Oculocerebrodental Syndrome

Mendelian MONDO:0034145 Pathograph 3 Show in embeddings browser Ciliopathies

Oculocerebrodental syndrome (the MONDO term for the disorder named oculoskeletodental syndrome, OCSKD, OMIM:618440) is a rare autosomal recessive multisystem disorder caused by biallelic loss-of-function variants in PIK3C2A, a class II phosphoinositide 3-kinase that produces PI(3)P and PI(3,4)P2 and is required for primary cilium formation and function and for receptor-mediated endocytosis at the ciliary base. The phenotype combines short stature, coarse facial features, congenital cataracts (often with secondary glaucoma), multiple skeletal abnormalities, dental anomalies, and neurological manifestations; deafness has been reported. Patient-derived fibroblasts show impaired cilia formation and function and reduced proliferative capacity, placing the disorder within the primary-cilium ciliopathy spectrum as a Mendelian disorder of phosphoinositide metabolism. It shows phenotypic overlap with — yet is distinct from — Lowe syndrome, another disorder of phosphoinositide-metabolizing enzymes (OCRL).

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1
Inheritance
3
Pathophys.
7
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
1
Differentials
2
References
🏷

Classifications

Harrison's Chapter
GENETICS_ENVIRONMENT_DISEASE
Mechanistic Nosology
ciliopathy
👪

Inheritance

1
Autosomal Recessive
Oculocerebrodental (oculoskeletodental) syndrome is inherited in an autosomal recessive manner, caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in PIK3C2A. The original families were consanguineous with homozygous variants; compound heterozygous genotypes have since been reported.
Show evidence (2 references)
PMID:31034465 SUPPORT Human Clinical
"We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings"
Establishes biallelic (homozygous) PIK3C2A loss of function in three consanguineous families, defining the autosomal recessive basis and the cardinal multisystem phenotype.
DOI:10.1111/cge.70005 SUPPORT Human Clinical
"Using trio exome sequencing, we identified two novel compound heterozygous variants in"
Documents compound heterozygous PIK3C2A genotypes in a fifth family, consistent with recessive inheritance.
⚙

Pathophysiology

3
PIK3C2A Loss and Primary Cilium Dysfunction
PIK3C2A is a class II phosphoinositide 3-kinase that phosphorylates phosphatidylinositol (PI) to PI(3)P and PI(4)P to PI(3,4)P2. These phosphoinositides are required at the ciliary base and on the endosomal/peri-ciliary membrane for primary cilium formation and function and for receptor-mediated endocytosis. Biallelic loss-of-function variants abolish or inactivate PIK3C2A, depleting its phosphoinositide products and producing defective ciliogenesis and a functionally incompetent primary cilium. Patient-derived fibroblasts lacking functional PIK3C2A show impaired cilia formation and function and reduced proliferative capacity, identifying the primary cilium as the cellular locus of disease.
Fibroblast CL:0000057
Cilium Assembly GO:0060271 ↓ DECREASED Phosphatidylinositol-3-phosphate Biosynthesis GO:0036092 ↓ DECREASED Receptor-mediated Endocytosis GO:0006898 ⚠ ABNORMAL
Primary Cilium GO:0005929
Downstream
Impaired Ciliary Hedgehog Signal Transduction Defective ciliogenesis and a functionally incompetent primary cilium disrupt cilium-dependent developmental signaling, principally the Hedgehog pathway that the primary cilium is obligately required to transduce.
Show evidence (4 references)
PMID:31034465 SUPPORT In Vitro
"PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2"
Defines PIK3C2A as a class II PI3K producing PI(3)P and PI(3,4)P2, the biochemical basis of the phosphoinositide-metabolism defect.
PMID:31034465 SUPPORT In Vitro
"At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions"
Establishes the cilium and receptor-mediated endocytosis as the cellular functions of PIK3C2A whose loss drives the disorder, supporting conformance to the ciliary basal-body/biogenesis trigger node.
PMID:31034465 SUPPORT In Vitro
"Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity"
Patient fibroblast data directly demonstrate impaired cilia formation and function as the cellular phenotype of PIK3C2A loss.
+ 1 more reference
Impaired Ciliary Hedgehog Signal Transduction
The primary cilium is the obligate organelle for vertebrate Hedgehog signal transduction: SMO and the GLI transcription factors traffic through the ciliary compartment to convert Hedgehog ligand into a transcriptional response. Because biallelic PIK3C2A loss produces defective ciliogenesis and a functionally incompetent primary cilium, cilium-dependent Hedgehog signal transduction is disrupted. As Hedgehog signaling patterns the limb, skeleton, and CNS, this defect provides the mechanistic link between the upstream ciliary lesion and the syndrome's skeletal (short stature, multiple skeletal abnormalities) and neurological features. The 2025 functional study frames the disorder explicitly as a functional SHH (Sonic hedgehog) primary cilia defect.
Hedgehog (smoothened) signaling pathway GO:0007224 ↕ DYSREGULATED
Primary Cilium GO:0005929
Downstream
Impaired Ciliary Signaling and Multisystem Developmental Pleiotropy Disrupted cilium-dependent Hedgehog signaling during development contributes to the skeletal, craniofacial, and neurological components of the multisystem phenotype.
Show evidence (2 references)
PMID:27881449 SUPPORT Other
"It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals."
Establishes the obligate role of the primary cilium in mammalian Hedgehog signal transduction, so that the PIK3C2A-driven ciliogenesis defect impairs cilium-dependent Hedgehog signaling. Evidence source is OTHER (review).
PMID:31034465 SUPPORT In Vitro
"Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity"
Patient fibroblasts show impaired cilia formation and function; because the primary cilium is the obligate site of Hedgehog transduction, this ciliary defect disrupts the cilium-dependent Hedgehog signaling that patterns the skeleton and CNS.
Impaired Ciliary Signaling and Multisystem Developmental Pleiotropy
Because the primary cilium is a near-ubiquitous sensory-signaling organelle, PIK3C2A-dependent ciliary dysfunction during development produces a multisystem disorder rather than a single-organ phenotype. The convergent clinical end state combines ocular (cataract, secondary glaucoma), skeletal (short stature, multiple skeletal abnormalities), craniofacial/dental, and neurological features, with hearing loss in a subset — the characteristic pleiotropy of a ciliopathy.
Cilium Assembly GO:0060271 ↓ DECREASED
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings"
Enumerates the multisystem (ocular, skeletal, craniofacial, neurological) pleiotropy that defines the ciliopathy phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Oculocerebrodental Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Ear 1
Hearing Impairment Hearing impairment HP:0000365
Show evidence (1 reference)
DOI:10.1111/cge.70005 SUPPORT Human Clinical
"characterized by pulverulent cataracts and deafness"
Documents deafness as part of the clinical spectrum in an additional family, expanding the phenotype.
Eye 2
Cataract Cataract HP:0000518
Show evidence (2 references)
PMID:31034465 SUPPORT Human Clinical
"cataracts with secondary glaucoma, multiple skeletal abnormalities"
Cataract (with secondary glaucoma) is a cardinal ocular feature of the syndrome.
DOI:10.1111/cge.70005 SUPPORT Human Clinical
"characterized by pulverulent cataracts and deafness"
Confirms cataract (pulverulent type) as a presenting ocular feature in an additional family.
Secondary Glaucoma Glaucoma HP:0000501
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"cataracts with secondary glaucoma"
Secondary glaucoma is reported in association with the cataracts.
Head and Neck 1
Coarse Facial Features Coarse facial features HP:0000280
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"short stature, coarse facial features, cataracts with secondary glaucoma"
Coarse facial features are enumerated among the defining dysmorphic features.
Nervous System 1
Neurological Manifestations Abnormality of the nervous system HP:0000707
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"multiple skeletal abnormalities, neurological manifestations, among other findings"
Neurological manifestations are listed among the cardinal clinical features of the syndrome.
Growth 1
Short Stature Short stature HP:0004322
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities"
Short stature is enumerated among the cardinal features of the syndrome.
Other 1
Multiple Skeletal Abnormalities Abnormal skeletal morphology HP:0011842
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"multiple skeletal abnormalities, neurological manifestations"
Multiple skeletal abnormalities are a cardinal feature of the syndrome.
🧬

Genetic Associations

1
PIK3C2A Loss-of-Function Variants (Causative)
Gene: PIK3C2A hgnc:8971
Show evidence (2 references)
PMID:31034465 SUPPORT Human Clinical
"We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families"
Original report identifying biallelic PIK3C2A loss of function as the cause of the syndrome.
DOI:10.1111/cge.70005 SUPPORT Human Clinical
"Using trio exome sequencing, we identified two novel compound heterozygous variants in"
Independent identification of additional (compound heterozygous) PIK3C2A variants, confirming the gene and expanding the mutational spectrum.
💊

Medical Actions

3
Supportive and Multidisciplinary Care
Action: supportive care MAXO:0000950
There is no disease-modifying therapy. Management is supportive and multidisciplinary, addressing the ophthalmologic, skeletal, neurological, and audiologic manifestations through specialist follow-up and early intervention.
Cataract and Glaucoma Surgery
Action: surgical procedure MAXO:0000004
Surgical management of the congenital cataracts and secondary glaucoma is performed as clinically indicated to preserve vision.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Autosomal recessive inheritance entails a 25% recurrence risk for siblings. Once the biallelic PIK3C2A variants are identified, carrier testing and prenatal/preimplantation genetic testing become available to families.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Oculocerebrodental Syndrome:

Lowe Syndrome
Overlapping Features Lowe (oculocerebrorenal) syndrome is caused by variants in OCRL, a PI-5-phosphatase, and shares congenital cataracts and neurological involvement. The considerable phenotypic overlap between the two disorders, yet their distinct features, highlights the non-redundant roles of phosphoinositide-metabolizing enzymes in development.
Show evidence (1 reference)
PMID:31034465 SUPPORT Human Clinical
"the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL"
Establishes Lowe syndrome (OCRL) as the principal phosphoinositide-disorder differential, with overlapping yet distinct features.
{ }

Source YAML

click to show 
name: Oculocerebrodental Syndrome
creation_date: "2026-06-19T20:00:00Z"
category: Mendelian
description: >-
  Oculocerebrodental syndrome (the MONDO term for the disorder named
  oculoskeletodental syndrome, OCSKD, OMIM:618440) is a rare autosomal recessive
  multisystem disorder caused by biallelic loss-of-function variants in PIK3C2A,
  a class II phosphoinositide 3-kinase that produces PI(3)P and PI(3,4)P2 and is
  required for primary cilium formation and function and for receptor-mediated
  endocytosis at the ciliary base. The phenotype combines short stature, coarse
  facial features, congenital cataracts (often with secondary glaucoma), multiple
  skeletal abnormalities, dental anomalies, and neurological manifestations;
  deafness has been reported. Patient-derived fibroblasts show
  impaired cilia formation and function and reduced proliferative capacity,
  placing the disorder within the primary-cilium ciliopathy spectrum as a
  Mendelian disorder of phosphoinositide metabolism. It shows phenotypic overlap
  with — yet is distinct from — Lowe syndrome, another disorder of
  phosphoinositide-metabolizing enzymes (OCRL).
disease_term:
  preferred_term: oculocerebrodental syndrome
  term:
    id: MONDO:0034145
    label: oculocerebrodental syndrome
parents:
- Ciliopathies
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: ciliopathy
inheritance:
- name: Autosomal Recessive
  description: >-
    Oculocerebrodental (oculoskeletodental) syndrome is inherited in an autosomal
    recessive manner, caused by biallelic (homozygous or compound heterozygous)
    loss-of-function variants in PIK3C2A. The original families were consanguineous
    with homozygous variants; compound heterozygous genotypes have since been
    reported.
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified homozygous loss-of-function mutations in PIK3C2A in children
      from three independent consanguineous families with short stature, coarse
      facial features, cataracts with secondary glaucoma, multiple skeletal
      abnormalities, neurological manifestations, among other findings
    explanation: >-
      Establishes biallelic (homozygous) PIK3C2A loss of function in three
      consanguineous families, defining the autosomal recessive basis and the
      cardinal multisystem phenotype.
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using trio exome sequencing, we identified two novel compound heterozygous
      variants in
    explanation: >-
      Documents compound heterozygous PIK3C2A genotypes in a fifth family,
      consistent with recessive inheritance.
prevalence:
- population: Published clinical reports
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  percentage: Fewer than 10 reported families
  notes: >-
    Oculocerebrodental/oculoskeletodental syndrome is extremely rare. The
    disorder was first delineated in three consanguineous families in 2019, and
    fewer than 10 families have been reported in total, with a fifth family
    described in 2025.
  evidence:
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe here the fifth family presenting a
    explanation: >-
      Confirms the rarity of the disorder; this 2025 report describes only the
      fifth family worldwide.
pathophysiology:
- name: PIK3C2A Loss and Primary Cilium Dysfunction
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >-
    PIK3C2A is a class II phosphoinositide 3-kinase that phosphorylates
    phosphatidylinositol (PI) to PI(3)P and PI(4)P to PI(3,4)P2. These
    phosphoinositides are required at the ciliary base and on the
    endosomal/peri-ciliary membrane for primary cilium formation and function and
    for receptor-mediated endocytosis. Biallelic loss-of-function variants
    abolish or inactivate PIK3C2A, depleting its phosphoinositide products and
    producing defective ciliogenesis and a functionally incompetent primary
    cilium. Patient-derived fibroblasts lacking functional PIK3C2A show impaired
    cilia formation and function and reduced proliferative capacity, identifying
    the primary cilium as the cellular locus of disease.
  biological_processes:
  - preferred_term: Cilium Assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  - preferred_term: Phosphatidylinositol-3-phosphate Biosynthesis
    term:
      id: GO:0036092
      label: phosphatidylinositol-3-phosphate biosynthetic process
    modifier: DECREASED
  - preferred_term: Receptor-mediated Endocytosis
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Impaired Ciliary Hedgehog Signal Transduction
    description: >-
      Defective ciliogenesis and a functionally incompetent primary cilium
      disrupt cilium-dependent developmental signaling, principally the Hedgehog
      pathway that the primary cilium is obligately required to transduce.
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family
      that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P
      and the phosphorylation of PI(4)P into PI(3,4)P2
    explanation: >-
      Defines PIK3C2A as a class II PI3K producing PI(3)P and PI(3,4)P2, the
      biochemical basis of the phosphoinositide-metabolism defect.
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      At the cellular level, PIK3C2A is critical for the formation of cilia and
      for receptor mediated endocytosis, among other biological functions
    explanation: >-
      Establishes the cilium and receptor-mediated endocytosis as the cellular
      functions of PIK3C2A whose loss drives the disorder, supporting conformance
      to the ciliary basal-body/biogenesis trigger node.
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cellular studies of patient-derived fibroblasts found that they lacked
      PIK3C2A protein, had impaired cilia formation and function, and
      demonstrated reduced proliferative capacity
    explanation: >-
      Patient fibroblast data directly demonstrate impaired cilia formation and
      function as the cellular phenotype of PIK3C2A loss.
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ciliary and cellular phenotype studies showed in the patient's cells
      impaired cilia formation and function as well as a reduced proliferative
      capacity
    explanation: >-
      Independent functional confirmation in a second family that PIK3C2A
      deficiency impairs cilia formation and function.
- name: Impaired Ciliary Hedgehog Signal Transduction
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >-
    The primary cilium is the obligate organelle for vertebrate Hedgehog signal
    transduction: SMO and the GLI transcription factors traffic through the
    ciliary compartment to convert Hedgehog ligand into a transcriptional
    response. Because biallelic PIK3C2A loss produces defective ciliogenesis and
    a functionally incompetent primary cilium, cilium-dependent Hedgehog signal
    transduction is disrupted. As Hedgehog signaling patterns the limb, skeleton,
    and CNS, this defect provides the mechanistic link between the upstream
    ciliary lesion and the syndrome's skeletal (short stature, multiple skeletal
    abnormalities) and neurological features. The 2025 functional study frames
    the disorder explicitly as a functional SHH (Sonic hedgehog) primary cilia
    defect.
  role: central_effector
  biological_processes:
  - preferred_term: Hedgehog (smoothened) signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  downstream:
  - target: Impaired Ciliary Signaling and Multisystem Developmental Pleiotropy
    description: >-
      Disrupted cilium-dependent Hedgehog signaling during development
      contributes to the skeletal, craniofacial, and neurological components of
      the multisystem phenotype.
  evidence:
  - reference: PMID:27881449
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It has been a decade since it was discovered that primary cilia have an
      essential role in Hedgehog (Hh) signaling in mammals.
    explanation: >-
      Establishes the obligate role of the primary cilium in mammalian Hedgehog
      signal transduction, so that the PIK3C2A-driven ciliogenesis defect impairs
      cilium-dependent Hedgehog signaling. Evidence source is OTHER (review).
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cellular studies of patient-derived fibroblasts found that they lacked
      PIK3C2A protein, had impaired cilia formation and function, and
      demonstrated reduced proliferative capacity
    explanation: >-
      Patient fibroblasts show impaired cilia formation and function; because the
      primary cilium is the obligate site of Hedgehog transduction, this ciliary
      defect disrupts the cilium-dependent Hedgehog signaling that patterns the
      skeleton and CNS.
- name: Impaired Ciliary Signaling and Multisystem Developmental Pleiotropy
  conforms_to: "ciliopathy_dysfunction#Multisystem Pleiotropic Ciliopathy Phenotype"
  description: >-
    Because the primary cilium is a near-ubiquitous sensory-signaling organelle,
    PIK3C2A-dependent ciliary dysfunction during development produces a
    multisystem disorder rather than a single-organ phenotype. The convergent
    clinical end state combines ocular (cataract, secondary glaucoma), skeletal
    (short stature, multiple skeletal abnormalities), craniofacial/dental, and
    neurological features, with hearing loss in a subset — the characteristic
    pleiotropy of a ciliopathy.
  biological_processes:
  - preferred_term: Cilium Assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with short stature, coarse facial features, cataracts with secondary
      glaucoma, multiple skeletal abnormalities, neurological manifestations,
      among other findings
    explanation: >-
      Enumerates the multisystem (ocular, skeletal, craniofacial, neurological)
      pleiotropy that defines the ciliopathy phenotype.
phenotypes:
- name: Short Stature
  category: Growth
  description: >-
    Short stature is a consistent feature of PIK3C2A-related syndrome.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with short stature, coarse facial features, cataracts with secondary
      glaucoma, multiple skeletal abnormalities
    explanation: >-
      Short stature is enumerated among the cardinal features of the syndrome.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Congenital cataracts (including pulverulent cataracts), frequently
    complicated by secondary glaucoma, are a defining ocular feature.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cataracts with secondary glaucoma, multiple skeletal abnormalities
    explanation: >-
      Cataract (with secondary glaucoma) is a cardinal ocular feature of the
      syndrome.
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by pulverulent cataracts and deafness
    explanation: >-
      Confirms cataract (pulverulent type) as a presenting ocular feature in an
      additional family.
- name: Secondary Glaucoma
  category: Ophthalmologic
  description: >-
    Secondary glaucoma develops as a complication of the congenital cataracts in
    affected individuals.
  phenotype_term:
    preferred_term: Secondary glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cataracts with secondary glaucoma
    explanation: >-
      Secondary glaucoma is reported in association with the cataracts.
- name: Multiple Skeletal Abnormalities
  category: Skeletal
  description: >-
    Multiple skeletal abnormalities (reported features include scoliosis, delayed
    bone age, and metaphyseal changes) are part of the syndrome and contribute to
    its classification among the skeletal ciliopathies.
  phenotype_term:
    preferred_term: Abnormal skeletal morphology
    term:
      id: HP:0011842
      label: Abnormal skeletal morphology
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      multiple skeletal abnormalities, neurological manifestations
    explanation: >-
      Multiple skeletal abnormalities are a cardinal feature of the syndrome.
- name: Coarse Facial Features
  category: Craniofacial
  description: >-
    Coarse facial features are part of the characteristic craniofacial
    dysmorphism of the syndrome.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature, coarse facial features, cataracts with secondary glaucoma
    explanation: >-
      Coarse facial features are enumerated among the defining dysmorphic
      features.
- name: Neurological Manifestations
  category: Neurologic
  description: >-
    Neurological manifestations occur as part of the multisystem phenotype.
  phenotype_term:
    preferred_term: Neurological manifestations
    term:
      id: HP:0000707
      label: Abnormality of the nervous system
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      multiple skeletal abnormalities, neurological manifestations, among other
      findings
    explanation: >-
      Neurological manifestations are listed among the cardinal clinical features
      of the syndrome.
- name: Hearing Impairment
  category: Otologic
  description: >-
    Deafness has been reported as part of the PIK3C2A-related
    syndrome spectrum.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by pulverulent cataracts and deafness
    explanation: >-
      Documents deafness as part of the clinical spectrum in an additional
      family, expanding the phenotype.
genetic:
- name: PIK3C2A Loss-of-Function Variants
  association: Causative
  gene_term:
    preferred_term: PIK3C2A
    term:
      id: hgnc:8971
      label: PIK3C2A
  notes: >-
    Biallelic loss-of-function variants in PIK3C2A (11p15.1), encoding a class II
    phosphoinositide 3-kinase, cause oculocerebrodental (oculoskeletodental)
    syndrome. The originally reported families carried homozygous variants;
    compound heterozygous genotypes requiring functional validation have also
    been described. PIK3C2A produces PI(3)P and PI(3,4)P2 required for primary
    cilium formation and function.
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified homozygous loss-of-function mutations in PIK3C2A in children
      from three independent consanguineous families
    explanation: >-
      Original report identifying biallelic PIK3C2A loss of function as the cause
      of the syndrome.
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using trio exome sequencing, we identified two novel compound heterozygous
      variants in
    explanation: >-
      Independent identification of additional (compound heterozygous) PIK3C2A
      variants, confirming the gene and expanding the mutational spectrum.
diagnosis:
- name: Clinical and Molecular Diagnosis
  description: >-
    The syndrome is suspected from the combination of short stature, coarse facial
    features, congenital cataracts (with secondary glaucoma), and multiple
    skeletal abnormalities, and is confirmed by identification of biallelic
    PIK3C2A pathogenic variants. Functional studies of patient fibroblasts
    (cilia formation/function) may be required to interpret variants of uncertain
    significance.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: DOI:10.1111/cge.70005
    reference_title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using trio exome sequencing, we identified two novel compound heterozygous
      variants in
    explanation: >-
      Illustrates exome sequencing as the molecular diagnostic approach, with
      functional testing for variant interpretation.
differential_diagnoses:
- name: Lowe Syndrome
  description: >-
    Lowe (oculocerebrorenal) syndrome is caused by variants in OCRL, a
    PI-5-phosphatase, and shares congenital cataracts and neurological
    involvement. The considerable phenotypic overlap between the two disorders,
    yet their distinct features, highlights the non-redundant roles of
    phosphoinositide-metabolizing enzymes in development.
  evidence:
  - reference: PMID:31034465
    reference_title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the considerable phenotypic overlap, yet distinct features, between this
      syndrome and Lowe's syndrome, which is caused by mutations in the
      PI-5-phosphatase OCRL
    explanation: >-
      Establishes Lowe syndrome (OCRL) as the principal phosphoinositide-disorder
      differential, with overlapping yet distinct features.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    There is no disease-modifying therapy. Management is supportive and
    multidisciplinary, addressing the ophthalmologic, skeletal, neurological, and
    audiologic manifestations through specialist follow-up and early intervention.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Cataract and Glaucoma Surgery
  description: >-
    Surgical management of the congenital cataracts and secondary glaucoma is
    performed as clinically indicated to preserve vision.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance entails a 25% recurrence risk for siblings.
    Once the biallelic PIK3C2A variants are identified, carrier testing and
    prenatal/preimplantation genetic testing become available to families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
references:
- reference: PMID:31034465
  title: "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction."
- reference: DOI:10.1111/cge.70005
  title: "PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect."
📚

References & Deep Research

References

2
PMID:31034465
Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.
No top-level findings curated for this source.
DOI:10.1111/cge.70005
PIK3C2A-Related Clinical Phenotype and Cellular Characterization Linked to Functional SHH Primary Cilia Defect.
No top-level findings curated for this source.