Alopecia-Intellectual Disability Syndromes (APMR series)

name: Alopecia-Intellectual Disability Syndromes
display_name: Alopecia-Intellectual Disability Syndromes (APMR series)
creation_date: '2026-08-26T09:00:00Z'
description: >-
  The alopecia-intellectual disability syndromes (APMR; historically "alopecia with
  mental retardation syndrome", also Perniola-Krajewska-Carnevale syndrome) are a
  numbered series of rare autosomal recessive neuroectodermal disorders that pair
  congenital total or near-total absence of scalp, eyebrow and eyelash hair with
  intellectual disability of variable degree. Four forms are recognised, and they are
  genetically distinct rather than a severity spectrum of one gene: APMR1 maps to
  3q26.33-q27.3 and is caused by AHSG (alpha-2-HS-glycoprotein / fetuin-A) at 3q27.3;
  APMR4 is caused by LSS (lanosterol synthase) at 21q22.3; and the APMR2
  (3q26.2-q26.31) and APMR3 (18q11.2-q12.2) loci remain uncharacterised, with no
  causal gene assigned to either.

  The grouping exists because the series is a real differential-diagnostic set — a
  child presenting with congenital atrichia plus developmental delay is an APMR
  presentation before it is any particular numbered form, and the forms are separated
  only by gene testing — while the members are genuinely different diseases whose
  mechanisms have nothing in common. APMR4 is a defect of the committed cyclization
  step of cholesterol biosynthesis; APMR1 is a defect of a secreted plasma glycoprotein
  whose route to hair and brain is not established. Modelling the series as one Disease
  with has_subtypes would assert a shared mechanism that does not exist and would
  attach four incompatible pathophysiology chains to a single entry.

  Only the two molecularly characterised forms are listed as members. APMR2 and APMR3
  are recorded in the notes as locus-only concepts, deliberately not curated as Disease
  entries: a dismech Disease entry needs a mechanism, and a linkage interval with an
  explicitly excluded candidate-gene list is not one.
grouping_basis:
- SHARED_PHENOTYPE
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on the shared two-component phenotype — congenital alopecia/atrichia together
  with intellectual disability — and on the clinical and nosological convention (an OMIM
  phenotypic series, PS203650, and a MONDO grouping class) that treats the numbered
  forms as one set. It is emphatically NOT grouped on a shared mechanism. The two
  characterised members converge on no pathway: LSS is an endoplasmic-reticulum enzyme
  catalysing the rate-limiting cyclization of (S)-2,3-oxidosqualene to lanosterol, and
  its APMR4 phenotype is attributed to locally reduced cholesterol biosynthesis in skin
  and brain; AHSG encodes a liver-secreted plasma glycoprotein best characterised as an
  inhibitor of ectopic calcification and an antagonist of TGF-beta family signalling,
  and no established route links it to the hair follicle or the developing cortex. The
  two genes sit on different chromosomes (3q27.3 and 21q22.3).

  The criteria are NECESSARY rather than NECESSARY_AND_SUFFICIENT. Congenital alopecia
  plus intellectual disability is required for membership, but it does not by itself
  make a disorder an APMR: the same pairing occurs in several ectodermal dysplasias and
  in syndromic hypotrichoses, and atrichia with papular lesions (HR, 8p21.3) sits in the
  same clinical differential without belonging to this series. Membership additionally
  requires assignment to the APMR numbered series by a causal gene mapping to one of its
  loci.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008756
      label: alopecia - intellectual disability syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      exactMatch: MONDO:0008756 is the root class of the APMR numbered series and its
      extension is the series itself, which is exactly what this grouping enumerates. It
      is bound to a Grouping rather than to a Disease entry because it subsumes four
      genetically distinct entities; binding it to a Disease would require has_subtypes
      over four different causal genes on different chromosomes.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Alignment is conceptual, and deliberately narrower extensionally. MONDO:0008756
        subsumes all four numbered forms (MONDO:0021035 APMR1, MONDO:0012487 APMR2,
        MONDO:0013492 APMR3, MONDO:0030009 APMR4), but only APMR1 and APMR4 have a causal
        gene and therefore a curatable mechanism. APMR2 and APMR3 are listed here as
        known curation gaps rather than as members, and they should not be treated as
        outstanding dismech work until a gene is published for either locus.
membership_criteria:
- description: >-
    A disorder belongs to the alopecia-intellectual disability syndromes if it presents
    with BOTH congenital or early-onset alopecia (total or near-total absence of scalp
    hair, typically with sparse or absent eyebrows and eyelashes) AND intellectual
    disability, inherited as an autosomal recessive trait, AND is assigned to the APMR
    numbered series by a causal gene mapping to one of the four APMR loci. Either
    clinical feature alone is insufficient, and the phenotype pairing alone is
    insufficient without the series assignment.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Alopecia, congenital or early onset, affecting scalp and usually eyebrows and eyelashes.
      phenotype_term:
        preferred_term: Alopecia
        term:
          id: HP:0001596
          label: Alopecia
    - criterion_predicate: HAS_PHENOTYPE
      description: Intellectual disability, of any severity from mild to severe.
      phenotype_term:
        preferred_term: Intellectual disability
        term:
          id: HP:0001249
          label: Intellectual disability
    - criterion_predicate: HAS_INHERITANCE
      description: Autosomal recessive inheritance.
      inheritance_term:
        preferred_term: Autosomal recessive inheritance
        term:
          id: HP:0000007
          label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33881165
    reference_title: "Alopecia-mental retardation syndrome: Molecular genetics of a rare neuro-dermal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by heterogeneous phenotypic features, that is, absence of hair on the scalp, eyelashes, and eyebrows and mild to severe intellectual disability."
    explanation: >-
      States the two-component phenotype and its severity range, which is the shared
      criterion this grouping is drawn on.
  - reference: PMID:33881165
    reference_title: "Alopecia-mental retardation syndrome: Molecular genetics of a rare neuro-dermal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alopecia-mental retardation syndrome (APMR) is a rare autosomal recessive neuro-dermal disorder."
    explanation: Establishes the autosomal recessive conjunct of the membership criteria.
members:
- member: Alopecia-Intellectual Disability Syndrome 1
  member_type: DISEASE
  disease_term:
    preferred_term: alopecia-intellectual disability syndrome 1
    term:
      id: MONDO:0021035
      label: alopecia-intellectual disability syndrome 1
  differentiating_mechanisms:
  - description: >-
      The only member whose gene product is a secreted plasma glycoprotein rather than a
      metabolic enzyme, and the only one whose mechanism is unresolved. AHSG (3q27.3)
      encodes fetuin-A, whose established roles are systemic inhibition of ectopic
      calcification and antagonism of TGF-beta family signalling; neither predicts hair
      or cortical involvement, and the constitutive Ahsg-null mouse is reported as
      phenotypically normal. Two further features are unique to this member within the
      series. First, the causal allele is a single homozygous missense substitution
      (p.Arg317His) from one consanguineous family, so the gene-disease assertion is
      curated as provisional rather than established. Second, the proposed route to
      alopecia runs through loss of TGF-beta antagonism in the hair follicle, an
      explicitly hypothetical model with no cholesterol-pathway involvement at all.
    gene:
      preferred_term: AHSG
      term:
        id: hgnc:349
        label: AHSG
    evidence:
    - reference: PMID:28054173
      reference_title: "Association of AHSG with alopecia and mental retardation (APMR) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our study revealed a novel predicted pathogenic, homozygous missense mutation in the AHSG (OMIM 138680) gene (AHSG: NM_001622:exon7:c.950G>A:p.Arg317His)."
      explanation: >-
        Identifies AHSG and the specific allele that distinguishes this member from the
        LSS-related form.
  evidence:
  - reference: PMID:28054173
    reference_title: "Association of AHSG with alopecia and mental retardation (APMR) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alopecia with mental retardation syndrome (APMR) is a very rare autosomal recessive condition that is associated with total or partial absence of hair from the scalp and other parts of the body as well as variable intellectual disability."
    explanation: >-
      Confirms this member satisfies the alopecia, intellectual disability, and autosomal
      recessive membership conjuncts.
- member: Alopecia-Intellectual Disability Syndrome 4
  member_type: DISEASE
  disease_term:
    preferred_term: alopecia-intellectual disability syndrome 4
    term:
      id: MONDO:0030009
      label: alopecia-intellectual disability syndrome 4
  differentiating_mechanisms:
  - description: >-
      The only member with a defined metabolic lesion. LSS (21q22.3) encodes lanosterol
      synthase, which catalyses the rate-limiting cyclization of (S)-2,3-oxidosqualene to
      lanosterol, the first sterol of the cholesterol biosynthesis pathway; biallelic
      hypomorphic variants are proposed to reduce local cholesterol synthesis in
      high-demand tissues including skin and brain, while circulating cholesterol stays
      normal. Clinically this member is distinguished by frequent early-onset epilepsy
      and by additional dermatological features (scaly skin/ichthyosis) and male genital
      anomalies not described in APMR1. It is also allelic with two other Mendelian
      traits — congenital cataract 44 and autosomal recessive hypotrichosis 14 — giving
      it a phenotypic spectrum the other members do not have.
    gene:
      preferred_term: LSS
      term:
        id: hgnc:6708
        label: LSS
    evidence:
    - reference: PMID:30723320
      reference_title: "Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol."
      explanation: >-
        Places this member's gene in the cholesterol biosynthesis pathway, the mechanism
        that distinguishes it from the AHSG-related form.
  evidence:
  - reference: PMID:30723320
    reference_title: "Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features."
    explanation: >-
      Confirms this member satisfies the alopecia/hypotrichosis, intellectual disability,
      and autosomal recessive membership conjuncts.
discussions:
- discussion_id: apmr_series_uncharacterized_loci
  prompt: >-
    Should APMR2 and APMR3 be curated as dismech Disease entries while their loci have no
    causal gene?
  kind: CURATION_TODO
  status: OPEN
  rationale: >-
    This gap concerns the member list above. It carries no `attaches_to` anchor because
    `entity_refs.SECTION_KEYS` maps only Disease sections, so `members#` is not a
    resolvable prefix and `just check-entity-refs` rejects it; adding the prefix is
    tracked separately as an infrastructure change rather than folded into a curation PR.

    APMR2 (3q26.2-q26.31) and APMR3 (18q11.2-q12.2) each have a MONDO class and an OMIM
    number, so an ontology-driven curation queue will keep proposing them. They are
    deliberately excluded from the member list: each is a linkage interval from a single
    Pakistani kindred with a published list of candidate genes that were sequenced and
    excluded, and a dismech Disease entry needs a mechanism to model. Curating them now
    would produce two entries whose pathophysiology sections could only say "unknown".
    They should be added as members when, and only when, a causal gene is published for
    either locus. Note also that APMR2's interval is adjacent to but does not overlap
    APMR1's, so the two are not the same locus despite both being on 3q26-q27.
  evidence:
  - reference: PMID:17451405
    reference_title: "Mapping of a gene for alopecia with mental retardation syndrome (APMR3) on chromosome 18q11.2-q12.2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A disease locus was mapped to a 10.9 cM region, flanked by markers D18S866 and D18S811, on chromosome 18q11.2-q12.2."
    explanation: >-
      The primary APMR3 locus report places the locus on chromosome 18, far from LSS on
      chromosome 21, and assigns no causal gene.
  - reference: PMID:16922726
    reference_title: "A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2."
    explanation: >-
      Establishes APMR2 as a distinct, non-overlapping locus with no gene assigned.
notes: >-
  Created for issue #8364, which targeted MONDO:0008756 as CURATE_ROOT_WITH_SUBTYPES. The
  root is modelled as a Grouping instead of as a Disease with has_subtypes because the
  numbered forms have different causal genes on different chromosomes and share no
  mechanism. This follows the modelling note already recorded in the APMR4 entry, which
  deferred creating the grouping until a second member existed; APMR1 is that member.

  Gene attributions in this series are a documented Named Entity Confusion risk. For the
  record, traced to primary sources: APMR1 = AHSG (3q27.3), locus 3q26.33-q27.3
  (PMID:16273389, PMID:28054173); APMR2 = locus 3q26.2-q26.31, no gene (PMID:16922726);
  APMR3 = locus 18q11.2-q12.2, no gene (PMID:17451405); APMR4 = LSS (21q22.3)
  (PMID:30723320). LSS belongs to APMR4 only. The HR (hairless) gene at 8p21.3 belongs to
  atrichia with papular lesions, a different disease in the same clinical differential,
  and is not an APMR locus.