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.

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.

Treatment of Manifestations

Surveillance

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].

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

Literature Cited

• Al-Ata J, Paquet M, Teebi AS. Congenital heart disease in Robinow syndrome. Am J Med Genet. 1998;77:332–3. [PubMed: 9600746]
• 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]
• Danyel M, Kortüm F, Dathe K, Kutsche K, Horn D. Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation. Am J Med Genet A. 2018;176:992–6. [PubMed: 29575616]
• 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]
• Roifman M, Marcelis CL, Paton T, Marshall C, Silver R, Lohr JL, Yntema HG, Venselaar H, Kayserili H, van Bon B, Seaward G, Brunner HG, Chitayat D, et al. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype. Clin Genet. 2015;87:34–41. [PubMed: 24716670]
• Schambony A, Wedlich D. Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Dev Cell. 2007;12:779–92. [PubMed: 17488628]
• Soliman AT, Rajab A, Alsalmi I, Bedair SM. Recessive Robinow syndrome: with emphasis on endocrine functions. Metabolism. 1998;47:1337–43. [PubMed: 9826209]
• Tevosian SG. Gone without the WNT: a requirement for WNT5A in germ cell migration and testis development. Biol Reprod. 2012;86:1–2. [PMC free article: PMC3313660] [PubMed: 21957192]
• Webber SA, Wargowski DS, Chitayat D, Sandor GG. Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome? Am J Med Genet. 1990;37:519–21. [PubMed: 2260599]
• White J, Mazzeu JF, Hoischen A, Jhangiani SN, Gambin T, Calijorne Alcino M, Penney S, Saraiva JM, Hove H, Skovby F, Kayserili H, Estrella E, Vulto-van Silfhout A, Steehouwer M, Muzny DM, Sutton VR, Gibbs RA, Lupski JR, Brunner HG, van Bon BWM, Carvalho CMB, et al. CVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum Genet. 2015;96:612–22. [PMC free article: PMC4385180] [PubMed: 25817016]
• White JJ, Mazzeu JF, Coban-Akdemir Z, Bayram Y, Bahrambeigi V, Hoischen A, van Bon BWM, Gezdirici A, Gulec EY, Ramond F, Touraine R, Thevenon J, Shinawi M, Beaver E, Heeley J, Hoover-Fong J, Durmaz CD, Karabulut HG, Marzioglu-Ozdemir E, Cayir A, Duz MB, Seven M, Price S, Ferreira BM, Vianna-Morgante AM, Ellard S, Parrish A, Stals K, Flores-Daboub J, Jhangiani SN, Gibbs RA, Brunner HG, Sutton VR, Lupski JR, Carvalho CMB, et al. WNT signaling perturbations underlie the genetic heterogeneity of Robinow syndrome. Am J Hum Genet. 2018;102:27–43. [PMC free article: PMC5777383] [PubMed: 29276006]
• White JJ, Mazzeu JF, Hoischen A, Bayram Y, Withers M, Gezdirici A, Kimonis V, Steehouwer M, Jhangiani SN, Muzny DM, Gibbs RA, van Bon BWM, Sutton VR, Lupski JR, Brunner HG, Carvalho CMB, et al. DVL3 alleles resulting in a -1 frameshift of the last exon mediate autosomal-dominant Robinow syndrome. Am J Hum Genet. 2016;98:553–61. [PMC free article: PMC4800044] [PubMed: 26924530]
• Wilcox DT, Quinn FM, Ng CS, Dicks-Mireaux C, Mouriquand PD. Redefining the genital abnormality in the Robinow syndrome. J Urol. 1997;157:2312–4. [PubMed: 9146662]
• Xiong S, Chitayat D, Wei X, Zhu J, Lu W, Sun LM, Chopra M. A novel de-novo WNT5A mutation in a Chinese patient with Robinow syndrome. Clin Dysmorphol. 2016;25:186–9. [PubMed: 27092434]