Genetic hypogonadotropic hypogonadism (developmental and degenerative forms)

name: Congenital and Syndromic Hypogonadotropic Hypogonadism
display_name: Genetic hypogonadotropic hypogonadism (developmental and degenerative forms)
creation_date: "2026-08-01T00:00:00Z"
description: >-
  Genetic disorders in which gonadal failure is CENTRAL — the gonads are intrinsically
  capable, but hypothalamic GnRH secretion or its pituitary transduction is deficient,
  so LH and FSH are low or inappropriately normal in the face of low sex steroids.
  Members converge on that final common pathway by two distinguishable routes: a
  DEVELOPMENTAL route, in which GnRH neurons fail to be specified, to migrate from the
  olfactory placode to the hypothalamus, or to signal once there (giving congenital,
  often anosmic, absent puberty); and a DEGENERATIVE route, in which GnRH neurons or
  their hypothalamic-pituitary context are lost postnatally as part of a
  neurodegenerative process (giving acquired-onset hypogonadism alongside ataxia,
  dementia, or chorioretinal dystrophy). A third set of members reaches the same
  endpoint as one feature of a broader syndromic developmental defect.
grouping_basis:
- SHARED_PHENOTYPE
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared FINAL COMMON MECHANISM (deficient GnRH drive to the pituitary
  gonadotrope) that is also a shared defining phenotype, NOT on a shared etiology: the
  members reach GnRH deficiency by developmental and degenerative routes that have
  nothing molecular in common. That split is the point of the grouping and is recorded
  per member in differentiating_mechanisms, because it is the distinction that matters
  clinically (a developmental member never enters puberty and is a candidate for
  pulsatile GnRH or gonadotropin induction of fertility; a degenerative member had
  normal puberty and then lost it, and carries a progressive neurological prognosis)
  and it is exactly what the OMIM phenotypic series PS147950 and the MONDO
  hypogonadotropic-hypogonadism class do not record. Members are kept as separate
  Disease entries because their extra-reproductive phenotypes — anosmia, ataxia,
  chorioretinal dystrophy, alopecia and diabetes, arhinia, arthrogryposis — are what
  drive diagnosis and management, and because several are syndromes in which
  hypogonadism is one feature among many rather than the presenting complaint. The
  criteria are NECESSARY, not sufficient: hypogonadotropic hypogonadism is entailed by
  membership, but it also occurs acquired (pituitary tumour and surgery, opioid and
  glucocorticoid exposure, hyperprolactinaemia, functional hypothalamic amenorrhoea)
  and those forms are deliberately outside this genetic grouping.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018555
      label: hypogonadotropic hypogonadism
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      Direction, stated explicitly to avoid broad/narrow ambiguity: this grouping is
      NARROWER than MONDO:0018555 on the etiologic axis (genetic forms only, excluding
      the acquired central hypogonadism the clinical class also covers) and BROADER on
      the syndromic axis (it admits Woodhouse-Sakati, Schaaf-Yang and Bosma arhinia
      microphthalmia, which MONDO classifies primarily elsewhere and which are not
      is-a descendants of MONDO:0018555). Neither direction of subsumption holds, hence
      relatedMatch. MONDO:0015770 (congenital hypogonadotropic hypogonadism) is the
      closer match for the developmental arm alone and is the natural recipient of the
      OMIMPS:147950 mapping — see
      docs/reports/omim-phenotypic-series-groupings-2026-08-01.md.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        4 of 7 members (Kallmann syndrome, FGFR1-related HH, cerebellar
        ataxia-hypogonadism syndrome, Boucher-Neuhauser syndrome) are is-a descendants
        of MONDO:0018555; Woodhouse-Sakati, Schaaf-Yang and Bosma arhinia
        microphthalmia are not, because MONDO classifies them by their leading
        syndromic feature. The mapping is conceptual (central GnRH-deficient
        hypogonadism is the shared feature), not an is-a correspondence, and the
        mismatch is expected rather than an error to repair.
membership_criteria:
- description: >-
    A member presents with hypogonadotropic (central) hypogonadism — low or
    inappropriately normal gonadotropins with low sex steroids — as a consistent feature.
    The germline-genetic-cause requirement that also holds of every member is stated in
    grouping_rationale rather than encoded here: there is no criterion predicate for "has a
    germline cause" (HAS_GENE would demand one named gene, which the members do not share),
    so leaving it out of the boolean keeps the logic an honest statement of what is
    machine-checkable.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_PHENOTYPE
    description: >-
      Hypogonadotropic hypogonadism, whether congenital (absent or arrested puberty)
      or acquired within a degenerative course.
    phenotype_term:
      preferred_term: Hypogonadotropic hypogonadism
      term:
        id: HP:0000044
        label: Hypogonadotropic hypogonadism
members:
- member: Kallmann Syndrome
  member_type: DISEASE
  display_name: Kallmann syndrome (anosmic congenital HH)
  differentiating_mechanisms:
  - description: >-
      DEVELOPMENTAL route, migration defect — the prototype. GnRH neurons and olfactory
      axons share a migratory path from the olfactory placode to the forebrain, so
      ANOS1 (and FGFR1, PROKR2/PROK2, FGF8, CHD7) lesions that disrupt that migration
      produce absent puberty TOGETHER WITH anosmia or hyposmia and olfactory bulb
      aplasia. Anosmia is the discriminating feature that separates Kallmann syndrome
      from normosmic congenital HH, and the entry is also a worked oligogenic example
      (variants at two loci in the same proband).
    gene:
      preferred_term: ANOS1
      term:
        id: hgnc:6211
        label: ANOS1
- member: FGFR1-Related Hypogonadotropic Hypogonadism
  member_type: DISEASE
  display_name: FGFR1-related HH (KAL2; anosmic or normosmic)
  differentiating_mechanisms:
  - description: >-
      DEVELOPMENTAL route, signalling defect. FGFR1 haploinsufficiency impairs the
      FGF8-FGFR1 signalling required for GnRH neuron specification and survival rather
      than for migration alone, which is why the same gene produces BOTH anosmic (Kallmann)
      and normosmic congenital HH, sometimes in the same family, and why reversal of
      the hypogonadism after treatment is described. FGFR1 also gives a craniofacial
      arm (cleft lip/palate, dental agenesis) absent from ANOS1 disease.
    gene:
      preferred_term: FGFR1
      term:
        id: hgnc:3688
        label: FGFR1
- member: Cerebellar Ataxia-Hypogonadism Syndrome
  member_type: DISEASE
  display_name: Gordon Holmes syndrome (RNF216/OTUD4/STUB1)
  differentiating_mechanisms:
  - description: >-
      DEGENERATIVE route, ubiquitin-proteostasis. Biallelic RNF216 (E3 ubiquitin
      ligase), digenic RNF216-OTUD4, or STUB1/CHIP lesions cause progressive cerebellar
      ataxia with dementia and hypogonadism that is often acquired AFTER apparently
      normal or partial pubertal development — the opposite temporal profile to the
      developmental members. Hypogonadism here is a consequence of a proteostasis-driven
      neurodegenerative process, not of a patterning failure.
    gene:
      preferred_term: RNF216
      term:
        id: hgnc:21698
        label: RNF216
- member: Boucher-Neuhauser Syndrome
  member_type: DISEASE
  display_name: Boucher-Neuhauser syndrome (PNPLA6)
  differentiating_mechanisms:
  - description: >-
      DEGENERATIVE route, membrane-lipid homeostasis. Biallelic PNPLA6
      (neuropathy-target esterase) lesions give the ataxia-hypogonadism-chorioretinal
      dystrophy triad; the chorioretinal dystrophy is the feature that separates it from
      the RNF216 form of Gordon Holmes syndrome, and the same gene grades into
      Oliver-McFarlane and spastic paraplegia phenotypes by residual esterase activity.
    gene:
      preferred_term: PNPLA6
      term:
        id: hgnc:16268
        label: PNPLA6
- member: Woodhouse-Sakati Syndrome
  member_type: DISEASE
  display_name: Woodhouse-Sakati syndrome (DCAF17)
  differentiating_mechanisms:
  - description: >-
      SYNDROMIC route, multi-endocrine. Biallelic DCAF17 (a nucleolar substrate
      receptor for the CUL4-DDB1 ubiquitin ligase) produces hypogonadism as one member
      of an endocrine-plus-neurologic cluster — alopecia, diabetes mellitus,
      sensorineural deafness, and extrapyramidal movement disorder with characteristic
      brain white-matter and iron-deposition changes. The hypogonadism is
      hypergonadotropic in some reported patients, so this member sits at the boundary
      of the grouping and is the one to re-audit if the criteria are ever tightened to
      require central hypogonadism in every case.
    gene:
      preferred_term: DCAF17
      term:
        id: hgnc:25784
        label: DCAF17
- member: Schaaf-Yang Syndrome
  member_type: DISEASE
  display_name: Schaaf-Yang syndrome (MAGEL2)
  differentiating_mechanisms:
  - description: >-
      SYNDROMIC route, imprinted Prader-Willi-region gene. Truncating variants on the
      paternal MAGEL2 allele give neonatal hypotonia, feeding difficulty, distal
      arthrogryposis, autism and intellectual disability, with hypogonadism and
      hypogenitalism as part of the Prader-Willi-like hypothalamic phenotype rather
      than as an isolated GnRH-axis lesion. This member also belongs to the fetal
      akinesia / arthrogryposis space, and is the clearest case in this grouping of
      hypogonadism as a downstream feature of generalized hypothalamic dysfunction.
      Weakest member against the criteria: the sources dismech cites report
      "hypogonadism" (cryptorchidism, micropenis, pubertal abnormality) without
      documenting the gonadotropin profile, so central origin is inferred from the
      Prader-Willi-like hypothalamic phenotype rather than measured. Re-audit this
      member if the criteria are tightened to demand documented low gonadotropins.
    gene:
      preferred_term: MAGEL2
      term:
        id: hgnc:6814
        label: MAGEL2
- member: Bosma Arhinia Microphthalmia Syndrome
  member_type: DISEASE
  display_name: Bosma arhinia microphthalmia syndrome (SMCHD1)
  differentiating_mechanisms:
  - description: >-
      SYNDROMIC route, chromatin/epigenetic regulator. SMCHD1 ATPase-domain missense
      variants give congenital absence of the nose with microphthalmia AND
      hypogonadotropic hypogonadism — the developmental link being the shared
      olfactory-placode origin of the nose and of migrating GnRH neurons, which makes
      this the anatomically most extreme expression of the same placodal mechanism
      Kallmann syndrome expresses as anosmia. Mechanistically striking because
      loss-of-function variants in the SAME gene instead cause FSHD2, a muscular
      dystrophy with no reproductive phenotype.
    gene:
      preferred_term: SMCHD1
      term:
        id: hgnc:29090
        label: SMCHD1
notes: >-
  Created as a worked example from the OMIM phenotypic series audit
  (docs/reports/omim-phenotypic-series-groupings-2026-08-01.md). PS147950
  ("Hypogonadotropic hypogonadism with or without anosmia") is a genuine Mendelian
  series — unlike PS212750 for celiac disease — which is why a grouping is well formed
  here; but the OMIM series covers only the developmental arm, so this grouping is
  NOT the series and deliberately admits the degenerative and syndromic members too.
  Advisory membership audit: 6 of 7 members satisfy the criterion. Building this
  grouping surfaced one real curation defect and one genuine open question. The defect:
  FGFR1-Related Hypogonadotropic Hypogonadism annotated only the parent term HP:0000135
  (Hypogonadism) despite hypogonadotropic hypogonadism being its defining feature — that
  entry already carried the GeneReviews sentence establishing low LH/FSH with low sex
  steroids, so it has been refined to HP:0000044 in the same change. The open question:
  Schaaf-Yang Syndrome stays NOT_SATISFIED because its sources document hypogonadism
  without a gonadotropin profile; it is retained as a member on hypothalamic grounds and
  flagged in its differentiating_mechanisms rather than silently admitted. Obvious future members as they are curated: the
  normosmic congenital HH genes (GNRHR, GNRH1, KISS1R, TAC3/TACR3, PROKR2, CHD7),
  CHARGE syndrome, and Prader-Willi syndrome.