Autosomal Dominant Robinow Syndrome

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 (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. 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. When present, cardiac defects are a major cause of morbidity and mortality.

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, in addition to the typical features described above.

Diagnosis/testing.

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.

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. Periodic hearing assessments in childhood. 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, cesarean 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 a pregnancy at increased risk is possible if the DVL1, DVL3, or WNT5A pathogenic variant has been identified in an affected family member.

Suggestive Findings

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

Clinical Findings

Skeletal

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

Genital

• In males: micropenis / webbed penis, hypoplastic scrotum, and 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. Affected mother in infancy

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...)

Establishing the Diagnosis

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 (or likely pathogenic) variant in DVL1, DVL3, or WNT5A through molecular genetic testing (see Table 1).

Note: (1) If a heterozygous pathogenic variant is not identified in DVL1, DVL3, or WNT5A, it is appropriate to exclude the presence of biallelic ROR2 or NXN pathogenic variants (which cause autosomal recessive Robinow syndrome) and a heterozygous pathogenic variant in FZD2 (which causes autosomal dominant omodysplasia type 2). (2) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing):

• Single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
  Perform sequence analysis of DVL1 and the DVL3 first. Sequence analysis of WNT5A should be considered either concurrently or as a reflex if no pathogenic variants are identified in DLV1 or DLV3.
  Note: All reported disease-associated variants in DVL1 and DVL3 are frameshift variants located in the ultimate and penultimate exons (14 and 15).
• A multigene panel that includes DVL1, DVL3, WNT5A, FZD2, ROR2, NXN, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. Care should be taken that coverage of exons 14 and 15 in DVL1 and DVL3 are well covered in the assay (see Table 1, footnote 12).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Robinow Syndrome

Clinical Description

Autosomal dominant Robinow syndrome (ADRS) is a skeletal dysplasia in which affected individuals typically have short stature, mesomelic limb shortening (predominantly of the upper limbs), and brachydactyly. A variety of other (variably present) anomalies may also suggest the diagnosis.

Facial. Craniofacial features of ADRS are summarized in Suggestive Findings. These features are most recognizable at birth or in early childhood. The distinctive facial features become less apparent with age.

• In addition to macrocephaly, 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 age 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 (see Phenotype Correlations by Gene).

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).
• 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 cesarean section because of cephalopelvic disproportion.

Cardiac abnormalities occur in a minority (<25%) 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.

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

• Renal anomalies (usually hydronephrosis)
• Radial head dislocation
• Vertebral abnormalities and scoliosis
• Persistent primary teeth requiring extraction
• Nail dysplasia
• Cleft lip/palate

Phenotype Correlations by Gene

DVL1. A subset of individuals with DVL1-associated ADRS exhibit a final stature in the low-normal range, 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].

DVL3. Three out of four individuals with DVL3-associated ADRS had cardiac abnormalities; osteosclerosis has not been reported.

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

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation is known.

Prevalence

ADRS is very rare. The exact prevalence of the disorder is unknown. Fewer than 80 families with ADRS have been described in the literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant Robinow syndrome (ADRS), the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Robinow Syndrome

Treatment of Manifestations

Table 3.

Treatment of Manifestations in Individuals with Autosomal Dominant Robinow Syndrome

Surveillance

Table 4.

Recommended Surveillance for Individuals with Autosomal Dominant Robinow Syndrome

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 DVL1, DVL3, or WNT5A 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, cesarean section may be required for abnormal presentation and/or cephalopelvic disproportion. Breech presentation requiring cesarean section has been reported in one case of ADRS [Roifman et al 2015].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Robinow syndrome caused by pathogenic variants in DVL1, DVL3, or WNT5A is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with autosomal dominant Robinow syndrome (ADRS) have an affected parent.
• A proband with ADRS may have the disorder as a result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo DVL1, DVL3, or WNT5A pathogenic variant include complete physical examination for associated clinical features and testing for the pathogenic variant identified in the proband.
• If the DVL1, DVL3, or WNT5A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or neither parent has clinical evidence of the disorder, the pathogenic variant likely occurred de novo. Alternatively, a proband with ADRS may have the disorder as a result of germline mosaicism in one of the parents.
• Evaluation of the 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.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [White et al 2018].

Sibs of a proband. The risk to the sibs of a 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 DVL1, DVL3, or WNT5A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

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, the parent's 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 the pathogenic variant or clinical evidence of the disorder, the pathogenic variant likely occurred de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the DVL1, DVL3, or WNT5A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. However, the severity of clinical manifestations cannot be predicted from the results of molecular genetic testing.

Fetal ultrasound evaluation. Short long bones (measuring -2SD), macrocephaly, and typical facial features (widely spaced eyes, broad nasal bridge, and flattened frontal bone) can be detected by fetal ultrasound evaluation at approximately 20 weeks' gestation [Castro et al 2014, Roifman et al 2015].

Molecular Pathogenesis

The Wnt family of proteins regulates critical morphogenic events, including embryonic patterning, and cell differentiation, growth, and migration. Wnt signaling pathways fall into two categories: canonic, which involve β-catenin, and non-canonic, which are independent of β-catenin.

WNT5A, which functions in the both the canonic and non-canonic pathways, is a Wnt family member critical for developmental processes requiring cell migration (reviewed in Nishita et al [2010]). WNT5A is a known coreceptor 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.

DVL1 and DVL3 encode segment polarity protein disheveled homolog DVL-1 (DVL1) and DVL-3, respectively, which are essential downstream mediators of Wnt signaling – specifically, the Wnt5a-ROR2 non-canonic pathway [White et al 2015, White et al 2016].

DVL1

Gene structure. DVL1 comprises 15 exons.

Pathogenic variants. Thus far, all variants associated with ADRS are frameshift variants in exons 14 and 15 (see examples in Table 5) [Bunn et al 2015, White et al 2015, White et al 2016]. The proposed gain-of-function mechanism (see Abnormal gene product) suggests that these variants, located in the ultimate and penultimate exons, produce truncated transcripts that escape nonsense-mediated decay.

Table 5.

DVL1 Selected Pathogenic Variants

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 canonic and non-canonic Wnt signaling (OMIM 601365).

Abnormal gene product. The abnormal gene product resulting from a frameshift in exons 14 and 15 is thought to impair Wnt signaling via a gain-of-function or dominant-negative mechanism, which may explain the unique skeletal phenotype of normal stature, macrocephaly, and increased bone density [White et al 2015].

DVL3

Gene structure. DVL3 comprises 15 exons.

Pathogenic variants. Similar to DVL1, the majority of variants associated with ADRS are frameshift variants in exons 14 and 15 (see examples in Table 6) [White et al 2015, White et al 2016]. Splice site variants at the intron 14 acceptor site have also been reported [White et al 2016]. The proposed gain-of-function mechanism (see Abnormal gene product) suggests that these variants, located in the ultimate and penultimate exons, produce truncated transcripts that escape nonsense-mediated decay.

Table 6.

DVL3 Selected Pathogenic Variants

Normal gene product. DVL3 is a member of the disheveled family of intracellular scaffolding proteins, located downstream of the Wnt receptor. DVL3 plays a role in transducing both canonic and non-canonic Wnt signaling.

Abnormal gene product. The abnormal gene product resulting from a frameshift in exons 14 and 15 is thought to impair Wnt signaling via a gain-of-function or dominant-negative mechanism, which may explain the unique skeletal phenotype of normal stature, macrocephaly, and increased bone density [White et al 2015].

WNT5A

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 variants. Pathogenic missense variants (Table 7) as well as an in-frame duplication and an in-frame deletion/duplication have been identified in five families with autosomal dominant Robinow syndrome [Person et al 2010, Roifman et al 2015, White et al 2018].

Table 7.

WNT5A Selected Pathogenic Variants

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.

The 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].

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 appear 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. Although the mechanism of WNT5A-related disease is not known, the reports of disease-associated missense or in-frame variants clustering in specific locations of the protein could indicate altered protein function as a disease mechanism.

Revision History

• 3 October 2019 (aa) Revision: NXN added to Differential Diagnosis
• 9 August 2018 (ma) Comprehensive update posted live
• 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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