Pure Hair and Nail Ectodermal Dysplasias (PHNED)

name: Pure Hair and Nail Ectodermal Dysplasias
display_name: Pure Hair and Nail Ectodermal Dysplasias (PHNED)
creation_date: "2026-08-17T00:00:00Z"
description: >-
  A curated grouping of the molecularly resolved pure hair and nail ectodermal
  dysplasia (PHNED) disease entries. Members share a phenotype restricted to two
  ectodermal appendages - congenital hypotrichosis or alopecia together with
  nail dystrophy - with sweat glands and dentition spared. That restriction is
  the point of the grouping: it is what separates PHNED from the hypohidrotic
  ectodermal dysplasias, which are grouped separately as
  `Hypohidrotic_Ectodermal_Dysplasias`. All three members are autosomal
  recessive and all three causal genes (KRT85, KRT74, HOXC13) lie in the same
  12q12-q14.1 interval containing the type II hair keratin and HOXC clusters,
  which is both why they were discovered as a series and why they are so easily
  confused for one another.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
- SHARED_PATHWAY
grouping_rationale: >-
  Modeled as an explicit curated union over three already-distinct Disease
  entries rather than as one umbrella Disease with `has_subtypes`. Three reasons.
  First, each gene-level form already carries its own MONDO identifier
  (MONDO:0011177 ECTD4, MONDO:0013975 ECTD7, MONDO:0013976 ECTD9) as a child of
  MONDO:0019071, and `KRT85_Ectodermal_Dysplasia` was already curated as a
  standalone entry - folding it into a new umbrella file would either duplicate
  that content or require retargeting an existing entry. Second, the ectodermal
  dysplasia curation work in this KB has followed a one-entry-per-gene
  convention, and `Hypohidrotic_Ectodermal_Dysplasias` is the direct precedent
  for expressing the umbrella as a Grouping with a `skos:closeMatch` to the
  MONDO parent. Third, the members are not mechanistically interchangeable: two
  are structural keratin defects and one is a transcription factor defect
  upstream of those very keratins, a distinction a blended umbrella pathograph
  would erase.

  The originating curation issue tagged this target `CURATE_ROOT_WITH_SUBTYPES`.
  Per the policy recorded in dismech#8727 and #8661, that dashboard label is a
  priority hint about where curation effort is worth spending, not a
  lump-versus-split ruling, so it does not override the split adopted here.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019071
      label: pure hair and nail ectodermal dysplasia
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch rather than exactMatch. The grouping corresponds to the MONDO
      class but is an explicit curated union over the three gene-resolved
      dismech Disease entries, not an automatic closure over every MONDO
      descendant. MONDO:0019071's own Orphanet-derived definition also states
      autosomal dominant transmission, which describes the historical
      gene-unresolved clinical cohort; every molecularly characterized member of
      this grouping is autosomal recessive, so the extensions are not identical.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Members are the three gene-resolved MONDO children of MONDO:0019071
        curated in dismech. The inheritance statement in the parent term's
        definition (autosomal dominant) is inconsistent with all three
        molecularly resolved children, which are autosomal recessive; see the
        discussion recorded on this grouping.
membership_criteria:
- description: >-
    A member is a Disease entry whose phenotype is restricted to hair and nail
    ectodermal appendages: it must carry a hair-deficiency phenotype
    (alopecia, sparse hair, or sparse scalp hair) and a nail dystrophy
    phenotype, and it must be caused by one of the three established PHNED
    genes. The defining sparing of sweat glands and dentition is asserted on
    each member with `frequency: EXCLUDED` phenotypes but is deliberately not
    encoded as a `negated` leaf here; see `notes` for why.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - operator: OR
      description: Has a hair-deficiency phenotype.
      operands:
      - criterion_predicate: HAS_PHENOTYPE
        description: Alopecia.
        phenotype_term:
          preferred_term: Alopecia
          term:
            id: HP:0001596
            label: Alopecia
      - criterion_predicate: HAS_PHENOTYPE
        description: Sparse hair, including sparse scalp hair.
        phenotype_term:
          preferred_term: Sparse hair
          term:
            id: HP:0008070
            label: Sparse hair
    - criterion_predicate: HAS_PHENOTYPE
      description: Nail dystrophy.
      phenotype_term:
        preferred_term: Nail dystrophy
        term:
          id: HP:0008404
          label: Nail dystrophy
    - operator: OR
      description: Caused by one of the three established PHNED genes.
      operands:
      - criterion_predicate: HAS_GENE
        description: KRT85 (ECTD4).
        gene:
          preferred_term: KRT85
          term:
            id: hgnc:6462
            label: KRT85
      - criterion_predicate: HAS_GENE
        description: KRT74 (ECTD7).
        gene:
          preferred_term: KRT74
          term:
            id: hgnc:28929
            label: KRT74
      - criterion_predicate: HAS_GENE
        description: HOXC13 (ECTD9).
        gene:
          preferred_term: HOXC13
          term:
            id: hgnc:5125
            label: HOXC13
- description: >-
    All molecularly resolved members are autosomal recessive. This is recorded
    as a separate NECESSARY block because it is a property of the gene-solved
    entities rather than of the clinical PHNED concept, whose MONDO/Orphanet
    definition still describes autosomal dominant transmission of the older
    gene-unresolved pedigrees. The assertion is kept because it holds for all
    three members and is the precise point on which this grouping diverges from
    its MONDO parent. (This block used to report UNKNOWN for every member
    because `evaluate_grouping` did not implement HAS_INHERITANCE; it now does,
    so naming the term below makes the block checkable and all three members
    resolve to SATISFIED.)
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_INHERITANCE
    description: Autosomal recessive inheritance (HP:0000007).
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
members:
- member: KRT85-Related Pure Hair-Nail Ectodermal Dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ECTD4 (MONDO:0011177). KRT85 encodes a type II hair keratin of the hair
      cortex and cuticle that pairs with KRT35; biallelic variants destabilize
      or abolish K85-K35 intermediate filament assembly, so the lesion is
      structural and sits in the hair shaft cortex itself. Distinguished from
      its keratin sibling ECTD7 by compartment (hair cortex/cuticle and nail
      matrix versus inner root sheath) and from ECTD9 by acting as a structural
      protein rather than as the transcription factor that regulates it.
    gene:
      preferred_term: KRT85
      term:
        id: hgnc:6462
        label: KRT85
    module: null
- member: KRT74-Related Pure Hair-Nail Ectodermal Dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ECTD7 (MONDO:0013975). KRT74 encodes a type II keratin of the hair
      follicle inner root sheath, also expressed in nail matrix, nail bed, and
      hyponychium. The single reported allele (homozygous p.Phe274Ser, coil 1B)
      abolishes detectable keratin-74 protein, a loss-of-function mechanism.
      Uniquely among the members, KRT74 is allelic with a dominant disease:
      heterozygous KRT74 variants cause autosomal dominant woolly
      hair/hypotrichosis simplex (curated as the ADWH subtype of
      `Isolated_Woolly_Hair`), which acts dominant-negatively and generally
      spares the nails.
    gene:
      preferred_term: KRT74
      term:
        id: hgnc:28929
        label: KRT74
- member: HOXC13-Related Pure Hair-Nail Ectodermal Dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ECTD9 (MONDO:0013976). HOXC13 is not a structural protein but the
      homeodomain transcription factor that drives the terminal differentiation
      program of hair- and nail-forming keratinocytes. Its reported targets
      include FOXN1, KRT35, and KRT85 - so the HOXC13 form sits directly
      upstream of the KRT85 form within a single regulatory pathway, and the two
      are related as regulator and target rather than as mere phenocopies.
      Alleles reach loss of function by three routes (nonsense-mediated decay,
      impaired DNA binding, reduced protein stability), and this member alone
      has large-animal models (knockout pig, rabbit).
    gene:
      preferred_term: HOXC13
      term:
        id: hgnc:5125
        label: HOXC13
    biological_processes:
    - preferred_term: regulation of transcription by RNA polymerase II
      term:
        id: GO:0006357
        label: regulation of transcription by RNA polymerase II
      modifier: DECREASED
discussions:
- discussion_id: phned_inheritance_mismatch_with_mondo_parent
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the autosomal dominant PHNED pedigrees behind MONDO:0019071's definition
    represent a fourth, still gene-unresolved PHNED locus, or were they
    misclassified?
  rationale: >-
    MONDO:0019071 inherits its definition from Orphanet ORPHA:69084, which
    states that fewer than 20 cases have been reported and that "the mode of
    transmission is autosomal dominant". Every one of the three molecularly
    resolved forms grouped here is autosomal recessive. The dominant statement
    therefore describes the older clinical cohort that was described before any
    causal gene was known, and the discrepancy is unresolved in the literature:
    either those pedigrees carry variants at a locus not yet identified, or the
    dominant transmission was an artifact of ascertainment or of conflation with
    the dominant KRT74 woolly-hair phenotype, which is allelic to ECTD7 and
    shares the hair findings. A 2017 report notes that five PHNED forms have
    been described at molecular level with three genes known and two loci with
    no gene yet, which is consistent with an unresolved fourth and fifth locus
    but does not settle the inheritance question.
  proposed_experiments:
  - experiment_id: phned_ad_pedigree_reanalysis
    name: Genome sequencing of the historical autosomal dominant PHNED pedigrees
    description: >-
      Re-ascertain and genome-sequence the classically described dominant PHNED
      families to determine whether they carry variants at one of the two mapped
      but unresolved PHNED loci, a heterozygous KRT74 woolly-hair allele, or
      something else. Resolution would either add a fourth member to this
      grouping or retire the dominant claim from the parent MONDO definition.
notes: >-
  Scope. This grouping covers only the gene-resolved PHNED entities. It
  deliberately excludes: the hypohidrotic ectodermal dysplasias (grouped
  separately as `Hypohidrotic_Ectodermal_Dysplasias`), syndromic entries such as
  `TP63_Ectodermal_Dysplasia_Spectrum` and `Cranioectodermal_Dysplasia`, the
  immunodeficiency-associated ectodermal dysplasias, and `Isolated_Woolly_Hair`
  - the last of which is the closest trap, since its ADWH subtype is caused by
  heterozygous variants in KRT74, the same gene as member ECTD7, but is a
  different disease with different zygosity, a dominant-negative mechanism, and
  no nail involvement. Also excluded is HR-related atrichia with papular lesions
  (MONDO:0008847): despite prominent alopecia it is not a PHNED and is not a child
  of MONDO:0019071 - it sits under MONDO:0004907 alopecia / disorder of the
  pilosebaceous unit, its second cardinal feature is papular lesions rather than
  nail dystrophy, and it fails this grouping's hair-AND-nail criterion on the
  merits.

  ECTD numbering. The originating curation issue dismech#8656 labeled the members
  as ECTD8 (HOXC13) and ECTD9 (HR); both are wrong. MONDO and the literature place
  HOXC13 at ECTD9 (MONDO:0013976), there is no ECTD8 gene among these members, and
  HR is not a PHNED gene at all (see the exclusion above). The member list and
  rationale here follow the corrected MONDO numbering: KRT85 = ECTD4, KRT74 =
  ECTD7, HOXC13 = ECTD9.

  Why the sparing of teeth and sweat glands is not a `negated` criteria leaf.
  Each member records the sparing explicitly, as phenotypes with `frequency:
  EXCLUDED` and `modifier: ABSENT` on HP:0000966 Hypohidrosis and HP:0000668
  Hypodontia. That is the KB's established way to carry an informative negative.
  It cannot currently be lifted into a `negated: true` HAS_PHENOTYPE leaf here,
  because `evaluate_grouping` collects every `phenotype_term` HP id from a
  member without consulting `frequency`, so an EXCLUDED phenotype is
  indistinguishable from a present one at criteria-evaluation time
  (`modifier: ABSENT` is not read at all). This was tried and measured: adding
  the negated leaves flipped the KRT74 and HOXC13 members to NOT_SATISFIED
  while KRT85 - which curates neither exclusion and is simply silent about
  sweating and teeth - continued to pass. The inversion is the point: the two
  members that do the curation the criteria ask for are the two reported as
  contradicting them, and silence is rewarded. The criteria above are therefore
  positive only; the exclusion is stated in the criteria `description` and
  enforced by curation review rather than by the evaluator.

  Making the evaluator honour `frequency: EXCLUDED` as phenotype-absent is the
  real fix and would let every future grouping express an informative negative,
  but it changes verdicts for all groupings and for the existing entries already
  using EXCLUDED, so it belongs in its own PR rather than in a curation change.