Autosomal Dominant Robinow Syndrome 3

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous pathogenic DVL3 variants cause autosomal dominant disease. De novo variants are confirmed in individual reports, but their overall fraction is unknown. Two founding probands had clinically affected parents who had not undergone molecular testing, so those family histories do not establish variant segregation. An affected heterozygote has a 50% transmission probability with variable expression; parental assessment and testing refine recurrence counseling.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"We identified the novel de novo splice acceptor mutation c.1715-2A > C in DVL3 in a 15-year-old female patient with typical features of Robinow syndrome."

A molecularly reported de novo case, not a population de novo rate.

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."

Transmission probability applies to a heterozygous affected parent, with variable clinical expression.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"He has yet to be tested for DVL3 mutations."

Supplemental report explicitly states that BAB7990's clinically affected father was untested.

+ 1 more reference

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Discussions and Knowledge Gaps

1

Which effects of the altered DVL3 C terminus account for developmental abnormalities, especially the cardiac phenotype?

KNOWLEDGE GAP dvl3_frameshift_mode_of_action

Attached to

pathophysiology#Abnormal Dishevelled-mediated WNT transduction pathophysiology#Cardiac morphogenetic disruption

Terminal phosphorylation, polymerization and receptor interactions are plausible mechanisms, but the cited DVL3 patient studies measure RNA and clinical findings rather than these functional outcomes. DVL1 canonical reporter direction depends on cell system and expression context, and its nuclear enrichment is observed in HEK cells but not fly follicle cells. No equivalent DVL3 variant-versus-stop experiment in the reviewed sources resolves a universal gain or loss. Dvl3-null mouse heart defects support a developmental role without proving the effect of human terminal alleles. The comparison uses the DVL1 studies PMID:36916233 and PMID:42424595; their constructs and model-specific outcomes are not DVL3 functional measurements.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Other

"Further work is necessary to elucidate the mechanism by which these speciﬁc mutations in DVL1 and DVL3 result in DRS and their interactions within the global Wnt signalosome."

The discovery authors explicitly identify an unresolved mechanism, supporting this knowledge gap rather than serving as the positive evidence for WNT involvement.

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Pathophysiology

9

Selected DVL3 terminal-region alteration

Selected heterozygous coding deletions in the final two exons and splice-acceptor variants alter the terminal reading frame. Both single-base and four-base coding deletions are reported. The disease association depends on sequence consequence rather than any arbitrary DVL3 truncation.

DVL3 hgnc:3087

Genetic context DVL3 hgnc:3087 zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN

Selected terminal-sequence alterations; dominant-negative and gain-of-function contributions are not resolved for DVL3.

Downstream

Altered terminal DVL3 reading frame Coding indels directly change frame, while selected splice variants do so through altered exon processing.

Show evidence (2 references)

PMID:26924530 SUPPORT PRIMARY RESULT Human Clinical

"including two splice acceptor mutations and three 1 bp deletions."

The founding series contained two molecular variant classes, not three distinct mutational mechanisms.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"Two individuals (2 out of 22, 9%) were found to have novel variants in DVL3."

Table 1 reports a de novo c.1751_1754delATCG coding deletion and c.1715-2delA with unknown inheritance; the selected fraction is not prevalence.

Altered terminal DVL3 reading frame

Selected coding and splice variants generate the characteristic minus-one frame. In the 2018 c.1715-2A>C case, patient RNA showed deletion of four nucleotides at the start of exon 15. The two 2016 splice substitutions were instead predicted to use a cryptic acceptor two bases downstream; that computational result must not be confused with the later observed four-base deletion.

Downstream

Persistence of mutant DVL3 transcript The terminal premature stop architecture predicts escape from nonsense-mediated decay; selected patient transcripts were measured.

Show evidence (2 references)

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"Mutant DVL3 mRNAs were found to harbor a deletion of four nucleotides at the beginning of exon 15 and encode a protein product with a distinct -1 reading-frame C-terminus."

Direct RNA result for c.1715-2A>C in one patient.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Computational

"In silico prediction of the splice-altering SNVs by the Human Splicing Finder ... web tool predicts the activation of a ... cryptic splice acceptor site 2 bp down- stream of the canonical splice acceptor site in both mutant tran- scripts."

Human Splicing Finder prediction for c.1715-1G>A and c.1715-2A>G; patient RNA was not reported for these two alleles.

Persistence of mutant DVL3 transcript

Both normal and altered transcripts are detectable in tested patient-derived samples. The 2016 coding-deletion case showed no reduction in overall DVL3 RNA expression, and the 2018 splice case also expressed both alleles. These observations support escape from nonsense-mediated decay for the assayed variants, without measuring protein abundance in developing organs.

Downstream

Altered DVL3 C-terminal sequence Persistent RNA permits translation of a predicted altered protein; physiological protein abundance is unmeasured.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"both mutant and wild-type transcripts of DVL3 were expressed"

The 2016 lymphoblastoid cell study examined the c.1716delC carrier BAB4569.

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"By studying DVL3 transcripts in this patient, we confirmed expression of both wild-type and mutant alleles."

Independent patient RNA observation for a splice-acceptor variant.

Altered DVL3 C-terminal sequence

The altered frame replaces the native DVL3 C terminus with a distinctive peptide, while preserving upstream functional domains. The 2018 sequence analysis identifies 83 shared novel residues before the stop codon. Sequence inference and RNA detection do not establish mutant protein stability, localization or signaling direction in patient tissues.

Downstream

Abnormal Dishevelled-mediated WNT transduction Altered terminal sequence plausibly changes Dishevelled interactions, but DVL3-variant-specific functional intermediates remain incompletely defined.

Show evidence (1 reference)

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"mutant DVL3 proteins associated with Robinow syndrome show truncation of the C-terminus and share 83 novel amino acid residues before the stop codon"

C-terminal consequence inferred from the confirmed RNA sequence; no direct patient-protein assay is claimed.

Abnormal Dishevelled-mediated WNT transduction

Mechanism confidence: Provisional

DVL proteins route canonical and noncanonical WNT signals. DVL3 terminal variants are proposed to perturb phosphorylation, localization, multimerization or receptor interactions, but their physiological signaling effect has not been established by the cited patient studies. Context-dependent DVL1 reporter and localization results do not determine the DVL3 mechanism.

Wnt signaling pathway GO:0016055 ⚠ ABNORMAL Wnt signaling pathway, planar cell polarity pathway GO:0060071 ⚠ ABNORMAL

Downstream

Skeletal morphogenetic disruption Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular intermediates remain unresolved.

Craniofacial morphogenetic disruption Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular intermediates remain unresolved.

Genital morphogenetic disruption Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular intermediates remain unresolved.

Cardiac morphogenetic disruption Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular intermediates remain unresolved.

Show evidence (1 reference)

PMID:35047859 SUPPORT BACKGROUND Other

"Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A)."

The study summarizes pathway convergence including DVL3. This supports the pathway-level placement, not a measured direction or exact cellular effect of the disease-associated terminal alleles.

Skeletal morphogenetic disruption

Mechanism confidence: Provisional

DVL3 disease affects limb development, causing variable shortening and digital anomalies. The reported patient series do not directly measure growth-plate polarity or chondrocyte differentiation; Ror2-null and DVL1 overexpression findings cannot establish a DVL3-specific cellular lesion. Pectus excavatum is also reported in a molecularly characterized DVL3 patient. Radial head dislocation, hemivertebrae and scoliosis are retained from the cross-genotype GeneReviews baseline; unlike the primary DVL3 digit and pectus findings cited here, these sources do not establish a DVL3-specific developmental association, so this node does not assign them a causal edge.

Downstream

Mesomelic Limb Shortening Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Short Stature Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Brachydactyly Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Broad hallux Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Clinodactyly Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Hypoplastic phalanges Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Syndactyly Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Camptodactyly Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Broad thumb Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Bifid phalanges Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Pectus excavatum A thoracic skeletal finding reported in a DVL3 proband; the specific developmental intermediates are unknown.

Show evidence (1 reference)

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"The phenotype of the Robinow syndrome-affected female reported here is typical as she shows mesomelia and mild hand anomalies as well as characteristic facial anomalies."

Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.

Craniofacial morphogenetic disruption

Mechanism confidence: Provisional

Development of facial and oral structures is altered, with variable eye spacing, nasal, mandibular, dental, tongue and cleft findings. A single frontonasal outgrowth defect has not been demonstrated to explain all DVL3-associated features.

Downstream

Hypertelorism Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Bifid Tongue Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Hypodontia Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Frontal bossing Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Anteverted nares Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Midface retrusion Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Dental malocclusion Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Dental crowding Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Delayed eruption of permanent teeth Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Gingival overgrowth Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Wide nasal bridge Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Depressed nasal bridge Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Prominent eyes Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Short nose Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

High anterior hairline Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Broad nasal tip Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Long philtrum Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Low-set ears Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Wide retromolar ridge Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Alveolar ridge deformation Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Cleft lip Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Cleft palate Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Triangular mouth Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

High forehead Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Upslanted palpebral fissures Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Telecanthus Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Micrognathia Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Long eyelashes Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Blue sclerae Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Epicanthus Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Show evidence (1 reference)

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"The phenotype of the Robinow syndrome-affected female reported here is typical as she shows mesomelia and mild hand anomalies as well as characteristic facial anomalies."

Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.

Genital morphogenetic disruption

Mechanism confidence: Provisional

Genital developmental abnormalities occur in both sexes, with variable expression. Male hypoplasia is a core finding across genotype groups, whereas only one of four assessed DVL3 females in the 2022 compilation had genital hypoplasia. The DVL3-specific tissue mechanism remains unresolved.

Downstream

Micropenis Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Cryptorchidism Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Hypoplastic Labia Majora Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Clitoral Hypoplasia Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Small scrotum Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Buried penis Clinical anatomical association; the underlying DVL3-specific genital developmental mechanism remains unresolved.

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"female genital hypoplasia (25%, N = 1 out of 4)"

Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.

Cardiac morphogenetic disruption

Mechanism confidence: Provisional

Structural heart defects are prominent in the selected DVL3 literature, including complex lesions. Mouse Dvl3 loss-of-function studies provide developmental context, but the cardiac effect of the distinctive human terminal alleles cannot be equated with a null allele.

Downstream

Congenital Heart Defect Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Hypoplastic right heart Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Hypoplastic left heart Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Pulmonary atresia Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Aberrant subclavian artery Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Ventricular septal defect Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Patent ductus arteriosus Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Patent foramen ovale Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Tricuspid regurgitation Clinical developmental association; feature-specific tissue intermediates remain incompletely established.

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"Congenital heart defects were more common in RS subjects who have pathogenic variants in DVL3 (78%, N = 7 out of 9)"

Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.

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Pathograph

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Phenotypes

68

Cardiovascular 9

Congenital Heart Defect Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"Congenital heart defects were more common in RS subjects who have pathogenic variants in DVL3 (78%, N = 7 out of 9)"

DVL3-specific case count with missing data and overlap with previously published cohorts.

Hypoplastic right heart Hypoplastic right ventricle HP:0010954

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Hypoplastic left heart Hypoplastic left ventricle HP:0004383

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Pulmonary atresia Pulmonary artery atresia HP:0004935

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Aberrant subclavian artery Abnormal subclavian artery morphology HP:0031251

The source does not establish a right-sided aberrant artery or a right aortic arch. The anatomy binding therefore remains at subclavian artery morphology without imposing either configuration.

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"She was born with a VSD."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Patent ductus arteriosus HP:0001643

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"persistent ductus arteriosus (PDA), patent foramen ovale ( PFO) and tricuspid regurgitation."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Patent foramen ovale HP:0001655

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"persistent ductus arteriosus (PDA), patent foramen ovale ( PFO) and tricuspid regurgitation."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Tricuspid regurgitation HP:0005180

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"persistent ductus arteriosus (PDA), patent foramen ovale ( PFO) and tricuspid regurgitation."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Digestive 3

Umbilical hernia HP:0001537

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Umbilical hernia /C0/C0 /C0 þ Seizures /C0/C0 /C0 /C0 Hearing loss /C0/C0 þ /C0"

Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction. Clinical counts were checked against the HTML table; these are selected-case observations.

Omphalocele HP:0001539

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"increased prevalence of omphalocele (43%, N = 3 out of 7)"

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Congenital short gut Congenital shortened small intestine HP:0030889

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"born with omphalocele, short gut, multiple congenital heart defects"

Supplemental case report of a molecularly characterized DVL3 proband; recorded as an individual clinical observation without assigning population frequency or mechanistic causality.

Ear 2

Low-set ears HP:0000369

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 across dominant Robinow genotypes; this is a clinical synthesis rather than a DVL3-specific frequency estimate.

Hearing Loss Hearing impairment HP:0000365

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"She has bilateral cataracts and 50% unilateral hearing loss."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Eye 3

Hypertelorism HP:0000316

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 DVL3-specific frequency estimate.

Blue sclerae HP:0000592

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Blue sclerae þ ND þ/C0 Epicanthal folds /C0 ND þ/C0"

Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction. Clinical counts were checked against the HTML table; these are selected-case observations.

Cataract HP:0000518

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"She has bilateral cataracts and 50% unilateral hearing loss."

Supplemental case report of a molecularly characterized DVL3 proband; recorded as an individual clinical observation without assigning population frequency or mechanistic causality.

Genitourinary 6

Micropenis HP:0000054

Show evidence (2 references)

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 DVL3-specific frequency estimate.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"His penis was buried but of normal size"

Supplemental BAB7982 description distinguishes appearance from penile length.

Cryptorchidism HP:0000028

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 DVL3-specific frequency estimate.

Hypoplastic Labia Majora HP:0000059

Show evidence (2 references)

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 DVL3-specific frequency estimate.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"female genital hypoplasia (25%, N = 1 out of 4)"

Combined female-genital endpoint, not separate penetrance for labial and clitoral findings.

Clitoral Hypoplasia HP:0000060

Show evidence (2 references)

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 DVL3-specific frequency estimate.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"female genital hypoplasia (25%, N = 1 out of 4)"

Combined female-genital endpoint, not separate penetrance for labial and clitoral findings.

Small scrotum HP:0000046

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 DVL3-specific frequency is inferred.

Vesicoureteral reflux HP:0000076

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"She has pectus excavatum and urinary reflux."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Head and Neck 26

Bifid Tongue HP:0010297

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"downslanted mouth corners, bifid short tongue, gingival hyperplasia,"

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Hypodontia HP:0000668

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 DVL3-specific frequency estimate.

Frontal bossing HP:0002007

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 DVL3-specific frequency is inferred.

Anteverted nares HP:0000463

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 DVL3-specific frequency is inferred.

Midface retrusion HP:0011800

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 DVL3-specific frequency is inferred.

Dental malocclusion HP:0000689

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 DVL3-specific frequency is inferred.

Dental crowding HP:0000678

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 DVL3-specific frequency is inferred.

Delayed eruption of permanent teeth HP:0000696

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 DVL3-specific frequency is inferred.

Gingival overgrowth HP:0000212

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 DVL3. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.

Wide nasal bridge HP:0000431

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 DVL3. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.

Depressed nasal bridge HP:0005280

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 DVL3. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.

Short nose HP:0003196

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 DVL3. This is a selected retrospective dataset, not a general-population penetrance estimate.

High anterior hairline HP:0009890

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 across dominant Robinow genotypes; this is a clinical synthesis rather than a DVL3-specific frequency estimate.

Broad nasal tip HP:0000455

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 across dominant Robinow genotypes; this is a clinical synthesis rather than a DVL3-specific frequency estimate.

Long philtrum HP:0000343

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 across dominant Robinow genotypes; this is a clinical synthesis rather than a DVL3-specific frequency estimate.

Alveolar ridge deformation Abnormal alveolar ridge morphology HP:0006477

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 across dominant Robinow genotypes; this is a clinical synthesis rather than a DVL3-specific frequency estimate.

Cleft lip HP:0410030

Show evidence (2 references)

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.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"cleft lip and/or palate (67%, N = 6 out of 9)"

Combined endpoint; no separate lip-only or palate-only penetrance is inferred.

Cleft palate HP:0000175

Show evidence (2 references)

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.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"cleft lip and/or palate (67%, N = 6 out of 9)"

Combined endpoint; no separate lip-only or palate-only penetrance is inferred.

Macrocephaly HP:0000256

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"was found in two of four individuals with DVL3 mutations and therefore cannot be used to distinguish between DVL1- and DVL3- mediated forms of Robinow syn- drome."

Small discovery series; no universal macrocephaly or absence is asserted.

Triangular mouth HP:0000207

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Triangular mouth /C0/C0 þ /C0 Thin upper lip /C0/C0 /C0 /C0"

Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction. Clinical counts were checked against the HTML table; these are selected-case observations.

High forehead HP:0000348

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"High forehead /C0þ /C0 /C0 Midface hypoplasia þþ þ þ Hypertelorism þþ /C0 /C0"

Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction. Clinical counts were checked against the HTML table; these are selected-case observations.

Upslanted palpebral fissures HP:0000582

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"prominent eyes, upslanted palpebral fissures, long eyelashes, hypertelorism"

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Upslanting palpebral ﬁssures þþ /C0 þ Long eyelashes þþ /C0 /C0"

Table 1 describes four DVL3 probands: þ indicates presence and /C0 absence. The feature-specific count is 3/4; adjacent row context is retained where needed. This is a selected series, not population penetrance.

Telecanthus HP:0000506

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"two out of four individuals had telecan- thus noted instead of true hypertelorism."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Micrognathia HP:0000347

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"gingival hyperplasia, micrognathia, widely spaced nipples,"

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Short neck /C0/C0 /C0 webbed Micrognathia þþ þ /C0"

Table 1 describes four DVL3 probands: þ indicates presence and /C0 absence. The feature-specific count is 3/4; adjacent row context is retained where needed. This is a selected series, not population penetrance.

Long eyelashes HP:0000527

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"prominent eyes, upslanted palpebral fissures, long eyelashes, hypertelorism"

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Epicanthus HP:0000286

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Blue sclerae þ ND þ/C0 Epicanthal folds /C0 ND þ/C0"

Table 1 identifies epicanthal folds in one of three evaluated DVL3 probands; the affected but untested father is not included in that denominator.

Limbs 7

Mesomelic Limb Shortening Mesomelia HP:0003027

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 DVL3-specific frequency estimate.

Dislocated Radial Head HP:0003083

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 DVL3-specific frequency estimate.

Brachydactyly HP:0001156

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 DVL3-specific frequency estimate.

Broad hallux HP:0010055

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 DVL3. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.

Clinodactyly HP:0030084

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"broad and wide fingers, 5th finger clinodactyly."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Skeletal Features Mesomelia þþ þ þ Brachydactyly þþ þ þ Clinodactyly þþ þ þ Syndactyly þ/C0 /C0 /C0"

Table 1 describes four DVL3 probands: þ indicates presence and /C0 absence. The feature-specific count is 4/4; adjacent row context is retained where needed. This is a selected series, not population penetrance.

Syndactyly HP:0001159

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"large duplicated thumb, camptodactyly, syndactyly."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Broad thumb HP:0011304

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Camptodactyly þ/C0 /C0 /C0 Broad thumb þ/C0 /C0 /C0"

Table 1 records a broad thumb in one of four DVL3 probands. The supplemental description of thumb duplication is a separate anatomical observation, not the basis for inferring width.

Musculoskeletal 5

Hemivertebrae HP:0002937

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 DVL3-specific frequency estimate.

Scoliosis HP:0002650

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 DVL3-specific frequency estimate.

Pectus excavatum HP:0000767

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"She has pectus excavatum and urinary reflux."

Supplemental BAB7990 report specifies the chest phenotype; the similarly affected untested father is not counted as a molecularly confirmed case.

Camptodactyly HP:0012385

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"large duplicated thumb, camptodactyly, syndactyly."

Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description and table retain the selected-series context.

Supraumbilical raphe HP:0410276

Show evidence (1 reference)

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"She also exhibited a supraumbilical midline abdominal raphe which has not been observed in other patients with Robinow syndrome."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Respiratory 1

Tracheomalacia HP:0002779

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"chronic lung disease with tracheomalacia and cleft palate, requiring multiple surgeries and a tracheostomy."

Supplemental case report of a molecularly characterized DVL3 proband; recorded as an individual clinical observation without assigning population frequency or mechanistic causality.

Growth 1

Short Stature HP:0004322

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"It is noteworthy that all indi- viduals with DVL3 mutations have short stature,"

Observation restricted to the four clinically described founding probands, superseded as a universal claim by a later normal-height case.

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"In contrast to the clinical data of four previously reported individuals with DVL3-related Robinow syndrome, short stature was not present in this individual at the age of 15 years."

Primary counterexample to obligatory short stature; normal height does not exclude DVL3 disease.

Other 5

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 DVL3. 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 across dominant Robinow genotypes; this is a clinical synthesis rather than a DVL3-specific frequency estimate.

Hypoplastic phalanges

Needs a precise term: the aggregate source does not uniformly identify fingers versus toes or which phalanx is affected. Available HPO search results specify a hand, thumb or distal segment and would add unsupported anatomical precision.

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"hypoplastic phalanges (50%, N = 3 out of 6) among DVL3-associated RS."

Direct clinical observation in a selected reported series; not a population penetrance estimate.

Bifid phalanges

Needs a precise term: the table does not resolve digit identity versus segment numbering, or hand versus foot. A thumb, toe or specific distal-phalanx HPO term would overinterpret the available anatomy.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"Biﬁd ﬁrst and second phalanges þ/C0 /C0 /C0 Hypoplastic phalanges þþ (ﬁfth) /C0/C0"

Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction. Clinical counts were checked against the HTML table; these are selected-case observations.

Buried penis

Needs a precise term: the ontology search returned microphallus, whose definition requires short length with hypospadias. Neither feature is established in this case, so that binding was not used.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"His penis was buried but of normal size"

Supplemental BAB7982 description distinguishes appearance from penile length.

🧬

Genetic Associations

1

DVL3

Gene: DVL3 hgnc:3087 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:26924530 SUPPORT PRIMARY RESULT Human Clinical

"including two splice acceptor mutations and three 1 bp deletions."

The founding series contained two molecular variant classes, not three distinct mutational mechanisms.

PMID:29575616 SUPPORT PRIMARY RESULT Human Clinical

"Mutant DVL3 mRNAs were found to harbor a deletion of four nucleotides at the beginning of exon 15 and encode a protein product with a distinct -1 reading-frame C-terminus."

Direct RNA result for c.1715-2A>C in one patient.

💊

Medical Actions

6

Corrective Surgery for Genital and Orofacial Anomalies

Action: surgical procedure 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 care 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 DVL3-specific frequency is inferred.

Orthodontic Treatment

Action: orthodontic treatment 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: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

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 DVL3-confirmed disease or correction of its developmental mechanism.

Mechanism Target:

Short Stature — May improve growth rate through an endocrine axis in selected patients with deficiency. Genotype-uncharacterized Robinow treatment evidence does not establish correction of DVL3 developmental morphology or genotype-specific efficacy.

Show evidence (2 references)

PMID:10417975 SUPPORT INDIRECT PRIMARY RESULT 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 DVL3-related disease is indirect.

PMID:10417975 SUPPORT INDIRECT PRIMARY RESULT 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: Pharmacotherapy NCIT:C15986

Agent: human chorionic gonadotropin CHEBI:81570 testosterone CHEBI:17347

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 DVL3-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

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Each child of an affected heterozygote has a 50% chance of inheriting the variant; severity cannot be predicted reliably. Offer family-specific counseling, parental assessment/testing and prenatal or preimplantation testing once the familial pathogenic variant is identified. The overall de novo fraction is unknown. 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 (3 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 DVL3-specific recurrence rate.

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."

Transmission probability applies to a heterozygous affected parent; variable expression limits prediction of severity.

🔬

Diagnosis

2

Molecular Genetic Testing

Clinical recognition should be followed by molecular testing for a heterozygous pathogenic or likely pathogenic DVL3 variant with an appropriate terminal-sequence consequence. A VUS neither establishes nor excludes disease. A Robinow/skeletal-dysplasia panel or exome/genome analysis should assess overlapping dominant and recessive genes and adequately cover DVL3 exons 14 and 15 and splice regions, including small indels. High GC content prevented an exome call in one discovery case; assess coverage before interpreting a negative result. The original targeted research protocol does not establish a universal first-line clinical test.

genetic testing NCIT:C15709

Show evidence (3 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.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"heteroge- neous coverage, presumably due to poor capture resulting from high GC content of the region, prevented identiﬁca- tion of this variant allele in our analytical informatics pipe- line."

One coding-deletion case was missed by the initial exome pipeline; this supports checking coverage, not a general exome sensitivity estimate.

Baseline organ and skeletal evaluation

Characterize limb, chest, vertebral and skull findings with appropriate radiographs. Obtain baseline echocardiography, hearing assessment and renal ultrasound; cardiac evaluation is particularly relevant given the observed DVL3 lesion burden. Assess oral clefts, dentition, development, abdominal wall and genital findings, with urologic/endocrine assessment and female pelvic ultrasound as indicated. These are cross-genotype baseline recommendations supplemented by DVL3 case observations.

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 recommends baseline assessment for renal anomalies and hydronephrosis across dominant Robinow genotypes.

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

The founding molecular series identified five unrelated probands, with detailed clinical data for four. The 2022 compilation included ten unrelated DVL3 subjects with variant data. These selected published-case counts are not population prevalence estimates or a current worldwide total.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf SUPPORT PRIMARY RESULT Human Clinical

"In total, one individual with a variant in DVL1 and ﬁve individuals with variants in DVL3 were identiﬁed from the above-described approach."

The ascertainment combines two differently selected referral cohorts; it does not estimate population frequency.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Robinow Syndrome 3:

Aarskog-Scott syndrome Not Yet Curated MONDO:0010589

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 3
synonyms:
- DRS3
- DVL3-related Robinow syndrome
- Robinow syndrome, autosomal dominant 3
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal dominant Robinow syndrome 3
  term:
    id: MONDO:0014819
    label: autosomal dominant Robinow syndrome 3
description: >-
  DVL3-related dominant Robinow syndrome is a developmental disorder with variable limb shortening, craniofacial
  and oral findings, genital abnormalities and a substantial reported burden of congenital heart defects. Cleft
  lip or palate and abdominal wall defects occur in selected series. Short stature is common but not obligatory.

  Selected coding deletions and splice-site variants alter the terminal reading frame of DVL3, producing a
  distinctive C-terminal sequence. Patient RNA studies support persistence of tested mutant transcripts, including
  a directly confirmed splice consequence. The precise effect on Dishevelled signaling remains unresolved;
  DVL1 overexpression findings are mechanistic comparisons rather than measurements of DVL3 disease.

  Diagnosis depends on clinical assessment and appropriate molecular interpretation. Care addresses the individual
  skeletal, craniofacial, cardiac, genital and other findings, with family-specific counseling.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: >-
  This entry covers DVL3-related disease, with other Robinow genes treated as molecular differentials. GeneReviews
  supplies a cross-genotype clinical baseline, not DVL3-specific population frequencies. The 2016 clinical
  table covers four probands, and the 2022 compilation combines selected new and published cases with missing
  phenotype data and overlapping cohorts. Variant-specific RNA observations are distinguished from predicted
  splicing, protein-sequence inference and untested cellular mechanisms. The proportion of de novo cases and
  population penetrance remain unknown. Short stature and macrocephaly vary between patients. Rare renal, nail
  and neurodevelopmental findings inform baseline assessment and surveillance without unsupported DVL3-specific
  frequencies. Clinical findings without a supported mechanistic route remain associations rather than forced
  causal edges. Cataracts, tracheomalacia and congenital short gut are retained as reported single-patient
  observations, without inferring DVL3-specific mechanisms. Other adult medical events in the supplement, including
  ovarian cysts and premature menopause, are not established syndrome-defining findings; broad reproductive
  surveillance or endocrine causation is not inferred from that case. Omphalocele remains a DVL3-associated
  abdominal-wall finding without an invented upstream abdominal-wall mechanism; neither the skeletal nor the
  cardiac node establishes its pathogenesis.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian developmental disorder of a defined signalling pathway.
  isds_skeletal_category:
  - classification_value: mesomelic_and_rhizomesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 15 "Mesomelic and rhizo-mesomelic dysplasias", row
      NOS 15-0070, listed as "Robinow syndrome, DVL3-related" (MIM 616894, AD).
      The 2019 revision (Mortier et al., PMID:31633310) numbered the same group
      17.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The founding molecular series identified five unrelated probands, with detailed clinical data for four.
    The 2022 compilation included ten unrelated DVL3 subjects with variant data. These selected published-case
    counts are not population prevalence estimates or a current worldwide total.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In total, one individual with a variant in DVL1 and ﬁve individuals with variants in DVL3 were identiﬁed
      from the above-described approach.
    explanation: >-
      The ascertainment combines two differently selected referral cohorts; it does not estimate population
      frequency.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous pathogenic DVL3 variants cause autosomal dominant disease. De novo variants are confirmed
    in individual reports, but their overall fraction is unknown. Two founding probands had clinically affected
    parents who had not undergone molecular testing, so those family histories do not establish variant segregation.
    An affected heterozygote has a 50% transmission probability with variable expression; parental assessment
    and testing refine recurrence counseling.
  evidence:
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified the novel de novo splice acceptor mutation c.1715-2A > C in DVL3 in a 15-year-old female
      patient with typical features of Robinow syndrome.
    explanation: >-
      A molecularly reported de novo case, not a population de novo rate.
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    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: >-
      Transmission probability applies to a heterozygous affected parent, with variable clinical expression.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      He has yet to be tested for DVL3 mutations.
    explanation: >-
      Supplemental report explicitly states that BAB7990's clinically affected father was untested.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The mother is reported to have a similar phenotype but she was not examined or tested.
    explanation: >-
      Supplemental 015902 family report; an affected-parent history is not molecularly proven transmission.
pathophysiology:
- name: Selected DVL3 terminal-region alteration
  description: >-
    Selected heterozygous coding deletions in the final two exons and splice-acceptor variants alter the terminal
    reading frame. Both single-base and four-base coding deletions are reported. The disease association depends
    on sequence consequence rather than any arbitrary DVL3 truncation.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:26924530
    reference_title: DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      including two splice acceptor mutations and three 1 bp deletions.
    explanation: >-
      The founding series contained two molecular variant classes, not three distinct mutational mechanisms.
  - 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: >-
      Two individuals (2 out of 22, 9%) were found to have novel variants in DVL3.
    explanation: >-
      Table 1 reports a de novo c.1751_1754delATCG coding deletion and c.1715-2delA with unknown inheritance;
      the selected fraction is not prevalence.
  role: trigger
  genes:
  - preferred_term: DVL3
    term:
      id: hgnc:3087
      label: DVL3
  genetic_context:
    gene:
      preferred_term: DVL3
      term:
        id: hgnc:3087
        label: DVL3
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: Selected terminal-sequence alterations; dominant-negative and gain-of-function contributions are not resolved for DVL3.
  downstream:
  - target: Altered terminal DVL3 reading frame
    causal_link_type: DIRECT
    description: >-
      Coding indels directly change frame, while selected splice variants do so through altered exon processing.
- name: Altered terminal DVL3 reading frame
  description: >-
    Selected coding and splice variants generate the characteristic minus-one frame. In the 2018 c.1715-2A>C
    case, patient RNA showed deletion of four nucleotides at the start of exon 15. The two 2016 splice substitutions
    were instead predicted to use a cryptic acceptor two bases downstream; that computational result must not
    be confused with the later observed four-base deletion.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Mutant DVL3 mRNAs were found to harbor a deletion of four nucleotides at the beginning of exon 15 and
      encode a protein product with a distinct -1 reading-frame C-terminus.
    explanation: >-
      Direct RNA result for c.1715-2A>C in one patient.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In silico prediction of the splice-altering SNVs by the Human Splicing Finder ... web tool predicts the
      activation of a ... cryptic splice acceptor site 2 bp down- stream of the canonical splice acceptor site
      in both mutant tran- scripts.
    explanation: >-
      Human Splicing Finder prediction for c.1715-1G>A and c.1715-2A>G; patient RNA was not reported for these
      two alleles.
  downstream:
  - target: Persistence of mutant DVL3 transcript
    causal_link_type: DIRECT
    description: >-
      The terminal premature stop architecture predicts escape from nonsense-mediated decay; selected patient
      transcripts were measured.
- name: Persistence of mutant DVL3 transcript
  description: >-
    Both normal and altered transcripts are detectable in tested patient-derived samples. The 2016 coding-deletion
    case showed no reduction in overall DVL3 RNA expression, and the 2018 splice case also expressed both alleles.
    These observations support escape from nonsense-mediated decay for the assayed variants, without measuring
    protein abundance in developing organs.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      both mutant and wild-type transcripts of DVL3 were expressed
    explanation: >-
      The 2016 lymphoblastoid cell study examined the c.1716delC carrier BAB4569.
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      By studying DVL3 transcripts in this patient, we confirmed expression of both wild-type and mutant alleles.
    explanation: >-
      Independent patient RNA observation for a splice-acceptor variant.
  downstream:
  - target: Altered DVL3 C-terminal sequence
    causal_link_type: DIRECT
    description: >-
      Persistent RNA permits translation of a predicted altered protein; physiological protein abundance is
      unmeasured.
- name: Altered DVL3 C-terminal sequence
  description: >-
    The altered frame replaces the native DVL3 C terminus with a distinctive peptide, while preserving upstream
    functional domains. The 2018 sequence analysis identifies 83 shared novel residues before the stop codon.
    Sequence inference and RNA detection do not establish mutant protein stability, localization or signaling
    direction in patient tissues.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      mutant DVL3 proteins associated with Robinow syndrome show truncation of the C-terminus and share 83
      novel amino acid residues before the stop codon
    explanation: >-
      C-terminal consequence inferred from the confirmed RNA sequence; no direct patient-protein assay is claimed.
  downstream:
  - target: Abnormal Dishevelled-mediated WNT transduction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered terminal sequence plausibly changes Dishevelled interactions, but DVL3-variant-specific functional
      intermediates remain incompletely defined.
- name: Abnormal Dishevelled-mediated WNT transduction
  description: >-
    DVL proteins route canonical and noncanonical WNT signals. DVL3 terminal variants are proposed to perturb
    phosphorylation, localization, multimerization or receptor interactions, but their physiological signaling
    effect has not been established by the cited patient studies. Context-dependent DVL1 reporter and localization
    results do not determine the DVL3 mechanism.
  biological_scale: CELLULAR
  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: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar
      cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A).
    explanation: >-
      The study summarizes pathway convergence including DVL3. This supports the pathway-level placement, not
      a measured direction or exact cellular effect of the disease-associated terminal alleles.
  role: central_effector
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: 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: Skeletal morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular
      intermediates remain unresolved.
  - target: Craniofacial morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular
      intermediates remain unresolved.
  - target: Genital morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular
      intermediates remain unresolved.
  - target: Cardiac morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human genotype-phenotype association supports a developmental consequence, but tissue-specific molecular
      intermediates remain unresolved.
- name: Skeletal morphogenetic disruption
  description: >-
    DVL3 disease affects limb development, causing variable shortening and digital anomalies. The reported
    patient series do not directly measure growth-plate polarity or chondrocyte differentiation; Ror2-null
    and DVL1 overexpression findings cannot establish a DVL3-specific cellular lesion. Pectus excavatum is
    also reported in a molecularly characterized DVL3 patient. Radial head dislocation, hemivertebrae and scoliosis
    are retained from the cross-genotype GeneReviews baseline; unlike the primary DVL3 digit and pectus findings
    cited here, these sources do not establish a DVL3-specific developmental association, so this node does
    not assign them a causal edge.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The phenotype of the Robinow syndrome-affected female reported here is typical as she shows mesomelia
      and mild hand anomalies as well as characteristic facial anomalies.
    explanation: >-
      Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Broad hallux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Clinodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Hypoplastic phalanges
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Syndactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Camptodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Broad thumb
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Bifid phalanges
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Pectus excavatum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A thoracic skeletal finding reported in a DVL3 proband; the specific developmental intermediates are
      unknown.
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        She has pectus excavatum and urinary reflux.
      explanation: >-
        Supplemental BAB7990 report specifies the chest phenotype; the similarly affected untested father is
        not counted as a molecularly confirmed case.
- name: Craniofacial morphogenetic disruption
  description: >-
    Development of facial and oral structures is altered, with variable eye spacing, nasal, mandibular, dental,
    tongue and cleft findings. A single frontonasal outgrowth defect has not been demonstrated to explain all
    DVL3-associated features.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The phenotype of the Robinow syndrome-affected female reported here is typical as she shows mesomelia
      and mild hand anomalies as well as characteristic facial anomalies.
    explanation: >-
      Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Bifid Tongue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Hypodontia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Frontal bossing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Anteverted nares
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Midface retrusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Dental malocclusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Dental crowding
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Delayed eruption of permanent teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Gingival overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Wide nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Depressed nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Prominent eyes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Short nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: High anterior hairline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Broad nasal tip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Long philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Wide retromolar ridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Alveolar ridge deformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Cleft lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Triangular mouth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: High forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Upslanted palpebral fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Telecanthus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Long eyelashes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Blue sclerae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Epicanthus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
- name: Genital morphogenetic disruption
  description: >-
    Genital developmental abnormalities occur in both sexes, with variable expression. Male hypoplasia is a
    core finding across genotype groups, whereas only one of four assessed DVL3 females in the 2022 compilation
    had genital hypoplasia. The DVL3-specific tissue mechanism remains unresolved.
  biological_scale: TISSUE
  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: >-
      female genital hypoplasia (25%, N = 1 out of 4)
    explanation: >-
      Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Micropenis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Hypoplastic Labia Majora
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Clitoral Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Small scrotum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Buried penis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical anatomical association; the underlying DVL3-specific genital developmental mechanism remains unresolved.
- name: Cardiac morphogenetic disruption
  description: >-
    Structural heart defects are prominent in the selected DVL3 literature, including complex lesions. Mouse
    Dvl3 loss-of-function studies provide developmental context, but the cardiac effect of the distinctive
    human terminal alleles cannot be equated with a null allele.
  biological_scale: TISSUE
  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: >-
      Congenital heart defects were more common in RS subjects who have pathogenic variants in DVL3 (78%, N
      = 7 out of 9)
    explanation: >-
      Clinical genotype-phenotype observation; downstream tissue mechanisms remain incompletely established.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Congenital Heart Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Hypoplastic right heart
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Hypoplastic left heart
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Pulmonary atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Aberrant subclavian artery
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Patent ductus arteriosus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Patent foramen ovale
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
  - target: Tricuspid regurgitation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue intermediates remain incompletely established.
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 DVL3-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Growth
  name: Short Stature
  description: >-
    Short stature occurred in all four clinically characterized founding probands, but is not obligatory: the
    2018 splice-variant patient had normal stature at age 15. Clinical expression varies and the selected early
    series is not population penetrance.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      It is noteworthy that all indi- viduals with DVL3 mutations have short stature,
    explanation: >-
      Observation restricted to the four clinically described founding probands, superseded as a universal
      claim by a later normal-height case.
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In contrast to the clinical data of four previously reported individuals with DVL3-related Robinow syndrome,
      short stature was not present in this individual at the age of 15 years.
    explanation: >-
      Primary counterexample to obligatory short stature; normal height does not exclude DVL3 disease.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Increased spacing between the eyes is one component of the characteristic facial phenotype. Prominence
    of the eyes is recorded separately.
  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 DVL3-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. The founding
    DVL3 boy had a buried penis of normal size, so that case does not establish true micropenis.
  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 DVL3-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      His penis was buried but of normal size
    explanation: >-
      Supplemental BAB7982 description distinguishes appearance from penile length.
- 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 DVL3-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Hypoplastic Labia Majora
  description: >-
    Underdevelopment of the labia majora is among the female genital findings described across dominant Robinow
    genotypes. The selected 2022 DVL3 compilation found female genital hypoplasia in only one of four assessed
    females; a cross-gene description does not make it obligatory.
  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 DVL3-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: >-
      female genital hypoplasia (25%, N = 1 out of 4)
    explanation: >-
      Combined female-genital endpoint, not separate penetrance for labial and clitoral findings.
- category: Genitourinary
  name: Clitoral Hypoplasia
  description: >-
    Hypoplasia of the clitoris, named with the labial hypoplasia as the female genital presentation. The selected
    2022 DVL3 compilation found female genital hypoplasia in only one of four assessed females; a cross-gene
    description does not make it obligatory.
  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 DVL3-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: >-
      female genital hypoplasia (25%, N = 1 out of 4)
    explanation: >-
      Combined female-genital endpoint, not separate penetrance for labial and clitoral findings.
- category: Skeletal
  name: Dislocated Radial Head
  description: >-
    Radial head dislocation is a less-common finding across dominant Robinow genotypes; no DVL3-specific frequency
    is established here.
  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 DVL3-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Hemivertebrae
  description: >-
    Vertebral segmentation anomalies are part of the cross-genotype dominant Robinow spectrum. GeneReviews
    does not supply a DVL3-specific frequency; they are not established 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 DVL3-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 DVL3-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Bifid Tongue
  description: >-
    A bilobed tongue is a characteristic oral finding across dominant Robinow genotypes and was recorded in
    all three founding DVL3 patients with available tongue data.
  phenotype_term:
    preferred_term: Bifid tongue
    term:
      id: HP:0010297
      label: Bifid tongue
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      downslanted mouth corners, bifid short tongue, gingival hyperplasia,
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Congenital heart defects were reported in 7 of 9 assessed DVL3 cases in the selected 2022 compilation,
    including complex ventricular and outflow lesions. The small retrospective fraction is not a population
    penetrance estimate. Cardiac evaluation is part of the baseline assessment.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  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: >-
      Congenital heart defects were more common in RS subjects who have pathogenic variants in DVL3 (78%, N
      = 7 out of 9)
    explanation: >-
      DVL3-specific case count with missing data and overlap with previously published cohorts.
- 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 DVL3-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 DVL3-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 DVL3-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 DVL3-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 DVL3-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 DVL3-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 DVL3-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 DVL3-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 DVL3-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 DVL3 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 DVL3. 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 DVL3 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 DVL3. 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 DVL3 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 DVL3. 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 DVL3 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 DVL3. 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 DVL3 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 DVL3. 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 DVL3 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 DVL3. 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 DVL3-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 across dominant Robinow genotypes; this is a clinical synthesis rather
      than a DVL3-specific frequency estimate.
- 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 DVL3-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 across dominant Robinow genotypes; this is a clinical synthesis rather
      than a DVL3-specific frequency estimate.
- 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 DVL3-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 across dominant Robinow genotypes; this is a clinical synthesis rather
      than a DVL3-specific frequency estimate.
- 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 DVL3-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 across dominant Robinow genotypes; this is a clinical synthesis rather
      than a DVL3-specific frequency estimate.
- 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 DVL3-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 across dominant Robinow genotypes; this is a clinical synthesis rather
      than a DVL3-specific frequency estimate.
  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 DVL3-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 across dominant Robinow genotypes; this is a clinical synthesis rather
      than a DVL3-specific frequency estimate.
  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: >-
    Orofacial clefting is prominent in selected DVL3 series. The 2022 compilation reports combined cleft lip
    and/or palate in 6 of 9 assessed cases; this cannot be assigned as the frequency of either component alone.
    The founding clinical table recorded palate clefts in three patients, including one with a lip cleft.
  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.
  - 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: >-
      cleft lip and/or palate (67%, N = 6 out of 9)
    explanation: >-
      Combined endpoint; no separate lip-only or palate-only penetrance is inferred.
- name: Cleft palate
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  description: >-
    Orofacial clefting is prominent in selected DVL3 series. The 2022 compilation reports combined cleft lip
    and/or palate in 6 of 9 assessed cases; this cannot be assigned as the frequency of either component alone.
    The founding clinical table recorded palate clefts in three patients, including one with a lip cleft.
  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.
  - 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: >-
      cleft lip and/or palate (67%, N = 6 out of 9)
    explanation: >-
      Combined endpoint; no separate lip-only or palate-only penetrance is inferred.
- category: Craniofacial
  name: Macrocephaly
  description: >-
    Macrocephaly was recorded in two of four founding probands and does not by itself distinguish DVL3 from
    DVL1 disease.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      was found in two of four individuals with DVL3 mutations and therefore cannot be used to distinguish
      between DVL1- and DVL3- mediated forms of Robinow syn- drome.
    explanation: >-
      Small discovery series; no universal macrocephaly or absence is asserted.
- category: Auditory
  name: Hearing Loss
  description: >-
    Hearing Loss was recorded in one of four clinically characterized founding DVL3 probands. This selected-case
    count is not population penetrance.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has bilateral cataracts and 50% unilateral hearing loss.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Triangular mouth
  category: Craniofacial
  description: >-
    Triangular mouth was recorded in one of four clinically characterized founding DVL3 probands. This selected-case
    count is not population penetrance.
  phenotype_term:
    preferred_term: Triangular mouth
    term:
      id: HP:0000207
      label: Triangular mouth
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Triangular mouth /C0/C0 þ /C0 Thin upper lip /C0/C0 /C0 /C0
    explanation: >-
      Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction.
      Clinical counts were checked against the HTML table; these are selected-case observations.
- name: High forehead
  category: Craniofacial
  description: >-
    High forehead was recorded in one of four clinically characterized founding DVL3 probands. This selected-case
    count is not population penetrance.
  phenotype_term:
    preferred_term: High forehead
    term:
      id: HP:0000348
      label: High forehead
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      High forehead /C0þ /C0 /C0 Midface hypoplasia þþ þ þ Hypertelorism þþ /C0 /C0
    explanation: >-
      Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction.
      Clinical counts were checked against the HTML table; these are selected-case observations.
- name: Umbilical hernia
  category: Abdominal
  description: >-
    Umbilical hernia was recorded in one of four clinically characterized founding DVL3 probands. This selected-case
    count is not population penetrance.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Umbilical hernia /C0/C0 /C0 þ Seizures /C0/C0 /C0 /C0 Hearing loss /C0/C0 þ /C0
    explanation: >-
      Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction.
      Clinical counts were checked against the HTML table; these are selected-case observations.
- name: Upslanted palpebral fissures
  category: Craniofacial
  description: >-
    Upslanted palpebral fissures was recorded in three of four clinically characterized founding DVL3 probands.
    This selected-case count is not population penetrance.
  phenotype_term:
    preferred_term: Upslanted palpebral fissure
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      prominent eyes, upslanted palpebral fissures, long eyelashes, hypertelorism
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Upslanting palpebral ﬁssures þþ /C0 þ Long eyelashes þþ /C0 /C0
    explanation: >-
      Table 1 describes four DVL3 probands: þ indicates presence and /C0 absence. The feature-specific count
      is 3/4; adjacent row context is retained where needed. This is a selected series, not population penetrance.
- name: Telecanthus
  category: Craniofacial
  description: >-
    Increased inner-canthal spacing, distinct from true ocular hypertelorism, was noted in two founding DVL3
    probands.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      two out of four individuals had telecan- thus noted instead of true hypertelorism.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
- name: Clinodactyly
  category: Skeletal
  description: >-
    Angulated digits were recorded in all four founding probands. Digit and joint location are not uniformly
    specified.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      broad and wide fingers, 5th finger clinodactyly.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Skeletal Features Mesomelia þþ þ þ Brachydactyly þþ þ þ Clinodactyly þþ þ þ Syndactyly þ/C0 /C0 /C0
    explanation: >-
      Table 1 describes four DVL3 probands: þ indicates presence and /C0 absence. The feature-specific count
      is 4/4; adjacent row context is retained where needed. This is a selected series, not population penetrance.
- name: Micrognathia
  category: Craniofacial
  description: >-
    A small mandible was recorded in three of four founding DVL3 probands.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      gingival hyperplasia, micrognathia, widely spaced nipples,
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Short neck /C0/C0 /C0 webbed Micrognathia þþ þ /C0
    explanation: >-
      Table 1 describes four DVL3 probands: þ indicates presence and /C0 absence. The feature-specific count
      is 3/4; adjacent row context is retained where needed. This is a selected series, not population penetrance.
- name: Omphalocele
  category: Abdominal
  description: >-
    Omphalocele was reported in three of seven assessed DVL3 cases in the 2022 compilation. It is distinct
    from an umbilical hernia.
  phenotype_term:
    preferred_term: Omphalocele
    term:
      id: HP:0001539
      label: Omphalocele
  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: >-
      increased prevalence of omphalocele (43%, N = 3 out of 7)
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
- name: Hypoplastic phalanges
  category: Skeletal
  description: >-
    Underdeveloped phalanges were reported in three of six assessed DVL3 cases in the 2022 compilation.
  phenotype_term:
    preferred_term: Hypoplastic phalanges
  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: >-
      hypoplastic phalanges (50%, N = 3 out of 6) among DVL3-associated RS.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
  notes: >-
    Needs a precise term: the aggregate source does not uniformly identify fingers versus toes or which phalanx
    is affected. Available HPO search results specify a hand, thumb or distal segment and would add unsupported
    anatomical precision.
- name: Hypoplastic right heart
  category: Cardiovascular
  description: >-
    Right-heart hypoplasia is among the complex lesions reported with DVL3 disease. The HPO binding captures
    the defining hypoplastic right ventricle; it does not imply every associated valve lesion.
  phenotype_term:
    preferred_term: Hypoplastic right heart
    term:
      id: HP:0010954
      label: Hypoplastic right ventricle
  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: >-
      individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic
      right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
- name: Hypoplastic left heart
  category: Cardiovascular
  description: >-
    Left-heart hypoplasia is reported in the DVL3 cohort. The phenotype term captures ventricular hypoplasia
    without asserting every accompanying mitral, aortic or arch lesion.
  phenotype_term:
    preferred_term: Hypoplastic left heart
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  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: >-
      individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic
      right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
- name: Pulmonary atresia
  category: Cardiovascular
  description: >-
    Pulmonary atresia is among the complex DVL3-associated cardiac defects and can coexist with ventricular
    hypoplasia.
  phenotype_term:
    preferred_term: Pulmonary atresia
    term:
      id: HP:0004935
      label: Pulmonary artery atresia
  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: >-
      individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic
      right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
- name: Aberrant subclavian artery
  category: Cardiovascular
  description: >-
    An aberrant subclavian artery is reported in the DVL3 cohort; the aggregate text does not specify laterality
    or the precise origin.
  phenotype_term:
    preferred_term: Aberrant subclavian artery
    term:
      id: HP:0031251
      label: Abnormal subclavian artery morphology
  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: >-
      individuals carrying DVL3 pathogenic variants tended to have more complex defects, including hypoplastic
      right heart syndrome, hypoplastic left heart syndrome, pulmonary atresia, and aberrant subclavian artery.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
  notes: >-
    The source does not establish a right-sided aberrant artery or a right aortic arch. The anatomy binding
    therefore remains at subclavian artery morphology without imposing either configuration.
- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    A ventricular septal defect was recorded in two of the four founding DVL3 probands.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She was born with a VSD.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Patent ductus arteriosus
  category: Cardiovascular
  description: >-
    A patent ductus arteriosus was recorded in one founding DVL3 proband.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      persistent ductus arteriosus (PDA), patent foramen ovale ( PFO) and tricuspid regurgitation.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Patent foramen ovale
  category: Cardiovascular
  description: >-
    A patent foramen ovale was recorded in one founding DVL3 proband; this observation alone does not establish
    the cause of another cardiac lesion.
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      persistent ductus arteriosus (PDA), patent foramen ovale ( PFO) and tricuspid regurgitation.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Tricuspid regurgitation
  category: Cardiovascular
  description: >-
    Tricuspid regurgitation was recorded in one founding DVL3 proband, without specifying an underlying valve
    malformation.
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      persistent ductus arteriosus (PDA), patent foramen ovale ( PFO) and tricuspid regurgitation.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Long eyelashes
  category: Ophthalmologic
  description: >-
    Long eyelashes were recorded in two of four founding DVL3 probands.
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      prominent eyes, upslanted palpebral fissures, long eyelashes, hypertelorism
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Blue sclerae
  category: Ophthalmologic
  description: >-
    Blue sclerae were recorded in two of three founding DVL3 probands with available data.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Blue sclerae þ ND þ/C0 Epicanthal folds /C0 ND þ/C0
    explanation: >-
      Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction.
      Clinical counts were checked against the HTML table; these are selected-case observations.
- name: Epicanthus
  category: Ophthalmologic
  description: >-
    Epicanthal folds were recorded in one of three founding DVL3 probands with available data.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Blue sclerae þ ND þ/C0 Epicanthal folds /C0 ND þ/C0
    explanation: >-
      Table 1 identifies epicanthal folds in one of three evaluated DVL3 probands; the affected but untested
      father is not included in that denominator.
- name: Vesicoureteral reflux
  category: Genitourinary
  description: >-
    Urinary reflux was recorded in one of the four founding DVL3 probands. Renal/urinary assessment is part
    of the cross-genotype clinical baseline.
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has pectus excavatum and urinary reflux.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Pectus excavatum
  category: Skeletal
  description: >-
    Pectus excavatum was specifically documented in molecularly characterized proband BAB7990. Other pectus
    anomalies in the founding table are not assigned this subtype without individual description.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has pectus excavatum and urinary reflux.
    explanation: >-
      Supplemental BAB7990 report specifies the chest phenotype; the similarly affected untested father is
      not counted as a molecularly confirmed case.
- name: Syndactyly
  category: Skeletal
  description: >-
    Syndactyly was recorded in one founding DVL3 proband; this small selected series does not establish its
    population frequency.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      large duplicated thumb, camptodactyly, syndactyly.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Camptodactyly
  category: Skeletal
  description: >-
    Camptodactyly was recorded in one founding DVL3 proband; this small selected series does not establish
    its population frequency.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      large duplicated thumb, camptodactyly, syndactyly.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; the wider clinical description
      and table retain the selected-series context.
- name: Broad thumb
  category: Skeletal
  description: >-
    Broad thumb was recorded in one founding DVL3 proband; this small selected series does not establish its
    population frequency.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Camptodactyly þ/C0 /C0 /C0 Broad thumb þ/C0 /C0 /C0
    explanation: >-
      Table 1 records a broad thumb in one of four DVL3 probands. The supplemental description of thumb duplication
      is a separate anatomical observation, not the basis for inferring width.
- name: Bifid phalanges
  category: Skeletal
  description: >-
    Bifid first and second phalanges were recorded in one founding DVL3 proband.
  phenotype_term:
    preferred_term: Bifid phalanges
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Biﬁd ﬁrst and second phalanges þ/C0 /C0 /C0 Hypoplastic phalanges þþ (ﬁfth) /C0/C0
    explanation: >-
      Table 1, four DVL3 probands: þ denotes presence, /C0 absence and ND missing data in this PDF extraction.
      Clinical counts were checked against the HTML table; these are selected-case observations.
  notes: >-
    Needs a precise term: the table does not resolve digit identity versus segment numbering, or hand versus
    foot. A thumb, toe or specific distal-phalanx HPO term would overinterpret the available anatomy.
- name: Supraumbilical raphe
  category: Abdominal
  description: >-
    A supraumbilical midline raphe was described in the 2018 splice-variant patient. It is a single-case observation,
    without an established DVL3-specific frequency.
  phenotype_term:
    preferred_term: Supraumbilical raphe
    term:
      id: HP:0410276
      label: Supraumbilical raphe
  evidence:
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She also exhibited a supraumbilical midline abdominal raphe which has not been observed in other patients
      with Robinow syndrome.
    explanation: >-
      Direct clinical observation in a selected reported series; not a population penetrance estimate.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Bilateral cataracts were described in adult proband BAB4569. This single-case observation does not establish
    the frequency, onset or a DVL3-specific lens mechanism.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has bilateral cataracts and 50% unilateral hearing loss.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; recorded as an individual clinical
      observation without assigning population frequency or mechanistic causality.
- name: Tracheomalacia
  category: Respiratory
  description: >-
    Tracheomalacia with chronic lung disease and tracheostomy was reported in proband BAB7990. The causal relation
    to DVL3 and its population frequency are unestablished.
  phenotype_term:
    preferred_term: Tracheomalacia
    term:
      id: HP:0002779
      label: Tracheomalacia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      chronic lung disease with tracheomalacia and cleft palate, requiring multiple surgeries and a tracheostomy.
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; recorded as an individual clinical
      observation without assigning population frequency or mechanistic causality.
- name: Congenital short gut
  category: Gastrointestinal
  description: >-
    Short gut was reported as present at birth in proband BAB7990 together with omphalocele. The report does
    not establish bowel length, malabsorption severity or a DVL3-specific intestinal mechanism.
  phenotype_term:
    preferred_term: Congenital short gut
    term:
      id: HP:0030889
      label: Congenital shortened small intestine
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      born with omphalocele, short gut, multiple congenital heart defects
    explanation: >-
      Supplemental case report of a molecularly characterized DVL3 proband; recorded as an individual clinical
      observation without assigning population frequency or mechanistic causality.
- name: Buried penis
  category: Genitourinary
  description: >-
    The founding male DVL3 proband had a buried penis of normal size. This describes concealment of a normally
    sized organ, not true micropenis or microphallus.
  phenotype_term:
    preferred_term: Buried penis
  notes: >-
    Needs a precise term: the ontology search returned microphallus, whose definition requires short length
    with hypospadias. Neither feature is established in this case, so that binding was not used.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      His penis was buried but of normal size
    explanation: >-
      Supplemental BAB7982 description distinguishes appearance from penile length.
genetic:
- name: DVL3
  gene_term:
    preferred_term: DVL3
    term:
      id: hgnc:3087
      label: DVL3
  relationship_type: CAUSATIVE
  notes: >-
    DVL3 encodes a Dishevelled paralog. Disease-associated variants include selected one-base and four-base
    coding deletions in the final exons and splice-acceptor substitutions/deletions that converge on the terminal
    minus-one frame. Patient RNA confirmed a four-nucleotide exon-15 deletion for c.1715-2A>C, whereas other
    splice effects remain predicted. De novo cases and familial clinical observations occur; the population
    de novo fraction and penetrance are not established. A variant requires appropriate classification and
    sequence-context interpretation rather than gene membership alone.
  evidence:
  - reference: PMID:26924530
    reference_title: DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      including two splice acceptor mutations and three 1 bp deletions.
    explanation: >-
      The founding series contained two molecular variant classes, not three distinct mutational mechanisms.
  - reference: PMID:29575616
    reference_title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Mutant DVL3 mRNAs were found to harbor a deletion of four nucleotides at the beginning of exon 15 and
      encode a protein product with a distinct -1 reading-frame C-terminus.
    explanation: >-
      Direct RNA result for c.1715-2A>C in one patient.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Clinical recognition should be followed by molecular testing for a heterozygous pathogenic or likely pathogenic
    DVL3 variant with an appropriate terminal-sequence consequence. A VUS neither establishes nor excludes
    disease. A Robinow/skeletal-dysplasia panel or exome/genome analysis should assess overlapping dominant
    and recessive genes and adequately cover DVL3 exons 14 and 15 and splice regions, including small indels.
    High GC content prevented an exome call in one discovery case; assess coverage before interpreting a negative
    result. The original targeted research protocol does not establish a universal first-line clinical test.
  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.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      heteroge- neous coverage, presumably due to poor capture resulting from high GC content of the region,
      prevented identiﬁca- tion of this variant allele in our analytical informatics pipe- line.
    explanation: >-
      One coding-deletion case was missed by the initial exome pipeline; this supports checking coverage, not
      a general exome sensitivity estimate.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
- name: Baseline organ and skeletal evaluation
  description: >-
    Characterize limb, chest, vertebral and skull findings with appropriate radiographs. Obtain baseline echocardiography,
    hearing assessment and renal ultrasound; cardiac evaluation is particularly relevant given the observed
    DVL3 lesion burden. Assess oral clefts, dentition, development, abdominal wall and genital findings, with
    urologic/endocrine assessment and female pelvic ultrasound as indicated. These are cross-genotype baseline
    recommendations supplemented by DVL3 case observations.
  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 recommends baseline assessment for renal anomalies and hydronephrosis across dominant Robinow
      genotypes.
  - 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.
differential_diagnoses:
- name: WNT5A-related Robinow syndrome
  description: >-
    Heterozygous WNT5A disease shares limb, facial and genital findings. Variant-specific ligand biology does
    not establish a universal hypomorphic mechanism or a strict height/head-size distinction. Molecular testing
    separates this disorder from DVL3 disease.
  disease_term:
    preferred_term: autosomal dominant Robinow syndrome 1
    term:
      id: MONDO:0024455
      label: autosomal dominant Robinow syndrome 1
  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
- name: DVL1-related Robinow syndrome
  description: >-
    DVL1-related disease shares the selected terminal-frame architecture and many clinical findings. Macrocephaly
    and osteosclerosis are prominent in its reported cohorts, but height can be normal or short. Macrocephaly
    also occurs with DVL3, and the early absence of reported DVL3 osteosclerosis was not based on systematic
    exclusion. Molecular testing provides the distinction.
  disease_term:
    preferred_term: autosomal dominant Robinow syndrome 2
    term:
      id: MONDO:0014591
      label: autosomal dominant Robinow syndrome 2
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      None of the individuals with DVL3 variants have been reported to have osteosclerosis, but no speciﬁc
      investigation was conducted to exclude it.
    explanation: >-
      The founding paper explicitly limits the proposed skeletal discriminator.
  - 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
    explanation: >-
      Selected DVL1 cohort establishes variable height, not a categorical distinction from DVL3.
- 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:35047859
    reference_title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      AR-RS is associated with biallelic loss-of-function (LoF) variants in the orphan tyrosine kinase receptor,
      ROR2 ... and in the oxidative stress response protein, NXN
    explanation: >-
      Literature synthesis in the cohort introduction establishes the recessive gene 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.
  disease_term:
    preferred_term: Aarskog-Scott syndrome, X-linked
    term:
      id: MONDO:0010589
      label: Aarskog-Scott syndrome, X-linked
- name: ROR2-related autosomal recessive Robinow syndrome
  description: >-
    Biallelic ROR2 variants cause a recessive Robinow syndrome that often has more severe skeletal and vertebral
    involvement. Severity overlaps with dominant forms, and vertebral anomalies do not categorically exclude
    a dominant etiology. Inheritance and molecular testing provide the distinction.
  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: OTHER
    quote_role: BACKGROUND
    snippet: >-
      AR-RS is associated with biallelic loss-of-function (LoF) variants in the orphan tyrosine kinase receptor,
      ROR2 ... and in the oxidative stress response protein, NXN
    explanation: >-
      Literature synthesis in the cohort introduction establishes the recessive gene differential.
  disease_term:
    preferred_term: autosomal recessive Robinow syndrome
    term:
      id: MONDO:0009999
      label: autosomal recessive Robinow syndrome
- name: FZD2-related omodysplasia / Robinow spectrum
  description: >-
    Heterozygous FZD2 variants can produce overlapping limb, facial and genital findings. Phenotypic clustering
    varies by allele class; the molecular result distinguishes this receptor-associated disorder.
  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: >-
      Probands with variants in FZD2 exhibited two phenotypic clusters
    explanation: >-
      Primary phenotype comparison supports overlap while showing allele-associated variation within FZD2 disease.
  disease_term:
    preferred_term: autosomal dominant omodysplasia
    term:
      id: MONDO:0008123
      label: autosomal dominant omodysplasia
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 DVL3-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 DVL3-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: Short Stature
    description: >-
      May improve growth rate through an endocrine axis in selected patients with deficiency. Genotype-uncharacterized
      Robinow treatment evidence does not establish correction of DVL3 developmental morphology or genotype-specific
      efficacy.
  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 DVL3-related disease is indirect.
    quote_role: PRIMARY_RESULT
  - 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
    quote_role: PRIMARY_RESULT
- 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 DVL3-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: >-
    Each child of an affected heterozygote has a 50% chance of inheriting the variant; severity cannot be predicted
    reliably. Offer family-specific counseling, parental assessment/testing and prenatal or preimplantation
    testing once the familial pathogenic variant is identified. The overall de novo fraction is unknown. 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 DVL3-specific
      recurrence rate.
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    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: >-
      Transmission probability applies to a heterozygous affected parent; variable expression limits prediction
      of severity.
  action_category: COUNSELING_INFORMATIONAL
discussions:
- discussion_id: dvl3_frameshift_mode_of_action
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which effects of the altered DVL3 C terminus account for developmental abnormalities, especially the cardiac
    phenotype?
  attaches_to:
  - pathophysiology#Abnormal Dishevelled-mediated WNT transduction
  - pathophysiology#Cardiac morphogenetic disruption
  rationale: >-
    Terminal phosphorylation, polymerization and receptor interactions are plausible mechanisms, but the cited
    DVL3 patient studies measure RNA and clinical findings rather than these functional outcomes. DVL1 canonical
    reporter direction depends on cell system and expression context, and its nuclear enrichment is observed
    in HEK cells but not fly follicle cells. No equivalent DVL3 variant-versus-stop experiment in the reviewed
    sources resolves a universal gain or loss. Dvl3-null mouse heart defects support a developmental role without
    proving the effect of human terminal alleles. The comparison uses the DVL1 studies PMID:36916233 and PMID:42424595;
    their constructs and model-specific outcomes are not DVL3 functional measurements.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      Further work is necessary to elucidate the mechanism by which these speciﬁc mutations in DVL1 and DVL3
      result in DRS and their interactions within the global Wnt signalosome.
    explanation: >-
      The discovery authors explicitly identify an unresolved mechanism, supporting this knowledge gap rather
      than serving as the positive evidence for WNT involvement.
references:
- reference: PMID:26924530
  title: DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.
- reference: PMID:35047859
  title: 'Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.'
- reference: PMID:29575616
  title: Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.
- reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
  title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf
  findings:
  - statement: Publisher full article plus supplemental information for PMID:26924530. The PMID cache contains only the abstract. Main-text and supplemental patient descriptions are included; some PDF table symbols extract as þ (present) and /C0 (absent), and table counts were cross-checked against the fetched PMC HTML version.
- reference: PMID:25577943
  title: Autosomal Dominant Robinow Syndrome.
  tags:
  - GeneReviews
- 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 NBK268648, updated 2019; cross-genotype clinical, diagnostic, management and counseling baseline.
- reference: PMID:36916233
  title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
- reference: PMID:42424595
  title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
- reference: PMID:10417975
  title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'

📚

References & Deep Research

References

9

PMID:26924530

DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.

No top-level findings curated for this source.

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:29575616

Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.

No top-level findings curated for this source.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf

https://ars.els-cdn.com/content/image/1-s2.0-S0002929716000094-mmc2.pdf

1 finding

Publisher full article plus supplemental information for PMID:26924530. The PMID cache contains only the abstract. Main-text and supplemental patient descriptions are included; some PDF table symbols extract as þ (present) and /C0 (absent), and table counts were cross-checked against the fetched PMC HTML version.

PMID:25577943

Autosomal Dominant 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 NBK268648, updated 2019; cross-genotype clinical, diagnostic, management and counseling baseline.

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:42424595

The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.

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.

Autosomal Dominant Robinow Syndrome 3

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References