or inhibiting HDAC6 improves growth-plate bone growth in a mouse thanatophoric dysplasia model (PMID:27506979). That is the inverse manipulation to this disease, so HDAC6 excess would be predicted to stabilize FGFR3. - hdac6_ciliary_resorption: HDAC6 is the effector of regulated primary-cilium disassembly via HEF1/NEDD9 and Aurora A (PMID:17604723), and growth-plate chondrocytes depend on the cilium for Hedgehog signalling. This one came from the deep-research pass. Deep research: research/X-linked_Dominant_Chondrodysplasia_Chassaing-Lacombe_Type-deep-research-openscientist.md, provider openscientist, 14 citations, 14/14 resolved, confabulation rate 0.0. just preflight-dr returns PASS against MONDO:0010463 (HDAC6 mentioned 81 times, no rival gene above 9). Reconciling it contributed the Hdac6-knockout mouse (PMID:18180281) and the cilium hypothesis (PMID:17604723). The knockout is the dosage control and is curated in animal_models as FAILS_TO_RECAPITULATE: mice with no HDAC6 at all are viable and fertile with hyperacetylated tubulin, and losing the gene gives only a small increase in cancellous bone mineral density, described by its authors as a minor role in bone biology. The skeleton tolerates complete absence of HDAC6 almost without comment, which is the argument for HYPERMORPHIC on the lesion node and against any loss-of-function reading. Its causal chain marks steps 4-6 [INFERRED] and states the ciliary-Hedgehog mechanism is 'inferred, not directly demonstrated in patients'. That matches the reading this entry had reached independently and is why conforms_to ciliopathy_dysfunction stays unset: HDAC6 does act on cilia, but nothing in either paper about this disease examines them. What was NOT taken from the report, and the reason matters. Its phenotype table lists intrauterine growth retardation, macrocephaly, frontal bossing, low-set ears, thin ribs, eleven rib pairs, iliac wing hypoplasia and poor skull mineralization, attributing them to PMID:16001442 plus the OMIM 300863 clinical synopsis. None appears in the cached abstract of PMID:16001442, which is the only text a snippet can be verified against here, and an OMIM clinical synopsis is not a quotable source in this repository. They are left out rather than curated against a quote that does not exist. The same applies to its LOD score of 3.30 and its bone-histology description. This is a real coverage cost of the exact-quote rule and is recorded rather than worked around. Its ClinVar missense candidate p.Thr697Ile is recorded as an OPEN_QUESTION discussion rather than curated, because the ClinVar record was not read as part of this curation. One drafting error, caught by validation and recorded because the pattern recurred across this session: the brachydactyly phenotype originally quoted the describing paper's TITLE as its snippet. Reference validation rejected it, and it was replaced with the abstract's metaphyseal-cupping result sentence, marked INDIRECT because that sentence reports the radiographic lesion rather than the clinical sign. Separately, NCIT:C38101 was written from memory as 'Radiography'; its canonical label is 'X-Ray Imaging', caught as a WARN by just validate-terms. Validation. just validate passes with 38/38 snippets verified. just validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys and check-coarse-phenotypes all pass. just check-genereviews reports NO_CHAPTER for both collections against the committed Bookshelf index snapshot of 2026-09-10.
Disease: X-linked Dominant Chondrodysplasia, Chassaing–Lacombe Type Identifiers: OMIM #300863 · ORPHA:163966 · MONDO:0010463 · MedGen C3275476/C4304401 Causal gene: HDAC6 (Xp11.23; OMIM *300272; HGNC:14064) Category: Mendelian, X-linked dominant (male-lethal)
CRITICAL NOTE ON ETIOLOGY. The template header pairs this disease with MBTPS2. That is incorrect. The verified causal gene for Chassaing–Lacombe chondrodysplasia (OMIM #300863) is HDAC6, via a 3′-UTR regulatory variant (Simon et al. 2010, PMID: 20181727). MBTPS2 causes a different set of X-linked disorders (IFAP/BRESHECK, keratosis follicularis spinulosa decalvans, X-linked Olmsted syndrome, and one form of osteogenesis imperfecta) and is discussed here only as a differential-diagnosis / look-alike gene. All etiologic, mechanistic, and therapeutic statements below refer to HDAC6.
X-linked dominant chondrodysplasia of the Chassaing–Lacombe type is an ultra-rare, X-linked dominant, male-lethal skeletal dysplasia first delineated in a single large four-generation French family (Chassaing et al. 2005, PMID: 16001442). Hemizygous males present with a severe, perinatally lethal congenital chondrodysplasia — severe platyspondyly, distinctive metaphyseal cupping of the metacarpals/metatarsals/phalanges, hydrocephaly with macrocephaly, and microphthalmia — while heterozygous females are far more mildly and variably affected, showing short stature, body/limb asymmetry, and mild intellectual disability. This male-severe/female-mild dichotomy with male lethality is the signature of X-linked dominant inheritance with variable expression in heterozygous carriers.
The molecular cause is a 3′-untranslated region (3′-UTR) variant in HDAC6, NM_006044.4:c.*281A>T, which lies precisely within the seed-match site for the microRNA hsa-miR-433 (Simon et al. 2010, PMID: 20181727). The variant abolishes miR-433–mediated post-transcriptional repression of HDAC6, leading to HDAC6 over-expression and, downstream, to profound α-tubulin hypoacetylation — the biochemical signature of excess HDAC6 tubulin-deacetylase activity. This is a gain-of-expression (dosage) mechanism, at the opposite end of the dosage axis from loss of function: Hdac6-knockout mice are viable and fertile, underscoring that it is HDAC6 excess, not deficiency, that drives disease.
Because the entire disease-defining evidence base rests on two primary papers (2005 clinical delineation; 2010 molecular mechanism) describing a single family, many downstream sections of a standard disease template — natural-history cohorts, treatment trials, prognostic biomarkers, faithful animal models — are essentially empty for this specific condition. The pathophysiological bridge from HDAC6 over-expression to the skeletal phenotype is best explained through HDAC6's established role in primary cilium disassembly (the HEF1/NEDD9–Aurora-A–HDAC6 pathway) and the cilium's central role in growth-plate Hedgehog signaling — but this bridge is inferred, not directly demonstrated in patients. Confidence is HIGH for the causal gene/variant, inheritance, and core phenotype; MODERATE for the α-tubulin-hypoacetylation biomarker (single study); and LOW/INFERRED for the ciliary-Hedgehog growth-plate mechanism and any therapeutic rationale.
Overview. X-linked dominant chondrodysplasia, Chassaing–Lacombe type, is a rare Mendelian skeletal dysplasia characterized in affected males by severe chondrodysplasia with platyspondyly, distinctive brachydactyly with metaphyseal cupping, hydrocephaly, and microphthalmia, with perinatal lethality; heterozygous females show a milder, variable phenotype (short stature, body asymmetry, mild intellectual disability). It was originally delineated by Chassaing, Lacombe and colleagues in 2005.
Key identifiers.
| Resource | Identifier |
|---|---|
| OMIM | #300863 — "Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia" |
| Orphanet | ORPHA:163966 |
| MONDO | MONDO:0010463 |
| MedGen | C3275476 / C4304401 |
| Gene | HDAC6 (OMIM *300272; HGNC:14064; Xp11.23) |
| ICD-10 / ICD-11 | No disease-specific code (grouped under skeletal dysplasias / Q77–Q78) |
| MeSH | No dedicated MeSH descriptor |
Synonyms / alternative names. Chassaing–Lacombe chondrodysplasia; X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia. Orphanet classifies it among X-linked syndromic intellectual disability disorders (germline HDAC6 mutation), last reviewed February 2011 by Pr Didier Lacombe.
Data provenance. Information derives from aggregated disease-level resources (OMIM, Orphanet, MONDO, MedGen, ClinVar) and from individual-patient clinical/molecular reports of a single extended family — not from EHR or large registries.
Primary cause (genetic). The disease is monogenic and X-linked. The causal lesion is the germline HDAC6 3′-UTR variant c.*281A>T, which segregates completely with disease in the founding family and disrupts the hsa-miR-433 seed site, de-repressing HDAC6 (Simon et al. 2010, PMID: 20181727).
"We have identified a variant (c.*281A>T) in the 3′ untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433." — Simon et al. 2010
Genetic risk factors. The disease-causing variant itself is the sole established genetic determinant. In heterozygous females, the pattern of X-inactivation acts as a modifier of expressivity: skewing toward expression of the mutant allele in a given tissue increases local severity (see Sections 5 and 9).
Environmental risk factors / protective factors / gene–environment interactions. Not applicable / none reported. As a fully penetrant Mendelian variant, there are no established environmental risk factors, protective alleles, or gene–environment interactions. No modifier genes beyond X-inactivation status have been identified.
Phenotypes are drawn from Chassaing et al. 2005 (PMID: 16001442) and the OMIM #300863 clinical synopsis. The phenotype is strongly sex-dimorphic.
| Phenotype | HPO term | Type | Notes |
|---|---|---|---|
| Intrauterine growth retardation | HP:0001511 | Growth | Prenatal onset |
| Hydrocephaly | HP:0000238 | CNS/structural | Detectable prenatally |
| Macrocephaly | HP:0000256 | Craniofacial | |
| Frontal bossing | HP:0002007 | Craniofacial | |
| Microphthalmia | HP:0000568 | Ocular | |
| Small, low-set ears | HP:0000369 | Craniofacial | |
| Short flat nose | HP:0003196 / HP:0005280 | Craniofacial | |
| Poor skull mineralization | HP:0005830 | Skeletal | |
| Severe platyspondyly | HP:0000926 | Skeletal | Core radiographic sign |
| Thin ribs | HP:0000883 | Skeletal | |
| Eleven pairs of ribs | HP:0000878 | Skeletal | In 2 patients |
| Iliac wing hypoplasia | HP:0002866 | Skeletal | Poor pubic ossification |
| Metaphyseal cupping (metacarpals/metatarsals/phalanges) | HP:0003021 | Skeletal | Distinctive sign |
| Brachydactyly | HP:0001156 | Skeletal | |
| Hypoplastic calcaneus | — | Skeletal |
Bone histology (males): severe flattening of poorly delimited, under-ossified vertebral body anlagen; intervertebral disks thickened with abnormal craniocaudal orientation of fibroblasts.
| Phenotype | HPO term | Type |
|---|---|---|
| Short stature | HP:0004322 | Growth |
| Body/limb asymmetry | HP:0001010 | Physical |
| Mild intellectual disability | HP:0001256 | Neurodevelopmental |
"Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation." — Chassaing et al. 2005
Characteristics. Onset: congenital/prenatal in males; childhood-apparent in females. Severity: severe (males) vs. mild (females). Progression: males die perinatally (no progression observed); female features are essentially stable/static. Frequency: within the single reported family, described features were present in essentially all affected males; female features were milder and variable. Quality-of-life data (EQ-5D/SF-36) are not available for this ultra-rare disease.
Causal gene. HDAC6 (histone deacetylase 6), Xp11.23; OMIM *300272; HGNC:14064; NCBI Gene 10013.
Pathogenic variant. - Founding variant: NM_006044.4:c.*281A>T, in the 3′-UTR (exon 29), within the hsa-miR-433 seed match. Variant type: non-coding regulatory (3′-UTR / miRNA-binding-site). Functional consequence: gain of expression — loss of miR-433 repression → HDAC6 over-expression (demonstrated at protein level in affected fetal thymus). Origin: germline. Classification: pathogenic in the context of complete segregation (LOD 3.30) and functional validation, though it predates formal ACMG/AMP frameworks. - Additional candidate: ClinVar lists a separate missense candidate NM_006044.4(HDAC6):c.2090C>T (p.Thr697Ile), RCV001198391, annotated to this disease — suggesting possible further allelic heterogeneity, though not independently validated here.
"The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus." — Simon et al. 2010
Allele frequency. The private c.*281A>T variant is not a population polymorphism; no meaningful gnomAD frequency is expected for a private, disease-segregating, male-lethal allele.
Functional consequence class. Gain of expression / gain of function at the pathway level (excess deacetylase activity), NOT loss of function. This is the key dosage insight: Hdac6-null mice are viable and fertile (Zhang et al. 2008, PMID: 18180281).
Modifier genes / epigenetics. The principal modifier of expression in females is X-chromosome inactivation (tissue-level mosaicism); the disease mechanism itself is a post-transcriptional (miRNA-regulation) defect. No DNA-methylation or histone-modification disease signatures are reported.
Chromosomal abnormalities. None; the disorder is a point variant, not a structural/aneuploidy syndrome.
Not applicable. No environmental factors, toxins, lifestyle factors, or infectious agents are implicated. This is a purely genetic Mendelian disorder.
Branch (females): X-inactivation mosaicism determines, tissue-by-tissue, whether the mutant allele is expressed → focal HDAC6 over-expression → lateralized/asymmetric skeletal and growth phenotype.
"Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased." — Simon et al. 2010
"The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts." — Simon et al. 2010
c.*281A>T (HDAC6 3'-UTR, miR-433 seed)
│ abolishes miR-433 binding [DEMONSTRATED]
▼
HDAC6 over-expression [DEMONSTRATED - fetal thymus]
│ excess tubulin deacetylase
▼
α-tubulin HYPOacetylation [DEMONSTRATED - fetal thymus]
│
▼ (HEF1/NEDD9–AuroraA–HDAC6)
Primary cilium destabilization [INFERRED]
│
▼
↓ ciliary IHH / mechano-signaling [INFERRED]
│
▼
Disorganized growth-plate ossification [INFERRED]
│
▼
Platyspondyly · metaphyseal cupping · chondrodysplasia
Molecular pathways / cellular processes. Post-transcriptional gene regulation (microRNA silencing), tubulin acetylation/deacetylation homeostasis, primary-cilium assembly/disassembly cycle, and (inferred) Hedgehog signaling in the growth plate. Suggested GO terms: histone deacetylase activity (GO:0004407), tubulin deacetylase activity (GO:0042903), protein deacetylation (GO:0006476), cilium disassembly (GO:0061523), smoothened signaling pathway (GO:0007224), endochondral ossification (GO:0001958). Suggested CL terms: chondrocyte (CL:0000138), growth-plate chondrocyte.
Protein dysfunction. HDAC6 (class IIb deacetylase; two catalytic domains + ZnF-UBP ubiquitin-binding domain) is over-abundant; substrates include α-tubulin, HSP90, and cortactin, and it mediates aggresome formation/autophagic clearance (Zhu 2023 PMID: 37002569; Su 2010 PMID: 21416996). Excess deacetylase activity, not misfolding, is the defect.
Metabolic / immune / biochemical. No specific metabolic or immune abnormality is implicated in the disease itself. The measurable biochemical abnormality is decreased acetylated α-tubulin.
"interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly" — Pugacheva et al. 2007, PMID: 17604723
Plk1 also activates HDAC6 to drive ciliary deacetylation/resorption before mitosis (Wang et al. 2013, PMID: 23345402).
"Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies. A fourth affected male died at 6 days of life." — Chassaing et al. 2005
"The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3′ untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease." — Simon et al. 2010
"Selective HDAC6 inhibitors resulted in α-tubulin acetylation with no impact on histone acetylation" — Depetter et al. 2019
"HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues... the lack of HDAC6 results in a small increase in cancellous bone mineral density." — Zhang et al. 2008
The unifying model is a dosage disorder of a tubulin deacetylase driven by loss of microRNA control. A single non-coding base change (c.*281A>T) removes miR-433 repression, HDAC6 protein rises, and α-tubulin becomes hypoacetylated. Because HDAC6 is the effector deacetylase in the HEF1/NEDD9–Aurora-A–HDAC6 (and Plk1) primary-cilium disassembly pathway, its over-abundance plausibly destabilizes cilia in chondrocytes, blunting ciliary Hedgehog/mechanotransduction that orchestrates growth-plate maturation and endochondral ossification — producing platyspondyly, metaphyseal cupping, and the broader chondrodysplasia. The X-inactivation branch elegantly explains the female phenotype: the direct demonstration that the mutant allele was expressed (and HDAC6 over-expressed) only in the hypotrophic left-arm fibroblasts of an asymmetric female ties tissue-level mosaicism directly to lateralized disease.
Two dosage anchors bracket the model: loss of HDAC6 (knockout mouse) is benign, while gain (this disease) is severe and male-lethal — establishing that the pathogenic direction is over-expression, and that HDAC6-selective inhibition is the mechanistically logical (if unproven) countermeasure.
| Feature | Males (hemizygous) | Females (heterozygous) |
|---|---|---|
| HDAC6 expression | Uniformly ↑ | Mosaic ↑ (X-inactivation-dependent) |
| Skeletal phenotype | Severe, generalized | Mild, asymmetric |
| CNS/eye | Hydrocephaly, microphthalmia | Mild ID |
| Outcome | Perinatal lethal | Near-normal lifespan |
| PMID | Paper (abbrev.) | Role |
|---|---|---|
| 16001442 | X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia (Chassaing et al. 2005) | Clinical/radiographic delineation; pedigree; inheritance; male lethality |
| 20181727 | A mutation in the 3′-UTR of HDAC6 abolishing hsa-miR-433 regulation... (Simon et al. 2010) | Defining molecular paper — causal variant, HDAC6 over-expression, α-tubulin hypoacetylation, X-inactivation–asymmetry link |
| 18180281 | Mice lacking HDAC6... (Zhang et al. 2008) | Establishes dosage model (loss-of-function benign); bone-density role |
| 17604723 | HEF1-dependent Aurora A activation induces disassembly of the primary cilium (Pugacheva et al. 2007) | Basis for inferred HDAC6→cilium mechanism; HDAC6 inhibitors stabilize cilia |
| 23345402 | PCM1 recruits Plk1... (Wang et al. 2013) | Plk1–HDAC6 ciliary resorption, reinforcing cilium mechanism |
| 30694564 | Selective pharmacological inhibitors of HDAC6... (Depetter et al. 2019) | HDAC6-selective inhibitors restore α-tubulin acetylation — therapeutic rationale |
| 24844691 | Tubastatin A/ACY-1215... (2014) | Further HDAC6-inhibitor pharmacology |
| 37002569 / 21416996 | HDAC6 biology reviews | Structure, substrates, aggresome/autophagy roles |
| 19361614, 23316014, 20672378, 34655156 | MBTPS2 disorder papers | Background on allelic look-alike gene — NOT causal for this disease |
Important correction embedded in the evidence base: early iterations of this investigation initially attributed the disease to MBTPS2 (an X-linked intramembrane protease in the SREBP/cholesterol pathway). That attribution was overturned — MBTPS2 variants cause IFAP/KFSD/Olmsted syndromes and one form of osteogenesis imperfecta, distinct X-linked disorders. The definitive genetic mapping and functional work (Simon et al. 2010) unambiguously identifies HDAC6 as causal for Chassaing–Lacombe chondrodysplasia.
Confidence grading: HIGH — causal gene/variant (HDAC6 c.*281A>T), X-linked dominant male-lethal inheritance, and core male/female phenotype (directly demonstrated). MODERATE — α-tubulin-hypoacetylation biomarker (single study). LOW / INFERRED — cilium–Hedgehog growth-plate mechanism and HDAC6-inhibitor therapeutic rationale (extrapolated, untested in this disease).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 14 |
| Resolved | 14 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 14 |
| On topic | 6 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 37 |
| Resolved | 34 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 3 |
| Terms whose name was checked | 30 |
| Terms named correctly | 17 |
| Terms named as a different term | 5 |
| Terms whose name is worth a second look | 8 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0010463 (2 mentions) - the report calls it "MONDO"; MONDO calls it X-linked dominant chondrodysplasia, Chassaing-Lacombe typeHP:0005830 (1 mention) - the report calls it "Poor skull mineralization"; HP calls it Flexion contracture of toeHP:0001010 (1 mention) - the report calls it "Body/limb asymmetry"; HP calls it Hypopigmentation of the skinUBERON:0005430 (1 mention) - the report calls it "growth plate"; UBERON calls it ansa cervicalisNCIT:C1531 (1 mention) - the report calls it "histone deacetylase inhibitor"; NCIT calls it Recombinant EotaxinThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0000238 (1 mention) - the report calls it "Hydrocephaly"; HP calls it Hydrocephalus, and lists "Hydrocephaly" among its other namesHP:0000369 (1 mention) - the report calls it "Small, low-set ears"; HP calls it Low-set earsHP:0000926 (1 mention) - the report calls it "Severe platyspondyly"; HP calls it PlatyspondylyHP:0000878 (1 mention) - the report calls it "Eleven pairs of ribs"; HP calls it 11 pairs of ribsHP:0002866 (1 mention) - the report calls it "Iliac wing hypoplasia"; HP calls it Hypoplastic iliac wing, and lists "Small iliac wings" among its other namesHP:0003021 (1 mention) - the report calls it "Metaphyseal cupping (metacarpals/metatarsals/phalanges)"; HP calls it Metaphyseal cuppingUBERON:0001434 (1 mention) - the report calls it "skeleton / skeletal system"; UBERON calls it skeletal systemGO:0005930 (1 mention) - the report calls it "ciliary axoneme"; GO calls it axoneme, and lists "ciliary axoneme" among its other namesThe report gives these identifiers more than one name of its own:
CL:0000138 - called "chondrocyte", "chondrocytes"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.