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Autosomal Dominant Robinow Syndrome

Synonym: Fetal Face Syndrome

, MD, , MD, , MD, , PhD, and , MD.

Author Information

Initial Posting: ; Last Revision: July 30, 2015.

Summary

Clinical characteristics.

Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly); genital abnormalities (in males: micropenis/webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora); dysmorphic facial features; dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth); bilobed tongue; occasional prenatal macrocephaly with postnatal decrease in head circumference. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defect, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality.

A variant of Robinow syndrome, associated with osteosclerosis and caused by DVL1 pathogenic variants, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above.

Diagnosis/testing.

The diagnosis of ADRS is established in a proband with typical suggestive findings and a family history consistent with autosomal dominant inheritance. The diagnosis is supported by identification of a heterozygous WNT5A or DVL1 pathogenic variant.

Management.

Treatment of manifestations: Corrective surgeries as needed for cryptorchidism, abnormal penile insertion/penoscrotal position, and cleft lip/palate. Hormone therapy may be helpful for males with micropenis. Orthodontic treatment is typically required.

Surveillance: 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, or more frequently as needed if cognitive delays are identified. Dental evaluation every six to 12 months or as recommended. Regular cardiac and renal assessment as needed by respective specialists if abnormalities are identified.

Evaluation of relatives at risk: Evaluation of the sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and surveillance.

Pregnancy management: Pregnancy in affected women appears to be generally uncomplicated. For an affected fetus, cæsarean section may be required for abnormal presentation and/or cephalopelvic disproportion.

Genetic counseling.

ADRS is inherited in an autosomal dominant manner. A proband may have the disorder as a result of either an inherited or de novo pathogenic variant. 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. Prenatal testing for pregnancies at increased risk is possible if the pathogenic WNT5A or DVL1 variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

Autosomal dominant Robinow syndrome (ADRS) should be suspected in individuals with the following clinical findings [Mazzeu et al 2007, Person et al 2010, Beiraghi et al 2011, Roifman et al 2015]:

Skeletal

  • Short stature
  • Mesomelic limb shortening predominantly affecting the upper limbs
  • Brachydactyly

Genital

  • In males: micropenis/webbed penis, hypoplastic scrotum, cryptorchidism
  • In females: hypoplastic clitoris and labia majora

Craniofacial

  • Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See Figure 1 and Figure 2.)
  • Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
Figure 1. . A mother and son, both affected with WNT5A-associated autosomal dominant Robinow syndrome A.

Figure 1.

A mother and son, both affected with WNT5A-associated autosomal dominant Robinow syndrome A. Affected mother in infancy B, C. Affected son at birth D. Mother (age 39 years) and son (age 2 years) E. Son at age 3 years Note the widely spaced and prominent (more...)

Figure 2. . A boy with WNT5A-associated autosomal dominant Robinow syndrome at different ages.

Figure 2.

A boy with WNT5A-associated autosomal dominant Robinow syndrome at different ages. Note the widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad (more...)

Other features less frequently seen (<25% of cases) [Mazzeu et al 2007, Person et al 2010, Roifman et al 2015]:

  • Post natal decrease in head circumference
  • Renal anomalies (usually hydronephrosis)
  • Radial head dislocation
  • Vertebral abnormalities and scoliosis
  • Persistent primary teeth requiring extraction
  • Nail dysplasia
  • Cardiac defect
  • Cleft lip/palate
  • Cognitive delay

Establishing the Diagnosis

The diagnosis of autosomal dominant Robinow syndrome is established in a proband with both of the following:

The diagnosis of ADRS is supported by an identified heterozygous WNT5A or DVL1 pathogenic variant (see Table 1).

Note: If a heterozygous pathogenic variant is not identified in WNT5A or DVL1, it is appropriate to exclude the presence of biallelic ROR2 pathogenic variants (which cause autosomal recessive Robinow syndrome).

Molecular genetic testing of WNT5A or DVL1 begins with sequence analysis, followed by deletion/duplication analysis if no pathogenic variant is identified.

Table 1.

Summary of Molecular Genetic Testing Used in Autosomal Dominant Robinow Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
WNT5ASequence analysis 25 families 3 / ~50 families reported (unknown number of families tested)
Deletion/duplication analysis 4Unknown
DVL1Sequence analysis 210 families 5 (unknown number of families tested)
Deletion/duplication analysis 4Unknown
Unknown 6NA
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.
4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.
6.

Individuals with a skeletal dysplasia suggestive of ADRS with atypical features (with short-limbed dwarfism without a mesomelic pattern, with less typical facial features and/or absence of genital hypoplasia) have not been associated with WNT5A, DVL1, or ROR2 pathogenic variants and, therefore, may reflect locus heterogeneity in this disorder [Authors’ personal experience].

Clinical Characteristics

Clinical Description

Facial. Clinical features of autosomal dominant Robinow syndrome (ADRS) are noticeable at birth or in early childhood. The distinctive facial features become less apparent with age.

Prominent facial features in adulthood include widely spaced eyes, wide nasal bridge, and broad nasal tip.

Dental malocclusion becomes apparent in early childhood and persists into adulthood, affecting the permanent dentition as well. One case of persistent primary dentition requiring extraction at age 18 years has been reported [Roifman et al 2015].

Skeletal. Short stature is almost always present at birth and sometimes identified prenatally (on detailed fetal ultrasound) as early as 20 weeks [Mazzeu et al 2007, Castro et al 2014, Roifman et al 2015].

Short stature persists into adulthood but is typically not severe, with a final adult height either at or just below -2SD in most cases [Mazzeu et al 2007, Person et al 2010, Roifman et al 2015].

Some individuals with DVL1-associated ADRS have a unique skeletal phenotype, exhibiting normal stature, increased bone mineral density with osteosclerosis of the skull, and macrocephaly (ranging from +2.5SD to >+6SD) [Bunn et al 2015, White et al 2015].

Urogenital. Hypoplastic genitalia are apparent at birth for males and females.

Micropenis may be present. However, in some cases, the penis may measure normally but appear small because it is webbed/embedded in the scrotal tissue or because of the abnormal insertion of penile crura inferiorly and posteriorly onto the medial aspect of the ischial tuberosity [Wilcox et al 1997]. These cases may be amenable to cosmetic reconstruction (see Management). Of note, micropenis appears to be common in ADRS (and is a constant feature of autosomal recessive Robinow syndrome). The frequency of penoscrotal transposition in ADRS is unclear at this time.

Puberty and fertility. To the best of the authors’ knowledge, both puberty and fertility are normal and affected females can carry pregnancies to term; delivery may need to be by cæsarean section due to cephalopelvic disproportion.

Cardiac abnormalities occur in a minority of individuals with ADRS. Cardiac defects reported in Robinow syndrome (in both dominant and recessive types) include pulmonary valve stenosis/atresia, atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [Webber et al 1990, Al-Ata et al 1998]. When present, cardiac defects are a major cause of morbidity and mortality.

Hearing loss (bilateral, mixed) has been reported in some individuals with DVL1-associated ADRS [Bunn et al 2015, White et al 2015].

Umbilical hernia has been reported in some individuals with DVL1-associated ADRS [White et al 2015].

Intelligence is usually normal; cognitive delay occurs in a minority of individuals with ADRS.

Genotype-Phenotype Correlations

No known clear genotype-phenotype correlation exists at this time.

Roifman et al [2015] reported that the five families with WNT5A-associated ADRS identified to date harbor domain-specific pathogenic variants in the WNT5A protein and may represent a specific clinical phenotype with classic ADRS features (with characteristic face, short stature, mesomelic limb shortening, and genital hypoplasia).

DVL1-associated RS pathogenic variants appear to be highly specific. Thus far, all cases have been associated with frameshift variants in exon 14 likely leading to a truncated transcript that escapes nonsense-mediated decay [Bunn et al 2015, White et al 2015]. A gain-of-function or dominant-negative mechanism (which may explain the unique skeletal phenotype of normal stature, macrocephaly, and increased bone density) has been proposed [White et al 2015].

Penetrance

Penetrance appears to be complete with no difference between males and females. All cases presented with features noticeable at birth or in early childhood.

Prevalence

ADRS is very rare. The exact prevalence of the disorder is unknown. Fewer than 50 families with ADRS have been described in the literature; five of these families have been found to have pathogenic variants in WNT5A [Person et al 2010, Roifman et al 2015]. Thus far, ten families have been reported to have pathogenic variants in DVL1 [Bunn et al 2015, White et al 2015].

Differential Diagnosis

ROR2-related Robinow syndrome is an autosomal recessive skeletal dysplasia caused by biallelic pathogenic variants in ROR2. Features similar to those of ADRS include the distinctive fetal face features, short stature, mesomelic limb shortening, and genital hypoplasia. ROR2-related Robinow syndrome appears to be more severe than ADRS, with renal anomalies, congenital heart defects, vertebral defects, rib fusions, scoliosis, and cognitive delay occurring more frequently than in ADRS. A distinguishing feature of ROR2-related Robinow syndrome is clefting of the distal phalanges, mainly of the thumbs.

Aarskog syndrome (OMIM 305400). Facial features (high anterior hairline, frontal bossing, widely spaced eyes, and anteverted nares) are similar to those of ADRS. Pulmonary valve stenosis has been reported. Genital hypoplasia in males with Aarskog syndrome is characterized by a shawl scrotum in contrast to the wider spectrum of genital hypoplasia found in ADRS. Other distinguishing features include widow’s peak and ligamentous laxity. The vertebral abnormalities and delayed teeth eruption of ADRS are not observed in Aarskog syndrome. Typical limb abnormalities in Aarskog syndrome include brachydactyly, syndactyly, and fifth finger clinodactyly.

Autosomal dominant Opitz G/BBB syndrome (ADOS) and X-linked Opitz G/BBB syndrome (XLOS) are associated with deletion in 22q11.2 and mutation of MID1, respectively. Similarities with ADRS include facial features (high anterior hairline, frontal bossing, widely spaced eyes, wide nasal bridge, anteverted nares) and genitourinary abnormalities (hypospadias, cryptorchidism, hypoplastic/bifid scrotum). XLOS is also characterized by laryngotracheoesophageal defects (not found in ADRS) and brain abnormalities, developmental delay and cleft lip and/or palate (much more common in ADOS and XLOS [50% of affected individuals] than ADRS). ADOS and XLOS are not usually associated with short stature or mesomelic limb shortening.

Achondroplasia is an autosomal dominant disorder caused by mutation of FGFR3. Facial features characteristic of achondroplasia are similar to those of ADRS (macrocephaly, high anterior hairline and frontal bossing, depressed nasal bridge, pointed nose, and midface retrusion). Unlike ADRS, the head circumference of individuals with achondroplasia is larger with continued macrocephaly throughout life and an increased incidence of hydrocephalus. Distinctive skeletal features in achondroplasia include trident appearance of the fingers, lumbar gibbus and hypotonia in infancy, hyperlordosis, bowing of the legs later in childhood, and more severe shortening of all long bones. Widely spaced eyes are not a feature of achondroplasia.

Omodysplasia type 2 (OMIM 164745) is a rare autosomal dominant disorder characterized by skeletal findings, hypoplastic male genitalia (including micropenis, hypospadias, and cryptorchidism), and dysmorphic facial features. Distinct features include normal stature, rhizomelic upper limb shortening, shortened first metacarpals, and shortened humeri with hypoplastic condyles. The legs are normal. Facial features include frontal bossing, depressed nasal bridge with bifid nasal tip, and a long philtrum. Individuals with omodysplasia type 2 do not have widely spaced eyes.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant Robinow syndrome (ADRS), the following evaluations are recommended:

  • Radiographs of the limbs, chest, vertebrae and skull to establish the extent of skeletal involvement
  • Assessment for possible abnormal penile insertion/penoscrotal position for consideration of reconstructive surgery
  • Assessment for possible cryptorchidism
  • Clinical assessment for presence of cleft lip/palate and the need for surgical repair
  • Abdominal ultrasound examination for investigation of renal anomalies
  • Echocardiogram to evaluate for a cardiac defect
  • Endocrine consultation to assess the possibility of hormone therapy in the treatment of males with micropenis
  • Urology consultation in males with cryptorchidism and abnormal penile insertion/penoscrotal transposition for consideration of reconstructive surgery
  • Orthodontics consultation as needed for misaligned teeth or persistent primary dentition
  • Hearing assessment
  • Formal cognitive assessment if developmental delay is present
  • Medical genetics consultation

Treatment of Manifestations

Corrective surgeries may be required for repair of:

  • Cryptorchidism
  • Abnormal penile insertion/penoscrotal position
  • Cleft lip/palate

Hormone therapy may be helpful for males with micropenis. Injection of human chorionic gonadotropin and testosterone improved penile length and testicular volume in three boys with severe micropenis [Soliman et al 1998]. Hormone therapy should be initiated and monitored by a pediatric endocrinologist.

Orthodontic treatment is typically required.

Surveillance

The following are appropriate:

  • Head circumference measurements every three months in infancy and every six months to one year thereafter
  • Developmental assessment every three months in infancy and every six months to one year thereafter, or more frequently as needed if delays identified
  • Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment
  • Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified

Evaluation of Relatives at Risk

It is appropriate to evaluate the sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and surveillance. If the WNT5A or DVL1 pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy in affected women appears to be generally uncomplicated. For an affected fetus, cæsarean section may be required for abnormal presentation and/or cephalopelvic disproportion. Breech presentation requiring cæsarean section has been reported in one case of ADRS [Roifman et al 2015].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Autosomal dominant Robinow syndrome (ADRS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with ADRS have an affected parent.
  • The family history may appear to be negative because of failure to recognize the disorder in family members.
  • A proband with ADRS may have the disorder as a result of de novo mutation.
    • When neither parent has the pathogenic variant identified in the proband and/or clinical evidence of the disorder, the mutation likely occurred de novo.
    • Recommendations for the evaluation of parents of a proband with apparent de novo mutation of WNT5A or DVL1 include complete physical examination for associated clinical features and testing for the pathogenic variant identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
  • Alternatively, if the WNT5A or DVL1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, a proband with ADRS may have the disorder as a result of germline mosaicism in one of the parents. Although no instances of germline mosaicism have been reported, it remains a possibility.

Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%. However, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the WNT5A or DVL1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. 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.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, the mutation likely occurred de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the WNT5A or DVL1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for the gene of interest or custom prenatal testing. However, the severity of clinical manifestations cannot be predicted from the results of molecular genetic testing.

Fetal ultrasound evaluation. Short long bones (measuring -2SD) as well as mesomelic shortening and macrocephaly can be detected by fetal ultrasound evaluation at approximately 20 weeks’ gestation [Castro et al 2014, Roifman et al 2015].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the WNT5A or DVL1 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
    Email: contactus@magicfoundation.org
  • Restricted Growth Association (RGA)
    PO Box 15755
    Solihull B93 3FY
    United Kingdom
    Phone: +44 0300 111 1970
    Fax: +44 0300 111 2454
    Email: office@restrictedgrowth.co.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Autosomal Dominant Robinow Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Autosomal Dominant Robinow Syndrome (View All in OMIM)

164975WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 5A; WNT5A
180700ROBINOW SYNDROME, AUTOSOMAL DOMINANT 1; DRS1
601365DISHEVELLED 1; DVL1
616331ROBINOW SYNDROME, AUTOSOMAL DOMINANT 2; DRS2

Molecular Genetic Pathogenesis

WNT5A

WNT5A is a member of the Wnt family of proteins, which regulate critical morphogenic events, including embryonic patterning, and cell differentiation, growth, and migration. WNT5A is critical for developmental processes requiring cell migration [reviewed in Nishita et al 2010].

WNT5A is a known co-receptor of the orphan tyrosine kinase receptor, ROR2 [Oishi et al 2003, Mikels & Nusse 2006, Schambony & Wedlich 2007], which would explain the overlap in clinical phenotype of WNT5A- and ROR2-associated Robinow syndrome. WNT5A signaling gradient in the limb bud has been shown to control limb elongation [Gao et al 2011]. The murine ortholog of WNT5A was also shown to control several steps in gonadal development of mice models [Tevosian 2012]

Gene structure. WNT5A comprises five exons. Alternate splicing results in multiple transcript variants. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Table 2 lists the pathogenic variants identified in five families with autosomal dominant Robinow syndrome [Person et al 2010, Roifman et al 2015].

Table 2.

WNT5A Selected Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.257A>G 2p.Tyr86CysNM_003392​.4
NP_003383​.2
c.206G>Ap.Cys69Tyr
c.248G>Cp.Cys83Ser
c.544_545delinsTC
(544–545CT>TC)
p.Cys182Ser
(Cys182Arg)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Two families had this variant.

Normal gene product. WNT5A is critical for developmental processes requiring cell migration [reviewed in Nishita et al 2010]. The three-dimensional structure of the WNT5A protein is still unknown.

Abnormal gene product. Based on a WNT5A homology model using the experimentally solved structure of WNT8, Roifman et al [2015] showed that pathogenic variants found in all individuals with WNT5A-associated ADRS seem to be located on one side of the protein and may affect interactions with other proteins in the Wnt pathway by disrupting normal complex formation and/or intra-protein bonds.

DVL1

DVL1 encodes segment polarity protein dishevelled homolog DVL-1 (DVL1), an essential downstream mediator of Wnt signaling, specifically the Wnt5a-ROR2 non-canonical pathway [White et al 2015].

Gene structure. DVL1 comprises 15 exons.

Pathogenic allelic variants. See Table 3.

Table 3.

DVL1 Selected Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1570_1571delinsCp.Phe524ProfsTer125NM_004421​.2
NP_004412​.2
c.1505_1517delp.His502ProfsTer143
c.1519delpTrp507GlyfsTer142
c.1508delp.Pro503ArgfsTer146
c.1615delp.Ser539AlafsTer110
c.1529delp.Gly510ValfsTer139
c.1562delp.Pro521HisfsTer128
c.1576_1583delinsGp.Pro526AlafsTer121

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. DVL1 is a member of the disheveled family of intracellular scaffolding proteins, located downstream of the Wnt receptor. DVL1 plays a role in transducing both canonical and non-canonical Wnt signaling (OMIM 601365).

Abnormal gene product. All reported pathogenic variants in DVL1-associated RS have been frameshift variants within exon 14, likely leading to a truncated transcript that escapes nonsense mediated decay [Bunn et al 2015, White et al 2015]. The resultant abnormal gene product is thought to impair Wnt signaling via a gain-of-function or dominant-negative mechanism [White et al 2015].

References

Literature Cited

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  • Beiraghi S, Leon-Salazar V, Larson BE, John MT, Cunningham ML, Petryk A, Lohr JL. Craniofacial and intraoral phenotype of Robinow syndrome forms. Clin Genet. 2011;80:15–24. [PubMed: 21496006]
  • Bunn KJ, Daniel P, Rosken HS, O’Neill AC, Cameron-Christie SR, Morgan T, Brunner HG, Lai A, Kunst HPM, Markie DM, Robertson SP. Mutations in DVL1 cause an osteosclerotic form of Robinow Syndrome. Am J Hum Genet. 2015;96:623–30. [PMC free article: PMC4385193] [PubMed: 25817014]
  • Castro S, Peraza E, Barraza A, Zapata M. Prenatal diagnosis of Robinow syndrome: a case report. J Clin Ultrasound. 2014;42:297–300. [PubMed: 24151023]
  • Gao B, Song H, Bishop K, Elliot G, Garrett L, English MA, Andre P, Robinson J, Sood R, Minami Y, Economides AN, Yang Y. Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev Cell. 2011;20:163–76. [PMC free article: PMC3062198] [PubMed: 21316585]
  • Mazzeu JF, Pardono E, Vianna-Morgante AM, Richieri-Costa A, Ae Kim C, Brunoni D, Martelli L, de Andrade CE, Colin G, Otto PA. Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome. Am J Med Genet A. 2007;143:320–5. [PubMed: 17256787]
  • Mikels AJ, Nusse R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol. 2006;4:e115. [PMC free article: PMC1420652] [PubMed: 16602827]
  • Nishita M, Enomoto M, Yamagata K, Minami Y. Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells. Trends Cell Biol. 2010;20:346–54. [PubMed: 20359892]
  • Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells. 2003;8:645–54. [PubMed: 12839624]
  • Person AD, Beiraghi S, Sieben CM, Hermanson S, Neumann AN, Robu ME, Schleiffarth JR, Billington CJ Jr, van Bokhoven H, Hoogeboom JM, Mazzeu JF, Petryk A, Schimmenti LA, Brunner HG, Ekker SC, Lohr JL. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn. 2010;239:327–37. [PMC free article: PMC4059519] [PubMed: 19918918]
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Chapter Notes

Revision History

  • 30 July 2015 (aa) Revision: DVL1 and related citations added
  • 8 January 2015 (me) Review posted live
  • 18 June 2014 (mr) Original submission
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