Autosomal Dominant Robinow Syndrome 2

🏷

Classifications

Harrison's Part

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal dominant, usually de novo HP:0000006

Autosomal dominant. In the families where parental samples were available, the variants were de novo, so an unaffected-parent pedigree does not argue against the diagnosis.

Autosomal dominant inheritance De novo rate: majority

Show evidence (2 references)

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.

PMID:25817016 SUPPORT Human Clinical

"In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations."

Establishes de novo origin in the families that could be tested.

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Discussions and Knowledge Gaps

1

Does the nuclear-mislocalized frameshift protein alter transcription, and is that what produces the skeletal phenotype and the DVL1-specific osteosclerosis?

KNOWLEDGE GAP dvl1_frameshift_mode_of_action

Attached to

pathophysiology#Nuclear Mislocalization of Altered Dishevelled

The 2026 comparison against a stop codon at the same position settled that the reduced canonical and JNK-PCP signalling is a consequence of losing the wild-type C-terminus, not of the novel peptide — yet only the frameshift perturbs morphogenesis, and only it goes to the nucleus. Something the novel peptide does, beyond reduced signalling, is doing the work. The authors propose altered nuclear transcription; no target has been identified. The distinction is actionable: a gained nuclear activity is in principle a target for allele-specific knockdown, whereas a lost domain function is not. It would also explain why osteosclerosis is confined to this genotype.

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Pathophysiology

5

DVL1 Penultimate-Exon Frameshift Escaping Nonsense-Mediated Decay

The variants are confined to the penultimate exon, so the premature termination codon falls in the last exon and the transcript escapes nonsense-mediated decay. Both wild-type and variant transcripts are detectable in patient leukocytes, so the altered protein is genuinely made.

DVL1 hgnc:3084

Genetic context DVL1 hgnc:3084 allele_type: penultimate-exon -1 frameshift escaping nonsense-mediated decay variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

DOMINANT_NEGATIVE is a mechanistic reading of an NMD-escaping altered-C-terminus allele expressed alongside wild type. The 2026 functional work supports a mixed picture — reduced signalling shared with a plain truncation, plus a nuclear mislocalization unique to the frameshift — which no single enum value captures cleanly. See the ``dvl1_frameshift_mode_of_action`` discussion.

Downstream

Reduced WNT Signal Transduction Through Dishevelled The altered protein sits in the transducer position of the pathway.

Nuclear Mislocalization of Altered Dishevelled A property of the novel C-terminal peptide, not of losing the wild-type one.

Show evidence (2 references)

PMID:25817016 SUPPORT Human Clinical

"All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus."

States the NMD-escape architecture that defines this allele class.

PMID:25817016 SUPPORT Human Clinical

"Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD."

Patient-derived confirmation that the mutant transcript is expressed rather than degraded.

Reduced WNT Signal Transduction Through Dishevelled

In luciferase assays in facial mesenchyme, wild-type DVL1 activates both canonical and JNK-PCP WNT signalling, while the frameshift protein and a plain stop codon at the same position both signal significantly less. The loss-of-signalling component is therefore attributable to the missing wild-type C-terminus and is shared with an ordinary truncation.

non-canonical Wnt signaling pathway GO:0035567 ↓ DECREASED Wnt signaling pathway, planar cell polarity pathway GO:0060071 ↓ DECREASED

Downstream

Disrupted Planar Cell Polarity in Developing Skeleton and Face Reduced PCP transduction is the input to the developmental phenotype.

Show evidence (1 reference)

PMID:42424595 SUPPORT In Vitro

"In luciferase assays carried out in facial mesenchyme, wtDVL1 activated canonical and JNK-PCP WNT signalling whereas the DVL11519* and the DVL11519ΔT variant had significantly lower signaling activity."

Measures the signalling deficit and, by including the stop-codon construct, shows it is not specific to the frameshift.

Nuclear Mislocalization of Altered Dishevelled

Dishevelled is a cytoplasmic signal transducer. The protein made from the frameshift allele is found in the nucleus instead, while both wild-type DVL1 and the stop-codon construct stay cytoplasmic. In Drosophila, only the frameshift allele perturbs morphogenesis and signalling. This is the component of the allele's effect that a simple loss of the C-terminus does not reproduce, and the authors raise altered nuclear transcription as the candidate consequence.

Downstream

Disrupted Planar Cell Polarity in Developing Skeleton and Face Whether the nuclear protein alters transcription, and which targets, is not established.

Increased Cranial Bone Mineral Density Osteosclerosis is restricted to this genotype among molecularly characterized Robinow patients, so it is attributed to the DVL1-specific component of the allele's effect rather than to reduced PCP signalling shared with the other genes. The intermediate steps are unidentified.

Show evidence (2 references)

PMID:42424595 SUPPORT In Vitro

"We also determined that there is mislocalization of the protein expressed from DVL11519ΔT in the nucleus while the other two constructs were expressed in the cytoplasm."

Establishes that the mislocalization is specific to the frameshift product.

PMID:42424595 SUPPORT Model Organism

"In complementary Drosophila experiments using a variety of readouts, only the DVL11519ΔT variant and not the 1519* impacted morphogenesis and signaling."

The discriminating in vivo result: the frameshift perturbs morphogenesis where an equivalent truncation does not.

Disrupted Planar Cell Polarity in Developing Skeleton and Face

The shared endpoint of every Robinow genotype: 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 — reduced presomitic mesoderm, perturbed chondrocyte differentiation, midline outgrowth failure, genital tubercle reduction — comes from the Ror2-null mouse and is inherited here by pathway membership rather than demonstrated for DVL1.

Wnt signaling pathway, planar cell polarity pathway GO:0060071 ↓ DECREASED chondrocyte differentiation GO:0002062 ↓ DECREASED

Downstream

Mesomelic Limb Shortening Disordered growth plate chondrocyte behaviour shortens the middle limb segment.

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: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)."

Establishes that DVL1 disease shares a final common pathway with the other Robinow genes, which is what licenses the shared developmental model.

Increased Cranial Bone Mineral Density

The DVL1-specific bone phenotype. High-resolution peripheral quantitative CT in molecularly confirmed patients shows a distinctive pattern — low cortical but increased trabecular bone mineral density, with fewer and thicker trabeculations — and cranial osteosclerosis is confined to the DVL1 (and one GPC4) genotype.

osteoblast CL:0000062

bone development GO:0060348 ↕ DYSREGULATED

Downstream

Skull Osteosclerosis The radiographic expression of the cranial bone phenotype.

Increased Bone Mineral Density The DEXA-measurable expression of the same phenotype.

Macrocephaly Persistent macrocephaly travels with the osteosclerotic variant.

Hearing Loss Conductive hearing loss follows from skull-base osteosclerosis narrowing the middle-ear and foraminal spaces, in the same patients whose cranial nerve palsies arise the same way.

Show evidence (2 references)

PMID:32888393 SUPPORT Human Clinical

"Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS (1/1) subjects and in one case was complicated by choanal atresia, bilateral conductive hearing loss, and cranial nerve III, VI, and VII palsy."

Establishes the genotype restriction of the osteosclerosis and its clinical consequences.

PMID:32888393 SUPPORT Human Clinical

"HR-pQCT revealed a unique pattern of low cortical BMD, increased trabecular BMD, decreased number of trabeculations, and increased thickness of the trabeculations for the DVL1-RS subjects."

Gives the micro-architectural signature, which is not simply more bone everywhere.

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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

8

Ear 1

Hearing Loss FREQUENT Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:25577943 SUPPORT Human Clinical

"increased bone mineral density with skull osteosclerosis, and hearing loss"

Hearing loss is listed as part of the DVL1 osteosclerotic variant.

Eye 1

Fetal Facies VERY_FREQUENT Hypertelorism HP:0000316

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.

Head and Neck 1

Macrocephaly VERY_FREQUENT HP:0000256

Show evidence (1 reference)

PMID:25577943 SUPPORT Human Clinical

"A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss"

Persistent macrocephaly is named as part of the DVL1 variant.

Musculoskeletal 1

Increased Bone Mineral Density FREQUENT HP:0011001

Show evidence (1 reference)

PMID:32888393 SUPPORT Human Clinical

"DEXA scan measures revealed increased total body bone mineral density (BMD) (3/7), cranial BMD (5/7), and non-cranial BMD (1/7)."

Quantifies increased BMD by DEXA in the studied cohort.

Other 4

Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027

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 describes the skeletal phenotype of the dominant syndrome, of which this entry is one gene form.

Skull Osteosclerosis VERY_FREQUENT Calvarial osteosclerosis HP:0005450

Show evidence (1 reference)

PMID:25577943 SUPPORT Human Clinical

"A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss"

GeneReviews attributes the osteosclerotic variant specifically to DVL1.

Genital Hypoplasia VERY_FREQUENT Hypoplastic male external genitalia HP:0000050

Show evidence (1 reference)

PMID:25577943 SUPPORT Human Clinical

"genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora)"

Describes the genital phenotype of the dominant syndrome.

Dental Crowding and Malocclusion FREQUENT HP:0000678

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.

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Genetic Associations

1

DVL1

Gene: DVL1 hgnc:3084 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:25817016 SUPPORT Human Clinical

"In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1."

Establishes the gene, the allele class, and the exon restriction.

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Medical Actions

4

Orthodontic Treatment

Action: orthodontic treatment 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 crowding and malocclusion that follow 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 procedure 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.

Hearing and Head Circumference Surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Periodic hearing assessment matters more in this genotype than in the other Robinow forms, because the osteosclerosis that causes conductive loss is DVL1-specific and progressive foraminal narrowing is what produces the cranial nerve complications.

Mechanism Target:

Increased Cranial Bone Mineral Density — Surveillance is aimed at this node specifically: the osteosclerosis is what distinguishes DVL1-Robinow, and conductive hearing loss is its expected complication. Monitoring detects, it does not modify.

Show evidence (1 reference)

PMID:25577943 SUPPORT Human Clinical

"Measurement of head circumference regularly in infancy and throughout childhood."

States the head-circumference surveillance recommendation.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling 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 most 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.

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Diagnosis

1

Molecular Confirmation of a DVL1 Penultimate-Exon Frameshift

Confirmed by a heterozygous frameshift in the penultimate exon of DVL1. Because the alleles cluster in one exon, targeted sequencing of that exon in the DVL paralogs is a high-yield first step in a clinically typical dominant case; broad panel or exome testing is appropriate otherwise.

genetic testing NCIT:C15709

Show evidence (2 references)

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.

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"

Supports the targeted penultimate-exon strategy described here.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Eight subjects carrying six distinct DVL1 frameshifts in the defining series, with further cases since. No denominator-based estimate exists, so the count is recorded rather than a rate.

Show evidence (1 reference)

PMID:25817016 SUPPORT Human Clinical

"In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1."

Gives the cohort size on which the entity was delineated.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Robinow Syndrome 2:

Autosomal Dominant Robinow Syndrome 1

Overlapping Features The WNT5A form. Hypomorphic ligand missense alleles rather than an altered transducer, and without the osteosclerosis, macrocephaly and preserved stature that mark the DVL1 form.

Autosomal Dominant Robinow Syndrome 3

Overlapping Features The DVL3 form, mechanistically the closest relative: the same -1 frameshift architecture in the paralog. Distinguished by gene, not by phenotype.

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, and recessive inheritance.

Osteopetrosis and other sclerosing bone disorders

Overlapping Features Considered when cranial osteosclerosis dominates the presentation. The Robinow facial gestalt, mesomelia and genital hypoplasia separate them, as does the DVL1 micro-architecture — low cortical with high trabecular density, rather than uniformly dense bone.

{ }

Source YAML

click to show

name: Autosomal Dominant Robinow Syndrome 2
synonyms:
- DRS2
- DVL1-related Robinow syndrome
- Robinow syndrome, autosomal dominant 2
- osteosclerotic form of Robinow syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal dominant Robinow syndrome 2
  term:
    id: MONDO:0014591
    label: autosomal dominant Robinow syndrome 2
description: >-
  The DVL1 form of dominant Robinow syndrome, and the one that carries the
  osteosclerotic variant of the disease: normal stature, persistent
  macrocephaly, increased bone mineral density with skull osteosclerosis, and
  hearing loss, on top of the mesomelic limb shortening, genital hypoplasia and
  fetal facies shared across the syndrome.

  The allele class is unusually specific and is what makes this entity distinct
  from the WNT5A form. Every reported variant is a frameshift confined to the
  penultimate exon of DVL1, placing a premature termination codon in the last
  exon so the transcript escapes nonsense-mediated decay. The product is not
  absent Dishevelled but altered Dishevelled — an intact core with a novel -1
  reading-frame C-terminus, expressed alongside the wild-type allele.

  Functional work published in 2026 separates two effects that had been
  conflated. Compared against a plain stop codon at the same position, the
  frameshift protein transduces canonical and JNK-PCP WNT signal less
  efficiently — but so does the stop codon, so that part is loss of the
  C-terminus. Only the frameshift protein mislocalizes to the nucleus, and only
  it perturbs morphogenesis in Drosophila. The novel peptide therefore does
  something that merely losing the wild-type C-terminus does not.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: >-
  Scope. This entry covers the DVL1 form only (MONDO:0014591, DRS2). The
  dominant syndrome has at least three genes; the WNT5A form is
  ``Autosomal_Dominant_Robinow_Syndrome_1`` and the DVL3 form is
  ``Autosomal_Dominant_Robinow_Syndrome_3``. They are curated as separate
  entries and cross-referenced as differential diagnoses, with
  ``kb/groupings/Robinow_Syndrome.yaml`` holding the union.

  GeneReviews (PMID:25577943) describes the dominant syndrome across all three
  genes, so quoted clinical descriptions apply to the syndrome rather than
  exclusively to DVL1 patients; evidence explanations say so where it matters.
  The osteosclerosis statements are the exception — those are DVL1-specific and
  the sources say so explicitly.
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 15-0060, listed as "Robinow syndrome, DVL1-related" (MIM 616331, 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: >-
    Eight subjects carrying six distinct DVL1 frameshifts in the defining
    series, with further cases since. No denominator-based estimate exists, so
    the count is recorded rather than a rate.
  evidence:
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, six distinct frameshift mutations were found in eight subjects,
      and all were heterozygous truncating variants within the penultimate exon
      of DVL1.
    explanation: >-
      Gives the cohort size on which the entity was delineated.
inheritance:
- name: Autosomal dominant, usually de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: "majority"
  description: >-
    Autosomal dominant. In the families where parental samples were available,
    the variants were de novo, so an unaffected-parent pedigree does not argue
    against the diagnosis.
  evidence:
  - 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.
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In five families in which samples from unaffected parents were available,
      the variants were demonstrated to represent de novo mutations.
    explanation: >-
      Establishes de novo origin in the families that could be tested.
pathophysiology:
- name: DVL1 Penultimate-Exon Frameshift Escaping Nonsense-Mediated Decay
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DVL1
    term:
      id: hgnc:3084
      label: DVL1
  genetic_context:
    gene:
      preferred_term: DVL1
      term:
        id: hgnc:3084
        label: DVL1
    allele_type: penultimate-exon -1 frameshift escaping nonsense-mediated decay
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    notes: >-
      DOMINANT_NEGATIVE is a mechanistic reading of an NMD-escaping
      altered-C-terminus allele expressed alongside wild type. The 2026
      functional work supports a mixed picture — reduced signalling shared with
      a plain truncation, plus a nuclear mislocalization unique to the
      frameshift — which no single enum value captures cleanly. See the
      ``dvl1_frameshift_mode_of_action`` discussion.
  description: >-
    The variants are confined to the penultimate exon, so the premature
    termination codon falls in the last exon and the transcript escapes
    nonsense-mediated decay. Both wild-type and variant transcripts are
    detectable in patient leukocytes, so the altered protein is genuinely made.
  evidence:
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variant alleles are predicted to result in a premature termination
      codon within the last exon, escape nonsense-mediated decay (NMD), and most
      likely generate a C-terminally truncated protein with a distinct -1
      reading-frame terminus.
    explanation: >-
      States the NMD-escape architecture that defines this allele class.
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Study of the transcripts extracted from affected subjects' leukocytes
      confirmed expression of both wild-type and variant alleles, supporting the
      hypothesis that mutant mRNA escapes NMD.
    explanation: >-
      Patient-derived confirmation that the mutant transcript is expressed
      rather than degraded.
  downstream:
  - target: Reduced WNT Signal Transduction Through Dishevelled
    causal_link_type: DIRECT
    description: >-
      The altered protein sits in the transducer position of the pathway.
  - target: Nuclear Mislocalization of Altered Dishevelled
    causal_link_type: DIRECT
    description: >-
      A property of the novel C-terminal peptide, not of losing the wild-type
      one.
- name: Reduced WNT Signal Transduction Through Dishevelled
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    In luciferase assays in facial mesenchyme, wild-type DVL1 activates both
    canonical and JNK-PCP WNT signalling, while the frameshift protein and a
    plain stop codon at the same position both signal significantly less. The
    loss-of-signalling component is therefore attributable to the missing
    wild-type C-terminus and is shared with an ordinary truncation.
  biological_processes:
  - preferred_term: non-canonical Wnt signaling pathway
    modifier: DECREASED
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    modifier: DECREASED
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
  evidence:
  - reference: PMID:42424595
    reference_title: "The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In luciferase assays carried out in facial mesenchyme, wtDVL1 activated
      canonical and JNK-PCP WNT signalling whereas the DVL11519* and the
      DVL11519ΔT variant had significantly lower signaling activity.
    explanation: >-
      Measures the signalling deficit and, by including the stop-codon
      construct, shows it is not specific to the frameshift.
  downstream:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    causal_link_type: DIRECT
    description: >-
      Reduced PCP transduction is the input to the developmental phenotype.
- name: Nuclear Mislocalization of Altered Dishevelled
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Dishevelled is a cytoplasmic signal transducer. The protein made from the
    frameshift allele is found in the nucleus instead, while both wild-type
    DVL1 and the stop-codon construct stay cytoplasmic. In Drosophila, only the
    frameshift allele perturbs morphogenesis and signalling. This is the
    component of the allele's effect that a simple loss of the C-terminus does
    not reproduce, and the authors raise altered nuclear transcription as the
    candidate consequence.
  evidence:
  - reference: PMID:42424595
    reference_title: "The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also determined that there is mislocalization of the protein expressed
      from DVL11519ΔT in the nucleus while the other two constructs were
      expressed in the cytoplasm.
    explanation: >-
      Establishes that the mislocalization is specific to the frameshift
      product.
  - reference: PMID:42424595
    reference_title: "The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In complementary Drosophila experiments using a variety of readouts, only
      the DVL11519ΔT variant and not the 1519* impacted morphogenesis and
      signaling.
    explanation: >-
      The discriminating in vivo result: the frameshift perturbs morphogenesis
      where an equivalent truncation does not.
  downstream:
  - target: Disrupted Planar Cell Polarity in Developing Skeleton and Face
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Whether the nuclear protein alters transcription, and which targets, is
      not established.
  - target: Increased Cranial Bone Mineral Density
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Osteosclerosis is restricted to this genotype among molecularly
      characterized Robinow patients, so it is attributed to the DVL1-specific
      component of the allele's effect rather than to reduced PCP signalling
      shared with the other genes. The intermediate steps are unidentified.
- name: Disrupted Planar Cell Polarity in Developing Skeleton and Face
  role: central_effector
  biological_scale: TISSUE
  description: >-
    The shared endpoint of every Robinow genotype: 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 — reduced presomitic mesoderm, perturbed chondrocyte
    differentiation, midline outgrowth failure, genital tubercle reduction —
    comes from the Ror2-null mouse and is inherited here by pathway membership
    rather than demonstrated for DVL1.
  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: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: >-
      Establishes that DVL1 disease shares a final common pathway with the other
      Robinow genes, which is what licenses the shared developmental model.
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: DIRECT
    description: >-
      Disordered growth plate chondrocyte behaviour shortens the middle limb
      segment.
  - 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.
- name: Increased Cranial Bone Mineral Density
  role: consequence
  biological_scale: TISSUE
  description: >-
    The DVL1-specific bone phenotype. High-resolution peripheral quantitative CT
    in molecularly confirmed patients shows a distinctive pattern — low cortical
    but increased trabecular bone mineral density, with fewer and thicker
    trabeculations — and cranial osteosclerosis is confined to the DVL1 (and one
    GPC4) genotype.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone development
    modifier: DYSREGULATED
    term:
      id: GO:0060348
      label: bone development
  evidence:
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS
      (1/1) subjects and in one case was complicated by choanal atresia,
      bilateral conductive hearing loss, and cranial nerve III, VI, and VII
      palsy.
    explanation: >-
      Establishes the genotype restriction of the osteosclerosis and its
      clinical consequences.
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HR-pQCT revealed a unique pattern of low cortical BMD, increased
      trabecular BMD, decreased number of trabeculations, and increased
      thickness of the trabeculations for the DVL1-RS subjects.
    explanation: >-
      Gives the micro-architectural signature, which is not simply more bone
      everywhere.
  downstream:
  - target: Skull Osteosclerosis
    causal_link_type: DIRECT
    description: >-
      The radiographic expression of the cranial bone phenotype.
  - target: Increased Bone Mineral Density
    causal_link_type: DIRECT
    description: >-
      The DEXA-measurable expression of the same phenotype.
  - target: Macrocephaly
    causal_link_type: DIRECT
    description: >-
      Persistent macrocephaly travels with the osteosclerotic variant.
  - target: Hearing Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Conductive hearing loss follows from skull-base osteosclerosis narrowing
      the middle-ear and foraminal spaces, in the same patients whose cranial
      nerve palsies arise the same way.
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: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 describes the skeletal phenotype of the dominant syndrome, of
      which this entry is one gene form.
- category: Skeletal
  name: Skull Osteosclerosis
  description: >-
    Increased cranial bone density, restricted among molecularly characterized
    Robinow patients to this genotype. It can cause choanal atresia, conductive
    hearing loss and cranial nerve palsies through foraminal narrowing.
  phenotype_term:
    preferred_term: Calvarial osteosclerosis
    term:
      id: HP:0005450
      label: Calvarial osteosclerosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A variant of Robinow syndrome, associated with osteosclerosis and caused
      by a heterozygous pathogenic variant in DVL1, is characterized by normal
      stature, persistent macrocephaly, increased bone mineral density with
      skull osteosclerosis, and hearing loss
    explanation: >-
      GeneReviews attributes the osteosclerotic variant specifically to DVL1.
- category: Skeletal
  name: Increased Bone Mineral Density
  phenotype_term:
    preferred_term: Increased bone mineral density
    term:
      id: HP:0011001
      label: Increased bone mineral density
  frequency: FREQUENT
  evidence:
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DEXA scan measures revealed increased total body bone mineral density
      (BMD) (3/7), cranial BMD (5/7), and non-cranial BMD (1/7).
    explanation: >-
      Quantifies increased BMD by DEXA in the studied cohort.
- category: Craniofacial
  name: Macrocephaly
  description: >-
    Macrocephaly may be present prenatally and persists postnatally; it is a
    constant feature of the osteosclerotic variant.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A variant of Robinow syndrome, associated with osteosclerosis and caused
      by a heterozygous pathogenic variant in DVL1, is characterized by normal
      stature, persistent macrocephaly, increased bone mineral density with
      skull osteosclerosis, and hearing loss
    explanation: >-
      Persistent macrocephaly is named as part of the DVL1 variant.
- category: Auditory
  name: Hearing Loss
  description: >-
    At least partly conductive, arising from cranial osteosclerosis.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      increased bone mineral density with skull osteosclerosis, and hearing loss
    explanation: >-
      Hearing loss is listed as part of the DVL1 osteosclerotic variant.
- 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.
- 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:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genital abnormalities (in males: micropenis / webbed penis, hypoplastic
      scrotum, cryptorchidism; in females: hypoplastic clitoris and labia
      majora)
    explanation: >-
      Describes the genital phenotype 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: DVL1
  gene_term:
    preferred_term: DVL1
    term:
      id: hgnc:3084
      label: DVL1
  relationship_type: CAUSATIVE
  notes: >-
    Dishevelled 1. The pathogenic alleles are frameshifts confined to the
    penultimate exon — an unusually tight positional constraint that is
    diagnostically useful, since a truncating variant elsewhere in DVL1 should
    not be called causal for this entity on the strength of the gene alone.
  evidence:
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, six distinct frameshift mutations were found in eight subjects,
      and all were heterozygous truncating variants within the penultimate exon
      of DVL1.
    explanation: >-
      Establishes the gene, the allele class, and the exon restriction.
diagnosis:
- name: Molecular Confirmation of a DVL1 Penultimate-Exon Frameshift
  description: >-
    Confirmed by a heterozygous frameshift in the penultimate exon of DVL1.
    Because the alleles cluster in one exon, targeted sequencing of that exon in
    the DVL paralogs is a high-yield first step in a clinically typical dominant
    case; broad panel or exome testing is appropriate otherwise.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - 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.
  - 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: >-
      Supports the targeted penultimate-exon strategy described here.
differential_diagnoses:
- name: Autosomal Dominant Robinow Syndrome 1
  description: >-
    The WNT5A form. Hypomorphic ligand missense alleles rather than an altered
    transducer, and without the osteosclerosis, macrocephaly and preserved
    stature that mark the DVL1 form.
- name: Autosomal Dominant Robinow Syndrome 3
  description: >-
    The DVL3 form, mechanistically the closest relative: the same -1 frameshift
    architecture in the paralog. Distinguished by gene, not by phenotype.
- 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, and
    recessive inheritance.
- name: Osteopetrosis and other sclerosing bone disorders
  description: >-
    Considered when cranial osteosclerosis dominates the presentation. The
    Robinow facial gestalt, mesomelia and genital hypoplasia separate them, as
    does the DVL1 micro-architecture — low cortical with high trabecular
    density, rather than uniformly dense bone.
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 crowding and malocclusion that follow 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: Hearing and Head Circumference Surveillance
  description: >-
    Periodic hearing assessment matters more in this genotype than in the other
    Robinow forms, because the osteosclerosis that causes conductive loss is
    DVL1-specific and progressive foraminal narrowing is what produces the
    cranial nerve complications.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Increased Cranial Bone Mineral Density
    description: >-
      Surveillance is aimed at this node specifically: the osteosclerosis is what
      distinguishes DVL1-Robinow, and conductive hearing loss is its expected
      complication. Monitoring detects, it does not modify.
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Measurement of head circumference regularly in infancy and throughout
      childhood.
    explanation: >-
      States the head-circumference surveillance recommendation.
- 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 most
    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: dvl1_frameshift_mode_of_action
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the nuclear-mislocalized frameshift protein alter transcription, and is
    that what produces the skeletal phenotype and the DVL1-specific
    osteosclerosis?
  attaches_to:
  - pathophysiology#Nuclear Mislocalization of Altered Dishevelled
  rationale: >-
    The 2026 comparison against a stop codon at the same position settled that
    the reduced canonical and JNK-PCP signalling is a consequence of losing the
    wild-type C-terminus, not of the novel peptide — yet only the frameshift
    perturbs morphogenesis, and only it goes to the nucleus. Something the novel
    peptide does, beyond reduced signalling, is doing the work. The authors
    propose altered nuclear transcription; no target has been identified. The
    distinction is actionable: a gained nuclear activity is in principle a
    target for allele-specific knockdown, whereas a lost domain function is not.
    It would also explain why osteosclerosis is confined to this genotype.
references:
- reference: PMID:25577943
  title: "Autosomal Dominant Robinow Syndrome."
  tags:
  - GeneReviews
- reference: PMID:42424595
  title: "The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes."

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2

PMID:25577943

Autosomal Dominant Robinow Syndrome.

No top-level findings curated for this source.

PMID:42424595

The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.

No top-level findings curated for this source.

Autosomal Dominant Robinow Syndrome 2

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