COVESDEM SYNDROME, FORMERLY ROBINOW SYNDROME, AUTOSOMAL RECESSIVE, WITH APLASIA/HYPOPLASIA OF PHALANGES AND METACARPALS/METATARSALS, INCLUDED
ROBINOW SYNDROME, AUTOSOMAL RECESSIVE, WITH BRACHY-SYN-POLYDACTYLY, INCLUDED
COSTOVERTEBRAL SEGMENTATION DEFECT WITH MESOMELIA, FORMERLY
RRS
Costovertebral segmentation defect - mesomelia
COVESDEM syndrome
A recessive form of Robinow syndrome was suggested by the reports of Wadia (1978, 1979) and Wadlington et al. (1973). Features common in both the dominant (180700) and recessive forms are the characteristic facial features, orodental abnormalities, and ... A recessive form of Robinow syndrome was suggested by the reports of Wadia (1978, 1979) and Wadlington et al. (1973). Features common in both the dominant (180700) and recessive forms are the characteristic facial features, orodental abnormalities, and hypoplastic genitalia. Bain et al. (1986) suggested that the main discriminating feature is the occurrence of multiple rib and vertebral anomalies in the recessive form. Robinow (1987) suggested that the term COVESDEM syndrome be removed from the literature to avoid confusion of terminology. He suggested that the cases so designated represent a recessive form of Robinow syndrome. Glaser et al. (1989) described Robinow syndrome in a child of a consanguineous Turkish couple. In addition to the 'fetal face' and mesomelic dwarfism of Robinow syndrome, the infant showed severe abnormalities of the vertebral column. Glaser et al. (1989) suggested that such changes in the vertebral column are particularly characteristic of the recessive form of Robinow syndrome. In 2 sibships related as first cousins and both with consanguineous parents, Teebi (1990) observed the features of autosomal recessive Robinow syndrome: short stature, mesomelic and acromelic brachymelia, characteristic face with hypertelorism, wide palpebral fissures, midface hypoplasia and large mouth, and hypogenitalism. Nazer et al. (1990) reported 2 children, offspring of first-cousin Saudi parents, with the 'fetal face syndrome.' Both of the children also had the Crigler-Najjar syndrome, as did 2 previously born sibs who did not have the fetal face syndrome. Schorderet et al. (1992) described a brother and sister with Robinow syndrome in a Kurdish family from Turkey. The daughter had short stature, macrocephaly, hypertelorism, hepatosplenomegaly, short forearms, and marked vertebral anomalies. Her brother had hypertelorism, hypertrophied alveolar ridges, hepatosplenomegaly, short forearms, a rib anomaly, and ambiguous genitalia. The brother was mosaic for a Y-chromosome abnormality. Balci et al. (1991) reported 14 patients, all but 1 of whom were the offspring of consanguineous marriages, and Robinow (1991) quoted Baxova of Bratislava, Czechoslovakia, as suggesting that the condition is not rare in Czechoslovakia, where all cases occurred in the offspring of consanguineous gypsy parents (see Baxova et al., 1989). Robinow (1991) also had reports of recessive cases from Saudi Arabia and Kuwait. In addition, he pointed out that some cases thought to be of the dominant variety are probably cases of omodysplasia of Maroteaux (164745), including the 2 patients reported by Bain et al. (1986). Balci et al. (1998) described a 14-year-old girl in whom the diagnosis of Robinow syndrome had been made at the age of 2 months by Balci et al. (1993) on the basis of fetal face, gingival hyperplasia, mesomelic shortness, hemivertebrae between T10 and L2 with scoliosis, and an extra hypoplastic right middle finger. Intravenous pyelogram showed calyectasia. At the age of 14 years, she had a history of recurrent severe abdominal pain for the previous 6 months. She had not yet experienced menarche. Hematocolpos related to vaginal atresia was discovered. She underwent vaginoplasty with cervical construction. Vaginal atresia with cervical agenesis had apparently not been observed previously in Robinow syndrome. This was thought to represent a recessive form of Robinow syndrome. Aksit et al. (1997) reported 4 unrelated cases of Robinow syndrome, all with cardinal features of the condition, including vertebral and costal anomalies. In addition, 1 patient showed extensive webbing of the toes and an epigastric hernia. In 2 cases there was parental consanguinity. Sabry et al. (1997) reported 2 unrelated consanguineous families with Robinow syndrome. In a child of a Kuwaiti family, they reported associated intrauterine growth retardation; laxity of ligaments, joints, and skin; severe normocytic anemia; and repeated infection associated with increased total T cells and an increased CD4:CD8 ratio. In a child of a Pakistani family, there was associated congenital heart disease with right atrial isomerism, atrial and ventricular septal defects, double outlet right ventricle, and pulmonary stenosis. Soliman et al. (1998) outlined the characteristics of recessive Robinow syndrome as follows: short stature, mesomelic and acromelic brachymelia, thick, abnormally modeled radius and ulna, characteristic face (with hypertelorism, wide palpebral fissures, broad-based nose, everted nares), large mouth, gum hypertrophy with irregular and crowded teeth, costovertebral anomalies, and micropenis in males. Endocrine dysfunction has also been observed. All children with the syndrome have been found to have empty sella. There is also partial insensitivity of Leydig cells to human chorionic gonadotropin (see 118860), low basal testosterone in prepubertal boys, and a defective sex-steroid feedback mechanism (Soliman et al., 1998). Aksit et al. (1997) noted that of the 80 cases of Robinow syndrome reported to that time, 19 were born to Turkish couples, as were the 4 cases they reported. Mazzeu et al. (2007) reported detailed clinical features of 37 and 51 patients with recessive and dominant Robinow syndrome, respectively. More than 75% of patients with either form had hypertelorism, large nasal bridge, short, upturned nose, midface hypoplasia, mesomelic limb shortening, brachydactyly, clinodactyly, micropenis, and short stature. Hemivertebrae and scoliosis were present in more than 75% of patients with the recessive form, but in less than 25% with the dominant form. Umbilical hernia (32%) and supernumerary teeth (10%) were found exclusively in patients with the dominant form. Beiraghi et al. (2011) compared the craniofacial and intraoral phenotypes of 9 patients with dominant Robinow syndrome to 3 patients with recessive Robinow syndrome. Although there was overlap, particularly with regard to the most prevalent features such as hypertelorism, short, wide nose, and anteverted naries, the craniofacial dysmorphology was more severe in patients with the recessive disorder. In contrast, intraoral features were more severe in patients with the dominant disorder, and included wide retromolar ridge, alveolar ridge deformation, malocclusion, gingival enlargement, dental crowding, and hypodontia. In both types, facial characteristics became less pronounced in older individuals. Beiraghi et al. (2011) suggested that the differential diagnosis may be enhanced by noting differences in the alveolar ridge deformation pattern and severity of other intraoral characteristics.
- Recessive Robinow Syndrome with Severe Malformations of the Hands and Feet
In a large Turkish kindred in which many members over at least 6 generations had dominant BDB1, Schwabe et al. (2000) described a man, ... - Recessive Robinow Syndrome with Severe Malformations of the Hands and Feet In a large Turkish kindred in which many members over at least 6 generations had dominant BDB1, Schwabe et al. (2000) described a man, born of consanguineous parents with BDB1, who was homozygous for a 5-bp deletion proximal to the TK domain, resulting in frameshift at the arg441 residue (602337.0008). His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he had vertebral anomalies, brachymelia anomalies (short arms), and a ventricular septal defect--features reminiscent of Robinow syndrome. The phenotype in this patient suggested a specific mutation effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome. Schwarzer et al. (2009) reported an R441X mutation in the ROR2 gene (602337.0014) in an Omani patient exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4. The Omani parents were healthy, had no features of Robinow syndrome or BDB1, and were distantly related by mothers of the same tribal background. The R441X mutation was located at the same position as the frameshift mutation at arg441. Transfection experiments with a series of mutant transcripts revealed that recessive Robinow syndrome (RRS) mutant proteins, such as Q502X and W720X (602337.0006), were less abundant and retained intracellularly, whereas BDB1 mutants, such as W749X, were stable and predominantly located at the cell membrane. Both the frameshift mutation and the R441X mutation showed an intermediate pattern with membrane localization but also high ER retention, although the R441X mutant had a significantly lower total protein level and less membrane-associated protein than the frameshift mutant. There was a correlation between the severity of BDB1, the location of the mutation, and the amount of membrane-associated ROR2. Membrane protein fraction quantification revealed a gradient of distribution and stability correlating 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. Schwarzer et al. (2009) proposed a model in which the phenotypic outcome of ROR2 mutations is determined by 2 threshold levels: the degree of protein retention/degradation determines the RRS phenotype, whereas the amount of mutant protein reaching the plasma membrane determines the severity of the BDB1 phenotype. A mixture of both effects can result in a balance of gain of function and loss of function and, consequently, an overlapping phenotype.
Afzal et al. (2000) reported homozygous missense mutations in both intracellular and extracellular domains of ROR2 (602337) in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation (602337.0004) that removed the tyrosine kinase domain and all ... Afzal et al. (2000) reported homozygous missense mutations in both intracellular and extracellular domains of ROR2 (602337) in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation (602337.0004) that removed the tyrosine kinase domain and all subsequent 3-prime regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggested that the autosomal recessive form of Robinow syndrome is caused by loss of ROR2 activity. Simultaneously and independently, van Bokhoven et al. (2000) studied 11 families, 10 of which were derived from Turkey where autosomal recessive Robinow syndrome is unusually frequent, and 1 from Pakistan. The parents of all except one of the families were consanguineous, and for the most part first cousins. The authors mapped the gene for this disorder to 9q21-q22. They demonstrated mutations in the ROR2 gene resulting in premature stop codons and predicted nonfunctional proteins. The characteristic abnormal morphogenesis of the face and external genitalia along with short-limbed dwarfism and vertebral segmentation anomalies were emphasized as clinical features by van Bokhoven et al. (2000). A remarkable finding of van Bokhoven et al. (2000) was the fact that among the 10 families of Turkish descent, 4 homozygous nonsense mutations were detected in 6, including W720X (602337.0006) and R205X (602337.0007) (in 3 families). The families originated from different regions of Turkey, namely from the Black Sea coast (for the W720X mutation), eastern Turkey (for the 3 families with R205X) and central Turkey. Tufan et al. (2005) described 2 adult patients with autosomal recessive Robinow syndrome. In a 28-year-old Turkish man, born of first-cousin parents, Tufan et al. (2005) identified homozygosity for a deletion (602337.0010) in the ROR2 gene. The patient had 4 unaffected sibs and 1 sib with cleft palate who died of unknown cause in infancy. Besides typical skeletal and facial features, the patient developed hydronephrosis, nephrocalcinosis, and renal failure. In a 40-year-old German man with characteristic skeletal manifestations including severe spinal involvement and endocrinologic abnormalities including elevated gonadotropic hormones, Tufan et al. (2005) identified compound heterozygosity for a missense and a nonsense mutation in the ROR2 gene (see 602337.0005). The patient's nonconsanguineous parents were heterozygous for the mutations, respectively; he had 3 unaffected sibs. Tufan et al. (2005) noted that the facial phenotype in both patients remained distinctive into adulthood. In 2 sib pairs with Robinow syndrome from the same extended family, Brunetti-Pierri et al. (2008) identified homozygosity for deletion of exons 6 and 7 of the ROR2 gene (602337.0012). All 4 unaffected parents were heterozygous for the deletion. The patients demonstrated intrafamilial variability with respect to cleft lip, cleft palate, and cardiac abnormalities. One of the sibs presented at age 17 with back pain, and spine MRI revealed a thoracic syringomyelia; the authors noted that syringomyelia had not previously been reported in Robinow syndrome.
The diagnosis of ROR2-related Robinow syndrome is based on the presence of characteristic facies, short stature, limb defects, and genital abnormalities....
DiagnosisClinical DiagnosisThe 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 (click here for full text)]:Macrocephaly Broad prominent forehead Marked ocular hypertelorismProminent 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 palateGum hypertrophy Crowded and misaligned teeth Ankyloglossia, with bifid tongue in severe cases Micrognathia Simple, low-set ears, which can be posteriorly rotated Skeletal abnormalitiesShort 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 digitsHemivertebrae 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 TestingGene. ROR2 is the gene in which mutations cause autosomal recessive ROR2-related Robinow syndrome. Clinical testing Sequence analysis. ROR2-related Robinow syndrome is caused by missense, nonsense, or frameshift mutations 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 disease-causing mutation; however, compound heterozygotes have been reported [Tufan et al 2005]. Van Bokhoven et al [2000] reported mutations in seven of 11 families (by analysis of exons 2-9 only) and Afzal et al [2000] reported mutations 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1Test AvailabilityROR2Sequence analysis Sequence variants 27/11 families 3, 10/10 families 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Van Bokhoven et al [2000]4. Afzal et al [2000]5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 6. Frequency is unknown, but exonic deletions have been reported [Brunetti-Pierri et al 2008]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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 mutation detection rate may result from the difficulty in distinguishing between autosomal recessive and autosomal dominant inheritance in a family, undetected promoter mutations, or undetected partial or whole-gene deletions and/or locus heterogeneity.Testing StrategyConfirmation of the diagnosis in a proband includes sequence analysis of ROR2. If no mutation or only one mutation 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 disease-causing mutations 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 disease-causing mutations in the family.Genetically Related (Allelic) DisordersBrachydactyly type B1 (BDB1) is caused by heterozygous truncating mutations (nonsense and frameshift) in ROR2. Mutations causing BDB1 are located in exons 8 and 9 and affect the intracellular portion of the ROR2 protein [Oldridge et al 2000, Schwabe et al 2000]. BDB1 affects the fourth and fifth digits more severely with shortening of the middle phalanges and absence of the terminal phalanges. Affected individuals may show mildly abnormal facial features including wide-spaced eyes, downslanting palpebral fissures, short philtrum, and prominent nose. Inheritance is autosomal dominant.
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. ...
Natural HistoryFacial 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 gonadotrophin 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].
Mutations in ROR2 cause 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 mutation, 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]....
Genotype-Phenotype CorrelationsMutations in ROR2 cause 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 mutation, 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 mutations 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 mutations 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].
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: ...
Differential DiagnosisAutosomal 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 missense mutations 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 (see Spondylothoracic Dysostosis) 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]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with ROR2-related Robinow syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 transpositionEndocrine 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: 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 gonadotrophin 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 ComplicationsThe 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. Surveillance 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 InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDROR29q22.31Tyrosine-protein kinase transmembrane receptor ROR2ROR2 @ LOVDROR2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 268310ROBINOW SYNDROME, AUTOSOMAL RECESSIVE; RRS 602337RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTOR 2; ROR2Normal allelic variants. ROR2 comprises nine exons encoding a 4092-bp transcript. The reference sequence is NM_004560.3.Pathologic allelic variants. Missense, nonsense, and frameshift mutations in exons 3, 5, 7, 8, and 9 in the homozygous (or compound heterozygous) state cause ROR2-related Robinow syndrome. Missense mutations are found in the cysteine-rich, kringle, and tyrosine kinase domains. Terminating mutations 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 mutation [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. Mutations that cause ROR2-related Robinow syndrome cause loss of function of the protein. Changes in cysteine content are predicted to affect protein folding. Missense mutations 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]. Mutations that truncate the protein in the tyrosine kinase domain are predicted to affect phosphorylation and abolish kinase activity [Afzal et al 2000].