Clinical characteristics.

ROR2-related Robinow syndrome is characterized by distinctive craniofacial features, skeletal abnormalities, and other anomalies. Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism, prominent eyes, midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia. Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly. Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy. The disorder is recognizable at birth or in early childhood.

Diagnosis/testing.

The diagnosis of ROR2-related Robinow syndrome is established in a proband with typical suggestive findings and biallelic ROR2 pathogenic variants identified on molecular genetic testing.

Management.

Treatment of manifestations: Corrective surgery for limb and spine defects and for facial abnormalities; orthodontic treatment as needed; surgery for males with scrotal transposition as needed; hormone therapy as needed for the treatment of micropenis.

Genetic counseling.

ROR2-related Robinow syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected with Robinow syndrome, a 50% chance of being a heterozygote (carrier) and usually asymptomatic, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members, prenatal diagnosis for pregnancies at increased risk, and preimplantation genetic testing are possible when the ROR2 pathogenic variants have been identified in the family.

Suggestive Findings

ROR2-related Robinow syndrome should be suspected in individuals with the following clinical findings and family history.

Establishing the Diagnosis

The diagnosis of ROR2-related Robinow syndrome is established in a proband with typical suggestive findings in whom biallelic ROR2 pathogenic variants have been identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ROR2-related Robinow syndrome is well described, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ROR2-related Robinow syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

ROR2-related Robinow syndrome is characterized by distinctive craniofacial features, skeletal abnormalities, and other anomalies.

Craniofacial. Facies are characteristic at birth and in early childhood (see Suggestive Findings). The face in early childhood resembles a fetal face at eight weeks' gestation; this becomes less noticeable with age. Accelerated growth of the nose in adolescence gives the face a more normal appearance, but the broad forehead, broad nasal root, and ocular hypertelorism persist into adulthood.

Midline cleft lip and palate has been reported but is not a common finding. A rather unusual form of clefting involving the lower lip has been described in some individuals.

Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome.

Hyperplastic gingival tissues may also interfere with dental eruption and orthodontic treatments [Grothe et al 2008, Beiraghi et al 2011].

Skeletal. Short stature is almost always present in childhood and persists into adulthood; however, the final degree of short stature may be mild [Tufan et al 2005].

The forearms are more noticeably affected by mesomelic or acromesomelic shortening than the lower limbs, often with radioulnar dislocation.

The phalanges and carpal bones may be fused. Partial cutaneous syndactyly or ectrodactyly (i.e., split hand) may be seen. Hand function is not severely affected.

Kyphoscoliosis is often severe. The chest may be deformed and ribs are often fused, as in spondylocostal dysostosis; some ribs may even be absent. Primary lung function is normal, but changes in the chest wall and thoracic vertebrae may reduce cough effort and predispose to respiratory infections [Sleesman & Tobias 2003].

Urogenital. At birth, the genitalia are abnormal, sometimes leading (primarily in males) to issues related to sex assignment. In males, the penis is small; scrotum and testes are normal. Cryptorchidism has been reported. In females, clitoral size is reduced; labia majora may be hypoplastic.

Wilcox et al [1997] determined that in Robinow syndrome the penis is buried inferiorly and posteriorly within the scrotum because the penile crura insert inferiorly and posteriorly onto the medial aspect of the ischial tuberosity (rather than onto the anteromedial aspect of the pubic bone). Thus, a normal-sized penis appears shorter and inferiorly placed in the scrotum.

Endocrine investigations are usually normal; however, Soliman et al [1998] reported low basal serum testosterone concentration and low testosterone response to human chorionic gonadotropin stimulation in boys. Puberty is usually normal.

Renal abnormalities may be associated with the genital abnormalities. Hydronephrosis is common and cystic dysplasia of the kidney has been reported.

Other

• Congenital heart defects are seen in 15%. In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [Al-Ata et al 1998]. Congenital heart defects are the major cause of early death.
• Nail hypoplasia or dystrophy may be present.
• Intellect is usually within the normal range; however, developmental delay has been reported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Nomenclature

Other names by which Robinow syndrome has been known in the past:

• Costovertebral segmentation defect with mesomelia (COVESDEM): this name is no longer used because it causes confusion with similar vertebral defect syndromes, and in ROR2-related Robinow syndrome, acromesomelia as well as mesomelia is present.
• Robinow-Silverman syndrome

Prevalence

ROR2-related Robinow syndrome is rare. More than 100 cases have been reported in the literature. It commonly occurs in consanguineous families; for example, those of Turkish and Omani origin.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ROR2-related Robinow syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Clinical assessment for presence of cleft lip/palate and the need for surgical repair
• Orthodontics consultation as needed for misaligned, crowded teeth
• Clinical and radiographic evaluation of the spine and rib cage to assess the severity of kyphoscoliosis and vertebral and rib anomalies, as these can lead to postural and respiratory complications [Wilcox et al 1997]
• Radiographic documentation of radioulnar synostosis, forearm shortening, and brachydactyly
• Urology consultation in males with cryptorchidism and abnormal penile insertion / penoscrotal transposition for consideration of reconstructive surgery
• Endocrine consultation to assess the possibility of hormone therapy for males with micropenis
• Renal ultrasound examination
• Echocardiogram to evaluate for structural heart defects
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Corrective surgeries may be required for the following:

• Syndactyly
• Severe scoliosis secondary to hemivertebrae and rib abnormalities
• Cleft lip/palate
• Abnormal penile insertion / penoscrotal transposition. Although it was not possible to detach the abnormal insertion of the penile crura, which can cause a normal-sized penis to be buried in the scrotum and thus appear small, Wilcox et al [1997] improved the cosmetic appearance by transposing the scrotum downward.

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

Orthodontic treatment is usually required.

Perioperative management of individuals with Robinow syndrome should include the following [Macdonald & Dearlove 1995, Lirk et al 2003, Sleesman & Tobias 2003]:

• Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications
• Preoperative cardiac evaluation for the presence of congenital heart defects
• Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia

Surveillance

The following are appropriate:

• Surveillance for evidence of scoliosis until growth is completed
• 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

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

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

ROR2-related Robinow syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one ROR2 pathogenic variant).
• Heterozygotes may display findings consistent with brachydactyly type B1 [Oldridge et al 2000, Schwabe et al 2000].
• Molecular genetic testing of parents could be considered for confirmation studies and for future prenatal testing purposes.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygote and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes may display findings consistent with brachydactyly type B1.

Offspring of a proband

• The offspring of an individual with Robinow syndrome are obligate heterozygotes for an ROR2 pathogenic variant.
• The risk that the offspring of a proband will be affected is small unless the reproductive partner is related to the proband or has a family history of ROR2-related Robinow syndrome (see Prevalence).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ROR2 pathogenic variant.

Heterozygote Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and may display findings consistent with brachydactyly type B1.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ROR2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Ultrasonagraphy. High-resolution ultrasound examination may detect skeletal and cardiac abnormalities in high-risk pregnancies [Percin et al 2001]. Real-time ultrasound may also detect the following in an affected fetus: increased nuchal translucency, reduced humerus and femur length, shortening of the forearms, frontal bossing, mild hypertelorism, reduced thoracic perimeter, and hemivertebrae at the thoracic level [Percin et al 2001, Guven et al 2006].

Molecular Pathogenesis

ROR2 encodes a member of the ROR-family receptor tyrosine kinases, which functions in diverse intracellular signaling cascades and cell and tissue functions including multiple processes that regulate embryonic development (reviewed by Stricker et al [2017]).

Gene structure. ROR2 comprises nine exons encoding a 4,099-bp transcript (NM_004560.3). See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. ROR2-related Robinow syndrome is caused by biallelic pathogenic missense, nonsense, or frameshift variants that are distributed throughout the gene, affecting the regions encoding both the extracellular and the intracellular domains of the ROR2 protein [Afzal et al 2000, van Bokhoven et al 2000, Afzal & Jeffery 2003]; reviewed by Stricker et al [2017].

Homozygous deletions involving exons 6 and 7 have also been reported in Robinow syndrome [Brunetti-Pierri et al 2008].

Normal gene product. The 943-amino-acid ROR2 protein is a tyrosine-protein kinase transmembrane receptor (NP_004551.2) [Masiakowski & Carroll 1992]. It has an extracellular portion with domains responsible for protein-protein interactions and an intracellular portion responsible for catalytic kinase activity that regulates relevant signaling pathways. The known interacting proteins and binding regions in the ROR2 receptor were reviewed by Stricker et al [2017].

ROR2 is essential for normal bone growth. Murine Ror2 is expressed early in embryo development in the developing face, proliferative chondrocytes, genital tubercle, heart, lungs, kidney, and thymus [Matsuda et al 2001].

Abnormal gene product. Biallelic pathogenic variants that cause ROR2-related Robinow syndrome result in loss of function of ROR2. Changes in cysteine content are predicted to affect protein folding. Pathogenic missense variants in the catalytic domain are predicted to abolish enzyme function. Nonsense-mediated mRNA decay and abnormal protein trafficking or degradation are suspected molecular consequences of some pathogenic variants [Afzal & Jeffery 2003]. Pathogenic variants that truncate the protein in the tyrosine kinase domain are predicted to affect phosphorylation and abolish kinase activity [Afzal et al 2000].

Studies by Schwarzer et al [2009] of affected individuals and murine models provide strong evidence that the phenotypic differences between ROR2-related Robinow syndrome and BDB1 are determined by the relative degree of ROR2 retention/degradation and the amount of mutated protein reaching the plasma membrane (see Genetically Related Disorders, Brachydactyly type B1.

Author History

Ali R Afzal, MD, MSc, PhD; St George's Hospital Medical School (2004-2011)
Carlos A Bacino, MD (2011-present)
Rohan Taylor, SRCS, MRCPath; St George's Healthcare NHS Trust (2004-2011)

Revision History

• 12 September 2019 (aa) Revision: NXN-related Robinow syndrome added to Differential Diagnosis
• 26 July 2018 (bp) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 28 July 2005 (me) Review posted live
• 8 November 2004 (aa) Original submission

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