Autosomal Dominant Robinow Syndrome 1

Mendelian MONDO:0024455 Pathograph 43 Show in embeddings browser Robinow Syndrome Skeletal Dysplasia

WNT5A-related autosomal dominant Robinow syndrome is a congenital skeletal and craniofacial developmental disorder caused by heterozygous missense or selected in-frame WNT5A variants. Characteristic findings include mesomelic limb shortening, short stature, brachydactyly, widely spaced eyes and genital hypoplasia. This entry covers the WNT5A form; other genes can produce overlapping Robinow phenotypes. Altered WNT5A signaling disrupts coordinated tissue morphogenesis, but a universal reduction in pathway activity is not established. Founding zebrafish and Xenopus assays supported partial loss of function. Later C83S chicken-limb experiments showed disordered chondrocyte polarity and delayed hypertrophy, while cellular signaling depended on receptor and assay context. A mouse C83S preprint reports a distinct spatial phenotype and no inhibition of wild-type signaling in its cell assays, with important founder-mosaicism limitations. These results support abnormal signaling and morphogenesis without settling hypomorphic, dominant-interference or neomorphic mechanisms in humans. The abnormalities arise during development; subsequent growth, scoliosis and dental complications still require follow-up. Management addresses manifestations and associated abnormalities. No molecular correction of the WNT5A defect is established in the cited clinical sources.

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1
Inheritance
8
Pathophys.
36
Phenotypes
1
Gaps
43
Pathograph
1
Genes
6
Medical Actions
7
Differentials
14
References
1
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant transmission, with inherited and de novo cases and variable expressivity. Each child of a heterozygous affected individual has a 50% chance of inheriting the variant; severity is not predicted reliably. The fraction of de novo cases is unknown. Parental examination and testing can identify mild disease or mosaicism; blood-negative parents do not exclude germline mosaicism.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Each child of an individual with ADRS has a 50% chance of inheriting the pathogenic variant; however, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing."
The GeneReviews Genetic Counseling statement, giving both the recurrence risk and the limit on genotype-based prognosis.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"The proportion of cases caused by a de novo pathogenic variant is unknown."
Do not substitute the research report's unsupported 50% de novo estimate.
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Discussions and Knowledge Gaps

1
How do heterozygous WNT5A variants cause dominant disease despite context-dependent activity and retained wild-type signaling?
KNOWLEDGE GAP OPEN wnt5a_dominant_mechanism
Attached to
pathophysiology#Altered WNT5A receptor signaling
Founding embryo assays support hypomorphism, chicken C83S studies support dominant interference with chondrogenesis, and the mouse/cell preprint proposes a distinct non-loss-of-function phenotype without measured wild-type inhibition. The readouts, expression systems and embryonic tissues differ; no universal functional category is assigned.
Show evidence (1 reference)
PMID:41510274 SUPPORT PRIMARY RESULT In Vitro
"Across all four models, induction of C83S expression did not reduce the signaling output from wild-type WNT5A, whether supplied as recombinant protein, co-expressed in the same cells, presented on neighboring cells, or provided by co-cultured donor cells."
Preprint cell-based tests constrain dominant-negative models in those assay contexts; they do not rule out human tissue-specific effects.
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Pathophysiology

8
Heterozygous WNT5A coding alteration
Selected missense substitutions and in-frame variants alter the secreted WNT5A ligand. Many change conserved cysteines. Both inherited and de novo variants occur, including a reported mosaic in-frame duplication; a null allele is not assumed to produce the same dominant disorder.
WNT5A hgnc:12784 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WNT5A (hgnc:12784). hgnc:12784 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context WNT5A hgnc:12784 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns WNT5A (hgnc:12784). hgnc:12784 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
The dominant functional mechanism is unresolved and varies by experimental context. Founding variants retain activity, C83S affects protein abundance and signaling in cell assays, and model systems support competing interpretations.
Downstream
Altered WNT5A receptor signaling Variant ligand changes signaling output; direction depends on receptor, tissue and assay context.
Reduced C83S protein abundance and secretion Demonstrated for the C83S construct; not generalized to every WNT5A variant.
Show evidence (2 references)
PMID:19918918 SUPPORT Human Clinical
"we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome"
The gene-disease assignment and the variant class, from the discovery study.
PMID:19918918 SUPPORT Human Clinical
"One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient."
Segregation in the originally described pedigree, which is the strongest single piece of evidence tying WNT5A to this entity.
Reduced C83S protein abundance and secretion
Mechanism confidence: Provisional
C83S-expressing chicken fibroblasts contain less intracellular and secreted WNT5A. The 2019 experiments did not show preferential degradation of mutant protein; an unfolded-protein response was proposed but not directly demonstrated. Reduced abundance alone does not explain the dominant developmental phenotype. The 2025 preprint also reports impaired C83S secretion without suppression of wild-type WNT5A secretion.
Downstream
Altered WNT5A receptor signaling Altered ligand availability can affect signaling context, but it is not established as the sufficient disease mechanism.
Show evidence (1 reference)
PMID:31032853 SUPPORT PRIMARY RESULT In Vitro
"Unexpectedly, the C83S change caused a reduction in the amount of protein being synthesized and secreted, compared to wtWNT5A."
Stable RCAS-infected DF1 chicken fibroblasts and protein assays; secretion and synthesis are not inferred from the human genotype alone.
Altered WNT5A receptor signaling
Mechanism confidence: Provisional
WNT5A signals through receptor complexes including ROR2 and Frizzled to Dishevelled and noncanonical pathways. Founding embryonic assays showed reduced activity, whereas C83S cell assays retained JNK-PCP activation and showed receptor-dependent changes in canonical antagonism. Neither a universal decrease in every branch nor a universal gain is established.
non-canonical Wnt signaling pathway GO:0035567 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal non-canonical Wnt signaling pathway (GO:0035567). GO:0035567 is a biological process from the Gene Ontology. Wnt signaling pathway, planar cell polarity pathway GO:0060071 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Wnt signaling pathway, planar cell polarity pathway (GO:0060071). GO:0060071 is a biological process from the Gene Ontology.
Downstream
Disordered chondrocyte planar orientation Altered WNT signaling is linked to disordered orientation in experimental cartilage; the precise human intermediate and direction of activity remain unresolved.
Craniofacial morphogenetic disruption WNT5A-associated developmental disease affects this tissue, but the variant-specific causal intermediates are incompletely characterized.
Genital morphogenetic disruption WNT5A-associated developmental disease affects this tissue, but the variant-specific causal intermediates are incompletely characterized.
Delayed chondrocyte hypertrophy C83S affects cartilage maturation; the signaling intermediates responsible are unresolved.
Show evidence (2 references)
PMID:19918918 SUPPORT Model Organism
"These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development."
The functional demonstration that the variants reduce signalling. Typed MODEL_ORGANISM because the assays are in zebrafish and Xenopus embryos.
PMID:31032853 SUPPORT PRIMARY RESULT In Vitro
"Biochemical assays revealed that C83S variant was able to activate the Jun N-terminal kinase-PCP pathway similar to wtWNT5A; however, the activity of the variant ligand was influenced by receptor availability."
Primary limb-mesenchyme and HEK293 reporter assays; this does not measure signaling in patient growth plates.
Disordered chondrocyte planar orientation
Mechanism confidence: Provisional
C83S misexpression in chicken limbs disrupts Golgi-based chondrocyte orientation and Prickle localization before marked cartilage dysmorphology. This is experimental developmental cartilage, not a patient biopsy. A 2025 preprint reports spatially uniform chondrocyte misalignment in CRISPR-edited mouse embryos; its F0-only design cannot exclude mosaic or biallelic editing. Local misalignment is a morphological readout, not direct measurement of pathway activation.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
cartilage tissue UBERON:0002418 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cartilage tissue (UBERON:0002418). UBERON:0002418 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Disordered Growth Plate and Skeletal Patterning Loss of coordinated cell orientation is proposed to impair cartilage elongation; the specifically mesomelic distribution in patients is not directly explained by the model.
Show evidence (2 references)
PMID:31032853 SUPPORT PRIMARY RESULT Model Organism
"Instead of stereotypical stacking of chondrocytes, the WNT5AC83S-infected cartilage was composed of randomly oriented chondrocytes and that had diffuse, rather than concentrated Prickle staining, both signs of disrupted planar cell polarity (PCP) mechanisms."
RCAS misexpression in embryonic chicken limb; measured Golgi orientation and qualitative Prickle staining support polarity disruption.
PMID:41510274 SUPPORT PRIMARY RESULT Model Organism
"Although we selected embryos with approximately 50% correct template-mediated repair based on next-generation sequencing, we cannot exclude that some cells carry edits on both alleles."
Preprint limitation: initial CRISPR-edited embryos were used because cleft-palate lethality prevented breeding; uniform heterozygosity was not demonstrated.
Delayed chondrocyte hypertrophy
Mechanism confidence: Provisional
In C83S-infected chicken limbs, COL10A1 expression and hypertrophic enlargement are delayed. This accompanies impaired cartilage elongation; no equivalent patient-tissue measurement is available.
hypertrophic chondrocyte CL:0000743 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hypertrophic chondrocyte (CL:0000743). CL:0000743 is a cell type from the Cell Ontology.
Downstream
Disordered Growth Plate and Skeletal Patterning Reduced hypertrophic enlargement and delayed ossification contribute to shortened skeletal elements in the chicken model.
Show evidence (2 references)
PMID:31032853 SUPPORT PRIMARY RESULT Model Organism
"The C83S mutation also dominantly interferes with the expansion of chondrocytes as shown by the lack of lacunae in Alcian blue stained sections."
Chicken limb histology and COL10A1 staining support delayed maturation; this is distinct from cell orientation.
PMID:31032853 SUPPORT PRIMARY RESULT Model Organism
"the mutant protein prevented COL10A1 expression in all embryos."
The authors describe absent COL10A1 at the assessed stage, with later bone formation possible. This supports delayed hypertrophy rather than a permanently absent lineage.
Disordered Growth Plate and Skeletal Patterning
Abnormal cartilage elongation and skeletal patterning underlie the shortened limb phenotype. Chicken C83S experiments demonstrate shortened, widened cartilage and delayed ossification. The contribution of orientation versus hypertrophy and the human mesomelic distribution remain incompletely resolved.
cartilage tissue UBERON:0002418 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cartilage tissue (UBERON:0002418). UBERON:0002418 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Mesomelic Limb Shortening The developmental skeletal phenotype is consistent with abnormal growth and patterning, but the variant-specific intermediate is incompletely defined.
Short Stature The developmental skeletal phenotype is consistent with abnormal growth and patterning, but the variant-specific intermediate is incompletely defined.
Brachydactyly The developmental skeletal phenotype is consistent with abnormal growth and patterning, but the variant-specific intermediate is incompletely defined.
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"
The GeneReviews Clinical Characteristics description of the skeletal phenotype, including the upper-limb predominance of the mesomelic shortening.
PMID:31032853 SUPPORT PRIMARY RESULT Model Organism
"Strikingly, WNT5AC83S consistently caused a delay in ossification and bones were more than 50% shorter and 200% wider than controls."
Experimental chicken limb dimensions, not patient effect sizes or penetrance.
Craniofacial morphogenetic disruption
Developmental abnormalities of craniofacial structures produce the characteristic face and oral/dental findings. Tissue-specific intermediates for WNT5A patient variants remain incompletely resolved.
Downstream
Hypertelorism Craniofacial developmental association; no specific WNT5A-dependent intermediate is established for this feature.
Bifid Tongue Craniofacial developmental association; no specific WNT5A-dependent intermediate is established for this feature.
Hypodontia Craniofacial developmental association; no specific WNT5A-dependent intermediate is established for this feature.
Frontal bossing Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Anteverted nares Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Midface retrusion Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Dental malocclusion Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Dental crowding Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Delayed eruption of permanent teeth Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Gingival overgrowth Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
Wide nasal bridge Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
Depressed nasal bridge Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
Prominent eyes Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
Short nose Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
High anterior hairline Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
Broad nasal tip Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
Long philtrum Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
Low-set ears Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
Wide retromolar ridge Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
Alveolar ridge deformation Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
Cleft lip Reported craniofacial developmental association; no specific WNT5A-dependent fusion intermediate is established.
Cleft palate Reported craniofacial developmental association; no specific WNT5A-dependent fusion intermediate is established.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"
The GeneReviews description of the craniofacial phenotype.
Genital morphogenetic disruption
Abnormal external genital development causes hypoplasia in both sexes. Micropenis must be distinguished clinically from a normally sized but webbed or embedded penis; the latter is an anatomical insertion abnormality.
Downstream
Micropenis External genital developmental association; the precise tissue intermediate remains unresolved.
Clitoral Hypoplasia External genital developmental association; the precise tissue intermediate remains unresolved.
Hypoplastic Labia Majora External genital developmental association; the precise tissue intermediate remains unresolved.
Small scrotum Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
Cryptorchidism Associated genital developmental outcome; the pathway to impaired testicular descent is unresolved.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora)"
The GeneReviews description of the genital phenotype in both sexes.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Robinow Syndrome 1 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

36
Cardiovascular 1
Congenital Heart Defect Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"When present, cardiac defects are a major cause of morbidity and mortality."
Establishes both the conditional nature and the clinical weight of the cardiac phenotype. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Ear 1
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears"
GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected individuals.
Eye 1
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"
Describes the widely spaced prominent eyes this record captures. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Genitourinary 5
Micropenis HP:0000054 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micropenis (HP:0000054). HP:0000054 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism"
Names micropenis among the male genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism"
Names cryptorchidism among the male genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Hypoplastic Labia Majora HP:0000059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic labia majora (HP:0000059). HP:0000059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"in females: hypoplastic clitoris and labia majora"
Names hypoplastic labia majora among the female genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Clitoral Hypoplasia HP:0000060 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clitoral hypoplasia (HP:0000060). HP:0000060 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"in females: hypoplastic clitoris and labia majora"
Names clitoral hypoplasia among the female genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Small scrotum HP:0000046 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small scrotum (HP:0000046). HP:0000046 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Head and Neck 19
Bifid Tongue HP:0010297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid tongue (HP:0010297). HP:0010297 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally"
Places the bilobed tongue within the oral and dental findings of the GeneReviews clinical description, alongside the dental abnormalities that share a craniofacial developmental origin. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"The prevalence of bifid tongue is 38% (N = 3 out of 8) in our cohort of individuals with pathogenic WNT5A variation, comparable with other genotypes."
Small selected retrospective series with missing phenotype information; not a general-population penetrance estimate.
Hypodontia HP:0000668 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypodontia (HP:0000668). HP:0000668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)"
The GeneReviews dental findings, which name hypodontia among them. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"occasional prenatal macrocephaly that persists postnatally"
GeneReviews qualifies macrocephaly as occasional, which is the basis for the frequency here. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Frontal bossing HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Anteverted nares HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Dental malocclusion HP:0000689 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental malocclusion (HP:0000689). HP:0000689 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Dental crowding HP:0000678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental crowding (HP:0000678). HP:0000678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Delayed eruption of permanent teeth HP:0000696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed eruption of permanent teeth (HP:0000696). HP:0000696 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)"
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Gingival overgrowth HP:0000212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival overgrowth (HP:0000212). HP:0000212 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were observed in more than 60% of individuals in each genotype."
The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were observed in more than 60% of individuals in each genotype."
The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.
Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were observed in more than 60% of individuals in each genotype."
The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.
Short nose HP:0003196 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short nose (HP:0003196). HP:0003196 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"Notably, the prevalence of short nose is greater than 90% in other genotypes, but only 50% in NXN individuals (N = 2 out of 4)."
The other genotype groups include WNT5A. This is a selected retrospective dataset, not a general-population penetrance estimate.
High anterior hairline HP:0009890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High anterior hairline (HP:0009890). HP:0009890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears"
GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected individuals.
Broad nasal tip HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears"
GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected individuals.
Long philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears"
GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected individuals.
Alveolar ridge deformation Abnormal alveolar ridge morphology HP:0006477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alveolar ridge deformation, annotated with Abnormal alveolar ridge morphology (HP:0006477). HP:0006477 is a phenotype from the Human Phenotype Ontology.
GeneReviews does not specify the type of deformation; the morphology term intentionally does not assert overgrowth, atrophy or clefting.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue"
GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected individuals.
Cleft lip HP:0410030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip (HP:0410030). HP:0410030 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."
Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as evidence that a human cleft is present.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."
Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as evidence that a human cleft is present.
Limbs 4
Mesomelic Limb Shortening Mesomelia HP:0003027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mesomelia (HP:0003027). HP:0003027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"mesomelic limb shortening predominantly of the upper limbs"
States both the mesomelic pattern and its upper-limb predominance. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Dislocated Radial Head HP:0003083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dislocated radial head (HP:0003083). HP:0003083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."
Names radial head dislocation among the less common findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"
GeneReviews names brachydactyly as one of the three core skeletal findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Broad hallux HP:0010055 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad hallux (HP:0010055). HP:0010055 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were observed in more than 60% of individuals in each genotype."
The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.
Musculoskeletal 2
Hemivertebrae HP:0002937 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemivertebrae (HP:0002937). HP:0002937 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."
Names hemivertebrae among the vertebral abnormalities. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."
Names scoliosis among the vertebral abnormalities. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"
Lists short stature among the defining skeletal findings. This chapter covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Short stature is almost always present at birth and sometimes identified prenatally"
Chapter clinical natural history; the earliest ultrasound detection is not a universal screening sensitivity.
Other 2
Prominent eyes
Needs a precise term: OLS HPO searches for prominent eyes returned proptosis, whose definition requires anterior globe displacement. The cohort description does not establish that anatomy, so no proptosis binding is inferred.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were observed in more than 60% of individuals in each genotype."
The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.
Wide retromolar ridge
Needs a precise term: OLS HPO searches for wide retromolar ridge and retromolar returned no matching term. Broad alveolar ridge describes a different anatomical ridge and was not substituted.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue"
GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected individuals.
🧬

Genetic Associations

1
WNT5A
Gene: WNT5A hgnc:12784 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WNT5A (hgnc:12784). hgnc:12784 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:19918918 SUPPORT Human Clinical
"we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome"
The gene-disease assignment and the variant class.
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular genetic testing"
Cross-gene GeneReviews diagnostic statement; the WNT5A component applies here. The chapter-era gene list is not a complete current differential.
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"The majority of WNT5A variants involve substitution or creation of a cysteine residue."
Primary variant compilation; the paper also includes a biallelic frameshift and a Cys154Phe family classified as VUS in its table, so not every compiled variant is promoted to an established dominant cause.
+ 2 more references
💊

Medical Actions

6
Corrective Surgery for Genital and Orofacial Anomalies
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical correction of cryptorchidism, abnormal penile insertion or penoscrotal position, and cleft lip or palate where present addresses established anatomical abnormalities.
Mechanism Target:
Cryptorchidism — Corrective surgery addresses anatomical manifestations; it does not reverse the prenatal signaling defect.
Craniofacial morphogenetic disruption — Corrective surgery addresses anatomical manifestations; it does not reverse the prenatal signaling defect.
Genital morphogenetic disruption — Corrective surgery addresses anatomical manifestations; it does not reverse the prenatal signaling defect.
Cleft lip — Repairs an existing anatomical cleft where present.
Cleft palate — Repairs an existing anatomical cleft where present.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Corrective surgeries as needed for cryptorchidism, abnormal penile insertion / penoscrotal position, and cleft lip/palate."
The GeneReviews Management recommendation for the surgical manifestations.
Structured Multisystem Surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Measure head circumference through infancy and childhood. Assess development every three months in infancy and every six to twelve months thereafter. Arrange dental review every six to twelve months, periodic hearing assessment in childhood, and specialist cardiac or renal monitoring if abnormalities are identified. These are GeneReviews recommendations across dominant Robinow genotypes.
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Measurement of head circumference regularly in infancy and throughout childhood. Developmental assessment every three months in infancy and every six months to one year thereafter"
The GeneReviews Surveillance schedule, quoted for the elements it specifies by interval.
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Dental evaluation every six to 12 months or as recommended. Periodic hearing assessments in childhood. Regular cardiac and renal assessment as needed by respective specialists if abnormalities are identified."
GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
Orthodontic Treatment
Action: orthodontic treatmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthodontic treatment (NCIT:C64248). NCIT:C64248 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthodontic Treatment NCIT:C64248
Platform: Device
Orthodontic management is typically required, reflecting the dental crowding, malocclusion, hypodontia and delayed eruption that accompany the craniofacial phenotype.
Mechanism Target:
Craniofacial morphogenetic disruption — Addresses the dental consequences of abnormal craniofacial development.
Show evidence (1 reference)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Orthodontic treatment is typically required."
The GeneReviews Management statement on orthodontic need.
Growth Hormone Therapy (selected patients)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: somatropin NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Consider growth hormone replacement when endocrine evaluation demonstrates deficiency. A small 1999 clinical series reported increased growth velocity in treated patients, but their molecular subtypes were uncharacterized. This supports selected treatment of coexisting deficiency without establishing efficacy in WNT5A-confirmed disease or correction of its developmental mechanism.
Mechanism Target:
Disordered Growth Plate and Skeletal Patterning — Acts on growth-plate output through an independent endocrine axis; it does not restore planar cell polarity.
Show evidence (2 references)
PMID:10417975 SUPPORT INDIRECT Human Clinical
"Recombinant human GH therapy in our patient and the three patients from the NCGS resulted in a significant increase in the growth rate per year."
Clinical growth-rate response in patients of unknown genotype; transfer to WNT5A-related disease is indirect.
PMID:10417975 SUPPORT INDIRECT Human Clinical
"We propose its association with GH deficiency and that treatment with rhGH can result in a significant increase in the growth rate of these children."
The authors propose the association from a small series; neither the prevalence of GH deficiency nor routine treatment efficacy is established.
Hormone Therapy for Micropenis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: human chorionic gonadotropin CHEBI:81570 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses human chorionic gonadotropin, annotated with Chorionic gonadotropin (CHEBI:81570). CHEBI:81570 is a therapeutic agent from Chemical Entities of Biological Interest. testosterone CHEBI:17347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses testosterone (CHEBI:17347). CHEBI:17347 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
Hormone therapy in affected males with micropenis, listed by GeneReviews among the treatments of manifestations. Like the surgical entries, it addresses an established morphogenetic outcome rather than the pathway that produced it. Refer for endocrine assessment; GeneReviews reports hCG and testosterone experience in three boys, without establishing WNT5A-specific efficacy.
Mechanism Target:
Genital morphogenetic disruption — Acts on the genital phenotype; it does not restore planar cell polarity.
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"Hormone therapy may be helpful for males with micropenis."
The GeneReviews Management statement. Note its hedge - "may be helpful" - which is why this is recorded without any efficacy claim.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Injection of human chorionic gonadotropin and testosterone improved penile length and testicular volume in three boys with severe micropenis"
Small historical treatment experience summarized by GeneReviews; molecular subtype and general efficacy are not established.
Genetic and reproductive counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Offer family-specific counseling, examination/testing of parents and at-risk relatives, and discussion of prenatal or preimplantation testing once the familial variant is known. A molecular result cannot predict severity. If the variant is absent from both parents' blood, sibling recurrence remains low but nonzero because germline mosaicism cannot be excluded; GeneReviews quotes less than 1% for this circumstance across ADRS.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Once the DVL1, DVL3, or WNT5A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
Family-specific reproductive testing and counseling, not prevention of the developmental mechanism.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism."
Applies after a proband variant is undetectable in both parents' leukocyte DNA; not a measured WNT5A-specific recurrence rate.
🔬

Diagnosis

2
Molecular Genetic Testing
Clinical recognition of Robinow syndrome should be followed by molecular testing that distinguishes WNT5A-related disease from overlapping forms. A heterozygous pathogenic or likely pathogenic WNT5A variant supports this specific diagnosis; a VUS neither establishes nor excludes it. A multigene skeletal-dysplasia/Robinow panel or exome/genome analysis can assess WNT5A, DVL1/DVL3, FZD2 and recessive ROR2/NXN disease, with gene content updated by the laboratory. Ensure adequate coverage and small-indel detection; a negative result does not settle a different molecular etiology.
Show evidence (2 references)
PMID:25577943 SUPPORT REVIEW SYNTHESIS Other
"The diagnosis of autosomal dominant Robinow syndrome is established in a proband with typical suggestive findings and/or by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular genetic testing."
The GeneReviews Diagnosis/Testing criterion in full.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Identification of a heterozygous DVL1, DVL3, or WNT5A variant of uncertain significance does not establish or rule out the diagnosis."
Variant uncertainty must remain distinct from molecular confirmation.
Baseline organ and skeletal evaluation
Assess skeletal extent with radiographs of limbs, chest, vertebrae and skull. Obtain echocardiography, renal ultrasound and hearing assessment; consider pelvic ultrasound for females and urologic/endocrine evaluation for genital abnormalities. Assess dental/craniofacial findings and development. These are cross-genotype baseline recommendations, not assertions that every feature is frequent in WNT5A disease.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Renal ultrasound To assess for renal anomalies & hydronephrosis"
GeneReviews baseline evaluation table; the small 2022 WNT5A subgroup had no renal anomalies among six assessed, which does not eliminate the rationale for baseline screening.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Cardiovascular Echocardiogram To evaluate for congenital heart defect"
Baseline echocardiography differs from subsequent specialist monitoring only when abnormalities are found.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other
"Radiographs of limbs, chest, vertebrae, & skull To establish the extent of skeletal involvement"
Baseline skeletal characterization can detect vertebral complications without asserting they arise directly from a growth-plate lesion.
📊

Prevalence

1
Worldwide
Cases In Literature
No population prevalence is established for the WNT5A form specifically. Robinow syndrome as a whole had over 100 reported patients across dominant and recessive forms at the time of the WNT5A discovery; the WNT5A subset is a small fraction of that. The historical literature count is not a population prevalence or a current WNT5A-specific case count.
Show evidence (1 reference)
PMID:19918918 SUPPORT BACKGROUND Other
"Over 100 patients with Robinow syndrome have since been identified in families with both autosomal dominant and autosomal recessive inheritance patterns"
Historical background count across Robinow genes and inheritance modes; it does not estimate WNT5A-specific prevalence.
🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Robinow Syndrome 1:

Omodysplasia MONDO:0017136
Overlapping Features FZD2-related omodysplasia/Robinow-spectrum disease overlaps substantially with WNT5A-related disease. Predominantly humeral shortening, a short first metacarpal and elbow restriction can be informative, but height and facial appearance do not reliably exclude either diagnosis. The 2018 discovery cohort and 2022 phenotypic analysis support a shared spectrum; molecular testing is decisive.
Distinguishing Features
  • Predominantly humeral shortening rather than generalized mesomelic shortening
  • Short first metacarpal
  • Elbow restriction from hypoplastic, dislocated proximal radii
  • Heterozygous FZD2 variants; clinical overlap with the Robinow spectrum requires molecular differentiation
Show evidence (5 references)
PMID:29383834 SUPPORT Human Clinical
"skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies"
Predominantly humeral shortening can inform the differential but is not an absolute clinical separator.
PMID:29383834 SUPPORT Human Clinical
"He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism"
The molecularly confirmed FZD2 proband had short stature, not preserved stature. This is why the description states the distinction as a pattern-of-shortening contrast against the WNT5A form rather than as a height difference.
PMID:29383834 SUPPORT Human Clinical
"thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals"
Sources the elbow-restriction and short-first-metacarpal distinguishing features.
+ 2 more references
Biallelic WNT5A loss-of-function disease
Overlapping Features A severe allelic presentation with recessive inheritance has been described in an infant with a homozygous frameshift, diaphragmatic hernia, genital ambiguity, adactyly and a ventricular septal defect. It is distinct from the selected heterozygous coding changes underlying dominant DRS1.
Show evidence (1 reference)
PMID:29575631 SUPPORT PRIMARY RESULT Human Clinical
"we identified a homozygous frameshifting single nucleotide deletion in WNT5A in a previously reported, deceased infant"
Single-family report establishes the distinct allelic context; it is not a dominant DRS1 subtype.
Aarskog-Scott syndrome
Overlapping Features FGD1-related Aarskog-Scott syndrome can resemble Robinow syndrome in facial, limb and genital findings. Its X-linked inheritance and molecular cause distinguish it; it is a relevant alternative after negative Robinow-gene testing.
Show evidence (1 reference)
PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical
"pathogenic variants in FGD1 are the most frequent molecular diagnostic finding in clinically diagnosed RS with otherwise negative testing"
Selected cohort finding supports including FGD1 in the molecular differential; it does not estimate prevalence in all referrals.
{ }

Source YAML

click to show 
name: Autosomal Dominant Robinow Syndrome 1
creation_date: '2026-08-26T21:00:00Z'
category: Mendelian
disease_term:
  preferred_term: autosomal dominant Robinow syndrome 1
  term:
    id: MONDO:0024455
    label: autosomal dominant Robinow syndrome 1
synonyms:
- DRS1
- WNT5A-related Robinow syndrome
- fetal face syndrome
description: >-
  WNT5A-related autosomal dominant Robinow syndrome is a congenital skeletal and craniofacial developmental
  disorder caused by heterozygous missense or selected in-frame WNT5A variants. Characteristic findings include
  mesomelic limb shortening, short stature, brachydactyly, widely spaced eyes and genital hypoplasia. This
  entry covers the WNT5A form; other genes can produce overlapping Robinow phenotypes.

  Altered WNT5A signaling disrupts coordinated tissue morphogenesis, but a universal reduction in pathway activity
  is not established. Founding zebrafish and Xenopus assays supported partial loss of function. Later C83S
  chicken-limb experiments showed disordered chondrocyte polarity and delayed hypertrophy, while cellular signaling
  depended on receptor and assay context. A mouse C83S preprint reports a distinct spatial phenotype and no
  inhibition of wild-type signaling in its cell assays, with important founder-mosaicism limitations. These
  results support abnormal signaling and morphogenesis without settling hypomorphic, dominant-interference
  or neomorphic mechanisms in humans.

  The abnormalities arise during development; subsequent growth, scoliosis and dental complications still require
  follow-up. Management addresses manifestations and associated abnormalities. No molecular correction of the
  WNT5A defect is established in the cited clinical sources.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population prevalence is established for the WNT5A form specifically. Robinow syndrome as a whole had
    over 100 reported patients across dominant and recessive forms at the time of the WNT5A discovery; the
    WNT5A subset is a small fraction of that. The historical literature count is not a population prevalence
    or a current WNT5A-specific case count.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Over 100 patients with Robinow syndrome have since been identified in families with both autosomal dominant
      and autosomal recessive inheritance patterns
    explanation: >-
      Historical background count across Robinow genes and inheritance modes; it does not estimate WNT5A-specific
      prevalence.
    quote_role: BACKGROUND
pathophysiology:
- name: Heterozygous WNT5A coding alteration
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: WNT5A
    term:
      id: hgnc:12784
      label: WNT5A
  description: >-
    Selected missense substitutions and in-frame variants alter the secreted WNT5A ligand. Many change conserved
    cysteines. Both inherited and de novo variants occur, including a reported mosaic in-frame duplication;
    a null allele is not assumed to produce the same dominant disorder.
  genetic_context:
    gene:
      preferred_term: WNT5A
      term:
        id: hgnc:12784
        label: WNT5A
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      The dominant functional mechanism is unresolved and varies by experimental context. Founding variants
      retain activity, C83S affects protein abundance and signaling in cell assays, and model systems support
      competing interpretations.
  downstream:
  - target: Altered WNT5A receptor signaling
    causal_link_type: DIRECT
    description: Variant ligand changes signaling output; direction depends on receptor, tissue and assay context.
  - target: Reduced C83S protein abundance and secretion
    causal_link_type: DIRECT
    description: Demonstrated for the C83S construct; not generalized to every WNT5A variant.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly
      conserved cysteines, are associated with autosomal dominant Robinow syndrome
    explanation: The gene-disease assignment and the variant class, from the discovery study.
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One mutation has been found in all living affected members of the original family described by Meinhard
      Robinow and another in a second unrelated patient.
    explanation: >-
      Segregation in the originally described pedigree, which is the strongest single piece of evidence tying
      WNT5A to this entity.
- name: Reduced C83S protein abundance and secretion
  description: >-
    C83S-expressing chicken fibroblasts contain less intracellular and secreted WNT5A. The 2019 experiments
    did not show preferential degradation of mutant protein; an unfolded-protein response was proposed but
    not directly demonstrated. Reduced abundance alone does not explain the dominant developmental phenotype.
    The 2025 preprint also reports impaired C83S secretion without suppression of wild-type WNT5A secretion.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:31032853
    reference_title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Unexpectedly, the C83S change caused a reduction in the amount of protein being synthesized and secreted,
      compared to wtWNT5A.
    explanation: >-
      Stable RCAS-infected DF1 chicken fibroblasts and protein assays; secretion and synthesis are not inferred
      from the human genotype alone.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Altered WNT5A receptor signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered ligand availability can affect signaling context, but it is not established as the sufficient
      disease mechanism.
- name: Altered WNT5A receptor signaling
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    WNT5A signals through receptor complexes including ROR2 and Frizzled to Dishevelled and noncanonical pathways.
    Founding embryonic assays showed reduced activity, whereas C83S cell assays retained JNK-PCP activation
    and showed receptor-dependent changes in canonical antagonism. Neither a universal decrease in every branch
    nor a universal gain is established.
  biological_processes:
  - preferred_term: non-canonical Wnt signaling pathway
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
    modifier: ABNORMAL
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
    modifier: ABNORMAL
  downstream:
  - target: Disordered chondrocyte planar orientation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered WNT signaling is linked to disordered orientation in experimental cartilage; the precise human
      intermediate and direction of activity remain unresolved.
  - target: Craniofacial morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      WNT5A-associated developmental disease affects this tissue, but the variant-specific causal intermediates
      are incompletely characterized.
  - target: Genital morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      WNT5A-associated developmental disease affects this tissue, but the variant-specific causal intermediates
      are incompletely characterized.
  - target: Delayed chondrocyte hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: C83S affects cartilage maturation; the signaling intermediates responsible are unresolved.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus
      development.
    explanation: >-
      The functional demonstration that the variants reduce signalling. Typed MODEL_ORGANISM because the assays
      are in zebrafish and Xenopus embryos.
  - reference: PMID:31032853
    reference_title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biochemical assays revealed that C83S variant was able to activate the Jun N-terminal kinase-PCP pathway
      similar to wtWNT5A; however, the activity of the variant ligand was influenced by receptor availability.
    explanation: >-
      Primary limb-mesenchyme and HEK293 reporter assays; this does not measure signaling in patient growth
      plates.
    quote_role: PRIMARY_RESULT
  mechanism_confidence: PROVISIONAL
- name: Disordered chondrocyte planar orientation
  role: central_effector
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    C83S misexpression in chicken limbs disrupts Golgi-based chondrocyte orientation and Prickle localization
    before marked cartilage dysmorphology. This is experimental developmental cartilage, not a patient biopsy.
    A 2025 preprint reports spatially uniform chondrocyte misalignment in CRISPR-edited mouse embryos; its
    F0-only design cannot exclude mosaic or biallelic editing. Local misalignment is a morphological readout,
    not direct measurement of pathway activation.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  locations:
  - preferred_term: cartilage tissue
    term:
      id: UBERON:0002418
      label: cartilage tissue
  downstream:
  - target: Disordered Growth Plate and Skeletal Patterning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of coordinated cell orientation is proposed to impair cartilage elongation; the specifically mesomelic
      distribution in patients is not directly explained by the model.
  evidence:
  - reference: PMID:31032853
    reference_title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Instead of stereotypical stacking of chondrocytes, the WNT5AC83S-infected cartilage was composed of randomly
      oriented chondrocytes and that had diffuse, rather than concentrated Prickle staining, both signs of
      disrupted planar cell polarity (PCP) mechanisms.
    explanation: >-
      RCAS misexpression in embryonic chicken limb; measured Golgi orientation and qualitative Prickle staining
      support polarity disruption.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41510274
    reference_title: Local Misalignment Scoring Reveals Spatially Uniform Chondrocyte Disorganization in a Wnt5a-C83S Knock-in Model of Robinow Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although we selected embryos with approximately 50% correct template-mediated repair based on next-generation
      sequencing, we cannot exclude that some cells carry edits on both alleles.
    explanation: >-
      Preprint limitation: initial CRISPR-edited embryos were used because cleft-palate lethality prevented
      breeding; uniform heterozygosity was not demonstrated.
    quote_role: PRIMARY_RESULT
- name: Delayed chondrocyte hypertrophy
  description: >-
    In C83S-infected chicken limbs, COL10A1 expression and hypertrophic enlargement are delayed. This accompanies
    impaired cartilage elongation; no equivalent patient-tissue measurement is available.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:31032853
    reference_title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The C83S mutation also dominantly interferes with the expansion of chondrocytes as shown by the lack
      of lacunae in Alcian blue stained sections.
    explanation: >-
      Chicken limb histology and COL10A1 staining support delayed maturation; this is distinct from cell orientation.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31032853
    reference_title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the mutant protein prevented COL10A1 expression in all embryos.
    explanation: >-
      The authors describe absent COL10A1 at the assessed stage, with later bone formation possible. This supports
      delayed hypertrophy rather than a permanently absent lineage.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Disordered Growth Plate and Skeletal Patterning
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced hypertrophic enlargement and delayed ossification contribute to shortened skeletal elements in
      the chicken model.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
- name: Disordered Growth Plate and Skeletal Patterning
  role: effector
  biological_scale: TISSUE
  description: >-
    Abnormal cartilage elongation and skeletal patterning underlie the shortened limb phenotype. Chicken C83S
    experiments demonstrate shortened, widened cartilage and delayed ossification. The contribution of orientation
    versus hypertrophy and the human mesomelic distribution remain incompletely resolved.
  locations:
  - preferred_term: cartilage tissue
    term:
      id: UBERON:0002418
      label: cartilage tissue
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)
    explanation: >-
      The GeneReviews Clinical Characteristics description of the skeletal phenotype, including the upper-limb
      predominance of the mesomelic shortening.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:31032853
    reference_title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Strikingly, WNT5AC83S consistently caused a delay in ossification and bones were more than 50% shorter
      and 200% wider than controls.
    explanation: Experimental chicken limb dimensions, not patient effect sizes or penetrance.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The developmental skeletal phenotype is consistent with abnormal growth and patterning, but the variant-specific
      intermediate is incompletely defined.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The developmental skeletal phenotype is consistent with abnormal growth and patterning, but the variant-specific
      intermediate is incompletely defined.
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The developmental skeletal phenotype is consistent with abnormal growth and patterning, but the variant-specific
      intermediate is incompletely defined.
- name: Craniofacial morphogenetic disruption
  role: effector
  biological_scale: ORGANISM
  description: >-
    Developmental abnormalities of craniofacial structures produce the characteristic face and oral/dental
    findings. Tissue-specific intermediates for WNT5A patient variants remain incompletely resolved.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface
      retrusion)
    explanation: The GeneReviews description of the craniofacial phenotype.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Craniofacial developmental association; no specific WNT5A-dependent intermediate is established for this
      feature.
  - target: Bifid Tongue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Craniofacial developmental association; no specific WNT5A-dependent intermediate is established for this
      feature.
  - target: Hypodontia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Craniofacial developmental association; no specific WNT5A-dependent intermediate is established for this
      feature.
  - target: Frontal bossing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Anteverted nares
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Midface retrusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Dental malocclusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Dental crowding
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Delayed eruption of permanent teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Gingival overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
  - target: Wide nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
  - target: Depressed nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
  - target: Prominent eyes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
  - target: Short nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific tissue intermediate remains unresolved.
  - target: High anterior hairline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
  - target: Broad nasal tip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
  - target: Long philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
  - target: Wide retromolar ridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
  - target: Alveolar ridge deformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed craniofacial developmental outcome; the variant-specific human tissue intermediate remains unresolved.
  - target: Cleft lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported craniofacial developmental association; no specific WNT5A-dependent fusion intermediate is established.
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported craniofacial developmental association; no specific WNT5A-dependent fusion intermediate is established.
- name: Genital morphogenetic disruption
  role: effector
  biological_scale: ORGANISM
  description: >-
    Abnormal external genital development causes hypoplasia in both sexes. Micropenis must be distinguished
    clinically from a normally sized but webbed or embedded penis; the latter is an anatomical insertion abnormality.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females:
      hypoplastic clitoris and labia majora)
    explanation: The GeneReviews description of the genital phenotype in both sexes.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Micropenis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: External genital developmental association; the precise tissue intermediate remains unresolved.
  - target: Clitoral Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: External genital developmental association; the precise tissue intermediate remains unresolved.
  - target: Hypoplastic Labia Majora
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: External genital developmental association; the precise tissue intermediate remains unresolved.
  - target: Small scrotum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed developmental outcome; the WNT5A-specific tissue intermediate is unresolved.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated genital developmental outcome; the pathway to impaired testicular descent is unresolved.
phenotypes:
- category: Skeletal
  name: Mesomelic Limb Shortening
  description: >-
    Shortening of the middle limb segments - forearm and lower leg - with upper-limb predominance. The mesomelic
    pattern is the skeletal signature of this condition and what distinguishes it from proportionate short
    stature.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: mesomelic limb shortening predominantly of the upper limbs
    explanation: >-
      States both the mesomelic pattern and its upper-limb predominance. This chapter covers dominant Robinow
      syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Growth
  name: Short Stature
  description: >-
    Short stature from abnormal skeletal development. A subset of DVL1-associated cases has low-normal stature,
    but normal height is not a universal DVL1 discriminator. Short stature is usually evident at birth and
    persists into adulthood.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)
    explanation: >-
      Lists short stature among the defining skeletal findings. This chapter covers dominant Robinow syndrome
      across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Short stature is almost always present at birth and sometimes identified prenatally
    explanation: >-
      Chapter clinical natural history; the earliest ultrasound detection is not a universal screening sensitivity.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Widely spaced, prominent eyes - the most recognisable single element of the facial configuration historically
    called fetal facies.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface
      retrusion)
    explanation: >-
      Describes the widely spaced prominent eyes this record captures. This chapter covers dominant Robinow
      syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Micropenis
  description: >-
    Reduced penile length can occur, but an apparently small penis may instead be normally sized and webbed
    or embedded; clinical assessment determines the appropriate hormonal or surgical approach.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: >-
      Names micropenis among the male genital findings. This chapter covers dominant Robinow syndrome across
      genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Cryptorchidism
  description: Undescended testes can occur among the male genital abnormalities and warrant urologic assessment.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: >-
      Names cryptorchidism among the male genital findings. This chapter covers dominant Robinow syndrome across
      genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Hypoplastic Labia Majora
  description: >-
    The female counterpart of the male genital hypoplasia. Curated because the entry otherwise recorded only
    the male findings, which would make the genital phenotype look sex-limited when the source describes it
    in both.
  phenotype_term:
    preferred_term: Hypoplastic labia majora
    term:
      id: HP:0000059
      label: Hypoplastic labia majora
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in females: hypoplastic clitoris and labia majora'
    explanation: >-
      Names hypoplastic labia majora among the female genital findings. This chapter covers dominant Robinow
      syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Clitoral Hypoplasia
  description: Hypoplasia of the clitoris, named with the labial hypoplasia as the female genital presentation.
  phenotype_term:
    preferred_term: Clitoral hypoplasia
    term:
      id: HP:0000060
      label: Clitoral hypoplasia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in females: hypoplastic clitoris and labia majora'
    explanation: >-
      Names clitoral hypoplasia among the female genital findings. This chapter covers dominant Robinow syndrome
      across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Dislocated Radial Head
  description: >-
    Dislocation of the radial head, named by GeneReviews among the less common findings and already described
    in prose by the growth-plate pathophysiology node.
  phenotype_term:
    preferred_term: Dislocated radial head
    term:
      id: HP:0003083
      label: Dislocated radial head
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Names radial head dislocation among the less common findings. This chapter covers dominant Robinow syndrome
      across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Hemivertebrae
  description: >-
    Vertebral segmentation defects, reported in some WNT5A-associated cases; they are not demonstrated consequences
    of a growth-plate lesion.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Names hemivertebrae among the vertebral abnormalities. This chapter covers dominant Robinow syndrome
      across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Scoliosis
  description: Curvature of the spine, named alongside hemivertebrae as the vertebral presentation.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Names scoliosis among the vertebral abnormalities. This chapter covers dominant Robinow syndrome across
      genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Bifid Tongue
  description: >-
    A bilobed tongue - an unusual and clinically distinctive oral finding that helps separate Robinow syndrome
    from other mesomelic dysplasias.
  phenotype_term:
    preferred_term: Bifid tongue
    term:
      id: HP:0010297
      label: Bifid tongue
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth),
      bilobed tongue, and occasional prenatal macrocephaly that persists postnatally
    explanation: >-
      Places the bilobed tongue within the oral and dental findings of the GeneReviews clinical description,
      alongside the dental abnormalities that share a craniofacial developmental origin. This chapter covers
      dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The prevalence of bifid tongue is 38% (N = 3 out of 8) in our cohort of individuals with pathogenic WNT5A
      variation, comparable with other genotypes.
    explanation: >-
      Small selected retrospective series with missing phenotype information; not a general-population penetrance
      estimate.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Cardiac defects are uncommon but disproportionately important, being identified as a major cause of morbidity
    and mortality when present - which is why cardiac assessment features in surveillance despite the low frequency.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: When present, cardiac defects are a major cause of morbidity and mortality.
    explanation: >-
      Establishes both the conditional nature and the clinical weight of the cardiac phenotype. This chapter
      covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Brachydactyly
  description: Short digits accompanying the skeletal developmental phenotype.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)
    explanation: >-
      GeneReviews names brachydactyly as one of the three core skeletal findings. This chapter covers dominant
      Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Dental
  name: Hypodontia
  description: >-
    Missing teeth may coexist with dental crowding, malocclusion and delayed permanent eruption; each is a
    separate feature and orthodontic needs depend on the actual dentition.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)
    explanation: >-
      The GeneReviews dental findings, which name hypodontia among them. This chapter covers dominant Robinow
      syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Macrocephaly
  description: >-
    Prenatal macrocephaly persisting after birth. Occasional in the WNT5A form; persistent macrocephaly is
    a defining feature of the DVL1 form, which is one of the discriminators in the differential.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: occasional prenatal macrocephaly that persists postnatally
    explanation: >-
      GeneReviews qualifies macrocephaly as occasional, which is the basis for the frequency here. This chapter
      covers dominant Robinow syndrome across genes; it is not a WNT5A-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- name: Frontal bossing
  category: Craniofacial
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  description: Frontal bossing is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface
      retrusion)
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Anteverted nares
  category: Craniofacial
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  description: Anteverted nares is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface
      retrusion)
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Midface retrusion
  category: Craniofacial
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  description: Midface retrusion is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface
      retrusion)
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Dental malocclusion
  category: Dental
  phenotype_term:
    preferred_term: Dental malocclusion
    term:
      id: HP:0000689
      label: Dental malocclusion
  description: Dental malocclusion is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Dental crowding
  category: Dental
  phenotype_term:
    preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  description: Dental crowding is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Delayed eruption of permanent teeth
  category: Dental
  phenotype_term:
    preferred_term: Delayed eruption of permanent teeth
    term:
      id: HP:0000696
      label: Delayed eruption of permanent teeth
  description: >-
    Delayed eruption of permanent teeth is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Small scrotum
  category: Genitourinary
  phenotype_term:
    preferred_term: Small scrotum
    term:
      id: HP:0000046
      label: Small scrotum
  description: Small scrotum is part of the clinical spectrum; expression varies between individuals.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Gingival overgrowth
  category: Oral
  phenotype_term:
    preferred_term: Gingival overgrowth
    term:
      id: HP:0000212
      label: Gingival overgrowth
  description: >-
    Gingival overgrowth is part of the reported clinical spectrum; its frequency in the general WNT5A population
    is not established.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival
      hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were
      observed in more than 60% of individuals in each genotype.
    explanation: >-
      The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected
      cohorts, missing assessments and shared literature cases limit generalization; no population frequency
      is assigned.
- name: Broad hallux
  category: Skeletal
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  description: >-
    Broad hallux is part of the reported clinical spectrum; its frequency in the general WNT5A population is
    not established.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival
      hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were
      observed in more than 60% of individuals in each genotype.
    explanation: >-
      The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected
      cohorts, missing assessments and shared literature cases limit generalization; no population frequency
      is assigned.
- name: Wide nasal bridge
  category: Craniofacial
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  description: >-
    Wide nasal bridge is part of the reported clinical spectrum; its frequency in the general WNT5A population
    is not established.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival
      hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were
      observed in more than 60% of individuals in each genotype.
    explanation: >-
      The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected
      cohorts, missing assessments and shared literature cases limit generalization; no population frequency
      is assigned.
- name: Depressed nasal bridge
  category: Craniofacial
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  description: >-
    Depressed nasal bridge is part of the reported clinical spectrum; its frequency in the general WNT5A population
    is not established.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival
      hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were
      observed in more than 60% of individuals in each genotype.
    explanation: >-
      The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected
      cohorts, missing assessments and shared literature cases limit generalization; no population frequency
      is assigned.
- name: Prominent eyes
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Prominent eyes
  description: >-
    Prominent eyes is part of the reported clinical spectrum; its frequency in the general WNT5A population
    is not established.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      midface hypoplasia, hypertelorism, prominent eyes, anteverted nares, wide, low nasal bridge, gingival
      hyperplasia, limb length anomaly, brachydactyly, broad first toe, and male hypoplastic genitalia were
      observed in more than 60% of individuals in each genotype.
    explanation: >-
      The primary retrospective analysis reports this core feature across each genotype, including WNT5A. Selected
      cohorts, missing assessments and shared literature cases limit generalization; no population frequency
      is assigned.
  notes: 'Needs a precise term: OLS HPO searches for prominent eyes returned proptosis, whose definition requires anterior globe displacement. The cohort description does not establish that anatomy, so no proptosis binding is inferred.'
- name: Short nose
  category: Craniofacial
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  description: >-
    Short nose is part of the reported clinical spectrum; its frequency in the general WNT5A population is
    not established.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Notably, the prevalence of short nose is greater than 90% in other genotypes, but only 50% in NXN individuals
      (N = 2 out of 4).
    explanation: >-
      The other genotype groups include WNT5A. This is a selected retrospective dataset, not a general-population
      penetrance estimate.
- name: High anterior hairline
  category: Craniofacial
  phenotype_term:
    preferred_term: High anterior hairline
    term:
      id: HP:0009890
      label: High anterior hairline
  description: >-
    High anterior hairline contributes to the characteristic craniofacial/oral phenotype; no WNT5A-specific
    frequency is assigned.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short
      nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion,
      and low-set ears
    explanation: >-
      GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected
      individuals.
- name: Broad nasal tip
  category: Craniofacial
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  description: >-
    Broad nasal tip contributes to the characteristic craniofacial/oral phenotype; no WNT5A-specific frequency
    is assigned.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short
      nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion,
      and low-set ears
    explanation: >-
      GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected
      individuals.
- name: Long philtrum
  category: Craniofacial
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  description: >-
    Long philtrum contributes to the characteristic craniofacial/oral phenotype; no WNT5A-specific frequency
    is assigned.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short
      nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion,
      and low-set ears
    explanation: >-
      GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected
      individuals.
- name: Low-set ears
  category: Craniofacial
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  description: >-
    Low-set ears contributes to the characteristic craniofacial/oral phenotype; no WNT5A-specific frequency
    is assigned.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short
      nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion,
      and low-set ears
    explanation: >-
      GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected
      individuals.
- name: Wide retromolar ridge
  category: Oral
  phenotype_term:
    preferred_term: Wide retromolar ridge
  description: >-
    Wide retromolar ridge contributes to the characteristic craniofacial/oral phenotype; no WNT5A-specific
    frequency is assigned.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar
      ridge, alveolar ridge deformation, and bilobed tongue
    explanation: >-
      GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected
      individuals.
  notes: 'Needs a precise term: OLS HPO searches for wide retromolar ridge and retromolar returned no matching term. Broad alveolar ridge describes a different anatomical ridge and was not substituted.'
- name: Alveolar ridge deformation
  category: Oral
  phenotype_term:
    preferred_term: Alveolar ridge deformation
    term:
      id: HP:0006477
      label: Abnormal alveolar ridge morphology
  description: >-
    Alveolar ridge deformation contributes to the characteristic craniofacial/oral phenotype; no WNT5A-specific
    frequency is assigned.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar
      ridge, alveolar ridge deformation, and bilobed tongue
    explanation: >-
      GeneReviews suggestive findings; its clinical figures also demonstrate the facial pattern in WNT5A-affected
      individuals.
  notes: GeneReviews does not specify the type of deformation; the morphology term intentionally does not assert overgrowth, atrophy or clefting.
- name: Cleft lip
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  description: A less-common finding across dominant Robinow genotypes; the presence and anatomical extent require individual assessment.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as
      evidence that a human cleft is present.
- name: Cleft palate
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  description: A less-common finding across dominant Robinow genotypes; the presence and anatomical extent require individual assessment.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as
      evidence that a human cleft is present.
genetic:
- name: WNT5A
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: WNT5A
    term:
      id: hgnc:12784
      label: WNT5A
  notes: >-
    WNT5A variants include missense substitutions, often involving cysteines, and selected in-frame variants.
    Inherited, de novo and mosaic presentations occur. In the 2018 cohort a de novo c.487_492dup (NM_003392.4;
    p.Gly163_Cys164dup) was found in 16/70 mapped reads (23%), consistent with blood mosaicism. This is not
    a germline transmission probability. Biallelic loss-of-function disease is a distinct, more severe allelic
    presentation. Protein folding, secretion and signaling can all be affected; a uniformly secreted but merely
    less active ligand is not established.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly
      conserved cysteines, are associated with autosomal dominant Robinow syndrome
    explanation: The gene-disease assignment and the variant class.
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular
      genetic testing
    explanation: >-
      Cross-gene GeneReviews diagnostic statement; the WNT5A component applies here. The chapter-era gene list
      is not a complete current differential.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The majority of WNT5A variants involve substitution or creation of a cysteine residue.
    explanation: >-
      Primary variant compilation; the paper also includes a biallelic frameshift and a Cys154Phe family classified
      as VUS in its table, so not every compiled variant is promoted to an established dominant cause.
    quote_role: PRIMARY_RESULT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5777383/
    reference_title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The variant was observed in 16/70 (23%) mapped reads, which is consistent with a mosaic state of the
      mutant allele.
    explanation: >-
      WNT5A c.487_492dup in the 2018 cohort; this is a read fraction in sampled DNA, not the fraction of germ
      cells or transmission risk.
  - reference: PMID:29575631
    reference_title: Biallelic loss-of-function WNT5A mutations in an infant with severe and atypical manifestations of Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The parents, who are both heterozygous for the deletion, appear clinically unaffected.
    explanation: >-
      The severe homozygous frameshift case supports distinction from selected dominant missense/in-frame variants;
      one family is not proof that every heterozygous null is benign.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant transmission, with inherited and de novo cases and variable expressivity. Each child
    of a heterozygous affected individual has a 50% chance of inheriting the variant; severity is not predicted
    reliably. The fraction of de novo cases is unknown. Parental examination and testing can identify mild
    disease or mosaicism; blood-negative parents do not exclude germline mosaicism.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with ADRS has a 50% chance of inheriting the pathogenic variant; however,
      the severity of the clinical manifestations cannot be predicted from the results of molecular genetic
      testing.
    explanation: >-
      The GeneReviews Genetic Counseling statement, giving both the recurrence risk and the limit on genotype-based
      prognosis.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The proportion of cases caused by a de novo pathogenic variant is unknown.
    explanation: Do not substitute the research report's unsupported 50% de novo estimate.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Clinical recognition of Robinow syndrome should be followed by molecular testing that distinguishes WNT5A-related
    disease from overlapping forms. A heterozygous pathogenic or likely pathogenic WNT5A variant supports this
    specific diagnosis; a VUS neither establishes nor excludes it. A multigene skeletal-dysplasia/Robinow panel
    or exome/genome analysis can assess WNT5A, DVL1/DVL3, FZD2 and recessive ROR2/NXN disease, with gene content
    updated by the laboratory. Ensure adequate coverage and small-indel detection; a negative result does not
    settle a different molecular etiology.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of autosomal dominant Robinow syndrome is established in a proband with typical suggestive
      findings and/or by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through
      molecular genetic testing.
    explanation: The GeneReviews Diagnosis/Testing criterion in full.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Identification of a heterozygous DVL1, DVL3, or WNT5A variant of uncertain significance does not establish
      or rule out the diagnosis.
    explanation: Variant uncertainty must remain distinct from molecular confirmation.
- name: Baseline organ and skeletal evaluation
  description: >-
    Assess skeletal extent with radiographs of limbs, chest, vertebrae and skull. Obtain echocardiography,
    renal ultrasound and hearing assessment; consider pelvic ultrasound for females and urologic/endocrine
    evaluation for genital abnormalities. Assess dental/craniofacial findings and development. These are cross-genotype
    baseline recommendations, not assertions that every feature is frequent in WNT5A disease.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Renal ultrasound To assess for renal anomalies & hydronephrosis
    explanation: >-
      GeneReviews baseline evaluation table; the small 2022 WNT5A subgroup had no renal anomalies among six
      assessed, which does not eliminate the rationale for baseline screening.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Cardiovascular Echocardiogram To evaluate for congenital heart defect
    explanation: >-
      Baseline echocardiography differs from subsequent specialist monitoring only when abnormalities are found.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Radiographs of limbs, chest, vertebrae, & skull To establish the extent of skeletal involvement
    explanation: >-
      Baseline skeletal characterization can detect vertebral complications without asserting they arise directly
      from a growth-plate lesion.
treatments:
- name: Corrective Surgery for Genital and Orofacial Anomalies
  therapeutic_modality: SURGERY
  description: >-
    Surgical correction of cryptorchidism, abnormal penile insertion or penoscrotal position, and cleft lip
    or palate where present addresses established anatomical abnormalities.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Cryptorchidism
    description: >-
      Corrective surgery addresses anatomical manifestations; it does not reverse the prenatal signaling defect.
  - target: Craniofacial morphogenetic disruption
    description: >-
      Corrective surgery addresses anatomical manifestations; it does not reverse the prenatal signaling defect.
  - target: Genital morphogenetic disruption
    description: >-
      Corrective surgery addresses anatomical manifestations; it does not reverse the prenatal signaling defect.
  - target: Cleft lip
    description: Repairs an existing anatomical cleft where present.
  - target: Cleft palate
    description: Repairs an existing anatomical cleft where present.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Corrective surgeries as needed for cryptorchidism, abnormal penile insertion / penoscrotal position,
      and cleft lip/palate.
    explanation: The GeneReviews Management recommendation for the surgical manifestations.
    quote_role: REVIEW_SYNTHESIS
- name: Structured Multisystem Surveillance
  therapeutic_modality: OTHER
  description: >-
    Measure head circumference through infancy and childhood. Assess development every three months in infancy
    and every six to twelve months thereafter. Arrange dental review every six to twelve months, periodic hearing
    assessment in childhood, and specialist cardiac or renal monitoring if abnormalities are identified. These
    are GeneReviews recommendations across dominant Robinow genotypes.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Measurement of head circumference regularly in infancy and throughout childhood. Developmental assessment
      every three months in infancy and every six months to one year thereafter
    explanation: The GeneReviews Surveillance schedule, quoted for the elements it specifies by interval.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dental evaluation every six to 12 months or as recommended. Periodic hearing assessments in childhood.
      Regular cardiac and renal assessment as needed by respective specialists if abnormalities are identified.
    explanation: >-
      GeneReviews clinical baseline across dominant Robinow genotypes; no WNT5A-specific frequency is inferred.
- name: Orthodontic Treatment
  therapeutic_modality: DEVICE
  description: >-
    Orthodontic management is typically required, reflecting the dental crowding, malocclusion, hypodontia
    and delayed eruption that accompany the craniofacial phenotype.
  treatment_term:
    preferred_term: orthodontic treatment
    term:
      id: NCIT:C64248
      label: Orthodontic Treatment
  target_mechanisms:
  - target: Craniofacial morphogenetic disruption
    description: Addresses the dental consequences of abnormal craniofacial development.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Orthodontic treatment is typically required.
    explanation: The GeneReviews Management statement on orthodontic need.
    quote_role: REVIEW_SYNTHESIS
- name: Growth Hormone Therapy (selected patients)
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Consider growth hormone replacement when endocrine evaluation demonstrates deficiency. A small 1999 clinical
    series reported increased growth velocity in treated patients, but their molecular subtypes were uncharacterized.
    This supports selected treatment of coexisting deficiency without establishing efficacy in WNT5A-confirmed
    disease or correction of its developmental mechanism.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  target_mechanisms:
  - target: Disordered Growth Plate and Skeletal Patterning
    description: >-
      Acts on growth-plate output through an independent endocrine axis; it does not restore planar cell polarity.
  evidence:
  - reference: PMID:10417975
    reference_title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recombinant human GH therapy in our patient and the three patients from the NCGS resulted in a significant
      increase in the growth rate per year.
    explanation: >-
      Clinical growth-rate response in patients of unknown genotype; transfer to WNT5A-related disease is indirect.
  - reference: PMID:10417975
    reference_title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose its association with GH deficiency and that treatment with rhGH can result in a significant
      increase in the growth rate of these children.
    explanation: >-
      The authors propose the association from a small series; neither the prevalence of GH deficiency nor
      routine treatment efficacy is established.
    directness: INDIRECT
- name: Hormone Therapy for Micropenis
  therapeutic_modality: OTHER
  description: >-
    Hormone therapy in affected males with micropenis, listed by GeneReviews among the treatments of manifestations.
    Like the surgical entries, it addresses an established morphogenetic outcome rather than the pathway that
    produced it. Refer for endocrine assessment; GeneReviews reports hCG and testosterone experience in three
    boys, without establishing WNT5A-specific efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human chorionic gonadotropin
      term:
        id: CHEBI:81570
        label: Chorionic gonadotropin
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_mechanisms:
  - target: Genital morphogenetic disruption
    description: Acts on the genital phenotype; it does not restore planar cell polarity.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hormone therapy may be helpful for males with micropenis.
    explanation: >-
      The GeneReviews Management statement. Note its hedge - "may be helpful" - which is why this is recorded
      without any efficacy claim.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Injection of human chorionic gonadotropin and testosterone improved penile length and testicular volume
      in three boys with severe micropenis
    explanation: >-
      Small historical treatment experience summarized by GeneReviews; molecular subtype and general efficacy
      are not established.
- name: Genetic and reproductive counseling
  description: >-
    Offer family-specific counseling, examination/testing of parents and at-risk relatives, and discussion
    of prenatal or preimplantation testing once the familial variant is known. A molecular result cannot predict
    severity. If the variant is absent from both parents' blood, sibling recurrence remains low but nonzero
    because germline mosaicism cannot be excluded; GeneReviews quotes less than 1% for this circumstance across
    ADRS.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once the DVL1, DVL3, or WNT5A pathogenic variant has been identified in an affected family member, prenatal
      and preimplantation genetic testing are possible.
    explanation: Family-specific reproductive testing and counseling, not prevention of the developmental mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the risk to sibs is presumed to be slightly greater than that of the general population (though still
      <1%) because of the theoretic possibility of parental germline mosaicism.
    explanation: >-
      Applies after a proband variant is undetectable in both parents' leukocyte DNA; not a measured WNT5A-specific
      recurrence rate.
differential_diagnoses:
- name: DVL1-related autosomal dominant Robinow syndrome
  description: >-
    DVL1-related Robinow syndrome can include persistent macrocephaly, skull osteosclerosis and hearing loss,
    with low-normal stature in a subset. C-terminal frameshift variants alter the intracellular adaptor. Canonical
    co-expression assays have reported both increased and decreased activity; JNK-PCP readouts also depend
    on cellular and species context. These differences remain unresolved and do not establish the direction
    of WNT5A signaling.
  distinguishing_features:
  - Low-normal stature in a subset; short stature also occurs
  - Increased bone mineral density with skull osteosclerosis
  - Hearing loss
  - Persistent macrocephaly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic
      variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral
      density with skull osteosclerosis, and hearing loss
    explanation: >-
      Osteosclerotic DVL1 subgroup described by GeneReviews; normal stature is not universal across DVL1-related
      disease.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt
      signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals
    explanation: Attributes the DVL1-osteosclerosis subtype to its primary report.
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than
      that in the wild-type construct alone
    explanation: >-
      Co-expression increased canonical WNT output in this assay. Other DVL1 constructs and cellular systems
      have yielded decreased activity; these results do not settle the dominant mechanism of WNT5A disease.
      The DVL1-1519ΔT co-expression decrease is recounted in PMID:42424595; the competing coexpression_canonical_wnt_gain_model
      is represented in Autosomal_Dominant_Robinow_Syndrome_2.
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations all delete the DVL1 C terminus and replace it, in each instance, with a novel, highly basic
      sequence.
    explanation: The primary DVL1 report identifies altered C-terminal sequence after frameshifting.
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We showed the presence of mutant transcript in fibroblasts from one individual with RS-OS and demonstrated
      unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift mutation.
    explanation: >-
      Patient fibroblast transcript and transfected protein stability are separate observations; neither establishes
      the behavior of WNT5A variants.
  - reference: PMID:42424595
    reference_title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This is the first study to show that the novel C-terminus of DVL1 is sufficient to interfere with the
      function of DVL1 protein expressed from the normal allele in heterozygous, autosomal dominant RS.
    explanation: >-
      Sources the interference-with-the-normal-allele claim. The bare label "dominant-negative" is deliberately
      not used in the prose - this is the experimental statement behind it. Graded MODEL_ORGANISM rather than
      IN_VITRO because this concluding claim rests on the study's chick limb and *Drosophila* wing readouts
      as well as its culture work; the luciferase item below is the cell-based measurement and stays IN_VITRO.
  - reference: PMID:42424595
    reference_title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      wtDVL1 activated canonical and JNK-PCP WNT signalling whereas the DVL11519* and the DVL11519ΔT variant
      had significantly lower signaling activity
    explanation: >-
      Direct measurement that the DVL1 variant signals below wild type on the non-canonical JNK-PCP branch
      as well as the canonical one. This is the evidence for the reduced-signalling framing, and it is in tension
      with the same group's earlier chick and *Drosophila* work reporting a gain of JNK/PCP signalling (PMID:36916233,
      cited below); the description records the disagreement rather than picking a side.
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, the variants caused a loss of canonical and gain of non-canonical Wnt signaling in several
      assays.
    explanation: >-
      The study includes HEK293 reporter assays plus chicken and Drosophila experiments. JNK activation varies
      by variant and context; the 2026 paper explicitly contrasts lower activation in chicken facial mesenchyme
      with MMP1 upregulation in Drosophila.
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      only 38% (N = 8 out of 21) of DVL1 individuals have short stature, which contrasts with the prevalence
      of short stature in all other RS types (69%–100%)
    explanation: >-
      Primary retrospective comparison confirms variable stature; the between-genotype trend was not statistically
      significant.
  disease_term:
    preferred_term: autosomal dominant Robinow syndrome 2
    term:
      id: MONDO:0014591
      label: autosomal dominant Robinow syndrome 2
- name: Omodysplasia
  description: >-
    FZD2-related omodysplasia/Robinow-spectrum disease overlaps substantially with WNT5A-related disease. Predominantly
    humeral shortening, a short first metacarpal and elbow restriction can be informative, but height and facial
    appearance do not reliably exclude either diagnosis. The 2018 discovery cohort and 2022 phenotypic analysis
    support a shared spectrum; molecular testing is decisive.
  disease_term:
    preferred_term: omodysplasia
    term:
      id: MONDO:0017136
      label: omodysplasia
  distinguishing_features:
  - Predominantly humeral shortening rather than generalized mesomelic shortening
  - Short first metacarpal
  - Elbow restriction from hypoplastic, dislocated proximal radii
  - Heterozygous FZD2 variants; clinical overlap with the Robinow spectrum requires molecular differentiation
  evidence:
  - reference: PMID:29383834
    reference_title: 'Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism
      (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of
      genitourinary anomalies
    explanation: >-
      Predominantly humeral shortening can inform the differential but is not an absolute clinical separator.
  - reference: PMID:29383834
    reference_title: 'Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism
    explanation: >-
      The molecularly confirmed FZD2 proband had short stature, not preserved stature. This is why the description
      states the distinction as a pattern-of-shortening contrast against the WNT5A form rather than as a height
      difference.
  - reference: PMID:29383834
    reference_title: 'Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals
    explanation: Sources the elbow-restriction and short-first-metacarpal distinguishing features.
  - reference: PMID:29276006
    reference_title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four families with variants in FZD2 were identified as well as three individuals from two families with
      biallelic variants in NXN that co-segregate with the phenotype
    explanation: >-
      Establishes FZD2 as a further Robinow-pathway gene distinct from WNT5A, ROR2, DVL1 and DVL3, found by
      genomic studies of clinically diagnosed families left unsolved for those four.
  - reference: PMID:29276006
    reference_title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved
    explanation: >-
      Historical unsolved fraction motivating the study, not a current testing yield or a WNT5A-specific proportion.
    quote_role: BACKGROUND
- name: ROR2-related autosomal recessive Robinow syndrome
  description: >-
    Biallelic ROR2 disease affects a receptor involved in WNT5A signaling and often has more marked skeletal
    and vertebral abnormalities. Clinical severity overlaps; recessive inheritance and molecular testing are
    the reliable distinctions.
  distinguishing_features:
  - Autosomal recessive inheritance
  - More severe skeletal, vertebral and craniofacial abnormalities
  - Biallelic ROR2 variants rather than heterozygous WNT5A
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with
      mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative
      WNT5A receptor
    explanation: >-
      States the recessive form's gene, its greater severity, and the ligand-receptor relationship that explains
      the phenotypic overlap.
    quote_role: BACKGROUND
  disease_term:
    preferred_term: autosomal recessive Robinow syndrome
    term:
      id: MONDO:0009999
      label: autosomal recessive Robinow syndrome
- name: Biallelic WNT5A loss-of-function disease
  description: >-
    A severe allelic presentation with recessive inheritance has been described in an infant with a homozygous
    frameshift, diaphragmatic hernia, genital ambiguity, adactyly and a ventricular septal defect. It is distinct
    from the selected heterozygous coding changes underlying dominant DRS1.
  evidence:
  - reference: PMID:29575631
    reference_title: Biallelic loss-of-function WNT5A mutations in an infant with severe and atypical manifestations of Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      we identified a homozygous frameshifting single nucleotide deletion in WNT5A in a previously reported,
      deceased infant
    explanation: Single-family report establishes the distinct allelic context; it is not a dominant DRS1 subtype.
- name: DVL3-related Robinow syndrome
  description: >-
    Overlapping dominant skeletal and craniofacial findings with a higher reported burden of cardiac abnormalities
    in small series. Molecular testing separates this adaptor-related disorder from WNT5A-related disease.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Three out of four individuals with DVL3-associated ADRS had cardiac abnormalities; osteosclerosis has
      not been reported.
    explanation: Small chapter-era series, not a stable population frequency or a rule excluding osteosclerosis.
  disease_term:
    preferred_term: autosomal dominant Robinow syndrome 3
    term:
      id: MONDO:0014819
      label: autosomal dominant Robinow syndrome 3
- name: NXN-related recessive Robinow syndrome
  description: >-
    Biallelic NXN variants produce a clinically overlapping recessive syndrome. Inheritance and molecular testing
    distinguish it; phenotype severity alone is unreliable.
  evidence:
  - reference: PMID:29276006
    reference_title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype
    explanation: Primary cohort establishes the recessive differential.
  disease_term:
    preferred_term: robinow syndrome, autosomal recessive 2
    term:
      id: MONDO:0032800
      label: robinow syndrome, autosomal recessive 2
- name: Aarskog-Scott syndrome
  description: >-
    FGD1-related Aarskog-Scott syndrome can resemble Robinow syndrome in facial, limb and genital findings.
    Its X-linked inheritance and molecular cause distinguish it; it is a relevant alternative after negative
    Robinow-gene testing.
  evidence:
  - reference: PMID:35047859
    reference_title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      pathogenic variants in FGD1 are the most frequent molecular diagnostic finding in clinically diagnosed
      RS with otherwise negative testing
    explanation: >-
      Selected cohort finding supports including FGD1 in the molecular differential; it does not estimate prevalence
      in all referrals.
notes: >-
  WNT5A-related dominant Robinow syndrome is distinct from DVL1/DVL3/FZD2 and recessive forms, despite clinical
  overlap. GeneReviews provides a cross-gene clinical baseline; its frequencies are not assumed to be WNT5A-specific.
  Primary cohorts are small, selected and incompletely phenotyped. The 2025 mouse study is a preprint with
  F0 editing limitations and does not definitively resolve the human functional mechanism. Renal anomalies,
  hearing loss and other less-common cross-gene findings are included in baseline assessment where genotype-specific
  support is sparse; zero events in a small WNT5A subgroup do not prove absence. Nail dysplasia remains a less-common
  cross-gene finding without an established WNT5A-specific frequency. Cleft lip and palate are represented
  separately because they are actionable anatomical findings. No quantified penetrance or population prevalence
  is inferred from selected case series.
references:
- reference: PMID:25577943
  title: Autosomal Dominant Robinow Syndrome.
  tags:
  - GeneReviews
- reference: PMID:19918918
  title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
- reference: PMID:25817014
  title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
- reference: PMID:10417975
  title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
- reference: PMID:29276006
  title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
- reference: PMID:29383834
  title: 'Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.'
- reference: PMID:42424595
  title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
- reference: PMID:36916233
  title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
- reference: PMID:31032853
  title: Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
- reference: PMID:41510274
  title: Local Misalignment Scoring Reveals Spatially Uniform Chondrocyte Disorganization in a Wnt5a-C83S Knock-in Model of Robinow Syndrome.
  findings:
  - statement: >-
      Research Square preprint, DOI:10.21203/rs.3.rs-8283811/v1; interpretation is provisional, and founder
      embryos may contain mosaic or biallelic editing.
- reference: PMID:35047859
  title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
- reference: PMID:29575631
  title: Biallelic loss-of-function WNT5A mutations in an infant with severe and atypical manifestations of Robinow syndrome.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
  findings:
  - statement: >-
      Full GeneReviews chapter Autosomal Dominant Robinow Syndrome (NBK268648), updated 2019; complements the
      PMID:25577943 abstract with baseline evaluation, variant interpretation and reproductive counseling.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5777383/
  title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome - PMC
  findings:
  - statement: Full-text version of PMID:29276006, WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. The PMID cache currently contains only the abstract; the URL cache supplies the mosaic read-count result.
discussions:
- discussion_id: wnt5a_dominant_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    How do heterozygous WNT5A variants cause dominant disease despite context-dependent activity and retained
    wild-type signaling?
  attaches_to:
  - pathophysiology#Altered WNT5A receptor signaling
  rationale: >-
    Founding embryo assays support hypomorphism, chicken C83S studies support dominant interference with chondrogenesis,
    and the mouse/cell preprint proposes a distinct non-loss-of-function phenotype without measured wild-type
    inhibition. The readouts, expression systems and embryonic tissues differ; no universal functional category
    is assigned.
  status: OPEN
  evidence:
  - reference: PMID:41510274
    reference_title: Local Misalignment Scoring Reveals Spatially Uniform Chondrocyte Disorganization in a Wnt5a-C83S Knock-in Model of Robinow Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Across all four models, induction of C83S expression did not reduce the signaling output from wild-type
      WNT5A, whether supplied as recombinant protein, co-expressed in the same cells, presented on neighboring
      cells, or provided by co-cultured donor cells.
    explanation: >-
      Preprint cell-based tests constrain dominant-negative models in those assay contexts; they do not rule
      out human tissue-specific effects.
    quote_role: PRIMARY_RESULT
📚

References & Deep Research

References

14
PMID:25577943
Autosomal Dominant Robinow Syndrome.
No top-level findings curated for this source.
PMID:19918918
WNT5A mutations in patients with autosomal dominant Robinow syndrome.
No top-level findings curated for this source.
PMID:25817014
Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
No top-level findings curated for this source.
PMID:10417975
Robinow syndrome with growth hormone deficiency: treatment with growth hormone.
No top-level findings curated for this source.
PMID:29276006
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
No top-level findings curated for this source.
PMID:29383834
Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.
No top-level findings curated for this source.
PMID:42424595
The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
No top-level findings curated for this source.
PMID:36916233
Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
No top-level findings curated for this source.
PMID:31032853
Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.
No top-level findings curated for this source.
PMID:41510274
Local Misalignment Scoring Reveals Spatially Uniform Chondrocyte Disorganization in a Wnt5a-C83S Knock-in Model of Robinow Syndrome.
1 finding
Research Square preprint, DOI:10.21203/rs.3.rs-8283811/v1; interpretation is provisional, and founder embryos may contain mosaic or biallelic editing.
PMID:35047859
Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.
No top-level findings curated for this source.
PMID:29575631
Biallelic loss-of-function WNT5A mutations in an infant with severe and atypical manifestations of Robinow syndrome.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
1 finding
Full GeneReviews chapter Autosomal Dominant Robinow Syndrome (NBK268648), updated 2019; complements the PMID:25577943 abstract with baseline evaluation, variant interpretation and reproductive counseling.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5777383/
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome - PMC
1 finding
Full-text version of PMID:29276006, WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. The PMID cache currently contains only the abstract; the URL cache supplies the mosaic read-count result.

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 (4)

Correct DVL1 competing-model attribution from mouse to chick/Drosophila; cite PMID:36916233 · 2026-09-17T16:13:32Z · View source

Round-3 review response (PR #9810). BLOCKING: the entry description and one evidence explanation attributed the competing "loss of canonical, gain of JNK/PCP" reading to "a separate mouse model". Resolved PMC10120075 via the NCBI ID converter to PMID:36916233 (DOI 10.1242/dmm.049844, Dis Model Mech 2023), titled "Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome" - chick limb misexpression plus Drosophila wing, not mouse. Fetched it with just fetch-reference and cited it on the DVL1 differential with an exact abstract quote, so the contested direction of effect is sourced on both sides rather than asserted. Confirmed from cache frontmatter that PMID:36916233 and PMID:42424595 share five authors (Akarsu, Gignac, Fu, Verheyen, Richman), so the prose now says the disagreement is between two readouts of one experimental programme, not between species or independent groups. SUGGESTION 1: moved the repo-provenance sentence about the deep-research artifact framing DVL1/DVL3 as gain-of-function out of the disease-facing description into the existing "Deep-research handling" paragraph in notes, recording there that the report's own model table lists PMC10120075 as chick/Drosophila. SUGGESTION 2: regraded the PMID:42424595 conclusion-sentence evidence item from IN_VITRO to MODEL_ORGANISM, since that claim rests on chick and Drosophila readouts as well as culture work. The luciferase item stays IN_VITRO. The snippet appears once in kb/, so this creates no split grading. Validation: just validate passed; just validate-terms passed; check-duplicate-keys and check-entity-refs clean; check-folded-hyphens clean; count-verified-snippets 48/48 (was 47/47, +1 for the new item).

Review round 2: source the DVL1 mechanism prose, evidence the Omodysplasia differential · 2026-09-12T12:46:04Z · View source

Second round on PR #9810, responding to the review's two blocking items plus one of the non-blocking notes. Item 1 - the replacement prose asserted an unsourced mechanism. Three claims were unsupported by anything in the file: reduced non-canonical/PCP signalling, escape from nonsense-mediated decay, and dominant-negative action. - Fetched PMID:42424595 [Tophkhane et al., the DVL1 C-terminus study the review pointed at] and cited it twice on the DVL1 differential. Its facial-mesenchyme luciferase result is the direct measurement behind the reduced-signalling claim: wtDVL1 activated both canonical and JNK-PCP signalling while both variant constructs signalled significantly lower. Its concluding sentence is the experimental statement behind "dominant negative": the novel C-terminus is sufficient to interfere with the protein expressed from the normal allele. - Dropped the bare label "dominant-negative" from both prose passages, keeping the sourced description of what was measured instead. - Cited PMID:25817014 for the novel basic C-terminus and for the transcript-present/protein-stable observation. Deliberately stopped short of asserting NMD escape: the abstract reports mutant transcript in patient fibroblasts and unimpaired protein stability but does not itself name nonsense-mediated decay, so the prose now states what was measured. - Acknowledged the competing model rather than flattening it, as the review asked. The description now says the direction of effect on each branch is contested, naming the mouse model reporting loss of canonical with gain of JNK/PCP and noting that this entry's deep-research artifact frames DVL1/DVL3 as gain-of-function throughout. The tension is also recorded in the explanation on the PMID:42424595 signalling item. Item 2 - the Omodysplasia differential's clinical features had no supporting evidence. Added three evidence items from PMID:29383834, already cached on main and already what kb/disorders/Omodysplasia.yaml cites for these features: the OMOD2 characterization sentence, the proband presentation, and the radiological findings. The review's specific catch here was right and changed the content, not just the citations. That paper's molecularly confirmed FZD2 proband had "rhizomelic short stature with elbow restriction", so "relatively preserved stature" was not merely unsourced but contradicted. The differential now separates on the pattern of shortening [predominantly humeral rather than generalized mesomelic] instead of on height, and the distinguishing_features list was changed to match: "Genitourinary anomalies more prominent than in the WNT5A form" was dropped as an unsourced comparative claim, replaced with the sourced elbow-restriction feature. Non-blocking note taken: "A third gene" changed to "A further gene", since the same sentence names the four genes that precede FZD2. Non-blocking note not taken: the differential stays bound to MONDO:0017136 [omodysplasia] rather than MONDO:0008123. The intent is to cross-reference the whole Omodysplasia entry, which covers both the dominant and recessive forms, and that entry is itself bound to the parent term. Validation run: just validate [47/47 snippets verified], just validate-terms [passed], just check-entity-refs, just check-duplicate-keys, just check-folded-hyphens, just check-reference-titles [no findings for this entry].

Review response: phenotypes, terms, evidence grading, DR artifact · 2026-08-27T04:43:56Z · View source

Response to the first review round. Added brachydactyly (HP:0001156, VERY_FREQUENT), which GeneReviews names as one of the three core skeletal findings and the entry had omitted, plus hypodontia (HP:0000668) and macrocephaly (HP:0000256, OCCASIONAL). Rebound Orthodontic Treatment from the generic NCIT:C15747 Supportive Care to NCIT:C64248 Orthodontic Treatment. Downgraded the 1999 growth-hormone case series from SUPPORT to PARTIAL: it predates the 2010 WNT5A discovery by eleven years, so those patients' genotype is unknown and may be DVL1, DVL3 or recessive ROR2. Regraded a background sentence about non-canonical Wnt signalling in a zebrafish paper from HUMAN_CLINICAL to OTHER. Committed the deep-research report and its citations sidecar; regenerating it showed the CREATE record's account of the run was wrong in one respect, in that the report does carry a reference_validation block resolving all 13 references with no confabulation, and what it actually flagged was relevance at 8 of 13 on topic. The preflight DVL1-at-52-percent warning did reproduce. Also added somatropin (NCIT:C837) as the growth-hormone therapeutic agent, the micropenis hormone therapy from the GeneReviews Management section, and changed surveillance modality from BEHAVIORAL to OTHER. A second pass then curated the female genital findings the entry had omitted - hypoplastic labia majora (HP:0000059) and clitoral hypoplasia (HP:0000060) - plus cryptorchidism (HP:0000028), all named in the same GeneReviews sentence that already supported the micropenis record. Curating only the male findings would have made the genital phenotype look sex-limited when the source describes it in both. A further round then corrected therapeutic_modality on the micropenis hormone therapy from PROTEIN_REPLACEMENT to OTHER - GeneReviews says only that hormone therapy may help, without naming the hormone, and conventional practice is testosterone, a steroid rather than a protein - and curated the three less-common skeletal findings the growth-plate node already named in prose: dislocated radial head (HP:0003083), hemivertebrae (HP:0002937) and scoliosis (HP:0002650), all OCCASIONAL off the same GeneReviews sentence. 38/38 snippets verified and separately confirmed verbatim by a raw substring audit bypassing validator normalization.

Create: Autosomal Dominant Robinow Syndrome 1 (WNT5A) · 2026-08-27T04:04:47Z · View source

New entry for WNT5A-related autosomal dominant Robinow syndrome (MONDO:0024455). Scoped deliberately to the WNT5A form: DVL1 and DVL3 dominant disease act through truncated adaptors with an apparent gain of function on the canonical branch, opposite in direction to the hypomorphic ligand curated here, so they are differential diagnoses rather than subtypes. The GeneReviews chapter PMID:25577943 is tagged and mined across all four sections its abstract carries. The deep-research report is committed under research/; its reference validation resolved all 13 references with no confabulation but judged only 8 on topic, and preflight warned DVL1 was mentioned at 52% the rate of WNT5A, so those sections were used only for differentials and every reference cited here was fetched and verified individually. Two evidence items initially quoted paper titles; both were replaced with real abstract quotes after checking the caches, which also strengthened the growth-hormone efficacy evidence and added the DVL1 allele-interaction mechanism. 28/28 snippets verified.

Claude Code ▸
Autosomal Dominant Robinow Syndrome 1 (DRS1) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 26 citations 2026-08-27T04:34:31.160438

Autosomal Dominant Robinow Syndrome 1 (DRS1) — Comprehensive Research Report

1. Disease Information

Overview. Robinow syndrome is a rare, genetically heterogeneous skeletal dysplasia first described in 1969 by Meinhard Robinow, Frederic Silverman, and Hugo Smith, who reported a mother and three children with "mesomelic brachymelia, hemivertebrae, peculiar facies and genital hypoplasia," a constellation they termed a form of dwarfism with fetal facies [Robinow, Silverman & Smith, Am J Dis Child, 1969] (PMC, PMC). Autosomal Dominant Robinow Syndrome 1 (DRS1) is the specific molecular subtype caused by heterozygous pathogenic variants in WNT5A (chromosome 3p14.3) — the original locus in the family Robinow himself described. It is distinguished from the more recently identified dominant subtypes DRS2 (DVL1, 1p36.33) and DRS3 (DVL3, 3q27.1), and from the autosomal recessive forms caused by biallelic ROR2 or NXN variants (OMIM #180700; OMIM #616331; GeneReviews NBK268648).

Key identifiers: - OMIM: #180700 (ROBINOW SYNDROME, AUTOSOMAL DOMINANT 1; DRS1) - Disease Ontology: DOID:0060766 - Orphanet: ORPHA:3107 (Autosomal dominant Robinow syndrome) - Gene: WNT5A (HGNC:12784), chromosome 3p14.3 - MedGen: C4551475 ("Autosomal dominant Robinow syndrome 1") - Related dominant entries: OMIM #616331 (DRS2/DVL1), #616894 (DRS3/DVL3) - Related recessive entries: OMIM #268310 (RRS1/ROR2)

Synonyms: Robinow syndrome, dominant type; Fetal face syndrome; Mesomelic dwarfism, Robinow type; Robinow-Silverman-Smith syndrome (historic).

Evidence basis: Robinow syndrome information is derived overwhelmingly from aggregated, curated disease-level resources (OMIM, GeneReviews, Orphanet) built from an accumulation of published case reports and small case series — the disease is too rare for large EHR-derived cohort data. Fewer than 80 dominant-Robinow-syndrome families have been reported across all three dominant genes combined (GeneReviews NBK268648); Orphanet estimates prevalence <1/1,000,000 for the dominant form with roughly 100 cases reported in the literature (Orphanet ORPHA:3107).

Suggested MONDO/HPO grounding: MONDO term for the WNT5A subtype should map to OMIM:180700/DOID:0060766/ORPHA:3107.

2. Etiology

Disease Causal Factor

DRS1 is caused by heterozygous, typically de novo, missense variants (and in-frame duplications/deletion-duplications) in WNT5A, which encodes the non-canonical Wnt ligand WNT5A (Person et al. 2010, Dev Dyn, PMID:19918918). Person et al. identified two distinct missense substitutions of highly conserved cysteine residues in WNT5A — one found in all living affected members of Robinow's original family, another in a second unrelated proband — both of which caused decreased WNT5A activity in zebrafish and Xenopus functional assays.

Genetic Risk Factors

  • Causal variants: Missense substitutions affecting conserved cysteines and other residues clustering on one face of the WNT5A protein (modeled on WNT8 homology), thought to disrupt protein-protein interactions within the Wnt pathway rather than gross folding (GeneReviews NBK268648).
  • The recurrent p.Cys83Ser (C83S) variant is the best-studied WNT5A allele. Its mechanism has been debated — dominant-negative, loss-of-function, or hypomorphic — but recent zebrafish/Xenopus and mouse chondrocyte-orientation work supports a hypomorphic, non-dominant-negative model in which the variant perturbs the spatial gradient of Wnt/PCP signaling rather than simply reducing total signal (Human Molecular Genetics, 2019; Research Square 2025 preprint).
  • ~9.5% of clinically diagnosed Robinow syndrome cases overall are attributable to WNT5A missense variants, per cohort sequencing studies (WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome, AJHG).
  • De novo occurrence: Approximately half of all ADRS cases (across genes) arise de novo; the remainder are inherited from an affected, mildly-expressing parent (GeneReviews NBK268648).

Environmental Risk Factors

None established. This is a monogenic Mendelian disorder with no known environmental, infectious, or lifestyle contributory factors identified in the literature.

Protective Factors

None reported (genetic or environmental) — not applicable to this monogenic dominant disorder.

Gene-Environment Interactions

Not established or investigated; the disorder's severity and penetrance appear driven by variant-specific effects on WNT5A protein function (genotype), not by external modifiers.

3. Phenotypes

Craniofacial ("fetal facies")

  • Broad, prominent forehead / frontal bossing — HP:0011220 (Prominent forehead)
  • Hypertelorism — HP:0000316
  • Prominent, widely spaced eyes — HP:0000488 / HP:0000316
  • Short, upturned nose with depressed/wide nasal bridge — HP:0000407 / HP:0000431
  • Midface hypoplasia / midface retrusion — HP:0011800
  • Broad, triangular mouth — HP:0000175 (Bifid uvula) not applicable; use HP:0002000 (Short columella) / free text
  • Macrocephaly (often present prenatally, persisting postnatally) — HP:0000256
  • Micrognathia in some — HP:0000347
  • Cleft lip/palate (minority) — HP:0000175 / HP:0000202

Dental/Oral

  • Malocclusion — HP:0000689
  • Dental crowding — HP:0000678
  • Hypodontia — HP:0000668
  • Delayed eruption of permanent teeth — HP:0000684
  • Gingival hypertrophy — HP:0000212
  • Bifid/bilobed tongue — HP:0010297

Skeletal

  • Short stature, typically ≤ −2 SD in adults — HP:0004322
  • Mesomelic limb shortening, predominantly upper limbs (forearms) — HP:0003027
  • Brachydactyly — HP:0001156
  • Clinodactyly — HP:0030084
  • Hemivertebrae — HP:0002937
  • Scoliosis — HP:0002650
  • Radial head dislocation (minority) — HP:0003083
  • Broad thumbs/first toes reported in some subtypes — HP:0011304

Genital/Urogenital

  • Males: micropenis / webbed or buried penis — HP:0000054; hypoplastic scrotum — HP:0000047; cryptorchidism — HP:0000028
  • Females: hypoplastic clitoris and labia majora — HP:0000053
  • Renal anomalies (minority, <25%) — HP:0000077

Cardiac and Other

  • Congenital cardiac defects (minority but "a major cause of morbidity and mortality" when present) — HP:0001627
  • Nail dysplasia — HP:0008404
  • Hearing loss (more classically reported with DVL1/DRS2) — HP:0000365
  • Cognitive delay — rare — HP:0001256

Onset/course: Congenital; craniofacial "fetal face" gestalt is most striking in infancy/early childhood and becomes less apparent with age. Fetal ultrasound can detect mesomelic shortening and facial features by ~20 weeks gestation (GeneReviews NBK268648). The disease course is generally stable/non-progressive apart from scoliosis, which can worsen through growth. Severity is variable even within families carrying the same variant.

Frequency data: Cardiac defects, renal anomalies, radial head dislocation, vertebral defects, nail dysplasia, cleft lip/palate, and cognitive delay are each reported in <25% of cases; craniofacial, skeletal, dental, and genital features are near-penetrant/core diagnostic features.

Quality of life: No disease-specific QoL instrument was identified in the literature search; impact is inferred from surgical burden (orthopedic, dental, urogenital, cardiac interventions) and short stature. Cognitive function is typically normal, which is an important prognostic/QoL distinguishing feature versus the more severe recessive (ROR2) form.

4. Genetic/Molecular Information

Causal gene: WNT5A (HGNC:12784; NCBI Gene ID: 7474; Ensembl ENSG00000114251); OMIM gene entry *164975.

Variant classes: Predominantly missense substitutions (notably affecting conserved cysteine residues, e.g., p.Cys83Ser, p.Cys182Arg), plus in-frame duplications and in-frame deletion-duplications clustering on one face of the modeled WNT5A protein structure, implicating disrupted protein-protein interaction surfaces rather than global misfolding (GeneReviews NBK268648; Person et al. 2010, PMID:19918918).

Variant classification (ACMG/ClinVar): Reported WNT5A variants in Robinow syndrome are classified Pathogenic/Likely Pathogenic in ClinVar; sequence analysis detects the great majority of pathogenic variants (large deletions/duplications are not expected to be disease-relevant given the mechanism).

Functional consequence: Debated between loss-of-function, dominant-negative, and hypomorphic mechanisms; current evidence (zebrafish, Xenopus, and mouse Wnt5a-C83S knock-in chondrocyte-polarity studies) favors a hypomorphic, gradient-disrupting model rather than simple haploinsufficiency or classic dominant-negative antagonism (HMG 2019; PMC12776500, 2025). Notably, this contrasts with the DVL1/DVL3-associated forms (DRS2/DRS3), where all identified variants are heterozygous frameshift mutations clustering in the penultimate/ultimate exon (exon 14/15), producing truncated proteins that escape nonsense-mediated decay — consistent with a gain-of-function mechanism distinct from WNT5A's (White et al. 2015, AJHG, PMID:25817016; Roifman et al. 2015, PMID:25817014, osteosclerotic DVL1-Robinow).

Germline origin: All reported DRS1 variants are germline (constitutional), inherited or de novo; no somatic/mosaic Robinow cohort data were identified.

Modifier genes: None formally established for DRS1; phenotypic variability within families with the same WNT5A variant suggests unidentified modifiers or stochastic developmental variation.

Epigenetics: No disease-specific epigenetic (DNA methylation/histone) data identified for WNT5A-Robinow syndrome in the literature searched.

Chromosomal abnormalities: Not a feature — DRS1 is a single-gene point-mutation disorder, not a copy-number/structural disorder.

Suggested HGNC/gene term: hgnc:12784 (WNT5A).

5. Environmental Information

No environmental toxins, occupational exposures, radiation, or infectious agents are established contributors to DRS1 — it is a fully monogenic Mendelian disorder. No lifestyle/behavioral risk-modifying factors (smoking, diet, exercise) are documented in the literature. Not applicable: infectious agents.

6. Mechanism / Pathophysiology

Molecular Pathway

WNT5A is the prototypic ligand for non-canonical Wnt signaling, principally the Wnt/Planar Cell Polarity (Wnt/PCP) pathway, and can also modulate canonical (β-catenin-dependent) Wnt signaling depending on receptor context. WNT5A signals through the receptor tyrosine kinase ROR2 (and related receptors) and downstream through Disheveled (DVL1/DVL3) as an obligate intracellular adaptor, activating small GTPases (RhoA, Rac1, Cdc42) and JNK signaling rather than β-catenin/TCF transcription (GeneReviews NBK268648; Mechanistic studies in Drosophila and chicken, DMM 2023, PMC10120075). Suggested GO term: GO:0035567 (non-canonical Wnt signaling pathway) / GO:0060071 (Wnt signaling pathway, planar cell polarity pathway).

Causal chain: WNT5A ligand (reduced/altered activity due to missense variant) → diminished/dysregulated ROR2-mediated non-canonical Wnt signal transduction → impaired DVL-dependent PCP effector activation (Rho/Rac/JNK) → loss of coordinated, polarized cell behavior in developing tissues (chondrocyte columnar alignment, convergent-extension-like elongation movements) → shortened, disorganized cartilage growth plates and abnormal skeletal elongation (mesomelic limb shortening, short stature) plus disrupted craniofacial and genital morphogenesis.

Cellular Processes

  • Chondrocyte planar polarity and columnar organization in growth-plate cartilage is disrupted: WNT5A-C83S-expressing cartilage shows randomly oriented (rather than columnar) chondrocytes and diffuse (rather than polarized) Prickle protein localization, a direct readout of disrupted PCP (Human Molecular Genetics 2019; Research Square/PMC12776500 2025).
  • Convergent-extension-like cell movements required for axial elongation and limb bud patterning depend on non-canonical Wnt (Wnt5/Wnt11) signaling in vertebrate models; impaired Wnt5a signaling is analogous to zebrafish pipetail (wnt5) mutant phenotypes affecting gastrulation cell-shape and movement (PMC1299299; general zebrafish CE literature).
  • Limb bud initiation, digit patterning, joint formation, limb rotation, and proximal-distal axis establishment are all regulated by Wnt/PCP signaling gradients, explaining the mesomelic (mid-segment) predominance of limb shortening.

Protein Dysfunction

WNT5A is a secreted, lipid-modified signaling glycoprotein. Disease variants cluster on a modeled protein surface implicated in receptor/co-receptor engagement, consistent with altered protein-protein interaction rather than global misfolding or complete loss of secretion.

Tissue Damage / Organ-Level Mechanism

No classical oxidative-stress, ischemic, or fibrotic tissue-injury mechanism; pathology is developmental/morphogenetic rather than degenerative — abnormal patterning is established prenatally and is largely static postnatally (apart from progressive scoliosis in some).

Comparative Genotype-Mechanism Note

This is a key mechanistic distinction curators should capture: WNT5A (DRS1) variants act through the ligand with a hypomorphic/altered-signaling effect, while DVL1/DVL3 (DRS2/DRS3) variants act through downstream truncated adaptor proteins with a putative gain-of-function effect — both converging on the same non-canonical Wnt/PCP pathway but via mechanistically distinct routes, which may explain phenotypic differences (e.g., osteosclerosis/increased bone density specifically associated with DVL1, cardiac defects more frequent with DVL3) (GeneReviews NBK268648; PMC10120075).

Craniofacial-Specific Mechanism

In mandibular development, abnormal WNT5A signaling has been shown to specifically cause mandibular hypoplasia through effects on neural-crest-derived skeletal precursors (Hosseini-Farahabadi et al. 2017, J Dent Res). Conditional mouse loss- vs. gain-of-function Wnt5a alleles produce distinct, sometimes opposite craniofacial phenotypes (loss-of-function: midface hypoplasia, hypertelorism trend; gain-of-function: macrocephaly, shortened hard palate, micrognathia), mirroring the phenotypic heterogeneity seen clinically across Robinow syndrome subtypes (JBMR Plus 2024; PMC12330612, 2025).

Molecular Profiling / Omics

No large-scale transcriptomic, proteomic, metabolomic, or single-cell dataset specific to human WNT5A-Robinow syndrome tissue was identified; mechanistic insight instead derives from model-organism functional assays (zebrafish, Xenopus, chicken, Drosophila, mouse knock-in) rather than human -omics profiling — an important evidentiary caveat for curation (favor evidence_source: MODEL_ORGANISM/IN_VITRO for most mechanistic claims, HUMAN_CLINICAL only for phenotype/variant description).

Suggested GO biological process terms: GO:0035567 (non-canonical Wnt signaling pathway), GO:0060071 (PCP pathway), GO:0001501 (skeletal system development), GO:0060349 (bone morphogenesis). Suggested CL cell type terms: CL:0000138 (chondrocyte), CL:0000058 (chondroblast).

7. Anatomical Structures Affected

Organ level (primary): Skeletal system (long bones — mesomelic segments; axial skeleton — vertebrae), craniofacial skeleton, external genitalia. Secondary: cardiovascular system (minority with structural heart defects), renal system (minority), dentition.

Body systems: Skeletal, craniofacial, genitourinary, and (variably) cardiovascular and renal systems — UBERON: limb (UBERON:0002101), forearm/mesomelic segment, vertebral column (UBERON:0001130), mandible (UBERON:0000926), external genitalia (UBERON:0000474), heart (UBERON:0000948), kidney (UBERON:0002113).

Tissue/cell level: Growth-plate cartilage (chondrocytes, CL:0000138) is the principal affected tissue — polarity/columnar organization defects there directly underlie the limb-shortening phenotype. Craniofacial neural-crest-derived skeletal precursors are also implicated (Hosseini-Farahabadi 2017).

Subcellular: WNT5A is a secreted glycoprotein (extracellular space, GO:0005615); receptor complex assembly occurs at the plasma membrane; downstream Disheveled (DVL1) acts in the cytoplasm as a scaffolding adaptor (GO:0005737).

Localization/laterality: Skeletal and craniofacial involvement is generally bilateral/symmetric; mesomelic shortening classically affects forearms more than legs.

8. Temporal Development

Onset: Congenital — features (mesomelic shortening, facial gestalt) are often visible on prenatal ultrasound by ~20 weeks gestation and are present at birth (GeneReviews NBK268648).

Onset pattern: Present from birth (not acute/insidious in the acquired-disease sense).

Progression/course: Largely stable/non-progressive developmental phenotype. The characteristic "fetal facies" gestalt is most pronounced in infancy and becomes less distinctive with age. Scoliosis (when hemivertebrae are present) can be progressive through growth and requires surveillance. Short stature persists into adulthood (typically ≤ −2 SD).

Disease duration: Chronic, lifelong condition; not self-limited.

Remission patterns: Not applicable (structural/developmental disorder, not a relapsing-remitting disease).

Critical periods: Prenatal skeletal and craniofacial morphogenesis (embryonic/fetal limb bud and branchial arch development) is the critical window during which WNT5A signaling perturbation produces the phenotype; postnatal management is chiefly supportive/corrective rather than preventive of primary pathology.

9. Inheritance and Population

Epidemiology: Robinow syndrome overall is very rare; approximately 200 cases have been reported cumulatively across dominant and recessive forms. For the dominant form specifically, Orphanet lists ~100 cases reported, prevalence <1/1,000,000, equal male:female ratio, with cases described from the USA, Arab countries, Turkey, Czech Republic/Slovakia, the Indian subcontinent, and Brazil (Orphanet ORPHA:3107). Fewer than 80 dominant-Robinow families total have been reported in the literature across all three known dominant genes (~8 WNT5A probands, ~18 DVL1, ~7 DVL3, per GeneReviews) (GeneReviews NBK268648).

Inheritance pattern: Autosomal dominant. Approximately 50% of cases are de novo; the remainder are inherited from an affected (often mildly expressing) parent, consistent with Robinow's original multi-generation family.

Penetrance: Appears high/complete for the core skeletal-craniofacial phenotype, though expressivity is markedly variable — severity differs even among relatives sharing the identical WNT5A variant (per Robinow's original family report).

Genetic anticipation: Not reported/established for WNT5A-Robinow syndrome (this is not a repeat-expansion disorder).

Germline mosaicism: Considered a theoretical possibility for recurrence in unaffected parents of a de novo proband; GeneReviews estimates sibling recurrence risk at roughly ~1% in such cases, reflecting this low but non-zero mosaicism risk.

Founder effects/consanguinity: Not documented for the dominant WNT5A form (consanguinity and founder effects are more relevant to the recessive ROR2/NXN forms, which are enriched in certain consanguineous populations, e.g., Turkish, Middle Eastern, Omani cohorts — relevant differential/background context, not DRS1 itself).

Carrier frequency: Not applicable in the traditional sense (dominant disorder); population allele frequency of pathogenic WNT5A missense variants in gnomAD is expected to be essentially absent/private, consistent with a rare, largely de novo dominant disorder (specific gnomAD frequency data not retrieved in this search pass).

Population demographics: No specific ethnic enrichment established for WNT5A-associated DRS1; case reports span multiple continents/ethnicities as above. Sex ratio approximately 1:1.

10. Diagnostics

Diagnostic criteria (GeneReviews): Diagnosis established by (1) typical clinical findings (fetal facies, mesomelic limb shortening, genital hypoplasia ± vertebral/renal anomalies) and/or (2) identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A by molecular genetic testing (GeneReviews NBK268648).

Molecular testing strategy: 1. First-tier: sequence analysis of DVL1 and DVL3 (the more commonly implicated genes), concurrently or sequentially 2. Reflex: WNT5A sequence analysis if DVL1/DVL3 negative 3. Alternative: multigene skeletal-dysplasia panel, or exome/genome sequencing 4. Detection rate: sequence analysis identifies >99% of pathogenic DVL1/DVL3 variants; deletion/duplication analysis is low-yield given the presumed gain-of-function mechanism for those genes.

Imaging/clinical tests: - Skeletal radiographs (mesomelic long-bone shortening, hemivertebrae, brachydactyly) - Prenatal ultrasound (limb shortening, facial features detectable ~20 weeks) - Echocardiography (screen for congenital heart defects) - Renal ultrasound (screen for renal anomalies) - Dental/orthodontic and craniofacial evaluation - Hearing assessment - Developmental assessment

Genetic testing modalities: Single-gene sequencing (WNT5A), multigene panel (WNT5A + DVL1 + DVL3 + ROR2 + NXN + FZD2), or exome/genome sequencing. Chromosomal microarray/karyotype not diagnostically useful (point-mutation disorder). Prenatal molecular testing available once a familial variant is known.

Differential diagnosis:

Condition Distinguishing features
ROR2-related (autosomal recessive) Robinow syndrome Biallelic ROR2 variants; more severe, higher rates of renal/cardiac/cognitive involvement, distal phalangeal clefting (GeneReviews NBK1240)
NXN-related (autosomal recessive) Robinow syndrome Biallelic NXN variants; NXN normally stabilizes Disheveled proteins in the WNT5A-ROR2-DVL axis
DVL3-related (DRS3) Frequent cardiac abnormalities; no osteosclerosis reported
DVL1-related (DRS2) Distinctive macrocephaly (+2.5 to >+6 SD) with osteosclerosis/increased bone density, bilateral hearing loss
Aarskog syndrome (X-linked) Shawl scrotum, widow's peak, ligamentous laxity, syndactyly; lacks mesomelic shortening
Opitz G/BBB syndrome Higher rate of clefting (~50%), laryngotracheoesophageal defects; lacks mesomelic shortening
Achondroplasia Rhizomelic (not mesomelic) shortening, trident hand, leg bowing
FZD2-related Omodysplasia type 2 Normal stature, rhizomelic shortening, no hypertelorism
Smith-Lemli-Opitz syndrome Autosomal recessive cholesterol biosynthesis defect (DHCR7); 2-3 toe syndactyly, polydactyly, distinct biochemical (elevated 7-DHC) signature

Screening: No population-based newborn screening exists (too rare); cascade family testing recommended once a familial variant is identified, given variable expressivity that may mean a "carrier" parent is only subtly affected.

11. Outcome/Prognosis

Survival/mortality: Life expectancy is generally considered normal, in marked contrast to some skeletal dysplasias, except when significant congenital cardiac defects are present — cardiac defects are explicitly described as "a major cause of morbidity and mortality" in ADRS when they occur (GeneReviews NBK268648).

Morbidity/function: Main long-term morbidity drivers are orthopedic (progressive scoliosis, limb-length/short stature issues), dental/orthodontic burden, and (for a minority) renal or cardiac complications. Cognitive function is typically normal, an important prognostic distinction from the recessive ROR2 form, which carries higher rates of developmental delay.

Complications: Progressive scoliosis from hemivertebrae, malocclusion requiring extensive orthodontic/surgical correction, cryptorchidism, hearing loss (more DVL1-associated), and — when present — structural cardiac lesions requiring surgical correction.

Recovery/prognostic factors: Prognosis correlates with which organ systems are involved (particularly cardiac and renal) more than with limb/facial severity per se; genotype (WNT5A vs. DVL1 vs. DVL3) is associated with somewhat different complication profiles (see Section 6/10).

Pregnancy: "Pregnancy in affected women appears to be generally uncomplicated," though cesarean delivery may be needed for abnormal fetal presentation or cephalopelvic disproportion related to maternal skeletal anatomy (GeneReviews NBK268648).

12. Treatment

There is no disease-modifying/curative therapy; management is multidisciplinary and manifestation-directed.

Pharmacotherapy: - Recombinant human growth hormone (rhGH) has been used in children with Robinow syndrome, particularly with documented growth hormone deficiency, with reported significant increase in growth velocity (case example: 0.7 U/kg/week starting at age 4, height rising from <1st to 44th percentile) (Robinow syndrome and its response to growth hormone treatment, PMID:36917807; PMID:10417975). Suggested NCIT term: NCIT:C15986 (Pharmacotherapy) with a specific growth-hormone therapeutic agent. - Hormonal therapy (hCG/testosterone) for micropenis in affected males — NCIT:C15986.

Surgical/Interventional: - Craniofacial team surgical correction of cleft lip/palate — NCIT:C15329 (Surgical Procedure) - Orthopedic surgery for severe scoliosis (hemivertebral/costal anomalies), syndactyly — NCIT:C16186 (Orthopedic Surgical Procedure) - Orchidopexy for cryptorchidism; urological correction for anomalous penile insertion — NCIT:C15329 - Standard cardiothoracic surgical management for congenital heart defects when present

Supportive/rehabilitative: - Orthodontic treatment for malocclusion/crowding — NCIT:C15302-adjacent dental care code, or general therapeutic procedure - Bracing, casting, physical therapy as first-line for musculoskeletal issues before surgery is considered — NCIT:C15302 (Physical Therapy) - Hearing intervention (amplification) for documented hearing loss - Genetic counseling — NCIT:C15240

Experimental/advanced therapeutics: No gene therapy, RNA-based therapy, or targeted molecular therapy specific to WNT5A-Robinow syndrome was identified in the literature searched; this remains a management-only (not mechanism-correcting) treatment landscape at present. No relevant ClinicalTrials.gov interventional trials specific to DRS1 were surfaced in this search.

Treatment strategy/surveillance schedule (per GeneReviews): - Craniofacial/dental evaluation every 6–12 months - Developmental assessment at each visit through childhood/adolescence - Cardiac and renal monitoring if abnormalities identified at baseline - Regular head-circumference measurement in infancy/childhood

13. Prevention

Primary prevention: Not applicable in the classic sense (monogenic disorder); the only "primary prevention" avenue is reproductive genetic counseling and prenatal/preimplantation genetic testing once a familial WNT5A variant is identified.

Secondary prevention (early detection): Prenatal ultrasound can detect the mesomelic limb-shortening and craniofacial phenotype from ~20 weeks gestation in at-risk pregnancies, enabling early postnatal multidisciplinary planning (GeneReviews NBK268648).

Tertiary prevention: Scheduled surveillance (craniofacial, cardiac, renal, developmental, scoliosis) is aimed at preventing/mitigating secondary complications rather than the primary skeletal dysplasia itself.

Genetic counseling: Central to prevention/family planning — 50% recurrence risk to offspring of an affected parent; ~1% empiric recurrence risk to siblings of a de novo proband (accounting for possible parental germline mosaicism); prenatal and preimplantation genetic testing available once the familial variant is known.

Screening: No population-level screening program exists given the extreme rarity; family cascade testing is the operative screening paradigm.

Immunization/infectious prophylaxis: Not applicable — non-infectious etiology.

14. Other Species / Natural Disease

Taxonomy of affected species used in models: Danio rerio (zebrafish, NCBITaxon:7955), Xenopus laevis (NCBITaxon:8355), Gallus gallus (chicken, NCBITaxon:9031), Drosophila melanogaster (NCBITaxon:7227), Mus musculus (mouse, NCBITaxon:10090).

Naturally occurring disease in other species: A DVL1-related Robinow syndrome phenotype has been documented in chicken (Gallus gallus), catalogued in OMIA as OMIA:002654-9031 (OMIA) — this is the DVL1 (DRS2) ortholog rather than WNT5A/DRS1 specifically, but is relevant comparative context within the same gene family/pathway. No naturally occurring WNT5A-specific Robinow phenotype in a companion-animal or veterinary population was identified in this search (contrast with the well-documented naturally occurring ROR2-related "brachycephalic/mesomelic dwarfism" in some cattle and dog breeds, which is a separate ROR2-pathway veterinary correlate worth checking OMIA directly if curating comparative content).

Orthologous gene: WNT5A is highly conserved across vertebrates; mouse Wnt5a, zebrafish wnt5b (a paralog performing an analogous non-canonical signaling role), chicken WNT5A, and Xenopus Wnt5a orthologs are all used experimentally (see Section 15).

Comparative pathology: Across species, loss or dysregulation of Wnt5a/non-canonical Wnt signaling produces convergent phenotypes of shortened/disorganized body axis, disrupted convergent-extension gastrulation movements, and craniofacial/limb skeletal patterning defects — indicating strong evolutionary conservation of the underlying PCP mechanism (see zebrafish pipetail mutant, PMC1299299).

Zoonotic potential: Not applicable — this is a developmental/genetic disorder, not a transmissible disease.

15. Model Organisms

Model Type Key findings
Mouse Wnt5a germline knockout Genetic (knockout), mammalian Non-viable beyond birth; embryos show major shortening of the body axis, appendicular skeleton, and jaws, with disrupted chondrocyte polarity — directly recapitulating limb-shortening and craniofacial pathology (general Wnt5a knockout literature; Bone Research overview)
Mouse Wnt5a-C83S knock-in Genetic (patient-variant knock-in), mammalian Models the recurrent human C83S allele; shows spatially disorganized/randomized chondrocyte alignment and diffuse Prickle localization in cartilage, directly linking the human variant to PCP disruption (HMG 2019; PMC12776500, 2025)
Mouse conditional Wnt5a loss- and gain-of-function (craniofacial/bone-specific) Genetic, conditional, mammalian Produces distinct, sometimes opposite craniofacial phenotypes (LOF: midface hypoplasia/hypertelorism; GOF: macrocephaly, shortened palate, micrognathia), modeling the phenotypic heterogeneity seen across human Robinow subtypes (JBMR Plus 2024; PMC12330612)
Zebrafish (Danio rerio) WNT5A functional assay Genetic/induced, non-mammalian vertebrate Person et al. used zebrafish assays to demonstrate that both identified WNT5A missense variants cause decreased WNT5A activity (PMID:19918918); pipetail (wnt5) mutants show classic convergent-extension gastrulation defects analogous to disrupted PCP signaling
Xenopus laevis WNT5A overexpression/functional assay Genetic/induced, non-mammalian vertebrate Used alongside zebrafish to confirm reduced signaling activity of disease variants (PMID:19918918)
Chicken (Gallus gallus) DVL1 mechanistic model Genetic/induced, avian Used with Drosophila to dissect DVL1 mechanism (loss of canonical β-catenin signaling with gain of non-canonical JNK/PCP signaling) — DRS2 pathway-comparator, catalogued as naturally-relevant in OMIA:002654-9031 (DMM 2023, PMC10120075)
Drosophila melanogaster DVL1-variant wing/disease model Genetic, invertebrate Expression of patient-derived DVL1 variants causes major disorganization of wing morphology versus wild-type, supporting a gain-of-function/PCP-disruption mechanism transferable conceptually to the WNT5A pathway (bioRxiv 2024.09.10.612347; Developmental Dynamics 2025)

Model limitations: No model fully recapitulates the complete human multi-organ phenotype (craniofacial + skeletal + genital + cardiac + renal) simultaneously; mouse germline Wnt5a nulls are non-viable, limiting study of postnatal/adult phenotype, which is why knock-in (patient-variant) and conditional models have become the preferred tools for modeling the milder, viable human dominant phenotype. Non-mammalian models (zebrafish, Xenopus, chicken, Drosophila) are valuable for rapid functional variant classification (gain vs. loss of function) but cannot model human-specific structures (dentition, genital anatomy) or long-term skeletal growth-plate biology as faithfully as mammalian systems.

Applications: These models collectively support (1) variant functional classification (pathogenic missense vs. benign), (2) mechanistic dissection of canonical-vs-non-canonical Wnt pathway involvement, (3) chondrocyte planar-polarity read-outs as a cellular biomarker of pathogenicity, and (4) comparative dissection of WNT5A (ligand-level, hypomorphic) versus DVL1/DVL3 (adaptor-level, gain-of-function) disease mechanisms within the same overall pathway.

Summary of Key Ontology Term Suggestions for KB Curation

Category Suggested term(s)
Disease OMIM:180700, DOID:0060766, ORPHA:3107
Causal gene hgnc:12784 (WNT5A)
Pathway/BP GO:0035567 (non-canonical Wnt signaling), GO:0060071 (Wnt/PCP pathway), GO:0001501 (skeletal system development)
Cell type CL:0000138 (chondrocyte)
Anatomy UBERON:0002101 (limb), UBERON:0001130 (vertebral column), UBERON:0000926 (mandible), UBERON:0000474 (external genitalia)
Key phenotypes HP:0003027 (mesomelic limb shortening), HP:0004322 (short stature), HP:0000316 (hypertelorism), HP:0000256 (macrocephaly), HP:0002937 (hemivertebrae), HP:0001156 (brachydactyly), HP:0000054 (micropenis), HP:0001627 (abnormal heart morphology)
Treatment NCIT:C15986 (Pharmacotherapy — GH, hCG/testosterone), NCIT:C16186 (Orthopedic Surgical Procedure), NCIT:C15302 (Physical Therapy), NCIT:C15329 (Surgical Procedure), NCIT:C15240 (Genetic Counseling)

Notable Evidence Gaps for Curators

  1. DRS1 (WNT5A) is under-represented in recent mechanistic literature relative to DRS2/DRS3 (DVL1/DVL3) — most 2023–2025 primary mechanistic papers found in this search (Drosophila, chicken, zebrafish DVL work) concern DVL1/DVL3, not WNT5A directly; WNT5A mechanistic evidence is mostly from Person et al. 2010 plus the C83S knock-in mouse line (2019, 2025).
  2. No human transcriptomic/proteomic/single-cell dataset specific to WNT5A-Robinow patient tissue was located — mechanistic claims should be sourced as MODEL_ORGANISM/IN_VITRO, not HUMAN_CLINICAL.
  3. Exact PMID for the original 1969 Robinow, Silverman & Smith description was not resolved via search (pre-PubMed-indexing era article); if required for citation, retrieve directly from Am J Dis Child 1969;117:645–651 via a library/DOI lookup rather than PubMed search.
  4. No NCT-registered interventional trial specific to DRS1/WNT5A-Robinow syndrome was identified.

Sources: OMIM #180700 · OMIM #616331 · OMIM #616894 · GeneReviews — Autosomal Dominant Robinow Syndrome (NBK268648) · GeneReviews — ROR2-Related Robinow Syndrome (NBK1240) · Orphanet ORPHA:3107 · Person et al. 2010, Dev Dyn, PMID:19918918 · White et al. 2015, AJHG, PMID:25817016 · Roifman et al. 2015, PMID:25817014 · Human Molecular Genetics 2019 — WNT5A-C83S dominant interference · PMC12776500 — Wnt5a-C83S knock-in chondrocyte polarity 2025 · PMC10120075 — DVL1 mechanistic studies in Drosophila/chicken · JBMR Plus 2024 — Wnt5a gain/loss-of-function craniofacial bone · PMC12330612 · Hosseini-Farahabadi et al. 2017, J Dent Res · Robinow syndrome and growth hormone treatment, PMID:36917807 · PMID:10417975 · OMIA:002654-9031 (chicken DVL1-related Robinow) · Disease Ontology DOID:0060766

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