Mesomelic Dysplasia, Savarirayan Type

🏷

Classifications

Harrison's Part

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal dominant, de novo HP:0000006

Every reported rearrangement — microdeletion or inversion — has arisen de novo. No transmitted case has been described, which is unsurprising given the severity of the lower-limb phenotype and the small number of patients.

Autosomal dominant inheritance De novo rate: all reported cases

Show evidence (2 references)

PMID:42069959 SUPPORT Human Clinical

"However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

Documents the de novo origin of the inversion allele.

PMID:26032025 SUPPORT Human Clinical

"We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3."

Documents the de novo origin of the deletion alleles in three unrelated patients.

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Discussions and Knowledge Gaps

1

Has ID4 actually been shown to be misexpressed in the limb bud in this disorder, or is the attribution still entirely positional?

KNOWLEDGE GAP mdst_id4_misexpression_unmeasured

Attached to

pathophysiology#Enhancer Adoption by ID4 in the Limb Bud

Both papers state the model as a prediction from breakpoint position — "could result", "we predict", "likely to place" — and neither reports an expression measurement. The comparison case is instructive: at the HOXD locus the equivalent hypothesis was settled by an engineered mouse inversion plus an in-cis null rescue. Nothing equivalent exists here, and with five patients worldwide the route to it is a mouse model of the rearrangement rather than more human genetics.

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Pathophysiology

3

Structural Rearrangement at 6p22.3

The originally described patients carry overlapping de novo 2 Mb microdeletions removing MBOAT1, E2F3, CDKAL1 and SOX4; a fifth patient with the same radiographic phenotype has a de novo inversion and no deletion at all on array. The negative results are what make the case: none of the deleted genes is known to act in skeletal development, and a patient with a larger deletion that did include ID4 had intellectual disability and no skeletal abnormality. Loss of the deleted material therefore does not explain the phenotype.

ID4 hgnc:5363

Genetic context ID4 hgnc:5363 allele_type: 6p22.3 microdeletion (~2 Mb) or inversion; ID4 coding sequence intact variant_origin: DE_NOVO zygosity: HETEROZYGOUS

Downstream

Enhancer Adoption by ID4 in the Limb Bud Removing or crossing regulatory boundaries lets limb enhancers reach ID4.

Show evidence (2 references)

PMID:26032025 SUPPORT Human Clinical

"We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated..."

The dissociation that rules out simple haploinsufficiency: the patient who lost more, including ID4 itself, had no skeletal phenotype.

PMID:42069959 SUPPORT Human Clinical

"No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

A copy-number-neutral allele producing the same phenotype, which is independent evidence against a dosage mechanism.

Enhancer Adoption by ID4 in the Limb Bud

Both allele classes are predicted to disrupt topologically associating domains at 6p22.3 and place ID4 nearer to limb enhancers that normally cannot reach it. ID4 is an inhibitor-of-DNA-binding HLH protein — a dominant-negative regulator of bHLH transcription factors — so misexpressing it in the limb bud would be expected to interfere with, rather than augment, the differentiation programs those factors run. Both papers state this as a prediction from breakpoint position, not as a measured expression change.

Enhancer-driven regulation of ID4 transcription in the limb bud GO:0006357 ↕ DYSREGULATED limb development GO:0060173 ↕ DYSREGULATED

Downstream

Lower-Limb Mesomelic Shortening Misexpression in the limb bud produces the zeugopod phenotype.

Show evidence (2 references)

PMID:26032025 SUPPORT Human Clinical

"Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia."

States the enhancer-adoption model. The source says "could result", and no expression measurement is reported, so this is PARTIAL.

PMID:42069959 SUPPORT Human Clinical

"we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression"

The same model applied to the inversion allele, again explicitly as a prediction ("we predict", "likely", "could", "potentially").

Lower-Limb Mesomelic Shortening

Severe shortness of the middle segment of the lower limb, with hypoplastic triangular tibiae and hypoplastic or abnormally shaped fibulae. The restriction to the lower limb is the diagnostic signature and distinguishes this disorder from the SHOX- and HOXD-related mesomelic dysplasias.

Downstream

Lower-Limb Mesomelia The zeugopod of the lower limb is the segment that fails; the upper limbs are spared, which is the disorder's diagnostic signature.

Hypoplastic Triangular Tibia The triangular tibia is the characteristic radiographic form the shortened segment takes.

Fibular Hypoplasia The fibula is hypoplastic or abnormally shaped alongside the tibia.

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae."

Gives the defining radiographic phenotype.

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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

3

Limbs 1

Hypoplastic Triangular Tibia VERY_FREQUENT Short tibia HP:0005736

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae."

Names the triangular hypoplastic tibia as a defining radiographic feature.

Other 2

Lower-Limb Mesomelia VERY_FREQUENT HP:0003027

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae."

Records the phenotype in all patients of the defining series and its restriction to the lower limbs.

Fibular Hypoplasia VERY_FREQUENT HP:0003038

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae."

Records fibular hypoplasia in all patients of the defining series.

🧬

Genetic Associations

1

ID4 (6p22.3 regulatory landscape)

Gene: ID4 hgnc:5363 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:26032025 SUPPORT Human Clinical

"The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4."

Names the genes actually removed, which are not the gene the disorder is attributed to.

PMID:42069959 SUPPORT Human Clinical

"Thus, this case broadens the genetic spectrum in MDST and provides further support to the role of ID4 dysregulation as the main underlying molecular mechanism of this ultra-rare skeletal disorder."

States the ID4-dysregulation attribution, at the strength the source gives it ("further support", not proof).

🔬

Diagnosis

2

Radiographic Recognition

Suspected from severe lower-limb mesomelia with hypoplastic triangular tibiae and hypoplastic or abnormally shaped fibulae, with normal upper limbs. The radiographic picture is characteristic enough that the 2026 inversion case was recognized clinically before any variant was found.

diagnostic radiography NCIT:C17369

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"a 9 year-old female with severe mesomelic lower limb shortening and characteristic radiographic findings, highly resembling those identified in previous MDST patients"

Supports radiographic recognizability: the diagnosis was made on imaging resemblance to prior cases.

Structural-Variant Analysis of 6p22.3

Array CGH identifies the microdeletion alleles. A negative array does not exclude the diagnosis: the fifth reported patient had a normal array and a de novo inversion found only on whole-genome sequencing. In a radiographically typical case with a negative array, WGS is the next step.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

Directly supports the recommendation to proceed to WGS after a negative array.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Five reported patients as of the 2026 inversion case: four with 6p22.3 microdeletions and one with an inversion. No denominator-based estimate exists.

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case"

Gives the cumulative case count directly, the basis for the ULTRA_RARE band.

🔀

Differential Diagnoses

3

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

Mesomelic dysplasia, Kantaputra type

Overlapping Features The same class of lesion — enhancer adoption after a structural rearrangement — at a different locus (HOXD, 2q31), with all four limbs affected and carpal and tarsal synostoses. The mechanistic parallel is close enough that the two disorders are best read together.

KINSSHIP syndrome

Overlapping Features Named in the KINSSHIP acronym for its Savarirayan-like limb radiographs, but a different condition per the nosology's own comment: AFF3-related, and with horseshoe kidney, seizures, and intellectual disability that this disorder does not produce.

Langer mesomelic dysplasia

Overlapping Features Biallelic SHOX deficiency, which affects the forearms as well as the lower legs and has no 6p22.3 lesion.

{ }

Source YAML

click to show

name: Mesomelic Dysplasia, Savarirayan Type
synonyms:
- Mesomelic dysplasia (Savarirayan type), ID4-related
- MDST
- mesomelic dysplasia with absent fibulae and triangular tibiae
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Mesomelic dysplasia of the Savarirayan type is an ultra-rare skeletal
  dysplasia in which the middle segment of the lower limb is severely short,
  with hypoplastic triangular tibiae and hypoplastic or abnormally shaped
  fibulae, and the upper limbs are spared. It is caused by de novo structural
  variants at 6p22.3 — microdeletions in the originally described patients and,
  more recently, an inversion. The mechanism is not loss of any deleted gene:
  none of the genes inside the deleted interval has a known role in skeletal
  development, and the one patient whose deletion was largest had intellectual
  disability and no skeletal abnormality at all. What the rearrangements share
  is that they remove or cross regulatory boundaries and bring limb enhancers
  within reach of ID4, so ID4 is misexpressed in the limb bud. Savarirayan-type
  mesomelic dysplasia is therefore, like the HOXD-related mesomelic dysplasias,
  an enhancer-adoption disorder rather than a gene-dosage one.
disease_term:
  preferred_term: mesomelic dysplasia, Savarirayan type
  term:
    id: MONDO:0011530
    label: mesomelic dysplasia, Savarirayan type
parents:
- Skeletal Dysplasia
- Mesomelic Dysplasia
notes: >-
  The gene attribution here needs reading carefully. ID4 is named in the ISDS
  row and in the disorder's dyadic name, but no ID4 coding variant has been
  reported in any patient: ID4 lies outside the smallest deleted interval, and
  its involvement is inferred from the position of the rearrangement breakpoints
  relative to limb enhancers and topological boundaries. The 2026 inversion case
  strengthens that inference — an inversion cannot act by dosage — without
  converting it into a demonstration. The entry states the mechanism at that
  strength.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A de novo 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 15-0150, listed as "Mesomelic dysplasia (Savarirayan type),
      ID4-related" (MIM 605274, AD), with the row's own comment recording the
      cause as microdeletions on 6p22.3. The KINSSHIP row in the same group
      (NOS 15-0160) names this type in its acronym but carries an explicit
      comment that it is a different condition. 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: >-
    Five reported patients as of the 2026 inversion case: four with 6p22.3
    microdeletions and one with an inversion. No denominator-based estimate
    exists.
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an
      ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions.
      To date, only four cases have been reported. Here, we report a fifth case
    explanation: >-
      Gives the cumulative case count directly, the basis for the ULTRA_RARE
      band.
inheritance:
- name: Autosomal dominant, de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: "all reported cases"
  description: >-
    Every reported rearrangement — microdeletion or inversion — has arisen de
    novo. No transmitted case has been described, which is unsurprising given
    the severity of the lower-limb phenotype and the small number of patients.
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, whole genome sequencing (WGS) revealed a de novo inversion at
      6p22.3.
    explanation: >-
      Documents the de novo origin of the inversion allele.
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed array comparative genomic hybridisation in three unrelated
      patients with mesomelic dysplasia Savarirayan type and identified 2 Mb
      overlapping de novo microdeletions on chromosome 6p22.3.
    explanation: >-
      Documents the de novo origin of the deletion alleles in three unrelated
      patients.
pathophysiology:
- name: Structural Rearrangement at 6p22.3
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ID4
    term:
      id: hgnc:5363
      label: ID4
  genetic_context:
    gene:
      preferred_term: ID4
      term:
        id: hgnc:5363
        label: ID4
    allele_type: 6p22.3 microdeletion (~2 Mb) or inversion; ID4 coding sequence intact
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
  description: >-
    The originally described patients carry overlapping de novo 2 Mb
    microdeletions removing MBOAT1, E2F3, CDKAL1 and SOX4; a fifth patient with
    the same radiographic phenotype has a de novo inversion and no deletion at
    all on array. The negative results are what make the case: none of the
    deleted genes is known to act in skeletal development, and a patient with a
    larger deletion that did include ID4 had intellectual disability and no
    skeletal abnormality. Loss of the deleted material therefore does not
    explain the phenotype.
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a fourth patient with intellectual disability and an
      overlapping slightly larger do novo deletion also encompassing the
      flanking gene ID4. Given the fact that the fourth patient had no skeletal
      abnormalities and none of the genes in the deleted interval are known to
      be associated with abnormalities in skeletal development, other mutational
      mechanisms than loss of function of the deleted genes have to be
      considered.
    explanation: >-
      The dissociation that rules out simple haploinsufficiency: the patient who
      lost more, including ID4 itself, had no skeletal phenotype.
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No deletion was identified by array. However, whole genome sequencing
      (WGS) revealed a de novo inversion at 6p22.3.
    explanation: >-
      A copy-number-neutral allele producing the same phenotype, which is
      independent evidence against a dosage mechanism.
  downstream:
  - target: Enhancer Adoption by ID4 in the Limb Bud
    causal_link_type: DIRECT
    description: >-
      Removing or crossing regulatory boundaries lets limb enhancers reach ID4.
- name: Enhancer Adoption by ID4 in the Limb Bud
  biological_scale: CELLULAR
  description: >-
    Both allele classes are predicted to disrupt topologically associating
    domains at 6p22.3 and place ID4 nearer to limb enhancers that normally
    cannot reach it. ID4 is an inhibitor-of-DNA-binding HLH protein — a
    dominant-negative regulator of bHLH transcription factors — so misexpressing
    it in the limb bud would be expected to interfere with, rather than augment,
    the differentiation programs those factors run. Both papers state this as a
    prediction from breakpoint position, not as a measured expression change.
  biological_processes:
  - preferred_term: Enhancer-driven regulation of ID4 transcription in the limb bud
    modifier: DYSREGULATED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  - preferred_term: limb development
    modifier: DYSREGULATED
    term:
      id: GO:0060173
      label: limb development
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of the genomic region showed that the deletion removes two
      regulatory boundaries and brings several potential limb enhancers into
      close proximity of ID4. Thus, the deletion could result in the aberrant
      activation and misexpression of ID4 in the limb bud, thereby causing the
      mesomelic dysplasia.
    explanation: >-
      States the enhancer-adoption model. The source says "could result", and no
      expression measurement is reported, so this is PARTIAL.
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we predict that the structural variant disrupts several topologically
      associated domains (TADs) in the region and is likely to place ID4 in
      closer proximity to more telomerically located limb enhancers, which could
      result in enhancer adoption and potentially lead to ID4 limb misexpression
    explanation: >-
      The same model applied to the inversion allele, again explicitly as a
      prediction ("we predict", "likely", "could", "potentially").
  downstream:
  - target: Lower-Limb Mesomelic Shortening
    causal_link_type: DIRECT
    description: >-
      Misexpression in the limb bud produces the zeugopod phenotype.
- name: Lower-Limb Mesomelic Shortening
  biological_scale: ORGANISM
  description: >-
    Severe shortness of the middle segment of the lower limb, with hypoplastic
    triangular tibiae and hypoplastic or abnormally shaped fibulae. The
    restriction to the lower limb is the diagnostic signature and distinguishes
    this disorder from the SHOX- and HOXD-related mesomelic dysplasias.
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the distinct deletion 6p22.3 is associated with
      mesomelic dysplasia Savarirayan type featuring hypoplastic,
      triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.
    explanation: >-
      Gives the defining radiographic phenotype.
  downstream:
  - target: Lower-Limb Mesomelia
    causal_link_type: DIRECT
    description: >-
      The zeugopod of the lower limb is the segment that fails; the upper limbs
      are spared, which is the disorder's diagnostic signature.
  - target: Hypoplastic Triangular Tibia
    causal_link_type: DIRECT
    description: >-
      The triangular tibia is the characteristic radiographic form the shortened
      segment takes.
  - target: Fibular Hypoplasia
    causal_link_type: DIRECT
    description: >-
      The fibula is hypoplastic or abnormally shaped alongside the tibia.
phenotypes:
- category: Skeletal
  name: Lower-Limb Mesomelia
  description: >-
    Mesomelic shortening confined to the lower limbs; the upper limbs are
    spared.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed mesomelia of the lower limbs with hypoplastic tibiae
      and fibulae.
    explanation: >-
      Records the phenotype in all patients of the defining series and its
      restriction to the lower limbs.
- category: Skeletal
  name: Hypoplastic Triangular Tibia
  phenotype_term:
    preferred_term: Short tibia
    term:
      id: HP:0005736
      label: Short tibia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the distinct deletion 6p22.3 is associated with
      mesomelic dysplasia Savarirayan type featuring hypoplastic,
      triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.
    explanation: >-
      Names the triangular hypoplastic tibia as a defining radiographic feature.
- category: Skeletal
  name: Fibular Hypoplasia
  phenotype_term:
    preferred_term: Fibular hypoplasia
    term:
      id: HP:0003038
      label: Fibular hypoplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed mesomelia of the lower limbs with hypoplastic tibiae
      and fibulae.
    explanation: >-
      Records fibular hypoplasia in all patients of the defining series.
genetic:
- name: ID4 (6p22.3 regulatory landscape)
  gene_term:
    preferred_term: ID4
    term:
      id: hgnc:5363
      label: ID4
  relationship_type: CAUSATIVE
  notes: >-
    The causal unit is a genomic region rather than a gene, and ID4 is named as
    the effector on positional grounds only — its coding sequence is intact and
    it lies outside the smallest deleted interval. Diagnostically this means ID4
    sequencing is uninformative; copy-number analysis finds the deletion alleles
    and whole-genome sequencing is needed for the copy-number-neutral ones. The
    deleted interval itself contains MBOAT1, E2F3, CDKAL1 and SOX4, none of them
    an established skeletal-development gene.
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4.
    explanation: >-
      Names the genes actually removed, which are not the gene the disorder is
      attributed to.
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, this case broadens the genetic spectrum in MDST and provides further
      support to the role of ID4 dysregulation as the main underlying molecular
      mechanism of this ultra-rare skeletal disorder.
    explanation: >-
      States the ID4-dysregulation attribution, at the strength the source gives
      it ("further support", not proof).
diagnosis:
- name: Radiographic Recognition
  description: >-
    Suspected from severe lower-limb mesomelia with hypoplastic triangular
    tibiae and hypoplastic or abnormally shaped fibulae, with normal upper
    limbs. The radiographic picture is characteristic enough that the 2026
    inversion case was recognized clinically before any variant was found.
  diagnosis_term:
    preferred_term: diagnostic radiography
    term:
      id: NCIT:C17369
      label: Imaging Procedure
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 9 year-old female with severe mesomelic lower limb shortening and
      characteristic radiographic findings, highly resembling those identified
      in previous MDST patients
    explanation: >-
      Supports radiographic recognizability: the diagnosis was made on imaging
      resemblance to prior cases.
- name: Structural-Variant Analysis of 6p22.3
  description: >-
    Array CGH identifies the microdeletion alleles. A negative array does not
    exclude the diagnosis: the fifth reported patient had a normal array and a
    de novo inversion found only on whole-genome sequencing. In a
    radiographically typical case with a negative array, WGS is the next step.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No deletion was identified by array. However, whole genome sequencing
      (WGS) revealed a de novo inversion at 6p22.3.
    explanation: >-
      Directly supports the recommendation to proceed to WGS after a negative
      array.
differential_diagnoses:
- name: Mesomelic dysplasia, Kantaputra type
  description: >-
    The same class of lesion — enhancer adoption after a structural rearrangement
    — at a different locus (HOXD, 2q31), with all four limbs affected and carpal
    and tarsal synostoses. The mechanistic parallel is close enough that the two
    disorders are best read together.
- name: KINSSHIP syndrome
  description: >-
    Named in the KINSSHIP acronym for its Savarirayan-like limb radiographs, but
    a different condition per the nosology's own comment: AFF3-related, and with
    horseshoe kidney, seizures, and intellectual disability that this disorder
    does not produce.
- name: Langer mesomelic dysplasia
  description: >-
    Biallelic SHOX deficiency, which affects the forearms as well as the lower
    legs and has no 6p22.3 lesion.
discussions:
- discussion_id: mdst_id4_misexpression_unmeasured
  kind: KNOWLEDGE_GAP
  prompt: >-
    Has ID4 actually been shown to be misexpressed in the limb bud in this
    disorder, or is the attribution still entirely positional?
  attaches_to:
  - pathophysiology#Enhancer Adoption by ID4 in the Limb Bud
  rationale: >-
    Both papers state the model as a prediction from breakpoint position — "could
    result", "we predict", "likely to place" — and neither reports an expression
    measurement. The comparison case is instructive: at the HOXD locus the
    equivalent hypothesis was settled by an engineered mouse inversion plus an
    in-cis null rescue. Nothing equivalent exists here, and with five patients
    worldwide the route to it is a mouse model of the rearrangement rather than
    more human genetics.
references:
- reference: PMID:26032025
  title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."

📚

References & Deep Research

References

2

PMID:26032025

Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type.

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, Savarirayan Type

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