Autosomal Dominant Robinow Syndrome
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 (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 pregnancies at increased risk is possible if the DVL1, DVL3, or WNT5A pathogenic 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 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
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...)
Family History
Family history is consistent with autosomal dominant inheritance. Note: Absence of a known family history of autosomal dominant Robinow syndrome does not preclude the diagnosis.
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 variant in DVL1, DVL3, or WNT5A through molecular genetic testing (see Table 1).
Note: 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).
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 at the most reasonable cost 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 Footnote 12 in Table 1).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
| Gene 1, 2 | Proportion of Autosomal Dominant Robinow Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Sequence Analysis 4, 5 |
|---|---|---|
| DVL1 | 18 probands 6 (unknown number of probands tested) | >99% 7 |
| DVL3 | 7 probands 8 (unknown number of probands tested) | >99% 7 |
| WNT5A | 8 probands 9 (unknown number of probands tested) | >99% |
| Unknown 10, 11 | NA |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
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.
- 5.
Since ADRS occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant.
- 6.
Bunn et al [2015], White et al [2015], White et al [2016], White et al [2018]
- 7.
All pathogenic variants identified to date are frameshift variants.
- 8.
White et al [2016], Danyel et al [2018], White et al [2018]
- 9.
Person et al [2010], Roifman et al [2015], Xiong et al [2016], White et al [2018]
- 10.
Pathogenic variants in RAC3 and GPC4 have also been reported in single individuals who had been given a clinical diagnosis of Robinow syndrome [White et al 2018].
- 11.
Omodysplasia type 2, caused by pathogenic variants in FZD2, shares many clinical features with ADRS; it is unclear if these two conditions are part of a phenotypic spectrum (see Differential Diagnosis).
Clinical Characteristics
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 due to 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.
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.
NXN-related Robinow syndrome (OMIM 618529), also inherited in an autosomal recessive manner, was described in three individuals with biallelic NXN pathogenic variants from two unrelated families. All three had classic clinical findings of Robinow syndrome including typical craniofacial features, mesomelic shortening, and brachydactyly [White et al 2018]. One individual, born to consanguineous parents, was homozygous for a nonsense NXN variant; the two affected sibs in the other family had compound heterozygous NXN pathogenic variants.
Note: The NXN protein is a relevant partner in the WNT5A signaling pathway that is intimately involved in Robinow syndrome causation. ROR2 binds to WNT5A and interacts with FZD2. The effect of this interaction is routed to disheveled proteins (DVL1, DVL3) that are further stabilized by NXN. This complex activates JNK signaling responsible for cytoskeletal reorganization and cell polarity.
Aarskog syndrome (OMIM 305400) is an X-linked disorder caused by mutation of FGD1. 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). Individuals with achondroplasia have a larger head circumference than those with ADRS, 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. A heterozygous pathogenic variant in FZD2 was found in four families with omodysplasia type 2 [White et al 2018]. Given the phenotypic overlap between omodysplasia type 2 and Robinow syndrome, some have postulated that this may actually fall into the clinical spectrum of Robinow syndrome with predominant short humeri and radial head dislocation.
Management
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
| System/Concern | Evaluation | Comment |
|---|---|---|
| Craniofacial | Clinical assessment for presence of orofacial clefting | Consider referral to craniofacial team |
| Orthodontics consultation | For misaligned teeth or persistent primary dentition | |
| Ears | Hearing assessment | |
| Cardiovascular | Echocardiogram | To evaluate for congenital heart defect |
| Genitourinary | Renal ultrasound | To assess for renal anomalies & hydronephrosis |
| Females: pelvic ultrasound | To evaluate for müllerian anomalies | |
| Males: assessment for abnormal penile insertion / penoscrotal position & cryptorchidism | Urology consultation, as appropriate | |
| If micropenis present, consider consultation w/endocrinologist for possible hormone therapy | ||
| Musculoskeletal | Radiographs of limbs, chest, vertebrae, & skull | To establish the extent of skeletal involvement |
| Neurologic | Assessment for developmental delay | Referral for formal neuropsychiatric/cognitive testing if present |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 3.
Treatment of Manifestations in Individuals with Autosomal Dominant Robinow Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Cleft lip/palate | Surgical correction | Management by multidisciplinary craniofacial team recommended |
| Misaligned teeth or persistent primary dentition | Standard orthodontic treatment | |
| Hearing loss | Standard treatment | See Hereditary Hearing Loss and Deafness Overview. |
| Congenital heart defects | Standard treatment per cardiologist &/or cardiothoracic surgery | |
| Cryptorchidism | Orchidopexy | |
| Abnormal penile insertion / penoscrotal position | Referral to urologist | Discussion of potential surgical correction |
| Micropenis | Consideration of hormonal therapy 1 | Referral to endocrinologist |
- 1.
Injection of human chorionic gonadotropin and testosterone improved penile length and testicular volume in three boys with severe micropenis [Soliman et al 1998].
Surveillance
Table 4.
Recommended Surveillance for Individuals with Autosomal Dominant Robinow Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Craniofacial | Dental evaluation | Every 6 months to 1 year or per dental professional |
| Ears | Hearing assessment | In childhood |
| Cardiovascular | Standard monitoring in those w/cardiac involvement | Per cardiologist |
| Genitourinary | Standard monitoring in those w/renal involvement | Per urologist |
| Neurologic | Assessment of developmental progress | At each visit in childhood/adolescence |
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.