Robinow syndrome (WNT/PCP pathway forms)

name: Robinow Syndrome
display_name: Robinow syndrome (WNT/PCP pathway forms)
creation_date: "2026-08-27T00:00:00Z"
description: >-
  Robinow syndrome is a genetically heterogeneous skeletal dysplasia defined by
  a triad of mesomelic limb shortening, genital hypoplasia and a distinctive
  "fetal face" — macrocephaly, a broad prominent forehead, ocular hypertelorism,
  a short upturned nose and midface retrusion.

  Every established causal gene encodes a component of one signalling module:
  the beta-catenin-independent WNT/planar cell polarity pathway. WNT5A is the
  ligand, ROR2 and FZD2 the co-receptors, DVL1 and DVL3 the cytoplasmic
  transducers, and NXN a redox regulator of Dishevelled. The syndrome therefore
  behaves as a pathway disease: genotypes that look unrelated produce one
  recognizable clinical entity.

  Severity tracks position in the cascade more closely than allele dosage.
  Receptor-level loss (biallelic ROR2) is the severe end, adding vertebral
  segmentation defects and rib fusions that no other form produces.
  Transducer-level lesions are milder — and biallelic NXN disease, despite being
  recessive, clusters phenotypically with the heterozygous DVL forms rather than
  with ROR2 disease.
grouping_basis:
- SHARED_PATHWAY
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared final-common-pathway mechanism: every member is caused by
  loss or alteration of a component of the WNT/planar cell polarity cascade, and
  the published framing is explicitly convergent — "six genes that converge on
  the WNT/planar cell polarity (PCP) signaling pathway" (PMID:35047859).

  The members are deliberately kept as separate Disease entries rather than
  merged into one. They differ in the causal gene, in inheritance mode
  (ROR2 and NXN recessive, the rest dominant), in the direction and nature of
  the molecular lesion (a hypomorphic ligand in WNT5A disease, absent receptor
  in ROR2 disease, an NMD-escaping altered transducer in the DVL forms), and in
  clinically separable features — vertebral segmentation defects and rib fusions
  confined to the ROR2 form, osteosclerosis with preserved stature confined to
  the DVL1 form. The ISDS Nosology lists them as six separate rows and MONDO
  gives most of them their own class.

  This is a grouping over distinct entities, not a lumping of them into one
  disease. Whether a single lumped Robinow entry would serve readers better
  remains an open question; the split is the current convention and the
  grouping is what makes the union visible without pre-empting that decision.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019978
      label: Robinow syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO Robinow syndrome class.
      exactMatch records the intended conceptual alignment; the FZD2-related
      form has no MONDO class of its own and is therefore a curation gap rather
      than evidence that the mapping is only a close match.
membership_criteria:
- description: >-
    A disorder belongs to the Robinow syndrome grouping if it is caused by
    variants in a gene encoding a component of the WNT/planar cell polarity
    signalling cascade AND presents with mesomelic limb shortening.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - operator: OR
      description: >-
        Caused by variants in one of the established WNT/PCP pathway genes.
      operands:
      - criterion_predicate: HAS_GENE
        gene:
          preferred_term: WNT5A
          term:
            id: hgnc:12784
            label: WNT5A
        description: The non-canonical WNT ligand.
      - criterion_predicate: HAS_GENE
        gene:
          preferred_term: ROR2
          term:
            id: hgnc:10257
            label: ROR2
        description: The WNT5A co-receptor.
      - criterion_predicate: HAS_GENE
        gene:
          preferred_term: DVL1
          term:
            id: hgnc:3084
            label: DVL1
        description: Cytoplasmic transducer.
      - criterion_predicate: HAS_GENE
        gene:
          preferred_term: DVL3
          term:
            id: hgnc:3087
            label: DVL3
        description: Cytoplasmic transducer, paralog of DVL1.
      - criterion_predicate: HAS_GENE
        gene:
          preferred_term: NXN
          term:
            id: hgnc:18008
            label: NXN
        description: Redox regulator of Dishevelled.
    - criterion_predicate: HAS_PHENOTYPE
      description: >-
        Mesomelic limb shortening, the skeletal component of the defining triad.
      phenotype_term:
        preferred_term: Mesomelia
        term:
          id: HP:0003027
          label: Mesomelia
members:
- member: Autosomal Dominant Robinow Syndrome 1
  member_type: DISEASE
  display_name: DRS1 (WNT5A-related)
  differentiating_mechanisms:
  - description: >-
      Heterozygous missense alleles substituting highly conserved cysteines in
      the WNT5A ligand. The alleles are hypomorphic rather than null in
      functional assays, which is consistent with the milder dominant phenotype
      relative to complete receptor loss. This is the only form in which the
      lesion is in the ligand itself.
    gene:
      preferred_term: WNT5A
      term:
        id: hgnc:12784
        label: WNT5A
- member: Autosomal Dominant Robinow Syndrome 2
  member_type: DISEASE
  display_name: DRS2 (DVL1-related)
  differentiating_mechanisms:
  - description: >-
      Heterozygous frameshifts confined to the penultimate exon of DVL1,
      escaping nonsense-mediated decay and producing an altered transducer with
      a novel -1 reading-frame C-terminus. Uniquely among the members, this form
      carries the osteosclerotic variant of the syndrome: normal stature,
      persistent macrocephaly, increased cranial bone mineral density and
      hearing loss.
    gene:
      preferred_term: DVL1
      term:
        id: hgnc:3084
        label: DVL1
- member: Autosomal Dominant Robinow Syndrome 3
  member_type: DISEASE
  display_name: DRS3 (DVL3-related)
  differentiating_mechanisms:
  - description: >-
      Heterozygous de novo splice-acceptor variants and single-base deletions in
      DVL3 that all converge on a -1 frameshift of the last exon — the same
      allele architecture as DVL1, in the paralog. Distinguished from DRS2 by
      gene and by the absence of the osteosclerotic phenotype.
    gene:
      preferred_term: DVL3
      term:
        id: hgnc:3087
        label: DVL3
- member: Autosomal Recessive Robinow Syndrome
  member_type: DISEASE
  display_name: RRS (ROR2-related)
  differentiating_mechanisms:
  - description: >-
      Biallelic loss-of-function alleles in the WNT5A co-receptor ROR2, reaching
      absence of the receptor either through nonsense-mediated decay of
      truncating transcripts or endoplasmic-reticulum retention of missense
      protein. The severe end of the spectrum, and the only form with vertebral
      segmentation defects and rib fusions — the features that gave it the
      original COVESDEM name.
    gene:
      preferred_term: ROR2
      term:
        id: hgnc:10257
        label: ROR2
- member: Robinow Syndrome, Autosomal Recessive 2
  member_type: DISEASE
  display_name: RRS2 (NXN-related)
  differentiating_mechanisms:
  - description: >-
      Biallelic variants in nucleoredoxin, a redox regulator of Dishevelled.
      Recessive like the ROR2 form, but phenotypically clustering with the
      dominant DVL-related forms — the observation that severity in this
      grouping tracks position in the cascade rather than allele dosage.
    gene:
      preferred_term: NXN
      term:
        id: hgnc:18008
        label: NXN
notes: >-
  Members not yet curated as their own entries.

  FZD2-related Robinow syndrome is listed by the ISDS Nosology as row
  NOS 15-0080 and was established alongside NXN in the WNT5A-interactome screen
  (PMID:29276006), but MONDO has no class for it and the nosology table gives it
  no MIM number, so there is nothing to key a dismech entry on. FZD2 also causes
  autosomal dominant omodysplasia, which IS curated
  (``kb/disorders/Omodysplasia.yaml``, the OMOD2 subtype), and the two
  presentations overlap clinically — whether they are one continuum is an open
  question recorded in that entry.

  DVL2 has a single reported Robinow-associated variant (PMID:35047859) and
  GPC4 and RAC3 are single-family candidates (PMID:29276006). None is an
  established subtype in MONDO or the ISDS Nosology, so none is a member here.
  They are described in the member entries' genetic sections with
  ``relationship_type: UNKNOWN``.

  Brachydactyly type B is allelic at ROR2 but is deliberately NOT a member: the
  alleles sit downstream of the Robinow positions and act by gain of function or
  dominant negative rather than loss of function, so it fails the mechanism
  premise of this grouping rather than merely differing in severity.
references:
- reference: PMID:35047859
  title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
- reference: PMID:29276006
  title: "WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome."