Alternative titles; symbols
SNOMEDCT: 48718006; ORPHA: 3103; DO: 5325;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p21.1 | Roberts-SC phocomelia syndrome | 268300 | Autosomal recessive | 3 | ESCO2 | 609353 |
A number sign (#) is used with this entry because of evidence that Roberts-SC phocomelia syndrome (RBS) is caused by homozygous or compound heterozygous mutation in the ESCO2 gene (609353) on chromosome 8p21.
Roberts-SC phocomelia syndrome (RBS) is a rare autosomal recessive disorder clinically characterized by prenatal-onset growth retardation that continues in the postnatal period, extremity malformations, craniofacial anomalies, impaired intellectual development, and cardiac and renal anomalies. Prenatal-onset growth retardation may be mild to severe. The upper limbs are more affected than the lower limbs, where variations from tetraphocomelia (symmetrical limb reduction) to hypomelia arising from mesomelic shortness are seen. Elbow and knee contractures, reduction in the number and length of fingers, thumb aplasia and hypoplasia, and clinodactyly may also be observed. Severely affected patients may die during pregnancy or the neonatal period, whereas slightly affected patients will reach adulthood (summary by Goh et al., 2010 and Sezer et al., 2019).
Roberts (1919) described 3 affected sibs of first-cousin Italian parents. Pictures were included. The bones of the legs were almost absent and those of the arms hypoplastic. Bilateral cleft lip and cleft palate were present. The skull looked oxycephalic with prominent eyes, as in Crouzon syndrome (123500). The patient of Stroer (1939), also of first-cousin parents, may have had the same disorder. Appelt et al. (1966) described cases and pointed out that clitoral or penile enlargement is a feature. Corneal opacities occur in this disorder.
In a family with surname beginning with S and another with surname beginning with C, Herrmann et al. (1969) described a syndrome consisting of the following features: (1) nearly symmetrical reductive malformations of the limbs, resembling phocomelia; (2) flexion contractures of various joints; (3) multiple minor anomalies, including capillary hemangioma of the face, forehead and ears, hypoplastic cartilages of the ears and nose, micrognathia, scanty, silvery-blond hair, and cloudy corneas; (4) intrauterine and extrauterine growth retardation; (5) possibly mental retardation, and (6) autosomal recessive inheritance.
Hall and Greenberg (1972) described an 8-year-old girl with SC syndrome who was mentally normal. They were impressed with hypotrichosis and midfacial hemangioma, for which reason they proposed the designation hypomelia-hypotrichosis-facial hemangioma syndrome. They emphasized a characteristic appearance of the face. Although the SC phocomelia syndrome is sometimes referred to as the pseudothalidomide syndrome, some cases of the Holt-Oram syndrome (142900) may be more deserving of that name (Lenz et al., 1974). Humeroradial synostosis was also a feature; see 143050 and 236400.
Freeman et al. (1974) reviewed the features of Roberts syndrome. They cited the differences thought to differentiate it from SC syndrome as prominence of the external genitalia, the lack of silvery-blond hair and blue sclerae, and presence of ulnar rather than radial abnormalities of the upper extremities.
Grosse et al. (1975) described a case of what they termed the tetraphocomelia-cleft palate syndrome. Capillary hemangioma of the glabella and lids and fine silvery-blond hair were described. The authors questioned the separateness of Roberts syndrome and SC phocomelia syndrome.
By an analysis of phenotype, Herrmann and Opitz (1977) could not tell whether the SC phocomelia syndrome and the Roberts syndrome were 'due to different recessive genes, different alleles, or the same recessive gene.'
Because of overlapping features in their patient, Waldenmaier et al. (1978) suggested that the SC phocomelia syndrome and the TAR syndrome (274000) are not separate from Roberts syndrome.
Tomkins et al. (1979) noted the uncertainty as to whether Roberts syndrome and the SC syndrome are separate entities. They found a consistent centromeric abnormality of the chromosomes, namely, puffing and splitting, in 4 patients who had certain clinical features in common: bilateral corneal opacities, microcephaly, absence of radii, limitation of extension at the elbows and knees, enlargement of the phallus, and survival beyond the neonatal period.
Qazi et al. (1979) described chromosomal abnormalities in SC phocomelia that were similar to those in Roberts syndrome.
Fryns et al. (1980) reported identical twins concordant for the tetraphocomelia-cleft palate syndrome. Since the twins showed the severe tetraphocomelia of Roberts syndrome and the less prominent craniofacial abnormalities of the pseudothalidomide syndrome, the authors favored the view that these two entities are one.
Stoll et al. (1979) raised the question of phenocopy of Roberts syndrome resulting from maternal ingestion of clonidine, an antihypertensive medication.
Da Silva and Bezerra (1982) reported 4 affected sibs with Roberts syndrome whose parents were first cousins.
In a Christian Lebanese family, BenEzra et al. (1982) observed 2 brothers with radial aplasia and abnormality of anterior chamber cleavage in the eye. Both showed a normal XY karyotype except for unusual sister chromatid disjunction at the centromeric region during prophase and metaphase. In the first brother, the radius and thumbs were absent and the tibia and fibula were relatively short; bilateral microphthalmia with central corneal leukoma was described, as well as moderate micrognathia and aplasia of the alae nasi. The second brother had extensive facial hemangioma, total cleft palate, total aplasia of the radius and ulna, marked shortening of the humerus, absent thumbs, absent fibula, and deformed tibia. Comment concerning parental consanguinity was not made. Presumably, this disorder falls into the same group as Roberts syndrome and SC phocomelia syndrome.
Tomkins and Sisken (1984) suggested that impediment to cellular growth is responsible for reduced pre- and postnatal growth rates and also for the developmental abnormalities in Roberts syndrome.
Parry et al. (1986) reported the cases of 2 middle-aged sisters with most of the manifestations of the SC phocomelia syndrome including postnatal growth retardation, symmetric limb deficiencies with radial aplasia and absent thumbs, facial anomalies with microcephaly, microphthalmia, hypoplastic nasal alae, and borderline to mild mental retardation. Unusual findings included congenital paralysis of some cranial nerves in both and malignant melanoma in 1. Tumor cells and cultured lymphocytes and fibroblasts of both patients showed premature separation of centromeric heterochromatin (PCS). PCS has been reported in lymphocytes and/or fibroblasts from at least 17 patients whose clinical phenotypes cover the range of the Roberts syndrome at the severe end and the SC phocomelia syndrome at the milder end (Parry et al., 1986). This argues that the 2 syndromes represent the same clinical entity.
Krassikoff et al. (1986) found that aneuploid cells from a metastatic melanoma in a patient with the Roberts/SC phocomelia syndrome, aged 32 years, showed a reduced frequency of PCS. Furthermore, when the patient's fibroblasts, which showed a high frequency of PCS, were cocultivated with either an immortal hamster cell line or with a human male fibroblast strain carrying a t(4;6) translocation, the phenomenon was neither corrected in the patient's cells nor induced in the other cells. In each experiment, only the patient's metaphase spreads showed PCS. In fusion hybrids between the patient's fibroblasts and an established Chinese cell line, however, the human chromosomes behaved normally. No chromatid repulsion (PCS) was observed, suggesting that the missing or mutant gene product in Roberts/SC phocomelia syndrome is supplied by the Chinese hamster genome.
Romke et al. (1987) reported a family in which 3 sibs had various manifestations of Roberts syndrome or SC phocomelia, leading them to conclude that the 2 syndromes are the same genetic entity.
Opitz and Lowry (1987) stated that early on they had the impression that the Roberts syndrome and the SC pseudothalidomide syndrome may occur in different members of the same sibship and that the identification of identical cytological markers complements the conclusion of nosologic identity (as well as effective prenatal diagnosis).
Fryns et al. (1987) described 2 sibs with tetraphocomelia typical of Roberts syndrome: there was almost complete reduction of the midparts of the upper and lower limbs, and characteristic oligodactyly with absent nails. Neither cleft lip/cleft palate nor eye anomalies were present. Furthermore, premature centromere separation was not observed. The facies was unusual, consisting of a beaked nose, short philtrum, and triangular mouth.
Holmes-Siedle et al. (1990) described what they called the Roberts/SC phocomelia syndrome in 3 sibs of second-cousin parents. One child survived to age 9. A somewhat unusual feature was craniosynostosis; overlap with the Baller-Gerold syndrome (218600), which has craniosynostosis as a feature, was discussed.
Huson et al. (1990) described a patient with craniostenosis and radial aplasia, which led to an initial diagnosis of Baller-Gerold syndrome. Mild fibular hypoplasia on skeletal survey led to review of the diagnosis, and similarity of the facial phenotype to that of Roberts syndrome was noted. Chromosome analysis showed the premature centromere separation characteristic of that condition. Huson et al. (1990) suggested that cases diagnosed as having Baller-Gerold syndrome should have cytogenetic analysis and, conversely, that known Roberts syndrome survivors should be reviewed for signs of craniostenosis.
Keppen et al. (1991) described an infant with the clinical diagnosis of Roberts syndrome, but without the premature separation of centromeric heterochromatin and typical abnormalities of the cell division cycle reported in this condition.
Maserati et al. (1991) described 5 cases of Roberts syndrome in 4 nuclear families; in 3 of the families, the parents were consanguineous. They pictured affected sisters at ages 23 and 15 and emphasized the wide range of variability in the phenotype. The affected sisters had bilateral radial aplasia, hypoplastic ulnas and malformed hands; in the lower limbs, they had aplasia of the fibula with a bent tibia and bilateral clubfoot. At the other extreme was severe tetraphocomelia with death at or soon after birth.
Feingold (1992) provided follow-up on the 'C-patient' originally reported by Herrmann et al. (1969). At age 14 the patient developed moyamoya disease (252350) causing left hemiparesis. Chromosome studies showed premature centromere separation characteristic of this syndrome, i.e., splaying of the heterochromatin, repulsion of the short arms of the acrocentric chromosomes, and splaying of Y chromosome heterochromatin. At the age of 23 the patient developed chest pain and electrocardiographic changes indicative of anterior myocardial infarction. Subsequently he was found to have an apical aneurysm of the left ventricle with apical thrombosis and died of congestive heart failure. He remained short throughout his life; his final height was 139 cm. Although his facial characteristics remained constant, his scanty silvery blond hair became brown and less sparse. Mild valvular aortic stenosis was diagnosed at one time. The same syndrome was probably described by O'Brien and Mustard (1921) in 3 of 8 children of normal parents who were related as double first cousins.
Van Den Berg and Francke (1993) provided a review of 100 cases of Roberts syndrome and defined a new rating system for quantitating severity.
Satar et al. (1994) described a male infant who, in addition to typical manifestations of Roberts syndrome, had atrial septal defect, rudimentary gallbladder, and accessory spleen.
Sinha et al. (1994) reviewed clinical heterogeneity of the skeletal dysplasia in Roberts syndrome. Sabry (1995) suggested that, in the light of contemporary molecular and developmental genetics, such heterogeneity would not be surprising with different mutations in the same gene or with mutations in closely related genes of the same family. Sabry (1995) raised the possibility that the mutations may lie in centromere-related proteins, which may also have a role in body patterning.
Urban et al. (1998) described a 13-year-old boy who illustrated the phenotypic overlap between Roberts syndrome and TAR syndrome. The mother had an isolated left cleft of the lip and a cleft palate. The boy presented at birth with bilateral cleft lip/cleft palate, phocomelia of upper limbs with normal hands, and mild symmetric deficiencies of the long bones of the lower limbs. A leukemoid reaction occurred during a urinary tract infection as well as intermittent thrombocytopenia and episodes of marked eosinophilia during the first 2 years of life. Intellectual development was normal.
Goh et al. (2010) studied a 31-year-old man who was referred for short stature and subaortic stenosis; the latter had been repaired at 8 years of age but recurred in adulthood, requiring reoperation. Upon examination he had short stature and dysmorphic features, including hypertelorism, downslanting palpebral fissures, prominent nasal bridge, and hypoplastic alae nasi with prominent columella. His ears were simple and slightly posteriorly angulated; he had a high palate and mild retrognathia. His extremities displayed no obvious defects, but careful measurement showed limb lengths ranging from less than the 50th centile to less than the 5th centile for adult males. Karyotype showed premature centromere separation in all metaphases. Skeletal survey showed no limb reduction defects, but there was evidence of hypertelorism, mild brachymetacarpalia, brachyphalangy, and short femoral necks. Analysis of the ESCO2 gene revealed homozygosity for a truncating mutation. Goh et al. (2010) reviewed previously reported adult cases of Roberts syndrome/SC phocomelia, and noted that this case highlighted the variability in the RBS/SC phocomelia spectrum and demonstrated that clinically apparent limb anomaly might not be an obligate feature for diagnosis of the condition.
Consanguinity in the family with RBS reported by Roberts (1919) suggested autosomal recessive inheritance. The transmission pattern of RBS in the families reported by Herrmann et al. (1969) was consistent with autosomal recessive inheritance.
Vega et al. (2010) established clinical criteria for a diagnosis of Roberts syndrome based on a cohort of 49 patients, including 18 reported previously, with the disorder confirmed by genetic analysis. The clinical criteria were delineated to include growth retardation, symmetric mesomelic shortening of the limbs in which the upper limbs were more commonly and severely affected than the lower limbs, and characteristic facies with microcephaly. The severity of malformations of the facies correlated with the severity of limb reduction. There were some significant associations: patients without corneal opacities were less likely to present with cardiac anomalies (p = 0.0022) and those with corneal opacities were more likely to present with mental retardation (p = 0.0006)
Prenatal Diagnosis
Hirschhorn and Kaffe (1992) pointed out that they had made a prenatal diagnosis of Roberts syndrome in a family at risk by detection of skeletal and renal abnormalities (Kaffe et al., 1977).
Zergollern and Hitrec (1982) concluded that the Roberts and SC phocomelia syndromes are one entity. In a sibship with 4 affected, they found silver-blond hair, typical of SC, in 1; 2 had cloudy corneas typical of SC. They described chromosomal changes similar to those described by others and proposed their use in prenatal diagnosis. The chromosomal abnormality involves the heterochromatic, C-banding regions of most chromosomes. In addition to the above noted puffing of heterochromatic regions around the centromeres and nucleolar organizers, the heterochromatin of the long arms of the Y chromosome is often widely separated in metaphase spreads. German (1979) suggested that these configurations result from a repulsion or lack of attraction between the chromatids in these regions leading to premature separation during prophase and metaphase. Maserati et al. (1991) used indirect immunofluorescence with serum antibodies from patients with CREST (181750) to demonstrate that the centromeric structures are normal in Roberts syndrome, thus confirming the assumption of German (1979) that chromatid repulsion is confined to the heterochromatin. Studies suggested that heterozygotes can be screened by the phenomenon of centromeric heterochromatin separation.
Jabs et al. (1991) presented evidence that Roberts syndrome is a 'mitotic mutant.' They emphasized that, in addition to previously described changes, aneuploidy with random chromosome loss and micronuclei and/or nuclear lobulation in the interphase cells are characteristic. They considered it unlikely that the defect in this disorder is in one of the structural proteins of the kinetochore. They suggested, however, that the defect might lie in one of the proteins transiently associated with the kinetochore and involved in its function. Stioui et al. (1992) detected premature centromere separation on chorionic villus sampling at 8 weeks' gestation in a woman at risk of recurrence of Roberts syndrome.
Lopez-Allen et al. (1996) pictured an afflicted newborn infant and the chromosome changes.
Allingham-Hawkins and Tomkins (1995) pointed out that some Roberts syndrome patients (referred to as RS+), but not others (RS-), have an abnormality of their constitutive heterochromatin and show cellular hypersensitivity to DNA damaging agents such as mitomycin C. Lymphoblastoid cell lines from 2 unrelated RS+ patients were fused and hybrid cells examined for correction of these 2 defects. Neither cellular defect was corrected in the 2 hybrid cell lines, suggesting that the patients represent a single complementation group. On the other hand, fusions between 1 RS+ cell line and 2 different RS- cell lines produced in each case hybrids demonstrating correction of both defects. This suggested that RS+ and RS- patients belong to different complementation groups and do not arise from the same single gene mutation.
McDaniel et al. (2000) described a new assay for in vitro complementation and assigned a severely affected patient to the same complementation group defined by other, less severely affected patients. They suggested that a single complementation group defines RBS patients with heterochromatic splaying regardless of clinical severity. McDaniel et al. (2005) used complementation of the abnormal cytogenetic phenotype of Roberts syndrome, referred to as 'heterochromatic repulsion,' to identify a specific region of the normal human genome capable of rendering phenotypic correction. Using a transient chromosome-transfer assay, they screened the entire human genome and demonstrated complementation exclusively after the transfer of proximal chromosome 8p, a result subsequently confirmed by stable microcell-mediated chromosome transfer. Additionally, homozygosity mapping was used to refine the interval of this complementing locus to 8p21. These findings were all consistent with those of Vega et al. (2005).
Bermejo-Sanchez et al. (2011) reported epidemiologic data on phocomelia from 19 birth defect surveillance programs, all members of the International Clearinghouse for Birth Defects Surveillance and Research. Depending on the program, data corresponded to a period from 1968 through 2006. A total of 22,740,933 live births, stillbirths, and, for some programs, elective terminations of pregnancy for fetal anomaly were monitored. After a detailed review of clinical data, only true phocomelia cases were included. Descriptive data were presented and additional analyses compared isolated cases with those with multiple congenital anomalies (MCA), excluding syndromes. Bermejo-Sanchez et al. (2011) also briefly compared congenital anomalies associated with nonsyndromic phocomelia with those presented with amelia (see 601360), another rare severe congenital limb defect. A total of 141 phocomelia cases registered gave an overall total prevalence of 0.62 per 100,000 births (95% confidence interval 0.52-0.73). Three programs, Australia Victoria, South America ECLAMC, and Italy North East, had significantly different prevalence estimates. Most cases (53.2%) had isolated phocomelia, while 9.9% had syndromes. Most nonsyndromic cases were monomelic (55.9%), with an excess of left (64.9%) and upper limb (64.9%) involvement. Most nonsyndromic cases (66.9%) were live births; most isolated cases (57.9%) weighed more than 2,499 grams; most MCA (60.7%) weighed less than 2,500 grams and were more likely stillbirths (30.8%) or terminations (15.4%) than isolated cases. The most common associated defects were musculoskeletal, cardiac, and intestinal.
Vega et al. (2005) identified 7 families affected with Roberts syndrome in 2 isolated villages near Bogota, Colombia. After discovering a common ancestor in the 18th century by genealogic studies of 4 families, they began a genomewide search for the disease-associated locus by homozygosity mapping. The final analysis reported linkage for 8p21.2-p12 between markers D8S258 and D8S505. With additional families and fine mapping, they confirmed a region of homozygosity in all 11 affected individuals studied. Multipoint analysis gave a maximum lod score of 13.4 at D8S1839.
Using a candidate gene approach, Vega et al. (2005) identified the ESCO2 gene within the Roberts syndrome critical region on chromosome 8 and found 8 different mutations in this gene in 18 affected individuals from 15 affected families of different ethnic backgrounds. They identified 1 missense mutation, 1 nonsense mutation, and 6 frameshift mutations (see, e.g., 609353.0001-609353.0003). The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
In one of the original families described by Herrmann et al. (1969) and in the sisters described by Parry et al. (1986) with SC phocomelia, Schule et al. (2005) found compound heterozygosity for mutations in the ESCO2 gene (see 609353.0004 and 609353.0006). Altogether Schule et al. (2005) found 7 novel mutations in exons 3 through 8 of the ESCO2 gene in 6 individuals with SC phocomelia from 5 families.
Gordillo et al. (2008) concluded that Roberts syndrome and SC phocomelia are the same syndrome with varying phenotypic expression. They analyzed the ESCO2 gene in 16 Roberts syndrome/SC phocomelia pedigrees with 17 affected individuals and identified 15 different mutations; 13 individuals were homozygous, and 4 were compound heterozygous for the mutations.
In an analysis of 49 patients with ESCO2 mutations, including 18 previously reported cases, Vega et al. (2010) found no clear genotype/phenotype correlation. However, the presence or absence of corneal opacities segregated with specific mutations in some cases. All 7 individuals from 4 families with the 750insG mutation (609353.0003) lacked corneal opacities, whereas all 5 patients with the R169X mutation (609353.0002) had corneal opacities. In addition, patients without corneal opacities were less likely to present with cardiac abnormalities, and patients with corneal opacities were more likely to present with mental retardation. Skeletal defects were more common in patients with cleft lip/palate. Vega et al. (2010) found that both Roberts syndrome and SC phocomelia could be caused by the same mutation in different members of the same family, indicating that the 2 disorders represent a phenotypic spectrum.
Urban et al. (1997) described a specimen of tetraphocomelia and bilaterally cleft lip recovered from what had been the Virchow Museum of Humboldt University in Berlin and showed convincingly that this was the specimen reported by Virchow (1898). This was clearly an instance of Roberts syndrome.
Bates (2003) reproduced the report of a case of Roberts syndrome by Francois Bouchard in 1672.
Kompanje (2009) commented on the report of Bates (2003), noting that Francois Bouchard had actually translated the original report that was written by the French surgeon Francois Deboze from Lyon. Other historical details were clarified.
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