Inactivating PTH/PTHrP Signalling Disorders (iPPSD)

name: Inactivating PTH/PTHrP Signalling Disorders
display_name: Inactivating PTH/PTHrP Signalling Disorders (iPPSD)
creation_date: "2026-09-24T00:00:00Z"
description: >-
  Inactivating PTH/PTHrP signalling disorders (iPPSD) are genetic disorders in
  which signalling from the type 1 PTH/PTHrP receptor through Gs-alpha, cAMP and
  protein kinase A is reduced. The shared consequences are
  end-organ resistance to parathyroid hormone and other Gs-coupled hormones,
  and a brachydactyly-predominant skeletal phenotype caused by impaired PTHrP
  signalling in the growth plate. The EuroPHP network proposed the term in
  2016 to replace the historical pseudohypoparathyroidism classification, which
  was built on biochemical response to exogenous PTH and left related disorders
  such as acrodysostosis and progressive osseous heteroplasia outside it.
grouping_basis:
- SHARED_PATHWAY
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on a shared pathway: every member reduces signalling at a different
  step of the PTH/PTHrP receptor to Gs-alpha to cAMP to PKA cascade. The members stay
  separate Disease entries because the lesion, its step in the cascade and its
  inheritance differ. Biallelic PTH1R loss removes the receptor. GNAS coding
  loss reduces Gs-alpha, and the parent of origin decides the phenotype:
  maternal transmission gives hormone resistance with Albright hereditary
  osteodystrophy (PHP1A), while paternal transmission gives the osteodystrophy
  without hormone resistance (pseudopseudohypoparathyroidism). GNAS methylation
  defects give mainly renal PTH resistance (PHP1B). PRKAR1A and PDE4D variants
  impair the cAMP-PKA step below Gs-alpha (acrodysostosis). The grouping is
  deliberately directional. Activating lesions in the same genes, such as
  Jansen metaphyseal chondrodysplasia (constitutively active PTH1R) and
  GNAS-related pituitary adenoma (somatic activating GNAS), are not members.
membership_criteria:
- description: >-
    A member is caused by a germline genetic or epigenetic lesion in a gene of
    the PTH/PTHrP receptor to cAMP-PKA cascade, and that lesion reduces signalling
    through the cascade. The gene criterion is not sufficient on its own. The
    same genes also carry activating lesions that fall outside this grouping,
    so the criteria are stated as necessary only.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - operator: OR
      description: Lesion in a gene of the PTH/PTHrP-Gs-alpha-cAMP-PKA cascade.
      operands:
      - criterion_predicate: HAS_GENE
        description: Type 1 PTH/PTHrP receptor.
        gene:
          preferred_term: PTH1R
          term:
            id: hgnc:9608
            label: PTH1R
      - criterion_predicate: HAS_GENE
        description: Gs-alpha, encoded at the imprinted GNAS locus.
        gene:
          preferred_term: GNAS
          term:
            id: hgnc:4392
            label: GNAS
      - criterion_predicate: HAS_GENE
        description: PKA regulatory subunit type I-alpha.
        gene:
          preferred_term: PRKAR1A
          term:
            id: hgnc:9388
            label: PRKAR1A
      - criterion_predicate: HAS_GENE
        description: cAMP-specific phosphodiesterase 4D.
        gene:
          preferred_term: PDE4D
          term:
            id: hgnc:8783
            label: PDE4D
    - criterion_predicate: OTHER
      description: >-
        The lesion reduces signalling through the cascade, not increases it.
        This excludes constitutively activating PTH1R and GNAS variants.
members:
- member: Chondrodysplasia Blomstrand Type
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss-of-function PTH1R variants remove the receptor itself,
      the most upstream and most complete block in the cascade. The result is
      a perinatally lethal osteochondrodysplasia with advanced endochondral
      ossification, not a postnatal endocrine phenotype.
    gene:
      preferred_term: PTH1R
      term:
        id: hgnc:9608
        label: PTH1R
- member: Pseudohypoparathyroidism
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reduced Gs-alpha expression in imprinted tissues, where the maternal
      allele predominates, produces renal PTH resistance. Maternal GNAS coding
      variants give PHP1A (PTH and multihormone resistance with Albright
      hereditary osteodystrophy). GNAS methylation defects give PHP1B
      (predominantly PTH resistance).
    gene:
      preferred_term: GNAS
      term:
        id: hgnc:4392
        label: GNAS
  evidence:
  - reference: PMID:36686455
    reference_title: Frequency of de novo variants and parental mosaicism in families with inactivating PTH/PTHrP signaling disorder type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: According to this new classification, nowadays PHP is now known as iPPSD2 and 3.
    explanation: Places pseudohypoparathyroidism inside the iPPSD classification, as its types 2 and 3.
- member: Pseudopseudohypoparathyroidism
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The same class of GNAS coding loss as PHP1A, but on the paternal allele.
      Gs-alpha falls in tissues that express both alleles, such as growth-plate
      chondrocytes and mesenchyme, so Albright hereditary osteodystrophy develops. Maternal
      Gs-alpha is preserved in imprinted tissues such as the renal proximal
      tubule, so PTH resistance is classically absent.
    gene:
      preferred_term: GNAS
      term:
        id: hgnc:4392
        label: GNAS
  evidence:
  - reference: PMID:36686455
    reference_title: Frequency of de novo variants and parental mosaicism in families with inactivating PTH/PTHrP signaling disorder type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: iPPSD2 (which includes PHP1A and PPHP/POH) is a rare inherited autosomal dominant endocrine disorder caused by inactivating GNAS pathogenic variants.
    explanation: Places PPHP in iPPSD2 together with PHP1A, defined by inactivating GNAS variants.
- member: Acrodysostosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous PRKAR1A variants (type 1) make PKA resistant to activation
      by cAMP. The block lies below Gs-alpha, downstream of the step affected in
      the GNAS disorders, and skeletal involvement is severe.
    gene:
      preferred_term: PRKAR1A
      term:
        id: hgnc:9388
        label: PRKAR1A
  - description: >-
      PDE4D-related acrodysostosis (type 2) perturbs cAMP degradation at the
      same downstream level of the cascade.
    gene:
      preferred_term: PDE4D
      term:
        id: hgnc:8783
        label: PDE4D
  evidence:
  - reference: PMID:27401862
    reference_title: From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH)
    explanation: >-
      Names acrodysostosis as one of the related disorders the old PHP
      classification excluded and the iPPSD classification was built to cover.
references:
- reference: PMID:27401862
  title: From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network.
  findings:
  - statement: >-
      The classification this grouping follows. It groups every disorder with
      reduced PTH and/or PTHrP cAMP-mediated signalling under one term.
    supporting_text: we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD)
notes: >-
  Membership follows the EuroPHP iPPSD scheme but is limited to disorders with
  a DisMech entry. Progressive osseous heteroplasia and osteoma cutis, which the
  scheme places with PPHP in iPPSD2, have no entries yet. The iPPSD numbers for
  pseudohypoparathyroidism and PPHP are quoted from PMID:36686455, and those for
  acrodysostosis (iPPSD4 and iPPSD5) come from that entry's own subtypes. No
  iPPSD number is asserted for Blomstrand chondrodysplasia. It is included
  because biallelic PTH1R loss meets the scheme's defining criterion of
  reduced PTH/PTHrP receptor signalling, not on the strength of a quoted
  subtype number.