Tetraamelia Syndrome 2

Mendelian MONDO:0060732 Pathograph 12 Show in embeddings browser Congenital Disorder Limb Malformation

Tetraamelia syndrome 2 (TETAMS2) is an autosomal recessive, typically lethal malformation syndrome caused by biallelic loss-of-function variants in RSPO2, which encodes the secreted WNT-potentiating ligand R-spondin 2. Affected fetuses lack all four limbs or retain only rudimentary appendages, and have aplasia of the lungs; orofacial clefting and mandibular hypoplasia are also recorded. RSPO2 normally amplifies WNT/beta-catenin signalling by antagonising the transmembrane E3 ligases RNF43 and ZNRF3, which otherwise clear WNT receptors from the cell surface. The human allelic series showed that the severity of the limb phenotype tracks the degree to which each allele loses this activity. Mouse Rspo2 mutants place the defect in failed maintenance of the apical ectodermal ridge of the limb bud, reduced lung branching, and reduced WNT signalling in the branchial arch. TETAMS2 is genetically distinct from tetraamelia syndrome 1, which is caused by WNT3.

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1
Inheritance
5
Pathophys.
6
Phenotypes
12
Pathograph
1
Genes
3
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic RSPO2 variants. The original report describes recessive mutations forming an allelic series in which phenotype severity follows residual protein function.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:29769720 SUPPORT Human Clinical
"Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
Establishes recessive RSPO2 mutations as the cause of this form of tetra-amelia syndrome.
⚙

Pathophysiology

5
Biallelic RSPO2 Loss of Function
Recessive RSPO2 alleles, ranging from an upstream point variant to nonsense, frameshift, and terminal intron-exon deletions, reduce or abolish R-spondin 2 function. The mutant proteins show impaired binding both to the LGR4/5/6 receptors and to the RNF43/ZNRF3 ligases.
RSPO2 hgnc:28583 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RSPO2 (hgnc:28583). hgnc:28583 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
binding to LGR4/5/6 receptors GO:0005102 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased binding to LGR4/5/6 receptors, annotated with signaling receptor binding (GO:0005102). GO:0005102 is a molecular function from the Gene Ontology. binding to the RNF43 and ZNRF3 ligases GO:0031625 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased binding to the RNF43 and ZNRF3 ligases, annotated with ubiquitin protein ligase binding (GO:0031625). GO:0031625 is a molecular function from the Gene Ontology.
Animal models
Holstein Friesian tetradysmelia (RSPO2 50-kb deletion) Cattle recapitulates Naturally occurring recessive RSPO2 null allele in a large mammal producing four-limb reduction.
Downstream
Unopposed RNF43 and ZNRF3 Activity with Reduced WNT Potentiation
Show evidence (1 reference)
PMID:29769720 SUPPORT In Vitro
"Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity."
Functional testing of the patient alleles shows loss of receptor and ligase binding.
Unopposed RNF43 and ZNRF3 Activity with Reduced WNT Potentiation
RSPO2 acts as a direct antagonistic ligand of the transmembrane E3 ligases RNF43 and ZNRF3. Without it, these ligases remain active and WNT/beta-catenin signalling in responsive tissues is not amplified. The limb-relevant activity does not require the LGR4/5/6 receptors: a ubiquitous triple Lgr4/5/6 knockout mouse does not reproduce the Rspo2 loss-of-function phenotype, whereas concurrent loss of rnf43 and znrf3 in Xenopus produces supernumerary limbs, the mirror image of amelia.
RNF43 hgnc:18505 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RNF43 (hgnc:18505). hgnc:18505 is a gene from the HUGO Gene Nomenclature Committee. ZNRF3 hgnc:18126 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZNRF3 (hgnc:18126). hgnc:18126 is a gene from the HUGO Gene Nomenclature Committee.
canonical Wnt signaling pathway GO:0060070 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology.
Downstream
Failure of Apical Ectodermal Ridge Maintenance
Reduced Lung Branching Morphogenesis
Reduced WNT Signalling in the Branchial Arch
Show evidence (2 references)
PMID:29769720 SUPPORT Model Organism
"Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification."
Identifies RNF43/ZNRF3 antagonism, not LGR4/5/6 signalling, as the RSPO2 activity that controls limb specification.
PMID:29769720 SUPPORT Model Organism
"Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs."
Loss of the two ligases produces the opposite of amelia, which supports their unopposed activity as the step through which RSPO2 loss acts.
Failure of Apical Ectodermal Ridge Maintenance
Rspo2 is expressed in the apical ectodermal ridge (AER) of all limb buds. In Rspo2-null mice the AER is induced normally, but expression of AER markers (Fgf8, Fgf4) and of beta-catenin targets within the AER is not maintained, and Shh signalling in the limb is reduced. Without a maintained AER the limb bud cannot grow out; in mice the defect is most severe distally and in the hindlimb, whereas human null alleles abolish all four limbs.
embryonic limb morphogenesis GO:0030326 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased embryonic limb morphogenesis (GO:0030326). GO:0030326 is a biological process from the Gene Ontology.
apical ectodermal ridge UBERON:0004356 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in apical ectodermal ridge (UBERON:0004356). UBERON:0004356 is an anatomical location from the Uberon multi-species anatomy ontology. limb bud UBERON:0004347 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in limb bud (UBERON:0004347). UBERON:0004347 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Rspo2 knockout mouse Mouse partially recapitulates
Downstream
Tetraamelia
Show evidence (3 references)
PMID:17904116 SUPPORT Model Organism
"Although the initiation of the expression of apical ectodermal ridge (AER)-specific genes, including fibroblast growth factor 8 (FGF8) and FGF4 occurred normally, the maintenance of these marker expressions was significantly defective in the hindlimb of Rspo2(-/-) mice."
Shows the AER forms but is not maintained without Rspo2.
PMID:17904116 SUPPORT Model Organism
"Consistent with the ligand role of R-spondins in the Wnt/beta-catenin signaling pathway, expression of Axin2 and Sp8, targets for beta-catenin signaling, within AER was greatly reduced in Rspo2(-/-) embryos."
Links the AER defect to reduced WNT/beta-catenin signalling.
PMID:18067586 SUPPORT Model Organism
"This study shows that Rspo2 is critical for maintenance of the AER and for growth and patterning in limb development."
Independent Rspo2 knockout confirming the AER maintenance role.
Reduced Lung Branching Morphogenesis
R-spondin 2 signalling through the canonical WNT pathway is needed for branching of the developing lung. Hypomorphic Rspo2 mice have hypoplastic lungs with reduced branching and reduced WNT reporter activity, and further loss of WNT co-receptor function (Lrp6) makes the hypoplasia more severe. In humans with RSPO2 null alleles the lungs fail to form.
epithelial tube branching involved in lung morphogenesis GO:0060441 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased epithelial tube branching involved in lung morphogenesis (GO:0060441). GO:0060441 is a biological process from the Gene Ontology.
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
footless (Rspo2 hypomorph) mouse Mouse partially recapitulates
Downstream
Bilateral lung agenesis
Show evidence (1 reference)
PMID:18256198 SUPPORT Model Organism
"Rspo2(Tg/Tg) lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3."
Shows reduced lung branching with reduced WNT signalling in an Rspo2 hypomorph.
Reduced WNT Signalling in the Branchial Arch
Rspo2-null mice show reduced WNT/beta-catenin signalling in the branchial arch (the source does not name which arch), with cleft lip and palate and mild facial skeletal defects. The location is therefore bound to the generic pharyngeal arch term rather than to pharyngeal arch 1.
canonical Wnt signaling pathway GO:0060070 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology.
branchial arch UBERON:0002539 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in branchial arch, annotated with pharyngeal arch (UBERON:0002539). UBERON:0002539 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Rspo2 knockout mouse Mouse recapitulates
Downstream
Orofacial cleft
Show evidence (1 reference)
PMID:19233133 SUPPORT Model Organism
"We showed the apparent reduction of Wnt/beta-catenin signaling activity at the branchial arch and the apical ectodermal ridge in Rspo2(-/-) mice."
Documents reduced WNT signalling in the branchial arch of Rspo2 knockout mice.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Tetraamelia Syndrome 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Head and Neck 4
Orofacial cleft HP:0000202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip/palate, annotated with Orofacial cleft (HP:0000202). HP:0000202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33176673 SUPPORT BACKGROUND Human Clinical
"Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
Summary-table row for the RSPO2 tetraamelia syndrome lists cleft lip/palate.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibular hypoplasia, annotated with Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33176673 SUPPORT BACKGROUND Human Clinical
"Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
Summary-table row for the RSPO2 tetraamelia syndrome lists mandibular hypoplasia and microretrognathia.
Retrognathia HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microretrognathia, annotated with Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33176673 SUPPORT BACKGROUND Human Clinical
"Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
Summary-table row for the RSPO2 tetraamelia syndrome lists microretrognathia.
Ankyloglossia HP:0010296 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankyloglossia (HP:0010296). HP:0010296 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33176673 SUPPORT BACKGROUND Human Clinical
"Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
Summary-table row for the RSPO2 tetraamelia syndrome lists ankyloglossia.
Limbs 1
Tetraamelia HP:0003057 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetraamelia (HP:0003057). HP:0003057 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29769720 SUPPORT Human Clinical
"Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
Defining feature of the syndrome in the original human report.
PMID:29769720 SUPPORT In Vitro
"Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity."
Loss of WNT potentiation was graded across the patient alleles and tracked the severity of each allele, supporting an allele-dependent severity spectrum.
PMID:33176673 SUPPORT REVIEW SYNTHESIS Human Clinical
"not only showed severe limb malformations or lack of all limbs, but also displayed other various phenotypes that correlated with the degree to which RSPO2 signalling was impaired by the mutations"
Secondary summary of the human fetal series: the limb phenotype ranged from severe malformation to complete absence, and the accompanying phenotypes tracked how strongly each allele impaired RSPO2 signalling.
Respiratory 1
Bilateral lung agenesis HP:0005944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lung aplasia, annotated with Bilateral lung agenesis (HP:0005944). HP:0005944 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29769720 SUPPORT Human Clinical
"Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
Lung aplasia is named as a defining feature of RSPO2-related tetra-amelia.
PMID:33176673 SUPPORT BACKGROUND Human Clinical
"Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
Summary-table row for the RSPO2 tetraamelia syndrome (OMIM 618021), recording bilateral lung agenesis.
🧬

Genetic Associations

1
RSPO2
Gene: RSPO2 hgnc:28583 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RSPO2 (hgnc:28583). hgnc:28583 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:29769720 SUPPORT Human Clinical
"Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
Identifies RSPO2 as the causal gene.
PMID:33176673 SUPPORT REVIEW SYNTHESIS Human Clinical
"that ranged from a point mutation in the upstream region of the human RSPO2 gene, to nonsense and frameshift mutations, and to a deletion of the last intron and exon"
Summarises the range of human RSPO2 variant types reported by Szenker-Ravi et al.
🐁

Animal Models

3
Rspo2 knockout mouse
Rspo2-null mice die at birth from respiratory failure with cleft lip and palate, distal limb loss, and lung hypoplasia.
Species
Mouse
Genotype
Rspo2 homozygous null
Publication
PMID:19233133
Pathograph links
Reduced WNT Signalling in the Branchial Arch recapitulates fidelity: moderate observes: tissue
Limitations: The craniofacial phenotype in mice is cleft lip and palate with mild facial skeletal defects; the human craniofacial spectrum is known only from a summary table.
Show evidence (1 reference)
PMID:19233133 SUPPORT Model Organism
"We showed the apparent reduction of Wnt/beta-catenin signaling activity at the branchial arch and the apical ectodermal ridge in Rspo2(-/-) mice."
Shows the branchial-arch signalling defect in this model.
Failure of Apical Ectodermal Ridge Maintenance partially recapitulates fidelity: moderate observes: tissue
Limitations: The mice lose distal limb elements rather than whole limbs, so they model a milder limb reduction than human tetra-amelia.
Show evidence (1 reference)
PMID:19233133 SUPPORT Model Organism
"Additionally, Rspo2(-/-) mice also exhibited distal limb loss and lung hypoplasia, and died immediately after birth with respiratory failure."
Distal limb loss and lung hypoplasia in the knockout.
footless (Rspo2 hypomorph) mouse
An insertional hypomorphic Rspo2 allele causes laryngeal-tracheal, limb, and palate malformations and lung hypoplasia. Combining it with Lrp6 loss removes all limb skeletal elements.
Species
Mouse
Genotype
Rspo2 Tg/Tg (footless insertional allele), alone and with Lrp6 null alleles
Publication
PMID:18256198
Pathograph links
Reduced Lung Branching Morphogenesis partially recapitulates fidelity: moderate observes: tissue
Limitations: The mice have lung hypoplasia, not the lung aplasia seen in humans with RSPO2 null alleles.
Readouts
Lung branching and WNT reporter activity
Direction: DECREASED
Interpretation: Direct measurement of the branching defect and its WNT dependence.
Show evidence (1 reference)
PMID:18256198 SUPPORT Model Organism
"Rspo2(Tg/Tg) lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3."
Reports the branching and reporter measurements.
Show evidence (1 reference)
PMID:18256198 SUPPORT Model Organism
"Rspo2(Tg/Tg) mice had severe malformations of laryngeal-tracheal cartilages, limbs and palate, and lung hypoplasia consistent with sites of Rspo2 expression."
The hypomorph reproduces the lung and limb organ involvement of the human disease.
Holstein Friesian tetradysmelia (RSPO2 50-kb deletion)
A recessive 50-kb deletion removing three coding exons of bovine RSPO2 segregates with tetradysmelia, a severe reduction of all limb parts distal to the shoulder and pelvic girdles.
Species
Cattle
Genotype
Homozygous 50-kb deletion spanning three RSPO2 exons
Publication
PMID:33176673
Pathograph links
Biallelic RSPO2 Loss of Function recapitulates fidelity: high observes: organism Naturally occurring recessive RSPO2 null allele in a large mammal producing four-limb reduction.
Show evidence (1 reference)
PMID:33176673 SUPPORT Model Organism
"We identified a 50-kb deletion on BTA14 that disrupts the coding sequence of the RSPO2 gene and is associated with bovine tetradysmelia."
A natural RSPO2 loss-of-function allele causing reduction of all four limbs.
{ }

Source YAML

click to show 
name: Tetraamelia Syndrome 2
creation_date: '2026-10-08T00:00:00Z'
description: >-
  Tetraamelia syndrome 2 (TETAMS2) is an autosomal recessive, typically lethal
  malformation syndrome caused by biallelic loss-of-function variants in RSPO2,
  which encodes the secreted WNT-potentiating ligand R-spondin 2. Affected fetuses
  lack all four limbs or retain only rudimentary appendages, and have aplasia of
  the lungs; orofacial clefting and mandibular hypoplasia are also recorded.
  RSPO2 normally amplifies WNT/beta-catenin signalling by antagonising the
  transmembrane E3 ligases RNF43 and ZNRF3, which otherwise clear WNT receptors
  from the cell surface. The human allelic series showed that the severity of
  the limb phenotype tracks the degree to which each allele loses this activity.
  Mouse Rspo2 mutants place the defect in failed maintenance of the apical
  ectodermal ridge of the limb bud, reduced lung branching, and reduced WNT
  signalling in the branchial arch. TETAMS2 is genetically distinct from
  tetraamelia syndrome 1, which is caused by WNT3.
category: Mendelian
parents:
- Congenital Disorder
- Limb Malformation
synonyms:
- TETAMS2
- RSPO2-related tetra-amelia
disease_term:
  preferred_term: tetraamelia syndrome 2
  term:
    id: MONDO:0060732
    label: tetraamelia syndrome 2
notes: >-
  The human disease is known from a single report of an allelic series of
  recessive RSPO2 mutations (PMID:29769720), whose PubMed abstract is the only
  text of that paper available to the reference cache. Phenotypes beyond limb
  absence and lung aplasia are therefore cited from the OMIM-derived summary
  table in the bovine tetradysmelia paper (PMID:33176673) and are marked as
  background quotes. A PubMed search for "RSPO2 AND (fetus OR fetal OR prenatal
  OR case report OR homozygous)" and for "tetra-amelia OR tetraamelia" (run
  2026-10-08) found no further human RSPO2 case reports. No treatment is
  described for this prenatally lethal condition, so no treatments are curated. No GeneReviews
  chapter covers this disease (Bookshelf index snapshot of 2026-09-10 plus a
  live PubMed title search). A falcon deep-research report
  (research/Tetraamelia_Syndrome_2-deep-research-falcon.md) read the full text
  of PMID:29769720. It describes 11 affected fetuses in five families and a
  per-fetus clinical table. One family carried a hypomorphic missense allele
  and had a milder limb phenotype, humerofemoral hypoplasia with radiotibial
  ray deficiency, which MONDO keeps as a separate disease (MONDO:0060733) and
  which is not curated here. That full text and its supplementary tables have
  no open-access copy, and only the abstract is in the reference cache, so the
  per-family variants, per-fetus phenotypes and any genital or visceral
  anomalies in the report are not quoted in this entry.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic RSPO2 variants. The original report describes recessive mutations
    forming an allelic series in which phenotype severity follows residual
    protein function.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
    explanation: Establishes recessive RSPO2 mutations as the cause of this form of tetra-amelia syndrome.
pathophysiology:
- name: Biallelic RSPO2 Loss of Function
  description: >-
    Recessive RSPO2 alleles, ranging from an upstream point variant to nonsense,
    frameshift, and terminal intron-exon deletions, reduce or abolish R-spondin 2
    function. The mutant proteins show impaired binding both to the LGR4/5/6
    receptors and to the RNF43/ZNRF3 ligases.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
  genes:
  - preferred_term: RSPO2
    term:
      id: hgnc:28583
      label: RSPO2
  molecular_functions:
  - preferred_term: binding to LGR4/5/6 receptors
    term:
      id: GO:0005102
      label: signaling receptor binding
    modifier: DECREASED
  - preferred_term: binding to the RNF43 and ZNRF3 ligases
    term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    modifier: DECREASED
  evidence:
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity."
    explanation: Functional testing of the patient alleles shows loss of receptor and ligase binding.
  downstream:
  - target: Unopposed RNF43 and ZNRF3 Activity with Reduced WNT Potentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29769720
      reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity."
      explanation: Loss of RNF43/ZNRF3 binding by the mutant alleles is accompanied by reduced WNT potentiation, graded by allele severity.
- name: Unopposed RNF43 and ZNRF3 Activity with Reduced WNT Potentiation
  description: >-
    RSPO2 acts as a direct antagonistic ligand of the transmembrane E3 ligases
    RNF43 and ZNRF3. Without it, these ligases remain active and WNT/beta-catenin
    signalling in responsive tissues is not amplified. The limb-relevant activity
    does not require the LGR4/5/6 receptors: a ubiquitous triple Lgr4/5/6 knockout
    mouse does not reproduce the Rspo2 loss-of-function phenotype, whereas
    concurrent loss of rnf43 and znrf3 in Xenopus produces supernumerary limbs,
    the mirror image of amelia.
  biological_scale: CELLULAR
  genes:
  - preferred_term: RNF43
    term:
      id: hgnc:18505
      label: RNF43
  - preferred_term: ZNRF3
    term:
      id: hgnc:18126
      label: ZNRF3
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification."
    explanation: Identifies RNF43/ZNRF3 antagonism, not LGR4/5/6 signalling, as the RSPO2 activity that controls limb specification.
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs."
    explanation: >-
      Loss of the two ligases produces the opposite of amelia, which supports
      their unopposed activity as the step through which RSPO2 loss acts.
  downstream:
  - target: Failure of Apical Ectodermal Ridge Maintenance
  - target: Reduced Lung Branching Morphogenesis
  - target: Reduced WNT Signalling in the Branchial Arch
- name: Failure of Apical Ectodermal Ridge Maintenance
  description: >-
    Rspo2 is expressed in the apical ectodermal ridge (AER) of all limb buds. In
    Rspo2-null mice the AER is induced normally, but expression of AER markers
    (Fgf8, Fgf4) and of beta-catenin targets within the AER is not maintained,
    and Shh signalling in the limb is reduced. Without a maintained AER the limb
    bud cannot grow out; in mice the defect is most severe distally and in the
    hindlimb, whereas human null alleles abolish all four limbs.
  biological_scale: TISSUE
  locations:
  - preferred_term: apical ectodermal ridge
    term:
      id: UBERON:0004356
      label: apical ectodermal ridge
  - preferred_term: limb bud
    term:
      id: UBERON:0004347
      label: limb bud
  biological_processes:
  - preferred_term: embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:17904116
    reference_title: "Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although the initiation of the expression of apical ectodermal ridge (AER)-specific genes, including fibroblast growth factor 8 (FGF8) and FGF4 occurred normally, the maintenance of these marker expressions was significantly defective in the hindlimb of Rspo2(-/-) mice."
    explanation: Shows the AER forms but is not maintained without Rspo2.
  - reference: PMID:17904116
    reference_title: "Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with the ligand role of R-spondins in the Wnt/beta-catenin signaling pathway, expression of Axin2 and Sp8, targets for beta-catenin signaling, within AER was greatly reduced in Rspo2(-/-) embryos."
    explanation: Links the AER defect to reduced WNT/beta-catenin signalling.
  - reference: PMID:18067586
    reference_title: "R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study shows that Rspo2 is critical for maintenance of the AER and for growth and patterning in limb development."
    explanation: Independent Rspo2 knockout confirming the AER maintenance role.
  downstream:
  - target: Tetraamelia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18067586
      reference_title: "R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "This study shows that Rspo2 is critical for maintenance of the AER and for growth and patterning in limb development."
      explanation: >-
        In mice, loss of AER maintenance produces limb truncation rather than
        complete amelia, so the step to total limb absence in humans is inferred
        from the more severe human null phenotype.
- name: Reduced Lung Branching Morphogenesis
  description: >-
    R-spondin 2 signalling through the canonical WNT pathway is needed for
    branching of the developing lung. Hypomorphic Rspo2 mice have hypoplastic
    lungs with reduced branching and reduced WNT reporter activity, and further
    loss of WNT co-receptor function (Lrp6) makes the hypoplasia more severe. In
    humans with RSPO2 null alleles the lungs fail to form.
  biological_scale: TISSUE
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: epithelial tube branching involved in lung morphogenesis
    term:
      id: GO:0060441
      label: epithelial tube branching involved in lung morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:18256198
    reference_title: "R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rspo2(Tg/Tg) lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3."
    explanation: Shows reduced lung branching with reduced WNT signalling in an Rspo2 hypomorph.
  downstream:
  - target: Bilateral lung agenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18256198
      reference_title: "R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Interbreeding the Rspo2(Tg) and Lrp6(-) alleles resulted in more severe defects consisting of marked lung hypoplasia and absence of tracheal-bronchial rings, laryngeal structures and all limb skeletal elements."
      explanation: >-
        Graded loss of Rspo2/WNT signalling produces graded lung hypoplasia in
        mice; human lung aplasia is taken as the extreme of this series.
- name: Reduced WNT Signalling in the Branchial Arch
  description: >-
    Rspo2-null mice show reduced WNT/beta-catenin signalling in the branchial
    arch (the source does not name which arch), with cleft lip and palate and
    mild facial skeletal defects. The location is therefore bound to the generic
    pharyngeal arch term rather than to pharyngeal arch 1.
  biological_scale: TISSUE
  locations:
  - preferred_term: branchial arch
    term:
      id: UBERON:0002539
      label: pharyngeal arch
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:19233133
    reference_title: "Craniofacial malformation in R-spondin2 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We showed the apparent reduction of Wnt/beta-catenin signaling activity at the branchial arch and the apical ectodermal ridge in Rspo2(-/-) mice."
    explanation: Documents reduced WNT signalling in the branchial arch of Rspo2 knockout mice.
  downstream:
  - target: Orofacial cleft
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19233133
      reference_title: "Craniofacial malformation in R-spondin2 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "These findings indicate that Rspo2 regulates midfacial, limb, and lung morphogenesis during development through the Wnt/beta-catenin signaling."
      explanation: >-
        The authors attribute the midfacial defect (cleft lip and palate) to loss
        of Rspo2-driven WNT signalling in mice; the same step in human fetuses is
        inferred from the shared clefting phenotype, not observed directly.
phenotypes:
- name: Tetraamelia
  category: Skeletal
  description: >-
    Total absence of all four limbs, or only rudimentary appendages, present from
    fetal life. Limb severity varies with the RSPO2 allele: alleles that keep
    some WNT-potentiating activity give less severe limb reduction than null
    alleles.
  phenotype_term:
    preferred_term: Tetraamelia
    term:
      id: HP:0003057
      label: Tetraamelia
  evidence:
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
    explanation: Defining feature of the syndrome in the original human report.
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity."
    explanation: >-
      Loss of WNT potentiation was graded across the patient alleles and tracked
      the severity of each allele, supporting an allele-dependent severity
      spectrum.
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "not only showed severe limb malformations or lack of all limbs, but also displayed other various phenotypes that correlated with the degree to which RSPO2 signalling was impaired by the mutations"
    explanation: >-
      Secondary summary of the human fetal series: the limb phenotype ranged from
      severe malformation to complete absence, and the accompanying phenotypes
      tracked how strongly each allele impaired RSPO2 signalling.
- name: Bilateral lung agenesis
  category: Respiratory
  description: >-
    Aplasia of both lungs, incompatible with postnatal survival.
  phenotype_term:
    preferred_term: Lung aplasia
    term:
      id: HP:0005944
      label: Bilateral lung agenesis
  evidence:
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
    explanation: Lung aplasia is named as a defining feature of RSPO2-related tetra-amelia.
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
    explanation: >-
      Summary-table row for the RSPO2 tetraamelia syndrome (OMIM 618021),
      recording bilateral lung agenesis.
- name: Orofacial cleft
  category: Craniofacial
  description: Cleft lip and/or cleft palate.
  phenotype_term:
    preferred_term: Cleft lip/palate
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
    explanation: Summary-table row for the RSPO2 tetraamelia syndrome lists cleft lip/palate.
- name: Micrognathia
  category: Craniofacial
  description: Mandibular hypoplasia with microretrognathia.
  phenotype_term:
    preferred_term: Mandibular hypoplasia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
    explanation: Summary-table row for the RSPO2 tetraamelia syndrome lists mandibular hypoplasia and microretrognathia.
- name: Retrognathia
  category: Craniofacial
  description: Posteriorly displaced mandible, recorded as microretrognathia.
  phenotype_term:
    preferred_term: Microretrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
    explanation: Summary-table row for the RSPO2 tetraamelia syndrome lists microretrognathia.
- name: Ankyloglossia
  category: Craniofacial
  description: Tongue tie.
  phenotype_term:
    preferred_term: Ankyloglossia
    term:
      id: HP:0010296
      label: Ankyloglossia
  evidence:
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Rudimentary appendages or complete absence of the limbs, bilateral agenesis of the lungs, cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, labioscrotal fold aplasia"
    explanation: Summary-table row for the RSPO2 tetraamelia syndrome lists ankyloglossia.
genetic:
- name: RSPO2
  relationship_type: CAUSATIVE
  notes: >-
    The reported human alleles range from a point variant upstream of the gene to
    nonsense and frameshift variants and a deletion of the last intron and exon.
    Severity of the malformation correlates with how far each allele reduces WNT
    potentiation. No ClinGen gene-disease validity record for RSPO2 was found in
    the reference cache, so no validity tier is recorded.
  gene_term:
    preferred_term: RSPO2
    term:
      id: hgnc:28583
      label: RSPO2
  evidence:
  - reference: PMID:29769720
    reference_title: "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs."
    explanation: Identifies RSPO2 as the causal gene.
  - reference: PMID:33176673
    reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "that ranged from a point mutation in the upstream region of the human RSPO2 gene, to nonsense and frameshift mutations, and to a deletion of the last intron and exon"
    explanation: Summarises the range of human RSPO2 variant types reported by Szenker-Ravi et al.
animal_models:
- name: Rspo2 knockout mouse
  species: Mouse
  genotype: Rspo2 homozygous null
  publication: PMID:19233133
  description: >-
    Rspo2-null mice die at birth from respiratory failure with cleft lip and
    palate, distal limb loss, and lung hypoplasia.
  modeled_mechanisms:
  - target: Reduced WNT Signalling in the Branchial Arch
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      The craniofacial phenotype in mice is cleft lip and palate with mild facial
      skeletal defects; the human craniofacial spectrum is known only from a
      summary table.
    evidence:
    - reference: PMID:19233133
      reference_title: "Craniofacial malformation in R-spondin2 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We showed the apparent reduction of Wnt/beta-catenin signaling activity at the branchial arch and the apical ectodermal ridge in Rspo2(-/-) mice."
      explanation: Shows the branchial-arch signalling defect in this model.
  - target: Failure of Apical Ectodermal Ridge Maintenance
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      The mice lose distal limb elements rather than whole limbs, so they model a
      milder limb reduction than human tetra-amelia.
    evidence:
    - reference: PMID:19233133
      reference_title: "Craniofacial malformation in R-spondin2 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Additionally, Rspo2(-/-) mice also exhibited distal limb loss and lung hypoplasia, and died immediately after birth with respiratory failure."
      explanation: Distal limb loss and lung hypoplasia in the knockout.
- name: footless (Rspo2 hypomorph) mouse
  species: Mouse
  genotype: Rspo2 Tg/Tg (footless insertional allele), alone and with Lrp6 null alleles
  publication: PMID:18256198
  description: >-
    An insertional hypomorphic Rspo2 allele causes laryngeal-tracheal, limb, and
    palate malformations and lung hypoplasia. Combining it with Lrp6 loss removes
    all limb skeletal elements.
  modeled_mechanisms:
  - target: Reduced Lung Branching Morphogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      The mice have lung hypoplasia, not the lung aplasia seen in humans with
      RSPO2 null alleles.
    readouts:
    - name: Lung branching and WNT reporter activity
      target: Reduced Lung Branching Morphogenesis
      direction: DECREASED
      interpretation: Direct measurement of the branching defect and its WNT dependence.
      evidence:
      - reference: PMID:18256198
        reference_title: "R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Rspo2(Tg/Tg) lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3."
        explanation: Reports the branching and reporter measurements.
    evidence:
    - reference: PMID:18256198
      reference_title: "R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Rspo2(Tg/Tg) mice had severe malformations of laryngeal-tracheal cartilages, limbs and palate, and lung hypoplasia consistent with sites of Rspo2 expression."
      explanation: The hypomorph reproduces the lung and limb organ involvement of the human disease.
- name: Holstein Friesian tetradysmelia (RSPO2 50-kb deletion)
  species: Cattle
  genotype: Homozygous 50-kb deletion spanning three RSPO2 exons
  publication: PMID:33176673
  description: >-
    A recessive 50-kb deletion removing three coding exons of bovine RSPO2
    segregates with tetradysmelia, a severe reduction of all limb parts distal to
    the shoulder and pelvic girdles.
  modeled_mechanisms:
  - target: Biallelic RSPO2 Loss of Function
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: Naturally occurring recessive RSPO2 null allele in a large mammal producing four-limb reduction.
    evidence:
    - reference: PMID:33176673
      reference_title: "A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We identified a 50-kb deletion on BTA14 that disrupts the coding sequence of the RSPO2 gene and is associated with bovine tetradysmelia."
      explanation: A natural RSPO2 loss-of-function allele causing reduction of all four limbs.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

The human disease is known from a single report of an allelic series of recessive RSPO2 mutations (PMID:29769720), whose PubMed abstract is the only text of that paper available to the reference cache. Phenotypes beyond limb absence and lung aplasia are therefore cited from the OMIM-derived summary table in the bovine tetradysmelia paper (PMID:33176673) and are marked as background quotes. A PubMed search for "RSPO2 AND (fetus OR fetal OR prenatal OR case report OR homozygous)" and for "tetra-amelia OR tetraamelia" (run 2026-10-08) found no further human RSPO2 case reports. No treatment is described for this prenatally lethal condition, so no treatments are curated. No GeneReviews chapter covers this disease (Bookshelf index snapshot of 2026-09-10 plus a live PubMed title search). A falcon deep-research report (research/Tetraamelia_Syndrome_2-deep-research-falcon.md) read the full text of PMID:29769720. It describes 11 affected fetuses in five families and a per-fetus clinical table. One family carried a hypomorphic missense allele and had a milder limb phenotype, humerofemoral hypoplasia with radiotibial ray deficiency, which MONDO keeps as a separate disease (MONDO:0060733) and which is not curated here. That full text and its supplementary tables have no open-access copy, and only the abstract is in the reference cache, so the per-family variants, per-fetus phenotypes and any genital or visceral anomalies in the report are not quoted in this entry.

Review round 1: Tetraamelia_Syndrome_2 · 2026-10-11T22:02:07Z · View source

Changes made in response to the first review of PR 13704. (1) Deep research: ran falcon (research/Tetraamelia_Syndrome_2-deep-research-falcon.md, committed with its citations file and artifacts). Its reference block shows 9 of 9 references resolved and none off topic. Its term block flags MONDO:0060732 as mislabelled only because the prompt template's 'MONDO ID ... (if available)' text was read as a label; the CURIE itself is correct. just preflight-dr could not run: it needs a local mondo.db that was not present and was not downloaded because disk space on the machine is limited. A manual check found the report is about RSPO2 throughout (72 mentions), the same causal gene MONDO records, with WNT3 named only as a differential. The report read the full text of PMID:29769720 (11 fetuses, 5 families, per-fetus table, family-level variants) and found that one family with a hypomorphic missense allele had humerofemoral hypoplasia with radiotibial ray deficiency, which is the separate MONDO disease MONDO:0060733. That full text and its supplement have no open-access copy and only the abstract is cached, so none of the per-fetus or per-variant detail could be quoted. That is recorded in the entry notes and is not curated. One quotable addition was made: the allele-dependent severity spectrum on the Tetraamelia phenotype, cited to the PMID:29769720 abstract (WNT potentiation correlated with allele severity) and to the human-series summary in PMID:33176673. The VERY_FREQUENT frequency was removed because the series is 7 severe fetuses. (2) The branchial-arch to Orofacial cleft edge is now directness INDIRECT, with an explanation. (3) The branchial-arch location was rebound from UBERON:0004362 pharyngeal arch 1 to UBERON:0002539 pharyngeal arch, because the source does not name which arch. (4) CI gene-activity grounding: the RSPO2 landing node now carries GO:0005102 signaling receptor binding and GO:0031625 ubiquitin protein ligase binding, both marked DECREASED and supported by the node's existing PMID:29769720 binding sentence. The branch was rebased onto origin/main. Validated with validate, validate-terms, count-verified-snippets (29/29), validate-disorders, and the CI check-* gates run locally, including check_gene_activity_grounding --against-ref origin/main.

Create: Tetraamelia_Syndrome_2 · 2026-10-08T15:42:05Z · View source

New entry for tetraamelia syndrome 2 (MONDO:0060732, RSPO2), curated directly from PubMed; no deep-research provider was run. Curated as a standalone Disease rather than a subtype: MONDO has separate leaf terms for TETAMS1 (WNT3) and TETAMS2 (RSPO2) under MONDO:0010110, there is no dismech entry for that parent, and the two genes act at different steps of WNT signalling. Human evidence rests on one paper (PMID:29769720, Szenker-Ravi 2018), available only as an abstract, which supports recessive inheritance, tetra-amelia and lung aplasia, and the RNF43/ZNRF3 mechanism. The craniofacial phenotypes (orofacial cleft, mandibular hypoplasia, retrognathia, ankyloglossia) are cited from the OMIM-derived summary table in the bovine RSPO2 paper (PMID:33176673) and marked quote_role BACKGROUND. Labioscrotal fold aplasia, listed in that same table row, was not curated because no HPO term clearly matches. The mechanism chain (AER maintenance failure, reduced lung branching, reduced branchial-arch WNT signalling) comes from Rspo2 mouse models (PMIDs 17904116, 18067586, 18256198, 19233133). Mouse-to-human edges are marked directness INDIRECT because the mice show limb truncation and lung hypoplasia, not complete amelia and lung aplasia. The jaw and tongue phenotypes have no causal edge because no source links them to a specific mechanism. No treatments, no ClinGen record, and no GeneReviews chapter were found. Validated with just validate, validate-terms, count-verified-snippets (27/27), check-duplicate-keys, check-entity-refs, check-causal-targets, check-enum-values, check-snippet-length, check-title-snippets, check-genereviews and validate-disorders.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 23 citations 2026-10-08T16:12:24.305036

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.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Tetraamelia Syndrome 2
  • MONDO ID: MONDO:0060732 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Tetraamelia Syndrome 2 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Tetra-amelia syndrome 2: disease-characteristics research report

Scope and evidence standard. This entry concerns the RSPO2-associated disorder, not every condition described as tetra-amelia. The principal human evidence is a 2018 study of 11 affected fetuses in five families; consequently, observations from those families are not population prevalence estimates or validated clinical criteria. The best-characterized subsequent evidence is comparative animal work, not a large human natural-history series. The gene–disease relationship is supported by human segregation, functional experiments and animal models. (szenkerravi2018rspo2inhibitionof pages 1-2, becker2020a50kbdeletion pages 6-9)

1. Disease information

Tetra-amelia syndrome 2 (TETAMS2) is a rare, congenital, autosomal-recessive developmental disorder caused by biallelic damaging RSPO2 variants. Its severe presentation includes absence of all four limbs and profoundly abnormal lung development, often with craniofacial and genital malformations. RSPO2 also causes a less severe, related phenotype called humerofemoral hypoplasia with radiotibial ray deficiency (HFH-RTRD); this phenotypic spectrum must not be collapsed into a single assertion that every person with biallelic RSPO2 variants has tetra-amelia. (szenkerravi2018rspo2inhibitionof pages 1-2)

Identifiers and terminology: the supplied target identifier is MONDO:0060732; the tetra-amelia syndrome 2 identifier cited in the literature is OMIM 618021. Open Targets additionally indexes RSPO2 against the broader “tetraamelia-multiple malformations syndrome,” MONDO:0010110, and HFH-RTRD, MONDO:0060733. These broader and related terms are not interchangeable with the requested subtype. Synonyms encountered include tetra-amelia syndrome type 2, RSPO2-related tetra-amelia and tetra-amelia with pulmonary aplasia. A subtype-specific Orphanet number, ICD-10/ICD-11 code and MeSH identifier were not independently verified in the retrieved evidence; do not substitute codes for the general limb defect without checking the relevant terminology release. The underlying observations are published, aggregated disease-level and familial fetal data, not a queried patient EHR. (OpenTargets Search: -RSPO2, szenkerravi2018rspo2inhibitionof pages 1-2, becker2020a50kbdeletion pages 2-4)

Defining primary source: Szenker-Ravi E, et al. “RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6.” Nature. May 2018;557:564–569. PMID: 29769720; DOI: 10.1038/s41586-018-0118-y. Its abstract states: “Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs.” (szenkerravi2018rspo2inhibitionof pages 1-2)

2. Etiology: causes, risk, protection and gene–environment interaction

Established causal factor: inherited biallelic, function-reducing RSPO2 variants impair an extracellular amplifier of embryonic WNT signaling. In the discovery series, a hypomorphic missense variant was associated with HFH-RTRD, whereas more disruptive truncating or deletion alleles were associated with the severe tetra-amelia presentation. Parental carrier status and consanguinity in some families support recessive inheritance; family history of an affected pregnancy raises recurrence risk. These are Mendelian reproductive risks, not environmental exposure risks. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2)

Not established for this subtype: a specific toxin, maternal behavior, pathogen, occupational exposure, sex-specific susceptibility, protective allele, dietary intervention or clinically demonstrated RSPO2–environment interaction. Teratogens and amniotic bands can cause superficially similar limb defects, but that does not establish that they cause RSPO2-related TETAMS2. Mouse ozone-injury research nominated Rspo2 among candidates at a lung-response locus but favored other genes; it is not evidence for an ozone interaction in the congenital human syndrome. The absence of identified protective factors should not be interpreted as proof that none exist. (chevallier2025therspo2gene pages 2-4, szenkerravi2018rspo2inhibitionof pages 1-2, tovar2022alocuson pages 11-11)

3. Phenotypes and ontology suggestions

All reported defining abnormalities originate prenatally and are structural clinical signs rather than acquired symptoms. No reliable population-based phenotype frequencies, severity scale, patient-reported quality-of-life scores or postnatal progression series were identified. In the ascertained 2018 series only, family 1 contained four affected fetuses with HFH-RTRD; families 2–5 together contained seven with the severe tetra-amelia phenotype. These fractions must not be presented as frequencies among all patients with TETAMS2. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 17-17)

Manifestation and suggested HPO search term Disease-specific description; onset, course, frequency and functional impact
Amelia / tetra-amelia — Amelia; check the current HPO entry for absence of all four limbs Severe fetal manifestation; complete four-limb absence in the seven severe fetuses as a group. Congenital and anatomically fixed. Expected profound dependence for mobility and self-care if survival is possible; no TETAMS2-specific quality-of-life measurements. (szenkerravi2018rspo2inhibitionof pages 1-2)
Humerofemoral hypoplasia, radial-ray and tibial deficiencies — Humeral hypoplasia, Femoral hypoplasia, Radial ray deficiency, Tibial aplasia, Preaxial polydactyly/digit absence only where documented Alternative, comparatively less severe RSPO2 phenotype in four family-1 fetuses; includes absent tibiae with or without femoral deficiency and preaxial digit loss. Do not assign these as universal findings of the severe subtype. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 17-17)
Pulmonary agenesis or hypoplasia — Pulmonary agenesis, Pulmonary hypoplasia Severe congenital respiratory-organ abnormality; lung absence is directly documented in at least one illustrated tetra-amelia fetus. The precise number with agenesis versus hypoplasia cannot be read reliably from the available fetal table. Bilateral agenesis is incompatible with sustained postnatal respiration; avoid asserting a numerical survival probability. (szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 1-2)
Cleft lip and/or palate — Cleft lip, Cleft palate Prenatal structural sign reported among severe fetuses; severity and later feeding implications are case-dependent; no trustworthy per-feature proportion. (szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 1-2)
Micrognathia/retrognathia and ankyloglossia — Micrognathia, Retrognathia, Ankyloglossia Reported in individual clinical descriptions; congenital, variable and potentially relevant to airway or feeding if a child survives. Not established as invariably present. (szenkerravi2018rspo2inhibitionof pages 17-17)
Labioscrotal-fold aplasia / genital malformation — use the HPO term for the precisely documented external-genital defect after ontology verification Described in the severe syndrome; individual frequencies and sex-specific expression cannot be established from the retrieved table. (szenkerravi2018rspo2inhibitionof pages 1-2)

These are term-label suggestions, not claims that a particular HPO accession or an ontology-listed frequency has been validated. More variable skeletal, facial and other fetal anomalies occur in clinical descriptions; the damaged supplementary table does not support defensible case-by-case rates for renal, cardiac or other visceral findings. (szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 11-17)

4. Genetic and molecular information

The causal gene is RSPO2, encoding the secreted protein R-spondin 2; Ensembl ENSG00000147655 is confirmed by Open Targets. The retrieved material does not independently confirm its HGNC accession, so the accession should be populated from HGNC rather than guessed. The primary study described the following germline RSPO2 allelic series; HGVS descriptions should be reconciled with a specified transcript and genome assembly before import into a variant registry. (OpenTargets Search: -RSPO2, szenkerravi2018rspo2inhibitionof pages 2-2)

Family / reported phenotype Human RSPO2 variant (HGVS as reported) Variant type Functional / phenotype inference
F1 — HFH-RTRD; 4 affected fetuses c.205C>T; p.Arg69Cys Homozygous missense Hypomorphic allele: reduced receptor/ligase binding and reduced WNT potentiation; associated with the comparatively milder humerofemoral hypoplasia with radiotibial ray deficiency phenotype. (szenkerravi2018rspo2inhibitionof pages 1-2)
F2 — TETAMS c.208C>T; p.Gln70* Homozygous nonsense Functionally null-like in the reported assays; associated with severe tetra-amelia syndrome. F2–F5 together comprised 7 affected fetuses; the publication does not support assigning that combined count to this family individually. (szenkerravi2018rspo2inhibitionof pages 1-2)
F3 — TETAMS ~154-kb homozygous deletion involving intron 5 and exon 6; reported coordinate chr8:108,809,266–108,963,256 (genome build unspecified here) Structural deletion / predicted loss of function Exon-disrupting biallelic deletion associated with severe tetra-amelia syndrome; identified by SNP array/array-CGH. F2–F5 collectively had 7 affected fetuses. (szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 8-11, szenkerravi2018rspo2inhibitionof pages 1-2)
F4 — TETAMS c.409G>T; p.Glu137* Homozygous nonsense Predicted truncating loss-of-function allele associated with severe tetra-amelia syndrome; no independent family-specific affected count should be inferred from the combined F2–F5 total. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2)
F5 — TETAMS c.123delG; p.Gly42Valfs*49 Homozygous frameshift Predicted early truncating loss of function associated with severe tetra-amelia syndrome; F2–F5 together comprised 7 affected fetuses. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2)
Evidence boundary Primary report: Szenker-Ravi et al., Nature (May 2018), DOI 10.1038/s41586-018-0118-y, PMID 29769720 Five-family allelic series Case counts are ascertained-cohort observations, not population frequencies. Variant descriptions and functional interpretations are from the primary publication; this table does not assert independently verified ClinVar classifications or formal variant-by-variant ACMG/AMP classifications. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2)

Table: Evidence-checked summary of the five-family 2018 RSPO2 allelic series, separating the four milder F1 cases from the seven severe TETAMS fetuses distributed collectively across F2–F5. Counts are cohort observations, and no independent ClinVar or ACMG/AMP classifications are asserted.

Interpretation: the p.Arg69Cys protein retains reduced activity—a hypomorphic allele—whereas p.Gln70 showed null-like activity in the reported WNT-potentiation assay. The other premature-stop and frameshift variants are predicted loss-of-function alleles; the 154-kb exon-disrupting deletion demonstrates that copy-number analysis is necessary. The authors provide compelling clinical/experimental pathogenicity evidence, but independently audited ClinVar variant-level assertions, formal ACMG/AMP classifications and exact gnomAD allele frequencies were not retrieved. None of these congenital variants should be labeled somatic. No confirmed disease-specific modifier locus, epigenetic signature, balanced rearrangement or aneuploidy was established; the reported chromosomal abnormality is a structural deletion within RSPO2***, not a newly identified chromosome syndrome. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 8-11)

5. Environmental information

There is no established toxin, radiation, pollution, smoking, alcohol, diet, infectious-agent or lifestyle cause of the defined biallelic RSPO2 disorder in the retrieved clinical series. Such factors remain relevant to the differential diagnosis of congenital limb reduction, not as proven contributors to TETAMS2. A specific CHEBI term for an etiologic chemical is therefore not applicable; the experimental WNT inhibitor Wnt-C59 is a laboratory perturbation, not a documented patient exposure or therapy. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-3)

6. Mechanism and pathophysiology

Ordered causal chain. Human observation and experimental support are distinguished where needed:

  1. Biallelic damaging germline RSPO2 variants lead to reduced amount or activity of secreted R-spondin 2; missense p.Arg69Cys leaves partial activity, while stronger alleles markedly reduce function. Human genetics plus in-vitro assays. (szenkerravi2018rspo2inhibitionof pages 1-2)
  2. Reduced functional RSPO2 leads to insufficient antagonism of the membrane E3 ligases RNF43 and ZNRF3. The requirement of those ligases for the developmental switch is supported experimentally; the exact binding consequences differ between mutant proteins. In vitro and model-organism evidence. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 5-6)
  3. Insufficient RNF43/ZNRF3 antagonism results in reduced WNT-receptor responsiveness and WNT/β-catenin pathway potentiation. This step is experimentally supported by ligand-interaction and WNT3A-responsive reporter assays; its complete quantitative trajectory in an affected human embryo is inferred. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2)
  4. Reduced developmental WNT signaling leads to failure of normal limb-bud signaling and apical ectodermal ridge maintenance/outgrowth, resulting in profound limb reduction or four-limb absence. The ridge-to-specific-human-fetal-defect linkage is inferred from animal and expression studies rather than serial measurement of affected human embryos. Branch A: limb phenotype. (szenkerravi2018rspo2inhibitionof pages 2-3, szenkerravi2018rspo2inhibitionof pages 3-4, szenkerravi2018rspo2inhibitionof pages 6-7, chevallier2025therspo2gene pages 10-12)
  5. Disrupted RSPO2-dependent signaling in developing lung tissues leads to pulmonary hypoplasia or aplasia, resulting in potentially lethal respiratory incapacity. The tissue association and human fetal findings are demonstrated; the exact human cell-by-cell sequence is inferred. Branch B: lung phenotype. (szenkerravi2018rspo2inhibitionof pages 2-3, szenkerravi2018rspo2inhibitionof pages 3-4, szenkerravi2018rspo2inhibitionof pages 1-2)
  6. Perturbed early embryonic patterning additionally leads to some craniofacial and genital anomalies; attribution of each non-limb abnormality to a defined RSPO2 target cell, versus secondary developmental consequences, remains inferred. Branch C: associated malformations. (szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 1-2)

Important mechanistic qualification: RSPO2 can act without obligatory LGR4/5/6 receptors in the examined developmental context: Lgr4/5/6 triple-null mouse embryos retained limbs and lungs, and RSPO2/3 still altered WNT responsiveness in receptor-null cells. This does not mean the human mutants retain normal binding; p.Arg69Cys and p.Gln70 showed impaired detectable binding in the tested constructs. Concurrent rnf43/znrf3 loss in Xenopus produced ectopic limbs, including 61 double-mutant froglets with polymelia in the reported experiments—the opposite-direction perturbation supporting pathway causality, not a faithful model of human limb absence. The study’s abstract concludes: “RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3*.” (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 5-6, szenkerravi2018rspo2inhibitionof pages 2-3)

Biological annotation proposals: GO biological processes canonical Wnt signaling pathway, limb development, limb bud formation/outgrowth, apical ectodermal ridge development and lung development; GO cellular components extracellular space for secreted RSPO2 and plasma membrane for RNF43/ZNRF3 and WNT receptors. Relevant proposed Cell Ontology labels are limb-bud ectodermal epithelial cell, limb-bud mesenchymal cell, lung epithelial cell and lung mesenchymal cell; verify exact CL IDs before import because expression domains, not subtype-resolved human single-cell profiles, underlie these suggestions. Expression analysis reported Rspo2, Wnt3, Lgr6 and Znrf3 in relevant developing-limb regions and Rspo2 and Znrf3 overlap in lung mesenchyme. No TETAMS2-specific human transcriptome, proteome, metabolome, lipidome, methylome, spatial transcriptome or CRISPR-screen signature was found; generalized RSPO2 studies in cancer or ovarian follicles must not be imported as fetal disease signatures. (szenkerravi2018rspo2inhibitionof pages 2-3, szenkerravi2018rspo2inhibitionof pages 3-4, chevallier2025therspo2gene pages 10-12)

7. Anatomical structures affected

Primary structures are bilateral upper- and lower-limb buds and the developing lungs. Associated sites include the lip/palate, mandible and external genital structures. In the milder RSPO2 phenotype, defects may preferentially involve humerus, femur, radius and tibia; in the severe phenotype, all four limbs can be absent. Lung epithelial and mesenchymal developmental compartments and the limb-bud ectodermal ridge/mesenchyme are implicated; these are developmental tissues, not proven selectively damaged adult cell populations. Proposed UBERON labels to map and verify are upper limb, lower limb, limb bud, apical ectodermal ridge, lung, lung mesenchyme, lip, palate, mandible and external genitalia. Bilaterality is intrinsic to documented four-limb absence, but other associated defects can vary in laterality. Protein-level localization is extracellular ligand versus membrane signaling machinery; nuclear β-catenin-dependent transcription is downstream rather than a demonstrated RSPO2 nuclear localization. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 3-4, szenkerravi2018rspo2inhibitionof pages 17-17)

8. Temporal development

Onset: embryonic, detectable as fetal structural abnormalities; illustrated affected fetuses were examined at approximately 20 and 26 gestational weeks. The clinical table includes terminations at different gestational ages and stillbirth; these dates are observation times, not the timing when the causal developmental defect began. Course: congenital anatomic malformations persist rather than follow a relapsing/remitting disease cycle. There are no validated early/intermediate/end stages, remission pattern, longitudinal progression rate or adult natural-history series for severe TETAMS2. The critical window is early limb and lung organogenesis, inferred from developmental experiments; prenatal detection creates an opportunity for diagnostic confirmation and counseling, not reversal of already absent organs. (szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 2-3, szenkerravi2018rspo2inhibitionof pages 6-7)

9. Inheritance, epidemiology and population

Inheritance is autosomal recessive in the reported human families, with biallelic/homozygous variants and clinically unaffected carrier parents. For two established carriers of the same recessive disorder, conventional Mendelian counseling gives a 25% affected conception risk, assuming both variants are disease-causing and no unusual reproductive mechanisms; this is a theoretical recurrence probability, not a measured population incidence. Affected fetuses included both sexes; the small ascertained sample cannot establish a sex ratio. Multiple families reported consanguinity, which increases the chance of homozygosity but is neither necessary nor sufficient for disease. Penetrance for a defined severe biallelic genotype, carrier frequency, founder effect, germline mosaicism rate, anticipation and geographic/ethnic prevalence are not quantified. The observation that different alleles produced different severity supports allele-dependent expressivity rather than a proven numerical penetrance estimate. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 11-17)

No reliable subtype-specific prevalence or annual incidence per 100,000 was located. Published figures for all forms of amelia or all congenital upper-limb malformations cannot be assigned to molecularly confirmed TETAMS2. No validated geographic distribution or age pyramid is available; the documented severe cases are predominantly fetuses. (szenkerravi2018rspo2inhibitionof pages 17-17, chevallier2025therspo2gene pages 1-2)

10. Diagnostics

Clinical recognition: detailed prenatal ultrasound can identify markedly reduced or absent limbs and investigate thoracic/lung anatomy, face, genitals and other structural anomalies; targeted fetal imaging and postmortem examination, when available, can refine classification. In an affected liveborn infant, radiographs and respiratory assessment would define extent and urgent clinical needs. The discovery study used fetal clinical assessment, exome sequencing in one family, and SNP-array/array-CGH for a homozygous RSPO2 deletion in another. These methods are documented applications; a universally validated TETAMS2-specific imaging or diagnostic guideline was not found. No distinctive blood, urine, enzyme, electrophysiological, biopsy, metabolomic or circulating-protein biomarker was established. (szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 8-11, szenkerravi2018rspo2inhibitionof pages 11-17)

Recommended molecular workflow, as an evidence-informed approach rather than a formal syndrome guideline: (1) review three-generation family history and fetal phenotype; (2) sequence RSPO2 with segregation testing of both parents, using a severe limb-malformation panel, trio WES or WGS as indicated; (3) perform copy-number/structural-variant assessment capable of detecting exon-level and approximately 154-kb deletions, especially if sequence testing is negative; (4) interpret variants against an explicit transcript, current population controls and functional/segregation evidence; (5) broaden the assessment when RSPO2 testing is nondiagnostic. WGS could help resolve structural or noncoding lesions, but its syndrome-specific incremental diagnostic yield has not been quantified. CMA can identify large deletions; karyotyping or FISH should be reserved for an independently suspected rearrangement, not used as substitutes for sequence/CNV analysis. Mitochondrial-DNA, repeat-expansion and liquid-biopsy testing have no established role. (szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 8-11, szenkerravi2018rspo2inhibitionof pages 1-2)

Differential: WNT3-related tetra-amelia is a distinct molecular condition: Niemann S, et al. “Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.” Am J Hum Genet. 2004;74:558–563. DOI:10.1086/382196. Consider other genetic limb-patterning disorders and non-genetic disruption, including amniotic-band defects, where morphology and evidence of constriction bands differ. Neither the shared word “tetra-amelia” nor four-limb involvement alone identifies the causal gene. There are no retrieved formally validated, subtype-specific clinical criteria or universal newborn screening program. Targeted familial prenatal and carrier testing become possible once pathogenic familial variants are established. (chevallier2025therspo2gene pages 14-15, chevallier2025therspo2gene pages 2-4, szenkerravi2018rspo2inhibitionof pages 1-2)

11. Outcomes and prognosis

The seven severe published human cases were described as affected fetuses, with terminations and stillbirth represented in the clinical table. Profound pulmonary aplasia—particularly complete bilateral absence—would prevent sustained unaided respiration; this is an anatomical inference, not a disease-specific survival curve. No verified TETAMS2 5-year or 10-year survival rate, life expectancy, cause-specific mortality rate, functional outcome score, EQ-5D/SF-36 estimate or prognostic model is available. Severity of lung formation is the most obvious anatomical prognostic consideration, but no validated threshold or prognostic biomarker has been measured. The potential life-long functional burden of limb absence must be distinguished from the severe subtype’s lack of documented survivor follow-up. Surgical or rehabilitation interventions cannot restore missing lung parenchyma or embryonic limb formation. (szenkerravi2018rspo2inhibitionof pages 17-17, szenkerravi2018rspo2inhibitionof pages 11-17, szenkerravi2018rspo2inhibitionof pages 1-2)

12. Treatment and current implementation

No disease-modifying pharmacotherapy, licensed genotype-directed treatment, gene therapy, cell therapy, RNA therapy, immunotherapy or validated WNT-pathway rescue was identified. A ClinicalTrials.gov search for tetra-amelia/tetraamelia produced no relevant syndrome-specific interventional trial or NCT identifier; this is a search result, not proof that no patient can ever enroll in broader supportive-care studies. Experimentally inhibiting WNT with Wnt-C59 worsened developmental limb/lung phenotypes in the model and is not treatment. (szenkerravi2018rspo2inhibitionof pages 2-3, szenkerravi2018rspo2inhibitionof pages 1-2)

Practical care is phenotype-directed and conditional on viability: prenatal maternal–fetal medicine and clinical genetics consultation; birth planning and respiratory assessment if live birth is anticipated; specialist evaluation of cleft/airway/feeding problems; and, for any surviving person with limb deficiency, individualized mobility aids, prosthetics, occupational/physical therapy and reconstructive procedures where anatomically feasible. These are general multidisciplinary principles, not efficacy-tested TETAMS2 regimens, and no disease-specific response rates or adverse-event rates are available. Suggested NCIT intervention concepts for later terminology mapping, not verified accessions, are genetic counseling, prenatal ultrasonography, prosthetic device, occupational therapy, physical therapy and cleft-palate repair. No TETAMS2-specific pharmacogenomic marker is reported. (szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 11-17, szenkerravi2018rspo2inhibitionof pages 1-2)

13. Prevention

Primary prevention of the molecular defect cannot be achieved through vaccination, infection control, diet or avoidance of a proven syndrome-specific toxin: none has been identified. In families with established pathogenic RSPO2 variants, reproductive genetic counseling, molecular carrier testing of relatives as appropriate, and discussion of preimplantation or prenatal testing can reduce recurrence of an affected birth according to family preferences; they do not alter Mendelian transmission. Secondary prevention consists of identifying fetal malformations early enough for diagnostic clarification and informed obstetric planning. Tertiary prevention, where postnatal survival is possible, focuses on complications and functional support. No universal newborn screening, prophylactic medication or public-health environmental intervention has demonstrated syndrome-specific benefit. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 8-11)

14. Naturally occurring disease in other species

Cattle — Bos taurus; proposed NCBI Taxon 9913; Holstein Friesian. Becker D, et al. “A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle.” Genetics Selection Evolution. November 2020. DOI:10.1186/s12711-020-00586-y. In a backcross family of 24 offspring, six were affected; a homozygous approximately 50-kb deletion affecting three RSPO2 exons segregated with severe four-limb reduction. The bovine phenotype resembles the human limb phenotype, but examined cattle lacked the gross lung malformations described in severe human fetuses. This is a naturally occurring comparative genetic disorder, not evidence of cross-species transmission. (becker2020a50kbdeletion pages 6-9, becker2020a50kbdeletion pages 9-11, becker2020a50kbdeletion pages 1-2, becker2020a50kbdeletion pages 4-5)

Dog — Canis lupus familiaris, NCBI Taxon 9615; Chihuahua. Chevallier L, et al. “The RSPO2 gene is associated with bilateral anterior amelia in Chihuahuas.” Mammalian Genome. March 2025. DOI:10.1007/s00335-025-10123-1. Among 13 affected dogs, 12 were homozygous for three associated candidate SNVs and one was heterozygous; 97/100 controls were reference homozygotes and 3/100 heterozygotes. The affected dogs chiefly lacked forelimb structures, with hindlimbs generally spared. The candidate SNVs are not proven causal; the authors discuss unobserved RSPO2 regulatory variation and cannot exclude a more complex inheritance model. A cropped thoracic-radiograph panel illustrates scapulae/short humeri and absence of more distal forelimb bones; this image is veterinary comparative evidence, not a human patient image. No verified VBO breed accession is supplied. These dog data must not be used to estimate human carrier frequency or penetrance. (chevallier2025therspo2gene pages 12-13, chevallier2025therspo2gene pages 1-2, chevallier2025therspo2gene media 4b7e9d18, chevallier2025therspo2gene pages 10-12)

The orthologs are bovine and canine RSPO2; the retrieved sources explicitly identify dog gene ID 482004, but no independently checked bovine or mouse ortholog Gene ID is provided. No zoonotic potential or infectious transmission exists for an inherited developmental phenotype. (chevallier2025therspo2gene pages 1-2, becker2020a50kbdeletion pages 1-2)

15. Experimental model organisms and resources

Mouse, Mus musculus: Rspo2 loss-of-function models show abnormal limb outgrowth/apical ectodermal ridge maintenance and lung, laryngeal–tracheal or craniofacial development, depending on the model and study; this supports organ-level causality without reproducing every human variant. In contrast, Lgr4/5/6 triple-knockout mice retain limbs and lungs, an important mechanistic negative control. The cited primary model literature includes Nam et al., Developmental Biology (2007), DOI:10.1016/j.ydbio.2007.08.023, and Yamada et al., Biochemical and Biophysical Research Communications (2009), DOI:10.1016/j.bbrc.2009.02.066. MGI and IMPC are appropriate resources for checking exact alleles and phenotypes; no particular stock number was verified. (szenkerravi2018rspo2inhibitionof pages 5-6, szenkerravi2018rspo2inhibitionof pages 2-3, szenkerravi2018rspo2inhibitionof pages 6-7, chevallier2025therspo2gene pages 14-15, chevallier2025therspo2gene pages 13-14)

Frog, Xenopus tropicalis: rnf43/znrf3 double mutants developed supernumerary, rather than absent, limbs; this is a pathway-mechanism model, not a direct phenocopy. Additional rspo2 disruption experiments produced limb-loss phenotypes in Xenopus. Human cell assays: HEK293T WNT3A-responsive SUPERTOPFLASH reporter testing and protein-interaction assays measured variant-specific functional effects; their limitation is that they do not recreate the whole human fetal limb and lung environment. No disease-specific patient-derived organoid, iPSC rescue, spatial transcriptomic atlas or multi-omics disease model was identified. Appropriate databases for future model curation are MGI, IMPC, Xenbase and the Alliance of Genome Resources; a verified strain/stock accession should be required before entry. (szenkerravi2018rspo2inhibitionof pages 1-2, szenkerravi2018rspo2inhibitionof pages 2-2, szenkerravi2018rspo2inhibitionof pages 5-6, chevallier2025therspo2gene pages 10-12)

Evidence and knowledge-base curation priorities

The strongest claim is the human recessive RSPO2 allelic series linked to an experimentally supported WNT-signaling mechanism (PMID 29769720). More recent 2025 papers extend comparative canine genetics and historical fetal anatomy but do not establish a new 2023–2024 human TETAMS2 cohort or a treatment. Before machine-readable import, independently verify the exact MONDO subtype mapping, OMIM cross-references, HGNC and ontology accessions, transcript/build-specific HGVS coordinates, ClinVar assertions and any HPO phenotype frequencies; retain explicit unknown/not measured values for epidemiology, survival and quality of life rather than substituting statistics for generic amelia. (OpenTargets Search: -RSPO2, szenkerravi2018rspo2inhibitionof pages 1-2, behunova2025facialbonedefects pages 1-2, chevallier2025therspo2gene pages 1-2)

References

  1. (szenkerravi2018rspo2inhibitionof pages 1-2): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  2. (becker2020a50kbdeletion pages 6-9): Doreen Becker, Rosemarie Weikard, Christoph Schulze, Peter Wohlsein, and Christa Kühn. A 50-kb deletion disrupting the rspo2 gene is associated with tetradysmelia in holstein friesian cattle. Genetics, Selection, Evolution : GSE, Nov 2020. URL: https://doi.org/10.1186/s12711-020-00586-y, doi:10.1186/s12711-020-00586-y. This article has 15 citations.

  3. (OpenTargets Search: -RSPO2): Open Targets Query (-RSPO2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  4. (becker2020a50kbdeletion pages 2-4): Doreen Becker, Rosemarie Weikard, Christoph Schulze, Peter Wohlsein, and Christa Kühn. A 50-kb deletion disrupting the rspo2 gene is associated with tetradysmelia in holstein friesian cattle. Genetics, Selection, Evolution : GSE, Nov 2020. URL: https://doi.org/10.1186/s12711-020-00586-y, doi:10.1186/s12711-020-00586-y. This article has 15 citations.

  5. (szenkerravi2018rspo2inhibitionof pages 2-2): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  6. (chevallier2025therspo2gene pages 2-4): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  7. (tovar2022alocuson pages 11-11): Adelaide Tovar, Gregory J. Smith, Morgan B. Nalesnik, Joseph M. Thomas, Kathryn M. McFadden, Jack R. Harkema, and Samir N. P. Kelada. A locus on chromosome 15 contributes to acute ozone-induced lung injury in collaborative cross mice. American Journal of Respiratory Cell and Molecular Biology, 67:528-538, Nov 2022. URL: https://doi.org/10.1165/rcmb.2021-0326oc, doi:10.1165/rcmb.2021-0326oc. This article has 10 citations and is from a peer-reviewed journal.

  8. (szenkerravi2018rspo2inhibitionof pages 17-17): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  9. (szenkerravi2018rspo2inhibitionof pages 11-17): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  10. (szenkerravi2018rspo2inhibitionof pages 8-11): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  11. (szenkerravi2018rspo2inhibitionof pages 2-3): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  12. (szenkerravi2018rspo2inhibitionof pages 5-6): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  13. (szenkerravi2018rspo2inhibitionof pages 3-4): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  14. (szenkerravi2018rspo2inhibitionof pages 6-7): Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B. de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaminck, Shalini S. Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, and Bruno Reversade. Rspo2 inhibition of rnf43 and znrf3 governs limb development independently of lgr4/5/6. Nature, 557:564-569, May 2018. URL: https://doi.org/10.1038/s41586-018-0118-y, doi:10.1038/s41586-018-0118-y. This article has 212 citations and is from a highest quality peer-reviewed journal.

  15. (chevallier2025therspo2gene pages 10-12): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  16. (chevallier2025therspo2gene pages 1-2): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  17. (chevallier2025therspo2gene pages 14-15): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  18. (becker2020a50kbdeletion pages 9-11): Doreen Becker, Rosemarie Weikard, Christoph Schulze, Peter Wohlsein, and Christa Kühn. A 50-kb deletion disrupting the rspo2 gene is associated with tetradysmelia in holstein friesian cattle. Genetics, Selection, Evolution : GSE, Nov 2020. URL: https://doi.org/10.1186/s12711-020-00586-y, doi:10.1186/s12711-020-00586-y. This article has 15 citations.

  19. (becker2020a50kbdeletion pages 1-2): Doreen Becker, Rosemarie Weikard, Christoph Schulze, Peter Wohlsein, and Christa Kühn. A 50-kb deletion disrupting the rspo2 gene is associated with tetradysmelia in holstein friesian cattle. Genetics, Selection, Evolution : GSE, Nov 2020. URL: https://doi.org/10.1186/s12711-020-00586-y, doi:10.1186/s12711-020-00586-y. This article has 15 citations.

  20. (becker2020a50kbdeletion pages 4-5): Doreen Becker, Rosemarie Weikard, Christoph Schulze, Peter Wohlsein, and Christa Kühn. A 50-kb deletion disrupting the rspo2 gene is associated with tetradysmelia in holstein friesian cattle. Genetics, Selection, Evolution : GSE, Nov 2020. URL: https://doi.org/10.1186/s12711-020-00586-y, doi:10.1186/s12711-020-00586-y. This article has 15 citations.

  21. (chevallier2025therspo2gene pages 12-13): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  22. (chevallier2025therspo2gene media 4b7e9d18): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  23. (chevallier2025therspo2gene pages 13-14): Lucie Chevallier, Marin Green, Julia Vo, Karen Vernau, Denis J. Marcellin-Little, Vidhya Jagannathan, Tosso Leeb, and Danika Bannasch. The rspo2 gene is associated with bilateral anterior amelia in chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society, Mar 2025. URL: https://doi.org/10.1007/s00335-025-10123-1, doi:10.1007/s00335-025-10123-1. This article has 3 citations.

  24. (behunova2025facialbonedefects pages 1-2): Jana Behunova, Helga Rehder, Anton Dobsak, Susanne G. Kircher, Lucas L. Boer, Andreas A. Mueller, Janina M. Patsch, Eduard Winter, Roelof-Jan Oostra, Eva Piehslinger, and Karoline M. Reich. Facial bone defects associated with lateral facial clefts tessier type 6, 7 and 8 in syndromic neurocristopathies: a detailed micro-ct analysis on historical museum specimens. Biology, 14:872, Jul 2025. URL: https://doi.org/10.3390/biology14070872, doi:10.3390/biology14070872. This article has 1 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 3
Resolved 3
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0060732 (2 mentions) - the report calls it "if available"; MONDO calls it tetraamelia syndrome 2