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

Biallelic ROR2 variants. Parental consanguinity is common, and a founder nonsense allele segregates in a large Omani cohort. Sibling recurrence risk is 25%.

Autosomal recessive inheritance

Show evidence (2 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.

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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#Loss of WNT5A/ROR2 Planar Cell Polarity Signalling

Nearly all the developmental mechanism in this entry comes from the single Ror2 knockout, whose phenotype is milder than the Wnt5a null because Ror1 covers part of the loss. The compound Ror1/Ror2 mutant is the closer phenocopy of complete pathway loss, but the published developmental decomposition was done in the single mutant. Whether the four lesions occur in the same proportions in human biallelic ROR2 disease — where there is no equivalent compensation question resolved — is untested.

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Pathophysiology

6

Biallelic ROR2 Loss of Function

Two routes to one endpoint. Truncating alleles predict nonfunctional protein and their transcripts are degraded by nonsense-mediated decay; missense alleles produce protein retained in the endoplasmic reticulum that never reaches the surface. Both converge on absence of the ROR2 receptor. Exonic deletions, which have no gain-of-function reading available to them, corroborate loss of function.

ROR2 hgnc:10257

Genetic context ROR2 hgnc:10257 allele_type: missense, nonsense, frameshift, or whole-exon deletion zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

ROR2 co-receptor engagement of WNT5A GO:0005109 ⇓ LOSS OF FUNCTION

Downstream

Loss of WNT5A/ROR2 Planar Cell Polarity Signalling Absence of the co-receptor blocks transduction at the membrane.

Show evidence (3 references)

PMID:10932187 SUPPORT Human Clinical

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

Establishes the loss-of-function consequence of the recessive alleles.

PMID:35344616 SUPPORT Human Clinical

"While truncating variant mRNAs are degraded by nonsense-mediated decay (Ben-Shachar et al. 2009), mutant protein caused by missense variants are retained in the endoplasmic reticulum and ultimately lead to the absence of the ROR2 receptor"

Supplies the two molecular routes by which different allele classes reach the same absent-receptor endpoint.

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."

Whole-exon deletions cannot act by gain of function, so they corroborate loss of function as the mechanism.

Loss of WNT5A/ROR2 Planar Cell Polarity Signalling

WNT5A is the soluble ligand of ROR2; together with the FZD2 transmembrane receptor they trigger the Dishevelled proteins to transduce the beta-catenin-independent signal. Losing the receptor removes the input to that cascade. PCP signalling orients cells within the plane of a tissue and drives the polarized behaviour on which axial elongation, limb outgrowth, midline fusion and genital tubercle formation depend.

non-canonical Wnt signaling pathway GO:0035567 ↓ DECREASED Wnt signaling pathway, planar cell polarity pathway GO:0060071 ↓ DECREASED

Downstream

Reduced Presomitic Mesoderm and Defective Somitogenesis Loss of PCP signalling reduces the presomitic mesoderm from which the vertebral column is segmented.

Perturbed Growth Plate Chondrocyte Differentiation PCP signalling orients and differentiates growth plate chondrocytes.

Craniofacial Midline Outgrowth Defect Midline outgrowth of the frontonasal prominence depends on the same cascade.

Genital Tubercle Outgrowth Defect Ror2 is expressed in the genital tubercle, which is reduced when the pathway is lost.

Renal Tract Abnormalities Renal tract anomalies are a recognized feature, but no published work connects them to a specific PCP-dependent step of nephrogenesis.

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"WNT5A acts as a soluble extracellular ligand of ROR2; and together with FZD2 transmembrane receptor they trigger the DVL homologs to transduce the β-catenin independent pathway."

Specifies the ligand-receptor-transducer architecture this node sits in.

Reduced Presomitic Mesoderm and Defective Somitogenesis

In the Ror2-null mouse, vertebral malformations trace to a reduced presomitic mesoderm and consequent defects in somitogenesis — not to a secondary effect of limb shortening. Because the vertebral column and ribs are segmented from that mesoderm, this is the developmental origin of the hemivertebrae and rib fusions that mark the recessive form.

somitogenesis GO:0001756 ↓ DECREASED

Animal models

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

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.

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

Mesomelic limb shortening arises from disturbed chondrocyte differentiation in the growth plate rather than from reduced limb bud initiation. In the recessive form the shortening extends beyond the middle segment, which is part of what makes this the severe end of the spectrum.

growth plate chondrocyte CL:0000138

chondrocyte differentiation GO:0002062 ↓ DECREASED endochondral ossification GO:0001958 ↓ DECREASED

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 the acral expression of the same defect, and ROR2 alleles at other positions produce isolated brachydactyly type B.

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

The fetal facies is a midline outgrowth failure of the frontonasal region rather than a collection of independent dysmorphisms. In the Ror2-null mouse the craniofacial phenotype is attributable to exactly that.

migratory neural crest cell CL:0000333

Animal models

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

Downstream

Fetal Facies Failed midline outgrowth produces the characteristic facial gestalt.

Prominent Forehead A component of the same midline outgrowth failure.

Short Nose The nasal component of the frontonasal outgrowth defect.

Gingival Overgrowth Gum hypertrophy accompanies the oral phenotype; the intermediates are not established.

Ankyloglossia Tongue tethering belongs to the same midline oral phenotype.

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

Genital hypoplasia is a primary developmental defect, not an endocrine one: Ror2 is expressed in the genital tubercle and the tubercle is reduced in Ror2-null mice. That predicts a structural micropenis responding only partially to androgen therapy.

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 A reduced tubercle yields hypoplastic external genitalia.

Micropenis The male expression of the tubercle defect.

Clitoral Hypoplasia The female expression of the same defect.

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.

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Pathograph

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

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Phenotypes

15

Eye 1

Fetal Facies VERY_FREQUENT Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

"Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism, prominent eyes, midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth with exposed incisors and upper gums, gum hypertrophy,..."

Enumerates the craniofacial features composing the gestalt.

Genitourinary 2

Micropenis VERY_FREQUENT HP:0000054

Show evidence (1 reference)

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.

Renal Tract Abnormalities OCCASIONAL Abnormality of the kidney HP:0000077

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

"renal tract abnormalities, and nail hypoplasia or dystrophy"

Renal tract abnormalities are listed among the common associated features.

Head and Neck 2

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."

Prominent forehead was present in all molecularly confirmed subjects.

Short Nose VERY_FREQUENT HP:0003196

Show evidence (1 reference)

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."

Short nose is among the features the same study reports in all subjects; this quote establishes the uniformity of the phenotype set.

Limbs 1

Brachydactyly VERY_FREQUENT HP:0001156

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

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

GeneReviews lists brachydactyly among the core skeletal abnormalities.

Musculoskeletal 2

Vertebral Segmentation Defects FREQUENT Hemivertebrae HP:0002937

Show evidence (1 reference)

PMID:10932187 SUPPORT Human Clinical

"The recessive form of Robinow syndrome (RRS; OMIM 268310), particularly frequent in Turkey, has a high incidence of abnormalities of the vertebral column such as hemivertebrae and rib fusions, which is not seen in the dominant form."

States both the frequency in this form and the absence from the dominant forms.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

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

Supports the vertebral involvement from which scoliosis follows. GeneReviews does not name scoliosis for the recessive form separately, hence PARTIAL.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"More pronounced skeletal involvement and marked short stature are observed in the autosomal recessive (AR) form of RS (AR-RS), initially described as COVESDEM syndrome"

Records short stature and its greater severity in this form.

Other 6

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."

Mesomelic limb shortening was present in all 22 molecularly confirmed ROR2 patients.

Rib Fusion OCCASIONAL HP:0000902

Show evidence (1 reference)

PMID:35344616 SUPPORT Human Clinical

"However, despite the more severe bone involvement in AR-RS, rib fusion is not universally present in AR-RS, evident by its absence in a small proportion of molecularly-confirmed cases."

Qualifies the claim: supports rib fusion as a feature while refuting its use as an obligate diagnostic criterion.

Gingival Overgrowth FREQUENT HP:0000212

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"

Gum hypertrophy is listed among the oral features.

Ankyloglossia FREQUENT 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.

Genital Hypoplasia VERY_FREQUENT Hypoplastic male external genitalia HP:0000050

Show evidence (1 reference)

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.

Clitoral Hypoplasia FREQUENT 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.

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Genetic Associations

1

ROR2

Gene: ROR2 hgnc:10257 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 the allelic spectrum in a molecularly confirmed cohort.

PMID:35344616 SUPPORT Human Clinical

"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.

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Medical Actions

3

Orthopedic Surgery for Limb and Spine Deformity

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

Corrective surgery for limb and spine defects, more often needed here than in the dominant forms because vertebral segmentation defects and scoliosis are prominent.

Mechanism Target:

Reduced Presomitic Mesoderm and Defective Somitogenesis — Corrects the vertebral segmentation and scoliosis consequences of the somitogenesis defect. It acts on the established anatomy, not on the signalling lesion that produced it.

Show evidence (1 reference)

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.

Androgen Therapy for Micropenis

Action: Pharmacotherapy NCIT:C15986

Agent: testosterone CHEBI:17347

Testosterone is used for micropenis. Because the genital phenotype originates in a developmental tubercle outgrowth defect rather than androgen deficiency, the response is symptomatic and often incomplete.

Mechanism Target:

Genital Tubercle Outgrowth Defect — Symptomatic. The genital phenotype arises from a developmental outgrowth defect rather than androgen deficiency, so testosterone acts downstream of the mechanism node and the response is often incomplete.

Show evidence (1 reference)

PMID:20301418 SUPPORT Human Clinical

"hormone therapy as needed for the treatment of micropenis"

GeneReviews lists hormone therapy for micropenis in management.

Genetic Counseling

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

A 25% sibling recurrence risk, with carrier testing and prenatal or preimplantation testing available once the family's variants are known. Consanguinity is common, which raises the counselling stakes for the wider family.

Show evidence (1 reference)

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.

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Diagnosis

3

Clinical and Radiographic Recognition

Recognizable at birth or in early childhood from the triad plus the axial findings. Recognition is unusually reliable for a rare dysplasia: in a molecularly confirmed cohort, 19 clinical features were each present in more than 75% of subjects. Vertebral imaging is the step that separates this form from the dominant ones.

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

Recognizable on second-trimester ultrasound, where macrocephaly, a flat face with frontal bossing, mesomelic shortening, hemivertebrae and micropenis cluster; molecular confirmation is then possible on amniocytes. This matters because the recessive form is the severe one and recurrence risk in an affected family is 25%.

prenatal ultrasonography NCIT:C17369

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 (1 reference)

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.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population-based estimate exists. A 2002 review counted over 100 published Robinow cases across both inheritance modes; the recessive form is over-represented in populations with high consanguinity, and a founder nonsense allele accounts for a large Omani cohort.

Show evidence (1 reference)

PMID:12011143 SUPPORT Human Clinical

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

Gives the order of magnitude of published cases as of 2002. PARTIAL because the count spans both inheritance modes rather than the recessive form alone.

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Differential Diagnoses

4

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

Brachydactyly type B

Overlapping Features Allelic at ROR2 but mechanistically distinct: heterozygous alleles located downstream of the Robinow positions, acting by gain of function or dominant negative rather than loss of function. Digital shortening without the facial, axial or genital components.

Show evidence (1 reference)

PMID:10932187 SUPPORT Human Clinical

"We detected several homozygous ROR2 mutations in our cohort of RRS patients that are located upstream from those previously found in BDB."

Establishes the positional separation of the two allele classes at the same locus.

Autosomal Dominant Robinow Syndrome 1

Overlapping Features The WNT5A form. Milder, without the vertebral segmentation defects and rib fusions, and dominantly inherited.

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.

Congenital adrenal hyperplasia

Overlapping Features A documented diagnostic trap in a neonate presenting with micropenis and impalpable testes. The Robinow facial gestalt and mesomelia are present from birth and CAH does not produce them.

Show evidence (1 reference)

PMID:41477475 SUPPORT Human Clinical

"He was suspected of having congenital adrenal hyperplasia and was started on glucocorticoid replacement."

Documents the misdiagnosis and the treatment it led to.

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Animal Models

1

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 and Defective Somitogenesis recapitulates fidelity: high Vertebral malformations trace to a reduced presomitic mesoderm and defective somitogenesis.

Limitations: Mouse Ror1 partially compensates for Ror2 loss, so the single mutant is milder than complete pathway loss; the compound Ror1/Ror2 mutant is the closer phenocopy.

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.

{ }

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: >-
  The ROR2 form, and the severe end of the Robinow spectrum. Biallelic
  loss-of-function variants in the WNT5A co-receptor ROR2 produce marked short
  stature with generalized rather than purely mesomelic limb shortening, the
  fetal-facies gestalt, genital hypoplasia — and, distinctively, segmental
  defects of the spine with hemivertebrae and rib fusions that the dominant
  forms do not produce. That axial involvement is why the entity was originally
  named COVESDEM, for costovertebral segmentation defect with mesomelia.

  Two molecular routes converge on the same endpoint. Truncating alleles
  introduce premature stop codons upstream of the positions that cause
  brachydactyly type B and predict nonfunctional protein, with the transcripts
  degraded by nonsense-mediated decay; missense alleles produce protein that is
  retained in the endoplasmic reticulum and never reaches the cell surface.
  Either way the receptor is absent. Whole-exon deletions, which cannot act by a
  gain-of-function route, corroborate loss of function as the mechanism.

  The Ror2-null mouse is the reference developmental model for the whole
  syndrome, and its value is that it resolves Robinow syndrome into separate
  lesions at separate sites rather than one global growth failure: reduced
  presomitic mesoderm behind the vertebral malformations, perturbed chondrocyte
  differentiation behind the mesomelia, a midline outgrowth defect behind the
  face, and a reduced genital tubercle behind the genital hypoplasia.
parents:
- Robinow Syndrome
- Skeletal Dysplasia
notes: >-
  Scope. This entry covers the ROR2 form only (MONDO:0009999). The NXN recessive
  form is ``Robinow_Syndrome_Autosomal_Recessive_2``; the dominant forms are
  curated separately; the union is ``kb/groupings/Robinow_Syndrome.yaml``.

  Brachydactyly type B is allelic at ROR2 but is a different disease with a
  different mechanism — heterozygous alleles located downstream of the Robinow
  positions, acting by gain of function or dominant negative rather than loss of
  function. It is a differential diagnosis here, not a subtype, and the
  positional separation of the two allele classes is what makes that call
  checkable rather than a matter of opinion.
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: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. A 2002 review counted over 100
    published Robinow cases across both inheritance modes; the recessive form is
    over-represented in populations with high consanguinity, and a founder
    nonsense allele accounts for a large Omani cohort.
  evidence:
  - reference: PMID:12011143
    reference_title: "Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      Gives the order of magnitude of published cases as of 2002. PARTIAL
      because the count spans both inheritance modes rather than the recessive
      form alone.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic ROR2 variants. Parental consanguinity is common, and a founder
    nonsense allele segregates in a large Omani cohort. Sibling recurrence risk
    is 25%.
  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.
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, or whole-exon deletion
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  description: >-
    Two routes to one endpoint. Truncating alleles predict nonfunctional protein
    and their transcripts are degraded by nonsense-mediated decay; missense
    alleles produce protein retained in the endoplasmic reticulum that never
    reaches the surface. Both converge on absence of the ROR2 receptor. Exonic
    deletions, which have no gain-of-function reading available to them,
    corroborate loss of function.
  molecular_functions:
  - preferred_term: ROR2 co-receptor engagement of WNT5A
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005109
      label: frizzled binding
  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: >-
      Establishes the loss-of-function consequence of the recessive alleles.
  - reference: PMID:35344616
    reference_title: "Phenotypic and mutational spectrum of ROR2-related Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While truncating variant mRNAs are degraded by nonsense-mediated decay
      (Ben-Shachar et al. 2009), mutant protein caused by missense variants are
      retained in the endoplasmic reticulum and ultimately lead to the absence
      of the ROR2 receptor
    explanation: >-
      Supplies the two molecular routes by which different allele classes reach
      the same absent-receptor endpoint.
  - 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: >-
      Whole-exon deletions cannot act by gain of function, so they corroborate
      loss of function as the mechanism.
  downstream:
  - target: Loss of WNT5A/ROR2 Planar Cell Polarity Signalling
    causal_link_type: DIRECT
    description: >-
      Absence of the co-receptor blocks transduction at the membrane.
- name: Loss of WNT5A/ROR2 Planar Cell Polarity Signalling
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    WNT5A is the soluble ligand of ROR2; together with the FZD2 transmembrane
    receptor they trigger the Dishevelled proteins to transduce the
    beta-catenin-independent signal. Losing the receptor removes the input to
    that cascade. PCP signalling orients cells within the plane of a tissue and
    drives the polarized behaviour on which axial elongation, limb outgrowth,
    midline fusion and genital tubercle formation depend.
  biological_processes:
  - preferred_term: non-canonical Wnt signaling pathway
    modifier: DECREASED
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    modifier: DECREASED
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
  evidence:
  - reference: PMID:35344616
    reference_title: "Phenotypic and mutational spectrum of ROR2-related Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WNT5A acts as a soluble extracellular ligand of ROR2; and together with
      FZD2 transmembrane receptor they trigger the DVL homologs to transduce the
      β-catenin independent pathway.
    explanation: >-
      Specifies the ligand-receptor-transducer architecture this node sits in.
  downstream:
  - target: Reduced Presomitic Mesoderm and Defective Somitogenesis
    causal_link_type: DIRECT
    description: >-
      Loss of PCP signalling reduces the presomitic mesoderm from which the
      vertebral column is segmented.
  - target: Perturbed Growth Plate Chondrocyte Differentiation
    causal_link_type: DIRECT
    description: >-
      PCP signalling orients and differentiates growth plate chondrocytes.
  - target: Craniofacial Midline Outgrowth Defect
    causal_link_type: DIRECT
    description: >-
      Midline outgrowth of the frontonasal prominence depends on the same
      cascade.
  - target: Genital Tubercle Outgrowth Defect
    causal_link_type: DIRECT
    description: >-
      Ror2 is expressed in the genital tubercle, which is reduced when the
      pathway is lost.
  - target: Renal Tract Abnormalities
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Renal tract anomalies are a recognized feature, but no published work
      connects them to a specific PCP-dependent step of nephrogenesis.
- name: Reduced Presomitic Mesoderm and Defective Somitogenesis
  role: consequence
  biological_scale: TISSUE
  description: >-
    In the Ror2-null mouse, vertebral malformations trace to a reduced
    presomitic mesoderm and consequent defects in somitogenesis — not to a
    secondary effect of limb shortening. Because the vertebral column and ribs
    are segmented from that mesoderm, this is the developmental origin of the
    hemivertebrae and rib fusions that mark the recessive form.
  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.
- name: Perturbed Growth Plate Chondrocyte Differentiation
  role: consequence
  biological_scale: CELLULAR
  description: >-
    Mesomelic limb shortening arises from disturbed chondrocyte differentiation
    in the growth plate rather than from reduced limb bud initiation. In the
    recessive form the shortening extends beyond the middle segment, which is
    part of what makes this the severe end of the spectrum.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  - preferred_term: endochondral ossification
    modifier: DECREASED
    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: DIRECT
    description: >-
      Digital shortening is the acral expression of the same defect, and ROR2
      alleles at other positions produce isolated brachydactyly type B.
- name: Craniofacial Midline Outgrowth Defect
  role: consequence
  biological_scale: TISSUE
  description: >-
    The fetal facies is a midline outgrowth failure of the frontonasal region
    rather than a collection of independent dysmorphisms. In the Ror2-null mouse
    the craniofacial phenotype is attributable to exactly that.
  cell_types:
  - preferred_term: migratory neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  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: Fetal Facies
    causal_link_type: DIRECT
    description: >-
      Failed midline outgrowth produces the characteristic facial gestalt.
  - target: Prominent Forehead
    causal_link_type: DIRECT
    description: >-
      A component of the same midline outgrowth failure.
  - target: Short Nose
    causal_link_type: DIRECT
    description: >-
      The nasal component of the frontonasal outgrowth defect.
  - target: Gingival Overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Gum hypertrophy accompanies the oral phenotype; the intermediates are not
      established.
  - target: Ankyloglossia
    causal_link_type: DIRECT
    description: >-
      Tongue tethering belongs to the same midline oral phenotype.
- name: Genital Tubercle Outgrowth Defect
  role: consequence
  biological_scale: TISSUE
  description: >-
    Genital hypoplasia is a primary developmental defect, not an endocrine one:
    Ror2 is expressed in the genital tubercle and the tubercle is reduced in
    Ror2-null mice. That predicts a structural micropenis responding only
    partially to androgen therapy.
  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: DIRECT
    description: >-
      A reduced tubercle yields hypoplastic external genitalia.
  - target: Micropenis
    causal_link_type: DIRECT
    description: >-
      The male expression of the tubercle defect.
  - target: Clitoral Hypoplasia
    causal_link_type: DIRECT
    description: >-
      The female expression of the same defect.
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.
  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: >-
      Mesomelic limb shortening was present in all 22 molecularly confirmed ROR2
      patients.
- category: Skeletal
  name: Short Stature
  description: >-
    Marked short stature; more pronounced than in the dominant forms.
  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: >-
      More pronounced skeletal involvement and marked short stature are observed
      in the autosomal recessive (AR) form of RS (AR-RS), initially described as
      COVESDEM syndrome
    explanation: >-
      Records short stature and its greater severity in this form.
- category: Skeletal
  name: Brachydactyly
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301418
    reference_title: "ROR2-Related Robinow Syndrome."
    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 lists brachydactyly among the core skeletal abnormalities.
- category: Skeletal
  name: Vertebral Segmentation Defects
  description: >-
    Hemivertebrae and thoracic vertebral fusion. Characteristic of this form and
    notably absent from the dominant forms — historically the main clinical
    discriminator between them, and the reason for the original COVESDEM name.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  frequency: FREQUENT
  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 recessive form of Robinow syndrome (RRS; OMIM 268310), particularly
      frequent in Turkey, has a high incidence of abnormalities of the vertebral
      column such as hemivertebrae and rib fusions, which is not seen in the
      dominant form.
    explanation: >-
      States both the frequency in this form and the absence from the dominant
      forms.
- 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: OCCASIONAL
  evidence:
  - reference: PMID:35344616
    reference_title: "Phenotypic and mutational spectrum of ROR2-related Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, despite the more severe bone involvement in AR-RS, rib fusion is
      not universally present in AR-RS, evident by its absence in a small
      proportion of molecularly-confirmed cases.
    explanation: >-
      Qualifies the claim: supports rib fusion as a feature while refuting its
      use as an obligate diagnostic criterion.
- category: Skeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301418
    reference_title: "ROR2-Related Robinow Syndrome."
    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: >-
      Supports the vertebral involvement from which scoliosis follows.
      GeneReviews does not name scoliosis for the recessive form separately,
      hence PARTIAL.
- category: Craniofacial
  name: Fetal Facies
  description: >-
    Macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism,
    prominent eyes, midface hypoplasia, short upturned nose with depressed nasal
    bridge and flared nostrils, and a large triangular mouth.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: VERY_FREQUENT
  evidence:
  - 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, prominent eyes, midface hypoplasia,
      short upturned nose with depressed nasal bridge and flared nostrils, large
      and triangular mouth with exposed incisors and upper gums, gum
      hypertrophy, misaligned teeth, ankyloglossia, and micrognathia.
    explanation: >-
      Enumerates the craniofacial features composing the gestalt.
- 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: >-
      Prominent forehead was present in all molecularly confirmed subjects.
- 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: >-
      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: >-
      Short nose is among the features the same study reports in all subjects;
      this quote establishes the uniformity of the phenotype set.
- 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.
- category: Oral
  name: Ankyloglossia
  phenotype_term:
    preferred_term: Ankyloglossia
    term:
      id: HP:0010296
      label: Ankyloglossia
  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: >-
      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.
- 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.
- category: Genitourinary
  name: Clitoral Hypoplasia
  phenotype_term:
    preferred_term: Clitoral hypoplasia
    term:
      id: HP:0000060
      label: Clitoral hypoplasia
  frequency: FREQUENT
  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
  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.
genetic:
- name: ROR2
  gene_term:
    preferred_term: ROR2
    term:
      id: hgnc:10257
      label: ROR2
  relationship_type: CAUSATIVE
  notes: >-
    Receptor tyrosine kinase-like orphan receptor 2, the WNT5A co-receptor.
    Reported alleles include missense, nonsense, frameshift and whole-exon
    deletions, concentrated in exons 5, 6 and 9. Heterozygous ROR2 alleles at
    different positions cause brachydactyly type B by a distinct,
    non-loss-of-function mechanism, so the position of a truncating variant
    matters for interpretation.
  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 the allelic spectrum in a molecularly confirmed cohort.
  - reference: PMID:35344616
    reference_title: "Phenotypic and mutational spectrum of ROR2-related Robinow syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
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 and Defective Somitogenesis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Vertebral malformations trace to a reduced presomitic mesoderm and
      defective somitogenesis.
    limitations: >-
      Mouse Ror1 partially compensates for Ror2 loss, so the single mutant is
      milder than complete pathway loss; the compound Ror1/Ror2 mutant is the
      closer phenocopy.
    readouts:
    - name: Presomitic mesoderm size
      target: Reduced Presomitic Mesoderm and Defective Somitogenesis
      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.
diagnosis:
- name: Clinical and Radiographic Recognition
  description: >-
    Recognizable at birth or in early childhood from the triad plus the axial
    findings. Recognition is unusually reliable for a rare dysplasia: in a
    molecularly confirmed cohort, 19 clinical features were each present in more
    than 75% of subjects. Vertebral imaging is the step that separates this form
    from the dominant ones.
  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: >-
    Recognizable on second-trimester ultrasound, where macrocephaly, a flat face
    with frontal bossing, mesomelic shortening, hemivertebrae and micropenis
    cluster; molecular confirmation is then possible on amniocytes. This matters
    because the recessive form is the severe one and recurrence risk in an
    affected family is 25%.
  diagnosis_term:
    preferred_term: prenatal ultrasonography
    term:
      id: NCIT:C17369
      label: Imaging Procedure
  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.
differential_diagnoses:
- name: Brachydactyly type B
  description: >-
    Allelic at ROR2 but mechanistically distinct: heterozygous alleles located
    downstream of the Robinow positions, acting by gain of function or dominant
    negative rather than loss of function. Digital shortening without the facial,
    axial or genital components.
  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: >-
      We detected several homozygous ROR2 mutations in our cohort of RRS
      patients that are located upstream from those previously found in BDB.
    explanation: >-
      Establishes the positional separation of the two allele classes at the
      same locus.
- name: Autosomal Dominant Robinow Syndrome 1
  description: >-
    The WNT5A form. Milder, without the vertebral segmentation defects and rib
    fusions, and dominantly inherited.
- 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.
- name: Congenital adrenal hyperplasia
  description: >-
    A documented diagnostic trap in a neonate presenting with micropenis and
    impalpable testes. The Robinow facial gestalt and mesomelia are present from
    birth and CAH does not produce them.
  evidence:
  - reference: PMID:41477475
    reference_title: "Robinow Syndrome Mimicking Congenital Adrenal Hyperplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was suspected of having congenital adrenal hyperplasia and was started
      on glucocorticoid replacement.
    explanation: >-
      Documents the misdiagnosis and the treatment it led to.
treatments:
- name: Orthopedic Surgery for Limb and Spine Deformity
  description: >-
    Corrective surgery for limb and spine defects, more often needed here than
    in the dominant forms because vertebral segmentation defects and scoliosis
    are prominent.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Reduced Presomitic Mesoderm and Defective Somitogenesis
    description: >-
      Corrects the vertebral segmentation and scoliosis consequences of the
      somitogenesis defect. It acts on the established anatomy, not on the
      signalling lesion that produced it.
  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.
- name: Androgen Therapy for Micropenis
  description: >-
    Testosterone is used for micropenis. Because the genital phenotype
    originates in a developmental tubercle outgrowth defect rather than androgen
    deficiency, the response is symptomatic and often incomplete.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_mechanisms:
  - target: Genital Tubercle Outgrowth Defect
    description: >-
      Symptomatic. The genital phenotype arises from a developmental outgrowth
      defect rather than androgen deficiency, so testosterone acts downstream of
      the mechanism node and the response is often incomplete.
  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.
- name: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    A 25% sibling recurrence risk, with carrier testing and prenatal or
    preimplantation testing available once the family's variants are known.
    Consanguinity is common, which raises the counselling stakes for the wider
    family.
  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.
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#Loss of WNT5A/ROR2 Planar Cell Polarity Signalling
  rationale: >-
    Nearly all the developmental mechanism in this entry comes from the single
    Ror2 knockout, whose phenotype is milder than the Wnt5a null because Ror1
    covers part of the loss. The compound Ror1/Ror2 mutant is the closer
    phenocopy of complete pathway loss, but the published developmental
    decomposition was done in the single mutant. Whether the four lesions occur
    in the same proportions in human biallelic ROR2 disease — where there is no
    equivalent compensation question resolved — is untested.
references:
- reference: PMID:20301418
  title: "ROR2-Related Robinow Syndrome."
  tags:
  - GeneReviews
- reference: PMID:35344616
  title: "Phenotypic and mutational spectrum of ROR2-related Robinow syndrome."

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2

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.

Autosomal Recessive Robinow Syndrome

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