Autosomal Recessive Robinow Syndrome

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive HP:0000007

Both homozygous and compound-heterozygous ROR2 pathogenic variants occur. Consanguinity is common but is not required. The usual 25% sibling recurrence risk applies when both parents carry a disease-causing allele; parental testing is important because a prenatal compound-heterozygous case included an apparently de novo allele.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20301418 SUPPORT Human Clinical

"ROR2-related Robinow syndrome is inherited in an autosomal recessive manner."

GeneReviews states the inheritance mode.

PMID:10932186 SUPPORT Human Clinical

"Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7..."

Documents homozygous alleles in consanguineous families and the Omani founder cohort.

PMID:38504427 SUPPORT Human Clinical

"Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene"

Direct evidence that the disease is not restricted to homozygous genotypes.

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Discussions and Knowledge Gaps

1

Does the Ror2-null mouse's four-lesion decomposition transfer quantitatively to human ROR2 disease, given that mouse Ror1 partially compensates for Ror2 loss?

HUMAN MODEL MISMATCH ror2_null_mouse_vs_human_recessive_disease

Attached to

pathophysiology#Reduced WNT5A-ROR2 Noncanonical Signalling

The single Ror2 knockout separates axial skeletal, chondrocyte, craniofacial and genital findings. Validated Ror1/Ror2 double-null mice have more severe developmental defects, supporting overlapping receptor functions in mice. The quantitative contribution of ROR1 in human ROR2 disease remains unresolved. Noncanonical WNT5A-ROR signaling should not be treated as synonymous with all core planar cell polarity signaling: Ho et al. found substantial phenotypic differences between Ror and Vangl double mutants.

Show evidence (1 reference)

url:https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf SUPPORT Model Organism

"Ror DKO mutants lacking all Ror signaling capacity have substantially non- overlapping phenotypes compared with mice with mutations in both members of the Vangl family"

Mouse comparative phenotypes challenge a universal equivalence between the Ror and core PCP pathways.

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Pathophysiology

10

Biallelic ROR2 Loss of Function

Mechanism confidence: Established

Biallelic ROR2 variants impair receptor function. Reported alleles include missense, nonsense, frameshift, splice, initiation-codon and deletion variants. Nonsense-mediated decay is supported for selected truncating alleles, while several tested missense proteins show defective trafficking. These observations do not establish that every variant eliminates all receptor protein or signaling.

ROR2 hgnc:10257

Genetic context ROR2 hgnc:10257 allele_type: missense, nonsense, frameshift, splice-region, initiation-codon, or deletion allele functional_impact_category: LOSS_OF_FUNCTION

Downstream

Reduced ROR2 Transcript Abundance Selected premature termination alleles trigger nonsense-mediated mRNA decay; this route is allele-dependent.

Defective ROR2 Trafficking to the Cell Surface Several experimentally tested missense and truncating proteins show intracellular retention; this is not universal for every disease-associated allele.

Reduced WNT5A-ROR2 Noncanonical Signalling Reduced receptor abundance or impaired receptor function decreases noncanonical WNT5A signaling. Some variants retain surface localization and partial signaling.

Impaired Osteogenic Differentiation of Marrow Stromal Cells ROR2 knockdown and variant-expression experiments suggest impaired osteogenic differentiation. Translation from this culture system to congenital skeletal disease remains provisional.

Show evidence (2 references)

PMID:10932187 SUPPORT Human Clinical

"The ROR2 mutations present in RRS result in premature stop codons and predict nonfunctional proteins."

The founding study predicts nonfunctional proteins from premature stop codons; it does not directly measure function for every allele.

PMID:35344616 SUPPORT Human Clinical

"The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome."

Clinical deletion alleles support the gene-level loss-of-function mechanism; deletion alone does not establish every downstream molecular consequence.

Reduced ROR2 Transcript Abundance

Mechanism confidence: Established

Nonsense-mediated decay reduces expression of selected ROR2 premature-termination alleles. Escape from this surveillance pathway contributes to the distinction between recessive Robinow and dominant brachydactyly alleles, but position alone does not explain all variants.

Downstream

Reduced WNT5A-ROR2 Noncanonical Signalling Reduced transcript abundance limits production of functional ROR2 protein.

Show evidence (1 reference)

PMID:19236432 SUPPORT In Vitro

"Our experiments show that triggering or escaping NMD may cause different phenotypes with a distinct mode of inheritance."

Experimental evidence for an allele-dependent contribution of nonsense-mediated decay.

Defective ROR2 Trafficking to the Cell Surface

Mechanism confidence: Established

Several Robinow-associated ROR2 variants are retained intracellularly and show impaired delivery to the plasma membrane. HeLa-cell localization and immortalized mouse-fibroblast assays support this mechanism. It is variant-dependent: R189W and R272C reached the cell surface in the 2024 rescue assay and retained more signaling than five severely affected variants.

Experimental models

HeLa ROR2 variant trafficking assay CELL LINE Selected variant proteins are retained intracellularly.

ROR1/ROR2-null iMEF rescue and Frizzled bypass system CELL LINE Five variants fail surface delivery, while R189W and R272C retain surface expression.

Downstream

Reduced WNT5A-ROR2 Noncanonical Signalling Impaired surface delivery reduces the receptor contribution to WNT5A signaling; functional assays also identify milder signaling deficits in surface-expressed variants.

Show evidence (3 references)

PMID:35344616 SUPPORT In Vitro

"Co-expression of Ror2 and EGFP-hRas or calnexin in Hela-cells showed that wild-type Ror2 localizes predominantly to the plasma membrane, while mutant Ror2 proteins do not migrate to the plasma membrane and are retained to the endoplasmic reticulum"

Transfected-cell localization directly supports intracellular retention for the tested constructs.

PMID:38780011 SUPPORT In Vitro

"C182Y, R184C, C223Y, G326A, and R366W all fail to traffic to the plasma membrane, whereas R189W and R272C are expressed on the cell surface"

Surface staining distinguishes severe trafficking defects from variants that retain surface expression.

PMID:17665217 SUPPORT In Vitro

"We establish the retention of the mutated proteins in the endoplasmic reticulum of HeLa cells and therefore failure to reach the plasma membrane."

The earlier study directly tested ER retention for two CRD mutations; its findings do not establish retention for all subsequently identified alleles.

Reduced WNT5A-ROR2 Noncanonical Signalling

Mechanism confidence: Established

ROR2 promotes Frizzled-dependent noncanonical WNT5A signaling. In an immortalized Ror1/Ror2-deficient mouse-fibroblast rescue system, Robinow-associated variants reduced GFP-Pdzrn3 reporter degradation and DVL2 phosphorylation to different degrees. The cysteine-rich domain was required for this activity, while constructs lacking the intracellular region retained activity in that assay. Residual signaling in cells lacking both ROR receptors argues against treating ROR2 loss as complete loss of every WNT5A response.

non-canonical Wnt signaling pathway GO:0035567 ↓ DECREASED

Experimental models

ROR1/ROR2-null iMEF rescue and Frizzled bypass system CELL LINE Variant rescue assays reveal strong or partial signaling deficits; mini-ROR2 and bivalent anti-Frizzled IgGs test distinct ways to restore the reporter response.

Primary embryonic fibroblast Ror deletion model PRIMARY CELL CULTURE Loss of Ror receptors lowers the Dvl2 phosphorylation readout.

Animal models

Ror1/Ror2 double-null mouse Mouse partially recapitulates Combined receptor loss produces developmental defects resembling Wnt5a loss.

Downstream

Reduced Presomitic Mesoderm Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.

Perturbed Growth Plate Chondrocyte Differentiation Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.

Craniofacial Midline Outgrowth Defect Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.

Genital Tubercle Outgrowth Defect Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.

Renal Tract Abnormalities Renal anomalies occur in ROR2 disease; the intermediate developmental processes are not resolved by the cited clinical evidence.

Hydronephrosis This specific renal lesion is reported in ROR2 disease. As for the existing renal-abnormality edge, the intermediate developmental events linking altered signaling to the lesion remain unresolved.

Cystic renal dysplasia This specific renal lesion is reported in ROR2 disease. As for the existing renal-abnormality edge, the intermediate developmental events linking altered signaling to the lesion remain unresolved.

Show evidence (4 references)

PMID:38780011 SUPPORT In Vitro

"three of the five CRD mutations (C182Y, R184C, and C223Y) and both Kr mutations (G326A and R366W) exhibited strongly reduced signaling capabilities"

Direct functional assay of Robinow-associated substitutions.

PMID:38780011 SUPPORT In Vitro

"The remaining two mutants (R189W and R272C) exhibited milder but still statistically significant signaling deficits"

Residual signaling varies among the assayed substitutions.

PMID:38780011 SUPPORT In Vitro

"ROR KO reporter cells without any ROR2 rescue still retained some basal WNT5A signaling activity, which remained dose-dependent with respect to WNT5A concentration"

Loss of ROR1 and ROR2 does not abolish every WNT5A response in this cell system.

+ 1 more reference

Reduced Presomitic Mesoderm

Mechanism confidence: Established

Ror2-null embryos have a reduced presomitic mesoderm. This is model-organism evidence for a developmental substrate of axial skeletal malformations, not a measurement in affected human embryos.

Animal models

Ror2-null mouse Mouse recapitulates Vertebral malformations trace to a reduced presomitic mesoderm and defective somitogenesis.

Downstream

Defective Somitogenesis Reduction of the presomitic mesoderm accompanies impaired somite formation in Ror2-null embryos.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Our results demonstrate that vertebral malformations in Ror2(-/-) mice are due to reductions in the presomitic mesoderm and defects in somitogenesis."

Directly supports the developmental mechanism this node asserts, in the mouse null for this entry's gene.

Defective Somitogenesis

Somitogenesis is abnormal in Ror2-null mice, providing a developmental explanation for their vertebral malformations and a model for the axial skeletal defects of human ROR2 disease.

somitogenesis GO:0001756 ↓ DECREASED

Downstream

Vertebral Segmentation Defects Segmentation of a reduced presomitic mesoderm yields hemivertebrae.

Rib Fusion The ribs segment from the same paraxial mesoderm.

Scoliosis Asymmetric vertebral segments impose a curve on the growing spine.

Thoracic vertebral fusion Abnormal somite formation provides a developmental model for the fused thoracic vertebrae described alongside hemivertebrae in human disease; the precise human intermediates are unresolved.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Our results demonstrate that vertebral malformations in Ror2(-/-) mice are due to reductions in the presomitic mesoderm and defects in somitogenesis."

Directly supports the developmental mechanism this node asserts, in the mouse null for this entry's gene.

Perturbed Growth Plate Chondrocyte Differentiation

Mechanism confidence: Established

Perturbed growth-plate chondrocyte differentiation contributes to mesomelic limb shortening in Ror2-null mice. The human developmental mechanism is inferred from the shared gene and skeletal phenotype.

growth plate chondrocyte CL:1000217

chondrocyte differentiation GO:0002062 ⚠ ABNORMAL endochondral ossification GO:0001958 ⚠ ABNORMAL

Animal models

Ror2-null mouse Mouse recapitulates Mesomelic limb shortening in the null mouse is attributed to perturbed chondrocyte differentiation.

Downstream

Mesomelic Limb Shortening Impaired growth plate chondrocyte differentiation shortens the limb.

Short Stature The same lesion summed over the long bones; stature loss is marked in this form.

Brachydactyly Digital shortening is a skeletal manifestation of ROR2 disease; the exact contribution of altered growth-plate differentiation to each digital anomaly is not directly established in humans.

Short palm The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.

Clinodactyly The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.

Broad thumb The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.

Broad hallux The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.

Limited forearm pronation and supination The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Mesomelic limb shortening in Ror2(-/-) mice is a consequence of perturbed chondrocyte differentiation."

Assigns the mesomelic shortening specifically to chondrocyte differentiation.

Craniofacial Midline Outgrowth Defect

Mechanism confidence: Established

Ror2-null mice show impaired craniofacial midline outgrowth. This supports a developmental contribution to the human craniofacial phenotype without proving that every individual facial or oral finding shares one direct cellular cause.

Animal models

Ror2-null mouse Mouse recapitulates The craniofacial phenotype is caused by a midline outgrowth defect.

Downstream

Hypertelorism Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.

Prominent Forehead Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.

Short Nose Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.

Gingival Overgrowth Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.

Ankyloglossia Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.

Wide nasal bridge Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Depressed nasal bridge Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Anteverted nares Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Abnormal nasal tip morphology Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Midface retrusion Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Micrognathia Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Retrognathia Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Bifid tongue Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Microglossia Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Moreover, we show that the craniofacial phenotype is caused by a midline outgrowth defect."

Attributes the craniofacial phenotype to a specific developmental mechanism.

Genital Tubercle Outgrowth Defect

Mechanism confidence: Hypothetical

Ror2 expression in the genital tubercle and reduced tubercle size in null mice support a developmental contribution to genital hypoplasia. These observations do not exclude endocrine abnormalities or establish the degree of response to hormone treatment in humans.

Animal models

Ror2-null mouse Mouse partially recapitulates Ror2 is expressed in the genital tubercle and the tubercle is reduced in the null mouse.

Downstream

Genital Hypoplasia Reduced genital-tubercle size in mice suggests a developmental contribution, but the exact anatomical and endocrine contributions to this human manifestation are unresolved.

Micropenis Reduced genital-tubercle size in mice suggests a developmental contribution, but the exact anatomical and endocrine contributions to this human manifestation are unresolved.

Clitoral Hypoplasia Reduced genital-tubercle size in mice suggests a developmental contribution, but the exact anatomical and endocrine contributions to this human manifestation are unresolved.

Hypospadias Abnormal genital-tubercle development may contribute to this clinically observed genital anomaly, but the specific human urethral-development steps are unresolved.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Ror2 expression in the genital tubercle and its reduced size in Ror2(-/-) mice makes it likely that Ror2 is involved in genital development."

Supports a primary developmental origin. The source hedges ("makes it likely") and this node inherits that hedge.

Impaired Osteogenic Differentiation of Marrow Stromal Cells

Mechanism confidence: Hypothetical

In marrow stromal-cell experiments, ROR2 knockdown or expression of c.904C>T was associated with reduced osteogenic differentiation. This is a candidate contribution to skeletal disease, distinct from the growth-plate chondrocyte defect demonstrated in null mice.

osteoblast differentiation GO:0001649 ↓ DECREASED

Experimental models

ROR2-depleted marrow stromal cells with sphingomyelin rescue PRIMARY CELL CULTURE The perturbations impair cellular osteogenic readouts, with rescue after sphingomyelin supplementation.

Downstream

Short Stature A possible skeletal contribution inferred from impaired cellular osteogenesis; the culture study did not test growth or stature in affected individuals.

Show evidence (1 reference)

DOI:10.32604/biocell.2023.028851 SUPPORT In Vitro

"The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1."

Cultured marrow stromal cells with ROR2 depletion or the c.904C>T construct show an osteogenic phenotype; its contribution to human congenital skeletal disease is unresolved.

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Pathograph

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Phenotypes

75

Cardiovascular 7

Congenital heart abnormalities OCCASIONAL Abnormal heart morphology HP:0001627

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Abnormal heart morphology (18.18%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Pulmonic stenosis HP:0001642

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia"

The chapter explicitly names this structural defect; it provides no lesion-specific frequency.

Atrial septal defect HP:0001631

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia"

The chapter explicitly names this structural defect; it provides no lesion-specific frequency.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia"

The chapter explicitly names this structural defect; it provides no lesion-specific frequency.

Coarctation of aorta HP:0001680

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia"

The chapter explicitly names this structural defect; it provides no lesion-specific frequency.

Tetralogy of Fallot HP:0001636

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia"

The chapter explicitly names this structural defect; it provides no lesion-specific frequency.

Tricuspid atresia HP:0011662

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia"

The chapter explicitly names this structural defect; it provides no lesion-specific frequency.

Digestive 1

Inguinal hernia OCCASIONAL HP:0000023

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Inguinal hernia (15.78%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Ear 2

Low-set ears FREQUENT HP:0000369

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Low-set ears (66.66%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hearing impairment OCCASIONAL HP:0000365

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Hearing impairment (13.63%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Eye 4

Hypertelorism VERY_FREQUENT HP:0000316

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.

Proptosis FREQUENT HP:0000520

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| 50-74 | Proptosis (63.63%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Ptosis OCCASIONAL HP:0000508

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Ptosis (13,63%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Strabismus OCCASIONAL HP:0000486

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Strabismus (19.04%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Genitourinary 10

Genital Hypoplasia VERY_FREQUENT Hypoplastic male external genitalia HP:0000050

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy."

Documents the genital phenotype in both sexes.

PMID:35344616 SUPPORT Human Clinical

"Genital hypoplasia was present in all male patients, but in less than 50% of the females."

The male frequency should not be generalized to female genital findings.

Micropenis VERY_FREQUENT HP:0000054

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy."

Micropenis is named as a common feature of this form.

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

The genital finding is explicitly restricted to male patients.

Clitoral Hypoplasia HP:0000060

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

"reduced clitoral size and hypoplasia of the labia majora in females"

Records the female genital phenotype.

Renal Tract Abnormalities OCCASIONAL Abnormality of the kidney HP:0000077

Coarse binding: source unspecified

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"renal tract abnormalities, and nail hypoplasia or dystrophy"

Renal tract abnormalities are listed among the common associated features.

PMID:35344616 SUPPORT Human Clinical

"| | Abnormality of the kidney (14.28%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Cryptorchidism FREQUENT HP:0000028

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Cryptorchidism (50.00%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hypoplastic labia minora HP:0000064

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Hypoplastic labia minora (36.36%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hypospadias OCCASIONAL HP:0000047

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Hypospadias (20.00%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hypoplastic labia majora HP:0000059

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Hypoplastic labia majora (16.67%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hydronephrosis HP:0000126

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Hydronephrosis is common and cystic dysplasia of the kidney has been reported."

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

Cystic renal dysplasia HP:0000800

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Hydronephrosis is common and cystic dysplasia of the kidney has been reported."

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

Head and Neck 31

Prominent Forehead VERY_FREQUENT HP:0011220

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.

Short Nose VERY_FREQUENT HP:0003196

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.

Gingival Overgrowth FREQUENT HP:0000212

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia"

Gum hypertrophy is listed among the oral features.

PMID:35344616 SUPPORT Human Clinical

Table II reports gingival overgrowth in 77.27%; the source spelling is preserved.

Ankyloglossia HP:0010296

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

"large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia"

Ankyloglossia is listed among the oral features.

Wide nasal bridge VERY_FREQUENT HP:0000431

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Wide nasal bridge (95.45%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Abnormal nasal tip morphology VERY_FREQUENT HP:0000436

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Anteverted nares VERY_FREQUENT HP:0000463

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Anteverted nares (95.45%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Midface retrusion VERY_FREQUENT HP:0011800

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Midface retrusion (95.45%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Downturned corners of mouth FREQUENT HP:0002714

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Downturned corners of mouth (77.27%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Bifid tongue FREQUENT HP:0010297

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Bifid tongue (77.27%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Abnormal dental morphology FREQUENT HP:0006482

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Long eyelashes FREQUENT HP:0000527

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Long eyelashes (72.72%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Long palpebral fissures FREQUENT HP:0000637

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Long palpebral fissures (68.18%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Upslanted palpebral fissures FREQUENT HP:0000582

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Upslanted palpebral fissures (50%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Depressed nasal bridge FREQUENT HP:0005280

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Depressed nasal bridge (68.18%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Long philtrum FREQUENT HP:0000343

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Long philtrum (50.00%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Triangular mouth FREQUENT HP:0000207

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Triangular mouth (72.72%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Thin upper lip vermilion FREQUENT HP:0000219

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Thin upper lip vermilion (59.09%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Micrognathia FREQUENT HP:0000347

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Micrognathia (68.18%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Retrognathia FREQUENT HP:0000278

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Retrognathia (68.18%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Short neck FREQUENT HP:0000470

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Short neck (63.63%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Downslanted palpebral fissures FREQUENT HP:0000494

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Cryptorchidism (50.00%) | | 25-49 | Dowslanted palpebral fissures (31.81%) | | | Epicanthus (31.81%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Epicanthus FREQUENT HP:0000286

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Epicanthus (31.81%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Short philtrum OCCASIONAL HP:0000322

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Short philtrum (27.27%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Microglossia FREQUENT HP:0000171

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

High narrow palate FREQUENT HP:0002705

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hypodontia FREQUENT HP:0000668

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Orofacial cleft OCCASIONAL HP:0000202

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Macrocephaly HP:0000256

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism"

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

PMID:20301418 SUPPORT Human Clinical

"Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism"

GeneReviews abstract explicitly includes macrocephaly.

Dental crowding HP:0000678

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome."

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

Dental malocclusion HP:0000689

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome."

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

Integument 3

Nail dysplasia FREQUENT HP:0002164

Show evidence (2 references)

PMID:35344616 SUPPORT Human Clinical

"| | Nail dysplasia (38.09%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

PMID:20301418 SUPPORT Human Clinical

"renal tract abnormalities, and nail hypoplasia or dystrophy"

GeneReviews independently identifies the nail phenotype.

Single transverse palmar crease OCCASIONAL HP:0000954

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Melanocytic nevus OCCASIONAL HP:0000995

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| 5-24 | Melanocytic nevus (20.00%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Limbs 9

Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.

Brachydactyly VERY_FREQUENT HP:0001156

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.

Short palm VERY_FREQUENT HP:0004279

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Short palms (86.36%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Clinodactyly VERY_FREQUENT HP:0030084

Table II gives 80.95%, whereas the discussion says 81.8%. The table estimate is retained without pooling or implying an exact common denominator.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Clinodactyly (80,95%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Limited forearm pronation and supination FREQUENT Limited pronation/supination of forearm HP:0006394

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Broad thumb FREQUENT HP:0011304

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Broad thumbs (59.09%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Syndactyly OCCASIONAL HP:0001159

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Syndactyly (28.57%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Broad hallux FREQUENT HP:0010055

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Hip dislocation OCCASIONAL HP:0002827

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Hip dislocation (15.78%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Musculoskeletal 6

Vertebral Segmentation Defects VERY_FREQUENT Hemivertebrae HP:0002937

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Hemivertebrae (86.36%) |"

Table II reports each finding in 86.36% of this 22-person cohort; neither is obligate.

Rib Fusion VERY_FREQUENT HP:0000902

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Rib fusion (86.36%) |"

Table II reports each finding in 86.36% of this 22-person cohort; neither is obligate.

Scoliosis FREQUENT HP:0002650

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Scoliosis is also a common finding that progresses with age and is the result of multiple vertebral anomalies. In our cohort it has been described in 69% of the patients."

Direct clinical support replaces inference from a general vertebral-feature list.

Pectus excavatum FREQUENT HP:0000767

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Pectus excavatum (47.61%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Camptodactyly OCCASIONAL HP:0012385

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| | Camptodactyly (19.04%) |"

Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.

Thoracic vertebral fusion Fused thoracic vertebrae HP:0030039

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly."

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

Nervous System 1

Developmental delay Neurodevelopmental delay HP:0012758

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Intellect is usually within the normal range; however, developmental delay has been reported."

GeneReviews clinical baseline; no cohort-specific frequency is inferred.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients."

Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.

🧬

Genetic Associations

1

ROR2

Gene: ROR2 hgnc:10257 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:35344616 SUPPORT Human Clinical

"We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions."

Documents candidate alleles in a clinically ascertained ROR2 cohort; some individual alleles remained uncertain significance.

PMID:35344616 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Gain-of-function (GoF) ROR2 variants have been associated with autosomal dominant brachydactyly type B (MIM 113000)"

Establishes the allelic-but-mechanistically-distinct relationship to brachydactyly type B.

🔬

Variants

11

ROR2 c.323G>A; p.(Arg108Gln) Likely Pathogenic

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: missense

Homozygous in A1 and A2; listed as likely pathogenic by the cohort assessment. Transcript NM_004560.4. This substitution was included in the HeLa trafficking assay. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A1 | c.323G>A | p.(Arg108Gln) | Hom | N | 25.7 | Likely Pathogenic PM2/PP4/PP5 | Parents not tested | Sanger sequencing |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.355C>T; p.(Arg119*) Pathogenic

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: nonsense

Homozygous nonsense allele in A3, listed as pathogenic. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A3 | c.355C>T | p.(Arg119*) | Hom | N | 35.0 | Pathogenic PVS1/PM2/PP4/PP5 | Parents not tested | NGS panel |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 exon 4–5 deletion Uncertain Significance

Gene: ROR2 hgnc:10257 deletion

Variant detail: exon deletion

A4 had a homozygous approximately 21-kb deletion, with heterozygous parents. The clinical study implicates this deletion in disease, but Table I gives an uncertain structural-variant classification (+0.45). Breakpoints are reported on GRCh37. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A4 | ... chr9:g.94498192_94519323del | p.? | Hom | Y | - | Uncertain +0.45 | Heterozygous parents | Sanger sequencing /MLPA/CMA |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.2074C>A; p.(Pro692Thr) Uncertain Significance

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: missense

Homozygous in A9 and A19, classified as uncertain significance in the cohort table despite the authors reporting defective trafficking in their selected-variant assay. Transcript NM_004560.4; Table I nomenclature is retained. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A9 | c.2074C>A | p.(Pro692Thr) | Hom | Y | 25.7 | Uncertain Significance PM2/PP3/PP4/PP5 | Heterozygous parents | Sanger sequencing |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.1970G>A; p.(Arg657His) Uncertain Significance

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: missense

A11 carried this missense VUS in trans with an approximately 470-kb deletion containing ROR2 and part of SPTLC1; Table I classifies the deletion as pathogenic. An apparently homozygous sequencing call was resolved through copy-number analysis. A21 also carried Arg657His with a different allele. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A11 | c.1970G>A ... chr9:g.94371974_94844329del | p.(Arg657His) - | Comp Het | Y, Y | 31.0 - | Uncertain significance PM2/PM3/PP4 Pathogenic +1.00 | Parents not tested | NGS panel/MLPA/CMA |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.2T>G Likely Pathogenic

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: initiation-codon

Homozygous initiation-codon variant in A13, listed as likely pathogenic, with heterozygous parents. The protein consequence is reported as p.?; no specific alternate protein is asserted. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A13 | c.2T>G | p.? | Hom | Y | 20.4 | Likely Pathogenic PVS1/PM2//PP4/PP5 | Heterozygous parents | Exome sequencing |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.1096C>T; p.(Arg366Trp) Likely Pathogenic

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: missense

Paternally inherited in A16 in trans with maternal c.2207G>A; p.(Arg736Gln). Both were classified as likely pathogenic in Table I. Both substitutions were included in the HeLa trafficking study. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Functional effects

ROR2 cell-surface trafficking

R366W failed to reach the plasma membrane in the 2024 rescue system and showed strongly reduced signaling; these functional findings are distinct from the source-dated clinical classification.

Show evidence (2 references)

PMID:35344616 SUPPORT Human Clinical

"| A16 | c.1096C>T c.2207G>A | p.(Arg366Trp) p.(Arg736Gln) | Comp Het | N, Y | 29.1 28.1 | Likely Pathogenic PM1/PM2/PM3/PP3/PP4/PP5 Likely Pathogenic PM2/ PM3/PP3/PP4/PP5 | Father: c.1096C>T Mother: c.2207G>A | Sanger sequencing |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

PMID:38780011 SUPPORT In Vitro

"C182Y, R184C, C223Y, G326A, and R366W all fail to traffic to the plasma membrane, whereas R189W and R272C are expressed on the cell surface"

Surface staining distinguishes severe trafficking defects from variants that retain surface expression.

ROR2 c.623–11G>A Uncertain Significance

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: intronic splice-region candidate

Homozygous intronic variant in A17/A18 with heterozygous parents, classified as uncertain significance. Its position suggests a possible splice effect, but the quoted cohort does not establish the aberrant transcript. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A17/A18 | c.623–11G>A | -- | Hom | Y | - | Uncertain significance PM2/PP4/PP5/BP7 | Heterozygous parents | Sanger sequencing |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.1324C>T; p.(Arg442*) Pathogenic

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: nonsense

A20 carried this paternal nonsense allele in trans with maternal c.1083delG; p.(His362Thrfs*83). Both were classified as pathogenic in Table I on NM_004560.4. Earlier protein nomenclature p.Arg441Ter is not automatically substituted for this transcript-specific annotation. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"| A20 | c.1083delG c.1324C>T | p.(His362Thrfs*83) p.(Arg442*) | Comp Het | Y, N | - 36.0 | Pathogenic PVS1/PM2/PM3/PP3/PP4/PP5 Pathogenic PVS1/PM2/PM3/PP4/PP5 | Father:c.1324C>T Mother:c.1083delG | Exome sequencing |"

Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.

ROR2 c.1366dup; p.(Leu456Profs*3) Pathogenic

Gene: ROR2 hgnc:10257 duplication

Variant detail: frameshift

Apparently de novo frameshift in a 2024 prenatal case, in trans with maternally inherited c.1324C>T; p.(Arg442*). The authors classified the compound-heterozygous variants as pathogenic; the abstract does not specify a transcript accession or prove the absence of parental mosaicism. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (1 reference)

PMID:38504427 SUPPORT Human Clinical

"Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo."

Documents the fetal compound-heterozygous genotype and the reported parental origins.

ROR2 c.904C>T; p.(Arg302Cys) Uncertain Significance

Gene: ROR2 hgnc:10257 single nucleotide variant

Variant detail: missense

Paternal missense allele in A21 in trans with maternal p.(Arg657His), classified as uncertain significance in the 2022 cohort on NM_004560.4. A 2023 study reported impaired localization, WNT5A interaction and osteogenic differentiation in variant-expression cultures. These functional findings are retained separately from the cohort classification. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.

Show evidence (2 references)

PMID:35344616 SUPPORT Human Clinical

"| A21 | c.904C>T c.1970G>A | p.(Arg302Cys) p.(Arg657His) | Comp Het | N, Y | 27.4 31.0 | Uncertain Significance PM2/ PP4 Uncertain significance PM2/PP3/PP4 | Father: c.904C>T Mother: c.1970G>A | Sanger sequencing |"

The source-dated cohort table reports both alleles as uncertain significance.

DOI:10.32604/biocell.2023.028851 SUPPORT In Vitro

"The ROR2: c.904C>T mutant altered the subcellular localization of the ROR2 protein, which caused an impaired interaction between ROR2 and Wnt5a."

Functional evidence from transfected cultures; this is not a new clinical classification.

💊

Medical Actions

10

Orthopedic Surgery for Limb and Spine Deformity

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Corrective surgery may be needed for syndactyly or severe scoliosis associated with vertebral and rib abnormalities.

Target Phenotypes: Scoliosis HP:0002650 Syndactyly HP:0001159

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"Treatment of manifestations: Corrective surgery for limb and spine defects and for facial abnormalities; orthodontic treatment as needed"

Lists corrective limb and spine surgery in the management of this form.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Corrective surgeries may be required for the following: ... Syndactyly ... Severe scoliosis secondary to hemivertebrae and rib abnormalities"

The full chapter specifies which skeletal manifestations may require surgery.

Androgen Therapy for Micropenis

Action: Hormone Therapy NCIT:C15445

Agent: testosterone CHEBI:17347

Platform: Small molecule

Hormone therapy may be considered for micropenis after specialist endocrine assessment. A developmental contribution to genital anatomy does not establish normal hormone function in every patient or predict a uniformly incomplete response.

Target Phenotypes: Micropenis HP:0000054

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"hormone therapy as needed for the treatment of micropenis"

GeneReviews lists hormone therapy for micropenis in management.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Injection of human chorionic gonadotropin and testosterone therapy improved penile length and testicular volume in three boys with severe micropenis"

The reported small clinical series used hCG and testosterone; this does not isolate the effect of testosterone alone.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Discuss recurrence risk based on parental variants, carrier testing, and available prenatal or preimplantation testing to support informed reproductive choices. The usual 25% sibling risk assumes that both parents carry a disease-causing allele. Some heterozygotes can have brachydactyly type B1 findings.

Show evidence (3 references)

PMID:20301418 SUPPORT Human Clinical

"At conception, each sib of an affected individual has a 25% chance of being affected with Robinow syndrome, a 50% chance of being a heterozygote (carrier) and usually asymptomatic, and a 25% chance of being unaffected and not a carrier."

Supplies the recurrence risk figures.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family."

Supports familial testing after identifying the causative variants.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Heterozygotes may display findings consistent with brachydactyly type B1."

Carrier status should not be equated with an invariably normal digital phenotype.

Human chorionic gonadotropin for micropenis

Action: Hormone Therapy NCIT:C15445

Agent: human chorionic gonadotropin CHEBI:81570

Platform: Peptide

Human chorionic gonadotropin was used with testosterone in a three-boy series summarized by GeneReviews. Treatment requires pediatric endocrine assessment and monitoring; a hormone deficiency is not assumed in every patient.

Target Phenotypes: Micropenis HP:0000054

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Injection of human chorionic gonadotropin and testosterone therapy improved penile length and testicular volume in three boys with severe micropenis"

Small clinical series summarized in GeneReviews; no comparative efficacy estimate or separate hCG effect is established.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Hormone therapy should be monitored by a pediatric endocrinologist."

Specifies specialist monitoring for the hormone intervention.

Orthodontic treatment

Category: Therapeutic Action: Orthodontic Treatment NCIT:C64248

Platform: Device

Orthodontic care addresses misaligned or crowded teeth and malocclusion.

Target Phenotypes: Dental crowding HP:0000678 Dental malocclusion HP:0000689

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Orthodontics consultation as needed for misaligned, crowded teeth"

GeneReviews management recommendation for ROR2-related Robinow syndrome.

Cleft repair

Category: Therapeutic Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Corrective surgery may be needed for cleft lip or palate.

Target Phenotypes: Orofacial cleft HP:0000202

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Clinical assessment for presence of cleft lip/palate and the need for surgical repair"

GeneReviews management recommendation for ROR2-related Robinow syndrome.

Surgery for abnormal penile insertion or penoscrotal transposition

Category: Therapeutic Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Reconstructive urologic surgery may improve appearance in selected patients. The cited report moved the scrotum downward; it did not detach the abnormal penile-crural insertion.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"improved the cosmetic appearance by transposing the scrotum downward."

GeneReviews management recommendation for ROR2-related Robinow syndrome.

Scoliosis surveillance

Category: Monitoring

Monitor for scoliosis until growth is complete.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Surveillance for evidence of scoliosis until growth is completed"

GeneReviews management recommendation for ROR2-related Robinow syndrome.

Dental surveillance

Category: Monitoring

Dental evaluation every six to twelve months, or on the schedule recommended at initial dental assessment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment"

GeneReviews management recommendation for ROR2-related Robinow syndrome.

Cardiac and renal follow-up

Category: Monitoring

Specialist follow-up is tailored to identified cardiac or renal abnormalities.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified"

GeneReviews management recommendation for ROR2-related Robinow syndrome.

🔬

Diagnosis

6

Clinical and Radiographic Recognition

Clinical recognition combines craniofacial, limb and genital findings with skeletal radiographs. Vertebral and rib anomalies strongly support ROR2 disease but are not universally present or exclusive to this gene. Molecular testing resolves the overlapping Robinow phenotypes.

physical examination NCIT:C20989

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"The disorder is recognizable at birth or in early childhood."

Supports clinical recognizability and its timing.

PMID:35344616 SUPPORT Human Clinical

"A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype."

Quantifies the phenotypic uniformity that makes recognition workable.

Prenatal Recognition

A reported fetus showed characteristic craniofacial, vertebral, digital and genital abnormalities at 24 + 3/7 weeks, with compound-heterozygous ROR2 variants identified in amniocytes. Recurrence counseling depends on parental segregation, including the possibility of an apparently de novo allele.

Ultrasound Imaging NCIT:C17230

Show evidence (2 references)

PMID:38504427 SUPPORT Human Clinical

"Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis."

Documents the prenatal findings and their gestational age.

PMID:38504427 SUPPORT Human Clinical

"Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene"

Establishes that molecular confirmation on amniocytes is achievable in the same pregnancy.

Molecular Confirmation

Confirmed by biallelic ROR2 pathogenic variants. Copy-number analysis is needed alongside sequencing, since whole-exon deletions are part of the allelic spectrum and would be missed by sequence calling alone.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:20301418 SUPPORT Human Clinical

"The diagnosis of ROR2-related Robinow syndrome is established in a proband with typical suggestive findings and biallelic ROR2 pathogenic variants identified on molecular genetic testing."

States the molecular confirmation criteria.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Homozygous deletions involving exons 6 and 7 have also been reported in Robinow syndrome"

Intragenic deletions are a documented allele class and motivate copy-number-aware testing.

Baseline renal ultrasonography

Renal ultrasound assesses the renal tract after diagnosis.

Ultrasound Imaging NCIT:C17230

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Renal ultrasound examination ... Echocardiogram to evaluate for structural heart defects"

GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.

Baseline echocardiography

Echocardiography evaluates congenital structural heart defects after diagnosis.

Echocardiography Test NCIT:C16525

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Echocardiogram to evaluate for structural heart defects"

GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.

Perioperative assessment

Assess the vertebrae and ribs and evaluate congenital heart disease before surgery. Midface hypoplasia can make endotracheal intubation difficult.

Physical Examination NCIT:C20989

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications"

GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Preoperative cardiac evaluation for the presence of ... heart defects"

GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/ SUPPORT Human Clinical

"Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia"

GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.

📊

Prevalence

1

Published Robinow syndrome cases across inheritance modes, as of 2002

Cases In Literature

The historical count exceeds 100 reported cases across both inheritance modes and is not a ROR2-specific count or population prevalence estimate.

Show evidence (1 reference)

PMID:12011143 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Over 100 cases have now been reported and we have reviewed the current knowledge of the clinical and genetic features of the syndrome."

Historical review of the mixed Robinow spectrum; this count is not a gene-specific prevalence estimate.

🔀

Differential Diagnoses

3

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

Brachydactyly type B

Overlapping Features An allelic ROR2 disorder, usually dominantly inherited, with severe digital abnormalities. Variant position alone does not separate the phenotypes: a nonsense allele at a site also affected by a BDB frameshift produced Robinow features with severe recessive brachydactyly.

Show evidence (1 reference)

PMID:19640924 SUPPORT Human Clinical

"The mutation is located at the same position as a previously described frame shift mutation causing dominant BDB1."

The primary comparison directly contradicts a universal positional separation.

Autosomal Dominant Robinow Syndrome 1

Overlapping Features The WNT5A form is usually milder skeletally. Vertebral anomalies and scoliosis are less frequent, but their absence is not a categorical discriminator; molecular testing distinguishes the forms.

Robinow Syndrome, Autosomal Recessive 2

Overlapping Features The NXN form. Also recessive, but its phenotype clusters with the dominant forms rather than with ROR2 disease.

🧫

Experimental Models

4

HeLa ROR2 variant trafficking assay CELL_LINE

Confocal localization of selected ROR2 variants (Arg108Gln, Arg366Trp, Pro692Thr and Arg736Gln) relative to the plasma-membrane marker EGFP-hRas and ER marker calnexin.

Cell source

Human HeLa cells transfected with wild-type or variant ROR2 constructs

Publication

PMID:35344616

Pathograph links

Defective ROR2 Trafficking to the Cell Surface partially recapitulates fidelity: moderate Selected variant proteins are retained intracellularly.

Limitations: Heterologous overexpression assay; does not establish that every Robinow-associated allele is retained in the ER.

Readouts

ROR2 plasma-membrane localization

Direction: DECREASED

Interpretation: Loss of membrane localization with ER retention for the assayed substitutions.

Show evidence (1 reference)

PMID:35344616 SUPPORT In Vitro

"Co-expression of Ror2 and EGFP-hRas or calnexin in Hela-cells showed that wild-type Ror2 localizes predominantly to the plasma membrane, while mutant Ror2 proteins do not migrate to the plasma membrane and are retained to the endoplasmic reticulum"

Transfected HeLa localization measures the selected receptor proteins, not an affected-patient cell phenotype.

Show evidence (1 reference)

PMID:35344616 SUPPORT In Vitro

"Co-expression of Ror2 and EGFP-hRas or calnexin in Hela-cells showed that wild-type Ror2 localizes predominantly to the plasma membrane, while mutant Ror2 proteins do not migrate to the plasma membrane and are retained to the endoplasmic reticulum"

Transfected HeLa localization measures the selected receptor proteins, not an affected-patient cell phenotype.

ROR1/ROR2-null iMEF rescue and Frizzled bypass system CELL_LINE

Conditional Ror1/Ror2 deletion is induced with 4-hydroxytamoxifen, followed by expression of mouse Ror2 constructs carrying domain deletions or Robinow-associated substitutions. GFP-Pdzrn3 degradation and DVL2 phosphorylation report signaling; surface staining and glycosidase sensitivity distinguish trafficking defects.

Cell source

E12.5 mouse embryonic fibroblasts immortalized by CRISPR ablation of Tp53

Publication

PMID:38780011

Pathograph links

Reduced WNT5A-ROR2 Noncanonical Signalling partially recapitulates fidelity: moderate Variant rescue assays reveal strong or partial signaling deficits; mini-ROR2 and bivalent anti-Frizzled IgGs test distinct ways to restore the reporter response.

Limitations: Immortalized mouse cells with transgene expression. Rescue of a reporter is not rescue of congenital malformations; monovalent F2.A Fab instead inhibits WNT5A-driven signaling.

Readouts

WNT5A-induced GFP-Pdzrn3 degradation

Direction: DECREASED

Interpretation: Disease-associated substitutions impair the reporter response to different degrees.

Show evidence (1 reference)

PMID:38780011 SUPPORT In Vitro

"The remaining two mutants (R189W and R272C) exhibited milder but still statistically significant signaling deficits"

The reporter assay distinguishes residual activity from the stronger defects of the other tested substitutions.

Show evidence (3 references)

PMID:38780011 SUPPORT In Vitro

"The remaining two mutants (R189W and R272C) exhibited milder but still statistically significant signaling deficits"

The reporter assay distinguishes residual activity from the stronger defects of the other tested substitutions.

+ 2 more references

Defective ROR2 Trafficking to the Cell Surface partially recapitulates fidelity: moderate Five variants fail surface delivery, while R189W and R272C retain surface expression.

Limitations: Construct and cell-context dependence limits transfer to patient tissues.

Show evidence (1 reference)

PMID:38780011 SUPPORT In Vitro

"C182Y, R184C, C223Y, G326A, and R366W all fail to traffic to the plasma membrane, whereas R189W and R272C are expressed on the cell surface"

Variant-specific surface staining directly distinguishes trafficking defects from retained surface expression.

Primary embryonic fibroblast Ror deletion model PRIMARY_CELL_CULTURE

Single- and double-receptor knockout cultures, including acute inducible deletion, compare endogenous Wnt5a-dependent signaling. Dvl2 phosphorylation decreases with loss of Ror receptors, while Wnt5a inhibition of canonical signaling and c-Jun phosphorylation were not dependent on Rors in this system.

Cell source

Primary mouse E12.5 embryonic fibroblasts used within five passages

Publication

PMID:22343533

Pathograph links

Reduced WNT5A-ROR2 Noncanonical Signalling partially recapitulates fidelity: moderate Loss of Ror receptors lowers the Dvl2 phosphorylation readout.

Limitations: Whole-gene mouse deletions do not reproduce every human missense genotype. Negative c-Jun and canonical-Wnt results are limited to this cell context.

Show evidence (1 reference)

url:https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf SUPPORT In Vitro

"Dvl2 phosphorylation is in- creasingly reduced in Ror1−/−, Ror2−/−, and Ror DKO MEFs"

Comparison of the mutant primary cultures shows a receptor-dose-dependent phosphorylation defect.

ROR2-depleted marrow stromal cells with sphingomyelin rescue PRIMARY_CELL_CULTURE

LV-shROR2 and LV-ROR2-c.904C>T cultures were compared with controls after osteogenic induction. Readouts included ALP activity, Alizarin Red staining, SMS1 transcripts, osteogenic markers, and ERK/P38/SMAD phosphorylation. Lipofectamine-delivered sphingomyelin was tested as a rescue intervention.

Cell source

Bone marrow mesenchymal stromal-cell culture; donor and species details are not clearly specified in the article methods

Publication

DOI:10.32604/biocell.2023.028851

Pathograph links

Impaired Osteogenic Differentiation of Marrow Stromal Cells partially recapitulates fidelity: low The perturbations impair cellular osteogenic readouts, with rescue after sphingomyelin supplementation.

Limitations: Single in-vitro study with incompletely described cell provenance and triplicate assays. Reduced SMS1 transcript is not a direct sphingomyelin measurement; supplementation does not prove a unique causal pathway or clinical benefit.

Readouts

Osteogenic mineralization and ALP activity

Direction: DECREASED

Interpretation: Reduced staining and activity after ROR2 depletion support impaired differentiation.

Show evidence (1 reference)

DOI:10.32604/biocell.2023.028851 SUPPORT In Vitro

"ROR2 depletion inhibited the Alizarin Red S accumulation in the Alizarin Red S staining assay and ALP staining in ALP activity assays"

Two cellular osteogenic readouts decrease in the reported perturbation experiment.

Show evidence (2 references)

DOI:10.32604/biocell.2023.028851 SUPPORT In Vitro

"The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1."

Cultured marrow stromal cells with ROR2 depletion or the c.904C>T construct show an osteogenic phenotype; its contribution to human congenital skeletal disease is unresolved.

+ 1 more reference

🐁

Animal Models

2

Ror2-null mouse

Constitutive Ror2 knockout, the reference developmental model for this form. Its value is that it resolves the syndrome into separate developmental defects at separate sites rather than one global growth failure.

Species

Mouse

Genotype

Ror2(-/-)

Publication

PMID:14745966

Pathograph links

Reduced Presomitic Mesoderm recapitulates fidelity: high Vertebral malformations trace to a reduced presomitic mesoderm and defective somitogenesis.

Limitations: The single Ror2 knockout does not establish the quantitative contributions of each developmental lesion in humans. Ror1/Ror2 double-null mice show more severe defects, but loss of two receptors is not the human ROR2 genotype.

Readouts

Presomitic mesoderm size

Direction: DECREASED

Interpretation: The reduced mesodermal pool is the measured antecedent of the vertebral malformations.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Our results demonstrate that vertebral malformations in Ror2(-/-) mice are due to reductions in the presomitic mesoderm and defects in somitogenesis."

Reports the reduction this readout records.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"The Ror2(-/-) mouse provides a suitable model that may help to explain many of the underlying developmental malformations in individuals with Robinow syndrome."

The authors' own statement that the model is informative for the human malformations.

Perturbed Growth Plate Chondrocyte Differentiation recapitulates fidelity: high Mesomelic limb shortening in the null mouse is attributed to perturbed chondrocyte differentiation.

Limitations: Assessed in the mouse growth plate; the corresponding human histology is not available, so the cellular claim transfers by inference from a shared gene and a shared limb phenotype.

Readouts

Growth plate chondrocyte differentiation

Direction: ALTERED

Interpretation: Disturbed differentiation is the cellular lesion behind the shortening.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Mesomelic limb shortening in Ror2(-/-) mice is a consequence of perturbed chondrocyte differentiation."

States the measured differentiation defect and its limb consequence.

Craniofacial Midline Outgrowth Defect recapitulates fidelity: moderate The craniofacial phenotype is caused by a midline outgrowth defect.

Limitations: Mouse and human midfacial morphology differ substantially, so the mechanism transfers more confidently than the morphology; the mouse does not reproduce the human facial gestalt as such.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Moreover, we show that the craniofacial phenotype is caused by a midline outgrowth defect."

Attributes the craniofacial phenotype to a specific mechanism.

Genital Tubercle Outgrowth Defect partially recapitulates fidelity: moderate Ror2 is expressed in the genital tubercle and the tubercle is reduced in the null mouse.

Limitations: The authors state only that Ror2 involvement in genital development is "likely"; expression plus reduced size is suggestive, not a demonstrated requirement.

Show evidence (1 reference)

PMID:14745966 SUPPORT Model Organism

"Ror2 expression in the genital tubercle and its reduced size in Ror2(-/-) mice makes it likely that Ror2 is involved in genital development."

Supports the link at the strength the source states it.

Ror1/Ror2 double-null mouse

Validated double-null embryos have more severe facial, caudal-axis and limb truncation than Ror2 single mutants; most die by E15.5. Their broad similarity to Wnt5a-null embryos supports overlapping developmental functions of Ror receptors.

Species

Mouse

Genotype

Ror1(-/-); Ror2(-/-)

Background

sv129/C57BL/6 hybrid

Publication

PMID:22343533

Pathograph links

Reduced WNT5A-ROR2 Noncanonical Signalling partially recapitulates fidelity: moderate Combined receptor loss produces developmental defects resembling Wnt5a loss.

Limitations: This removes two receptors, whereas the human disorder is caused by ROR2 variants. Hindlimb asymmetry and low-penetrance exencephaly distinguish the double-null mouse from Wnt5a-null embryos.

Show evidence (2 references)

PMID:22343533 SUPPORT Model Organism

"The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of..."

Whole-organism evidence for overlapping Ror-dependent developmental functions.

+ 1 more reference

{ }

Source YAML

click to show

name: Autosomal Recessive Robinow Syndrome
synonyms:
- RRS
- ROR2-related Robinow syndrome
- Robinow syndrome, autosomal recessive
- COVESDEM syndrome
- costovertebral segmentation defect with mesomelia
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
disease_term:
preferred_term: autosomal recessive Robinow syndrome
term:
id: MONDO:0009999
label: autosomal recessive Robinow syndrome
description: ROR2-related Robinow syndrome is an autosomal recessive developmental disorder caused by biallelic ROR2 loss-of-function variants. It combines short stature, mesomelic limb shortening, characteristic craniofacial findings, genital hypoplasia, and frequent vertebral segmentation defects and rib fusions. Axial skeletal abnormalities are more frequent than in dominant Robinow forms, but their presence or absence is not an absolute molecular discriminator. ROR2 dysfunction reduces noncanonical WNT5A signaling through variant-dependent defects in transcript abundance, protein trafficking, or signaling function. Some studied variants retain cell-surface expression and residual signaling. Ror2-null mice support distinct developmental contributions from presomitic mesoderm, growth-plate chondrocytes, craniofacial outgrowth, and genital tubercle development; transfer of these mechanisms to humans requires attention to model limitations.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: 'This entry covers ROR2-related Robinow syndrome (MONDO:0009999; OMIM:268310). NXN-related recessive Robinow syndrome and the dominant WNT5A/DVL forms are genetically distinct. Heterozygous ROR2 variants can cause brachydactyly type B1, but the distinction cannot be reduced to a universal upstream-versus-downstream positional rule: protein stability, trafficking, and residual surface expression influence the phenotype.'
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 15-0090, listed as "Robinow syndrome, recessive type, ROR2-related" (MIM 268310, AR). The row's own comment records that it subsumes the previous COVESDEM designation and cross-references brachydactyly type B. The 2019 revision (Mortier et al., PMID:31633310) numbered the same group 17.
prevalence:
- population: Published Robinow syndrome cases across inheritance modes, as of 2002
measure_type: CASES_IN_LITERATURE
notes: The historical count exceeds 100 reported cases across both inheritance modes and is not a ROR2-specific count or population prevalence estimate.
evidence:
- reference: PMID:12011143
reference_title: Robinow syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: Over 100 cases have now been reported and we have reviewed the current knowledge of the clinical and genetic features of the syndrome.
explanation: Historical review of the mixed Robinow spectrum; this count is not a gene-specific prevalence estimate.
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: Both homozygous and compound-heterozygous ROR2 pathogenic variants occur. Consanguinity is common but is not required. The usual 25% sibling recurrence risk applies when both parents carry a disease-causing allele; parental testing is important because a prenatal compound-heterozygous case included an apparently de novo allele.
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ROR2-related Robinow syndrome is inherited in an autosomal recessive manner.
explanation: GeneReviews states the inheritance mode.
- reference: PMID:10932186
reference_title: Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman.
explanation: Documents homozygous alleles in consanguineous families and the Omani founder cohort.
- reference: PMID:38504427
reference_title: Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene
explanation: Direct evidence that the disease is not restricted to homozygous genotypes.
pathophysiology:
- name: Biallelic ROR2 Loss of Function
role: trigger
biological_scale: MOLECULAR
genes:
- preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
genetic_context:
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
allele_type: missense, nonsense, frameshift, splice-region, initiation-codon, or deletion allele
functional_impact_category: LOSS_OF_FUNCTION
description: Biallelic ROR2 variants impair receptor function. Reported alleles include missense, nonsense, frameshift, splice, initiation-codon and deletion variants. Nonsense-mediated decay is supported for selected truncating alleles, while several tested missense proteins show defective trafficking. These observations do not establish that every variant eliminates all receptor protein or signaling.
evidence:
- reference: PMID:10932187
reference_title: Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The ROR2 mutations present in RRS result in premature stop codons and predict nonfunctional proteins.
explanation: The founding study predicts nonfunctional proteins from premature stop codons; it does not directly measure function for every allele.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.
explanation: Clinical deletion alleles support the gene-level loss-of-function mechanism; deletion alone does not establish every downstream molecular consequence.
downstream:
- target: Reduced ROR2 Transcript Abundance
causal_link_type: DIRECT
description: Selected premature termination alleles trigger nonsense-mediated mRNA decay; this route is allele-dependent.
- target: Defective ROR2 Trafficking to the Cell Surface
causal_link_type: DIRECT
description: Several experimentally tested missense and truncating proteins show intracellular retention; this is not universal for every disease-associated allele.
- target: Reduced WNT5A-ROR2 Noncanonical Signalling
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Reduced receptor abundance or impaired receptor function decreases noncanonical WNT5A signaling. Some variants retain surface localization and partial signaling.
- target: Impaired Osteogenic Differentiation of Marrow Stromal Cells
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: ROR2 knockdown and variant-expression experiments suggest impaired osteogenic differentiation. Translation from this culture system to congenital skeletal disease remains provisional.
mechanism_confidence: ESTABLISHED
- name: Reduced ROR2 Transcript Abundance
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: Nonsense-mediated decay reduces expression of selected ROR2 premature-termination alleles. Escape from this surveillance pathway contributes to the distinction between recessive Robinow and dominant brachydactyly alleles, but position alone does not explain all variants.
evidence:
- reference: PMID:19236432
reference_title: Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Our experiments show that triggering or escaping NMD may cause different phenotypes with a distinct mode of inheritance.
explanation: Experimental evidence for an allele-dependent contribution of nonsense-mediated decay.
downstream:
- target: Reduced WNT5A-ROR2 Noncanonical Signalling
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Reduced transcript abundance limits production of functional ROR2 protein.
- name: Defective ROR2 Trafficking to the Cell Surface
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
description: 'Several Robinow-associated ROR2 variants are retained intracellularly and show impaired delivery to the plasma membrane. HeLa-cell localization and immortalized mouse-fibroblast assays support this mechanism. It is variant-dependent: R189W and R272C reached the cell surface in the 2024 rescue assay and retained more signaling than five severely affected variants.'
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Co-expression of Ror2 and EGFP-hRas or calnexin in Hela-cells showed that wild-type Ror2 localizes predominantly to the plasma membrane, while mutant Ror2 proteins do not migrate to the plasma membrane and are retained to the endoplasmic reticulum
explanation: Transfected-cell localization directly supports intracellular retention for the tested constructs.
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: C182Y, R184C, C223Y, G326A, and R366W all fail to traffic to the plasma membrane, whereas R189W and R272C are expressed on the cell surface
explanation: Surface staining distinguishes severe trafficking defects from variants that retain surface expression.
- reference: PMID:17665217
reference_title: Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We establish the retention of the mutated proteins in the endoplasmic reticulum of HeLa cells and therefore failure to reach the plasma membrane.
explanation: The earlier study directly tested ER retention for two CRD mutations; its findings do not establish retention for all subsequently identified alleles.
downstream:
- target: Reduced WNT5A-ROR2 Noncanonical Signalling
causal_link_type: DIRECT
description: Impaired surface delivery reduces the receptor contribution to WNT5A signaling; functional assays also identify milder signaling deficits in surface-expressed variants.
pdb_structures:
- pdb_id: 9FSE
resolution_angstrom: 2.48
method: X-ray diffraction
target_protein: Human ROR2 cysteine-rich and Kringle domains
publication: PMID:38780011
description: Wild-type human CRD-Kr tandem structure used to interpret folding and variant effects. It is not a disease-mutant or drug-bound receptor structure.
- name: Reduced WNT5A-ROR2 Noncanonical Signalling
role: central_effector
biological_scale: CELLULAR
description: ROR2 promotes Frizzled-dependent noncanonical WNT5A signaling. In an immortalized Ror1/Ror2-deficient mouse-fibroblast rescue system, Robinow-associated variants reduced GFP-Pdzrn3 reporter degradation and DVL2 phosphorylation to different degrees. The cysteine-rich domain was required for this activity, while constructs lacking the intracellular region retained activity in that assay. Residual signaling in cells lacking both ROR receptors argues against treating ROR2 loss as complete loss of every WNT5A response.
biological_processes:
- preferred_term: non-canonical Wnt signaling pathway
modifier: DECREASED
term:
id: GO:0035567
label: non-canonical Wnt signaling pathway
evidence:
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: three of the five CRD mutations (C182Y, R184C, and C223Y) and both Kr mutations (G326A and R366W) exhibited strongly reduced signaling capabilities
explanation: Direct functional assay of Robinow-associated substitutions.
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The remaining two mutants (R189W and R272C) exhibited milder but still statistically significant signaling deficits
explanation: Residual signaling varies among the assayed substitutions.
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: ROR KO reporter cells without any ROR2 rescue still retained some basal WNT5A signaling activity, which remained dose-dependent with respect to WNT5A concentration
explanation: Loss of ROR1 and ROR2 does not abolish every WNT5A response in this cell system.
- reference: PMID:22343533
reference_title: Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a-Ror signaling.
explanation: Mouse loss-of-function studies identify a downstream signaling readout; this does not equate every WNT5A response with planar cell polarity.
downstream:
- target: Reduced Presomitic Mesoderm
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.
- target: Perturbed Growth Plate Chondrocyte Differentiation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.
- target: Craniofacial Midline Outgrowth Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.
- target: Genital Tubercle Outgrowth Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Ror2-null developmental findings support a connection to this tissue defect. The intervening steps linking altered receptor signaling to the anatomical outcome are incompletely resolved.
- target: Renal Tract Abnormalities
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Renal anomalies occur in ROR2 disease; the intermediate developmental processes are not resolved by the cited clinical evidence.
- target: Hydronephrosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: This specific renal lesion is reported in ROR2 disease. As for the existing renal-abnormality edge, the intermediate developmental events linking altered signaling to the lesion remain unresolved.
- target: Cystic renal dysplasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: This specific renal lesion is reported in ROR2 disease. As for the existing renal-abnormality edge, the intermediate developmental events linking altered signaling to the lesion remain unresolved.
mechanism_confidence: ESTABLISHED
- name: Reduced Presomitic Mesoderm
biological_scale: TISSUE
mechanism_confidence: ESTABLISHED
description: Ror2-null embryos have a reduced presomitic mesoderm. This is model-organism evidence for a developmental substrate of axial skeletal malformations, not a measurement in affected human embryos.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Our results demonstrate that vertebral malformations in Ror2(-/-) mice are due to reductions in the presomitic mesoderm and defects in somitogenesis.
explanation: Directly supports the developmental mechanism this node asserts, in the mouse null for this entry's gene.
downstream:
- target: Defective Somitogenesis
causal_link_type: DIRECT
description: Reduction of the presomitic mesoderm accompanies impaired somite formation in Ror2-null embryos.
- name: Defective Somitogenesis
role: consequence
biological_scale: TISSUE
description: Somitogenesis is abnormal in Ror2-null mice, providing a developmental explanation for their vertebral malformations and a model for the axial skeletal defects of human ROR2 disease.
biological_processes:
- preferred_term: somitogenesis
modifier: DECREASED
term:
id: GO:0001756
label: somitogenesis
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Our results demonstrate that vertebral malformations in Ror2(-/-) mice are due to reductions in the presomitic mesoderm and defects in somitogenesis.
explanation: Directly supports the developmental mechanism this node asserts, in the mouse null for this entry's gene.
downstream:
- target: Vertebral Segmentation Defects
causal_link_type: DIRECT
description: Segmentation of a reduced presomitic mesoderm yields hemivertebrae.
- target: Rib Fusion
causal_link_type: DIRECT
description: The ribs segment from the same paraxial mesoderm.
- target: Scoliosis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Asymmetric vertebral segments impose a curve on the growing spine.
- target: Thoracic vertebral fusion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal somite formation provides a developmental model for the fused thoracic vertebrae described alongside hemivertebrae in human disease; the precise human intermediates are unresolved.
- name: Perturbed Growth Plate Chondrocyte Differentiation
role: consequence
biological_scale: CELLULAR
description: Perturbed growth-plate chondrocyte differentiation contributes to mesomelic limb shortening in Ror2-null mice. The human developmental mechanism is inferred from the shared gene and skeletal phenotype.
cell_types:
- preferred_term: growth plate chondrocyte
term:
id: CL:1000217
label: growth plate cartilage chondrocyte
biological_processes:
- preferred_term: chondrocyte differentiation
modifier: ABNORMAL
term:
id: GO:0002062
label: chondrocyte differentiation
- preferred_term: endochondral ossification
modifier: ABNORMAL
term:
id: GO:0001958
label: endochondral ossification
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Mesomelic limb shortening in Ror2(-/-) mice is a consequence of perturbed chondrocyte differentiation.
explanation: Assigns the mesomelic shortening specifically to chondrocyte differentiation.
downstream:
- target: Mesomelic Limb Shortening
causal_link_type: DIRECT
description: Impaired growth plate chondrocyte differentiation shortens the limb.
- target: Short Stature
causal_link_type: DIRECT
description: The same lesion summed over the long bones; stature loss is marked in this form.
- target: Brachydactyly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Digital shortening is a skeletal manifestation of ROR2 disease; the exact contribution of altered growth-plate differentiation to each digital anomaly is not directly established in humans.
- target: Short palm
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.
- target: Clinodactyly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.
- target: Broad thumb
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.
- target: Broad hallux
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.
- target: Limited forearm pronation and supination
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The mouse chondrocyte defect supports a possible developmental contribution to the human limb phenotype. The contribution to this specific manifestation, including bone shape or secondary joint restriction, has not been directly measured.
mechanism_confidence: ESTABLISHED
- name: Craniofacial Midline Outgrowth Defect
role: consequence
biological_scale: TISSUE
description: Ror2-null mice show impaired craniofacial midline outgrowth. This supports a developmental contribution to the human craniofacial phenotype without proving that every individual facial or oral finding shares one direct cellular cause.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Moreover, we show that the craniofacial phenotype is caused by a midline outgrowth defect.
explanation: Attributes the craniofacial phenotype to a specific developmental mechanism.
downstream:
- target: Hypertelorism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.
- target: Prominent Forehead
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.
- target: Short Nose
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.
- target: Gingival Overgrowth
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.
- target: Ankyloglossia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse midline-outgrowth findings suggest a developmental contribution to the human craniofacial spectrum; the specific causal intermediates for this manifestation remain unresolved.
- target: Wide nasal bridge
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Depressed nasal bridge
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Anteverted nares
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Abnormal nasal tip morphology
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Midface retrusion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Micrognathia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Retrognathia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Bifid tongue
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
- target: Microglossia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Mouse craniofacial outgrowth findings suggest a developmental contribution to this clinically observed ROR2-associated feature. The specific tissue and cellular intermediates in humans remain unresolved.
mechanism_confidence: ESTABLISHED
- name: Genital Tubercle Outgrowth Defect
role: consequence
biological_scale: TISSUE
description: Ror2 expression in the genital tubercle and reduced tubercle size in null mice support a developmental contribution to genital hypoplasia. These observations do not exclude endocrine abnormalities or establish the degree of response to hormone treatment in humans.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Ror2 expression in the genital tubercle and its reduced size in Ror2(-/-) mice makes it likely that Ror2 is involved in genital development.
explanation: Supports a primary developmental origin. The source hedges ("makes it likely") and this node inherits that hedge.
downstream:
- target: Genital Hypoplasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced genital-tubercle size in mice suggests a developmental contribution, but the exact anatomical and endocrine contributions to this human manifestation are unresolved.
- target: Micropenis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced genital-tubercle size in mice suggests a developmental contribution, but the exact anatomical and endocrine contributions to this human manifestation are unresolved.
- target: Clitoral Hypoplasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced genital-tubercle size in mice suggests a developmental contribution, but the exact anatomical and endocrine contributions to this human manifestation are unresolved.
- target: Hypospadias
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Abnormal genital-tubercle development may contribute to this clinically observed genital anomaly, but the specific human urethral-development steps are unresolved.
mechanism_confidence: HYPOTHETICAL
- name: Impaired Osteogenic Differentiation of Marrow Stromal Cells
biological_scale: CELLULAR
mechanism_confidence: HYPOTHETICAL
description: In marrow stromal-cell experiments, ROR2 knockdown or expression of c.904C>T was associated with reduced osteogenic differentiation. This is a candidate contribution to skeletal disease, distinct from the growth-plate chondrocyte defect demonstrated in null mice.
biological_processes:
- preferred_term: osteoblast differentiation
modifier: DECREASED
term:
id: GO:0001649
label: osteoblast differentiation
evidence:
- reference: DOI:10.32604/biocell.2023.028851
reference_title: A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells (BMSCs)
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1.
explanation: Cultured marrow stromal cells with ROR2 depletion or the c.904C>T construct show an osteogenic phenotype; its contribution to human congenital skeletal disease is unresolved.
downstream:
- target: Short Stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: A possible skeletal contribution inferred from impaired cellular osteogenesis; the culture study did not test growth or stature in affected individuals.
phenotypes:
- category: Skeletal
name: Mesomelic Limb Shortening
description: Mesomelic or acromesomelic limb shortening. In the recessive form the shortening is more generalized than in the dominant forms. Present in all 22 patients in the 2022 clinically ascertained cohort.
phenotype_term:
preferred_term: Mesomelia
term:
id: HP:0003027
label: Mesomelia
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.
- category: Skeletal
name: Short Stature
description: Marked short stature; more pronounced than in the dominant forms. Present in all 22 patients in the 2022 clinically ascertained cohort.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.
- category: Skeletal
name: Brachydactyly
phenotype_term:
preferred_term: Brachydactyly
term:
id: HP:0001156
label: Brachydactyly
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.
description: ' Present in all 22 patients in the 2022 clinically ascertained cohort.'
- category: Skeletal
name: Vertebral Segmentation Defects
description: Hemivertebrae and vertebral fusions are frequent and clinically important in ROR2 disease. Vertebral anomalies can also occur in dominant Robinow forms, so they are not an absolute discriminator.
phenotype_term:
preferred_term: Hemivertebrae
term:
id: HP:0002937
label: Hemivertebrae
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hemivertebrae (86.36%) |'
explanation: Table II reports each finding in 86.36% of this 22-person cohort; neither is obligate.
- category: Skeletal
name: Rib Fusion
description: Proposed as near-pathognomonic for the recessive form, but not universally present in molecularly confirmed cases, so its absence does not exclude the diagnosis.
phenotype_term:
preferred_term: Rib fusion
term:
id: HP:0000902
label: Rib fusion
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Rib fusion (86.36%) |'
explanation: Table II reports each finding in 86.36% of this 22-person cohort; neither is obligate.
- category: Skeletal
name: Scoliosis
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Scoliosis is also a common finding that progresses with age and is the result of multiple vertebral anomalies. In our cohort it has been described in 69% of the patients.
explanation: Direct clinical support replaces inference from a general vertebral-feature list.
description: Scoliosis associated with vertebral anomalies may progress with age. Table II gives 68.18% in the 2022 cohort, described as 69% in the discussion; younger patients may not yet have developed it.
- category: Craniofacial
name: Hypertelorism
description: Ocular hypertelorism is a consistent component of the craniofacial phenotype; the accompanying forehead, nasal, oral and other findings are separately characterized. Present in all 22 patients in the 2022 clinically ascertained cohort.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.
- category: Craniofacial
name: Prominent Forehead
phenotype_term:
preferred_term: Prominent forehead
term:
id: HP:0011220
label: Prominent forehead
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.
description: ' Present in all 22 patients in the 2022 clinically ascertained cohort.'
- category: Craniofacial
name: Short Nose
phenotype_term:
preferred_term: Short nose
term:
id: HP:0003196
label: Short nose
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: Observed throughout the clinically ascertained 22-person cohort; this is not an unbiased population penetrance estimate.
description: ' Present in all 22 patients in the 2022 clinically ascertained cohort.'
- category: Oral
name: Gingival Overgrowth
phenotype_term:
preferred_term: Gingival overgrowth
term:
id: HP:0000212
label: Gingival overgrowth
frequency: FREQUENT
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia
explanation: Gum hypertrophy is listed among the oral features.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Downturned corners of mouth (77.27%) |

| | Gengival overgrowth (77.27%) |

| | Bifid tongue (77.27%) |'
explanation: Table II reports gingival overgrowth in 77.27%; the source spelling is preserved.
description: Reported in 77.27% of the 2022 cohort; the FREQUENT band reflects that cohort estimate.
- category: Oral
name: Ankyloglossia
phenotype_term:
preferred_term: Ankyloglossia
term:
id: HP:0010296
label: Ankyloglossia
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia
explanation: Ankyloglossia is listed among the oral features.
- category: Genitourinary
name: Genital Hypoplasia
phenotype_term:
preferred_term: Hypoplastic male external genitalia
term:
id: HP:0000050
label: Hypoplastic male external genitalia
frequency: VERY_FREQUENT
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy.
explanation: Documents the genital phenotype in both sexes.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Genital hypoplasia was present in all male patients, but in less than 50% of the females.
explanation: The male frequency should not be generalized to female genital findings.
description: Male external-genital hypoplasia; observed in all male participants in the 2022 cohort. Female findings have different frequencies and are represented separately.
- category: Genitourinary
name: Micropenis
phenotype_term:
preferred_term: Micropenis
term:
id: HP:0000054
label: Micropenis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy.
explanation: Micropenis is named as a common feature of this form.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients.
explanation: The genital finding is explicitly restricted to male patients.
description: Micropenis was reported in all male participants of the 2022 cohort. Buried penile anatomy can also contribute to apparent small size; endocrine status requires individual assessment.
- category: Genitourinary
name: Clitoral Hypoplasia
phenotype_term:
preferred_term: Clitoral hypoplasia
term:
id: HP:0000060
label: Clitoral hypoplasia
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: reduced clitoral size and hypoplasia of the labia majora in females
explanation: Records the female genital phenotype.
- category: Genitourinary
name: Renal Tract Abnormalities
phenotype_term:
preferred_term: Abnormality of the kidney
term:
id: HP:0000077
label: Abnormality of the kidney
coarse_binding_basis: SOURCE_UNSPECIFIED
frequency: OCCASIONAL
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: renal tract abnormalities, and nail hypoplasia or dystrophy
explanation: Renal tract abnormalities are listed among the common associated features.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Abnormality of the kidney (14.28%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
description: The 2022 cohort reports kidney abnormalities in 14.28% without specifying the lesions in its aggregate table. More specific reported renal manifestations require separate annotations.
- name: Wide nasal bridge
category: Craniofacial
phenotype_term:
preferred_term: Wide nasal bridge
term:
id: HP:0000431
label: Wide nasal bridge
description: Table II of the 2022 ROR2 cohort reports 95.45%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Wide nasal bridge (95.45%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Abnormal nasal tip morphology
category: Craniofacial
phenotype_term:
preferred_term: Abnormal nasal tip morphology
term:
id: HP:0000436
label: Abnormal nasal tip morphology
coarse_binding_basis: SOURCE_UNSPECIFIED
description: Table II of the 2022 ROR2 cohort reports 100%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Short nose (100%) |

| | Abnormality of the nasal tip (100%) |

| | Anteverted nares (95.45%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Anteverted nares
category: Craniofacial
phenotype_term:
preferred_term: Anteverted nares
term:
id: HP:0000463
label: Anteverted nares
description: Table II of the 2022 ROR2 cohort reports 95.45%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Anteverted nares (95.45%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Midface retrusion
category: Craniofacial
phenotype_term:
preferred_term: Midface retrusion
term:
id: HP:0011800
label: Midface retrusion
description: Table II of the 2022 ROR2 cohort reports 95.45%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Midface retrusion (95.45%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Downturned corners of mouth
category: Craniofacial
phenotype_term:
preferred_term: Downturned corners of mouth
term:
id: HP:0002714
label: Downturned corners of mouth
description: Table II of the 2022 ROR2 cohort reports 77.27%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Downturned corners of mouth (77.27%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Bifid tongue
category: Oral
phenotype_term:
preferred_term: Bifid tongue
term:
id: HP:0010297
label: Bifid tongue
description: Table II of the 2022 ROR2 cohort reports 77.27%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Bifid tongue (77.27%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Abnormal dental morphology
category: Dental
phenotype_term:
preferred_term: Abnormal dental morphology
term:
id: HP:0006482
label: Abnormal dental morphology
coarse_binding_basis: SOURCE_UNSPECIFIED
description: Table II of the 2022 ROR2 cohort reports 75%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Bifid tongue (77.27%) |

| | Abnormalities of the dentition (75%) |

| | Short stature (100%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Short palm
category: Skeletal
phenotype_term:
preferred_term: Short palm
term:
id: HP:0004279
label: Short palm
description: Table II of the 2022 ROR2 cohort reports 86.36%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Short palms (86.36%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Clinodactyly
category: Skeletal
phenotype_term:
preferred_term: Clinodactyly
term:
id: HP:0030084
label: Clinodactyly
description: Table II of the 2022 ROR2 cohort reports 80.95%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: VERY_FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Clinodactyly (80,95%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
notes: Table II gives 80.95%, whereas the discussion says 81.8%. The table estimate is retained without pooling or implying an exact common denominator.
- name: Proptosis
category: Ophthalmologic
phenotype_term:
preferred_term: Proptosis
term:
id: HP:0000520
label: Proptosis
description: Table II of the 2022 ROR2 cohort reports 63.63%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| 50-74 | Proptosis (63.63%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Long eyelashes
category: Ophthalmologic
phenotype_term:
preferred_term: Long eyelashes
term:
id: HP:0000527
label: Long eyelashes
description: Table II of the 2022 ROR2 cohort reports 72.72%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Long eyelashes (72.72%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Long palpebral fissures
category: Ophthalmologic
phenotype_term:
preferred_term: Long palpebral fissure
term:
id: HP:0000637
label: Long palpebral fissure
description: Table II of the 2022 ROR2 cohort reports 68.18%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Long palpebral fissures (68.18%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Upslanted palpebral fissures
category: Ophthalmologic
phenotype_term:
preferred_term: Upslanted palpebral fissure
term:
id: HP:0000582
label: Upslanted palpebral fissure
description: Table II of the 2022 ROR2 cohort reports 50%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Upslanted palpebral fissures (50%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Depressed nasal bridge
category: Craniofacial
phenotype_term:
preferred_term: Depressed nasal bridge
term:
id: HP:0005280
label: Depressed nasal bridge
description: Table II of the 2022 ROR2 cohort reports 68.18%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Depressed nasal bridge (68.18%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Long philtrum
category: Craniofacial
phenotype_term:
preferred_term: Long philtrum
term:
id: HP:0000343
label: Long philtrum
description: Table II of the 2022 ROR2 cohort reports 50%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Long philtrum (50.00%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Triangular mouth
category: Craniofacial
phenotype_term:
preferred_term: Triangular mouth
term:
id: HP:0000207
label: Triangular mouth
description: Table II of the 2022 ROR2 cohort reports 72.72%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Triangular mouth (72.72%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Thin upper lip vermilion
category: Craniofacial
phenotype_term:
preferred_term: Thin upper lip vermilion
term:
id: HP:0000219
label: Thin upper lip vermilion
description: Table II of the 2022 ROR2 cohort reports 59.09%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Thin upper lip vermilion (59.09%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Micrognathia
category: Craniofacial
phenotype_term:
preferred_term: Micrognathia
term:
id: HP:0000347
label: Micrognathia
description: Table II of the 2022 ROR2 cohort reports 68.18%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Micrognathia (68.18%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Retrognathia
category: Craniofacial
phenotype_term:
preferred_term: Retrognathia
term:
id: HP:0000278
label: Retrognathia
description: Table II of the 2022 ROR2 cohort reports 68.18%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Retrognathia (68.18%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Low-set ears
category: Craniofacial
phenotype_term:
preferred_term: Low-set ears
term:
id: HP:0000369
label: Low-set ears
description: Table II of the 2022 ROR2 cohort reports 66.66%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Low-set ears (66.66%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Short neck
category: Skeletal
phenotype_term:
preferred_term: Short neck
term:
id: HP:0000470
label: Short neck
description: Table II of the 2022 ROR2 cohort reports 63.63%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Short neck (63.63%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Limited forearm pronation and supination
category: Skeletal
phenotype_term:
preferred_term: Limited pronation/supination of forearm
term:
id: HP:0006394
label: Limited pronation/supination of forearm
description: Table II of the 2022 ROR2 cohort reports 65%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Scoliosis (68.18%) |

| | Limited pronation/ supination of forearm (65%) |

| | Broad thumbs (59.09%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Broad thumb
category: Skeletal
phenotype_term:
preferred_term: Broad thumb
term:
id: HP:0011304
label: Broad thumb
description: Table II of the 2022 ROR2 cohort reports 59.09%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Broad thumbs (59.09%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Cryptorchidism
category: Genitourinary
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
description: Table II of the 2022 ROR2 cohort reports 50%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Cryptorchidism (50.00%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Downslanted palpebral fissures
category: Ophthalmologic
phenotype_term:
preferred_term: Downslanted palpebral fissures
term:
id: HP:0000494
label: Downslanted palpebral fissures
description: Table II of the 2022 ROR2 cohort reports 31.81%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Cryptorchidism (50.00%) |

| 25-49 | Dowslanted palpebral fissures (31.81%) |

| | Epicanthus (31.81%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Epicanthus
category: Ophthalmologic
phenotype_term:
preferred_term: Epicanthus
term:
id: HP:0000286
label: Epicanthus
description: Table II of the 2022 ROR2 cohort reports 31.81%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Epicanthus (31.81%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Short philtrum
category: Craniofacial
phenotype_term:
preferred_term: Short philtrum
term:
id: HP:0000322
label: Short philtrum
description: Table II of the 2022 ROR2 cohort reports 27.27%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Short philtrum (27.27%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Microglossia
category: Oral
phenotype_term:
preferred_term: Microglossia
term:
id: HP:0000171
label: Microglossia
description: Table II of the 2022 ROR2 cohort reports 35.29%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Short philtrum (27.27%) |

| | Hypoplasia of the tongue (35.29%) |

| | Highly narrow palate (41,17%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: High narrow palate
category: Oral
phenotype_term:
preferred_term: High, narrow palate
term:
id: HP:0002705
label: High, narrow palate
description: Table II of the 2022 ROR2 cohort reports 41.17%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hypoplasia of the tongue (35.29%) |

| | Highly narrow palate (41,17%) |

| | Tooth agenesis (30.00%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hypodontia
category: Dental
phenotype_term:
preferred_term: Hypodontia
term:
id: HP:0000668
label: Hypodontia
description: Table II of the 2022 ROR2 cohort reports 30%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Highly narrow palate (41,17%) |

| | Tooth agenesis (30.00%) |

| | Pectus excavatum (47.61%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Pectus excavatum
category: Skeletal
phenotype_term:
preferred_term: Pectus excavatum
term:
id: HP:0000767
label: Pectus excavatum
description: Table II of the 2022 ROR2 cohort reports 47.61%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Pectus excavatum (47.61%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Nail dysplasia
category: Integumentary
phenotype_term:
preferred_term: Nail dysplasia
term:
id: HP:0002164
label: Nail dysplasia
description: Table II of the 2022 ROR2 cohort reports 38.09%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Nail dysplasia (38.09%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: renal tract abnormalities, and nail hypoplasia or dystrophy
explanation: GeneReviews independently identifies the nail phenotype.
- name: Syndactyly
category: Skeletal
phenotype_term:
preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
description: Table II of the 2022 ROR2 cohort reports 28.57%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Syndactyly (28.57%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Single transverse palmar crease
category: Skeletal
phenotype_term:
preferred_term: Single transverse palmar crease
term:
id: HP:0000954
label: Single transverse palmar crease
description: Table II of the 2022 ROR2 cohort reports 26.31%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Syndactyly (28.57%) |

| | Single transversal palmar crease (26.31%) |

| | Broad halux (47.05%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Broad hallux
category: Skeletal
phenotype_term:
preferred_term: Broad hallux
term:
id: HP:0010055
label: Broad hallux
description: Table II of the 2022 ROR2 cohort reports 47.05%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: FREQUENT
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Single transversal palmar crease (26.31%) |

| | Broad halux (47.05%) |

| | Hypoplastic labia minora (36.36%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hypoplastic labia minora
category: Genitourinary
phenotype_term:
preferred_term: Hypoplastic labia minora
term:
id: HP:0000064
label: Hypoplastic labia minora
description: Reported female genital finding in the 2022 cohort. The aggregate table percentage has an unclear sex-specific denominator, so no disease-wide frequency is assigned.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hypoplastic labia minora (36.36%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Melanocytic nevus
category: Integumentary
phenotype_term:
preferred_term: Melanocytic nevus
term:
id: HP:0000995
label: Melanocytic nevus
description: Table II of the 2022 ROR2 cohort reports 20%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| 5-24 | Melanocytic nevus (20.00%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Ptosis
category: Ophthalmologic
phenotype_term:
preferred_term: Ptosis
term:
id: HP:0000508
label: Ptosis
description: Table II of the 2022 ROR2 cohort reports 13.63%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Ptosis (13,63%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Strabismus
category: Ophthalmologic
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
description: Table II of the 2022 ROR2 cohort reports 19.04%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Strabismus (19.04%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Orofacial cleft
category: Craniofacial
phenotype_term:
preferred_term: Orofacial cleft
term:
id: HP:0000202
label: Orofacial cleft
description: Table II of the 2022 ROR2 cohort reports 22.72%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Strabismus (19.04%) |

| | Oral cleft (22.72%) |

| | Microtia (9,52%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Camptodactyly
category: Skeletal
phenotype_term:
preferred_term: Camptodactyly
term:
id: HP:0012385
label: Camptodactyly
description: Table II of the 2022 ROR2 cohort reports 19.04%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Camptodactyly (19.04%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hip dislocation
category: Skeletal
phenotype_term:
preferred_term: Hip dislocation
term:
id: HP:0002827
label: Hip dislocation
description: Table II of the 2022 ROR2 cohort reports 15.78%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hip dislocation (15.78%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hypospadias
category: Genitourinary
phenotype_term:
preferred_term: Hypospadias
term:
id: HP:0000047
label: Hypospadias
description: Table II of the 2022 ROR2 cohort reports 20%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hypospadias (20.00%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hypoplastic labia majora
category: Genitourinary
phenotype_term:
preferred_term: Hypoplastic labia majora
term:
id: HP:0000059
label: Hypoplastic labia majora
description: Reported female genital finding in the 2022 cohort. The aggregate table percentage has an unclear sex-specific denominator, so no disease-wide frequency is assigned.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hypoplastic labia majora (16.67%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Inguinal hernia
category: Abdominal
phenotype_term:
preferred_term: Inguinal hernia
term:
id: HP:0000023
label: Inguinal hernia
description: Table II of the 2022 ROR2 cohort reports 15.78%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Inguinal hernia (15.78%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Congenital heart abnormalities
category: Cardiovascular
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
coarse_binding_basis: SOURCE_UNSPECIFIED
description: Table II of the 2022 ROR2 cohort reports 18.18%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Abnormal heart morphology (18.18%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hearing impairment
category: Auditory
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
description: Table II of the 2022 ROR2 cohort reports 13.63%. The cohort included 22 patients, with feature-specific assessment denominators.
frequency: OCCASIONAL
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| | Hearing impairment (13.63%) |'
explanation: Table II gives the feature-specific percentage in a clinically ascertained cohort of 22 patients. Assessment and sex-specific denominators vary; this is not a population penetrance estimate.
- name: Hydronephrosis
category: Renal
phenotype_term:
preferred_term: Hydronephrosis
term:
id: HP:0000126
label: Hydronephrosis
description: A specifically described renal manifestation; the broader cohort kidney percentage is not assigned to this individual lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hydronephrosis is common and cystic dysplasia of the kidney has been reported.
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- name: Cystic renal dysplasia
category: Renal
phenotype_term:
preferred_term: Cystic renal dysplasia
term:
id: HP:0000800
label: Cystic renal dysplasia
description: Cystic renal dysplasia has been reported; its frequency is not given.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hydronephrosis is common and cystic dysplasia of the kidney has been reported.
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- name: Developmental delay
category: Neurologic
phenotype_term:
preferred_term: Neurodevelopmental delay
term:
id: HP:0012758
label: Neurodevelopmental delay
description: Developmental delay is reported, while intellect is usually within the normal range; intellectual disability is not an obligate feature.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Intellect is usually within the normal range; however, developmental delay has been reported.
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- name: Macrocephaly
category: Craniofacial
phenotype_term:
preferred_term: Macrocephaly
term:
id: HP:0000256
label: Macrocephaly
description: Macrocephaly is part of the described craniofacial spectrum; no precise frequency is assigned.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism
explanation: GeneReviews abstract explicitly includes macrocephaly.
- name: Dental crowding
category: Dental
phenotype_term:
preferred_term: Dental crowding
term:
id: HP:0000678
label: Dental crowding
description: Dental crowding is included in the clinical baseline and can require orthodontic assessment.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome.
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- name: Dental malocclusion
category: Dental
phenotype_term:
preferred_term: Dental malocclusion
term:
id: HP:0000689
label: Dental malocclusion
description: Malocclusion is distinct from missing teeth or crowding.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome.
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- name: Thoracic vertebral fusion
category: Skeletal
phenotype_term:
preferred_term: Fused thoracic vertebrae
term:
id: HP:0030039
label: Fused thoracic vertebrae
description: Thoracic vertebral fusion is a specific axial skeletal finding alongside hemivertebrae.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly.
explanation: GeneReviews clinical baseline; no cohort-specific frequency is inferred.
- name: Pulmonic stenosis
category: Cardiovascular
phenotype_term:
preferred_term: Pulmonic stenosis
term:
id: HP:0001642
label: Pulmonic stenosis
description: A reported cardiac manifestation in the GeneReviews clinical baseline. The overall congenital-heart-defect percentage is not assigned to this specific lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia
explanation: The chapter explicitly names this structural defect; it provides no lesion-specific frequency.
- name: Atrial septal defect
category: Cardiovascular
phenotype_term:
preferred_term: Atrial septal defect
term:
id: HP:0001631
label: Atrial septal defect
description: A reported cardiac manifestation in the GeneReviews clinical baseline. The overall congenital-heart-defect percentage is not assigned to this specific lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia
explanation: The chapter explicitly names this structural defect; it provides no lesion-specific frequency.
- name: Ventricular septal defect
category: Cardiovascular
phenotype_term:
preferred_term: Ventricular septal defect
term:
id: HP:0001629
label: Ventricular septal defect
description: A reported cardiac manifestation in the GeneReviews clinical baseline. The overall congenital-heart-defect percentage is not assigned to this specific lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia
explanation: The chapter explicitly names this structural defect; it provides no lesion-specific frequency.
- name: Coarctation of aorta
category: Cardiovascular
phenotype_term:
preferred_term: Coarctation of aorta
term:
id: HP:0001680
label: Coarctation of aorta
description: A reported cardiac manifestation in the GeneReviews clinical baseline. The overall congenital-heart-defect percentage is not assigned to this specific lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia
explanation: The chapter explicitly names this structural defect; it provides no lesion-specific frequency.
- name: Tetralogy of Fallot
category: Cardiovascular
phenotype_term:
preferred_term: Tetralogy of Fallot
term:
id: HP:0001636
label: Tetralogy of Fallot
description: A reported cardiac manifestation in the GeneReviews clinical baseline. The overall congenital-heart-defect percentage is not assigned to this specific lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia
explanation: The chapter explicitly names this structural defect; it provides no lesion-specific frequency.
- name: Tricuspid atresia
category: Cardiovascular
phenotype_term:
preferred_term: Tricuspid atresia
term:
id: HP:0011662
label: Tricuspid atresia
description: A reported cardiac manifestation in the GeneReviews clinical baseline. The overall congenital-heart-defect percentage is not assigned to this specific lesion.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia
explanation: The chapter explicitly names this structural defect; it provides no lesion-specific frequency.
genetic:
- name: ROR2
gene_term:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
relationship_type: CAUSATIVE
notes: ROR2 encodes a noncanonical WNT5A coreceptor. Homozygous and compound-heterozygous genotypes occur, including missense, nonsense, frameshift, splice, initiation-codon and deletion alleles. The 2022 study included variants classified as uncertain significance by its automated ACMG assessment, so its putative disease-associated set should not be equated with uniformly established pathogenicity. Protein trafficking and stability, rather than position alone, help distinguish Robinow and brachydactyly phenotypes.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions.
explanation: Documents candidate alleles in a clinically ascertained ROR2 cohort; some individual alleles remained uncertain significance.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: Gain-of-function (GoF) ROR2 variants have been associated with autosomal dominant brachydactyly type B (MIM 113000)
explanation: Establishes the allelic-but-mechanistically-distinct relationship to brachydactyly type B.
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
animal_models:
- name: Ror2-null mouse
species: Mouse
genotype: Ror2(-/-)
publication: PMID:14745966
description: Constitutive Ror2 knockout, the reference developmental model for this form. Its value is that it resolves the syndrome into separate developmental defects at separate sites rather than one global growth failure.
modeled_mechanisms:
- target: Reduced Presomitic Mesoderm
relationship: RECAPITULATES
fidelity: HIGH
description: Vertebral malformations trace to a reduced presomitic mesoderm and defective somitogenesis.
limitations: The single Ror2 knockout does not establish the quantitative contributions of each developmental lesion in humans. Ror1/Ror2 double-null mice show more severe defects, but loss of two receptors is not the human ROR2 genotype.
readouts:
- name: Presomitic mesoderm size
target: Reduced Presomitic Mesoderm
direction: DECREASED
interpretation: The reduced mesodermal pool is the measured antecedent of the vertebral malformations.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Our results demonstrate that vertebral malformations in Ror2(-/-) mice are due to reductions in the presomitic mesoderm and defects in somitogenesis.
explanation: Reports the reduction this readout records.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The Ror2(-/-) mouse provides a suitable model that may help to explain many of the underlying developmental malformations in individuals with Robinow syndrome.
explanation: The authors' own statement that the model is informative for the human malformations.
- target: Perturbed Growth Plate Chondrocyte Differentiation
relationship: RECAPITULATES
fidelity: HIGH
description: Mesomelic limb shortening in the null mouse is attributed to perturbed chondrocyte differentiation.
limitations: Assessed in the mouse growth plate; the corresponding human histology is not available, so the cellular claim transfers by inference from a shared gene and a shared limb phenotype.
readouts:
- name: Growth plate chondrocyte differentiation
target: Perturbed Growth Plate Chondrocyte Differentiation
direction: ALTERED
interpretation: Disturbed differentiation is the cellular lesion behind the shortening.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Mesomelic limb shortening in Ror2(-/-) mice is a consequence of perturbed chondrocyte differentiation.
explanation: States the measured differentiation defect and its limb consequence.
- target: Craniofacial Midline Outgrowth Defect
relationship: RECAPITULATES
fidelity: MODERATE
description: The craniofacial phenotype is caused by a midline outgrowth defect.
limitations: Mouse and human midfacial morphology differ substantially, so the mechanism transfers more confidently than the morphology; the mouse does not reproduce the human facial gestalt as such.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Moreover, we show that the craniofacial phenotype is caused by a midline outgrowth defect.
explanation: Attributes the craniofacial phenotype to a specific mechanism.
- target: Genital Tubercle Outgrowth Defect
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Ror2 is expressed in the genital tubercle and the tubercle is reduced in the null mouse.
limitations: The authors state only that Ror2 involvement in genital development is "likely"; expression plus reduced size is suggestive, not a demonstrated requirement.
evidence:
- reference: PMID:14745966
reference_title: Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Ror2 expression in the genital tubercle and its reduced size in Ror2(-/-) mice makes it likely that Ror2 is involved in genital development.
explanation: Supports the link at the strength the source states it.
- name: Ror1/Ror2 double-null mouse
species: Mouse
genotype: Ror1(-/-); Ror2(-/-)
background: sv129/C57BL/6 hybrid
publication: PMID:22343533
description: Validated double-null embryos have more severe facial, caudal-axis and limb truncation than Ror2 single mutants; most die by E15.5. Their broad similarity to Wnt5a-null embryos supports overlapping developmental functions of Ror receptors.
modeled_mechanisms:
- target: Reduced WNT5A-ROR2 Noncanonical Signalling
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Combined receptor loss produces developmental defects resembling Wnt5a loss.
limitations: This removes two receptors, whereas the human disorder is caused by ROR2 variants. Hindlimb asymmetry and low-penetrance exencephaly distinguish the double-null mouse from Wnt5a-null embryos.
evidence:
- reference: PMID:22343533
reference_title: Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures.
explanation: Whole-organism evidence for overlapping Ror-dependent developmental functions.
- reference: url:https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf
reference_title: https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 'Between the ages of E12.5 and E13.5, Ror DKO

embryos exhibit more severe phenotypes compared with Ror2

mutants'
explanation: Direct comparison supports a contribution of Ror1 in the mouse model.
diagnosis:
- name: Clinical and Radiographic Recognition
description: Clinical recognition combines craniofacial, limb and genital findings with skeletal radiographs. Vertebral and rib anomalies strongly support ROR2 disease but are not universally present or exclusive to this gene. Molecular testing resolves the overlapping Robinow phenotypes.
diagnosis_term:
preferred_term: physical examination
term:
id: NCIT:C20989
label: Physical Examination
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The disorder is recognizable at birth or in early childhood.
explanation: Supports clinical recognizability and its timing.
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype.
explanation: Quantifies the phenotypic uniformity that makes recognition workable.
- name: Prenatal Recognition
description: A reported fetus showed characteristic craniofacial, vertebral, digital and genital abnormalities at 24 + 3/7 weeks, with compound-heterozygous ROR2 variants identified in amniocytes. Recurrence counseling depends on parental segregation, including the possibility of an apparently de novo allele.
diagnosis_term:
preferred_term: Ultrasound Imaging
term:
id: NCIT:C17230
label: Ultrasound Imaging
evidence:
- reference: PMID:38504427
reference_title: Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis.
explanation: Documents the prenatal findings and their gestational age.
- reference: PMID:38504427
reference_title: Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene
explanation: Establishes that molecular confirmation on amniocytes is achievable in the same pregnancy.
- name: Molecular Confirmation
description: Confirmed by biallelic ROR2 pathogenic variants. Copy-number analysis is needed alongside sequencing, since whole-exon deletions are part of the allelic spectrum and would be missed by sequence calling alone.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The diagnosis of ROR2-related Robinow syndrome is established in a proband with typical suggestive findings and biallelic ROR2 pathogenic variants identified on molecular genetic testing.
explanation: States the molecular confirmation criteria.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Homozygous deletions involving exons 6 and 7 have also been reported in Robinow syndrome
explanation: Intragenic deletions are a documented allele class and motivate copy-number-aware testing.
- name: Baseline renal ultrasonography
description: Renal ultrasound assesses the renal tract after diagnosis.
diagnosis_term:
preferred_term: Ultrasound Imaging
term:
id: NCIT:C17230
label: Ultrasound Imaging
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal ultrasound examination ... Echocardiogram to evaluate for structural heart defects
explanation: GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.
- name: Baseline echocardiography
description: Echocardiography evaluates congenital structural heart defects after diagnosis.
diagnosis_term:
preferred_term: Echocardiography Test
term:
id: NCIT:C16525
label: Echocardiography Test
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Echocardiogram to evaluate for structural heart defects
explanation: GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.
- name: Perioperative assessment
description: Assess the vertebrae and ribs and evaluate congenital heart disease before surgery. Midface hypoplasia can make endotracheal intubation difficult.
diagnosis_term:
preferred_term: Physical Examination
term:
id: NCIT:C20989
label: Physical Examination
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications
explanation: GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Preoperative cardiac evaluation for the presence of ... heart defects
explanation: GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia
explanation: GeneReviews recommends this clinical assessment; it is not a test of ROR2 signaling.
differential_diagnoses:
- name: Brachydactyly type B
description: 'An allelic ROR2 disorder, usually dominantly inherited, with severe digital abnormalities. Variant position alone does not separate the phenotypes: a nonsense allele at a site also affected by a BDB frameshift produced Robinow features with severe recessive brachydactyly.'
evidence:
- reference: PMID:19640924
reference_title: A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The mutation is located at the same position as a previously described frame shift mutation causing dominant BDB1.
explanation: The primary comparison directly contradicts a universal positional separation.
- name: Autosomal Dominant Robinow Syndrome 1
description: The WNT5A form is usually milder skeletally. Vertebral anomalies and scoliosis are less frequent, but their absence is not a categorical discriminator; molecular testing distinguishes the forms.
- name: Robinow Syndrome, Autosomal Recessive 2
description: The NXN form. Also recessive, but its phenotype clusters with the dominant forms rather than with ROR2 disease.
treatments:
- name: Orthopedic Surgery for Limb and Spine Deformity
description: Corrective surgery may be needed for syndactyly or severe scoliosis associated with vertebral and rib abnormalities.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: orthopedic surgical procedure
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Treatment of manifestations: Corrective surgery for limb and spine defects and for facial abnormalities; orthodontic treatment as needed'
explanation: Lists corrective limb and spine surgery in the management of this form.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Corrective surgeries may be required for the following: ... Syndactyly ... Severe scoliosis secondary to hemivertebrae and rib abnormalities'
explanation: The full chapter specifies which skeletal manifestations may require surgery.
target_phenotypes:
- preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
- preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
- name: Androgen Therapy for Micropenis
description: Hormone therapy may be considered for micropenis after specialist endocrine assessment. A developmental contribution to genital anatomy does not establish normal hormone function in every patient or predict a uniformly incomplete response.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Hormone Therapy
term:
id: NCIT:C15445
label: Hormone Therapy
therapeutic_agent:
- preferred_term: testosterone
term:
id: CHEBI:17347
label: testosterone
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: hormone therapy as needed for the treatment of micropenis
explanation: GeneReviews lists hormone therapy for micropenis in management.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Injection of human chorionic gonadotropin and testosterone therapy improved penile length and testicular volume in three boys with severe micropenis
explanation: The reported small clinical series used hCG and testosterone; this does not isolate the effect of testosterone alone.
target_phenotypes:
- preferred_term: Micropenis
term:
id: HP:0000054
label: Micropenis
notes: The small reported series used hCG and testosterone. GeneReviews recommends pediatric endocrine monitoring and notes that apparent small penile size can also reflect abnormal insertion with a buried shaft.
- name: Genetic Counseling
action_category: COUNSELING_INFORMATIONAL
description: Discuss recurrence risk based on parental variants, carrier testing, and available prenatal or preimplantation testing to support informed reproductive choices. The usual 25% sibling risk assumes that both parents carry a disease-causing allele. Some heterozygotes can have brachydactyly type B1 findings.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301418
reference_title: ROR2-Related Robinow Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At conception, each sib of an affected individual has a 25% chance of being affected with Robinow syndrome, a 50% chance of being a heterozygote (carrier) and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
explanation: Supplies the recurrence risk figures.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family.
explanation: Supports familial testing after identifying the causative variants.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Heterozygotes may display findings consistent with brachydactyly type B1.
explanation: Carrier status should not be equated with an invariably normal digital phenotype.
- name: Human chorionic gonadotropin for micropenis
description: Human chorionic gonadotropin was used with testosterone in a three-boy series summarized by GeneReviews. Treatment requires pediatric endocrine assessment and monitoring; a hormone deficiency is not assumed in every patient.
treatment_term:
preferred_term: Hormone Therapy
term:
id: NCIT:C15445
label: Hormone Therapy
therapeutic_agent:
- preferred_term: human chorionic gonadotropin
term:
id: CHEBI:81570
label: Chorionic gonadotropin
target_phenotypes:
- preferred_term: Micropenis
term:
id: HP:0000054
label: Micropenis
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Injection of human chorionic gonadotropin and testosterone therapy improved penile length and testicular volume in three boys with severe micropenis
explanation: Small clinical series summarized in GeneReviews; no comparative efficacy estimate or separate hCG effect is established.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hormone therapy should be monitored by a pediatric endocrinologist.
explanation: Specifies specialist monitoring for the hormone intervention.
therapeutic_modality: PEPTIDE
- name: Orthodontic treatment
description: Orthodontic care addresses misaligned or crowded teeth and malocclusion.
action_category: THERAPEUTIC
treatment_term:
preferred_term: Orthodontic Treatment
term:
id: NCIT:C64248
label: Orthodontic Treatment
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Orthodontics consultation as needed for misaligned, crowded teeth
explanation: GeneReviews management recommendation for ROR2-related Robinow syndrome.
target_phenotypes:
- preferred_term: Dental crowding
term:
id: HP:0000678
label: Dental crowding
- preferred_term: Dental malocclusion
term:
id: HP:0000689
label: Dental malocclusion
therapeutic_modality: DEVICE
- name: Cleft repair
description: Corrective surgery may be needed for cleft lip or palate.
action_category: THERAPEUTIC
treatment_term:
preferred_term: Surgical Procedure
term:
id: NCIT:C15329
label: Surgical Procedure
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Clinical assessment for presence of cleft lip/palate and the need for surgical repair
explanation: GeneReviews management recommendation for ROR2-related Robinow syndrome.
therapeutic_modality: SURGERY
target_phenotypes:
- preferred_term: Orofacial cleft
term:
id: HP:0000202
label: Orofacial cleft
- name: Surgery for abnormal penile insertion or penoscrotal transposition
description: Reconstructive urologic surgery may improve appearance in selected patients. The cited report moved the scrotum downward; it did not detach the abnormal penile-crural insertion.
action_category: THERAPEUTIC
treatment_term:
preferred_term: Surgical Procedure
term:
id: NCIT:C15329
label: Surgical Procedure
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: improved the cosmetic appearance by transposing the scrotum downward.
explanation: GeneReviews management recommendation for ROR2-related Robinow syndrome.
therapeutic_modality: SURGERY
- name: Scoliosis surveillance
description: Monitor for scoliosis until growth is complete.
action_category: MONITORING
treatment_term:
preferred_term: Scoliosis surveillance
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Surveillance for evidence of scoliosis until growth is completed
explanation: GeneReviews management recommendation for ROR2-related Robinow syndrome.
- name: Dental surveillance
description: Dental evaluation every six to twelve months, or on the schedule recommended at initial dental assessment.
action_category: MONITORING
treatment_term:
preferred_term: Dental surveillance
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment
explanation: GeneReviews management recommendation for ROR2-related Robinow syndrome.
- name: Cardiac and renal follow-up
description: Specialist follow-up is tailored to identified cardiac or renal abnormalities.
action_category: MONITORING
treatment_term:
preferred_term: Cardiac and renal follow-up
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1240/
reference_title: ROR2-Related Robinow Syndrome - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified
explanation: GeneReviews management recommendation for ROR2-related Robinow syndrome.
discussions:
- discussion_id: ror2_null_mouse_vs_human_recessive_disease
kind: HUMAN_MODEL_MISMATCH
prompt: Does the Ror2-null mouse's four-lesion decomposition transfer quantitatively to human ROR2 disease, given that mouse Ror1 partially compensates for Ror2 loss?
attaches_to:
- pathophysiology#Reduced WNT5A-ROR2 Noncanonical Signalling
rationale: 'The single Ror2 knockout separates axial skeletal, chondrocyte, craniofacial and genital findings. Validated Ror1/Ror2 double-null mice have more severe developmental defects, supporting overlapping receptor functions in mice. The quantitative contribution of ROR1 in human ROR2 disease remains unresolved. Noncanonical WNT5A-ROR signaling should not be treated as synonymous with all core planar cell polarity signaling: Ho et al. found substantial phenotypic differences between Ror and Vangl double mutants.'
evidence:
- reference: url:https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf
reference_title: https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 'Ror DKO mutants

lacking all Ror signaling capacity have substantially non-

overlapping phenotypes compared with mice with mutations in

both members of the Vangl family'
explanation: Mouse comparative phenotypes challenge a universal equivalence between the Ror and core PCP pathways.
references:
- reference: PMID:20301418
title: ROR2-Related Robinow Syndrome.
tags:
- GeneReviews
- reference: PMID:35344616
title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
- reference: url:https://www.rcsb.org/structure/9FSE
title: 'RCSB PDB - 9FSE: Human ROR2 cysteine-rich domain (CRD) and Kringle domain'
variants:
- name: ROR2 c.323G>A; p.(Arg108Gln)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Homozygous in A1 and A2; listed as likely pathogenic by the cohort assessment. Transcript NM_004560.4. This substitution was included in the HeLa trafficking assay. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A1 | c.323G>A | p.(Arg108Gln) | Hom | N | 25.7 | Likely Pathogenic PM2/PP4/PP5 | Parents not tested | Sanger sequencing |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: LIKELY_PATHOGENIC
type: missense
variant_type: single nucleotide variant
- name: ROR2 c.355C>T; p.(Arg119*)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Homozygous nonsense allele in A3, listed as pathogenic. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A3 | c.355C>T | p.(Arg119*) | Hom | N | 35.0 | Pathogenic PVS1/PM2/PP4/PP5 | Parents not tested | NGS panel |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: PATHOGENIC
type: nonsense
variant_type: single nucleotide variant
- name: ROR2 exon 4–5 deletion
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: A4 had a homozygous approximately 21-kb deletion, with heterozygous parents. The clinical study implicates this deletion in disease, but Table I gives an uncertain structural-variant classification (+0.45). Breakpoints are reported on GRCh37. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A4 | ... chr9:g.94498192_94519323del | p.? | Hom | Y | - | Uncertain +0.45 | Heterozygous parents | Sanger sequencing /MLPA/CMA |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: UNCERTAIN_SIGNIFICANCE
type: exon deletion
variant_type: deletion
- name: ROR2 c.2074C>A; p.(Pro692Thr)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Homozygous in A9 and A19, classified as uncertain significance in the cohort table despite the authors reporting defective trafficking in their selected-variant assay. Transcript NM_004560.4; Table I nomenclature is retained. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A9 | c.2074C>A | p.(Pro692Thr) | Hom | Y | 25.7 | Uncertain Significance PM2/PP3/PP4/PP5 | Heterozygous parents | Sanger sequencing |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: UNCERTAIN_SIGNIFICANCE
type: missense
variant_type: single nucleotide variant
- name: ROR2 c.1970G>A; p.(Arg657His)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: A11 carried this missense VUS in trans with an approximately 470-kb deletion containing ROR2 and part of SPTLC1; Table I classifies the deletion as pathogenic. An apparently homozygous sequencing call was resolved through copy-number analysis. A21 also carried Arg657His with a different allele. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A11 | c.1970G>A ... chr9:g.94371974_94844329del | p.(Arg657His) - | Comp Het | Y, Y | 31.0 - | Uncertain significance PM2/PM3/PP4 Pathogenic +1.00 | Parents not tested | NGS panel/MLPA/CMA |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: UNCERTAIN_SIGNIFICANCE
type: missense
variant_type: single nucleotide variant
- name: ROR2 c.2T>G
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Homozygous initiation-codon variant in A13, listed as likely pathogenic, with heterozygous parents. The protein consequence is reported as p.?; no specific alternate protein is asserted. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A13 | c.2T>G | p.? | Hom | Y | 20.4 | Likely Pathogenic PVS1/PM2//PP4/PP5 | Heterozygous parents | Exome sequencing |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: LIKELY_PATHOGENIC
type: initiation-codon
variant_type: single nucleotide variant
- name: ROR2 c.1096C>T; p.(Arg366Trp)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Paternally inherited in A16 in trans with maternal c.2207G>A; p.(Arg736Gln). Both were classified as likely pathogenic in Table I. Both substitutions were included in the HeLa trafficking study. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A16 | c.1096C>T c.2207G>A | p.(Arg366Trp) p.(Arg736Gln) | Comp Het | N, Y | 29.1 28.1 | Likely Pathogenic PM1/PM2/PM3/PP3/PP4/PP5 Likely Pathogenic PM2/ PM3/PP3/PP4/PP5 | Father: c.1096C>T Mother: c.2207G>A | Sanger sequencing |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: C182Y, R184C, C223Y, G326A, and R366W all fail to traffic to the plasma membrane, whereas R189W and R272C are expressed on the cell surface
explanation: Surface staining distinguishes severe trafficking defects from variants that retain surface expression.
clinical_significance: LIKELY_PATHOGENIC
type: missense
variant_type: single nucleotide variant
functional_effects:
- function: ROR2 cell-surface trafficking
description: R366W failed to reach the plasma membrane in the 2024 rescue system and showed strongly reduced signaling; these functional findings are distinct from the source-dated clinical classification.
- name: ROR2 c.623–11G>A
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Homozygous intronic variant in A17/A18 with heterozygous parents, classified as uncertain significance. Its position suggests a possible splice effect, but the quoted cohort does not establish the aberrant transcript. Transcript NM_004560.4. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A17/A18 | c.623–11G>A | -- | Hom | Y | - | Uncertain significance PM2/PP4/PP5/BP7 | Heterozygous parents | Sanger sequencing |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: UNCERTAIN_SIGNIFICANCE
type: intronic splice-region candidate
variant_type: single nucleotide variant
- name: ROR2 c.1324C>T; p.(Arg442*)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: A20 carried this paternal nonsense allele in trans with maternal c.1083delG; p.(His362Thrfs*83). Both were classified as pathogenic in Table I on NM_004560.4. Earlier protein nomenclature p.Arg441Ter is not automatically substituted for this transcript-specific annotation. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A20 | c.1083delG c.1324C>T | p.(His362Thrfs*83) p.(Arg442*) | Comp Het | Y, N | - 36.0 | Pathogenic PVS1/PM2/PM3/PP3/PP4/PP5 Pathogenic PVS1/PM2/PM3/PP4/PP5 | Father:c.1324C>T Mother:c.1083delG | Exome sequencing |'
explanation: Table I reports this genotype and its source-dated classification. These automated 2021 classifications are not a current independent ACMG reassessment.
clinical_significance: PATHOGENIC
type: nonsense
variant_type: single nucleotide variant
- name: ROR2 c.1366dup; p.(Leu456Profs*3)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Apparently de novo frameshift in a 2024 prenatal case, in trans with maternally inherited c.1324C>T; p.(Arg442*). The authors classified the compound-heterozygous variants as pathogenic; the abstract does not specify a transcript accession or prove the absence of parental mosaicism. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:38504427
reference_title: Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo.
explanation: Documents the fetal compound-heterozygous genotype and the reported parental origins.
clinical_significance: PATHOGENIC
type: frameshift
variant_type: duplication
- name: ROR2 c.904C>T; p.(Arg302Cys)
gene:
preferred_term: ROR2
term:
id: hgnc:10257
label: ROR2
description: Paternal missense allele in A21 in trans with maternal p.(Arg657His), classified as uncertain significance in the 2022 cohort on NM_004560.4. A 2023 study reported impaired localization, WNT5A interaction and osteogenic differentiation in variant-expression cultures. These functional findings are retained separately from the cohort classification. The structured clinical-significance value records the cited study assessment, not a current independent reclassification.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| A21 | c.904C>T c.1970G>A | p.(Arg302Cys) p.(Arg657His) | Comp Het | N, Y | 27.4 31.0 | Uncertain Significance PM2/ PP4 Uncertain significance PM2/PP3/PP4 | Father: c.904C>T Mother: c.1970G>A | Sanger sequencing |'
explanation: The source-dated cohort table reports both alleles as uncertain significance.
- reference: DOI:10.32604/biocell.2023.028851
reference_title: A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells (BMSCs)
supports: SUPPORT
evidence_source: IN_VITRO
snippet: 'The ROR2: c.904C>T mutant altered the subcellular localization of the ROR2 protein, which caused an impaired interaction between ROR2 and Wnt5a.'
explanation: Functional evidence from transfected cultures; this is not a new clinical classification.
clinical_significance: UNCERTAIN_SIGNIFICANCE
type: missense
variant_type: single nucleotide variant
experimental_models:
- name: HeLa ROR2 variant trafficking assay
experimental_model_type: CELL_LINE
cell_source: Human HeLa cells transfected with wild-type or variant ROR2 constructs
publication: PMID:35344616
description: Confocal localization of selected ROR2 variants (Arg108Gln, Arg366Trp, Pro692Thr and Arg736Gln) relative to the plasma-membrane marker EGFP-hRas and ER marker calnexin.
modeled_mechanisms:
- target: Defective ROR2 Trafficking to the Cell Surface
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Selected variant proteins are retained intracellularly.
limitations: Heterologous overexpression assay; does not establish that every Robinow-associated allele is retained in the ER.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Co-expression of Ror2 and EGFP-hRas or calnexin in Hela-cells showed that wild-type Ror2 localizes predominantly to the plasma membrane, while mutant Ror2 proteins do not migrate to the plasma membrane and are retained to the endoplasmic reticulum
explanation: Transfected HeLa localization measures the selected receptor proteins, not an affected-patient cell phenotype.
readouts:
- name: ROR2 plasma-membrane localization
target: Defective ROR2 Trafficking to the Cell Surface
direction: DECREASED
interpretation: Loss of membrane localization with ER retention for the assayed substitutions.
evidence:
- reference: PMID:35344616
reference_title: Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Co-expression of Ror2 and EGFP-hRas or calnexin in Hela-cells showed that wild-type Ror2 localizes predominantly to the plasma membrane, while mutant Ror2 proteins do not migrate to the plasma membrane and are retained to the endoplasmic reticulum
explanation: Transfected HeLa localization measures the selected receptor proteins, not an affected-patient cell phenotype.
- name: ROR1/ROR2-null iMEF rescue and Frizzled bypass system
experimental_model_type: CELL_LINE
cell_source: E12.5 mouse embryonic fibroblasts immortalized by CRISPR ablation of Tp53
publication: PMID:38780011
description: Conditional Ror1/Ror2 deletion is induced with 4-hydroxytamoxifen, followed by expression of mouse Ror2 constructs carrying domain deletions or Robinow-associated substitutions. GFP-Pdzrn3 degradation and DVL2 phosphorylation report signaling; surface staining and glycosidase sensitivity distinguish trafficking defects.
modeled_mechanisms:
- target: Reduced WNT5A-ROR2 Noncanonical Signalling
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Variant rescue assays reveal strong or partial signaling deficits; mini-ROR2 and bivalent anti-Frizzled IgGs test distinct ways to restore the reporter response.
limitations: Immortalized mouse cells with transgene expression. Rescue of a reporter is not rescue of congenital malformations; monovalent F2.A Fab instead inhibits WNT5A-driven signaling.
evidence:
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The remaining two mutants (R189W and R272C) exhibited milder but still statistically significant signaling deficits
explanation: The reporter assay distinguishes residual activity from the stronger defects of the other tested substitutions.
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Signaling analyses by GFP-Pdzrn3 reporter degradation and DVL2 phosphorylation showed that mini-ROR2 can substantially rescue WNT5A signaling
explanation: A synthetic CRD-Kr membrane-tethered construct restores cellular reporter responses; anatomical or clinical rescue was not tested.
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: F2.A, in its bivalent IgG form and in the absence of any WNT5A, strongly induced GFP-Pdzrn3 reporter degradation, as well as DVL2 phosphorylation, in ROR cKO iMEFs, ROR KO iMEFs, and WT ROR2 rescued iMEFs
explanation: Frizzled-directed IgG activates the assay downstream of receptor loss; this is a mechanistic bypass experiment, not a Robinow treatment trial.
readouts:
- name: WNT5A-induced GFP-Pdzrn3 degradation
target: Reduced WNT5A-ROR2 Noncanonical Signalling
direction: DECREASED
interpretation: Disease-associated substitutions impair the reporter response to different degrees.
evidence:
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The remaining two mutants (R189W and R272C) exhibited milder but still statistically significant signaling deficits
explanation: The reporter assay distinguishes residual activity from the stronger defects of the other tested substitutions.
- target: Defective ROR2 Trafficking to the Cell Surface
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Five variants fail surface delivery, while R189W and R272C retain surface expression.
limitations: Construct and cell-context dependence limits transfer to patient tissues.
evidence:
- reference: PMID:38780011
reference_title: Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: C182Y, R184C, C223Y, G326A, and R366W all fail to traffic to the plasma membrane, whereas R189W and R272C are expressed on the cell surface
explanation: Variant-specific surface staining directly distinguishes trafficking defects from retained surface expression.
- name: Primary embryonic fibroblast Ror deletion model
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Primary mouse E12.5 embryonic fibroblasts used within five passages
publication: PMID:22343533
description: Single- and double-receptor knockout cultures, including acute inducible deletion, compare endogenous Wnt5a-dependent signaling. Dvl2 phosphorylation decreases with loss of Ror receptors, while Wnt5a inhibition of canonical signaling and c-Jun phosphorylation were not dependent on Rors in this system.
modeled_mechanisms:
- target: Reduced WNT5A-ROR2 Noncanonical Signalling
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Loss of Ror receptors lowers the Dvl2 phosphorylation readout.
limitations: Whole-gene mouse deletions do not reproduce every human missense genotype. Negative c-Jun and canonical-Wnt results are limited to this cell context.
evidence:
- reference: url:https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf
reference_title: https://greenberg.hms.harvard.edu/wp-content/uploads/2016/03/Ho-et-al-2012-Proc-Natl-Acad-Sci-USA.pdf
supports: SUPPORT
evidence_source: IN_VITRO
snippet: 'Dvl2 phosphorylation is in-

creasingly reduced in Ror1−/−, Ror2−/−, and Ror DKO MEFs'
explanation: Comparison of the mutant primary cultures shows a receptor-dose-dependent phosphorylation defect.
- name: ROR2-depleted marrow stromal cells with sphingomyelin rescue
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Bone marrow mesenchymal stromal-cell culture; donor and species details are not clearly specified in the article methods
publication: DOI:10.32604/biocell.2023.028851
description: LV-shROR2 and LV-ROR2-c.904C>T cultures were compared with controls after osteogenic induction. Readouts included ALP activity, Alizarin Red staining, SMS1 transcripts, osteogenic markers, and ERK/P38/SMAD phosphorylation. Lipofectamine-delivered sphingomyelin was tested as a rescue intervention.
modeled_mechanisms:
- target: Impaired Osteogenic Differentiation of Marrow Stromal Cells
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: The perturbations impair cellular osteogenic readouts, with rescue after sphingomyelin supplementation.
limitations: Single in-vitro study with incompletely described cell provenance and triplicate assays. Reduced SMS1 transcript is not a direct sphingomyelin measurement; supplementation does not prove a unique causal pathway or clinical benefit.
evidence:
- reference: DOI:10.32604/biocell.2023.028851
reference_title: A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells (BMSCs)
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1.
explanation: Cultured marrow stromal cells with ROR2 depletion or the c.904C>T construct show an osteogenic phenotype; its contribution to human congenital skeletal disease is unresolved.
- reference: DOI:10.32604/biocell.2023.028851
reference_title: A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells (BMSCs)
supports: SUPPORT
evidence_source: IN_VITRO
snippet: SM treatment could reverse the inhibition of osteoblastic differentiation in ROR2-depleted BMSCs.
explanation: Sphingomyelin supplementation is a cell-culture rescue result, without an animal or human therapeutic outcome.
readouts:
- name: Osteogenic mineralization and ALP activity
target: Impaired Osteogenic Differentiation of Marrow Stromal Cells
direction: DECREASED
interpretation: Reduced staining and activity after ROR2 depletion support impaired differentiation.
evidence:
- reference: DOI:10.32604/biocell.2023.028851
reference_title: A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells (BMSCs)
supports: SUPPORT
evidence_source: IN_VITRO
snippet: ROR2 depletion inhibited the Alizarin Red S accumulation in the Alizarin Red S staining assay and ALP staining in ALP activity assays
explanation: Two cellular osteogenic readouts decrease in the reported perturbation experiment.

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References & Deep Research

References

3

PMID:20301418

ROR2-Related Robinow Syndrome.

No top-level findings curated for this source.

PMID:35344616

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

No top-level findings curated for this source.

url:https://www.rcsb.org/structure/9FSE

RCSB PDB - 9FSE: Human ROR2 cysteine-rich domain (CRD) and Kringle domain

No top-level findings curated for this source.

Autosomal Recessive Robinow Syndrome

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