Orofaciodigital Syndrome 17

name: Orofaciodigital Syndrome 17
creation_date: "2026-06-20T00:00:00Z"
category: Mendelian
description: >-
  Orofaciodigital syndrome 17 (OFD17 / OFDS XVII) is a rare autosomal recessive
  ciliopathy caused by biallelic variants in INTU, characterized by the
  orofaciodigital combination of facial dysmorphism, oral anomalies (high palate,
  tongue nodules/lingual hamartomas), and digital anomalies (preaxial and
  postaxial polydactyly), together with developmental delay, brain malformations
  (including the molar tooth sign), congenital heart defects, and renal
  malformation. INTU (Inturned) is a subunit of the CPLANE (ciliogenesis and
  planar-cell-polarity effector) protein module that positions the ciliary basal
  body and is essential for the assembly of IFT-A particles and intraflagellar
  transport; biallelic loss of INTU function therefore disrupts primary-cilium
  assembly and function, producing the multisystem pleiotropy typical of
  ciliopathies. The INTU allelic spectrum also includes short-rib thoracic
  dysplasia 20 with polydactyly (SRTD20) and nephronophthisis, placing OFD17
  within the skeletal/orofaciodigital ciliopathy continuum.
disease_term:
  preferred_term: orofaciodigital syndrome 17
  term:
    id: MONDO:0033375
    label: orofaciodigital syndrome 17
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: ciliopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0033375
      label: orofaciodigital syndrome 17
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for orofaciodigital syndrome 17.
  - term:
      id: MONDO:1060154
      label: INTU-related skeletal ciliopathy
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      Per-locus MONDO node spanning the INTU allelic series; OFD17 is one branch of
      the INTU-related skeletal ciliopathy continuum that also includes short-rib
      thoracic dysplasia 20 with polydactyly and nephronophthisis.
parents:
- Ciliopathy
synonyms:
- OFD17
- OFDS XVII
- oral-facial-digital syndrome, type XVII
- INTU-related oral-facial-digital syndrome
notes: >-
  Nomenclature flux: INTU-related OFD was initially classified within the "OFD
  type VI" group (Bruel et al., 2018, PMID:29451301) on the basis of the
  molar-tooth-sign / polydactyly phenotype, but OMIM and MONDO now anchor the
  INTU-specific disorder as a distinct entity, orofaciodigital syndrome 17
  (OFD17 / OFD XVII; OMIM:617926; MONDO:0033375). This entry is kept distinct
  from the OFD1-caused Orofaciodigital_Syndrome_Type_I (OFD1 gene). OFD17 is one
  branch of the broader INTU allelic spectrum, which also includes short-rib
  thoracic dysplasia 20 with polydactyly (SRTD20) and nephronophthisis; only a
  handful of OFD17 families have been reported, so phenotype frequencies are not
  yet well established and `frequency:` qualifiers are intentionally omitted.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    OFD17 is inherited in an autosomal recessive manner, caused by biallelic
    (homozygous or compound heterozygous) variants in INTU.
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OFDS XVII is caused by biallelic variants in INTU gene and is inherited
      autosomal recessively
    explanation: >-
      States the autosomal recessive inheritance and biallelic INTU basis of OFD17.
  - reference: PMID:29451301
    reference_title: "INTU-related oral-facial-digital syndrome type VI: A confirmatory report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing and SNP array identified compound heterozygous
      variants in the INTU gene
    explanation: >-
      Documents biallelic (compound heterozygous) INTU variants consistent with
      recessive inheritance.
genetic:
- name: INTU
  association: Pathogenic biallelic variants
  gene_term:
    preferred_term: INTU
    term:
      id: hgnc:29239
      label: INTU
  notes: >-
    INTU (Inturned) encodes a subunit of the CPLANE (ciliogenesis and
    planar-cell-polarity effector) module. Biallelic pathogenic variants cause
    OFD17; the same gene's allelic spectrum includes short-rib thoracic dysplasia
    20 with polydactyly and nephronophthisis.
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      INTU pathogenic variants have been reported in two patients with OFDS XVII,
      in two patients with short-rib thoracic dysplasia-20 with polydactyly
      (SRTD20), and one with nephronophthisis so far
    explanation: >-
      Establishes INTU as the OFD17 gene and documents its broader allelic
      spectrum (SRTD20, nephronophthisis).
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified causal variants in five new genes (C2CD3, TMEM107, INTU,
      KIAA0753 and IFT57)
    explanation: >-
      Independent identification of INTU among the OFD-causing ciliary genes by
      whole-exome sequencing.
pathophysiology:
- name: INTU/CPLANE Ciliary Basal Body and Intraflagellar Transport Defect
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >-
    INTU (Inturned) is a subunit of the CPLANE (ciliogenesis and
    planar-cell-polarity effector) protein module. CPLANE positions the ciliary
    basal body and is required for the assembly of IFT-A particles that drive
    retrograde intraflagellar transport, the bidirectional transport system that
    builds and maintains the primary cilium. Biallelic loss-of-function INTU
    variants therefore impair basal-body positioning, IFT-A assembly, and
    intraflagellar transport, compromising primary-cilium assembly and signaling
    competence. Because the primary cilium is the organizing center for
    developmental signaling, this molecular lesion is the upstream driver of the
    multisystem OFD17 phenotype.
  biological_processes:
  - preferred_term: Cilium Assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  - preferred_term: Intraflagellar (Intraciliary) Transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: ABNORMAL
  - preferred_term: Establishment of Planar Polarity
    term:
      id: GO:0001736
      label: establishment of planar polarity
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Ciliary Basal Body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  cell_types:
  - preferred_term: Ciliated Cell
    term:
      id: CL:0000064
      label: ciliated cell
  downstream:
  - target: Multisystem Pleiotropic Ciliopathy Phenotype
    description: >-
      Defective ciliary assembly and intraflagellar transport disrupt
      cilium-dependent developmental signaling, producing the orofaciodigital,
      cerebral, cardiac, and renal pleiotropy of OFD17.
  evidence:
  - reference: PMID:29451301
    reference_title: "INTU-related oral-facial-digital syndrome type VI: A confirmatory report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      compound heterozygous variants in the INTU gene, which encodes a protein
      involved in the positioning of the ciliary basal body
    explanation: >-
      Establishes the molecular function of INTU in positioning the ciliary basal
      body, the upstream lesion of the OFD17 mechanism.
  - reference: PMID:29451301
    reference_title: "INTU-related oral-facial-digital syndrome type VI: A confirmatory report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      INTU is a subunit of the CPLANE multiprotein complex essential for the
      assembly of IFT-A particles and intraflagellar transport
    explanation: >-
      Defines INTU as a CPLANE subunit required for IFT-A assembly and
      intraflagellar transport.
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intu is part of the CPLANE protein module that has an essential role in the
      ciliary transport system and function
    explanation: >-
      Confirms INTU/CPLANE function in the ciliary transport system, supporting
      the basal-body/IFT conformance.
  - reference: PMID:29581513
    reference_title: "The CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Intu is known as a ciliogenesis and planar polarity effector (CPLANE)
      protein
    explanation: >-
      Independent molecular characterization of Intu as a CPLANE ciliogenesis and
      planar-cell-polarity effector protein.
- name: Multisystem Pleiotropic Ciliopathy Phenotype
  conforms_to: "ciliopathy_dysfunction#Multisystem Pleiotropic Ciliopathy Phenotype"
  description: >-
    Because the primary cilium coordinates developmental patterning across many
    tissues, the INTU/CPLANE ciliary defect converges on a pleiotropic
    multisystem phenotype: orofaciodigital malformation (facial dysmorphism, high
    palate, tongue nodules, polydactyly), brain malformation (including the molar
    tooth sign and cerebellar peduncle anomalies), congenital heart defects, and
    renal malformation, accompanied by developmental delay.
  cell_types:
  - preferred_term: Ciliated Cell
    term:
      id: CL:0000064
      label: ciliated cell
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OFDS XVII is a recently described subtype of OFDS that presents with
      developmental delay, facial dysmorphism, high palate, tongue nodules, brain
      malformations, cardiac anomaly, polydactyly, renal malformation, and various
      other findings
    explanation: >-
      Enumerates the multisystem pleiotropic OFD17 phenotype that the ciliary
      defect converges on.
  - reference: PMID:29451301
    reference_title: "INTU-related oral-facial-digital syndrome type VI: A confirmatory report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a child with preaxial and postaxial polydactyly, lingual hamartoma, a
      congenital heart defect, delayed development and cerebellar peduncles
      displaying the molar tooth sign
    explanation: >-
      Documents the co-occurrence of orofaciodigital, cardiac, and CNS features
      in an INTU-OFD patient.
phenotypes:
- name: Polydactyly
  category: Skeletal
  description: >-
    Preaxial and/or postaxial polydactyly is a cardinal digital feature of OFD17,
    reflecting the disrupted cilium-dependent limb patterning typical of
    skeletal ciliopathies.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:29451301
    reference_title: "INTU-related oral-facial-digital syndrome type VI: A confirmatory report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a child with preaxial and postaxial polydactyly, lingual hamartoma, a
      congenital heart defect
    explanation: >-
      Documents both preaxial and postaxial polydactyly in an INTU-OFD patient.
- name: Tongue Nodules
  category: Craniofacial
  description: >-
    Tongue nodules / lingual hamartomas are part of the oral-cavity anomalies that
    define the orofaciodigital phenotype of OFD17.
  phenotype_term:
    preferred_term: Tongue nodules
    term:
      id: HP:0000199
      label: Tongue nodules
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, facial dysmorphism, high palate, tongue nodules, brain
      malformations
    explanation: >-
      Tongue nodules are listed among the cardinal oral features of OFD17.
- name: High Palate
  category: Craniofacial
  description: >-
    A high (highly arched) palate is among the oral anomalies of OFD17.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, facial dysmorphism, high palate, tongue nodules
    explanation: >-
      High palate is listed among the cardinal oral features of OFD17.
- name: Abnormal Facial Shape
  category: Craniofacial
  description: >-
    Facial dysmorphism is a consistent feature of OFD17, part of the
    orofaciodigital triad of facial, oral, and digital anomalies.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OFDS XVII is a recently described subtype of OFDS that presents with
      developmental delay, facial dysmorphism
    explanation: >-
      Facial dysmorphism is a presenting feature of OFD17.
- name: Molar Tooth Sign
  category: Neurological
  description: >-
    The molar tooth sign - the characteristic midbrain-hindbrain malformation
    seen on axial brain MRI in ciliopathies - has been documented in INTU-OFD,
    reflecting the brain malformations associated with OFD17.
  phenotype_term:
    preferred_term: Molar tooth sign on MRI
    term:
      id: HP:0002419
      label: Molar tooth sign on MRI
  evidence:
  - reference: PMID:29451301
    reference_title: "INTU-related oral-facial-digital syndrome type VI: A confirmatory report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebellar peduncles displaying the molar tooth sign
    explanation: >-
      Documents the molar tooth sign on neuroimaging in an INTU-OFD patient.
- name: Global Developmental Delay
  category: Neurological
  description: >-
    Developmental delay is a consistent neurological feature of OFD17.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OFDS XVII is a recently described subtype of OFDS that presents with
      developmental delay
    explanation: >-
      Developmental delay is a presenting feature of OFD17.
- name: Congenital Heart Defect
  category: Cardiovascular
  description: >-
    Congenital heart defects (cardiac anomaly) occur in OFD17 and distinguish the
    INTU-OFD phenotype from the Intu hypomorphic mouse, which lacks a heart defect.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high palate, tongue nodules, brain malformations, cardiac anomaly,
      polydactyly, renal malformation
    explanation: >-
      Cardiac anomaly is listed among the cardinal features of OFD17.
- name: Renal Malformation
  category: Renal
  description: >-
    Renal malformation occurs in OFD17, consistent with the renal involvement
    (including nephronophthisis within the broader INTU allelic spectrum) typical
    of ciliopathies.
  phenotype_term:
    preferred_term: Renal malformation
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:34623732
    reference_title: "INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cardiac anomaly, polydactyly, renal malformation, and various other findings
    explanation: >-
      Renal malformation is listed among the cardinal features of OFD17.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    Management of OFD17 is supportive and symptomatic, coordinated across genetics,
    neurology, cardiology, nephrology, and craniofacial/orthopedic services to
    address the multisystem malformations and developmental delay.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Genetic Counseling
  description: >-
    Genetic counseling is indicated for families given the autosomal recessive
    inheritance and 25% sibling recurrence risk; molecular confirmation of
    biallelic INTU variants supports recurrence-risk counseling and reproductive
    options.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
differential_diagnoses:
- name: Orofaciodigital Syndrome Type I
  description: >-
    OFD1 (the most frequent OFD subtype, caused by heterozygous variants in the
    X-linked OFD1 gene) shares the orofaciodigital triad but differs in gene,
    inheritance (X-linked dominant with male lethality), and the absence of the
    autosomal recessive INTU/CPLANE mechanism.
- name: Joubert Syndrome
  description: >-
    Joubert syndrome and related disorders also feature the molar tooth sign and
    overlap clinically; OFD17 is distinguished by its INTU/CPLANE genetic basis and
    the prominent orofaciodigital (oral hamartoma, polydactyly) phenotype.