Acromesomelic Dysplasias (ISDS group 16)

name: Acromesomelic Dysplasias
display_name: Acromesomelic Dysplasias (ISDS group 16)
creation_date: "2026-08-27T00:00:00Z"
description: >-
  The acromesomelic dysplasias are skeletal dysplasias in which limb shortening
  falls disproportionately on the middle (forearm, lower leg) and distal (hand,
  foot) segments, sparing or largely sparing the proximal segment and the axial
  skeleton. They are group 16 of the ISDS Nosology of Genetic Skeletal
  Disorders. The grouping is radiographic in origin but has resolved into two
  molecular families: the CNP/NPR-B/cGKII growth-signalling axis, where NPR2
  variants cause the Maroteaux type and variants in its downstream kinase PRKG2
  cause a closely overlapping disorder, and the GDF5-BMPR1B ligand-receptor
  pair, where the severity of limb malformation tracks how much signalling the
  alleles leave behind - from du Pan syndrome at the mild end to Grebe dysplasia
  at the severe end, reachable from either the ligand or the receptor. The two
  families are radiographically separable at the bedside: the CNP-axis disorders
  affect the craniofacial and axial skeleton and leave all skeletal elements
  present but abnormally grown, whereas the GDF5-BMPR1B disorders spare the
  axial skeleton and delete or fuse distal elements outright.
grouping_basis:
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped because the ISDS Nosology Committee groups them: this is a
  transcription of an expert nosology group, whose organising principle is the
  radiographic distribution of limb shortening rather than a shared mechanism.
  Two distinct signalling pathways are represented, so SHARED_MECHANISM would
  overstate what the members have in common - hence SHARED_PHENOTYPE plus
  CLINICAL_CONVENTION. The members are kept as separate Disease entries because
  they differ in causal gene, pathway, inheritance detail, and the presence of
  extraskeletal involvement; two of them (Grebe dysplasia and du Pan syndrome)
  themselves lump OMIM entities that the nosology treats as one, and that
  lumping is recorded inside those entries rather than here.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019696
      label: acromesomelic dysplasia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO acromesomelic dysplasia
      class. exactMatch records the intended conceptual alignment; MONDO
      descendants without a dismech entry are curation gaps rather than evidence
      that the grouping is only a close match.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Every listed member binds a MONDO class that is a descendant of
        MONDO:0019696. Two descendants have no dismech Disease entry and are
        recorded as gaps rather than omissions: MONDO:0007219
        (Osebold-Remondini syndrome), which the 2023 nosology lists in group 16
        but which has no identified locus and therefore no curatable mechanism -
        it is held in stubs/Osebold-Remondini_Syndrome.yaml - and MONDO:0021805
        (acromesomelic dysplasia, Campailla Martinelli type), a historical
        eponym that the nosology does not list separately.
membership_criteria:
- description: >-
    A disorder belongs to this grouping if and only if the ISDS Nosology places
    it in group 16, recorded on the member Disease entry as
    classifications.isds_skeletal_category = acromesomelic_dysplasias. The
    grouping is a transcription of the committee's placement, so the
    classification is both necessary and sufficient; it is deliberately not
    extended to skeletal-phenotype disorders the committee chose not to list.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "isds_skeletal_category:acromesomelic_dysplasias"
    description: >-
      Assigned to ISDS group 16 (acromesomelic dysplasias) via
      classifications.isds_skeletal_category on the member Disease entry. Stated
      in the keyed `<slot>:<value>` form so the audit reads the structured
      classifications block.
- description: >-
    Clinically, every member shows disproportionate shortening of the
    appendicular skeleton that predominantly affects the middle and distal limb
    segments. This is recorded as the group's defining description rather than
    as machine-evaluable logic: the phenotype is annotated as Acromesomelia
    (HP:0003086) in the CNP-axis members but as element-specific findings
    (micromelia, fibular hypoplasia, complex brachydactyly) in the GDF5-BMPR1B
    members, which no single HP class subsumes without over- or under-reaching.
    It is also not invariable - one reported PRKG2 family had no acromesomelic
    shortening at all - so making it a necessary condition would contradict a
    curated member.
members:
- member: Acromesomelic Dysplasia Maroteaux Type
  member_type: DISEASE
  display_name: Acromesomelic dysplasia, Maroteaux type (AMDM, NPR2)
  differentiating_mechanisms:
  - description: >-
      Biallelic NPR2 loss of function disables natriuretic peptide receptor B,
      reducing CNP-stimulated cGMP production in growth-plate chondrocytes. The
      archetype of the CNP-axis half of the group, and the only member in which
      the craniofacial and axial skeleton are characteristically involved.
    gene:
      preferred_term: NPR2
      term:
        id: hgnc:7944
        label: NPR2
- member: Acromesomelic Dysplasia PRKG2 Type
  member_type: DISEASE
  display_name: Acromesomelic dysplasia, PRKG2 type (AMDP)
  differentiating_mechanisms:
  - description: >-
      Biallelic PRKG2 loss of function removes cGMP-dependent protein kinase II,
      the intracellular effector immediately downstream of NPR-B. The lesion sits
      one step below the Maroteaux type in the same axis, and the phenotype is
      correspondingly close, with progressive metaphyseal change and
      platyspondyly with anterior vertebral beaking as its distinguishing
      radiographic marks.
    gene:
      preferred_term: PRKG2
      term:
        id: hgnc:9416
        label: PRKG2
- member: Acromesomelic Dysplasia Grebe Type
  member_type: DISEASE
  display_name: Grebe dysplasia, GDF5-related (incl. Hunter-Thompson type)
  differentiating_mechanisms:
  - description: >-
      Biallelic GDF5 mature-domain variants abolish signalling through the
      BMPR1B receptor. The severe end of the GDF5-BMPR1B half of the group:
      rudimentary digits with absent and fused hand and foot elements on a
      spared axial skeleton. The classic missense allele is additionally
      dominant-negative, sequestering other BMP ligands, which is why
      heterozygous carriers have brachydactyly rather than being unaffected.
    gene:
      preferred_term: GDF5
      term:
        id: hgnc:4220
        label: GDF5
- member: Du Pan Syndrome
  member_type: DISEASE
  display_name: Du Pan syndrome (fibular hypoplasia and complex brachydactyly)
  differentiating_mechanisms:
  - description: >-
      Biallelic hypomorphic GDF5 variants leave partial ligand function. The
      mild end of the same ligand-receptor axis: fibular hypoplasia with complex
      brachydactyly on preserved stature and preserved long bones.
    gene:
      preferred_term: GDF5
      term:
        id: hgnc:4220
        label: GDF5
  - description: >-
      Biallelic hypomorphic BMPR1B variants produce the clinically
      indistinguishable receptor-side form. The functionally characterised
      p.Arg31Cys allele reduces receptor function less than the Grebe-causing
      p.Cys53Arg allele in the same gene, which is the direct evidence that the
      Grebe / du Pan split is a matter of residual signalling rather than of
      which gene is hit.
    gene:
      preferred_term: BMPR1B
      term:
        id: hgnc:1077
        label: BMPR1B
- member: Acromesomelic Dysplasia Demirhan Type
  member_type: DISEASE
  display_name: Grebe dysplasia, BMPR1B-related (Demirhan type)
  differentiating_mechanisms:
  - description: >-
      Biallelic BMPR1B loss of function removes the receptor rather than the
      ligand, producing a Grebe-like limb phenotype. The only member with
      reported extraskeletal involvement - uterine hypoplasia with ovarian
      dysfunction and hypergonadotrophic hypogonadism in the index patient -
      which is why the nosology keeps it separate from the GDF5-related Grebe
      entity. It is also the mechanistic contrast case for the dominant BMPR1B
      brachydactylies, which arise from dominant-negative rather than
      loss-of-function alleles.
    gene:
      preferred_term: BMPR1B
      term:
        id: hgnc:1077
        label: BMPR1B
notes: >-
  Created during a review of ISDS 2023 nosology group 16. The group has seven
  rows in the 2023 revision; five are curated here, the GDF5-related and
  BMPR1B-related du Pan rows being curated as one Du Pan Syndrome entry because
  MONDO carries a single concept for them and no published feature distinguishes
  them clinically. The seventh, Osebold-Remondini syndrome, has no identified
  locus and is held in the stub queue.