Opsismodysplasia is a rare autosomal recessive skeletal chondrodysplasia. Molecularly confirmed INPPL1-related opsismodysplasia is caused by biallelic loss-of-function mutations in INPPL1, which encodes the phosphoinositide 5-phosphatase SHIP2. The disease is characterized by prenatal-onset short stature, micromelia with extremely short hands and feet, platyspondyly, delayed skeletal maturation, and distinctive craniofacial features including relative macrocephaly, frontal bossing, midface retrusion, and anteverted nares. Growth plate histology shows a widened hypertrophic zone with irregular provisional calcification. Loss of SHIP2 catalytic activity disrupts phosphoinositide signaling, leading to elevated MEK-Erk1/2 activity in chondrocytes, impaired chondrocyte differentiation, and defective endochondral ossification. Some patients develop renal phosphate wasting with hypophosphatemic rickets, which is associated with a more severe phenotype. Prognosis is variable, with perinatal demise in some infants and survival into childhood and beyond in others. Bisphosphonate therapy has shown benefit for bone mineral density and motor function.
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name: Opsismodysplasia
creation_date: "2026-04-02T00:00:00Z"
updated_date: "2026-04-19T02:21:57Z"
category: Mendelian
description: >
Opsismodysplasia is a rare autosomal recessive skeletal chondrodysplasia.
Molecularly confirmed INPPL1-related opsismodysplasia is caused by biallelic
loss-of-function mutations in INPPL1, which encodes the phosphoinositide
5-phosphatase SHIP2. The disease is characterized by prenatal-onset short
stature, micromelia with extremely short hands and feet, platyspondyly, delayed
skeletal maturation, and distinctive craniofacial features including relative
macrocephaly, frontal bossing, midface retrusion, and anteverted nares. Growth
plate histology shows a widened hypertrophic zone with irregular provisional
calcification. Loss of SHIP2 catalytic activity disrupts phosphoinositide
signaling, leading to elevated MEK-Erk1/2 activity in chondrocytes, impaired
chondrocyte differentiation, and defective endochondral ossification. Some
patients develop renal phosphate wasting with hypophosphatemic rickets, which
is associated with a more severe phenotype. Prognosis is variable, with
perinatal demise in some infants and survival into childhood and beyond in
others. Bisphosphonate therapy has shown benefit for bone mineral density and
motor function.
disease_term:
preferred_term: opsismodysplasia
term:
id: MONDO:0009785
label: opsismodysplasia
parents:
- Spondylodysplastic dysplasia
- INPPL1-related skeletal dysplasia
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Opsismodysplasia follows autosomal recessive inheritance with biallelic
INPPL1 mutations required for disease expression. Consanguinity has been
reported in multiple families. INPPL1 mutations explain approximately 60%
of clinically diagnosed cases.
evidence:
- reference: PMID:23273567
reference_title: "Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting."
explanation: Establishes that biallelic INPPL1 mutations cause autosomal recessive opsismodysplasia.
- reference: PMID:10076884
reference_title: "Five familial cases of opsismodysplasia substantiate the hypothesis of autosomal recessive inheritance."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This observation supports the hypothesis of autosomal recessive transmission of opsismodysplasia."
explanation: Familial recurrence pattern confirmed autosomal recessive inheritance prior to gene identification.
prevalence:
- population: Global
percentage: Unknown
notes: >-
Extremely rare with fewer than 40 molecularly confirmed cases reported
worldwide as of 2025.
evidence:
- reference: PMID:39911177
reference_title: "A Case of Opsismodysplasia with a Novel INPPL1 Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Only 38 patients with a confirmed molecular diagnosis have been reported so far."
explanation: Indicates extreme rarity of molecularly confirmed cases.
pathophysiology:
- name: Loss of SHIP2 phosphoinositide phosphatase activity
description: >
INPPL1 encodes SHIP2, a phosphoinositide 5-phosphatase that dephosphorylates
PI(3,4,5)P3 to generate PI(3,4)P2. Loss-of-function mutations in INPPL1
abolish this catalytic activity, disrupting both PI(3,4,5)P3 turnover and
PI(3,4)P2 product-dependent phosphoinositide signaling in chondrocytes. Most
pathogenic variants are premature stop codons or missense mutations affecting
the catalytic domain, while some destabilize the protein through structural
disruption of the SH2 domain.
gene:
preferred_term: INPPL1
description: >
Inositol polyphosphate phosphatase-like 1, encoding the lipid phosphatase
SHIP2 that regulates phosphoinositide signaling by dephosphorylating
PI(3,4,5)P3.
modifier: DECREASED
term:
id: hgnc:6080
label: INPPL1
cell_types:
- preferred_term: Chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: Phosphatidylinositol dephosphorylation
term:
id: GO:0046856
label: phosphatidylinositol dephosphorylation
modifier: DECREASED
evidence:
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides."
explanation: Identifies the enzymatic function of INPPL1/SHIP2 in phosphoinositide signaling.
- reference: PMID:27708270
reference_title: "INPPL1 gene mutations in opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "skeletal disease seems to result from the loss of SHIP2 activity due to catalytic domain mutations or no SHIP2 protein due to premature stop codons."
explanation: Confirms that loss of SHIP2 enzymatic activity is the pathogenic mechanism.
- reference: PMID:24953221
reference_title: "Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the INPPL1 protein was barely detectable in patient cells."
explanation: Patient-derived lymphocytes show that the SH2-domain insertion destabilizes INPPL1 protein, supporting loss of SHIP2 activity as a disease mechanism.
- reference: PMID:27233067
reference_title: "Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The absence of SHIP2 was confirmed by immunoblot analysis of proband amniocytes."
explanation: Direct protein-level evidence showing complete loss of SHIP2 in a patient with compound heterozygous INPPL1 variants.
downstream:
- target: Impaired chondrocyte differentiation and endochondral ossification
description: Loss of SHIP2 function directly perturbs chondrocyte differentiation programs and downstream endochondral bone formation.
causal_link_type: DIRECT
evidence:
- reference: PMID:31519471
reference_title: "Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "They also highlight the important role of SHIP2 in chondrocytes during endochondral ossification and its different differentiation steps."
explanation: The catalytic knock-out mouse directly links SHIP2 loss to abnormal chondrocyte differentiation and impaired endochondral ossification.
- target: Defective cell migration and adhesion
description: SHIP2 deficiency directly perturbs phosphoinositide-dependent migration and adhesion signaling in patient-derived cells.
causal_link_type: DIRECT
evidence:
- reference: PMID:28869677
reference_title: "Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We conclude that both migration and adhesion are very much disrupted in OPS-derived fibroblasts."
explanation: Patient fibroblasts directly connect SHIP2 deficiency to combined migration and adhesion defects.
- name: Impaired chondrocyte differentiation and endochondral ossification
description: >
Loss of SHIP2 activity leads to elevated MEK-Erk1/2 signaling in chondrocytes,
resulting in altered chondrocyte differentiation and impaired matrix mineralization.
Growth plate histology shows a widened hypertrophic zone with irregular
provisional calcification and disrupted vascular invasion. These defects impair
endochondral ossification, the process by which cartilage is replaced by bone
during skeletal development.
cell_types:
- preferred_term: Hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
- preferred_term: Chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: Endochondral ossification
term:
id: GO:0001958
label: endochondral ossification
modifier: DECREASED
- preferred_term: Chondrocyte differentiation
term:
id: GO:0002062
label: chondrocyte differentiation
modifier: ABNORMAL
- preferred_term: MAPK cascade
term:
id: GO:0000165
label: MAPK cascade
modifier: INCREASED
- preferred_term: Bone mineralization
term:
id: GO:0030282
label: bone mineralization
modifier: DECREASED
evidence:
- reference: PMID:31519471
reference_title: "Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "levels of p-MEK and p-Erk1/2 were significantly increased in SHIP2-inactivated chondrocytes in response to serum and IGF-1, but not to FGF2, as compared to control chondrocytes."
explanation: Mouse model demonstrates that SHIP2 loss increases MEK-Erk1/2 signaling in chondrocytes.
- reference: PMID:31519471
reference_title: "Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Treatment of chondrocytes and bones in culture with a MEK inhibitor partially rescued the production of mineralized nodules, the size of the hypertrophic chondrocyte zone and bone growth, raising the possibility of a treatment that could partially reduce the phenotype of this severe condition."
explanation: MEK inhibition partially restores mineralization, confirming MEK-Erk1/2 pathway involvement.
- reference: PMID:6496568
reference_title: "Opsismodysplasia: a new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The growth cartilage studied in one case showed a wide hypertrophic area containing thick connective tissue septa, irregular provisional calcification, and vascular invasion."
explanation: Original description of growth plate histopathology in opsismodysplasia.
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification."
explanation: Links INPPL1 mutations to growth plate disorganization and impaired endochondral bone formation.
- name: Defective cell migration and adhesion
description: >
SHIP2 loss disrupts phosphoinositide-dependent cell migration and adhesion
signaling. Patient-derived fibroblasts show markedly reduced cell migration
and altered adhesion properties, suggesting that these cellular defects
contribute to impaired endochondral ossification by disrupting the normal
movement and organization of chondrocytes in the growth plate.
cell_types:
- preferred_term: Fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: Cell migration
term:
id: GO:0016477
label: cell migration
modifier: DECREASED
- preferred_term: Cell adhesion
term:
id: GO:0007155
label: cell adhesion
modifier: ABNORMAL
evidence:
- reference: PMID:28869677
reference_title: "Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "cell migration is very much decreased in fibroblasts derived from three OPS patients as compared with control individuals."
explanation: Patient fibroblasts directly demonstrate impaired migration due to SHIP2 deficiency.
- reference: PMID:28869677
reference_title: "Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "signaling events linked to migration and particularly to adhesion, which are lost in OPS patients, would prevent normal endochondral ossification."
explanation: Links cell migration and adhesion defects to the skeletal phenotype.
- name: Renal phosphate wasting
description: >
A subset of patients develops renal phosphate wasting with elevated FGF23 levels,
leading to hypophosphatemic rickets. Phosphate wasting is associated with more
severe bone demineralization and a more severe overall phenotype. The mechanism
linking SHIP2 loss to FGF23 elevation and renal phosphate handling is not fully
understood.
biological_processes:
- preferred_term: Phosphate ion homeostasis
term:
id: GO:0055062
label: phosphate ion homeostasis
modifier: ABNORMAL
evidence:
- reference: PMID:17315533
reference_title: "Hypophosphatemic rickets in opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We now demonstrate an association between opsismodysplasia, hypophosphatemic rickets, and FGF23 elevation."
explanation: First report demonstrating the link between opsismodysplasia and FGF23-mediated phosphate wasting.
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Renal phosphate wasting is associated with severe bone demineralization and a more severe phenotype."
explanation: Establishes that phosphate wasting worsens the skeletal phenotype.
phenotypes:
- name: Severe short stature
category: Clinical
description: >
Marked linear growth impairment is a core manifestation of
opsismodysplasia.
phenotype_term:
preferred_term: Severe short stature
term:
id: HP:0003510
label: Severe short stature
evidence:
- reference: PMID:40620719
reference_title: "Pamidronate Treatment of a Patient with Opsismodysplasia and a Novel INPPL1 Variant: Efficacy, Mechanism, and Clinical Outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Initial evaluations showed severe short stature and low bone mineral density (DEXA SDS: -3.16)."
explanation: Recent case evidence confirms severe short stature as a core phenotype.
- name: Micromelia
category: Clinical
description: >
Extremely short limbs with disproportionate shortening, particularly of the
hands and feet.
phenotype_term:
preferred_term: Micromelia
term:
id: HP:0002983
label: Micromelia
phenotype_contexts:
- onset:
onset_category: ANTENATAL
notes: The landmark molecular series described limb shortening as pre- and postnatal.
evidence:
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet."
explanation: Directly supports antenatal onset of micromelia.
evidence:
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet."
explanation: Micromelia with short hands and feet is a defining feature.
- name: Severe platyspondyly
category: Clinical
description: >
Flattened vertebral bodies are a consistent radiographic finding.
phenotype_term:
preferred_term: Severe platyspondyly
term:
id: HP:0004565
label: Severe platyspondyly
evidence:
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping."
explanation: The landmark molecular cohort identifies severe platyspondyly as a main radiographic feature.
- name: Delayed skeletal maturation
category: Clinical
description: >
Markedly delayed bone age with retarded ossification of epiphyses is a
hallmark radiographic finding.
phenotype_term:
preferred_term: Delayed skeletal maturation
term:
id: HP:0002750
label: Delayed skeletal maturation
evidence:
- reference: PMID:6496568
reference_title: "Opsismodysplasia: a new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "very retarded bone maturation; marked shortness of the bones of the hands and of the feet with concave metaphyses; and thin, lamellar vertebral bodies."
explanation: Original disease description emphasizing delayed bone maturation as a cardinal feature.
- name: Metaphyseal cupping
category: Clinical
description: >
Concave, cupped metaphyses of the long bones and tubular bones of the hands
and feet are characteristic radiographic findings.
phenotype_term:
preferred_term: Metaphyseal cupping
term:
id: HP:0003021
label: Metaphyseal cupping
evidence:
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping."
explanation: The defining molecular cohort lists metaphyseal cupping among the main radiographic abnormalities.
- name: Delayed epiphyseal ossification
category: Clinical
description: >
Delayed mineralization and appearance of secondary ossification centers is a
defining radiographic feature.
phenotype_term:
preferred_term: Delayed epiphyseal ossification
term:
id: HP:0002663
label: Delayed epiphyseal ossification
evidence:
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The main radiological features are severe platyspondyly, short long bones including squared metacarpals, delayed epiphyseal ossification, and metaphyseal flaring and cupping (7–10)."
explanation: This case-based review directly identifies delayed epiphyseal ossification as a core radiographic abnormality.
- name: Relative macrocephaly
category: Clinical
description: >
Head circumference is relatively large compared to the shortened trunk and
limbs, contributing to the characteristic craniofacial appearance.
phenotype_term:
preferred_term: Relative macrocephaly
term:
id: HP:0004482
label: Relative macrocephaly
evidence:
- reference: PMID:39911177
reference_title: "A Case of Opsismodysplasia with a Novel INPPL1 Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had dysmorphic findings including relative macrocephaly, midface hypoplasia, depressed nasal bridge, anteverted nostrils, long philtrum, small hands and feet, and brachydactyly."
explanation: Recent case evidence documents relative macrocephaly as part of the characteristic craniofacial gestalt.
- name: Large fontanelles
category: Clinical
description: >
Delayed closure and persistent widening of the anterior fontanelle have been
reported in surviving children.
phenotype_term:
preferred_term: Large fontanelles
term:
id: HP:0000239
label: Large fontanelles
evidence:
- reference: PMID:24953221
reference_title: "Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had wide open anterior fontanelles which closed at six years of age."
explanation: This patient report shows persistent large fontanelles well beyond infancy.
- name: Frontal bossing
category: Clinical
description: Prominent forehead.
phenotype_term:
preferred_term: Frontal bossing
term:
id: HP:0002007
label: Frontal bossing
evidence:
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Opsismodysplasia is an autosomal recessive osteochondrodysplasia disorders characterized by a severe delay in bone maturation. This leads to rhizomelic micromelia with small hands and feet, relative macrocephaly, and craniofacial dysmorphism including frontal bossing, short nose with anteverted nares and depressed nasal bridge, long philtrum, and abnormal ears."
explanation: Prenatal imaging demonstrates frontal bossing in an affected fetus.
- name: Midface retrusion
category: Clinical
description: Underdevelopment of the midface structures.
phenotype_term:
preferred_term: Midface hypoplasia
term:
id: HP:0011800
label: Midface retrusion
evidence:
- reference: PMID:39911177
reference_title: "A Case of Opsismodysplasia with a Novel INPPL1 Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had dysmorphic findings including relative macrocephaly, midface hypoplasia, depressed nasal bridge, anteverted nostrils, long philtrum, small hands and feet, and brachydactyly."
explanation: The reported midface hypoplasia corresponds to the characteristic midfacial retrusion seen in opsismodysplasia.
- name: Depressed nasal bridge
category: Clinical
description: Flattened nasal bridge.
phenotype_term:
preferred_term: Depressed nasal bridge
term:
id: HP:0005280
label: Depressed nasal bridge
evidence:
- reference: PMID:39911177
reference_title: "A Case of Opsismodysplasia with a Novel INPPL1 Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had dysmorphic findings including relative macrocephaly, midface hypoplasia, depressed nasal bridge, anteverted nostrils, long philtrum, small hands and feet, and brachydactyly."
explanation: The depressed nasal bridge is explicitly reported in a recent molecularly confirmed case.
- name: Short nose
category: Clinical
description: Shortened nasal length.
phenotype_term:
preferred_term: Short nose
term:
id: HP:0003196
label: Short nose
evidence:
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Examination of the newborn (case A) shows short limbs with small trident hands and feet, and craniofacial dysmorphism including hypertelorism, depressed nasal bridge, short nose with anteverted nares and depressed nasal bridge, long philtrum, and low set deformed ears."
explanation: The postnatal examination in a molecularly confirmed newborn documents a short nose.
- name: Anteverted nares
category: Clinical
description: Upturned nostrils.
phenotype_term:
preferred_term: Anteverted nares
term:
id: HP:0000463
label: Anteverted nares
evidence:
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Examination of the newborn (case A) shows short limbs with small trident hands and feet, and craniofacial dysmorphism including hypertelorism, depressed nasal bridge, short nose with anteverted nares and depressed nasal bridge, long philtrum, and low set deformed ears."
explanation: The newborn examination explicitly reports anteverted nares.
- name: Long philtrum
category: Clinical
description: Increased distance between the nasal base and upper lip.
phenotype_term:
preferred_term: Long philtrum
term:
id: HP:0000343
label: Long philtrum
evidence:
- reference: PMID:39911177
reference_title: "A Case of Opsismodysplasia with a Novel INPPL1 Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had dysmorphic findings including relative macrocephaly, midface hypoplasia, depressed nasal bridge, anteverted nostrils, long philtrum, small hands and feet, and brachydactyly."
explanation: The long philtrum is part of the recurrent craniofacial phenotype.
- name: Bowing of the long bones
category: Clinical
description: Bowed long bones, particularly of the lower extremities.
phenotype_term:
preferred_term: Bowing of the long bones
term:
id: HP:0006487
label: Bowing of the long bones
evidence:
- reference: PMID:27233067
reference_title: "Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographs of fetus #2 showed hydropic changes and short limbs with flaring and metaphyseal cupping were reported. Both distal femoral metaphyses appeared irregular and the radii, femora and tibae were bowed (Figure 1)."
explanation: Prenatal radiographs in a severe familial case document bowing of multiple long bones.
- name: Flat acetabular roof
category: Clinical
description: >
Pelvic radiographs can show horizontally oriented, dysplastic acetabular
roofs.
phenotype_term:
preferred_term: Flat acetabular roof
term:
id: HP:0003180
label: Flat acetabular roof
evidence:
- reference: PMID:27233067
reference_title: "Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The iliac bones were decreased in vertical height with horizontal orientation of the acetabular roofs."
explanation: This radiographic description directly supports a flat acetabular roof phenotype.
- name: Narrow chest
category: Clinical
description: >
A small thorax is a recurrent prenatal and postnatal finding and likely
contributes to respiratory compromise in severe cases.
phenotype_term:
preferred_term: Narrow chest
term:
id: HP:0000774
label: Narrow chest
evidence:
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Chest appears narrow and abdomen is protuberant."
explanation: Prenatal imaging demonstrates a narrow thorax in severe opsismodysplasia.
- name: Scoliosis
category: Clinical
description: >
Spinal curvature can develop in surviving children.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She was identified to have scoliosis with a 42° right thoracic curve, and a 57° left lumbar curve."
explanation: Detailed follow-up of a surviving child documents clinically significant scoliosis.
- name: Respiratory insufficiency
category: Clinical
description: >
Respiratory compromise ranges from neonatal distress to progressive
respiratory failure in more severe cases.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These cases provide evidence of the variability in severity of findings in siblings with opsismodysplasia and suggest that those with phosphate wasting have more severe skeletal findings and respiratory compromise."
explanation: The sibling case report identifies respiratory compromise as a major clinical complication.
- name: Hypoplasia of the odontoid process
category: Clinical
description: >
Craniocervical abnormalities can include odontoid hypoplasia, creating
potential concern for cervical instability.
phenotype_term:
preferred_term: Hypoplasia of the odontoid process
term:
id: HP:0003311
label: Hypoplasia of the odontoid process
evidence:
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cervical spine films show odontoid hypoplasia, with no evidence of atlantoaxial or occipitocervical instability."
explanation: Follow-up cervical imaging in a surviving child documented odontoid hypoplasia.
- name: Polyhydramnios
category: Clinical
description: >
Polyhydramnios has been reported during affected pregnancies and can be an
early prenatal clue.
phenotype_term:
preferred_term: Polyhydramnios
term:
id: HP:0001561
label: Polyhydramnios
evidence:
- reference: PMID:20422326
reference_title: "Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "During the antenatal period, polyhydramnios was noted."
explanation: This neonatal case report documents polyhydramnios as a prenatal finding.
- name: Hydrocephalus
category: Clinical
description: >
Hydrocephalus appears to be a rare associated finding rather than a core
manifestation.
phenotype_term:
preferred_term: Hydrocephalus
term:
id: HP:0000238
label: Hydrocephalus
evidence:
- reference: PMID:16473316
reference_title: "A further case of opsismodysplasia with hydrocephalus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She also had hydrocephaly, a rare finding in opsismodysplasia."
explanation: This report supports hydrocephalus as an uncommon but documented associated feature.
- name: Motor delay
category: Clinical
description: >
Delayed motor development has been reported in some survivors, likely
reflecting the severity of the skeletal disease.
phenotype_term:
preferred_term: Motor delay
term:
id: HP:0001270
label: Motor delay
evidence:
- reference: PMID:24953221
reference_title: "Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She achieved neuromotor developmental milestones late."
explanation: This long-term follow-up report documents delayed motor milestone acquisition.
- name: Hypophosphatemic rickets
category: Clinical
description: >
A subset of patients develops renal phosphate wasting with elevated FGF23,
leading to hypophosphatemic rickets and severe bone demineralization.
phenotype_term:
preferred_term: Hypophosphatemic rickets
term:
id: HP:0004912
label: Hypophosphatemic rickets
evidence:
- reference: PMID:17315533
reference_title: "Hypophosphatemic rickets in opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both children had hypophosphatemia, decreased TRP, and rickets."
explanation: Documents hypophosphatemic rickets in opsismodysplasia patients.
- reference: PMID:17315533
reference_title: "Hypophosphatemic rickets in opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We now demonstrate an association between opsismodysplasia, hypophosphatemic rickets, and FGF23 elevation."
explanation: Establishes the association with FGF23-mediated phosphate wasting.
- name: Renal phosphate wasting
category: Clinical
description: >
Renal phosphate wasting occurs in a subset of patients and can mark a more
severe course with osteodystrophy.
phenotype_term:
preferred_term: Renal phosphate wasting
term:
id: HP:0000117
label: Renal phosphate wasting
evidence:
- reference: PMID:23273567
reference_title: "Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting."
explanation: The gene discovery study identifies renal phosphate wasting as a clinically important subset phenotype.
- name: Reduced bone mineral density
category: Clinical
description: >
Decreased bone mineralization, ranging from osteopenia to severe
demineralization, particularly in patients with phosphate wasting.
phenotype_term:
preferred_term: Reduced bone mineral density
term:
id: HP:0004349
label: Reduced bone mineral density
evidence:
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Renal phosphate wasting is associated with severe bone demineralization and a more severe phenotype."
explanation: Bone demineralization is a feature, exacerbated by phosphate wasting.
- reference: PMID:40620719
reference_title: "Pamidronate Treatment of a Patient with Opsismodysplasia and a Novel INPPL1 Variant: Efficacy, Mechanism, and Clinical Outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Initial evaluations showed severe short stature and low bone mineral density (DEXA SDS: -3.16)."
explanation: Recent case evidence shows reduced bone mineral density even without hypophosphatemic rickets.
- name: Short foot
category: Clinical
description: >
Extremely short tubular bones of the feet with concave metaphyses.
phenotype_term:
preferred_term: Short foot
term:
id: HP:0001773
label: Short foot
evidence:
- reference: PMID:6496568
reference_title: "Opsismodysplasia: a new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "very retarded bone maturation; marked shortness of the bones of the hands and of the feet with concave metaphyses; and thin, lamellar vertebral bodies."
explanation: Short feet with concave metaphyses are defining features from the original description.
- name: Short metacarpal
category: Clinical
description: >
Hand radiographs show striking shortening of the metacarpals and phalanges.
phenotype_term:
preferred_term: Short metacarpal
term:
id: HP:0010049
label: Short metacarpal
evidence:
- reference: PMID:39911177
reference_title: "A Case of Opsismodysplasia with a Novel INPPL1 Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Delayed bone age, short metacarpals and phalanges, wide and irregular metaphysis, platyspondyly, anterior beaking of the vertebrae, T12 vertebral hypoplasia, and acetabular dysplasia were noted on X-rays."
explanation: This recent molecularly confirmed case documents the characteristic marked shortening of the metacarpals.
genetic:
- name: INPPL1 biallelic variants
gene_term:
preferred_term: INPPL1
term:
id: hgnc:6080
label: INPPL1
association: Causative
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "INPPL1-related opsismodysplasia is inherited in an autosomal recessive manner."
explanation: GeneReviews summarizes the Mendelian inheritance pattern for biallelic INPPL1-related disease.
notes: >
Over 25 distinct mutations have been identified across more than 20 families,
including nonsense, frameshift, missense, and splice-site variants. Most
pathogenic missense variants affect the catalytic 5-phosphatase domain.
Frameshift variants appear associated with lethal outcomes. Schneckenbecken
dysplasia is an allelic disorder with a uniformly lethal phenotype. INPPL1
mutations explain approximately 60% of clinically diagnosed cases; the genetic
basis of the remaining clinically diagnosed cases remains unresolved, so
INPPL1-related wording should be reserved for molecularly confirmed disease.
evidence:
- reference: PMID:23273569
reference_title: "Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet."
explanation: Landmark study identifying INPPL1 mutations as the cause of opsismodysplasia.
- reference: PMID:23273567
reference_title: "Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases."
explanation: Estimates the proportion of clinically diagnosed cases attributable to INPPL1 mutations.
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Schneckenbecken dysplasia and Opsismodysplasia are allelic disorders caused by pathogenic variants in INPPL1 gene with lethal outcomes in Schneckenbecken dysplasia and nonlethal prognosis in Opsismodysplasia."
explanation: Establishes the allelic relationship with Schneckenbecken dysplasia.
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Prediction of lethality is difficult to determine in prenatal‐onset skeletal dysplasia especially with borderline lethality indices measured in prenatal ultrasound."
explanation: Highlights the challenge of predicting lethal versus nonlethal outcomes in prenatal INPPL1-related skeletal dysplasia.
animal_models:
- species: Mouse
genotype: Inppl1 catalytic knock-out
description: >
An INPPL1 catalytic knock-out mouse model recapitulates the opsismodysplasia
phenotype with growth plate defects, altered chondrocyte differentiation, and
impaired matrix mineralization. Elevated MEK-Erk1/2 signaling was identified
in SHIP2-inactivated chondrocytes. Treatment with a MEK inhibitor partially
rescued mineralization defects and hypertrophic zone size, identifying MEK-Erk1/2
as a potential therapeutic target.
genes:
- preferred_term: Inppl1
term:
id: hgnc:6080
label: INPPL1
evidence:
- reference: PMID:31519471
reference_title: "Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Opsismodysplasia (OPS) is a rare but severe autosomal recessive skeletal chondrodysplasia caused by inactivating mutations in the Inppl1/Ship2 gene."
explanation: Describes the INPPL1 catalytic knock-out mouse model of opsismodysplasia.
- reference: PMID:31519471
reference_title: "Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Treatment of chondrocytes and bones in culture with a MEK inhibitor partially rescued the production of mineralized nodules, the size of the hypertrophic chondrocyte zone and bone growth, raising the possibility of a treatment that could partially reduce the phenotype of this severe condition."
explanation: MEK inhibition partially rescues the skeletal phenotype in the mouse model.
- species: Zebrafish
genotype: inppl1a mutant
description: >
Zebrafish inppl1a mutants are shorter from early larval stages and develop
notochord curvatures, thoracic scoliosis, and vertebral malformations.
The model demonstrates that inppl1a-dependent vacuolated cell expansion is
essential for normal notochord mechanics, spine morphogenesis, and
endochondral bone lengthening, providing conserved organismal support for
INPPL1-related skeletal pathophysiology.
genes:
- preferred_term: inppl1a
term:
id: hgnc:6080
label: INPPL1
evidence:
- reference: PMID:40209709
reference_title: "Cell expansion for notochord mechanics and endochondral bone lengthening in zebrafish depends on the 5'-inositol phosphatase Inppl1a."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We demonstrate that inppl1a-dependent vacuolated cell expansion is essential to establish normal mechanical properties of the notochord and to facilitate the development of a straight spine."
explanation: Zebrafish model demonstrates conserved role of INPPL1 in spine morphogenesis and endochondral bone lengthening.
diagnosis:
- name: Clinical and Radiographic Recognition
description: >-
Suspect INPPL1-related opsismodysplasia when prenatal-onset short stature,
short bowed limbs, characteristic craniofacial features, narrow thorax,
small hands and feet, delayed epiphyseal mineralization, metaphyseal cupping,
and platyspondyly form the clinical and radiographic pattern. Skeletal
survey or targeted radiographs establish this pattern and prioritize
molecular confirmation.
diagnosis_term:
preferred_term: clinical imaging procedure
term:
id: MAXO:0000005
label: clinical imaging procedure
evidence:
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
INPPL1-related opsismodysplasia is characterized by prenatal-onset short
stature, short, bowed limbs, characteristic facial features (relative
macrocephaly, prominent forehead, midface retrusion, depressed nasal
bridge, short nose, anteverted nares, relatively long philtrum), narrow
thorax, small hands and feet, delayed epiphyseal mineralization,
metaphyseal cupping, and platyspondyly.
explanation: >-
GeneReviews summarizes the core clinical and radiographic pattern that
should trigger diagnostic consideration.
- name: Molecular Confirmation of Biallelic INPPL1 Pathogenic Variants
description: >-
Molecular genetic testing confirms INPPL1-related opsismodysplasia by
identifying biallelic pathogenic variants in INPPL1. Because INPPL1 explains
only a subset of clinically diagnosed cases, negative INPPL1 testing should
prompt broader skeletal dysplasia evaluation rather than excluding the
clinical diagnosis outright.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of INPPL1-related opsismodysplasia is established in a proband with characteristic clinical and radiographic features and biallelic pathogenic variants in INPPL1 identified by molecular genetic testing."
explanation: >-
GeneReviews defines the biallelic INPPL1 molecular confirmation criterion
for INPPL1-related opsismodysplasia.
- reference: PMID:23273567
reference_title: "Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases."
explanation: >-
This supports preserving a distinction between clinically diagnosed
opsismodysplasia and the INPPL1-confirmed subset.
- name: INPPL1 Spectrum Differential Diagnosis
description: >-
Diagnostic interpretation should explicitly distinguish INPPL1-related
opsismodysplasia from Schneckenbecken dysplasia, the allelic lethal skeletal
dysplasia, and from other spondylodysplastic dysplasias in INPPL1-negative
clinically diagnosed cases.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:34094554
reference_title: "Prenatal-onset INPPL1-related skeletal dysplasia in two unrelated families: Diagnosis and prediction of lethality."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Schneckenbecken dysplasia and Opsismodysplasia are allelic disorders caused by pathogenic variants in INPPL1 gene with lethal outcomes in Schneckenbecken dysplasia and nonlethal prognosis in Opsismodysplasia."
explanation: >-
This establishes the key allelic differential and the lethal versus
nonlethal boundary within INPPL1-related skeletal dysplasia.
treatments:
- name: Bisphosphonate therapy
description: >
Intravenous pamidronate has improved bone mineral density and gross motor
function in patients with opsismodysplasia. Treatment benefit has been
demonstrated both in patients with and without hypophosphatemic rickets.
treatment_term:
preferred_term: bisphosphonate agent therapy
term:
id: MAXO:0000954
label: bisphosphonate agent therapy
evidence:
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This report represents the first described cases of opsismodysplasia treated with intravenous bisphosphonate (pamidronate)."
explanation: First report of bisphosphonate use in opsismodysplasia.
- reference: PMID:26157786
reference_title: "Opsismodysplasia: Phosphate Wasting Osteodystrophy Responds to Bisphosphonate Therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 10 years of age, he has stopped taking his wheelchair to school and runs during recess, demonstrating a remarkable progress presumably related to his pamidronate usage."
explanation: Demonstrates functional motor improvement with bisphosphonate therapy.
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intravenous bisphosphonate therapy has improved bone mineral density and gross motor function in two individuals with INPPL1-related opsismodysplasia."
explanation: GeneReviews confirms bisphosphonate benefit for bone density and motor function.
- reference: PMID:40620719
reference_title: "Pamidronate Treatment of a Patient with Opsismodysplasia and a Novel INPPL1 Variant: Efficacy, Mechanism, and Clinical Outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pamidronate is effective in treating OPS even in the absence of hypophosphatemic rickets, showing potential as a therapeutic option for this rare condition."
explanation: Demonstrates efficacy of pamidronate even without phosphate wasting.
- name: Phosphate and calcitriol supplementation
description: >
Oral phosphorus and calcitriol supplementation for patients with renal
phosphate wasting and hypophosphatemic rickets.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:17315533
reference_title: "Hypophosphatemic rickets in opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Oral phosphorus and calcitriol improved metaphyseal mineralization, yet serum phosphate levels remained relatively low and renal phosphate wasting persisted."
explanation: Directly documents the treatment response to phosphate and calcitriol supplementation.
- name: Multidisciplinary Surveillance and Supportive Care
description: >
Longitudinal supportive care monitors and manages fracture risk, cervical
spine instability or cord compression, scoliosis, respiratory insufficiency
or sleep apnea, swallowing and feeding issues, delayed gross motor skills,
bone demineralization, and renal phosphate wasting. Care is coordinated
across skeletal-dysplasia orthopedics/neurosurgery, endocrinology,
pulmonology, rehabilitation medicine, physical therapy, occupational therapy,
and other specialists as indicated.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Complications include increased risk of fractures, cervical spine abnormalities, scoliosis, bone pain, respiratory issues, and delayed gross motor skills."
explanation: >-
GeneReviews identifies the longitudinal complication targets for
supportive care and surveillance.
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cervical spine complications should be managed by specialists familiar with skeletal dysplasias involving the spine including an orthopedist and neurosurgeon; surgical stabilization should be performed to prevent progressive myelopathy"
explanation: >-
This supports specialist cervical-spine surveillance and escalation to
surgical stabilization when progressive myelopathy risk is present.
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical examination for scoliosis every six to 12 months with radiographs
when indicated; endocrinology evaluation for hypophosphatemia and renal
phosphate wasting every six to 12 months and when indicated
explanation: >-
GeneReviews provides frequency guidance for scoliosis and renal-phosphate
surveillance.
- reference: PMID:40504975
reference_title: "INPPL1-Related Opsismodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
pulmonary function studies, chest radiographs, swallowing evaluation, and
sleep study every six to 12 months and when indicated per pulmonologist;
swallowing evaluation as indicated to evaluate for aspiration;
developmental assessment to assess gross motor skills annually or as
needed; rehabilitation medicine, physical therapy, and occupational
therapy consultations when indicated
explanation: >-
This supports respiratory, swallowing, developmental, rehabilitation, and
therapy surveillance as part of supportive management.
datasets:
references:
- reference: PMID:40504975
title: "INPPL1-Related Opsismodysplasia."
tags:
- GeneReviews
findings: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Opsismodysplasia. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Opsismodysplasia is a rare Mendelian skeletal dysplasia characterized by delayed skeletal maturation and severe abnormalities of endochondral bone growth. An authoritative recent review describes opsismodysplasia as a skeletal dysplasia “primarily characterized by the delayed ossification of maturing bones.” (muller2024thefunctionalroles pages 14-15)
INPPL1/SHIP2 is a phosphoinositide 5-phosphatase that acts within the PI3K signaling network by turning over phosphatidylinositol lipids. One report summarizes SHIP2 as dephosphorylating the “lipid second messenger phosphoinositol (3,4,5)P3,” consistent with its canonical role in terminating or reshaping PI3K signaling outputs. (feist2016novelcompoundheterozygous pages 3-4)
In the discovery-era clinical genetics literature, INPPL1 is placed in the PI3K lipid-signaling axis: PI3K produces PtdIns(3,4,5)P3, which can be converted by 5-phosphatases (including SHIP2) to PtdIns(3,4)P2. (celine2013exomesequencingidentifies pages 4-4)
Opsismodysplasia is best conceptualized as a disorder of growth plate architecture and endochondral ossification.
Growth plate histopathology in opsismodysplasia demonstrates: - Loss of normal proliferative-zone organization (columnar arrangement) - Reduction of the hypertrophic zone and fewer hypertrophic chondrocytes
These features were explicitly reported in the initial AJHG cohort, indicating that the molecular defect produces a characteristic cellular disorganization of the growth plate that plausibly explains delayed epiphyseal ossification and skeletal shortening. (celine2013exomesequencingidentifies pages 1-2)
Primary pathophysiological mechanism: biallelic INPPL1 loss-of-function (or destabilizing) variants lead to dysregulated phosphoinositide metabolism and signaling, producing growth plate disorganization, impaired chondrocyte maturation, and delayed endochondral ossification.
Evidence supporting a loss-of-function mechanism includes mutation spectrum and protein loss: - In one AJHG series, most variants were truncating or splice-site, with missense variants clustering in the catalytic 5-phosphatase domain, consistent with disrupted enzymatic function. (celine2013exomesequencingidentifies pages 4-4, celine2013exomesequencingidentifies pages 1-2) - A fetal opsismodysplasia family showed no detectable SHIP2 protein in affected amniocytes, providing direct protein-level support for functional loss. (feist2016novelcompoundheterozygous pages 3-4, feist2016novelcompoundheterozygous media 56a554cb)
(a) Phosphoinositide metabolism / PI3K signaling - INPPL1/SHIP2 regulates PIP species (e.g., turnover of PtdIns(3,4,5)P3 and production of PtdIns(3,4)P2), which are second messengers organizing signaling and membrane–cytoskeleton processes. (celine2013exomesequencingidentifies pages 4-4, feist2016novelcompoundheterozygous pages 3-4) - A 2024 review provides functional context: SHIP2 activation reduces plasma membrane PtdIns(3,4,5)P3 and thereby inhibits AKT signaling, supporting a mechanistic link to PI3K–AKT output modulation. (muller2024thefunctionalroles pages 14-15)
(b) PI(3,4)P2-centered signaling as a mechanistic emphasis A mechanistic review highlighted that phenotypes in catalytically inactive SHIP2 models were attributed more to the lack of PI(3,4)P2 than to simplistic “hyperactive PI3K–Akt signaling,” suggesting that loss of specific phosphoinositide species (and their binding partners) may be central to developmental phenotypes. (edimo2014ship2signalingin pages 3-5)
(c) Developmental growth-factor signaling (FGF) connections (model-organism evidence) Zebrafish Ship2 knockdown perturbs outputs of FGF signaling (reported as dorsal fate expansion in early embryogenesis), supporting the plausibility that SHIP2-dependent phosphoinositide changes can rewire growth-factor pathway responses during development. (celine2013exomesequencingidentifies pages 4-6, edimo2014ship2signalingin pages 3-5)
Key cellular processes implicated by human pathology and SHIP2 biology include: - Chondrocyte proliferation/organization (loss of columnar organization in proliferative zone) (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2) - Chondrocyte hypertrophy/differentiation (reduced hypertrophic zone, fewer hypertrophic chondrocytes) (celine2013exomesequencingidentifies pages 1-2) - Cell expansion/size regulation and tissue mechanics (recent zebrafish evidence—see below) (voigt2024aconservedregulation pages 1-3)
Statistics (genetic contribution): In a cohort analyzed by whole-genome methods, INPPL1 mutations explained 7/12 kindreds (58%) and 5/10 simplex cases (50%), supporting genetic heterogeneity but also highlighting INPPL1 as a major contributor among clinically diagnosed cases. (below2013wholegenomeanalysisreveals pages 5-7)
Endogenous phosphoinositides - Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3)—substrate/regulated lipid messenger in SHIP2 pathway context. (celine2013exomesequencingidentifies pages 4-4, feist2016novelcompoundheterozygous pages 3-4) - Phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2)—product emphasized as mechanistically important in SHIP2-deficiency phenotypes. (edimo2014ship2signalingin pages 3-5)
Research/therapeutic probes (not established OPSMD therapies) A 2024 review describes SHIP2-selective inhibition (AS1949490) as increasing insulin-induced AKT phosphorylation and improving glycemic phenotypes in diabetic mouse models, reflecting active translational pharmacology around SHIP2. These compounds are best viewed as mechanistic tools and potential future repurposing leads rather than current opsismodysplasia therapies. (muller2024thefunctionalroles pages 14-15)
The disease-relevant cell types are growth plate chondrocytes: - Proliferative chondrocytes (loss of columnar arrangement) (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2) - Hypertrophic chondrocytes (reduced hypertrophic zone) (celine2013exomesequencingidentifies pages 1-2)
Primary tissues involved: - Growth plate cartilage (histologic disorganization) (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2) - Epiphyses (delayed ossification), vertebrae (platyspondyly), pelvis/acetabulum, long bones (radiographic manifestations) (below2013wholegenomeanalysisreveals pages 5-7, li2014opsismodysplasiaresultingfrom pages 1-3)
Evidence-supported GO-relevant processes include: - Endochondral ossification (delayed epiphyseal ossification; growth plate disruption) (celine2013exomesequencingidentifies pages 1-2, muller2024thefunctionalroles pages 14-15) - Chondrocyte differentiation and hypertrophy (reduced hypertrophic zone) (celine2013exomesequencingidentifies pages 1-2) - Chondrocyte proliferation/organization (disorganized proliferative zone; absent columnar organization) (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2) - Phosphoinositide metabolic process / phosphatidylinositol dephosphorylation (SHIP2 enzymatic function; mutation localization to catalytic domain) (celine2013exomesequencingidentifies pages 4-4, edimo2014ship2signalingin pages 3-5) - Regulation of AKT signaling (SHIP2 reduces membrane PIP3 and inhibits AKT signaling in reviewed contexts) (muller2024thefunctionalroles pages 14-15) - FGF signaling modulation (zebrafish knockdown evidence) (edimo2014ship2signalingin pages 3-5)
Opsismodysplasia mechanisms localize to compartments where SHIP2 acts on phosphoinositides: - Plasma membrane: phosphoinositide substrates and PI3K signaling lipids (PIP3/PIP2) are membrane-associated; SHIP2 activity affects membrane PIP3 and AKT signaling output. (muller2024thefunctionalroles pages 14-15) - Cytosolic signaling complexes / docking interactions: INPPL1 has described non-catalytic scaffold/docking roles interacting with cytoskeletal and receptor-associated proteins, potentially relevant to organized growth plate column formation. (celine2013exomesequencingidentifies pages 4-6)
Recent in vivo reinforcement (2024): Zebrafish inppl1a mutants are shorter from early larval stages and later develop notochord/spine abnormalities (thoracic scoliosis, vertebral malformations), supporting a conserved role in axial growth and endochondral lengthening. (voigt2024aconservedregulation pages 1-3)
Key clinical/radiographic phenotypes include: - Severe short stature and micromelia—consistent with impaired growth plate function and endochondral bone formation. (celine2013exomesequencingidentifies pages 4-4, celine2013exomesequencingidentifies pages 1-2) - Delayed epiphyseal and carpal ossification—directly matches the disease definition and endochondral ossification defect. (muller2024thefunctionalroles pages 14-15, li2014opsismodysplasiaresultingfrom pages 1-3) - Platyspondyly and skeletal undermineralization—consistent with defective ossification/mineralization. (below2013wholegenomeanalysisreveals pages 5-7, li2014opsismodysplasiaresultingfrom pages 1-3) - Scoliosis—reported clinically and supported by zebrafish model axial curvature. (celine2013exomesequencingidentifies pages 4-4, voigt2024aconservedregulation pages 1-3) - Narrow thorax / pulmonary hypoplasia in severe prenatal/perinatal cases—likely secondary to shortened ribs/vertebral anomalies and restricted thoracic development. (celine2013exomesequencingidentifies pages 4-4) - Low bone density and renal phosphate wasting have been described in an INPPL1-mutant case, suggesting that mineral metabolism abnormalities may modify skeletal outcomes in some patients. (li2014opsismodysplasiaresultingfrom pages 1-3)
A 2024 review consolidates SHIP2’s roles across human diseases and explicitly includes opsismodysplasia as an INPPL1/SHIP2-mutation disorder defined by delayed ossification. It also connects SHIP2 enzymology to AKT signaling modulation and summarizes pharmacologic tool compounds (e.g., AS1949490) demonstrating that SHIP2 is chemically tractable. (muller2024thefunctionalroles pages 14-15)
A 2024 zebrafish preprint provides new in vivo evidence that INPPL1 ortholog activity is required for cell expansion, notochord mechanics, spine morphogenesis, and endochondral bone lengthening—directly relevant to how opsismodysplasia could arise from altered cell/tissue growth mechanics in developing skeletal structures. (voigt2024aconservedregulation pages 1-3)
Real-world implementation is primarily through genetic testing (exome/genome sequencing) for INPPL1 variants in suspected skeletal dysplasia cases. Early discovery work established that biallelic INPPL1 variants can be found across multiple unrelated families, supporting INPPL1 as a key diagnostic target. (celine2013exomesequencingidentifies pages 1-2)
A 2014 clinical report described renal phosphate wasting and very low bone density in an affected individual; phosphate replacement improved ambulation and dental eruption, and pamidronate was administered for low bone mineral density. This illustrates that while no disease-modifying therapy for the core signaling defect exists, targeted supportive interventions may improve function in selected patients. (li2014opsismodysplasiaresultingfrom pages 1-3)
A key experimental/clinical evidence item is an immunoblot showing absence of SHIP2 protein in proband amniocytes (with α-tubulin loading control), supporting a loss-of-protein mechanism in at least some genotypes. (feist2016novelcompoundheterozygous media 56a554cb)
Below are curated tables intended for direct knowledge-base population.
| Concept/Mechanism | Molecular players (gene/protein/lipid) | Tissue/cell type | Key evidence (brief) | PMID/DOI | Publication year | URL |
|---|---|---|---|---|---|---|
| Causal genetic mechanism and growth-plate disorganization | INPPL1 / SHIP2; phosphoinositides | Growth plate cartilage; proliferative and hypertrophic chondrocytes | Exome sequencing identified 12 distinct INPPL1 mutations in 10 unrelated families with opsismodysplasia; histology showed loss of normal columnar arrangement of proliferative chondrocytes, reduced hypertrophic zone, and fewer hypertrophic chondrocytes, supporting a primary defect in endochondral ossification (celine2013exomesequencingidentifies pages 1-2) | DOI: 10.1016/j.ajhg.2012.11.015 | 2013 | https://doi.org/10.1016/j.ajhg.2012.11.015 |
| Proportion of cases explained by INPPL1 and supportive animal phenotype | INPPL1 / SHIP2 | Human skeleton; mouse axial/appendicular skeleton | Whole-genome analysis found INPPL1 mutations in 7/12 kindreds (58%) and 5/10 simplex cases (50%); truncating variants predicted loss of function. Mouse SHIP2-null/catalytic-dead models showed diminished growth, shortened facial profile, and body size reduction, supporting a developmental role for SHIP2 in skeletal growth (below2013wholegenomeanalysisreveals pages 5-7) | DOI: 10.1016/j.ajhg.2012.11.011 | 2013 | https://doi.org/10.1016/j.ajhg.2012.11.011 |
| Dysregulated phosphoinositide signaling and developmental pathway links | SHIP2; PI(3,4,5)P3, PI(3,4)P2; FGF signaling | Developing embryo; growth-related tissues | Review synthesis: SHIP2 loss reduces PI(3,4)P2 and perturbs phosphoinositide balance; phenotypes in catalytic-dead mice were attributed more to lack of PI(3,4)P2 than simple PI3K-AKT hyperactivation. In zebrafish, Ship2 knockdown perturbed FGF signaling and expanded dorsal fates, linking SHIP2 to developmental patterning mechanisms relevant to OPS (edimo2014ship2signalingin pages 3-5) | DOI: 10.1016/j.jbior.2013.09.002 | 2014 | https://doi.org/10.1016/j.jbior.2013.09.002 |
| Loss of SHIP2 protein and severe fetal growth-plate histopathology | INPPL1 / SHIP2; PIP3 | Fetal growth plate cartilage; amniocytes | Compound-heterozygous INPPL1 variants were associated with absence of detectable SHIP2 protein in fetal cells. Fetal growth plate cartilage showed disorganized proliferative zones with near absent columnar organization, correlating with delayed epiphyseal ossification and severe platyspondyly (feist2016novelcompoundheterozygous pages 3-4) | DOI: 10.1097/MCD.0000000000000136 | 2016 | https://doi.org/10.1097/MCD.0000000000000136 |
| Current disease definition and therapeutic context | INPPL1 / SHIP2; PtdIns(3,4,5)P3; AKT; SHIP2 inhibitors AS1949490, K118, K149, K161 | Skeletal tissue (disease context); broader cell signaling systems | 2024 review defines opsismodysplasia as a skeletal dysplasia “primarily characterized by the delayed ossification of maturing bones.” It places SHIP2 in PIP3-to-AKT regulation and notes selective/pan-SHIP inhibitors (e.g., AS1949490, K161) with experimental activity in other disease settings, highlighting translational relevance even though no OPS-targeted therapy is established (muller2024thefunctionalroles pages 14-15) | DOI: 10.3390/ijms25105254 | 2024 | https://doi.org/10.3390/ijms25105254 |
| Recent in vivo model for cell expansion, spine morphogenesis, and endochondral lengthening | Zebrafish inppl1a (ortholog of INPPL1/SHIP2) | Notochord vacuolated cells; spine; endochondral bone | 2024 zebrafish preprint shows inppl1a is required for cell expansion, normal notochord mechanics, spine morphogenesis, and endochondral bone lengthening. Homozygous mutants were shorter, had reduced viability, notochord curvatures, adult thoracic scoliosis, and vertebral malformations, providing recent organismal support for INPPL1-related skeletal pathophysiology (voigt2024aconservedregulation pages 1-3) | DOI: 10.1101/2024.08.12.607640 | 2024 | https://doi.org/10.1101/2024.08.12.607640 |
Table: This table compiles the main mechanistic and experimental evidence linking INPPL1/SHIP2 dysfunction to opsismodysplasia, spanning discovery genetics, phosphoinositide signaling, growth-plate pathology, and recent model-organism work. It is useful as a concise evidence map for disease knowledge-base curation.
| Entity type | Preferred label | ID (HGNC/GO/HP/CL/UBERON/CHEBI) | Evidence/notes |
|---|---|---|---|
| Gene | INPPL1 | HGNC:6091 | Causal gene for opsismodysplasia; encodes SHIP2, a phosphoinositide 5-phosphatase. Biallelic variants are predominantly truncating, splice-site, or catalytic-domain missense, consistent with loss of function; one cohort found INPPL1 variants in 7/12 kindreds (58%) and 5/10 simplex cases (below2013wholegenomeanalysisreveals pages 5-7, celine2013exomesequencingidentifies pages 1-2). |
| Gene | SHIP2 protein | UniProt/Q9Y5R2 | Protein product of INPPL1; absent in affected fetal cells/amniocytes in one family, supporting pathogenic protein loss (feist2016novelcompoundheterozygous pages 3-4, feist2016novelcompoundheterozygous media 56a554cb). |
| GO | phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | GO:0046856 | SHIP2 dephosphorylates PtdIns(3,4,5)P3, placing opsismodysplasia in the phosphoinositide signaling disease spectrum (feist2016novelcompoundheterozygous pages 3-4). |
| GO | phosphatidylinositol dephosphorylation | GO:0046854 | Core biochemical mechanism inferred from SHIP2 enzymatic function and disease-causing catalytic-domain variants (celine2013exomesequencingidentifies pages 4-4, edimo2014ship2signalingin pages 3-5). |
| GO | phosphoinositide metabolic process | GO:0046488 | INPPL1 regulates levels of specific phosphoinositides; disease likely reflects disrupted phosphoinositide turnover in skeletal development (celine2013exomesequencingidentifies pages 4-4, celine2013exomesequencingidentifies pages 1-2). |
| GO | phosphatidylinositol 3-kinase signaling | GO:0014065 | SHIP2 functions within the PI3K pathway by turning over PI3K-generated PtdIns(3,4,5)P3; loss is expected to alter PI3K pathway output (celine2013exomesequencingidentifies pages 4-4, feist2016novelcompoundheterozygous pages 3-4). |
| GO | positive regulation of AKT signaling | GO:0051897 | SHIP2 normally reduces PtdIns(3,4,5)P3 and can inhibit AKT signaling; thus disease-causing loss likely perturbs AKT pathway regulation, though cartilage-specific AKT readouts remain limited (muller2024thefunctionalroles pages 14-15). |
| GO | endochondral ossification | GO:0001958 | Most directly implicated developmental process; patient histology and skeletal findings indicate a primary defect in endochondral ossification with delayed epiphyseal ossification (celine2013exomesequencingidentifies pages 1-2, feist2016novelcompoundheterozygous pages 3-4). |
| GO | chondrocyte differentiation | GO:0002063 | Growth plate histology shows reduced hypertrophic zone and fewer hypertrophic chondrocytes, consistent with impaired chondrocyte maturation/differentiation (celine2013exomesequencingidentifies pages 1-2). |
| GO | chondrocyte proliferation | GO:0035988 | Near-absence of normal columnar organization in the proliferative zone supports altered proliferative chondrocyte behavior (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2). |
| GO | fibroblast growth factor receptor signaling pathway | GO:0008543 | Zebrafish Ship2 knockdown perturbs FGF signaling and developmental patterning, suggesting a plausible conserved mechanism relevant to skeletal morphogenesis (celine2013exomesequencingidentifies pages 4-6, edimo2014ship2signalingin pages 3-5). |
| GO | cell growth | GO:0016049 | Recent zebrafish inppl1a data support a role in cell expansion and endochondral bone lengthening, extending the growth-regulatory disease model (voigt2024aconservedregulation pages 1-3). |
| GO | establishment or maintenance of cell polarity | GO:0007163 | SHIP2 has non-catalytic roles in polarity/migration pathways, relevant because growth plate organization is disrupted in disease (celine2013exomesequencingidentifies pages 4-6, edimo2014ship2signalingin pages 3-5). |
| GO | cell migration | GO:0016477 | SHIP2 participates in migration/polarity signaling via phosphoinositides and cytoskeletal interactions; included as a plausible contributing process rather than OPS-specific proven mechanism (celine2013exomesequencingidentifies pages 4-6, edimo2014ship2signalingin pages 3-5). |
| GO | plasma membrane | GO:0005886 | SHIP2 acts on membrane phosphoinositides such as PtdIns(3,4,5)P3 at the plasma membrane (muller2024thefunctionalroles pages 14-15). |
| GO | cytosol | GO:0005829 | SHIP2 also functions in intracellular signaling complexes and docking interactions involving cytoskeletal/scaffold proteins (celine2013exomesequencingidentifies pages 4-6, feist2016novelcompoundheterozygous pages 4-7). |
| HP | Short stature | HP:0004322 | Severe pre- and postnatal growth deficiency is a consistent phenotype in surviving patients (celine2013exomesequencingidentifies pages 4-4, below2013wholegenomeanalysisreveals pages 5-7). |
| HP | Micromelia | HP:0002983 | Pre- and postnatal micromelia/short long bones are characteristic clinical findings (celine2013exomesequencingidentifies pages 4-4, celine2013exomesequencingidentifies pages 1-2). |
| HP | Delayed ossification of epiphyses | HP:0003093 | Delayed epiphyseal ossification is repeatedly described and is central to disease definition (muller2024thefunctionalroles pages 14-15, li2014opsismodysplasiaresultingfrom pages 1-3). |
| HP | Platyspondyly | HP:0000926 | Severe platyspondyly is a hallmark radiographic feature (feist2016novelcompoundheterozygous pages 3-4, li2014opsismodysplasiaresultingfrom pages 1-3). |
| HP | Scoliosis | HP:0002650 | Severe scoliosis has been reported in survivors; zebrafish inppl1a mutants also develop spinal curvature, supporting mechanistic relevance (celine2013exomesequencingidentifies pages 4-4, voigt2024aconservedregulation pages 1-3). |
| HP | Narrow thorax | HP:0000774 | Narrow chest/thorax contributes to respiratory compromise in severe neonatal presentations (celine2013exomesequencingidentifies pages 4-4). |
| HP | Pulmonary hypoplasia | HP:0002089 | Reported in severe prenatal/perinatal cases and likely secondary to restricted thoracic development (celine2013exomesequencingidentifies pages 4-4). |
| HP | Craniofacial abnormality | HP:0001999 | Craniofacial abnormalities/large neurocranium/shortened facial profile are reported in patients and mouse models (feist2016novelcompoundheterozygous pages 3-4, below2013wholegenomeanalysisreveals pages 5-7). |
| HP | Decreased bone mineral density | HP:0004349 | Low bone density/undermineralization has been documented clinically (below2013wholegenomeanalysisreveals pages 5-7, li2014opsismodysplasiaresultingfrom pages 1-3). |
| HP | Renal phosphate wasting | HP:0000117 | Renal phosphate wasting was described in an INPPL1-mutant patient, with phosphate replacement improving some outcomes (li2014opsismodysplasiaresultingfrom pages 1-3). |
| CL | chondrocyte | CL:0000138 | Principal disease-relevant cell type in growth plate cartilage (celine2013exomesequencingidentifies pages 1-2, feist2016novelcompoundheterozygous pages 3-4). |
| CL | hypertrophic chondrocyte | CL:0002333 | Reduced hypertrophic zone/fewer hypertrophic chondrocytes on histology implicate this maturation stage (celine2013exomesequencingidentifies pages 1-2). |
| CL | proliferative chondrocyte | CL:0002334 | Disorganized proliferative zones with near-absent columnar arrangement strongly implicate proliferative chondrocytes (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2). |
| UBERON | growth plate cartilage | UBERON:0003429 | Primary anatomic site of pathology based on fetal histology and endochondral growth defects (feist2016novelcompoundheterozygous pages 3-4, celine2013exomesequencingidentifies pages 1-2). |
| UBERON | epiphysis | UBERON:0004352 | Delayed epiphyseal ossification is a defining radiographic/clinical feature (muller2024thefunctionalroles pages 14-15, li2014opsismodysplasiaresultingfrom pages 1-3). |
| UBERON | vertebral column | UBERON:0001130 | Platyspondyly, vertebral abnormalities, and scoliosis indicate major vertebral involvement (below2013wholegenomeanalysisreveals pages 5-7, voigt2024aconservedregulation pages 1-3). |
| UBERON | long bone | UBERON:0002371 | Short long bones, bowing, and metaphyseal changes are prominent manifestations (celine2013exomesequencingidentifies pages 4-4, li2014opsismodysplasiaresultingfrom pages 1-3). |
| UBERON | pelvis | UBERON:0001270 | Poor ossification of pelvic bones and poorly formed acetabula are recurrent imaging findings (below2013wholegenomeanalysisreveals pages 5-7, feist2016novelcompoundheterozygous pages 4-7). |
| CHEBI | phosphatidylinositol 3,4,5-trisphosphate | CHEBI:16595 | Direct SHIP2 substrate; excess/abnormal handling is central to proposed disease mechanism (feist2016novelcompoundheterozygous pages 3-4, muller2024thefunctionalroles pages 14-15). |
| CHEBI | phosphatidylinositol 3,4-bisphosphate | CHEBI:17289 | Key SHIP2 product; reduced PI(3,4)P2 has been emphasized as mechanistically important in SHIP2-deficient phenotypes (edimo2014ship2signalingin pages 3-5). |
| CHEBI | AS1949490 | not available | SHIP2-selective inhibitor discussed in 2024 review; relevant as a mechanistic chemical probe, not an opsismodysplasia therapy (muller2024thefunctionalroles pages 14-15). |
Table: This table maps core opsismodysplasia mechanisms, phenotypes, cells, tissues, and chemicals to ontology-style identifiers suitable for knowledge-base curation. It emphasizes the INPPL1/SHIP2-centered phosphoinositide signaling defect and its links to growth plate disorganization and impaired endochondral ossification.
Opsismodysplasia is ultra-rare; as a result, the most direct growth-plate mechanistic evidence remains concentrated in the 2013 discovery literature and a limited number of follow-up reports. Recent (2023–2024) work strengthens general SHIP2 signaling context and provides new model-organism evidence for skeletal growth roles, but cartilage-specific PI3K–AKT/FGF pathway readouts in human growth plate cells remain sparse in the accessible literature set. (edimo2014ship2signalingin pages 3-5, muller2024thefunctionalroles pages 14-15, voigt2024aconservedregulation pages 1-3)
References
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(below2013wholegenomeanalysisreveals pages 5-7): Jennifer E. Below, Dawn L. Earl, Kathryn M. Shively, Margaret J. McMillin, Joshua D. Smith, Emily H. Turner, Mark J. Stephan, Lihadh I. Al-Gazali, Jozef L. Hertecant, David Chitayat, Sheila Unger, Daniel H. Cohn, Deborah Krakow, James M. Swanson, Elaine M. Faustman, Jay Shendure, Deborah A. Nickerson, and Michael J. Bamshad. Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia. American journal of human genetics, 92 1:137-43, Jan 2013. URL: https://doi.org/10.1016/j.ajhg.2012.11.011, doi:10.1016/j.ajhg.2012.11.011. This article has 67 citations and is from a highest quality peer-reviewed journal.
(celine2013exomesequencingidentifies pages 1-2): Céline Huber, Eissa Ali Faqeih, Deborah Bartholdi, Christine Bole-Feysot, Zvi Borochowitz, Denise P Cavalcanti, Amandine Frigo, Patrick Nitschke, Joelle Roume, Heloísa G Santos, Stavit A Shalev, Andrea Superti-Furga, Anne-Lise Delezoide, Martine Le Merrer, Arnold Munnich, and Valérie Cormier-Daire. Exome sequencing identifies inppl1 mutations as a cause of opsismodysplasia. American journal of human genetics, 92 1:144-9, Jan 2013. URL: https://doi.org/10.1016/j.ajhg.2012.11.015, doi:10.1016/j.ajhg.2012.11.015. This article has 62 citations and is from a highest quality peer-reviewed journal.
(feist2016novelcompoundheterozygous pages 3-4): Cori Feist, Paul Holden, and Jamie Fitzgerald. Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia. Clinical Dysmorphology, 25:152–155, Oct 2016. URL: https://doi.org/10.1097/mcd.0000000000000136, doi:10.1097/mcd.0000000000000136. This article has 10 citations and is from a peer-reviewed journal.
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(feist2016novelcompoundheterozygous pages 4-7): Cori Feist, Paul Holden, and Jamie Fitzgerald. Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia. Clinical Dysmorphology, 25:152–155, Oct 2016. URL: https://doi.org/10.1097/mcd.0000000000000136, doi:10.1097/mcd.0000000000000136. This article has 10 citations and is from a peer-reviewed journal.