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ROR2-Related Robinow Syndrome

Synonym: Fetal Face Syndrome
, MD
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas

Initial Posting: ; Last Update: August 25, 2011.


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 with growth retardation, 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.


ROR2-related Robinow syndrome is based on the presence of characteristic clinical findings. Mutation of ROR2 causes autosomal recessive ROR2-related Robinow syndrome.


Treatment of manifestations: Corrective surgery for limb and spine defects and for facial abnormalities; orthodontic treatment as needed; surgery for scrotal transposition as needed; growth hormone therapy if growth hormone deficiency is diagnosed; human chorionic gonadotropin and testosterone 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 and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.


Clinical Diagnosis

The diagnosis of ROR2-related Robinow syndrome is based on the presence of characteristic facies, short stature, limb defects, and genital abnormalities.

Clinical features that may be present include the following:

  • Characteristic facial appearance in early childhood [Tufan et al 2005, Brunetti-Pierri et al 2008] (full text):
    • Macrocephaly
    • Broad prominent forehead
    • Marked ocular hypertelorism
    • Prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid that gives the eyes a more prominent appearance
    • Midface hypoplasia
    • Short upturned nose with depressed nasal bridge and flared nostrils
    • Large and triangular mouth, usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum
    • Cleft lip and/or cleft palate
    • Gum hypertrophy
    • Crowded and misaligned teeth
    • Ankyloglossia, with bifid tongue in severe cases
    • Micrognathia
    • Simple, low-set ears, which can be posteriorly rotated
  • Skeletal abnormalities
    • Short stature with growth retardation. Birth length is reduced; height was consistently 2SD or more below the mean in one series [Soliman et al 1998].
    • Mesomelic or acromesomelic limb shortening, mostly in the forearms
    • Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; maldevelopment of the hands by clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
    • Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [Patton & Afzal 2002, Tufan et al 2005]
  • Genital hypoplasia: In males, micropenis with normal scrotum and testes, or cryptorchidism; in females, reduced clitoral size and hypoplasia of the labia majora
  • Renal tract abnormalities, usually hydronephrosis; occasionally cystic dysplasia associated with the genital abnormalities
  • Congenital heart defect in 15%, pulmonary valve stenosis and a wide range of other cardiac malformations [Al-Ata et al 1998]
  • Nail hypoplasia or dystrophy
  • Developmental delay in 10%-15%

Molecular Genetic Testing

Gene. ROR2 is the gene in which mutation causes autosomal recessive ROR2-related Robinow syndrome.

Clinical testing

  • Sequence analysis. ROR2-related Robinow syndrome is caused by pathogenic missense, nonsense, or frameshift variants distributed throughout the gene, affecting the regions encoding both the extracellular and the intracellular domains of the protein. Because ROR2-related Robinow syndrome is most frequently reported in consanguineous populations such as the Omani and Turks, most affected individuals reported to date are homozygous for the pathogenic variant; however, compound heterozygotes have been reported [Tufan et al 2005].

    Van Bokhoven et al [2000] reported pathogenic variants in seven of 11 families (by analysis of exons 2-9 only) and Afzal et al [2000] reported pathogenic variants in ten of ten families investigated.
  • Deletion/duplication analysis. The frequency of exonic or whole-gene deletions and duplications in this disorder is not known; exonic deletions have been reported in the literature [Tufan et al 2005, Brunetti-Pierri et al 2008].

Table 1.

Summary of Molecular Genetic Testing Used in ROR2-Related Robinow Syndrome

Gene 1Test MethodVariants Detected 2Variant Detection Frequency 3
ROR2Sequence analysis 4Sequence variants7/11 families 5
10/10 families 6
Deletion/duplication analysis 7Exon or whole-gene deletionsUnknown 8

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a pathogenic variant that is present in the indicated gene


Examples of variants detected by sequence analysis 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.


Testing that identifies deletions/duplications not readily 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.


Frequency is unknown, but exonic deletions have been reported [Brunetti-Pierri et al 2008]

Note: (1) It is important to determine if the mode of inheritance is autosomal recessive based on the clinical phenotype and family history. (2) Reduced variant detection rate may result from the difficulty in distinguishing between autosomal recessive and autosomal dominant inheritance in a family, undetected promoter variants, or undetected partial or whole-gene deletions and/or locus heterogeneity.

Testing Strategy

Confirmation of the diagnosis in a proband includes sequence analysis of ROR2. If no pathogenic variant or only one pathogenic variant is identified, deletion/duplication analysis should be carried out.

If autosomal dominant Robinow syndrome is suspected, WNT5A mutation studies (if available) could be considered. The autosomal dominant form of Robinow is typically less severe than the autosomal recessive form (see Differential Diagnosis).

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and display findings consistent with brachydactyly type B1.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Facial features. Facies are characteristic at birth and in early childhood (see Clinical Diagnosis). 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.

Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding and hypodontia are also common in Robinow syndrome. Dental abnormalities tend to be more severe in the autosomal dominant forms of Robinow compared to recessive forms.

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

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

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.

Cardiac abnormalities. 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.

Intelligence is usually normal; developmental delay occurs in 10%-15% of individuals with Robinow syndrome.

Growth hormone (GH) deficiency has been reported in Robinow syndrome [Castells et al 1999, Kawai et al 1997].

Genotype-Phenotype Correlations

Mutation of ROR2 causes dominant brachydactyly type B (BDB1) or recessive Robinow syndrome (RRS), each characterized by a distinct combination of phenotypic features. Studies have shown a correlation between the severity of BDB1, the location of the pathogenic variant, and the amount of membrane-associated ROR2. Membrane protein fraction quantification revealed that a gradient of distribution and stability correlated with the clinical phenotypes. This gradual model was confirmed by crossing mouse models for RRS and BDB1, yielding double-heterozygous animals that exhibited an intermediate phenotype. The researchers proposed that the phenotype (i.e., RRS vs BDB1) is determined by the relative degree of protein retention/degradation and the amount of mutant protein reaching the plasma membrane [Schwarzer et al 2009].

ROR2-related Robinow syndrome is caused by homozygous or compound heterozygous pathogenic variants in both intracellular and extracellular domains encoded by exons 3, 5, 7, 8, and 9.

Brachydactyly type B1, in contrast, is caused by heterozygous truncating pathogenic variants in the interdomain regions of the intracellular portion of the ROR2 protein encoded by exons 8 and 9, predicted to cause gain of function [Oldridge et al 2000, Schwabe et al 2000].


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 is not known.

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.

Differential Diagnosis

Autosomal dominant Robinow syndrome, described by Robinow et al [1969], is similar to but less severe than the autosomal recessive (ROR2-related) form, especially regarding the skeletal defects:

  • Vertebral anomalies and radial head dislocation are rare [Bain et al 1986];
  • Vertebral anomalies and scoliosis are seen in far fewer of those with AD Robinow syndrome (<25%) compared to those with AR Robinow syndrome (>75%) [Mazzeu et al 2007].
  • Height is usually nearer the normal range in AD Robinow syndrome.

Autosomal dominant Robinow syndrome is rarer than autosomal recessive Robinow syndrome.

Two different pathogenic missense variants in WNT5A that result in amino acid substitutions of highly conserved cysteines have been reported in autosomal dominant Robinow syndrome [Person et al 2010]. Of note, others have not yet confirmed these results. ROR2 has recently been identified as a putative WNT5A receptor.

Jarcho-Levin syndrome or spondylocostal dysostosis (see Spondylocostal Dysostosis, Autosomal Recessive). These disorders are diagnosed radiologically and show vertebral and rib abnormalities similar to those found in ROR2-related Robinow syndrome; short trunk and respiratory insufficiency are present.

I-cell disease (mucolipidosis type II) is a lysosomal storage disorder showing growth failure, coarse facial features, hypertrophic gums, skeletal abnormalities, developmental delay, and hypotonia.

Brachydactyly with dysmorphic facies. Facial features are mildly abnormal; the prominent nose with bulbous tip is not seen in ROR2-related Robinow syndrome.

Aarskog syndrome. Facial features are similar with wide-spaced eyes, anteverted nostrils, and broad upper lip. Vertebral abnormalities are not observed. The shawl scrotum and lax ligaments of Aarskog syndrome are not found in ROR2-related Robinow syndrome.

Omodysplasia is similar to ROR2-related Robinow syndrome, with short limbs and radial dislocation; however, no genital abnormalities are present [Venditti et al 2002].


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ROR2-related Robinow syndrome, the following evaluations are recommended:

  • Orofacial assessment to determine the need for plastic surgery (presence of cleft lip and/or cleft palate )
  • Dental assessment 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 the forearm shortening and hand anomalies
  • Assessment of micropenis for reconstructive surgery if due to penoscrotal transposition
  • Endocrine investigation to explore possible: (1) gonadotropin and testosterone deficiencies amenable to treatment in males with micropenis; and (2) growth hormone deficiency
  • Renal ultrasound examination
  • Echocardiogram to evaluate for structural heart defects

Treatment of Manifestations

Corrective surgeries may be required for the following:

  • Syndactyly repair
  • Severe scoliosis secondary to hemivertebrae and rib abnormalities
  • Cleft lip and cleft palate repair

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 (see Clinical Description), 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

Growth hormone deficiency in children with Robinow syndrome responds to growth hormone therapy [Castells et al 1999].

Prevention of Secondary Complications

The perioperative management of individuals with Robinow syndrome should include [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 the midface hypoplasia.

Because growth hormone therapy can exacerbate scoliosis, progression of the spinal curve needs to be monitored during the course of therapy.


The following are appropriate:

  • Scoliosis surveillance in childhood and through adolescence, until growth is completed
  • Surveillance of growth in childhood for evidence of growth hormone deficiency

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 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

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 and therefore carry one mutant allele.
  • Heterozygotes (carriers) display findings consistent with brachydactyly type B1 [Oldridge et al 2000, Schwabe et al 2000].
  • Molecular 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 (carrier) and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
  • Once it is determined that an at-risk sib does not have Robinow syndrome, the risk of his/her being a carrier (and having brachydactyly type B1) is 2/3.

Offspring of a proband

  • The offspring of an individual with Robinow syndrome are obligate heterozygotes (carriers) 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.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family.

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 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.

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 ROR2 pathogenic variants have been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk may be available from a clinical laboratory that offers either prenatal testing for the gene or custom testing.

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 in 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].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.


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.

  • Robinow Syndrome Foundation
    PO Box 1072
    Anoka MN 55303
    Phone: 763-434-1152
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
  • 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
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    1 AMS Circle
    Bethesda MD 20892-3675
    Phone: 877-226-4267 (toll-free); 301-565-2966 (TTY)
    Fax: 301-718-6366
  • Restricted Growth Association (RGA)
    PO Box 15755
    Solihull B93 3FY
    United Kingdom
    Phone: +44 0300 111 1970
    Fax: +44 0300 111 2454

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.

ROR2-Related Robinow Syndrome: Genes and Databases

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

Table B.

OMIM Entries for ROR2-Related Robinow Syndrome (View All in OMIM)


Gene structure. ROR2 comprises nine exons encoding a 4092-bp transcript. The reference sequence is NM_004560.3. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic missense, nonsense, and frameshift variants in exons 3, 5, 7, 8, and 9 in the homozygous (or compound heterozygous) state cause ROR2-related Robinow syndrome. Pathogenic missense variants are found in the cysteine-rich, kringle, and tyrosine kinase domains. Terminating variants are found 3' to the Ig-like domain [Afzal et al 2000, Van Bokhoven et al 2000, Afzal & Jeffery 2003]. Affected individuals from Oman appear to have a founder variant [Afzal et al 2000].

Homozygous exonic 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 an orphan receptor tyrosine kinase 2 (reference sequence NP_004551.2) [Masiakowski & Carroll 1992]. It is a transmembrane receptor whose intracellular cytoplasmic domain contains a tyrosine kinase with serine/threonine-rich and proline-rich structures. The extracellular portion contains an immunoglobulin-like domain, a frizzled-like cysteine rich domain, and a kringle domain. This portion is responsible for protein-protein interactions, and the intracellular portion is responsible for catalytic kinase activity that interacts with relevant signaling pathways. Ligands and signaling pathways are not well known. The tyrosine-protein kinase transmembrane receptor ROR2, encoded by ROR2, is essential for normal bone growth.

Mouse 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. Pathogenic variants that cause ROR2-related Robinow syndrome cause loss of function of the protein. 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 have been suspected to be involved [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].


Literature Cited

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  • Wilcox DT, Quinn FMJ, Ng CS, Mireaux-Dicks C, Mouriquand PDE. Redefining the genital abnormality in the Robinow syndrome. J Urol. 1997;157:2312–4. [PubMed: 9146662]

Suggested Reading

  • Afzal AR, Rajab A, Fenske C, Crosby A, Lahiri N, Ternes-Pereira E, Murday VA, Houlston R, Patton MA, Jeffery S. Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22. Hum Genet. 2000;106:351–4. [PubMed: 10798366]
  • Oldridge M, Wilkie AOM. ROR2 and brachydactyly type B and recessive Robinow syndrome. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development - The Molecular Basis of Clinical Disorders of Morphogenesis. Oxford, UK: Oxford University Press; 2004:886-94.

Chapter Notes

Author History

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

Revision History

  • 25 August 2011 (me) Comprehensive update posted live
  • 28 July 2005 (me) Review posted to live Web site
  • 8 November 2004 (aa) Original submission
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