Autosomal Dominant Robinow Syndrome 2

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous pathogenic variants cause dominant disease. De novo origin was demonstrated in five discovery families with available parental samples; this ascertainment does not establish a population de novo fraction. An affected heterozygote has a 50% variant-transmission probability, with severity incompletely predictable. Parental assessment and testing inform recurrence counseling.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"ADRS is inherited in an autosomal dominant manner."

GeneReviews states the inheritance mode for the dominant forms, of which this is one.

PMID:25817016 SUPPORT Human Clinical

"In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations."

Establishes de novo origin in the families that could be tested.

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Mechanistic Hypotheses

2

Neomorphic Nuclear Mislocalization Model

nuclear_mislocalization_transcription_model EMERGING

Evidence balance 1 support

Nuclear enrichment of altered DVL1 could change transcription or interactions with transcription factors, contributing to developmental abnormalities. This is a proposed consequence of the cellular localization result; no causal transcriptional target or direct connection to cranial osteosclerosis has been established. The model can coexist with altered cytoplasmic signaling.

Pathograph links

Altered DVL1 C-terminal protein sequence -> Nuclear enrichment of altered DVL1 DIRECT Tagged variants become enriched in nuclei of HEK cells; this distribution is not universal across species.

Show evidence (1 reference)

PMID:42424595 SUPPORT PRIMARY RESULT Other

"Further studies are needed to precisely determine whether nuclear DVL1 plays a transcriptional role in eliciting phenotypes in RS."

Author interpretation explicitly leaves the transcriptional consequence untested.

Dominant-Increase Canonical Wnt Co-Expression Model

coexpression_canonical_wnt_gain_model ALTERNATIVE

Evidence balance 1 support 1 refute

The 2015 C2C12 assay found increased canonical WNT reporter output when mutant and wild-type DVL1 were co-expressed. This could contribute to osteosclerosis, but the human bone link is untested. The 2023 HEK293 co-expression experiment instead found reduced output. Cell type, expression dose and experimental design differ, so neither assay is a universal physiological heterozygous state and the results remain unreconciled. Nuclear effects are not excluded by this model.

Pathograph links

Altered DVL1 C-terminal protein sequence -> Context-dependent WNT signal transduction DIRECT The altered C terminus changes transduction, with direction dependent on branch and context.

Show evidence (2 references)

PMID:25817014 SUPPORT In Vitro

"However, when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than that in the wild-type construct alone."

Canonical co-expression gain in a cell-based reporter assay; the proposed osteosclerosis consequence was not directly tested.

PMID:36916233 REFUTE PRIMARY RESULT In Vitro

"When plasmids expressing the variants were added in equimolar concentration with the wtDVL1 plasmid, all three had significant dominant-negative effects on wtDVL1"

Primary HEK293 experiment directly identifies the study recounted in PMID:42424595. The authors propose dose as a possible explanation for the discrepancy with C2C12; no direct reconciliation experiment is reported.

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Discussions and Knowledge Gaps

1

Which context-dependent effects of the altered DVL1 C terminus drive human developmental abnormalities and cranial osteosclerosis?

KNOWLEDGE GAP dvl1_frameshift_mode_of_action

Attached to

pathophysiology#Nuclear enrichment of altered DVL1 pathophysiology#Context-dependent WNT signal transduction mechanistic_hypotheses#coexpression_canonical_wnt_gain_model

Overexpression studies distinguish altered C-terminal sequence from a simple truncation, but both constructs retain some activity. Nuclear enrichment occurs in HEK cells and is not seen in fly follicle cells. Reporter direction depends on pathway and model. Direct targets, patient-tissue localization and the route to excess cranial bone remain unresolved. No allele-directed clinical treatment follows from these observations.

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Pathophysiology

11

Heterozygous DVL1 C-terminal alteration

Selected variants near the DVL1 C terminus cause a minus-one frameshift, replacing the native terminal sequence. Most are small coding insertions/deletions; c.1640-1C>T is a reported splice-acceptor variant with a predicted cryptic-splice/minus-one effect. A generic truncating variant elsewhere in the gene is not equivalent.

DVL1 hgnc:3084

Genetic context DVL1 hgnc:3084 zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN

Selected coding and splice alterations produce a distinctive C-terminal sequence; the composite dominant mechanism cannot be assigned one universal functional category.

Downstream

Persistence of mutant DVL1 transcript The terminal architecture predicts escape from nonsense-mediated decay; patient RNA provides additional support.

Show evidence (2 references)

PMID:25817016 SUPPORT PRIMARY RESULT Human Clinical

"In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1."

Human discovery cohort establishes a restricted allele class.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"BAB13797 was found to have a previously unreported heterozygous splicing variant in DVL1, which is the first splicing variant reported in this gene thus far."

The variant was classified as likely pathogenic; inheritance was unknown and its transcript consequence was predicted rather than measured.

Persistence of mutant DVL1 transcript

Both normal and variant DVL1 transcripts are detectable in sampled patient leukocytes. This supports escape from nonsense-mediated decay for the tested alleles; it is not direct measurement of mutant protein abundance in developing skeletal tissue.

Downstream

Altered DVL1 C-terminal protein sequence Persistent transcript permits production of the altered protein; abundance in human developmental tissue is unmeasured.

Show evidence (1 reference)

PMID:25817016 SUPPORT PRIMARY RESULT Human Clinical

"Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD."

Patient RNA observation, distinct from protein expression assays.

Altered DVL1 C-terminal protein sequence

The frameshift replaces most of the native C terminus while preserving upstream DIX, PDZ and DEP domains. Transfected constructs produce detectable altered protein, but expression level, tag and host cell influence assay interpretation. The novel sequence has effects that differ from a simple stop construct.

Dominant-Increase Canonical Wnt Co-Expression Model Neomorphic Nuclear Mislocalization Model

Downstream

Context-dependent WNT signal transduction The altered C terminus changes transduction, with direction dependent on branch and context.

Nuclear enrichment of altered DVL1 Tagged variants become enriched in nuclei of HEK cells; this distribution is not universal across species.

Cranial osteosclerosis DVL1 genotype is associated with cranial osteosclerosis, but the cellular link remains unresolved.

Altered peripheral bone microarchitecture DVL1-associated peripheral microarchitecture is clinically observed; the intervening cell mechanism is unknown.

Show evidence (1 reference)

PMID:25817014 SUPPORT PRIMARY RESULT In Vitro

"demonstrated unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift mutation."

Transfected GFP-tagged protein assay; no direct patient-bone protein measurement is claimed.

Context-dependent WNT signal transduction

Mechanism confidence: Provisional

DVL1 variants alter canonical and noncanonical WNT outputs. The 2015 C2C12 co-expression assay increased canonical activity, while 2023 HEK293 and fly assays supported reduced canonical output. JNK readouts increase for selected variants in HEK293 cells and in flies but are weaker in 2026 chicken facial cultures. These assays do not establish one direction in all patient tissues.

non-canonical Wnt signaling pathway GO:0035567 ⚠ ABNORMAL Wnt signaling pathway, planar cell polarity pathway GO:0060071 ⚠ ABNORMAL canonical Wnt signaling pathway GO:0060070 ⚠ ABNORMAL

Downstream

Impaired chondrocyte differentiation Altered WNT transduction accompanies impaired chondrogenesis in model tissues; branch-specific causal intermediates remain uncertain.

Disordered cartilage architecture Model cartilage organization is abnormal, but expression of wild-type DVL1 also affects early polarity readouts.

Craniofacial morphogenetic disruption The variant affects facial development in chicken; signaling-to-tissue intermediates are incompletely established.

Genital morphogenetic disruption The human genotype produces genital developmental abnormalities without a directly characterized DVL1-specific tissue pathway.

Show evidence (3 references)

PMID:36916233 SUPPORT PRIMARY RESULT In Vitro

"When plasmids expressing the variants were added in equimolar concentration with the wtDVL1 plasmid, all three had significant dominant-negative effects on wtDVL1"

Direct canonical reporter result in HEK293 cells; the later paper recounts this identifiable primary study.

PMID:42424595 SUPPORT PRIMARY RESULT In Vitro

"Thus, our data suggest that in primary cells, the Robinow syndrome variant DVL11519ΔT and the DVL11519* truncation are both able to weakly activate the WNT canonical and JNK/PCP pathways."

Primary chicken facial cells retain weak activation, unlike the same constructs in DVL-triple-knockout HEK cells.

PMID:36916233 SUPPORT PRIMARY RESULT Model Organism

"Both assays indicated that the DVL1 variants ectopically induced JNK signaling in the wing pouch"

Drosophila Mmp1 and puckered reporter results; wing-hair polarity alone cannot determine whether signaling increased or decreased.

Nuclear enrichment of altered DVL1

Mechanism confidence: Provisional

Tagged DVL1 frameshift proteins are more frequently nuclear in HEK293 cells. In the 2026 DVL-triple-knockout comparison, 1519ΔT is enriched in nuclei while wild type and the 1519-stop construct are mainly cytoplasmic. In Drosophila follicle cells, the human variants instead remain cytoplasmic/membrane-associated. Altered nuclear export or protein conformation is proposed; the exact export sequence and downstream transcriptional effects remain unresolved.

Show evidence (2 references)

PMID:42424595 SUPPORT PRIMARY RESULT In Vitro

"In contrast, the plasmid expressing Flag-tagged DVL11519ΔT were primarily localized within the nucleus"

Tagged-protein assay in HEK293T DVL-triple-knockout cells, not a patient tissue observation.

PMID:36916233 SUPPORT PRIMARY RESULT Model Organism

"The lack of nuclear expression of Flag-tagged human DVL1 variants in the Drosophila cells compared to predominantly nuclear expression in HEK293 cells may be due to differences in the cellular context."

The full-text comparison prevents generalizing nuclear localization to every model.

Impaired chondrocyte differentiation

Mechanism confidence: Provisional

DVL1-variant misexpression in chicken limbs creates regions of virus-positive, SOX9-negative mesenchyme within cartilage. In the face, 1519ΔT replaces portions of SOX9-positive prenasal cartilage with TWIST-positive mesenchyme; later cultured cartilage expansion is impaired. These model observations support disturbed differentiation, without proving a patient-cell transcriptional target.

chondrocyte CL:0000138

chondrocyte differentiation GO:0002062 ⚠ ABNORMAL

Downstream

Disordered cartilage architecture Mosaic differentiation delay can disrupt cartilage structure, with additional polarity and maturation abnormalities.

Craniofacial morphogenetic disruption Impaired prenasal cartilage differentiation can contribute to reduced midfacial outgrowth.

Show evidence (2 references)

PMID:36916233 SUPPORT PRIMARY RESULT Model Organism

"Some areas of the DVL11519ΔT-infected cartilage have GAG staining, but cells are undifferentiated as shown by the absence of SOX9 staining"

Figure-associated result from chicken limbs, supported by virus/SOX9 co-staining.

PMID:42424595 SUPPORT PRIMARY RESULT Model Organism

"These results suggest the DVL11519ΔT virus prevents neural crest-derived mesenchymal differentiation into cartilage that forms the template of the upper beak."

Chicken frontonasal cartilage observation; no neural-crest migration defect is inferred because injection follows migration.

Disordered cartilage architecture

Mechanism confidence: Provisional

Variant-expressing chicken cartilage is dysplastic, with irregular nuclei and patchy hypertrophic COL10A1 expression. Early Golgi-angle and cell-shape assays did not distinguish variants from wild-type DVL1 overexpression; only selected variant-versus-GFP comparisons were significant. Both wild type and variants shortened experimental bones. The specifically mesomelic human pattern is not fully explained.

chondrocyte CL:0000138

Downstream

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

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

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

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

Clinodactyly Clinical developmental association; feature-specific intermediates remain unresolved.

Bifid phalanges Clinical developmental association; feature-specific intermediates remain unresolved.

Show evidence (2 references)

PMID:36916233 SUPPORT PRIMARY RESULT Model Organism

"Variant-infected limbs had dysplastic cartilage morphology with disorganized chondrocytes and irregular borders that were not seen in the wtDVL1-infected limbs"

Experimental avian cartilage architecture; separate from early polarity measurements.

PMID:36916233 SUPPORT PRIMARY RESULT Model Organism

"Overall, the variants did not produce differences relative to wtDVL1 in stage 29 limbs in all the assays (proliferation, Golgi-nucleus angle, roundness and apoptosis)."

Early-stage negative comparisons constrain the claim of a variant-specific polarity mechanism.

Craniofacial morphogenetic disruption

Mechanism confidence: Provisional

DVL1-related disease alters development of multiple craniofacial and oral structures. As one experimental component, chicken 1519ΔT misexpression widens the frontonasal mass and impairs prenasal cartilage and premaxillary bone formation, with reduced proliferation at the later embryonic time point. This model does not directly explain every human facial or oral feature, and neither increased proliferation nor impaired neural-crest migration was demonstrated as the cause.

Downstream

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Upslanted palpebral fissures Clinical association with craniofacial development; specific intermediates remain unresolved.

Prominent eyes Clinical association with craniofacial development; precise tissue intermediates remain unresolved.

Micrognathia Clinical developmental association; feature-specific intermediates remain unresolved.

Show evidence (2 references)

PMID:42424595 SUPPORT PRIMARY RESULT Model Organism

"frontonasal mass width was significantly greater in the DVL11519ΔT embryos compared to GFP and wtDVL1"

Chicken morphometry supports impaired narrowing; it does not establish every facial feature through one pathway.

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 DVL1-specific frequency estimate.

Genital morphogenetic disruption

Mechanism confidence: Provisional

Genital hypoplasia affects both sexes in dominant Robinow syndrome. WNT pathway involvement is consistent with developmental morphogenesis, but a DVL1-specific genital-tubercle mechanism has not been directly established.

Downstream

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

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

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

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

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

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora)"

Cross-gene clinical baseline; not direct DVL1 tissue evidence.

Cranial osteosclerosis

Cranial osteosclerosis was observed in four DVL1 cases in a seven-person mixed-genotype study and also in its single GPC4 case. It is enriched in DVL1-related Robinow syndrome but not demonstrated to be genotype-exclusive or universal. Neither altered nuclear DVL1 nor a canonical reporter effect has been shown to cause the human cranial bone phenotype.

Downstream

Skull Osteosclerosis Radiographic manifestation of the cranial density abnormality.

Increased Bone Mineral Density Cranial density can contribute to high DXA measurements; peripheral bone compartments need not be uniformly dense.

Hearing Loss Osteosclerosis can accompany conductive hearing impairment; it does not explain all mixed or other hearing loss.

Show evidence (1 reference)

PMID:32888393 SUPPORT PRIMARY RESULT Human Clinical

"Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS (1/1) subjects and in one case was complicated by choanal atresia, bilateral conductive hearing loss, and cranial nerve III, VI, and VII palsy."

Small selected clinical cohort; the abstract does not identify the genotype of the individual with complications.

Altered peripheral bone microarchitecture

The DVL1 subgroup in a small HR-pQCT study showed lower cortical and higher trabecular density, with fewer and thicker trabeculations. These are peripheral measurements and must not be presented as direct imaging of cranial bone or proof of uniformly increased skeletal density.

Show evidence (1 reference)

PMID:32888393 SUPPORT PRIMARY RESULT Human Clinical

"HR-pQCT revealed a unique pattern of low cortical BMD, increased trabecular BMD, decreased number of trabeculations, and increased thickness of the trabeculations for the DVL1-RS subjects."

Observed peripheral microarchitecture in four selected DVL1 participants; no specific osteoblast mechanism was measured.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

47

Cardiovascular 1

Congenital Heart Defect Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"When present, cardiac defects are a major cause of morbidity and mortality."

Establishes both the conditional nature and the clinical weight of the cardiac phenotype. This chapter covers dominant Robinow syndrome across genes; it is not a DVL1-specific frequency estimate.

Digestive 1

Umbilical hernia HP:0001537

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"bilobed tongue (80%, N = 16 out of 20), and umbilical hernia (59%, N = 10 out of 17) were associated with DVL1 variant alleles"

Feature-specific denominator from a selected retrospective compilation; not a population penetrance estimate.

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 DVL1-specific frequency estimate.

Hearing Loss Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"increased bone mineral density with skull osteosclerosis, and hearing loss"

Hearing loss is listed as part of the DVL1 osteosclerotic variant.

Eye 1

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 DVL1-specific frequency estimate.

Genitourinary 5

Micropenis HP:0000054

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism"

Names micropenis among the male genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a DVL1-specific frequency estimate.

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 DVL1-specific frequency estimate.

Hypoplastic Labia Majora HP:0000059

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"in females: hypoplastic clitoris and labia majora"

Names hypoplastic labia majora among the female genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a DVL1-specific frequency estimate.

Clitoral Hypoplasia HP:0000060

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"in females: hypoplastic clitoris and labia majora"

Names clitoral hypoplasia among the female genital findings. This chapter covers dominant Robinow syndrome across genes; it is not a DVL1-specific frequency estimate.

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 DVL1-specific frequency is inferred.

Head and Neck 24

Bifid Tongue HP:0010297

Show evidence (2 references)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally"

Places the bilobed tongue within the oral and dental findings of the GeneReviews clinical description, alongside the dental abnormalities that share a craniofacial developmental origin. This chapter covers dominant Robinow syndrome across genes; it is not a DVL1-specific frequency estimate.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"bilobed tongue (80%, N = 16 out of 20), and umbilical hernia (59%, N = 10 out of 17) were associated with DVL1 variant alleles"

DVL1 subset of the selected compilation, with feature-specific denominators.

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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1. 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 DVL1. 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 DVL1. 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 DVL1. 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 DVL1-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 DVL1-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 DVL1-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 DVL1-specific frequency estimate.

Cleft lip HP:0410030

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."

Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as evidence that a human cleft is present.

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay."

Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as evidence that a human cleft is present.

Skull Osteosclerosis Calvarial osteosclerosis HP:0005450

Show evidence (1 reference)

PMID:32888393 SUPPORT PRIMARY RESULT Human Clinical

"Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS (1/1) subjects and in one case was complicated by choanal atresia, bilateral conductive hearing loss, and cranial nerve III, VI, and VII palsy."

Small selected clinical cohort; the abstract does not identify the genotype of the individual with complications.

Macrocephaly HP:0000256

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"DVL1-associated RS probands were significantly more likely to have macrocephaly (95%, N = 21 out of 22), triangular mouth (82%, N = 14 out of 17), and increased bone density (82%, N = 9 out of 11)."

Selected retrospective cohort; a genotype association does not establish that excess cranial bone causes macrocephaly.

Triangular mouth HP:0000207

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"DVL1-associated RS probands were significantly more likely to have macrocephaly (95%, N = 21 out of 22), triangular mouth (82%, N = 14 out of 17), and increased bone density (82%, N = 9 out of 11)."

Feature-specific denominator from a selected retrospective compilation; not a population penetrance estimate.

High forehead HP:0000348

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"an increased prevalence of high forehead (95%, N = 20 out of 21), bilobed tongue (80%, N = 16 out of 20), and umbilical hernia (59%, N = 10 out of 17) were associated with DVL1 variant alleles"

Feature-specific denominator from a selected retrospective compilation; not a population penetrance estimate.

Upslanted palpebral fissures HP:0000582

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"clinical findings suggest lower prevalence of upslanting palpebral fissures (26%, N = 5 out of 19) and short stature (38%, N = 8 out of 21)"

DVL1 subset with feature-specific denominators; the between-gene trend did not reach statistical significance.

Micrognathia HP:0000347

Show evidence (1 reference)

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

"Micrognathia + + - + + - - - - 4/9 Skeletal Mesomelia + + + + + + + + + 9/9"

Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article. Variable completeness and pooled literature observations preclude treating these table counts as population frequencies.

Limbs 5

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 DVL1-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 DVL1-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 DVL1-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 DVL1. Selected cohorts, missing assessments and shared literature cases limit generalization; no population frequency is assigned.

Clinodactyly HP:0030084

Show evidence (1 reference)

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

"Clinodactyly + + + + + - - + + 7/9 Bifid phalanges - - - - ND + + ND - 4/9"

Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article. Variable completeness and pooled literature observations preclude treating these table counts as population frequencies.

Musculoskeletal 3

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 DVL1-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 DVL1-specific frequency estimate.

Increased Bone Mineral Density HP:0011001

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"DVL1-associated RS probands were significantly more likely to have macrocephaly (95%, N = 21 out of 22), triangular mouth (82%, N = 14 out of 17), and increased bone density (82%, N = 9 out of 11)."

Feature-specific counts in a selected retrospective cohort; repeated subjects across publications are not independent observations.

Growth 1

Short Stature HP:0004322

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"only 38% (N = 8 out of 21) of DVL1 individuals have short stature"

Selected retrospective cohort with incomplete phenotype data; this is not population penetrance.

Other 4

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 DVL1. 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 DVL1-specific frequency estimate.

Pectus anomaly

Needs a precise term: this DVL1 table does not distinguish pectus excavatum, carinatum or another chest-wall configuration. The specifically described DVL3 pectus excavatum is not transferred to DVL1.

Show evidence (1 reference)

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

"Pectus anomaly + + + - ND + + + - 7/9 Increased bone density (skull) + ND + ND + - - + ND 7/9"

Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article. Variable completeness and pooled literature observations preclude treating these table counts as population frequencies.

Bifid phalanges

Needs a precise term: the table does not identify the affected digits or phalanx segments. Specific thumb, finger or toe terms would impose anatomical detail that is not established.

Show evidence (1 reference)

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

"Bifid phalanges - - - - ND + + ND - 4/9 Scoliosis or kyphosis + - - - + - - + + 4/10"

Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article. Variable completeness and pooled literature observations preclude treating these table counts as population frequencies.

🧬

Genetic Associations

1

DVL1

Gene: DVL1 hgnc:3084 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:25817016 SUPPORT Human Clinical

"In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1."

Discovery cohort establishes the initial coding-frameshift series; it does not exclude later splice-associated alleles.

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"BAB13797 was found to have a previously unreported heterozygous splicing variant in DVL1, which is the first splicing variant reported in this gene thus far."

The variant was classified as likely pathogenic; inheritance was unknown and its transcript consequence was predicted rather than measured.

💊

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 DVL1-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 DVL1-confirmed disease or correction of its developmental mechanism.

Mechanism Target:

Short Stature — Growth hormone may improve growth rate in selected patients through an endocrine growth axis. The supporting Robinow case does not establish correction of the DVL1 cartilage lesion or genotype-specific efficacy.

Show evidence (2 references)

PMID:10417975 SUPPORT INDIRECT Human Clinical

"Recombinant human GH therapy in our patient and the three patients from the NCGS resulted in a significant increase in the growth rate per year."

Clinical growth-rate response in patients of unknown genotype; transfer to DVL1-related disease is indirect.

PMID:10417975 SUPPORT INDIRECT Human Clinical

"We propose its association with GH deficiency and that treatment with rhGH can result in a significant increase in the growth rate of these children."

The authors propose the association from a small series; neither the prevalence of GH deficiency nor routine treatment efficacy is established.

Hormone Therapy for Micropenis

Action: 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 DVL1-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 DVL1-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

Typical findings warrant molecular testing to identify a heterozygous pathogenic or likely pathogenic DVL1 variant with an appropriate terminal-sequence effect. A variant of uncertain significance neither establishes nor excludes the diagnosis. Testing should cover relevant coding and splice regions and detect small indels, rather than assume every truncating allele is causal. A Robinow/skeletal-dysplasia panel or exome/genome analysis can assess overlapping dominant and recessive etiologies, with laboratory-specific gene content and coverage.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:25577943 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of autosomal dominant Robinow syndrome is established in a proband with typical suggestive findings and/or by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular genetic testing."

The GeneReviews Diagnosis/Testing criterion in full.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf SUPPORT REVIEW SYNTHESIS Other

"Identification of a heterozygous DVL1, DVL3, or WNT5A variant of uncertain significance does not establish or rule out the diagnosis."

Variant uncertainty must remain distinct from molecular confirmation.

Baseline organ and skeletal evaluation

Assess skeletal extent with radiographs of limbs, chest, vertebrae and skull, including cranial density and bone complications where indicated. Obtain echocardiography, renal ultrasound and hearing assessment; consider pelvic ultrasound in females and urologic/endocrine assessment for genital abnormalities. Evaluate development and dental/craniofacial findings. These are cross-genotype baseline recommendations, not DVL1-specific frequencies.

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 study identified eight subjects with six distinct frameshifts, including monozygotic twins. This selected discovery cohort is not a population prevalence estimate or a current case count.

Show evidence (1 reference)

PMID:25817016 SUPPORT Human Clinical

"In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1."

Gives the cohort size on which the entity was delineated.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Robinow Syndrome 2:

Aarskog-Scott syndrome

Overlapping Features FGD1-related Aarskog-Scott syndrome can resemble Robinow syndrome in facial, limb and genital findings. Its X-linked inheritance and molecular cause distinguish it; it is a relevant alternative after negative Robinow-gene testing.

Show evidence (1 reference)

PMID:35047859 SUPPORT PRIMARY RESULT Human Clinical

"pathogenic variants in FGD1 are the most frequent molecular diagnostic finding in clinically diagnosed RS with otherwise negative testing"

Selected cohort finding supports including FGD1 in the molecular differential; it does not estimate prevalence in all referrals.

Osteopetrosis and other sclerosing bone disorders

Overlapping Features Consider other sclerosing bone disorders when high cranial density dominates. The combined Robinow facial, limb and genital phenotype and DVL1 testing inform distinction. Regional cortical and trabecular measurements are not a universal rule separating all sclerosing bone disorders.

Show evidence (1 reference)

PMID:32888393 SUPPORT PRIMARY RESULT Human Clinical

"HR-pQCT revealed a unique pattern of low cortical BMD, increased trabecular BMD, decreased number of trabeculations, and increased thickness of the trabeculations for the DVL1-RS subjects."

Observed peripheral microarchitecture in four selected DVL1 participants; no specific osteoblast mechanism was measured.

{ }

Source YAML

click to show

name: Autosomal Dominant Robinow Syndrome 2
synonyms:
- DRS2
- DVL1-related Robinow syndrome
- Robinow syndrome, autosomal dominant 2
- osteosclerotic form of Robinow syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal dominant Robinow syndrome 2
  term:
    id: MONDO:0014591
    label: autosomal dominant Robinow syndrome 2
description: >-
  DVL1-related dominant Robinow syndrome is a developmental skeletal and craniofacial disorder with variable
  mesomelia, brachydactyly, facial features and genital abnormalities. Macrocephaly and cranial osteosclerosis
  are prominent in many reported patients, but normal stature and osteosclerosis are not universal diagnostic
  requirements.

  The characteristic alleles alter the C-terminal sequence through a selected minus-one frameshift; a splice-acceptor
  variant predicted to produce the same frame has also been reported. Mutant transcripts persist in sampled
  patient cells. Functional models reveal altered signaling, context-dependent nuclear enrichment and developmental
  abnormalities, but neither a universal direction of WNT activity nor the mechanism of excess cranial bone
  has been established.

  Clinical care addresses skeletal, dental, genital, hearing and other associated findings. Experimental reporter
  effects are not evidence that a pathway-directed treatment corrects the human disease.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: >-
  GeneReviews is a clinical baseline across dominant Robinow genotypes; its feature lists are not DVL1-specific
  frequencies. The 2022 phenotype compilation is retrospective, selected and incomplete, with overlapping published
  cohorts. The 2020 bone study contains four DVL1 cases among seven individuals of different genotypes. Nuclear
  enrichment and signaling results come from overexpression systems; physiological expression and patient tissue
  may differ. The two proposed functional models are not mutually exclusive and neither establishes the cause
  of cranial osteosclerosis. Less-common renal anomalies, nail dysplasia and developmental delay are included
  in baseline assessment and follow-up, without assigning DVL1-specific population frequencies. Umbilical hernia,
  macrocephaly, vertebral anomalies and cardiac defects remain clinical associations without invented causal
  intermediates.
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 15-0060, listed as "Robinow syndrome, DVL1-related" (MIM 616331, 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 study identified eight subjects with six distinct frameshifts, including monozygotic twins.
    This selected discovery cohort is not a population prevalence estimate or a current case count.
  evidence:
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, six distinct frameshift mutations were found in eight subjects,
      and all were heterozygous truncating variants within the penultimate exon
      of DVL1.
    explanation: >-
      Gives the cohort size on which the entity was delineated.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous pathogenic variants cause dominant disease. De novo origin was demonstrated in five discovery
    families with available parental samples; this ascertainment does not establish a population de novo fraction.
    An affected heterozygote has a 50% variant-transmission probability, with severity incompletely predictable.
    Parental assessment and testing inform recurrence counseling.
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ADRS is inherited in an autosomal dominant manner.
    explanation: >-
      GeneReviews states the inheritance mode for the dominant forms, of which
      this is one.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In five families in which samples from unaffected parents were available,
      the variants were demonstrated to represent de novo mutations.
    explanation: >-
      Establishes de novo origin in the families that could be tested.
pathophysiology:
- name: Heterozygous DVL1 C-terminal alteration
  description: >-
    Selected variants near the DVL1 C terminus cause a minus-one frameshift, replacing the native terminal
    sequence. Most are small coding insertions/deletions; c.1640-1C>T is a reported splice-acceptor variant
    with a predicted cryptic-splice/minus-one effect. A generic truncating variant elsewhere in the gene is
    not equivalent.
  evidence:
  - reference: PMID:25817016
    reference_title: DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating
      variants within the penultimate exon of DVL1.
    explanation: >-
      Human discovery cohort establishes a restricted allele class.
  - 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: >-
      BAB13797 was found to have a previously unreported heterozygous splicing variant in DVL1, which is the
      first splicing variant reported in this gene thus far.
    explanation: >-
      The variant was classified as likely pathogenic; inheritance was unknown and its transcript consequence
      was predicted rather than measured.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - &id001
    preferred_term: DVL1
    term:
      id: hgnc:3084
      label: DVL1
  genetic_context:
    gene: *id001
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: Selected coding and splice alterations produce a distinctive C-terminal sequence; the composite dominant mechanism cannot be assigned one universal functional category.
  downstream:
  - target: Persistence of mutant DVL1 transcript
    causal_link_type: DIRECT
    description: >-
      The terminal architecture predicts escape from nonsense-mediated decay; patient RNA provides additional
      support.
- name: Persistence of mutant DVL1 transcript
  description: >-
    Both normal and variant DVL1 transcripts are detectable in sampled patient leukocytes. This supports escape
    from nonsense-mediated decay for the tested alleles; it is not direct measurement of mutant protein abundance
    in developing skeletal tissue.
  evidence:
  - reference: PMID:25817016
    reference_title: DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type
      and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD.
    explanation: >-
      Patient RNA observation, distinct from protein expression assays.
  downstream:
  - target: Altered DVL1 C-terminal protein sequence
    causal_link_type: DIRECT
    description: >-
      Persistent transcript permits production of the altered protein; abundance in human developmental tissue
      is unmeasured.
  biological_scale: MOLECULAR
- name: Altered DVL1 C-terminal protein sequence
  description: >-
    The frameshift replaces most of the native C terminus while preserving upstream DIX, PDZ and DEP domains.
    Transfected constructs produce detectable altered protein, but expression level, tag and host cell influence
    assay interpretation. The novel sequence has effects that differ from a simple stop construct.
  evidence:
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      demonstrated unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift
      mutation.
    explanation: >-
      Transfected GFP-tagged protein assay; no direct patient-bone protein measurement is claimed.
  downstream:
  - target: Context-dependent WNT signal transduction
    causal_link_type: DIRECT
    description: >-
      The altered C terminus changes transduction, with direction dependent on branch and context.
    hypothesis_groups:
    - coexpression_canonical_wnt_gain_model
  - target: Nuclear enrichment of altered DVL1
    causal_link_type: DIRECT
    description: >-
      Tagged variants become enriched in nuclei of HEK cells; this distribution is not universal across species.
    hypothesis_groups:
    - nuclear_mislocalization_transcription_model
  - target: Cranial osteosclerosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      DVL1 genotype is associated with cranial osteosclerosis, but the cellular link remains unresolved.
  - target: Altered peripheral bone microarchitecture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      DVL1-associated peripheral microarchitecture is clinically observed; the intervening cell mechanism is
      unknown.
  biological_scale: MOLECULAR
- name: Context-dependent WNT signal transduction
  description: >-
    DVL1 variants alter canonical and noncanonical WNT outputs. The 2015 C2C12 co-expression assay increased
    canonical activity, while 2023 HEK293 and fly assays supported reduced canonical output. JNK readouts increase
    for selected variants in HEK293 cells and in flies but are weaker in 2026 chicken facial cultures. These
    assays do not establish one direction in all patient tissues.
  evidence:
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      When plasmids expressing the variants were added in equimolar concentration with the wtDVL1 plasmid,
      all three had significant dominant-negative effects on wtDVL1
    explanation: >-
      Direct canonical reporter result in HEK293 cells; the later paper recounts this identifiable primary
      study.
  - reference: PMID:42424595
    reference_title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Thus, our data suggest that in primary cells, the Robinow syndrome variant DVL11519ΔT and the DVL11519*
      truncation are both able to weakly activate the WNT canonical and JNK/PCP pathways.
    explanation: >-
      Primary chicken facial cells retain weak activation, unlike the same constructs in DVL-triple-knockout
      HEK cells.
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Both assays indicated that the DVL1 variants ectopically induced JNK signaling in the wing pouch
    explanation: >-
      Drosophila Mmp1 and puckered reporter results; wing-hair polarity alone cannot determine whether signaling
      increased or decreased.
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Impaired chondrocyte differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered WNT transduction accompanies impaired chondrogenesis in model tissues; branch-specific causal
      intermediates remain uncertain.
  - target: Disordered cartilage architecture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Model cartilage organization is abnormal, but expression of wild-type DVL1 also affects early polarity
      readouts.
  - target: Craniofacial morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The variant affects facial development in chicken; signaling-to-tissue intermediates are incompletely
      established.
  - target: Genital morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The human genotype produces genital developmental abnormalities without a directly characterized DVL1-specific
      tissue pathway.
  biological_processes:
  - preferred_term: non-canonical Wnt signaling pathway
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
    modifier: ABNORMAL
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
    modifier: ABNORMAL
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: ABNORMAL
- name: Nuclear enrichment of altered DVL1
  description: >-
    Tagged DVL1 frameshift proteins are more frequently nuclear in HEK293 cells. In the 2026 DVL-triple-knockout
    comparison, 1519ΔT is enriched in nuclei while wild type and the 1519-stop construct are mainly cytoplasmic.
    In Drosophila follicle cells, the human variants instead remain cytoplasmic/membrane-associated. Altered
    nuclear export or protein conformation is proposed; the exact export sequence and downstream transcriptional
    effects remain unresolved.
  evidence:
  - reference: PMID:42424595
    reference_title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      In contrast, the plasmid expressing Flag-tagged DVL11519ΔT were primarily localized within the nucleus
    explanation: >-
      Tagged-protein assay in HEK293T DVL-triple-knockout cells, not a patient tissue observation.
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      The lack of nuclear expression of Flag-tagged human DVL1 variants in the Drosophila cells compared to
      predominantly nuclear expression in HEK293 cells may be due to differences in the cellular context.
    explanation: >-
      The full-text comparison prevents generalizing nuclear localization to every model.
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
- name: Impaired chondrocyte differentiation
  description: >-
    DVL1-variant misexpression in chicken limbs creates regions of virus-positive, SOX9-negative mesenchyme
    within cartilage. In the face, 1519ΔT replaces portions of SOX9-positive prenasal cartilage with TWIST-positive
    mesenchyme; later cultured cartilage expansion is impaired. These model observations support disturbed
    differentiation, without proving a patient-cell transcriptional target.
  evidence:
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Some areas of the DVL11519ΔT-infected cartilage have GAG staining, but cells are undifferentiated as
      shown by the absence of SOX9 staining
    explanation: >-
      Figure-associated result from chicken limbs, supported by virus/SOX9 co-staining.
  - reference: PMID:42424595
    reference_title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      These results suggest the DVL11519ΔT virus prevents neural crest-derived mesenchymal differentiation
      into cartilage that forms the template of the upper beak.
    explanation: >-
      Chicken frontonasal cartilage observation; no neural-crest migration defect is inferred because injection
      follows migration.
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  downstream:
  - target: Disordered cartilage architecture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mosaic differentiation delay can disrupt cartilage structure, with additional polarity and maturation
      abnormalities.
  - target: Craniofacial morphogenetic disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired prenasal cartilage differentiation can contribute to reduced midfacial outgrowth.
  biological_scale: CELLULAR
- name: Disordered cartilage architecture
  description: >-
    Variant-expressing chicken cartilage is dysplastic, with irregular nuclei and patchy hypertrophic COL10A1
    expression. Early Golgi-angle and cell-shape assays did not distinguish variants from wild-type DVL1 overexpression;
    only selected variant-versus-GFP comparisons were significant. Both wild type and variants shortened experimental
    bones. The specifically mesomelic human pattern is not fully explained.
  evidence:
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Variant-infected limbs had dysplastic cartilage morphology with disorganized chondrocytes and irregular
      borders that were not seen in the wtDVL1-infected limbs
    explanation: >-
      Experimental avian cartilage architecture; separate from early polarity measurements.
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the variants did not produce differences relative to wtDVL1 in stage 29 limbs in all the assays
      (proliferation, Golgi-nucleus angle, roundness and apoptosis).
    explanation: >-
      Early-stage negative comparisons constrain the claim of a variant-specific polarity mechanism.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Broad hallux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Clinodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical developmental association; feature-specific intermediates remain unresolved.
  - target: Bifid phalanges
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical developmental association; feature-specific intermediates remain unresolved.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
- name: Craniofacial morphogenetic disruption
  description: >-
    DVL1-related disease alters development of multiple craniofacial and oral structures. As one experimental
    component, chicken 1519ΔT misexpression widens the frontonasal mass and impairs prenasal cartilage and
    premaxillary bone formation, with reduced proliferation at the later embryonic time point. This model does
    not directly explain every human facial or oral feature, and neither increased proliferation nor impaired
    neural-crest migration was demonstrated as the cause.
  evidence:
  - reference: PMID:42424595
    reference_title: The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      frontonasal mass width was significantly greater in the DVL11519ΔT embryos compared to GFP and wtDVL1
    explanation: >-
      Chicken morphometry supports impaired narrowing; it does not establish every facial feature through one
      pathway.
  - 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 DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Bifid Tongue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Hypodontia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Frontal bossing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Anteverted nares
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Midface retrusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Dental malocclusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Dental crowding
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Delayed eruption of permanent teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Gingival overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Wide nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Depressed nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Short nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: High anterior hairline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Broad nasal tip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Long philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Wide retromolar ridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Alveolar ridge deformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Cleft lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Triangular mouth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: High forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Upslanted palpebral fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical association with craniofacial development; specific intermediates remain unresolved.
  - target: Prominent eyes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical association with craniofacial development; precise tissue intermediates remain unresolved.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical developmental association; feature-specific intermediates remain unresolved.
  biological_scale: TISSUE
- name: Genital morphogenetic disruption
  description: >-
    Genital hypoplasia affects both sexes in dominant Robinow syndrome. WNT pathway involvement is consistent
    with developmental morphogenesis, but a DVL1-specific genital-tubercle mechanism has not been directly
    established.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females:
      hypoplastic clitoris and labia majora)
    explanation: >-
      Cross-gene clinical baseline; not direct DVL1 tissue evidence.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Micropenis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Hypoplastic Labia Majora
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Clitoral Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
  - target: Small scrotum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clinical developmental association; feature-specific tissue and molecular intermediates remain incompletely
      established.
- name: Cranial osteosclerosis
  description: >-
    Cranial osteosclerosis was observed in four DVL1 cases in a seven-person mixed-genotype study and also
    in its single GPC4 case. It is enriched in DVL1-related Robinow syndrome but not demonstrated to be genotype-exclusive
    or universal. Neither altered nuclear DVL1 nor a canonical reporter effect has been shown to cause the
    human cranial bone phenotype.
  evidence:
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS (1/1) subjects and in one case
      was complicated by choanal atresia, bilateral conductive hearing loss, and cranial nerve III, VI, and
      VII palsy.
    explanation: >-
      Small selected clinical cohort; the abstract does not identify the genotype of the individual with complications.
  downstream:
  - target: Skull Osteosclerosis
    causal_link_type: DIRECT
    description: >-
      Radiographic manifestation of the cranial density abnormality.
  - target: Increased Bone Mineral Density
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cranial density can contribute to high DXA measurements; peripheral bone compartments need not be uniformly
      dense.
  - target: Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Osteosclerosis can accompany conductive hearing impairment; it does not explain all mixed or other hearing
      loss.
  biological_scale: TISSUE
- name: Altered peripheral bone microarchitecture
  description: >-
    The DVL1 subgroup in a small HR-pQCT study showed lower cortical and higher trabecular density, with fewer
    and thicker trabeculations. These are peripheral measurements and must not be presented as direct imaging
    of cranial bone or proof of uniformly increased skeletal density.
  evidence:
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      HR-pQCT revealed a unique pattern of low cortical BMD, increased trabecular BMD, decreased number of
      trabeculations, and increased thickness of the trabeculations for the DVL1-RS subjects.
    explanation: >-
      Observed peripheral microarchitecture in four selected DVL1 participants; no specific osteoblast mechanism
      was measured.
  biological_scale: TISSUE
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 DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Growth
  name: Short Stature
  description: >-
    Stature is variable. Short stature was reported in 8 of 21 assessed DVL1 cases in the selected 2022 compilation;
    normal or low-normal stature does not exclude this diagnosis. The cross-genotype GeneReviews birth-onset
    description should not be read as universal for DVL1 disease.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  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: >-
      only 38% (N = 8 out of 21) of DVL1 individuals have short stature
    explanation: >-
      Selected retrospective cohort with incomplete phenotype data; this is not population penetrance.
- 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 DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Micropenis
  description: >-
    Reduced penile length can occur, but an apparently small penis may instead be normally sized and webbed
    or embedded; clinical assessment determines the appropriate hormonal or surgical approach.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: >-
      Names micropenis among the male genital findings. This chapter covers dominant Robinow syndrome across
      genes; it is not a DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Cryptorchidism
  description: Undescended testes can occur among the male genital abnormalities and warrant urologic assessment.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: >-
      Names cryptorchidism among the male genital findings. This chapter covers dominant Robinow syndrome across
      genes; it is not a DVL1-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.
  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 DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Clitoral Hypoplasia
  description: Hypoplasia of the clitoris, named with the labial hypoplasia as the female genital presentation.
  phenotype_term:
    preferred_term: Clitoral hypoplasia
    term:
      id: HP:0000060
      label: Clitoral hypoplasia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in females: hypoplastic clitoris and labia majora'
    explanation: >-
      Names clitoral hypoplasia among the female genital findings. This chapter covers dominant Robinow syndrome
      across genes; it is not a DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Dislocated Radial Head
  description: >-
    Radial head dislocation is a less-common finding across dominant Robinow genotypes; no DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Bifid Tongue
  description: >-
    A bilobed tongue - an unusual and clinically distinctive oral finding that helps separate Robinow syndrome
    from other mesomelic dysplasias.
  phenotype_term:
    preferred_term: Bifid tongue
    term:
      id: HP:0010297
      label: Bifid tongue
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth),
      bilobed tongue, and occasional prenatal macrocephaly that persists postnatally
    explanation: >-
      Places the bilobed tongue within the oral and dental findings of the GeneReviews clinical description,
      alongside the dental abnormalities that share a craniofacial developmental origin. This chapter covers
      dominant Robinow syndrome across genes; it is not a DVL1-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: >-
      bilobed tongue (80%, N = 16 out of 20), and umbilical hernia (59%, N = 10 out of 17) were associated
      with DVL1 variant alleles
    explanation: >-
      DVL1 subset of the selected compilation, with feature-specific denominators.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Cardiac defects are uncommon but disproportionately important, being identified as a major cause of morbidity
    and mortality when present - which is why cardiac assessment features in surveillance despite the low frequency.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: When present, cardiac defects are a major cause of morbidity and mortality.
    explanation: >-
      Establishes both the conditional nature and the clinical weight of the cardiac phenotype. This chapter
      covers dominant Robinow syndrome across genes; it is not a DVL1-specific frequency estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Brachydactyly
  description: Short digits accompanying the skeletal developmental phenotype.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)
    explanation: >-
      GeneReviews names brachydactyly as one of the three core skeletal findings. This chapter covers dominant
      Robinow syndrome across genes; it is not a DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1 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 DVL1. 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 DVL1 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 DVL1. 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 DVL1 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 DVL1. 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 DVL1 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 DVL1. 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 DVL1 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 DVL1. 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 DVL1 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 DVL1. 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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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 DVL1-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: A less-common finding across dominant Robinow genotypes; the presence and anatomical extent require individual assessment.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as
      evidence that a human cleft is present.
- name: Cleft palate
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  description: A less-common finding across dominant Robinow genotypes; the presence and anatomical extent require individual assessment.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as
      hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive
      delay.
    explanation: >-
      Human clinical review across dominant Robinow genotypes; the mouse preprint phenotype is not used as
      evidence that a human cleft is present.
- category: Skeletal
  name: Skull Osteosclerosis
  description: >-
    Increased cranial bone density is prominent in many reported DVL1 cases. It is not exclusive to this genotype:
    the 2020 mixed-genotype cohort also documented cranial sclerosis in its GPC4 case.
  phenotype_term:
    preferred_term: Calvarial osteosclerosis
    term:
      id: HP:0005450
      label: Calvarial osteosclerosis
  evidence:
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS (1/1) subjects and in one case
      was complicated by choanal atresia, bilateral conductive hearing loss, and cranial nerve III, VI, and
      VII palsy.
    explanation: >-
      Small selected clinical cohort; the abstract does not identify the genotype of the individual with complications.
- category: Skeletal
  name: Increased Bone Mineral Density
  phenotype_term:
    preferred_term: Increased bone mineral density
    term:
      id: HP:0011001
      label: Increased bone mineral density
  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: >-
      DVL1-associated RS probands were significantly more likely to have macrocephaly (95%, N = 21 out of 22),
      triangular mouth (82%, N = 14 out of 17), and increased bone density (82%, N = 9 out of 11).
    explanation: >-
      Feature-specific counts in a selected retrospective cohort; repeated subjects across publications are
      not independent observations.
  description: >-
    Increased bone density was documented in 9 of 11 evaluated DVL1 cases in the 2022 compilation. Regional
    measurements can differ; mixed-genotype DXA denominators do not measure DVL1 penetrance, and peripheral
    cortical and trabecular density are not uniformly increased.
- category: Craniofacial
  name: Macrocephaly
  description: >-
    Macrocephaly was documented in 21 of 22 assessed DVL1 cases in the 2022 compilation and may persist from
    prenatal life. It is characteristic but not universal, and the contribution of cranial osteosclerosis to
    head size has not been established.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  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: >-
      DVL1-associated RS probands were significantly more likely to have macrocephaly (95%, N = 21 out of 22),
      triangular mouth (82%, N = 14 out of 17), and increased bone density (82%, N = 9 out of 11).
    explanation: >-
      Selected retrospective cohort; a genotype association does not establish that excess cranial bone causes
      macrocephaly.
- category: Auditory
  name: Hearing Loss
  description: >-
    Hearing impairment accompanies the DVL1 osteosclerotic presentation. Conductive impairment can be associated
    with dense cranial bone, but neither a uniform hearing-loss type nor its population frequency is established.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:25577943
    reference_title: "Autosomal Dominant Robinow Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      increased bone mineral density with skull osteosclerosis, and hearing loss
    explanation: >-
      Hearing loss is listed as part of the DVL1 osteosclerotic variant.
    quote_role: REVIEW_SYNTHESIS
- name: Triangular mouth
  category: Craniofacial
  description: >-
    A triangular mouth was recorded in 14 of 17 assessed DVL1 cases in the selected 2022 compilation.
  phenotype_term:
    preferred_term: Triangular mouth
    term:
      id: HP:0000207
      label: Triangular mouth
  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: >-
      DVL1-associated RS probands were significantly more likely to have macrocephaly (95%, N = 21 out of 22),
      triangular mouth (82%, N = 14 out of 17), and increased bone density (82%, N = 9 out of 11).
    explanation: >-
      Feature-specific denominator from a selected retrospective compilation; not a population penetrance estimate.
- name: High forehead
  category: Craniofacial
  description: >-
    High forehead was recorded in 20 of 21 assessed DVL1 cases in the selected 2022 compilation. Forehead height
    differs from anterior hairline position.
  phenotype_term:
    preferred_term: High forehead
    term:
      id: HP:0000348
      label: High forehead
  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: >-
      an increased prevalence of high forehead (95%, N = 20 out of 21), bilobed tongue (80%, N = 16 out of
      20), and umbilical hernia (59%, N = 10 out of 17) were associated with DVL1 variant alleles
    explanation: >-
      Feature-specific denominator from a selected retrospective compilation; not a population penetrance estimate.
- name: Umbilical hernia
  category: Abdominal
  description: >-
    An umbilical hernia was recorded in 10 of 17 assessed DVL1 cases in the selected 2022 compilation; its
    developmental intermediates have not been established.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  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: >-
      bilobed tongue (80%, N = 16 out of 20), and umbilical hernia (59%, N = 10 out of 17) were associated
      with DVL1 variant alleles
    explanation: >-
      Feature-specific denominator from a selected retrospective compilation; not a population penetrance estimate.
- name: Upslanted palpebral fissures
  category: Craniofacial
  description: >-
    Upslanting palpebral fissures were reported in 5 of 19 assessed DVL1 cases in the 2022 compilation. This
    selected-case count does not measure population penetrance.
  phenotype_term:
    preferred_term: Upslanted palpebral fissure
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  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: >-
      clinical findings suggest lower prevalence of upslanting palpebral fissures (26%, N = 5 out of 19) and
      short stature (38%, N = 8 out of 21)
    explanation: >-
      DVL1 subset with feature-specific denominators; the between-gene trend did not reach statistical significance.
- name: Clinodactyly
  category: Skeletal
  description: >-
    Clinodactyly is reported in the DVL1 clinical compilation in the 2016 supplementary table. These selected
    observations do not establish population penetrance.
  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: >-
      Clinodactyly + + + + + - - + + 7/9 Bifid phalanges - - - - ND + + ND - 4/9
    explanation: >-
      Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article.
      Variable completeness and pooled literature observations preclude treating these table counts as population
      frequencies.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Micrognathia is reported in the DVL1 clinical compilation in the 2016 supplementary table. These selected
    observations do not establish population penetrance.
  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: >-
      Micrognathia + + - + + - - - - 4/9 Skeletal Mesomelia + + + + + + + + + 9/9
    explanation: >-
      Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article.
      Variable completeness and pooled literature observations preclude treating these table counts as population
      frequencies.
- name: Pectus anomaly
  category: Skeletal
  description: >-
    Pectus anomaly is reported in the DVL1 clinical compilation in the 2016 supplementary table. These selected
    observations do not establish population penetrance.
  phenotype_term:
    preferred_term: Pectus anomaly
  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: >-
      Pectus anomaly + + + - ND + + + - 7/9 Increased bone density (skull) + ND + ND + - - + ND 7/9
    explanation: >-
      Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article.
      Variable completeness and pooled literature observations preclude treating these table counts as population
      frequencies.
  notes: >-
    Needs a precise term: this DVL1 table does not distinguish pectus excavatum, carinatum or another chest-wall
    configuration. The specifically described DVL3 pectus excavatum is not transferred to DVL1.
- name: Bifid phalanges
  category: Skeletal
  description: >-
    Bifid phalanges is reported in the DVL1 clinical compilation in the 2016 supplementary table. These selected
    observations do not establish population penetrance.
  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 phalanges - - - - ND + + ND - 4/9 Scoliosis or kyphosis + - - - + - - + + 4/10
    explanation: >-
      Supplemental Table S1 is explicitly the DVL1 series, separate from the DVL3 table in the main article.
      Variable completeness and pooled literature observations preclude treating these table counts as population
      frequencies.
  notes: >-
    Needs a precise term: the table does not identify the affected digits or phalanx segments. Specific thumb,
    finger or toe terms would impose anatomical detail that is not established.
genetic:
- name: DVL1
  gene_term:
    preferred_term: DVL1
    term:
      id: hgnc:3084
      label: DVL1
  relationship_type: CAUSATIVE
  notes: >-
    Pathogenic DVL1 alleles characteristically alter the terminal reading frame and C-terminal sequence. The
    discovery series found penultimate-exon minus-one frameshifts; a 2022 report additionally classified c.1640-1C>T
    as likely pathogenic, with a cryptic acceptor and the same minus-one frame predicted computationally. The
    splice effect was not demonstrated in patient RNA. Neither an arbitrary DVL1 truncation nor every variant
    near the gene end establishes this diagnosis.
  evidence:
  - reference: PMID:25817016
    reference_title: "DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, six distinct frameshift mutations were found in eight subjects,
      and all were heterozygous truncating variants within the penultimate exon
      of DVL1.
    explanation: >-
      Discovery cohort establishes the initial coding-frameshift series; it does not exclude later splice-associated
      alleles.
  - 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: >-
      BAB13797 was found to have a previously unreported heterozygous splicing variant in DVL1, which is the
      first splicing variant reported in this gene thus far.
    explanation: >-
      The variant was classified as likely pathogenic; inheritance was unknown and its transcript consequence
      was predicted rather than measured.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Typical findings warrant molecular testing to identify a heterozygous pathogenic or likely pathogenic DVL1
    variant with an appropriate terminal-sequence effect. A variant of uncertain significance neither establishes
    nor excludes the diagnosis. Testing should cover relevant coding and splice regions and detect small indels,
    rather than assume every truncating allele is causal. A Robinow/skeletal-dysplasia panel or exome/genome
    analysis can assess overlapping dominant and recessive etiologies, with laboratory-specific gene content
    and coverage.
  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.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
- name: Baseline organ and skeletal evaluation
  description: >-
    Assess skeletal extent with radiographs of limbs, chest, vertebrae and skull, including cranial density
    and bone complications where indicated. Obtain echocardiography, renal ultrasound and hearing assessment;
    consider pelvic ultrasound in females and urologic/endocrine assessment for genital abnormalities. Evaluate
    development and dental/craniofacial findings. These are cross-genotype baseline recommendations, not DVL1-specific
    frequencies.
  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 craniofacial, genital and limb findings. Macrocephaly and short stature
    do not provide absolute gene separators; molecular testing distinguishes the ligand-associated disorder
    from DVL1 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: DVL3-related Robinow syndrome
  description: >-
    Overlapping dominant skeletal and craniofacial findings with a higher reported burden of cardiac abnormalities
    in small series. Molecular testing separates this adaptor-related disorder from DVL1-related disease.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Three out of four individuals with DVL3-associated ADRS had cardiac abnormalities; osteosclerosis has
      not been reported.
    explanation: Small chapter-era series, not a stable population frequency or a rule excluding osteosclerosis.
  - 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: >-
      Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a
      -1 frameshift
    explanation: >-
      Primary molecular series identifies a convergent reading-frame consequence for its DVL3 alleles. Molecular
      testing distinguishes the paralog-associated disorder; the discovery protocol is not a preferred clinical
      testing guideline.
  disease_term:
    preferred_term: autosomal dominant Robinow syndrome 3
    term:
      id: MONDO:0014819
      label: autosomal dominant Robinow syndrome 3
- name: NXN-related recessive Robinow syndrome
  description: >-
    Biallelic NXN variants produce a clinically overlapping recessive syndrome. Inheritance and molecular testing
    distinguish it; phenotype severity alone is unreliable.
  evidence:
  - reference: PMID: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.
- 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: omodysplasia
    term:
      id: MONDO:0017136
      label: omodysplasia
- name: Osteopetrosis and other sclerosing bone disorders
  description: >-
    Consider other sclerosing bone disorders when high cranial density dominates. The combined Robinow facial,
    limb and genital phenotype and DVL1 testing inform distinction. Regional cortical and trabecular measurements
    are not a universal rule separating all sclerosing bone disorders.
  evidence:
  - reference: PMID:32888393
    reference_title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      HR-pQCT revealed a unique pattern of low cortical BMD, increased trabecular BMD, decreased number of
      trabeculations, and increased thickness of the trabeculations for the DVL1-RS subjects.
    explanation: >-
      Observed peripheral microarchitecture in four selected DVL1 participants; no specific osteoblast mechanism
      was measured.
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 DVL1-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 DVL1-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: >-
      Growth hormone may improve growth rate in selected patients through an endocrine growth axis. The supporting
      Robinow case does not establish correction of the DVL1 cartilage lesion 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 DVL1-related disease is indirect.
  - reference: PMID:10417975
    reference_title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose its association with GH deficiency and that treatment with rhGH can result in a significant
      increase in the growth rate of these children.
    explanation: >-
      The authors propose the association from a small series; neither the prevalence of GH deficiency nor
      routine treatment efficacy is established.
    directness: INDIRECT
- name: Hormone Therapy for Micropenis
  therapeutic_modality: OTHER
  description: >-
    Hormone therapy in affected males with micropenis, listed by GeneReviews among the treatments of manifestations.
    Like the surgical entries, it addresses an established morphogenetic outcome rather than the pathway that
    produced it. Refer for endocrine assessment; GeneReviews reports hCG and testosterone experience in three
    boys, without establishing DVL1-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 DVL1-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
mechanistic_hypotheses:
- hypothesis_group_id: nuclear_mislocalization_transcription_model
  hypothesis_label: Neomorphic Nuclear Mislocalization Model
  status: EMERGING
  description: >-
    Nuclear enrichment of altered DVL1 could change transcription or interactions with transcription factors,
    contributing to developmental abnormalities. This is a proposed consequence of the cellular localization
    result; no causal transcriptional target or direct connection to cranial osteosclerosis has been established.
    The model can coexist with altered cytoplasmic signaling.
  evidence:
  - reference: PMID:42424595
    reference_title: "The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Further studies are needed to precisely determine whether nuclear DVL1 plays a transcriptional role in
      eliciting phenotypes in RS.
    explanation: >-
      Author interpretation explicitly leaves the transcriptional consequence untested.
    quote_role: PRIMARY_RESULT
- hypothesis_group_id: coexpression_canonical_wnt_gain_model
  hypothesis_label: Dominant-Increase Canonical Wnt Co-Expression Model
  status: ALTERNATIVE
  description: >-
    The 2015 C2C12 assay found increased canonical WNT reporter output when mutant and wild-type DVL1 were
    co-expressed. This could contribute to osteosclerosis, but the human bone link is untested. The 2023 HEK293
    co-expression experiment instead found reduced output. Cell type, expression dose and experimental design
    differ, so neither assay is a universal physiological heterozygous state and the results remain unreconciled.
    Nuclear effects are not excluded by this model.
  evidence:
  - reference: PMID:25817014
    reference_title: "Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, when the mutant and wild-type alleles were co-expressed,
      canonical Wnt activity was 2-fold higher than that in the wild-type
      construct alone.
    explanation: >-
      Canonical co-expression gain in a cell-based reporter assay; the proposed osteosclerosis consequence
      was not directly tested.
  - reference: PMID:36916233
    reference_title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      When plasmids expressing the variants were added in equimolar concentration with the wtDVL1 plasmid,
      all three had significant dominant-negative effects on wtDVL1
    explanation: >-
      Primary HEK293 experiment directly identifies the study recounted in PMID:42424595. The authors propose
      dose as a possible explanation for the discrepancy with C2C12; no direct reconciliation experiment is
      reported.
discussions:
- discussion_id: dvl1_frameshift_mode_of_action
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which context-dependent effects of the altered DVL1 C terminus drive human developmental abnormalities
    and cranial osteosclerosis?
  attaches_to:
  - pathophysiology#Nuclear enrichment of altered DVL1
  - pathophysiology#Context-dependent WNT signal transduction
  - mechanistic_hypotheses#coexpression_canonical_wnt_gain_model
  rationale: >-
    Overexpression studies distinguish altered C-terminal sequence from a simple truncation, but both constructs
    retain some activity. Nuclear enrichment occurs in HEK cells and is not seen in fly follicle cells. Reporter
    direction depends on pathway and model. Direct targets, patient-tissue localization and the route to excess
    cranial bone remain unresolved. No allele-directed clinical treatment follows from these observations.
references:
- reference: PMID:25577943
  title: "Autosomal Dominant Robinow Syndrome."
  tags:
  - GeneReviews
- reference: PMID:42424595
  title: "The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes."
- reference: PMID:25817016
  title: DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.
- reference: PMID:25817014
  title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
- reference: PMID:32888393
  title: "Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form."
- reference: PMID:35047859
  title: "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability."
- reference: PMID:36916233
  title: Mechanistic studies in Drosophila and chicken give new insights into functions of DVL1 in dominant Robinow syndrome.
- reference: PMID:26924530
  title: DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.
- reference: PMID:10417975
  title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf
  findings:
  - statement: >-
      Full GeneReviews chapter Autosomal Dominant Robinow Syndrome (NBK268648), updated 2019; complements the
      PMID:25577943 abstract with baseline evaluation, variant interpretation and reproductive counseling.
- reference: url:https://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 and supplementary information for PMID:26924530. Supplemental Table S1 and proband BAB8062 describe DVL1 disease, while the main clinical table describes DVL3 disease. Cohort identities are kept distinct.

📚

References & Deep Research

References

11

PMID:25577943

Autosomal 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:25817016

DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.

No top-level findings curated for this source.

PMID:25817014

Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.

No top-level findings curated for this source.

PMID:32888393

Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form.

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: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: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:10417975

Robinow syndrome with growth hormone deficiency: treatment with growth hormone.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf

https://www.ncbi.nlm.nih.gov/sites/books/NBK268648/pdf/Bookshelf_NBK268648.pdf

1 finding

Full GeneReviews chapter Autosomal Dominant Robinow Syndrome (NBK268648), updated 2019; complements the PMID:25577943 abstract with baseline evaluation, variant interpretation and reproductive counseling.

url:https://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 and supplementary information for PMID:26924530. Supplemental Table S1 and proband BAB8062 describe DVL1 disease, while the main clinical table describes DVL3 disease. Cohort identities are kept distinct.

Autosomal Dominant Robinow Syndrome 2

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