Mesomelic Dysplasia, Kantaputra Type

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal dominant HP:0000006

Transmitted as an autosomal dominant trait; the original pedigree segregated the phenotype through three generations with a linkage LOD score above 4. The nosology records that expression is variable even within families, so a mildly affected parent does not predict a mildly affected child.

Autosomal dominant inheritance Penetrance: COMPLETE Expressivity: VARIABLE

Show evidence (1 reference)

PMID:9609995 SUPPORT Human Clinical

"Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation."

States the inheritance mode together with the defining clinical features.

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Discussions and Knowledge Gaps

1

What rule maps a given 2q31 rearrangement geometry onto which limb segments and which limb pairs are affected?

KNOWLEDGE GAP mdk_geometry_to_phenotype_map

Attached to

pathophysiology#Reallocation of Limb Enhancer-Promoter Contacts

The locus produces at least three clinically separable conditions — the Kantaputra type affecting all four limbs, the Fryns type only the upper limbs, and a translocation form adding vertebral defects — from rearrangements that all sit within a megabase of each other. The mechanism is understood in the abstract (which enhancers reach HOXD13), but no published rule predicts the clinical picture from the breakpoints, and the nosology itself records that expression varies within families carrying the same allele. Until such a rule exists, a newly found 2q31 rearrangement cannot be given a prognosis, which is the practical question families ask.

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Pathophysiology

4

Copy-Number Rearrangement at the HOXD Locus

Array CGH in the Kantaputra family found two microduplications at 2q31.1-q31.2 of roughly 481 and 507 kb, separated by a segment of normal copy number, the centromeric one spanning the whole HOXD cluster plus EVX2 and MTX2. Crucially, the causal rearrangements at this locus need not disrupt any gene at all: the t(2;8) translocation that causes a similar phenotype breaks about 60 kb from the HOXD complex and interrupts no coding sequence. The lesion is positional.

HOXD13 hgnc:5136

Genetic context HOXD13 hgnc:5136 allele_type: 2q31 microduplication spanning the HOXD cluster; also translocation and inversion alleles zygosity: HETEROZYGOUS

Downstream

Reallocation of Limb Enhancer-Promoter Contacts A rearrangement that changes distances and topology changes which enhancers can reach which promoters.

Show evidence (2 references)

PMID:20648051 SUPPORT Human Clinical

"we performed array CGH and identified two microduplications on chromosome 2 (2q31.1-q31.2) encompassing ∼481 and 507 kb, separated by a segment of normal copy number. The more centromeric duplication encompasses the entire HOXD cluster, as well as the neighboring genes EVX2 and MTX2."

Identifies the specific rearrangement in the Kantaputra family and what it contains.

PMID:11944980 SUPPORT Human Clinical

"We show that this translocation does not disrupt any gene, hence it most likely exerts its deleterious effect by modifying gene regulation."

The clearest statement that the mechanism at this locus is regulatory rather than coding, from the allele class where that is unambiguous.

Reallocation of Limb Enhancer-Promoter Contacts

HOXD genes are read by enhancers in the two gene deserts flanking the cluster, one serving proximal and one distal limb territory, partitioned by topologically associating domain boundaries. Rearrangement moves genes across that partition. The consequences are not uniformly gain or loss: a duplication in the upstream regulatory desert has been shown to *down*-regulate transcription in developing digits by impairing physical contact between target genes and their enhancers, phenocopying deletion of those enhancers — so at this locus a duplication can produce a partial loss of function. In the mesomelic dysplasias the decisive event is the opposite one: HOXD13 is brought within reach of proximal enhancers.

Enhancer-driven regulation of HOXD transcription GO:0006357 ↕ DYSREGULATED

Downstream

Ectopic Proximal Expression of HOXD13 The specific reallocation that matters for mesomelic dysplasia is HOXD13 coming under proximal enhancer control.

Show evidence (2 references)

PMID:31591517 SUPPORT Human Clinical

"The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes."

Establishes the two-gene-desert regulatory architecture that the rearrangements reallocate.

PMID:23134724 SUPPORT Model Organism

"Unexpectedly, one such duplication led to a transcriptional down-regulation in developing digits by impairing physical interactions between the target genes and their upstream regulatory elements, thus phenocopying the effect obtained when these enhancer sequences are deleted."

Demonstrates in engineered mice that a duplication at this locus can cause loss of function, which is why the node's claim is reallocation rather than dosage gain.

Ectopic Proximal Expression of HOXD13

HOXD13 is normally a distal, digit-specifying transcription factor. When a rearrangement places it near proximal limb enhancers, those enhancers contact and activate it in proximal cells. Engineered mice carrying a 1 Mb inversion of the HoxD cluster develop mesomelic dysplasia by exactly this route, and — the decisive experiment — adding a HOXD13-null mutation in cis with the inversion completely rescues the skeletal phenotype. That rescue converts "HOXD13 is misexpressed" from a correlation into a demonstrated cause. The downstream damage appears to run through genes HOXD13 normally controls in distal cells, now switched on in the wrong territory.

anterior/posterior pattern specification in the limb GO:0009952 ↕ DYSREGULATED limb morphogenesis GO:0035108 ↕ DYSREGULATED

Animal models

HoxD 1 Mb inversion mouse Mouse recapitulates The inversion places Hoxd13 near proximal limb enhancers, which activate it there, and mesomelic dysplasia follows.

Downstream

Mesomelic Limb Shortening and Bowing Misspecified proximal limb mesenchyme fails to build a normal zeugopod.

Show evidence (3 references)

PMID:34408147 SUPPORT Model Organism

"Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia."

Direct demonstration that proximal enhancer capture of Hoxd13 induces the phenotype.

PMID:34408147 SUPPORT Model Organism

"We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly."

The in-cis rescue, which establishes ectopic HOXD13 as necessary for the phenotype rather than merely present.

PMID:34408147 SUPPORT Model Organism

"Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells."

Identifies the likely downstream targets. The source says "suggests", so this is PARTIAL and the effector genes are not named here.

Mesomelic Limb Shortening and Bowing

The clinical endpoint: severe shortening and bending of the middle limb segment, with carpal and tarsal synostosis and dorsolateral foot deviation in the Kantaputra type. The mouse Ulnaless inversion produces the same phenotype from the same locus, which is what licensed treating the human and mouse conditions as one problem.

Animal models

HoxD 1 Mb inversion mouse Mouse rescues Removing HOXD13 function in cis with the inversion completely rescues the skeletal alterations — a genetic rescue, not a treatment.

Downstream

Mesomelic Limb Shortening Ectopic proximal HOXD13 misspecifies the limb mesenchyme that should build the zeugopod.

Short Stature Stature loss follows from shortening of all four zeugopods, since the Kantaputra type affects both limb pairs.

Carpal Synostosis HOXD13 normally specifies the autopod, so expressing it outside its proper domain disturbs the segmentation that separates the carpal elements.

Tarsal Synostosis The lower-limb counterpart of the carpal fusion, and with the ankle involvement the source of the disorder's descriptive synonym.

Show evidence (2 references)

PMID:34408147 SUPPORT Human Clinical

"Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb."

States the human phenotype produced by 2q31 rearrangements at the HOXD locus.

PMID:34408147 SUPPORT Model Organism

"In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice."

The mouse correspondence that underpins the mechanistic work cited upstream. Split from the human sentence because the two carry different evidence sources.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Limbs 1

Tarsal Synostosis FREQUENT HP:0008368

Show evidence (1 reference)

PMID:9609995 SUPPORT Human Clinical

"Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation."

Names tarsal synostosis among the defining features; it, with the ankle involvement, gives the disorder its descriptive synonym.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:20648051 SUPPORT Human Clinical

"Mesomelic dysplasia Kantaputra type (MDK) is characterized by marked mesomelic shortening of the upper and lower limbs originally described in a Thai family."

Confirms that both limb pairs are markedly shortened, the basis of the short stature.

Other 2

Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027

Show evidence (1 reference)

PMID:9609995 SUPPORT Human Clinical

"Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation."

Names shortening of the forearms and lower legs as a defining feature.

Carpal Synostosis FREQUENT Synostosis of carpal bones HP:0005048

Show evidence (1 reference)

PMID:9609995 SUPPORT Human Clinical

"Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation."

Names carpal synostosis among the defining features.

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Genetic Associations

1

HOXD cluster (2q31.1-q31.2)

Gene: HOXD13 hgnc:5136 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20648051 SUPPORT Human Clinical

"We propose that MDK is caused by duplications that modify the topography of the locus and as such result in deregulation of HOXD gene expression."

States the causal model for this specific disorder: topographic modification of the locus, not a coding lesion.

PMID:9609995 SUPPORT Human Clinical

"These data indicated that the MDK locus is in the vicinity of D2S2284 and D2S2188 loci that are most likely mapped to 2q24-q32."

The original linkage mapping that placed the locus at 2q, later refined to the HOXD cluster.

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Diagnosis

2

Radiographic Recognition

Suspected from mesomelic shortening of all four limbs with carpal and tarsal synostosis and dorsolateral foot deviation, in a dominant pedigree. The synostoses are the discriminating feature against the SHOX-related mesomelic dysplasias, which do not produce them.

diagnostic radiography NCIT:C17369

Show evidence (1 reference)

PMID:9609995 SUPPORT Human Clinical

"Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation."

Enumerates the radiographic feature set on which recognition rests.

Structural-Variant Analysis of 2q31

Confirmed by demonstrating a copy-number or structural rearrangement spanning or flanking the HOXD cluster. Sequencing HOXD13 will be normal; array CGH, and where available mate-pair or long-read genome sequencing, are the informative assays, because orientation and insertion point — not just copy number — determine the phenotype.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:20648051 SUPPORT Human Clinical

"To identify the cause of MDK, we performed array CGH and identified two microduplications on chromosome 2 (2q31.1-q31.2)"

Array CGH is the assay that identified the causal rearrangement.

PMID:31591517 SUPPORT Human Clinical

"By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications..."

Shows that orientation — recoverable only with structural assays beyond copy-number arrays — is part of the diagnostic answer at this locus.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Known from a small number of families. The original Thai pedigree carried 15 affected members across three generations, which is large for the disorder; other reports are single families. No denominator-based estimate exists.

Show evidence (1 reference)

PMID:9609995 SUPPORT Human Clinical

"We studied a Thai family in which 15 members in 3 generations were affected with MDK."

Gives the size of the defining pedigree, which is the basis for the rarity band recorded here.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Mesomelic Dysplasia, Kantaputra Type:

Fryns type mesomelic dysplasia of the upper limbs

Overlapping Features Same locus, same mechanism, different geometry: inverted duplications inserted between the HOXD cluster and the telomeric enhancers, producing isolated ulnar dysplasia confined to the upper limbs. Listed in the same ISDS row as the Kantaputra type but kept separate in MONDO and delimited as its own dominant condition in the literature.

Show evidence (1 reference)

PMID:31591517 SUPPORT Human Clinical

"Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers."

Delimits the Fryns type as its own condition with its own rearrangement geometry, which is why it is a differential here rather than a subtype.

Mesomelic dysplasia with vertebral defects (t(2;8) translocation)

Overlapping Features A balanced translocation with a breakpoint about 60 kb from HOXD, causing upper-limb mesomelic dysplasia together with vertebral defects. The same regulatory mechanism reached by a different rearrangement class; the vertebral component reflects HOXD's role in axial as well as limb patterning.

Show evidence (1 reference)

PMID:11944980 SUPPORT Human Clinical

"The HOXD complex lies approximately 60 kb from the translocation breakpoint on chromosome 2. This cluster of genes has an important role in the development of both the vertebral column and the limbs."

Gives the breakpoint distance and the dual axial/limb role that explains the vertebral component.

Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia

Overlapping Features The SHOX-related mesomelic dysplasias. Neither produces carpal or tarsal synostosis, and a SHOX/PAR1 defect has been specifically excluded in Kantaputra-type patients.

Kantaputra-like mesomelic dysplasia without a HOXD lesion

Overlapping Features A Brazilian family with eight affected members over three generations has a Kantaputra-like phenotype — marked upper-limb shortening, lower-limb hypotrophy, clubfeet — but no synostosis, and neither array CNV analysis nor exome sequencing found a candidate. Males were more severely affected than females. This is a caution against reading "mesomelic dysplasia resembling Kantaputra" as "HOXD rearrangement": absence of synostosis and a negative array should prompt a search for another locus rather than a deeper hunt at 2q31.

Show evidence (1 reference)

PMID:37846940 SUPPORT Human Clinical

"This family presents marked shortening of the upper limbs with hypotrophy of the lower limbs and clubfeet without synostosis. Array-based CNV analysis and exome sequencing of four family members failed to show any region or gene candidate."

Documents a Kantaputra-like phenotype with no HOXD lesion and no candidate on exome, which is what makes it a genuine differential rather than a variant of the same disorder.

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Animal Models

1

HoxD 1 Mb inversion mouse

An engineered inversion that reproduces the human rearrangement geometry, paired with an in-cis rescue allele. The rescue arm is what makes this a causal test rather than a phenocopy.

Species

Mouse

Genotype

Engineered 1 Mb inversion including the HoxD cluster; and the same inversion in cis with a Hoxd13 null allele

Publication

PMID:34408147

Pathograph links

Ectopic Proximal Expression of HOXD13 recapitulates fidelity: high The inversion places Hoxd13 near proximal limb enhancers, which activate it there, and mesomelic dysplasia follows.

Limitations: The inversion is engineered to a chosen geometry rather than copied from a patient allele, and human MDK is caused by duplications rather than an inversion; the model tests the mechanism the duplications are thought to act through, not the duplications themselves.

Readouts

Proximal limb Hoxd13 expression

Direction: INCREASED

Interpretation: Activation of a distal gene in proximal cells is the measured misexpression event.

Show evidence (1 reference)

PMID:34408147 SUPPORT Model Organism

"we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia"

Reports both the ectopic activation and the resulting phenotype.

Show evidence (1 reference)

PMID:34408147 SUPPORT Model Organism

"We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly."

The in-cis rescue establishes necessity, which is the strongest form of model evidence available for a mechanism claim.

Mesomelic Limb Shortening and Bowing rescues fidelity: high Removing HOXD13 function in cis with the inversion completely rescues the skeletal alterations — a genetic rescue, not a treatment.

Limitations: The rescue is a germline in-cis allele engineered before development begins. It identifies the effector but offers no route to intervention in a patient whose limbs are already formed.

Show evidence (1 reference)

PMID:34408147 SUPPORT Model Organism

"We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly."

Reports the complete rescue that this link records.

{ }

Source YAML

click to show

name: Mesomelic Dysplasia, Kantaputra Type
synonyms:
- Mesomelic dysplasia, HOXD-related
- mesomelic dysplasia with ankle, carpal, and tarsal synostosis
- mesomelic dysplasia, Thai type
- MDK
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Mesomelic dysplasia of the Kantaputra type is an autosomal dominant skeletal
  dysplasia — dwarfism with marked shortening of the forearms and lower legs,
  carpal and tarsal synostosis, and dorsolateral deviation of the feet —
  originally described in a Thai family and caused by copy-number
  rearrangements at the HOXD cluster on 2q31. It is one of the clearest human
  examples of a disease of gene *regulation* rather than gene product: the
  rearrangements do not disrupt any coding sequence. They rewire which
  enhancers reach which HOXD genes, most consequentially by bringing HOXD13 —
  a digit-specific transcription factor — within reach of proximal limb
  enhancers, so that it is expressed where it does not belong and dominantly
  interferes with the patterning of the middle limb segment.
disease_term:
  preferred_term: mesomelic dysplasia, Kantaputra type
  term:
    id: MONDO:0007977
    label: mesomelic dysplasia, Kantaputra type
parents:
- Skeletal Dysplasia
- Mesomelic Dysplasia
notes: >-
  Scope. The ISDS 2023 table gives this entity one row, "Mesomelic dysplasia,
  HOXD-related", whose label collects three eponyms — Kim (Korean), Kantaputra,
  and Fryns. This entry is keyed to the Kantaputra type, which has its own MONDO
  class and the largest published pedigree, and the other two are curated as
  differential diagnoses rather than subtypes: MONDO keeps them separate, the
  Fryns type is explicitly delimited in the literature as an upper-limb-only
  condition, and their rearrangement geometries differ even though the locus and
  the mechanism are shared. The shared mechanism is curated once, here, and the
  differentials point at it.

  What varies between the eponymous types is not the gene but the geometry —
  which enhancers end up adjacent to which HOXD genes, and therefore which limb
  segment misexpresses HOXD13. That is why one HOXD-related mesomelic dysplasia
  affects both limb pairs and another only the forearms.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian skeletal dysplasia caused by a structural variant; tagged on
      the genetics axis.
  isds_skeletal_category:
  - classification_value: mesomelic_and_rhizomesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 15 "Mesomelic and rhizo-mesomelic dysplasias", row
      NOS 15-0110, listed as "Mesomelic dysplasia, HOXD-related (Kim or Korean
      type, Kantaputra type, Fryns type)" (MIM 156232, AD). The row's own
      comment states that the cause is duplications at the HOXD gene cluster
      locus and that the phenotype is variable even within families. This entry
      curates the Kantaputra type named in that row; the Kim/Korean and Fryns
      types are recorded as differential diagnoses. The 2019 revision (Mortier
      et al., PMID:31633310) numbered the same group 17.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Known from a small number of families. The original Thai pedigree carried 15
    affected members across three generations, which is large for the disorder;
    other reports are single families. No denominator-based estimate exists.
  evidence:
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a Thai family in which 15 members in 3 generations were
      affected with MDK.
    explanation: >-
      Gives the size of the defining pedigree, which is the basis for the rarity
      band recorded here.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >-
    Transmitted as an autosomal dominant trait; the original pedigree segregated
    the phenotype through three generations with a linkage LOD score above 4.
    The nosology records that expression is variable even within families, so a
    mildly affected parent does not predict a mildly affected child.
  evidence:
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal
      dominant skeletal dysplasia characterized by dwarfism, shortening of the
      forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot
      deviation.
    explanation: >-
      States the inheritance mode together with the defining clinical features.
pathophysiology:
- name: Copy-Number Rearrangement at the HOXD Locus
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HOXD13
    term:
      id: hgnc:5136
      label: HOXD13
  genetic_context:
    genes:
    - preferred_term: HOXD13
      term:
        id: hgnc:5136
        label: HOXD13
    allele_type: 2q31 microduplication spanning the HOXD cluster; also translocation and inversion alleles
    zygosity: HETEROZYGOUS
  description: >-
    Array CGH in the Kantaputra family found two microduplications at
    2q31.1-q31.2 of roughly 481 and 507 kb, separated by a segment of normal
    copy number, the centromeric one spanning the whole HOXD cluster plus EVX2
    and MTX2. Crucially, the causal rearrangements at this locus need not
    disrupt any gene at all: the t(2;8) translocation that causes a similar
    phenotype breaks about 60 kb from the HOXD complex and interrupts no coding
    sequence. The lesion is positional.
  evidence:
  - reference: PMID:20648051
    reference_title: "Mesomelic dysplasia Kantaputra type is associated with duplications of the HOXD locus on chromosome 2q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed array CGH and identified two microduplications on chromosome
      2 (2q31.1-q31.2) encompassing ∼481 and 507 kb, separated by a segment of
      normal copy number. The more centromeric duplication encompasses the
      entire HOXD cluster, as well as the neighboring genes EVX2 and MTX2.
    explanation: >-
      Identifies the specific rearrangement in the Kantaputra family and what it
      contains.
  - reference: PMID:11944980
    reference_title: "A t(2;8) balanced translocation with breakpoints near the human HOXD complex causes mesomelic dysplasia and vertebral defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that this translocation does not disrupt any gene, hence it most
      likely exerts its deleterious effect by modifying gene regulation.
    explanation: >-
      The clearest statement that the mechanism at this locus is regulatory
      rather than coding, from the allele class where that is unambiguous.
  downstream:
  - target: Reallocation of Limb Enhancer-Promoter Contacts
    causal_link_type: DIRECT
    description: >-
      A rearrangement that changes distances and topology changes which
      enhancers can reach which promoters.
- name: Reallocation of Limb Enhancer-Promoter Contacts
  biological_scale: MOLECULAR
  description: >-
    HOXD genes are read by enhancers in the two gene deserts flanking the
    cluster, one serving proximal and one distal limb territory, partitioned by
    topologically associating domain boundaries. Rearrangement moves genes
    across that partition. The consequences are not uniformly gain or loss: a
    duplication in the upstream regulatory desert has been shown to
    *down*-regulate transcription in developing digits by impairing physical
    contact between target genes and their enhancers, phenocopying deletion of
    those enhancers — so at this locus a duplication can produce a partial loss
    of function. In the mesomelic dysplasias the decisive event is the opposite
    one: HOXD13 is brought within reach of proximal enhancers.
  biological_processes:
  - preferred_term: Enhancer-driven regulation of HOXD transcription
    modifier: DYSREGULATED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:31591517
    reference_title: "Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The HoxD cluster is critical for vertebrate limb development. Enhancers
      located in both the telomeric and centromeric gene deserts flanking the
      cluster regulate the transcription of HoxD genes.
    explanation: >-
      Establishes the two-gene-desert regulatory architecture that the
      rearrangements reallocate.
  - reference: PMID:23134724
    reference_title: "Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly, one such duplication led to a transcriptional
      down-regulation in developing digits by impairing physical interactions
      between the target genes and their upstream regulatory elements, thus
      phenocopying the effect obtained when these enhancer sequences are deleted.
    explanation: >-
      Demonstrates in engineered mice that a duplication at this locus can cause
      loss of function, which is why the node's claim is reallocation rather
      than dosage gain.
  downstream:
  - target: Ectopic Proximal Expression of HOXD13
    causal_link_type: DIRECT
    description: >-
      The specific reallocation that matters for mesomelic dysplasia is HOXD13
      coming under proximal enhancer control.
- name: Ectopic Proximal Expression of HOXD13
  biological_scale: CELLULAR
  description: >-
    HOXD13 is normally a distal, digit-specifying transcription factor. When a
    rearrangement places it near proximal limb enhancers, those enhancers
    contact and activate it in proximal cells. Engineered mice carrying a 1 Mb
    inversion of the HoxD cluster develop mesomelic dysplasia by exactly this
    route, and — the decisive experiment — adding a HOXD13-null mutation in cis
    with the inversion completely rescues the skeletal phenotype. That rescue
    converts "HOXD13 is misexpressed" from a correlation into a demonstrated
    cause. The downstream damage appears to run through genes HOXD13 normally
    controls in distal cells, now switched on in the wrong territory.
  biological_processes:
  - preferred_term: anterior/posterior pattern specification in the limb
    modifier: DYSREGULATED
    term:
      id: GO:0009952
      label: anterior/posterior pattern specification
  - preferred_term: limb morphogenesis
    modifier: DYSREGULATED
    term:
      id: GO:0035108
      label: limb morphogenesis
  evidence:
  - reference: PMID:34408147
    reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we engineer 1 Mb inversion including the HoxD gene cluster, which
      positioned Hoxd13 close to proximal limb enhancers. Using this model, we
      show that these enhancers contact and activate Hoxd13 in proximal cells,
      inducing the formation of mesomelic dysplasia.
    explanation: >-
      Direct demonstration that proximal enhancer capture of Hoxd13 induces the
      phenotype.
  - reference: PMID:34408147
    reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that a secondary Hoxd13 null mutation in-cis with the inversion
      completely rescues the alterations, demonstrating that ectopic HOXD13 is
      directly responsible for this bone anomaly.
    explanation: >-
      The in-cis rescue, which establishes ectopic HOXD13 as necessary for the
      phenotype rather than merely present.
  - reference: PMID:34408147
    reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Single-cell expression analysis and evaluation of HOXD13 binding sites
      suggests that the phenotype arises primarily by acting through genes
      normally controlled by HOXD13 in distal limb cells.
    explanation: >-
      Identifies the likely downstream targets. The source says "suggests", so
      this is PARTIAL and the effector genes are not named here.
  downstream:
  - target: Mesomelic Limb Shortening and Bowing
    causal_link_type: DIRECT
    description: >-
      Misspecified proximal limb mesenchyme fails to build a normal zeugopod.
- name: Mesomelic Limb Shortening and Bowing
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint: severe shortening and bending of the middle limb
    segment, with carpal and tarsal synostosis and dorsolateral foot deviation
    in the Kantaputra type. The mouse Ulnaless inversion produces the same
    phenotype from the same locus, which is what licensed treating the human and
    mouse conditions as one problem.
  evidence:
  - reference: PMID:34408147
    reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human families with chromosomal rearrangements at 2q31, where the human
      HOXD locus maps, display mesomelic dysplasia, a severe shortening and
      bending of the limb.
    explanation: >-
      States the human phenotype produced by 2q31 rearrangements at the HOXD
      locus.
  - reference: PMID:34408147
    reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, the dominant Ulnaless inversion of the HoxD cluster produces a
      similar phenotype suggesting the same origin for these malformations in
      humans and mice.
    explanation: >-
      The mouse correspondence that underpins the mechanistic work cited
      upstream. Split from the human sentence because the two carry different
      evidence sources.
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: DIRECT
    description: >-
      Ectopic proximal HOXD13 misspecifies the limb mesenchyme that should build
      the zeugopod.
  - target: Short Stature
    causal_link_type: DIRECT
    description: >-
      Stature loss follows from shortening of all four zeugopods, since the
      Kantaputra type affects both limb pairs.
  - target: Carpal Synostosis
    causal_link_type: DIRECT
    description: >-
      HOXD13 normally specifies the autopod, so expressing it outside its proper
      domain disturbs the segmentation that separates the carpal elements.
  - target: Tarsal Synostosis
    causal_link_type: DIRECT
    description: >-
      The lower-limb counterpart of the carpal fusion, and with the ankle
      involvement the source of the disorder's descriptive synonym.
phenotypes:
- category: Skeletal
  name: Mesomelic Limb Shortening
  description: >-
    Shortening of the forearms and lower legs, affecting both limb pairs in the
    Kantaputra type — unlike the Fryns type, where involvement is confined to
    the upper limbs.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal
      dominant skeletal dysplasia characterized by dwarfism, shortening of the
      forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot
      deviation.
    explanation: >-
      Names shortening of the forearms and lower legs as a defining feature.
- category: Skeletal
  name: Carpal Synostosis
  description: >-
    Fusion of carpal bones, part of the acral component that distinguishes this
    type from the SHOX-related mesomelic dysplasias.
  phenotype_term:
    preferred_term: Synostosis of carpal bones
    term:
      id: HP:0005048
      label: Synostosis of carpal bones
  frequency: FREQUENT
  evidence:
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal
      dominant skeletal dysplasia characterized by dwarfism, shortening of the
      forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot
      deviation.
    explanation: >-
      Names carpal synostosis among the defining features.
- category: Skeletal
  name: Tarsal Synostosis
  phenotype_term:
    preferred_term: Tarsal synostosis
    term:
      id: HP:0008368
      label: Tarsal synostosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal
      dominant skeletal dysplasia characterized by dwarfism, shortening of the
      forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot
      deviation.
    explanation: >-
      Names tarsal synostosis among the defining features; it, with the ankle
      involvement, gives the disorder its descriptive synonym.
- category: Skeletal
  name: Short Stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20648051
    reference_title: "Mesomelic dysplasia Kantaputra type is associated with duplications of the HOXD locus on chromosome 2q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Kantaputra type (MDK) is characterized by marked
      mesomelic shortening of the upper and lower limbs originally described in
      a Thai family.
    explanation: >-
      Confirms that both limb pairs are markedly shortened, the basis of the
      short stature.
genetic:
- name: HOXD cluster (2q31.1-q31.2)
  gene_term:
    preferred_term: HOXD13
    term:
      id: hgnc:5136
      label: HOXD13
  relationship_type: CAUSATIVE
  notes: >-
    The causal unit here is a genomic region, not a gene. The gene_term binds
    HOXD13 because the mouse work identifies ectopic HOXD13 as the effector, but
    HOXD13's own coding sequence is intact in these patients — the pathogenic
    events are duplications, inversions, and translocations that reposition it
    relative to the flanking enhancer deserts. The centromeric duplication in
    the Kantaputra family also spans EVX2 and MTX2. Diagnostically this means
    HOXD13 sequencing is uninformative and copy-number or structural-variant
    analysis is required.
  evidence:
  - reference: PMID:20648051
    reference_title: "Mesomelic dysplasia Kantaputra type is associated with duplications of the HOXD locus on chromosome 2q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that MDK is caused by duplications that modify the topography
      of the locus and as such result in deregulation of HOXD gene expression.
    explanation: >-
      States the causal model for this specific disorder: topographic
      modification of the locus, not a coding lesion.
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicated that the MDK locus is in the vicinity of D2S2284 and
      D2S2188 loci that are most likely mapped to 2q24-q32.
    explanation: >-
      The original linkage mapping that placed the locus at 2q, later refined to
      the HOXD cluster.
animal_models:
- name: HoxD 1 Mb inversion mouse
  species: Mouse
  genotype: Engineered 1 Mb inversion including the HoxD cluster; and the same inversion in cis with a Hoxd13 null allele
  publication: PMID:34408147
  description: >-
    An engineered inversion that reproduces the human rearrangement geometry,
    paired with an in-cis rescue allele. The rescue arm is what makes this a
    causal test rather than a phenocopy.
  modeled_mechanisms:
  - target: Ectopic Proximal Expression of HOXD13
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The inversion places Hoxd13 near proximal limb enhancers, which activate
      it there, and mesomelic dysplasia follows.
    limitations: >-
      The inversion is engineered to a chosen geometry rather than copied from a
      patient allele, and human MDK is caused by duplications rather than an
      inversion; the model tests the mechanism the duplications are thought to
      act through, not the duplications themselves.
    readouts:
    - name: Proximal limb Hoxd13 expression
      target: Ectopic Proximal Expression of HOXD13
      direction: INCREASED
      interpretation: >-
        Activation of a distal gene in proximal cells is the measured
        misexpression event.
      evidence:
      - reference: PMID:34408147
        reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we show that these enhancers contact and activate Hoxd13 in proximal
          cells, inducing the formation of mesomelic dysplasia
        explanation: >-
          Reports both the ectopic activation and the resulting phenotype.
    evidence:
    - reference: PMID:34408147
      reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that a secondary Hoxd13 null mutation in-cis with the inversion
        completely rescues the alterations, demonstrating that ectopic HOXD13 is
        directly responsible for this bone anomaly.
      explanation: >-
        The in-cis rescue establishes necessity, which is the strongest form of
        model evidence available for a mechanism claim.
  - target: Mesomelic Limb Shortening and Bowing
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Removing HOXD13 function in cis with the inversion completely rescues the
      skeletal alterations — a genetic rescue, not a treatment.
    limitations: >-
      The rescue is a germline in-cis allele engineered before development
      begins. It identifies the effector but offers no route to intervention in
      a patient whose limbs are already formed.
    evidence:
    - reference: PMID:34408147
      reference_title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that a secondary Hoxd13 null mutation in-cis with the inversion
        completely rescues the alterations, demonstrating that ectopic HOXD13 is
        directly responsible for this bone anomaly.
      explanation: >-
        Reports the complete rescue that this link records.
diagnosis:
- name: Radiographic Recognition
  description: >-
    Suspected from mesomelic shortening of all four limbs with carpal and tarsal
    synostosis and dorsolateral foot deviation, in a dominant pedigree. The
    synostoses are the discriminating feature against the SHOX-related mesomelic
    dysplasias, which do not produce them.
  diagnosis_term:
    preferred_term: diagnostic radiography
    term:
      id: NCIT:C17369
      label: Imaging Procedure
  evidence:
  - reference: PMID:9609995
    reference_title: "The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal
      dominant skeletal dysplasia characterized by dwarfism, shortening of the
      forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot
      deviation.
    explanation: >-
      Enumerates the radiographic feature set on which recognition rests.
- name: Structural-Variant Analysis of 2q31
  description: >-
    Confirmed by demonstrating a copy-number or structural rearrangement
    spanning or flanking the HOXD cluster. Sequencing HOXD13 will be normal;
    array CGH, and where available mate-pair or long-read genome sequencing,
    are the informative assays, because orientation and insertion point — not
    just copy number — determine the phenotype.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20648051
    reference_title: "Mesomelic dysplasia Kantaputra type is associated with duplications of the HOXD locus on chromosome 2q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To identify the cause of MDK, we performed array CGH and identified two
      microduplications on chromosome 2 (2q31.1-q31.2)
    explanation: >-
      Array CGH is the assay that identified the causal rearrangement.
  - reference: PMID:31591517
    reference_title: "Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber
      fluorescent in situ hybridization, we studied patients from two families
      displaying mesomelic dysplasia limited to the upper limbs. We identified
      microduplications including the HOXD cluster and showed that
      microduplications were in an inverted orientation
    explanation: >-
      Shows that orientation — recoverable only with structural assays beyond
      copy-number arrays — is part of the diagnostic answer at this locus.
differential_diagnoses:
- name: Fryns type mesomelic dysplasia of the upper limbs
  description: >-
    Same locus, same mechanism, different geometry: inverted duplications
    inserted between the HOXD cluster and the telomeric enhancers, producing
    isolated ulnar dysplasia confined to the upper limbs. Listed in the same
    ISDS row as the Kantaputra type but kept separate in MONDO and delimited as
    its own dominant condition in the literature.
  evidence:
  - reference: PMID:31591517
    reference_title: "Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results highlight the existence of an autosomal dominant condition
      consisting of isolated ulnar dysplasia caused by microduplications
      inserted between the HOXD cluster and the telomeric enhancers.
    explanation: >-
      Delimits the Fryns type as its own condition with its own rearrangement
      geometry, which is why it is a differential here rather than a subtype.
- name: Mesomelic dysplasia with vertebral defects (t(2;8) translocation)
  description: >-
    A balanced translocation with a breakpoint about 60 kb from HOXD, causing
    upper-limb mesomelic dysplasia together with vertebral defects. The same
    regulatory mechanism reached by a different rearrangement class; the
    vertebral component reflects HOXD's role in axial as well as limb
    patterning.
  evidence:
  - reference: PMID:11944980
    reference_title: "A t(2;8) balanced translocation with breakpoints near the human HOXD complex causes mesomelic dysplasia and vertebral defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The HOXD complex lies approximately 60 kb from the translocation
      breakpoint on chromosome 2. This cluster of genes has an important role in
      the development of both the vertebral column and the limbs.
    explanation: >-
      Gives the breakpoint distance and the dual axial/limb role that explains
      the vertebral component.
- name: Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia
  description: >-
    The SHOX-related mesomelic dysplasias. Neither produces carpal or tarsal
    synostosis, and a SHOX/PAR1 defect has been specifically excluded in
    Kantaputra-type patients.
- name: Kantaputra-like mesomelic dysplasia without a HOXD lesion
  description: >-
    A Brazilian family with eight affected members over three generations has a
    Kantaputra-like phenotype — marked upper-limb shortening, lower-limb
    hypotrophy, clubfeet — but no synostosis, and neither array CNV analysis nor
    exome sequencing found a candidate. Males were more severely affected than
    females. This is a caution against reading "mesomelic dysplasia resembling
    Kantaputra" as "HOXD rearrangement": absence of synostosis and a negative
    array should prompt a search for another locus rather than a deeper hunt at
    2q31.
  evidence:
  - reference: PMID:37846940
    reference_title: "A mesomelic skeletal dysplasia, Kantaputra-like, not related to HOXD cluster region, and with phenotypic gender differences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This family presents marked shortening of the upper limbs with hypotrophy
      of the lower limbs and clubfeet without synostosis. Array-based CNV
      analysis and exome sequencing of four family members failed to show any
      region or gene candidate.
    explanation: >-
      Documents a Kantaputra-like phenotype with no HOXD lesion and no candidate
      on exome, which is what makes it a genuine differential rather than a
      variant of the same disorder.
discussions:
- discussion_id: mdk_geometry_to_phenotype_map
  kind: KNOWLEDGE_GAP
  prompt: >-
    What rule maps a given 2q31 rearrangement geometry onto which limb segments
    and which limb pairs are affected?
  attaches_to:
  - pathophysiology#Reallocation of Limb Enhancer-Promoter Contacts
  rationale: >-
    The locus produces at least three clinically separable conditions — the
    Kantaputra type affecting all four limbs, the Fryns type only the upper
    limbs, and a translocation form adding vertebral defects — from
    rearrangements that all sit within a megabase of each other. The mechanism
    is understood in the abstract (which enhancers reach HOXD13), but no
    published rule predicts the clinical picture from the breakpoints, and the
    nosology itself records that expression varies within families carrying the
    same allele. Until such a rule exists, a newly found 2q31 rearrangement
    cannot be given a prognosis, which is the practical question families ask.
references:
- reference: PMID:34408147
  title: "Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations."
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."

📚

References & Deep Research

References

2

PMID:34408147

Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations.

No top-level findings curated for this source.

PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

Mesomelic Dysplasia, Kantaputra Type

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