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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant with high penetrance, arising either by inheritance or de novo. An important counselling point is that severity cannot be predicted from the genotype, so a molecular result establishes the diagnosis and the recurrence risk but not the expected clinical course.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"Each child of an individual with ADRS has a 50% chance of inheriting the pathogenic variant; however, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing."

The GeneReviews Genetic Counseling statement, giving both the recurrence risk and the limit on genotype-based prognosis.

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Pathophysiology

5

Heterozygous WNT5A Missense Variant

A missense substitution in WNT5A, in the founding families replacing highly conserved cysteine residues. Cysteines matter disproportionately in a Wnt ligand because the fold depends on disulfide bonding, and the disease variants cluster on a surface implicated in receptor engagement rather than being scattered through the protein.

WNT5A hgnc:12784

Genetic context WNT5A hgnc:12784 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Partial loss of function rather than null: the functional assays show decreased activity, not abolished activity, and heterozygotes are affected while the corresponding mouse null is perinatally lethal with a more severe phenotype than any human patient.

Downstream

Reduced Non-Canonical WNT5A Signalling Through ROR2 The variant protein is the ligand; reduced ligand activity is reduced pathway input.

Show evidence (2 references)

PMID:19918918 SUPPORT Human Clinical

"we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome"

The gene-disease assignment and the variant class, from the discovery study.

PMID:19918918 SUPPORT Human Clinical

"One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient."

Segregation in the originally described pedigree, which is the strongest single piece of evidence tying WNT5A to this entity.

Reduced Non-Canonical WNT5A Signalling Through ROR2

The WNT5A/ROR2 axis transmits a beta-catenin-independent signal through Disheveled to Rho-family GTPases and JNK. This is the planar-cell-polarity branch of Wnt signalling - it tells cells which way to face and which way to move, rather than whether to divide or what to become. The functional evidence for reduced signalling is developmental-assay based: the patient variants decreased WNT5A activity in zebrafish and Xenopus systems. That is the measurement available, and it is made in embryos of other species rather than in human tissue.

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

Downstream

Loss of Planar Cell Polarity in Developing Tissues Planar cell polarity is the output this pathway produces, so reducing the signal degrades the polarity.

Show evidence (2 references)

PMID:19918918 SUPPORT Model Organism

"These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development."

The functional demonstration that the variants reduce signalling. Typed MODEL_ORGANISM because the assays are in zebrafish and Xenopus embryos.

PMID:19918918 SUPPORT Human Clinical

"This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development and that proper formation and growth of these structures is sensitive to variations in WNT5A function."

The authors' own framing of the pathway and of the dose sensitivity that makes a partial loss of function sufficient to cause disease.

Loss of Planar Cell Polarity in Developing Tissues

Cells that should adopt a coordinated orientation within the plane of a tissue fail to do so. In growth-plate cartilage this is directly observable - chondrocytes that should stack into ordered columns are randomly oriented - and it is the most concrete cellular readout available for this disease. PROVISIONAL because the chondrocyte polarity evidence comes from experimental systems expressing a disease variant rather than from patient growth plates, and because the step from disordered chondrocyte columns to the specifically mesomelic pattern of limb shortening is inferred rather than demonstrated.

chondrocyte CL:0000138

cartilage tissue UBERON:0002418

Downstream

Disordered Growth Plate and Skeletal Patterning Growth-plate elongation depends on ordered chondrocyte columns, so losing the order degrades the elongation.

Craniofacial and Genital Morphogenetic Disruption The same polarity defect is presumed to act in neural-crest-derived craniofacial precursors and in genital development, but the intermediate steps in those tissues are not established for WNT5A patient variants.

Show evidence (1 reference)

PMID:19918918 SUPPORT Other

"A non-canonical, β-catenin independent signal transduction pathway that controls cell polarity or movement has also been identified"

Background from the introduction of the WNT5A discovery paper, citing Heisenberg et al. 2000 - a zebrafish study. Graded OTHER because it is a review of prior model-organism work rather than a human observation or a result of the citing paper. It establishes that this pathway controls cell polarity in general, not that the polarity defect was measured in Robinow tissue.

Disordered Growth Plate and Skeletal Patterning

Shortened, disorganised endochondral growth with a mesomelic pattern - the middle segments of the limbs are affected more than the proximal or distal ones, and the upper limbs more than the lower. Brachydactyly, vertebral anomalies and radial head dislocation belong to the same developmental failure.

cartilage tissue UBERON:0002418

Downstream

Mesomelic Limb Shortening Disordered growth plate chondrocyte columns shorten the middle limb segment.

Short Stature The same growth plate lesion summed over the long bones.

Brachydactyly Digital shortening is the acral expression of the same patterning defect.

Dislocated Radial Head Disproportionate growth of the paired forearm bones, not a primary joint defect.

Hemivertebrae Segmentation of the paraxial mesoderm requires the same polarity signal.

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

Macrocephaly Macrocephaly accompanies the syndrome; no route from the growth plate lesion to calvarial growth has been established.

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"

The GeneReviews Clinical Characteristics description of the skeletal phenotype, including the upper-limb predominance of the mesomelic shortening.

Craniofacial and Genital Morphogenetic Disruption

The non-skeletal half of the phenotype: the distinctive facial configuration that gave the condition its old name of fetal face syndrome, and hypoplastic external genitalia. Both are morphogenetic failures established in utero rather than progressive processes.

Downstream

Hypertelorism Failed midline outgrowth of the frontonasal region widens the interorbital distance.

Bifid Tongue The tongue forms from paired swellings that must meet at the midline.

Hypodontia Reduced midfacial and jaw growth constrains tooth-germ development.

Micropenis The male expression of reduced genital tubercle outgrowth.

Cryptorchidism Testicular descent is itself WNT-dependent.

Clitoral Hypoplasia The female expression of the same tubercle defect.

Hypoplastic Labia Majora Part of the same female genital hypoplasia.

Congenital Heart Defect Wnt5a-null mice develop cardiac defects, so the phenotype belongs to pathway loss, but which PCP-dependent step of cardiac morphogenesis fails has not been established in this disease.

Show evidence (2 references)

PMID:25577943 SUPPORT Other

"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"

The GeneReviews description of the craniofacial phenotype.

PMID:25577943 SUPPORT Other

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

The GeneReviews description of the genital phenotype in both sexes.

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Pathograph

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

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Phenotypes

15

Cardiovascular 1

Congenital Heart Defect OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Establishes both the conditional nature and the clinical weight of the cardiac phenotype.

Eye 1

Hypertelorism VERY_FREQUENT HP:0000316

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion)"

Describes the widely spaced prominent eyes this record captures.

Genitourinary 2

Micropenis FREQUENT HP:0000054

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Names micropenis among the male genital findings.

Cryptorchidism FREQUENT HP:0000028

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Names cryptorchidism among the male genital findings.

Head and Neck 2

Hypodontia FREQUENT HP:0000668

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth)"

The GeneReviews dental findings, which name hypodontia among them.

Macrocephaly OCCASIONAL HP:0000256

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"occasional prenatal macrocephaly that persists postnatally"

GeneReviews qualifies macrocephaly as occasional, which is the basis for the frequency here.

Limbs 2

Dislocated Radial Head OCCASIONAL HP:0003083

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Names radial head dislocation among the less common findings.

Brachydactyly VERY_FREQUENT HP:0001156

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"

GeneReviews names brachydactyly as one of the three core skeletal findings.

Musculoskeletal 2

Hemivertebrae OCCASIONAL HP:0002937

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Names hemivertebrae among the vertebral abnormalities.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Names scoliosis among the vertebral abnormalities.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly)"

Lists short stature among the defining skeletal findings.

Other 4

Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"mesomelic limb shortening predominantly of the upper limbs"

States both the mesomelic pattern and its upper-limb predominance.

Hypoplastic Labia Majora FREQUENT HP:0000059

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"in females: hypoplastic clitoris and labia majora"

Names hypoplastic labia majora among the female genital findings.

Clitoral Hypoplasia FREQUENT HP:0000060

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"in females: hypoplastic clitoris and labia majora"

Names clitoral hypoplasia among the female genital findings.

Bifid Tongue FREQUENT HP:0010297

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

Places the bilobed tongue within the oral and dental findings of the GeneReviews clinical description, alongside the dental abnormalities that share a craniofacial developmental origin.

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Genetic Associations

1

WNT5A

Gene: WNT5A hgnc:12784 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:19918918 SUPPORT Human Clinical

"we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome"

The gene-disease assignment and the variant class.

PMID:25577943 SUPPORT Other

"by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular genetic testing"

PARTIAL because the GeneReviews diagnostic statement covers all three dominant genes; only the WNT5A arm applies to this entry. Cited because it is the diagnostic criterion a clinician actually applies, and because it makes explicit that WNT5A is one of three routes to the same clinical diagnosis.

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Medical Actions

5

Corrective Surgery for Genital and Orofacial Anomalies

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Surgical correction of cryptorchidism, abnormal penile insertion or penoscrotal position, and cleft lip or palate where present. This is management of established morphogenetic defects - the developmental window in which the pathway acted has long closed by the time of surgery.

Mechanism Target:

Craniofacial and Genital Morphogenetic Disruption — Corrects the anatomical result of the developmental defect; it does not act on the pathway.

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"Corrective surgeries as needed for cryptorchidism, abnormal penile insertion / penoscrotal position, and cleft lip/palate."

The GeneReviews Management recommendation for the surgical manifestations.

Structured Multisystem Surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

A defined surveillance schedule rather than symptomatic follow-up: head circumference through infancy and childhood, developmental assessment every three months in infancy and six-monthly to yearly thereafter, dental review every six to twelve months, periodic hearing assessment in childhood, and cardiac and renal assessment where abnormalities have been found. The cardiac element is the one with mortality attached, which is why it is curated as surveillance rather than folded into general follow-up.

Mechanism Target:

Disordered Growth Plate and Skeletal Patterning — Detects and manages complications of the established skeletal phenotype rather than modifying it.

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"Measurement of head circumference regularly in infancy and throughout childhood. Developmental assessment every three months in infancy and every six months to one year thereafter"

The GeneReviews Surveillance schedule, quoted for the elements it specifies by interval.

Orthodontic Treatment

Action: orthodontic treatment Ontology label: Orthodontic Treatment NCIT:C64248

Orthodontic management is typically required, reflecting the dental crowding, malocclusion, hypodontia and delayed eruption that accompany the craniofacial phenotype.

Mechanism Target:

Craniofacial and Genital Morphogenetic Disruption — Addresses the dental consequences of abnormal craniofacial development.

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"Orthodontic treatment is typically required."

The GeneReviews Management statement on orthodontic need.

Growth Hormone Therapy (selected patients)

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

Growth hormone for the subset of patients in whom GH deficiency is demonstrated. The reported series found GH deficiency on testing in four of five Robinow patients and a significant increase in growth rate on recombinant GH - but the authors present the association as a proposal, and five patients is not a trial. It treats a coexisting endocrine deficiency, not the WNT5A defect: nothing about supplying growth hormone restores planar cell polarity, and the mesomelic proportions are set prenatally. Curated as a selected-patient option contingent on documented deficiency, not as management of the skeletal phenotype.

Mechanism Target:

Disordered Growth Plate and Skeletal Patterning — Acts on growth-plate output through an independent endocrine axis; it does not restore planar cell polarity.

Show evidence (2 references)

PMID:10417975 SUPPORT INDIRECT Human Clinical

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

INDIRECT on gene attribution. This 1999 series predates the 2010 WNT5A discovery by a decade, so the patients were diagnosed clinically and their genotype is unknown - they may carry DVL1, DVL3, or the recessive ROR2 form rather than WNT5A. It reports a growth-rate response to recombinant GH in Robinow syndrome; it does not establish that response for the WNT5A form specifically. This is the same caveat the prevalence record carries, and for the same reason.

PMID:10417975 SUPPORT Human Clinical

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

PARTIAL because the authors frame the GH-deficiency association as a proposal from a small series rather than an established feature of the disease - which is why this treatment is curated as a selected-patient option contingent on demonstrated deficiency.

Hormone Therapy for Micropenis

Action: Pharmacotherapy NCIT:C15986

Hormone therapy in affected males with micropenis, listed by GeneReviews among the treatments of manifestations. Like the surgical entries, it addresses an established morphogenetic outcome rather than the pathway that produced it.

Mechanism Target:

Craniofacial and Genital Morphogenetic Disruption — Acts on the genital phenotype; it does not restore planar cell polarity.

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

"Hormone therapy may be helpful for males with micropenis."

The GeneReviews Management statement. Note its hedge - "may be helpful" - which is why this is recorded without any efficacy claim.

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Diagnosis

1

Molecular Genetic Testing

The diagnosis is established clinically by the characteristic combination of findings and confirmed by identifying a heterozygous pathogenic variant. Because three genes produce the dominant syndrome, a panel or exome approach is appropriate rather than single-gene testing, and the specific gene identified carries prognostic information - DVL1 predicts osteosclerosis and preserved stature, WNT5A does not.

Show evidence (1 reference)

PMID:25577943 SUPPORT Other

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

The GeneReviews Diagnosis/Testing criterion in full.

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Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

No population prevalence is established for the WNT5A form specifically. Robinow syndrome as a whole had over 100 reported patients across dominant and recessive forms at the time of the WNT5A discovery; the WNT5A subset is a small fraction of that.

Show evidence (1 reference)

PMID:19918918 SUPPORT Human Clinical

"Over 100 patients with Robinow syndrome have since been identified in families with both autosomal dominant and autosomal recessive inheritance patterns"

PARTIAL because the count is for Robinow syndrome across all genes and both inheritance modes, not for the WNT5A form curated here.

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Differential Diagnoses

2

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

DVL1-related autosomal dominant Robinow syndrome

Overlapping Features The osteosclerotic form. Same pathway, but the mechanism runs the other way - truncated DVL1 adaptors with an apparent gain of function rather than a hypomorphic ligand - and the phenotype separates on features that are easy to check: normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss. A patient with Robinow features and normal height is more likely DVL1 than WNT5A.

Distinguishing Features

Normal stature rather than short stature
Increased bone mineral density with skull osteosclerosis
Hearing loss
Persistent macrocephaly

Show evidence (3 references)

PMID:25577943 SUPPORT Other

"A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss"

The GeneReviews description of the DVL1 phenotype, which is what distinguishes it from the WNT5A form curated here.

PMID:25817014 SUPPORT Human Clinical

"we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals"

Attributes the DVL1-osteosclerosis subtype to its primary report.

PMID:25817014 SUPPORT In Vitro

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

The mechanistic contrast that separates DVL1 disease from WNT5A disease. The mutant allele alone is less active than wild type, but together they raise canonical Wnt signalling - so the osteosclerotic phenotype arises from an allele interaction increasing the canonical branch, where WNT5A disease is a hypomorphic ligand decreasing the non-canonical one.

{ }

Source YAML

click to show

name: Autosomal Dominant Robinow Syndrome 1
creation_date: '2026-08-26T21:00:00Z'
category: Mendelian
disease_term:
  preferred_term: autosomal dominant Robinow syndrome 1
  term:
    id: MONDO:0024455
    label: autosomal dominant Robinow syndrome 1
synonyms:
- DRS1
- WNT5A-related Robinow syndrome
- fetal face syndrome
description: 'A skeletal dysplasia caused by heterozygous missense variants in WNT5A, the prototypic
  ligand of non-canonical Wnt signalling. What is curated here is deliberately narrower than "Robinow
  syndrome": the autosomal dominant form has three genes, and this entry is the WNT5A one.

  That distinction is mechanistic, not bookkeeping. WNT5A variants act on the **ligand**, reducing
  its activity - the founding variants substitute highly conserved cysteines and measurably decrease
  WNT5A function in developmental assays. The other two dominant genes, DVL1 and DVL3, act through
  truncated intracellular adaptors downstream of the same pathway with an apparent gain of function,
  and they carry phenotypic differences to match (osteosclerosis and preserved stature with DVL1).
  Same pathway, opposite direction of effect, different clinical picture - so they are curated as
  differential diagnoses rather than merged in.

  The pathway is the non-canonical, beta-catenin-independent branch: WNT5A signals through ROR2 and
  Disheveled to Rho-family GTPases and JNK, governing planar cell polarity rather than proliferation
  or fate. The disease is therefore a disorder of polarised cell behaviour. In growth-plate cartilage
  the readout is direct - chondrocytes that should form ordered columns are randomly oriented - and
  mesomelic limb shortening is what that disorganisation produces at the level of a limb.

  The pathology is developmental rather than degenerative. It is established prenatally and is largely
  static afterwards, which is why management is corrective and supportive rather than disease-modifying.'
parents:
- Robinow Syndrome
- Skeletal Dysplasia
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: No population prevalence is established for the WNT5A form specifically. Robinow syndrome
    as a whole had over 100 reported patients across dominant and recessive forms at the time of
    the WNT5A discovery; the WNT5A subset is a small fraction of that.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Over 100 patients with Robinow syndrome have since been identified in families with
      both autosomal dominant and autosomal recessive inheritance patterns
    explanation: PARTIAL because the count is for Robinow syndrome across all genes and both inheritance
      modes, not for the WNT5A form curated here.
pathophysiology:
- name: Heterozygous WNT5A Missense Variant
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: WNT5A
    term:
      id: hgnc:12784
      label: WNT5A
  description: A missense substitution in WNT5A, in the founding families replacing highly conserved
    cysteine residues. Cysteines matter disproportionately in a Wnt ligand because the fold depends
    on disulfide bonding, and the disease variants cluster on a surface implicated in receptor engagement
    rather than being scattered through the protein.
  genetic_context:
    gene:
      preferred_term: WNT5A
      term:
        id: hgnc:12784
        label: WNT5A
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: 'Partial loss of function rather than null: the functional assays show decreased
      activity, not abolished activity, and heterozygotes are affected while the corresponding mouse
      null is perinatally lethal with a more severe phenotype than any human patient.'
  downstream:
  - target: Reduced Non-Canonical WNT5A Signalling Through ROR2
    causal_link_type: DIRECT
    description: The variant protein is the ligand; reduced ligand activity is reduced pathway input.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we show that two different missense mutations in WNT5A, which result in amino acid substitutions
      of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome
    explanation: The gene-disease assignment and the variant class, from the discovery study.
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One mutation has been found in all living affected members of the original family described
      by Meinhard Robinow and another in a second unrelated patient.
    explanation: Segregation in the originally described pedigree, which is the strongest single
      piece of evidence tying WNT5A to this entity.
- name: Reduced Non-Canonical WNT5A Signalling Through ROR2
  role: central_effector
  biological_scale: CELLULAR
  description: 'The WNT5A/ROR2 axis transmits a beta-catenin-independent signal through Disheveled
    to Rho-family GTPases and JNK. This is the planar-cell-polarity branch of Wnt signalling - it
    tells cells which way to face and which way to move, rather than whether to divide or what to
    become.

    The functional evidence for reduced signalling is developmental-assay based: the patient variants
    decreased WNT5A activity in zebrafish and Xenopus systems. That is the measurement available,
    and it is made in embryos of other species rather than in human tissue.'
  biological_processes:
  - preferred_term: non-canonical Wnt signaling pathway
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: Wnt signaling pathway, planar cell polarity pathway
    term:
      id: GO:0060071
      label: Wnt signaling pathway, planar cell polarity pathway
    modifier: DECREASED
  downstream:
  - target: Loss of Planar Cell Polarity in Developing Tissues
    causal_link_type: DIRECT
    description: Planar cell polarity is the output this pathway produces, so reducing the signal
      degrades the polarity.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These missense mutations result in decreased WNT5A activity in functional assays of
      zebrafish and Xenopus development.
    explanation: The functional demonstration that the variants reduce signalling. Typed MODEL_ORGANISM
      because the assays are in zebrafish and Xenopus embryos.
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human
      craniofacial and skeletal development and that proper formation and growth of these structures
      is sensitive to variations in WNT5A function.
    explanation: The authors' own framing of the pathway and of the dose sensitivity that makes a
      partial loss of function sufficient to cause disease.
- name: Loss of Planar Cell Polarity in Developing Tissues
  role: central_effector
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: 'Cells that should adopt a coordinated orientation within the plane of a tissue fail
    to do so. In growth-plate cartilage this is directly observable - chondrocytes that should stack
    into ordered columns are randomly oriented - and it is the most concrete cellular readout available
    for this disease.

    PROVISIONAL because the chondrocyte polarity evidence comes from experimental systems expressing
    a disease variant rather than from patient growth plates, and because the step from disordered
    chondrocyte columns to the specifically mesomelic pattern of limb shortening is inferred rather
    than demonstrated.'
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  locations:
  - preferred_term: cartilage tissue
    term:
      id: UBERON:0002418
      label: cartilage tissue
  downstream:
  - target: Disordered Growth Plate and Skeletal Patterning
    causal_link_type: DIRECT
    description: Growth-plate elongation depends on ordered chondrocyte columns, so losing the order
      degrades the elongation.
  - target: Craniofacial and Genital Morphogenetic Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The same polarity defect is presumed to act in neural-crest-derived craniofacial
      precursors and in genital development, but the intermediate steps in those tissues are not
      established for WNT5A patient variants.
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A non-canonical, β-catenin independent signal transduction pathway that controls cell
      polarity or movement has also been identified
    explanation: Background from the introduction of the WNT5A discovery paper, citing Heisenberg
      et al. 2000 - a zebrafish study. Graded OTHER because it is a review of prior model-organism
      work rather than a human observation or a result of the citing paper. It establishes that this
      pathway controls cell polarity in general, not that the polarity defect was measured in Robinow
      tissue.
- name: Disordered Growth Plate and Skeletal Patterning
  role: effector
  biological_scale: ORGANISM
  description: Shortened, disorganised endochondral growth with a mesomelic pattern - the middle
    segments of the limbs are affected more than the proximal or distal ones, and the upper limbs
    more than the lower. Brachydactyly, vertebral anomalies and radial head dislocation belong to
    the same developmental failure.
  locations:
  - preferred_term: cartilage tissue
    term:
      id: UBERON:0002418
      label: cartilage tissue
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: skeletal findings (short stature, mesomelic limb shortening predominantly of the upper
      limbs, and brachydactyly)
    explanation: The GeneReviews Clinical Characteristics description of the skeletal phenotype,
      including the upper-limb predominance of the mesomelic shortening.
  downstream:
  - target: Mesomelic Limb Shortening
    causal_link_type: DIRECT
    description: Disordered growth plate chondrocyte columns shorten the middle limb segment.
  - target: Short Stature
    causal_link_type: DIRECT
    description: The same growth plate lesion summed over the long bones.
  - target: Brachydactyly
    causal_link_type: DIRECT
    description: Digital shortening is the acral expression of the same patterning defect.
  - target: Dislocated Radial Head
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Disproportionate growth of the paired forearm bones, not a primary joint defect.
  - target: Hemivertebrae
    causal_link_type: DIRECT
    description: Segmentation of the paraxial mesoderm requires the same polarity signal.
  - target: Scoliosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Asymmetric vertebral segments impose a curve on the growing spine.
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Macrocephaly accompanies the syndrome; no route from the growth plate
      lesion to calvarial growth has been established.
- name: Craniofacial and Genital Morphogenetic Disruption
  role: effector
  biological_scale: ORGANISM
  description: 'The non-skeletal half of the phenotype: the distinctive facial configuration that
    gave the condition its old name of fetal face syndrome, and hypoplastic external genitalia. Both
    are morphogenetic failures established in utero rather than progressive processes.'
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted
      nares, midface retrusion)
    explanation: The GeneReviews description of the craniofacial phenotype.
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism;
      in females: hypoplastic clitoris and labia majora)'
    explanation: The GeneReviews description of the genital phenotype in both sexes.
  downstream:
  - target: Hypertelorism
    causal_link_type: DIRECT
    description: Failed midline outgrowth of the frontonasal region widens the interorbital distance.
  - target: Bifid Tongue
    causal_link_type: DIRECT
    description: The tongue forms from paired swellings that must meet at the midline.
  - target: Hypodontia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced midfacial and jaw growth constrains tooth-germ development.
  - target: Micropenis
    causal_link_type: DIRECT
    description: The male expression of reduced genital tubercle outgrowth.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Testicular descent is itself WNT-dependent.
  - target: Clitoral Hypoplasia
    causal_link_type: DIRECT
    description: The female expression of the same tubercle defect.
  - target: Hypoplastic Labia Majora
    causal_link_type: DIRECT
    description: Part of the same female genital hypoplasia.
  - target: Congenital Heart Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Wnt5a-null mice develop cardiac defects, so the phenotype belongs to
      pathway loss, but which PCP-dependent step of cardiac morphogenesis fails
      has not been established in this disease.

phenotypes:
- category: Skeletal
  name: Mesomelic Limb Shortening
  frequency: VERY_FREQUENT
  description: Shortening of the middle limb segments - forearm and lower leg - with upper-limb predominance.
    The mesomelic pattern is the skeletal signature of this condition and what distinguishes it from
    proportionate short stature.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: mesomelic limb shortening predominantly of the upper limbs
    explanation: States both the mesomelic pattern and its upper-limb predominance.
- category: Growth
  name: Short Stature
  frequency: VERY_FREQUENT
  description: Short stature, largely a consequence of the limb shortening. Notably preserved in
    the DVL1 form, which is one of the features separating that gene's phenotype from this one.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: skeletal findings (short stature, mesomelic limb shortening predominantly of the upper
      limbs, and brachydactyly)
    explanation: Lists short stature among the defining skeletal findings.
- category: Craniofacial
  name: Hypertelorism
  frequency: VERY_FREQUENT
  description: Widely spaced, prominent eyes - the most recognisable single element of the facial
    configuration historically called fetal facies.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted
      nares, midface retrusion)
    explanation: Describes the widely spaced prominent eyes this record captures.
- category: Genitourinary
  name: Micropenis
  frequency: FREQUENT
  description: Genital hypoplasia in affected males. Hormone therapy is sometimes used, and corrective
    surgery is required for the associated anomalies.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: Names micropenis among the male genital findings.
- category: Genitourinary
  name: Cryptorchidism
  frequency: FREQUENT
  description: Undescended testes, curated alongside micropenis because the source names them in
    the same list of male genital findings and the entry's surgical treatment covers both.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism'
    explanation: Names cryptorchidism among the male genital findings.
- category: Genitourinary
  name: Hypoplastic Labia Majora
  frequency: FREQUENT
  description: The female counterpart of the male genital hypoplasia. Curated because the entry
    otherwise recorded only the male findings, which would make the genital phenotype look
    sex-limited when the source describes it in both.
  phenotype_term:
    preferred_term: Hypoplastic labia majora
    term:
      id: HP:0000059
      label: Hypoplastic labia majora
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in females: hypoplastic clitoris and labia majora'
    explanation: Names hypoplastic labia majora among the female genital findings.
- category: Genitourinary
  name: Clitoral Hypoplasia
  frequency: FREQUENT
  description: Hypoplasia of the clitoris, named with the labial hypoplasia as the female genital
    presentation.
  phenotype_term:
    preferred_term: Clitoral hypoplasia
    term:
      id: HP:0000060
      label: Clitoral hypoplasia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'in females: hypoplastic clitoris and labia majora'
    explanation: Names clitoral hypoplasia among the female genital findings.
- category: Skeletal
  name: Dislocated Radial Head
  frequency: OCCASIONAL
  description: Dislocation of the radial head, named by GeneReviews among the less common findings
    and already described in prose by the growth-plate pathophysiology node.
  phenotype_term:
    preferred_term: Dislocated radial head
    term:
      id: HP:0003083
      label: Dislocated radial head
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities
      such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and
      (rarely) cognitive delay.
    explanation: Names radial head dislocation among the less common findings.
- category: Skeletal
  name: Hemivertebrae
  frequency: OCCASIONAL
  description: Segmentation defects of the vertebral bodies. The same failure of ordered axial
    patterning that the growth plate shows in the limbs.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities
      such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and
      (rarely) cognitive delay.
    explanation: Names hemivertebrae among the vertebral abnormalities.
- category: Skeletal
  name: Scoliosis
  frequency: OCCASIONAL
  description: Curvature of the spine, named alongside hemivertebrae as the vertebral presentation.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities
      such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and
      (rarely) cognitive delay.
    explanation: Names scoliosis among the vertebral abnormalities.
- category: Craniofacial
  name: Bifid Tongue
  frequency: FREQUENT
  description: A bilobed tongue - an unusual and clinically distinctive oral finding that helps separate
    Robinow syndrome from other mesomelic dysplasias.
  phenotype_term:
    preferred_term: Bifid tongue
    term:
      id: HP:0010297
      label: Bifid tongue
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of
      permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally
    explanation: Places the bilobed tongue within the oral and dental findings of the GeneReviews
      clinical description, alongside the dental abnormalities that share a craniofacial developmental
      origin.
- category: Cardiovascular
  name: Congenital Heart Defect
  frequency: OCCASIONAL
  description: Cardiac defects are uncommon but disproportionately important, being identified as
    a major cause of morbidity and mortality when present - which is why cardiac assessment features
    in surveillance despite the low frequency.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: When present, cardiac defects are a major cause of morbidity and mortality.
    explanation: Establishes both the conditional nature and the clinical weight of the cardiac phenotype.
- category: Skeletal
  name: Brachydactyly
  frequency: VERY_FREQUENT
  description: Short digits - the third of the three core skeletal findings, alongside short stature
    and mesomelic shortening. All three are consequences of the same disordered endochondral growth,
    expressed at different skeletal scales.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: skeletal findings (short stature, mesomelic limb shortening predominantly of the upper
      limbs, and brachydactyly)
    explanation: GeneReviews names brachydactyly as one of the three core skeletal findings.
- category: Dental
  name: Hypodontia
  frequency: FREQUENT
  description: Missing teeth, with crowding, malocclusion and delayed eruption of the permanent dentition.
    This is the phenotype the orthodontic treatment in this entry actually addresses.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of
      permanent teeth)
    explanation: The GeneReviews dental findings, which name hypodontia among them.
- category: Craniofacial
  name: Macrocephaly
  frequency: OCCASIONAL
  description: Prenatal macrocephaly persisting after birth. Occasional in the WNT5A form; persistent
    macrocephaly is a defining feature of the DVL1 form, which is one of the discriminators in the
    differential.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: occasional prenatal macrocephaly that persists postnatally
    explanation: GeneReviews qualifies macrocephaly as occasional, which is the basis for the frequency
      here.
genetic:
- name: WNT5A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: WNT5A
    term:
      id: hgnc:12784
      label: WNT5A
  notes: 'The secreted non-canonical Wnt ligand. Disease variants are missense and cluster on a modelled
    surface implicated in receptor or co-receptor engagement, which is consistent with altered protein-protein
    interaction rather than misfolding or failure of secretion - the protein is made and released,
    but signals poorly.

    Dose sensitivity is the reason a heterozygous partial loss of function suffices: the discovery
    study concluded that formation and growth of craniofacial and skeletal structures is sensitive
    to variation in WNT5A function.'
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we show that two different missense mutations in WNT5A, which result in amino acid substitutions
      of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome
    explanation: The gene-disease assignment and the variant class.
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through
      molecular genetic testing
    explanation: PARTIAL because the GeneReviews diagnostic statement covers all three dominant genes;
      only the WNT5A arm applies to this entry. Cited because it is the diagnostic criterion a clinician
      actually applies, and because it makes explicit that WNT5A is one of three routes to the same
      clinical diagnosis.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Autosomal dominant with high penetrance, arising either by inheritance or de novo.
    An important counselling point is that severity cannot be predicted from the genotype, so a molecular
    result establishes the diagnosis and the recurrence risk but not the expected clinical course.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Each child of an individual with ADRS has a 50% chance of inheriting the pathogenic
      variant; however, the severity of the clinical manifestations cannot be predicted from the
      results of molecular genetic testing.
    explanation: The GeneReviews Genetic Counseling statement, giving both the recurrence risk and
      the limit on genotype-based prognosis.
diagnosis:
- name: Molecular Genetic Testing
  description: The diagnosis is established clinically by the characteristic combination of findings
    and confirmed by identifying a heterozygous pathogenic variant. Because three genes produce the
    dominant syndrome, a panel or exome approach is appropriate rather than single-gene testing,
    and the specific gene identified carries prognostic information - DVL1 predicts osteosclerosis
    and preserved stature, WNT5A does not.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The diagnosis of autosomal dominant Robinow syndrome is established in a proband with
      typical suggestive findings and/or by the identification of a heterozygous pathogenic variant
      in DVL1, DVL3, or WNT5A through molecular genetic testing.
    explanation: The GeneReviews Diagnosis/Testing criterion in full.
treatments:
- name: Corrective Surgery for Genital and Orofacial Anomalies
  therapeutic_modality: SURGERY
  description: Surgical correction of cryptorchidism, abnormal penile insertion or penoscrotal position,
    and cleft lip or palate where present. This is management of established morphogenetic defects
    - the developmental window in which the pathway acted has long closed by the time of surgery.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Craniofacial and Genital Morphogenetic Disruption
    description: Corrects the anatomical result of the developmental defect; it does not act on the
      pathway.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Corrective surgeries as needed for cryptorchidism, abnormal penile insertion / penoscrotal
      position, and cleft lip/palate.
    explanation: The GeneReviews Management recommendation for the surgical manifestations.
- name: Structured Multisystem Surveillance
  therapeutic_modality: OTHER
  description: 'A defined surveillance schedule rather than symptomatic follow-up: head circumference
    through infancy and childhood, developmental assessment every three months in infancy and six-monthly
    to yearly thereafter, dental review every six to twelve months, periodic hearing assessment in
    childhood, and cardiac and renal assessment where abnormalities have been found.

    The cardiac element is the one with mortality attached, which is why it is curated as surveillance
    rather than folded into general follow-up.'
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Disordered Growth Plate and Skeletal Patterning
    description: Detects and manages complications of the established skeletal phenotype rather than
      modifying it.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Measurement of head circumference regularly in infancy and throughout childhood. Developmental
      assessment every three months in infancy and every six months to one year thereafter
    explanation: The GeneReviews Surveillance schedule, quoted for the elements it specifies by interval.
- name: Orthodontic Treatment
  therapeutic_modality: DEVICE
  description: Orthodontic management is typically required, reflecting the dental crowding, malocclusion,
    hypodontia and delayed eruption that accompany the craniofacial phenotype.
  treatment_term:
    preferred_term: orthodontic treatment
    term:
      id: NCIT:C64248
      label: Orthodontic Treatment
  target_mechanisms:
  - target: Craniofacial and Genital Morphogenetic Disruption
    description: Addresses the dental consequences of abnormal craniofacial development.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Orthodontic treatment is typically required.
    explanation: The GeneReviews Management statement on orthodontic need.
- name: Growth Hormone Therapy (selected patients)
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: 'Growth hormone for the subset of patients in whom GH deficiency is demonstrated.
    The reported series found GH deficiency on testing in four of five Robinow patients and a significant
    increase in growth rate on recombinant GH - but the authors present the association as a proposal,
    and five patients is not a trial.

    It treats a coexisting endocrine deficiency, not the WNT5A defect: nothing about supplying growth
    hormone restores planar cell polarity, and the mesomelic proportions are set prenatally. Curated
    as a selected-patient option contingent on documented deficiency, not as management of the skeletal
    phenotype.'
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  target_mechanisms:
  - target: Disordered Growth Plate and Skeletal Patterning
    description: Acts on growth-plate output through an independent endocrine axis; it does not restore
      planar cell polarity.
  evidence:
  - reference: PMID:10417975
    reference_title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: Recombinant human GH therapy in our patient and the three patients from the NCGS resulted
      in a significant increase in the growth rate per year.
    explanation: INDIRECT on gene attribution. This 1999 series predates the 2010 WNT5A discovery
      by a decade, so the patients were diagnosed clinically and their genotype is unknown - they
      may carry DVL1, DVL3, or the recessive ROR2 form rather than WNT5A. It reports a growth-rate
      response to recombinant GH in Robinow syndrome; it does not establish that response for the
      WNT5A form specifically. This is the same caveat the prevalence record carries, and for the
      same reason.
  - reference: PMID:10417975
    reference_title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We propose its association with GH deficiency and that treatment with rhGH can result
      in a significant increase in the growth rate of these children.
    explanation: PARTIAL because the authors frame the GH-deficiency association as a proposal from
      a small series rather than an established feature of the disease - which is why this treatment
      is curated as a selected-patient option contingent on demonstrated deficiency.
- name: Hormone Therapy for Micropenis
  therapeutic_modality: OTHER
  description: Hormone therapy in affected males with micropenis, listed by GeneReviews among the
    treatments of manifestations. Like the surgical entries, it addresses an established morphogenetic
    outcome rather than the pathway that produced it.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Craniofacial and Genital Morphogenetic Disruption
    description: Acts on the genital phenotype; it does not restore planar cell polarity.
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hormone therapy may be helpful for males with micropenis.
    explanation: The GeneReviews Management statement. Note its hedge - "may be helpful" - which
      is why this is recorded without any efficacy claim.
differential_diagnoses:
- name: DVL1-related autosomal dominant Robinow syndrome
  description: 'The osteosclerotic form. Same pathway, but the mechanism runs the other way - truncated
    DVL1 adaptors with an apparent gain of function rather than a hypomorphic ligand - and the phenotype
    separates on features that are easy to check: normal stature, persistent macrocephaly, increased
    bone mineral density with skull osteosclerosis, and hearing loss. A patient with Robinow features
    and normal height is more likely DVL1 than WNT5A.'
  distinguishing_features:
  - Normal stature rather than short stature
  - Increased bone mineral density with skull osteosclerosis
  - Hearing loss
  - Persistent macrocephaly
  evidence:
  - reference: PMID:25577943
    reference_title: Autosomal Dominant Robinow Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous
      pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased
      bone mineral density with skull osteosclerosis, and hearing loss
    explanation: The GeneReviews description of the DVL1 phenotype, which is what distinguishes it
      from the WNT5A form curated here.
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified de novo frameshift mutations in DVL1, a mediator of both canonical and
      non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis,
      in three unrelated individuals
    explanation: Attributes the DVL1-osteosclerosis subtype to its primary report.
  - reference: PMID:25817014
    reference_title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was
      2-fold higher than that in the wild-type construct alone
    explanation: The mechanistic contrast that separates DVL1 disease from WNT5A disease. The mutant
      allele alone is less active than wild type, but together they raise canonical Wnt signalling
      - so the osteosclerotic phenotype arises from an allele interaction increasing the canonical
      branch, where WNT5A disease is a hypomorphic ligand decreasing the non-canonical one.
- name: ROR2-related autosomal recessive Robinow syndrome
  description: The recessive form, caused by loss-of-function variants in ROR2 - the receptor for
    the ligand that is defective here. Phenotypically more severe, with more marked skeletal, vertebral
    and craniofacial involvement, and recessive rather than dominant transmission. The two entities
    are the ligand and the receptor of one signalling step, which is why they look alike.
  distinguishing_features:
  - Autosomal recessive inheritance
  - More severe skeletal, vertebral and craniofacial abnormalities
  - Biallelic ROR2 variants rather than heterozygous WNT5A
  evidence:
  - reference: PMID:19918918
    reference_title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the phenotypically more severe autosomal recessive form of Robinow syndrome has been
      associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently
      been identified as a putative WNT5A receptor
    explanation: States the recessive form's gene, its greater severity, and the ligand-receptor
      relationship that explains the phenotypic overlap.
notes: 'Scope. Autosomal dominant Robinow syndrome has three genes - WNT5A, DVL1 and DVL3 - and this
  entry covers only the WNT5A form (MONDO:0024455, DRS1). The GeneReviews chapter cited throughout
  describes the dominant syndrome across all three, so where its clinical descriptions are quoted
  they apply to the syndrome and not exclusively to WNT5A patients; evidence items say so where it
  matters. DVL1 and ROR2 forms are curated as differential diagnoses rather than subtypes, because
  their mechanisms differ in direction - a hypomorphic ligand here, an allele interaction raising
  canonical Wnt signalling in DVL1, and receptor loss of function in recessive ROR2 disease.

  Deep-research handling. The report is committed at
  research/Autosomal_Dominant_Robinow_Syndrome_1-deep-research-claude_code.md. Its reference
  validation resolved all 13 references with no confabulated citations, but judged only 8 of the 13
  on topic, and the preflight entity check warned that DVL1 was mentioned at 52% the rate of WNT5A -
  both signals of the same thing, that the report mixed in the DVL1/DVL3 forms. Those sections were
  used only for the differential-diagnosis entries, never as evidence for WNT5A claims, and every
  reference cited here was fetched and its snippet verified against the cache individually rather
  than trusted from the report.'
references:
- reference: PMID:25577943
  title: Autosomal Dominant Robinow Syndrome.
  tags:
  - GeneReviews
- reference: PMID:19918918
  title: WNT5A mutations in patients with autosomal dominant Robinow syndrome.
- reference: PMID:25817014
  title: Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
- reference: PMID:10417975
  title: 'Robinow syndrome with growth hormone deficiency: treatment with growth hormone.'

📚

References & Deep Research

References

4

PMID:25577943

Autosomal Dominant Robinow Syndrome.

No top-level findings curated for this source.

PMID:19918918

WNT5A mutations in patients with autosomal dominant Robinow syndrome.

No top-level findings curated for this source.

PMID:25817014

Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.

No top-level findings curated for this source.

PMID:10417975

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

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

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

claude-haiku-4-5-20251001, claude-sonnet-5 26 citations 2026-08-27T04:34:31.160438

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

1. Disease Information

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

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

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

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

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

2. Etiology

Disease Causal Factor

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

Genetic Risk Factors

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

Environmental Risk Factors

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

Protective Factors

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

Gene-Environment Interactions

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

3. Phenotypes

Craniofacial ("fetal facies")

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

Dental/Oral

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

Skeletal

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

Genital/Urogenital

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

Cardiac and Other

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

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

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

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

4. Genetic/Molecular Information

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

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

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

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

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

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

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

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

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

5. Environmental Information

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

6. Mechanism / Pathophysiology

Molecular Pathway

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

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

Cellular Processes

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

Protein Dysfunction

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

Tissue Damage / Organ-Level Mechanism

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

Comparative Genotype-Mechanism Note

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

Craniofacial-Specific Mechanism

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

Molecular Profiling / Omics

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

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

7. Anatomical Structures Affected

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

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

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

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

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

8. Temporal Development

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

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

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

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

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

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

9. Inheritance and Population

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

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

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

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

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

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

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

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

10. Diagnostics

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

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

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

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

Differential diagnosis:

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

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

11. Outcome/Prognosis

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

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

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

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

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

12. Treatment

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

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

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

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

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

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

13. Prevention

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

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

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

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

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

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

14. Other Species / Natural Disease

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

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

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

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

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

15. Model Organisms

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

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

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

Summary of Key Ontology Term Suggestions for KB Curation

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

Notable Evidence Gaps for Curators

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

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

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	13
On topic	8
Off topic	0

All extracted references resolved successfully.

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Diagnosis

Prevalence

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References

Deep Research

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

1. Disease Information

2. Etiology

Disease Causal Factor

Genetic Risk Factors

Environmental Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Craniofacial ("fetal facies")

Dental/Oral

Skeletal

Genital/Urogenital

Cardiac and Other

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Molecular Pathway

Cellular Processes

Protein Dysfunction

Tissue Damage / Organ-Level Mechanism

Comparative Genotype-Mechanism Note

Craniofacial-Specific Mechanism

Molecular Profiling / Omics

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions for KB Curation

Notable Evidence Gaps for Curators

Reference Validation