Autosomal Dominant Robinow Syndrome 3

Mendelian MONDO:0014819 Pathograph 11 Show in embeddings browser Robinow Syndrome Skeletal Dysplasia

The DVL3 form of dominant Robinow syndrome — mesomelic limb shortening, genital hypoplasia and the fetal-facies gestalt, from heterozygous de novo variants in the Dishevelled paralog DVL3. The gene was found by hypothesis rather than by an unbiased search, and that is the most instructive thing about this entity. Once the DVL1 alleles were known to be frameshifts confined to one exon, and given that DVL1, DVL2 and DVL3 are functionally redundant paralogs, the penultimate exon of all three was sequenced directly in Robinow patients who had tested negative for DVL1, WNT5A and ROR2. Five unrelated individuals turned out to carry heterozygous de novo DVL3 variants — two splice-acceptor changes and three single-base deletions — and although those are three different mutational events, every one produces the same -1 frameshift of the last exon. The allele architecture, not the gene, is what the disease is about.

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1
Inheritance
3
Pathophys.
5
Phenotypes
1
Gaps
11
Pathograph
1
Genes
3
Medical Actions
3
Differentials
2
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ISDS Skeletal Nosology
mesomelic and rhizomesomelic dysplasias
👪

Inheritance

1
Autosomal dominant, de novo HP:0000006
Autosomal dominant. Every variant in the delineating series arose de novo, so unaffected parents do not argue against the diagnosis.
Autosomal dominant inheritance De novo rate: all reported cases in the delineating series
Show evidence (2 references)
PMID:26924530 SUPPORT Human Clinical
"targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions"
States both the heterozygous dominant mode and the de novo origin.
PMID:25577943 SUPPORT Human Clinical
"ADRS is inherited in an autosomal dominant manner."
GeneReviews states the inheritance mode for the dominant forms, of which this is one.
?

Discussions and Knowledge Gaps

1
Does the DVL3 last-exon frameshift act the way the DVL1 one does — reduced signalling from loss of the wild-type C-terminus plus a gained nuclear activity from the novel peptide — or does the paralog differ?
KNOWLEDGE GAP dvl3_frameshift_mode_of_action
Attached to
pathophysiology#Altered Dishevelled-Mediated WNT Signal Transduction
The DVL1 allele has been dissected against a stop codon at the same position (PMID:42424595), separating a shared loss-of-signalling component from a nuclear mislocalization unique to the frameshift. No equivalent experiment exists for DVL3. The analogy is strong — the same reading-frame outcome in a redundant paralog — but it remains an analogy, and this entry deliberately claims only that transduction is altered. The question matters because DVL1 and DVL3 disease are clinically separable (osteosclerosis in DVL1), so the paralogs may not be doing the same thing after all.
⚙

Pathophysiology

3
DVL3 Last-Exon -1 Frameshift
Three different mutational mechanisms — two splice-acceptor changes and three single-base deletions — converge on one outcome: a -1 frameshift of the last exon, replacing the wild-type C-terminus of Dishevelled 3 with a novel peptide. That convergence is the signature of the allele class, and it mirrors exactly what the DVL1 alleles do. As with DVL1, the premature termination codon lies in the last exon, so the transcript is not expected to be degraded and the altered protein is made alongside the wild-type one.
DVL3 hgnc:3087 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DVL3 (hgnc:3087). hgnc:3087 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context DVL3 hgnc:3087 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns DVL3 (hgnc:3087). hgnc:3087 is a gene from the HUGO Gene Nomenclature Committee. allele_type: splice-acceptor variant or single-base deletion producing a -1 frameshift of the last exon variant_origin: DE_NOVO zygosity: HETEROZYGOUS
Downstream
Altered Dishevelled-Mediated WNT Signal Transduction The altered protein occupies the transducer position of the pathway.
Show evidence (1 reference)
PMID:26924530 SUPPORT Human Clinical
"all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome"
Establishes that mechanistically distinct variants converge on a single reading-frame outcome, which is the defining feature of this allele class.
Altered Dishevelled-Mediated WNT Signal Transduction
Dishevelled transduces the signal from the WNT5A/ROR2/FZD2 receptor complex into the beta-catenin-independent planar cell polarity branch. A Dishevelled protein carrying a novel C-terminus is an altered transducer rather than an absent one. How much of the effect is lost signalling and how much is gained activity has been measured for DVL1 and not for DVL3. This entry therefore asserts only that transduction is altered, which is what the DVL3 evidence supports, and keeps the direction question in a discussion.
Wnt signaling pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology. ↕ DYSREGULATED Wnt signaling pathway, planar cell polarity pathway GO:0060071 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Wnt signaling pathway, planar cell polarity pathway (GO:0060071). GO:0060071 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Disrupted Planar Cell Polarity in Developing Skeleton and Face Altered transduction reaches the developmental programs PCP signalling governs.
Show evidence (1 reference)
PMID:35047859 SUPPORT Human Clinical
"Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A)."
Places DVL3 in the same final common pathway as the other Robinow genes.
Disrupted Planar Cell Polarity in Developing Skeleton and Face
The shared endpoint across Robinow genotypes: loss of the polarized, directional cell behaviour that PCP signalling governs, in the growth plate, the frontonasal midline and the genital tubercle. The developmental decomposition comes from the Ror2-null mouse and is inherited here by pathway membership rather than demonstrated for DVL3.
Wnt signaling pathway, planar cell polarity pathway GO:0060071 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt signaling pathway, planar cell polarity pathway (GO:0060071). GO:0060071 is a biological process from the Gene Ontology. ↓ DECREASED chondrocyte differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chondrocyte differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mesomelic Limb Shortening Disordered growth plate chondrocyte behaviour shortens the middle limb segment.
Short Stature The same growth plate lesion summed over the long bones.
Fetal Facies Midline outgrowth failure of the frontonasal region.
Genital Hypoplasia Reduced genital tubercle outgrowth.
Dental Crowding and Malocclusion Small, retruded jaws leave insufficient arch length for the dentition.
Show evidence (1 reference)
PMID:29276006 SUPPORT Human Clinical
"These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway"
States the pathway-level model this node represents, from the study that confirmed DVL1 and DVL3 as the main dominant contributors.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Robinow Syndrome 3 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Eye 1
Fetal Facies VERY_FREQUENT Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"
Enumerates the facial features of the dominant syndrome, of which the DVL3 form is one.
Growth 1
Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"
GeneReviews lists short stature among the skeletal findings of the dominant syndrome.
Other 3
Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mesomelia (HP:0003027). HP:0003027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26924530 SUPPORT Human Clinical
"Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features."
Names mesomelic limb shortening as a defining feature of the disorder the DVL3 patients were ascertained for.
Genital Hypoplasia VERY_FREQUENT Hypoplastic male external genitalia HP:0000050 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic male external genitalia (HP:0000050). HP:0000050 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26924530 SUPPORT Human Clinical
"Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features."
Genital hypoplasia is one of the three defining features.
Dental Crowding and Malocclusion FREQUENT HP:0000678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental crowding (HP:0000678). HP:0000678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally"
Lists the dental phenotype of the dominant syndrome.
🧬

Genetic Associations

1
DVL3
Gene: DVL3 hgnc:3087 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DVL3 (hgnc:3087). hgnc:3087 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:26924530 SUPPORT Human Clinical
"targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions"
Establishes DVL3 as causative with de novo alleles in five unrelated individuals.
💊

Medical Actions

3
Orthodontic Treatment
Action: orthodontic treatmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthodontic treatment (NCIT:C64248). NCIT:C64248 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthodontic Treatment NCIT:C64248
Malocclusion, crowding, hypodontia and delayed eruption make orthodontic management a routine, long-running part of care.
Mechanism Target:
Disrupted Planar Cell Polarity in Developing Skeleton and Face — Manages the dental consequences of the craniofacial patterning defect. Corrective, not disease-modifying.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"Orthodontic treatment is typically required."
GeneReviews states that orthodontic treatment is typically required.
Genital Reconstructive Surgery
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Corrective surgery for cryptorchidism and abnormal penile insertion or penoscrotal position.
Mechanism Target:
Disrupted Planar Cell Polarity in Developing Skeleton and Face — Corrects the genital anatomy produced by the same PCP outgrowth defect. Anatomical correction only.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"Treatment of manifestations: Corrective surgeries as needed for cryptorchidism, abnormal penile insertion / penoscrotal position, and cleft lip/palate."
Lists the genital and orofacial procedures used in management.
Genetic Counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
A 50% recurrence risk for an affected individual's offspring, but a low recurrence risk for the unaffected parents of a sporadic case, since the reported alleles are de novo.
Show evidence (1 reference)
PMID:25577943 SUPPORT Human Clinical
"Each child of an individual with ADRS has a 50% chance of inheriting the pathogenic variant; however, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing."
Supports both the recurrence risk and the limit on genotype-based prognostication.
🔬

Diagnosis

1
Targeted Penultimate-Exon Sequencing of the DVL Paralogs
In a clinically typical dominant case negative for WNT5A, DVL1 and ROR2, direct sequencing of the penultimate exon of the DVL paralogs is the high-yield next step — that is how this entity was found. Broad panel or exome testing is appropriate otherwise, provided the analysis is not filtered in a way that discards last-exon frameshifts as presumed benign NMD-escapers.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26924530 SUPPORT Human Clinical
"we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants"
Describes the targeted strategy that identified this entity.
PMID:25577943 SUPPORT Human Clinical
"The diagnosis of autosomal dominant Robinow syndrome is established in a proband with typical suggestive findings and/or by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular genetic testing."
States the molecular confirmation criteria for the dominant forms.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Five unrelated individuals in the delineating series, with occasional reports since. No denominator-based estimate exists.
Show evidence (1 reference)
PMID:26924530 SUPPORT Human Clinical
"targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions"
Gives the cohort size on which the entity was delineated.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Robinow Syndrome 3:

Autosomal Dominant Robinow Syndrome 2
Overlapping Features The DVL1 form, mechanistically the closest relative — the same -1 frameshift architecture in the paralog. Distinguished by gene, and clinically by the osteosclerotic variant (normal stature, persistent macrocephaly, increased bone mineral density, hearing loss) that is attributed to DVL1 and not to DVL3.
Autosomal Dominant Robinow Syndrome 1
Overlapping Features The WNT5A form: hypomorphic missense alleles in the ligand rather than an altered intracellular transducer.
Autosomal Recessive Robinow Syndrome
Overlapping Features The ROR2 form. More severe skeletal involvement with vertebral segmentation defects and rib fusions, which the dominant forms do not produce.
{ }

Source YAML

click to show 
name: Autosomal Dominant Robinow Syndrome 3
synonyms:
- DRS3
- DVL3-related Robinow syndrome
- Robinow syndrome, autosomal dominant 3
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal dominant Robinow syndrome 3
  term:
    id: MONDO:0014819
    label: autosomal dominant Robinow syndrome 3
description: >-
  The DVL3 form of dominant Robinow syndrome — mesomelic limb shortening,
  genital hypoplasia and the fetal-facies gestalt, from heterozygous de novo
  variants in the Dishevelled paralog DVL3.

  The gene was found by hypothesis rather than by an unbiased search, and that
  is the most instructive thing about this entity. Once the DVL1 alleles were
  known to be frameshifts confined to one exon, and given that DVL1, DVL2 and
  DVL3 are functionally redundant paralogs, the penultimate exon of all three
  was sequenced directly in Robinow patients who had tested negative for DVL1,
  WNT5A and ROR2. Five unrelated individuals turned out to carry heterozygous de
  novo DVL3 variants — two splice-acceptor changes and three single-base
  deletions — and although those are three different mutational events, every
  one produces the same -1 frameshift of the last exon. The allele architecture,
  not the gene, is what the disease is about.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: >-
  Scope. This entry covers the DVL3 form only (MONDO:0014819, DRS3). The WNT5A
  form is ``Autosomal_Dominant_Robinow_Syndrome_1`` and the DVL1 form is
  ``Autosomal_Dominant_Robinow_Syndrome_2``; the union is
  ``kb/groupings/Robinow_Syndrome.yaml``.

  GeneReviews (PMID:25577943) describes the dominant syndrome across WNT5A,
  DVL1 and DVL3 together, so quoted clinical descriptions apply to the syndrome
  rather than exclusively to DVL3 patients, and the evidence explanations say so.
  The osteosclerotic variant described in that chapter is explicitly attributed
  to DVL1 and is NOT curated here.

  The functional dissection of the DVL1 frameshift (PMID:42424595) — reduced
  canonical and JNK-PCP signalling shared with a plain truncation, plus a
  nuclear mislocalization unique to the frameshift — has not been repeated for
  DVL3. It is cited in this entry's discussion as the leading hypothesis for
  DVL3 by analogy, not as evidence about DVL3.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian developmental disorder of a defined signalling pathway.
  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 15-0070, listed as "Robinow syndrome, DVL3-related" (MIM 616894, AD).
      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 unrelated individuals in the delineating series, with occasional
    reports since. No denominator-based estimate exists.
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      targeted sequencing identified five unrelated individuals harboring
      heterozygous, de novo frameshift variants in DVL3, including two splice
      acceptor mutations and three 1 bp deletions
    explanation: >-
      Gives the cohort size on which the entity was delineated.
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 in the delineating series"
  description: >-
    Autosomal dominant. Every variant in the delineating series arose de novo,
    so unaffected parents do not argue against the diagnosis.
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      targeted sequencing identified five unrelated individuals harboring
      heterozygous, de novo frameshift variants in DVL3, including two splice
      acceptor mutations and three 1 bp deletions
    explanation: >-
      States both the heterozygous dominant mode and the de novo origin.
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADRS is inherited in an autosomal dominant manner.
    explanation: >-
      GeneReviews states the inheritance mode for the dominant forms, of which
      this is one.
pathophysiology:
- name: DVL3 Last-Exon -1 Frameshift
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DVL3
    term:
      id: hgnc:3087
      label: DVL3
  genetic_context:
    gene:
      preferred_term: DVL3
      term:
        id: hgnc:3087
        label: DVL3
    allele_type: splice-acceptor variant or single-base deletion producing a -1 frameshift of the last exon
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
  description: >-
    Three different mutational mechanisms — two splice-acceptor changes and
    three single-base deletions — converge on one outcome: a -1 frameshift of
    the last exon, replacing the wild-type C-terminus of Dishevelled 3 with a
    novel peptide. That convergence is the signature of the allele class, and it
    mirrors exactly what the DVL1 alleles do. As with DVL1, the premature
    termination codon lies in the last exon, so the transcript is not expected to
    be degraded and the altered protein is made alongside the wild-type one.
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all variants in DVL3 result in a -1 frameshift, indicating that these
      highly specific alterations might be a common cause of dominant Robinow
      syndrome
    explanation: >-
      Establishes that mechanistically distinct variants converge on a single
      reading-frame outcome, which is the defining feature of this allele class.
  downstream:
  - target: Altered Dishevelled-Mediated WNT Signal Transduction
    causal_link_type: DIRECT
    description: >-
      The altered protein occupies the transducer position of the pathway.
- name: Altered Dishevelled-Mediated WNT Signal Transduction
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Dishevelled transduces the signal from the WNT5A/ROR2/FZD2 receptor complex
    into the beta-catenin-independent planar cell polarity branch. A Dishevelled
    protein carrying a novel C-terminus is an altered transducer rather than an
    absent one.

    How much of the effect is lost signalling and how much is gained activity
    has been measured for DVL1 and not for DVL3. This entry therefore asserts
    only that transduction is altered, which is what the DVL3 evidence supports,
    and keeps the direction question in a discussion.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: DYSREGULATED
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    modifier: DYSREGULATED
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
  evidence:
  - reference: PMID:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Robinow syndrome (RS) is a genetically heterogeneous disorder with six
      genes that converge on the WNT/planar cell polarity (PCP) signaling
      pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A).
    explanation: >-
      Places DVL3 in the same final common pathway as the other Robinow genes.
  downstream:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    causal_link_type: DIRECT
    description: >-
      Altered transduction reaches the developmental programs PCP signalling
      governs.
- name: Disrupted Planar Cell Polarity in Developing Skeleton and Face
  role: central_effector
  biological_scale: TISSUE
  description: >-
    The shared endpoint across Robinow genotypes: loss of the polarized,
    directional cell behaviour that PCP signalling governs, in the growth plate,
    the frontonasal midline and the genital tubercle. The developmental
    decomposition comes from the Ror2-null mouse and is inherited here by
    pathway membership rather than demonstrated for DVL3.
  biological_processes:
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    modifier: DECREASED
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
  - preferred_term: chondrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  evidence:
  - reference: PMID:29276006
    reference_title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data support an initial hypothesis that Robinow syndrome results
      from perturbation of the Wnt/PCP pathway
    explanation: >-
      States the pathway-level model this node represents, from the study that
      confirmed DVL1 and DVL3 as the main dominant contributors.
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: DIRECT
    description: >-
      Disordered growth plate chondrocyte behaviour shortens the middle limb
      segment.
  - target: Short Stature
    causal_link_type: DIRECT
    description: >-
      The same growth plate lesion summed over the long bones.
  - target: Fetal Facies
    causal_link_type: DIRECT
    description: >-
      Midline outgrowth failure of the frontonasal region.
  - target: Genital Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Reduced genital tubercle outgrowth.
  - target: Dental Crowding and Malocclusion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Small, retruded jaws leave insufficient arch length for the dentition.
phenotypes:
- category: Skeletal
  name: Mesomelic Limb Shortening
  description: >-
    Shortening of the forearms and lower legs, predominantly of the upper limbs
    in the dominant forms.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Robinow syndrome is a rare congenital disorder characterized by mesomelic
      limb shortening, genital hypoplasia, and distinctive facial features.
    explanation: >-
      Names mesomelic limb shortening as a defining feature of the disorder the
      DVL3 patients were ascertained for.
- category: Genitourinary
  name: Genital Hypoplasia
  description: >-
    Micropenis or webbed penis, hypoplastic scrotum and cryptorchidism in males;
    hypoplastic clitoris and labia majora in females.
  phenotype_term:
    preferred_term: Hypoplastic male external genitalia
    term:
      id: HP:0000050
      label: Hypoplastic male external genitalia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Robinow syndrome is a rare congenital disorder characterized by mesomelic
      limb shortening, genital hypoplasia, and distinctive facial features.
    explanation: >-
      Genital hypoplasia is one of the three defining features.
- category: Craniofacial
  name: Fetal Facies
  description: >-
    Widely spaced and prominent eyes, frontal bossing, anteverted nares and
    midface retrusion — the facial gestalt that named the syndrome.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features (widely spaced and prominent eyes, frontal
      bossing, anteverted nares, midface retrusion)
    explanation: >-
      Enumerates the facial features of the dominant syndrome, of which the DVL3
      form is one.
- category: Skeletal
  name: Short Stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal
      findings (short stature, mesomelic limb shortening predominantly of the
      upper limbs, and brachydactyly)
    explanation: >-
      GeneReviews lists short stature among the skeletal findings of the
      dominant syndrome.
- category: Oral
  name: Dental Crowding and Malocclusion
  description: >-
    Malocclusion, crowding, hypodontia and late eruption of the permanent
    dentition; orthodontic management is routinely required.
  phenotype_term:
    preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  frequency: FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late
      eruption of permanent teeth), bilobed tongue, and occasional prenatal
      macrocephaly that persists postnatally
    explanation: >-
      Lists the dental phenotype of the dominant syndrome.
genetic:
- name: DVL3
  gene_term:
    preferred_term: DVL3
    term:
      id: hgnc:3087
      label: DVL3
  relationship_type: CAUSATIVE
  notes: >-
    Dishevelled 3, paralog of DVL1. The pathogenic alleles are those producing a
    -1 frameshift of the last exon; a splice-acceptor variant and a single-base
    deletion both qualify, so allele class here is defined by reading-frame
    consequence rather than by variant type. A truncating variant elsewhere in
    DVL3 should not be called causal on the strength of the gene alone.
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      targeted sequencing identified five unrelated individuals harboring
      heterozygous, de novo frameshift variants in DVL3, including two splice
      acceptor mutations and three 1 bp deletions
    explanation: >-
      Establishes DVL3 as causative with de novo alleles in five unrelated
      individuals.
diagnosis:
- name: Targeted Penultimate-Exon Sequencing of the DVL Paralogs
  description: >-
    In a clinically typical dominant case negative for WNT5A, DVL1 and ROR2,
    direct sequencing of the penultimate exon of the DVL paralogs is the
    high-yield next step — that is how this entity was found. Broad panel or
    exome testing is appropriate otherwise, provided the analysis is not
    filtered in a way that discards last-exon frameshifts as presumed benign
    NMD-escapers.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:26924530
    reference_title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we elected to pursue direct Sanger sequencing of the penultimate exon of
      DVL1 and its paralogs DVL2 and DVL3 to search for potential
      disease-associated variants
    explanation: >-
      Describes the targeted strategy that identified this entity.
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of autosomal dominant Robinow syndrome is established in a
      proband with typical suggestive findings and/or by the identification of a
      heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular
      genetic testing.
    explanation: >-
      States the molecular confirmation criteria for the dominant forms.
differential_diagnoses:
- name: Autosomal Dominant Robinow Syndrome 2
  description: >-
    The DVL1 form, mechanistically the closest relative — the same -1 frameshift
    architecture in the paralog. Distinguished by gene, and clinically by the
    osteosclerotic variant (normal stature, persistent macrocephaly, increased
    bone mineral density, hearing loss) that is attributed to DVL1 and not to
    DVL3.
- name: Autosomal Dominant Robinow Syndrome 1
  description: >-
    The WNT5A form: hypomorphic missense alleles in the ligand rather than an
    altered intracellular transducer.
- name: Autosomal Recessive Robinow Syndrome
  description: >-
    The ROR2 form. More severe skeletal involvement with vertebral segmentation
    defects and rib fusions, which the dominant forms do not produce.
treatments:
- name: Orthodontic Treatment
  description: >-
    Malocclusion, crowding, hypodontia and delayed eruption make orthodontic
    management a routine, long-running part of care.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: orthodontic treatment
    term:
      id: NCIT:C64248
      label: Orthodontic Treatment
  target_mechanisms:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    description: >-
      Manages the dental consequences of the craniofacial patterning defect.
      Corrective, not disease-modifying.
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthodontic treatment is typically required.
    explanation: >-
      GeneReviews states that orthodontic treatment is typically required.
- name: Genital Reconstructive Surgery
  description: >-
    Corrective surgery for cryptorchidism and abnormal penile insertion or
    penoscrotal position.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    description: >-
      Corrects the genital anatomy produced by the same PCP outgrowth defect.
      Anatomical correction only.
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of manifestations: Corrective surgeries as needed for
      cryptorchidism, abnormal penile insertion / penoscrotal position, and
      cleft lip/palate.
    explanation: >-
      Lists the genital and orofacial procedures used in management.
- name: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    A 50% recurrence risk for an affected individual's offspring, but a low
    recurrence risk for the unaffected parents of a sporadic case, since the
    reported alleles are de novo.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with ADRS has a 50% chance of inheriting the
      pathogenic variant; however, the severity of the clinical manifestations
      cannot be predicted from the results of molecular genetic testing.
    explanation: >-
      Supports both the recurrence risk and the limit on genotype-based
      prognostication.
discussions:
- discussion_id: dvl3_frameshift_mode_of_action
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the DVL3 last-exon frameshift act the way the DVL1 one does — reduced
    signalling from loss of the wild-type C-terminus plus a gained nuclear
    activity from the novel peptide — or does the paralog differ?
  attaches_to:
  - pathophysiology#Altered Dishevelled-Mediated WNT Signal Transduction
  rationale: >-
    The DVL1 allele has been dissected against a stop codon at the same position
    (PMID:42424595), separating a shared loss-of-signalling component from a
    nuclear mislocalization unique to the frameshift. No equivalent experiment
    exists for DVL3. The analogy is strong — the same reading-frame outcome in a
    redundant paralog — but it remains an analogy, and this entry deliberately
    claims only that transduction is altered. The question matters because DVL1
    and DVL3 disease are clinically separable (osteosclerosis in DVL1), so the
    paralogs may not be doing the same thing after all.
references:
- reference: PMID:26924530
  title: "DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome."
- reference: PMID:25577943
  title: "Autosomal Dominant Robinow Syndrome."
  tags:
  - GeneReviews
📚

References & Deep Research

References

2
PMID:26924530
DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.
No top-level findings curated for this source.
PMID:25577943
Autosomal Dominant Robinow Syndrome.
No top-level findings curated for this source.