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 ... 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. Freeman et al. (1974) presented a good survey. Temtamy (1974) concluded that Roberts syndrome and the SC phocomelia syndrome (269000) are the same. By an analysis of phenotype, Herrmann and Opitz (1977) concluded that they could not tell whether the SC phocomelia syndrome and the Roberts syndrome are '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 the 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. 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 resulting from maternal ingestion of clonidine, an antihypertensive medication. Da Silva and Bezerra (1982) reported 4 affected sibs of first-cousin parents. 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. Premature centromere separation (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 may represent the same clinical entity. 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. 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. 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. Huson et al. (1990) described a patient with craniostenosis and radial aplasia which led to an initial diagnosis of Baller-Gerold syndrome (218600). 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 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. 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). 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. 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. 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. 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.
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. ... 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.
Using a candidate gene approach, Vega et al. (2005) screened a novel transcript containing D8S1839 and found 8 different mutations in 18 affected individuals from 15 families of different ethnic backgrounds. They identified 1 missense mutation, 1 nonsense ... Using a candidate gene approach, Vega et al. (2005) screened a novel transcript containing D8S1839 and found 8 different mutations in 18 affected individuals from 15 families of different ethnic backgrounds. They identified 1 missense mutation, 1 nonsense mutation, and 6 frameshift mutations (see, e.g., 609353.0001-609353.0003) in the ESCO2 gene. 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. Gordillo et al. (2008) stated that Roberts syndrome and SC phocomelia were considered to be the same syndrome with varying phenotypic expression, and that they would henceforth designate all such cases of Roberts syndrome/SC phocomelia as 'RBS.' The authors 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.
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 ... 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.
The diagnosis of Roberts syndrome (RBS; also known as Roberts-SC phocomelia syndrome) is suspected in individuals with the following: ...
DiagnosisClinical DiagnosisThe diagnosis of Roberts syndrome (RBS; also known as Roberts-SC phocomelia syndrome) is suspected in individuals with the following: Prenatal growth retardation ranging from mild to severe. Mean birth length and weight is below the third centile in most term and prematurely-born affected infants.Limb malformations including bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening. Upper limbs are more severely affected than lower limbs. Other limb malformations include oligodactyly with thumb aplasia or hypoplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures.Craniofacial abnormalities including bilateral cleft lip and/or palate, micrognathia, hypertelorism, exophthalmos, downslanting palpebral fissures, malar hypoplasia, hypoplastic nasal alae, and ear malformation. The diagnosis of RBS relies upon cytogenetic testing in peripheral blood of individuals with suggestive clinical findings.TestingCytogenetic testing. Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the characteristic chromosomal abnormality of premature centromere separation (PCS) and separation of the heterochromatic regions (also termed heterochromatin repulsion [HR]) in most chromosomes in all metaphases (Figure 1).FigureFigure 1. C-banding of metaphase chromosomes. Arrows show selected chromosomes with premature centromere separation. Large arrowhead points to 'splitting' of the Y chromosome heterochromatic region. Open arrows show selected chromosomes with normal C-banded (more...)Note on terminology used in RBS: The centromere and the heterochromatin are affected in RBS. (1) The term premature centromere separation (PCS) describes the cytogenetic abnormalities observed in standard cytogenetic preparations and the prematurely separating centromeres during metaphase rather than in anaphase. PCS is related to the most probable pathologic mechanism and associated spindle checkpoint activation and impaired cell proliferation. (2) The term "heterochromatin repulsion" only describes the cytogenetic abnormality of the heterochromatin and does not describe the abnormal process of sister chromatid cohesion, which is fundamental to the pathophysiology of RBS. (3) Until a better term is available to define the structural and functional characteristics of RBS, the authors prefer to use the combined term PCS/HR.Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.Note: PCS/HR is different from premature sister chromatid separation (PSCS) described in Cornelia de Lange syndrome and premature centromere division (PCD) associated with mosaic variegated aneuploidy syndrome, in which separation and splaying involves not only the centromeric regions but also the entire sister chromatids [Plaja et al 2001, Kaur et al 2005].Aneuploidy, micronucleation, and multilobulated nuclei are also common findings in RBS cell cultures.Carrier status cannot be determined by cytogenetic analysis.Molecular Genetic TestingGene. ESCO2 is the only gene with documented RBS-causing mutations [Vega et al 2005].Clinical testing Sequence analysis of ESCO2 is available; all individuals with a cytogenetic diagnosis of RBS have had mutations in ESCO2.Table 1. Summary Molecular Genetic Testing Used in Roberts SyndromeView in own windowGene SymbolTest Method Mutations Detected Mutation Detection Frequency by Test Method 1Test Availability ESCO2Sequence analysisSequence variants 2100% of reported mutations 3Clinical1. 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. To date, all individuals with a cytogenetic diagnosis of RBS also have mutations in ESCO2.Testing StrategyConfirming the diagnosis in a proband. Detection of the characteristic chromosomal abnormalities or identification of two ESCO2 mutations establishes the diagnosis of RBS in individuals with suggestive clinical findings.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 are not at risk of developing the disorder.Prenatal diagnosis for at-risk pregnancies requires ultrasound examination combined with cytogenetic testing [Kennelly & Moran 2007] or prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersTo date, no other phenotypes have been associated with mutations in ESCO2.
Little is known about the natural history of Roberts syndrome (RBS; also known as Roberts-SC phocomelia syndrome). Wide clinical variability is observed among affected individuals, including siblings. The prognosis for an individual with RBS depends on the malformations present: the severity of manifestations correlates with survival. Mortality is high among most of the severely affected pregnancies and newborns. Mildly affected children are more likely to survive to adulthood. The cause of death has not been reported for most affected individuals; in five cases it was reported to be infection [Herrmann & Opitz 1977]....
Natural HistoryLittle is known about the natural history of Roberts syndrome (RBS; also known as Roberts-SC phocomelia syndrome). Wide clinical variability is observed among affected individuals, including siblings. The prognosis for an individual with RBS depends on the malformations present: the severity of manifestations correlates with survival. Mortality is high among most of the severely affected pregnancies and newborns. Mildly affected children are more likely to survive to adulthood. The cause of death has not been reported for most affected individuals; in five cases it was reported to be infection [Herrmann & Opitz 1977].The following information is based on individuals reported in the literature or from the observation of individuals who have diagnostic cytogenetic findings of PCS/HR and/or an ESCO2 mutation.Growth retardation of prenatal onset is the most consistent finding in all affected individuals. Postnatal growth retardation can be moderate to severe and correlates with the severity of the limb and craniofacial malformations.Limb malformations include symmetric mesomelic shortening and anterior-posterior axis involvement in which the frequency and degree of involvement of long bones is, in decreasing order: radii, ulnae, and humeri in the upper limbs; fibulae, tibiae, and femur in the lower limbs. The degree of limb abnormalities follows a cephalo-caudal pattern: the upper limbs are more severely affected than the lower, with several cases of only upper limb malformations.Hand malformations include brachydactyly and oligodactyly. The thumb is most often affected by proximal positioning or digitalization, hypoplasia, or agenesis. The fifth finger is the next most affected digit with clinodactyly, hypoplasia, or agenesis. In severe cases, only three fingers are present (and rarely, only one finger).Craniofacial abnormalities include: cleft lip and/or cleft palate, premaxillary protrusion, micrognathia, microbrachycephaly, midfacial capillary hemangioma, malar hypoplasia, down-slanting palpebral fissures, ocular hypertelorism, exophthalmos resulting from shallow orbits, corneal clouding, hypoplastic nasal alae, beaked nose, and ear malformations. Mildly affected individuals have no palatal abnormalities or only a high-arched palate. The most severely affected individuals have fronto-ethmoid-nasal-maxillary encephalocele.Correlation between the degree of limb and facial involvement is observed. Individuals with mild limb abnormalities also have mild craniofacial malformations, while those with severely affected limbs present with extensive craniofacial abnormalities.Other abnormalities may be observed:Heart. Atrial septal defect, ventricular septal defect, patent ductus arteriosusKidneys. Polycystic kidney, horseshoe kidneyMale genitalia. Enlarged penis, relatively large appearance in relation to the reduced limbs; cryptorchidismFemale genitalia. Enlarged clitorisHair. Sparse hair, silvery blonde scalp hairCranial nerve paralysis (occasional)Moyamoya disease (occasional) Stroke (occasional)Intellectual ability. Intellectual disability is present in the majority of affected individuals; however, normal intellectual and social development has been reported [Petrinelli et al 1984, Stanley et al 1988, Maserati et al 1991, Holden et al 1992].
To date, correlation of genotype with specific phenotypic features has not been established. However, disparate clinical presentations among affected members within the same family suggest that modifier genes, epigenetic factors, and environment may play a role in expression of the clinical phenotype....
Genotype-Phenotype CorrelationsTo date, correlation of genotype with specific phenotypic features has not been established. However, disparate clinical presentations among affected members within the same family suggest that modifier genes, epigenetic factors, and environment may play a role in expression of the clinical phenotype.
While some syndromes share some of the clinical features of Roberts syndrome (RBS), a physical examination and skeletal survey followed by the finding of cytogenetic abnormalities should allow for differentiation between individuals with RBS and those with conditions that are clinically similar....
Differential DiagnosisWhile some syndromes share some of the clinical features of Roberts syndrome (RBS), a physical examination and skeletal survey followed by the finding of cytogenetic abnormalities should allow for differentiation between individuals with RBS and those with conditions that are clinically similar.In cases of mild manifestations, syndromes with associated preaxial reduction defects to be considered in the differential diagnosis include the following:Baller-Gerold syndrome, characterized by coronal craniosynostosis, manifest as abnormal shape of the skull (brachycephaly) with ocular proptosis and bulging forehead; radial ray defect, manifest as oligodactyly (reduction in number of digits), aplasia or hypoplasia of the thumb, and/or aplasia or hypoplasia of the radius; growth retardation and poikiloderma. Mutations in RECQL4 are associated with this syndrome. Phenotypic overlap of Baller-Gerold and RBS was noted in an individual with bicoronal synostosis and bilateral radial hypoplasia initially diagnosed with Baller-Gerold syndrome who was found later to have premature centromere separation [Huson et al 1990]. Inheritance is autosomal recessive.Fanconi anemia (FA), characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of 13 genes, which are responsible for the 13 FA complementation groups [A, B, C, D1 (BRCA2), D2, E, F, G, I, J, L, M, and N], and is used primarily for carrier detection and prenatal diagnosis. Inheritance is autosomal recessive.In cases of severe manifestations, the following syndromes should be considered in the differential diagnosis:Thrombocytopenia-absent radius (TAR) syndrome, characterized by bilateral absence of the radii and thrombocytopenia. Lower limbs and gastrointestinal, cardiovascular, and other systems may also be involved. The presence of cleft lip and palate associated with skeletal changes such as absent radius suggests RBS rather than TAR syndrome. Inheritance is autosomal recessive. Recently a microdeletion involving 11 genes on chromosome 1q21.1 has been found to be necessary but not sufficient to cause TAR syndrome [Klopocki et al 2007].Tetra-amelia, X-linked (Zimmer tetraphocomelia) (OMIM 273395), characterized by tetra-amelia, facial clefts, absence of ears and nose, and anal atresia. Other findings include: absence of frontal bones; pulmonary hypoplasia with adenomatoid malformation; absence of thyroid; dysplastic kidneys, gallbladder, spleen, uterus, and ovaries; and imperforate vagina.Tetra-amelia, autosomal recessive, characterized by amelia; severe lung hypoplasia and aplasia of the peripheral pulmonary vessels; cleft lip/palate; hypoplasia of the pelvis; malformed uterus; atresia of the urethra, vagina, and anus; diaphragmatic defect; and agenesis of the kidney, spleen, and adrenal glands. Mutations in WNT3 have been associated with this syndrome [Niemann et al 2004].Splenogonadal fusion with limb defects and micrognathia, characterized by abnormal fusion between the spleen and the gonad or the remnants of the mesonephros. Tetramelia and mild mandibular and oral abnormalities (micrognathia; multiple unerupted teeth; crowding of the upper incisors; and deep, narrow, V-shaped palate without cleft) have also been observed. Inheritance is autosomal dominant.DK phocomelia syndrome, characterized by phocomelia, thrombocytopenia, encephalocele, and urogenital abnormalities. Additional malformations include: cleft palate, absence of radius and digits, anal atresia, abnormal lobation of the lungs, and diaphragmatic agenesis. Inheritance is autosomal recessive.Holt-Oram syndrome (HOS) is characterized by (1) upper-extremity malformations involving radial, thenar, or carpal bones; (2) a personal and/or family history of congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum; and/or (3) cardiac conduction disease. Occasionally, phocomelia is observed. TBX5 is the only gene currently known to be associated with HOS. This syndrome can be excluded in individuals with congenital malformation of kidney, vertebra, craniofacies, auditory system (hearing loss or ear malformations), lower limb, anus, or eye. Inheritance is autosomal dominant.Thalidomide embryopathy, characterized by abnormalities of the long bones of the extremities. Upper limb bones are affected in an order of frequency starting with the thumb, followed by the radius, the humerus, the ulna, and finally the fingers on the ulnar side of the hand. In extreme cases, the radius, ulna, and humerus are lacking; and the hand bud arises from the shoulders. Legs may be affected but less severely. The second major group of defects involves the ears (anotia, microtia, accessory auricles) and the eyes (coloboma of the iris, anophthalmia, microphthalmia). Internal defects commonly involve the heart, kidneys, and urinary, alimentary, and genital tracts. First introduced as a sedative agent, thalidomide was also used to treat morning sickness. It was withdrawn from the market in the 1960s because of reports of teratogenicity. Currently, thalidomide is used to treat various cancers and dermatologic, neurologic, and inflammatory diseases [Franks et al 2004]. To reduce the risk of fetal exposure, the marketing and use of thalidomide in the United States is restricted through the mandatory System for Thalidomide Education and Prescribing Safety program [Zeldis et al 1999]. As of January 2005, more than 100,000 individuals have been prescribed thalidomide without any instances of drug-related birth defects [Uhl et al 2006].Disorders with similar but not the same cytogenetic findings (see Testing) include the following:Cornelia de Lange syndrome (CdLS), characterized by distinctive facial features, growth retardation, hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly. Craniofacial features include: synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly. Frequent findings include: cardiac septal defects, gastrointestinal dysfunction, and cryptorchidism or hypoplastic genitalia. Cytogenetic findings include premature sister chromatid separation (PSCS), in which separation and splaying involves not only the centromeric regions but also the entire sister chromatids [Kaur et al 2005]. Mutations in NIPBL are identified in 50% of affected individuals; mutations in SMC1A and SMC3 are identified in a small percentage of affected individuals [Krantz et al 2004, Tonkin et al 2004, Musio et al 2006, Deardorff et al 2007]. Inheritance is autosomal dominant. SMC1A mutations result in an X-linked form of CdLS with a dominant mode of expression [Musio et al 2006, Deardorff et al 2007].Mosaic variegated aneuploidy syndrome, characterized by severe microcephaly, growth deficiency, intellectual disability, childhood cancer predisposition, and constitutional mosaicism for chromosomal gains and losses. Cytogenetic findings include premature centromere division (PCD), in which mitotic cells show split centromeres and splayed chromatids in all or most chromosomes [Plaja et al 2001]. Mutations in BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint, have been found in individuals with this disease [Hanks et al 2004]. Inheritance is autosomal recessive.
To establish the extent of disease in an individual diagnosed with Roberts syndrome (RBS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Roberts syndrome (RBS), the following evaluations are recommended:Radiographic documentation of the craniofacial, limb, and hand anomaliesOrofacial and limb malformation assessment to determine the need for management and plastic surgeryOphthalmologic evaluationEchocardiogram or evaluation by cardiologist to assess for structural heart defectsUltrasound evaluation of the kidneys for cystsMultidisciplinary evaluation including psychological assessment and formal, age-appropriate developmental assessmentNote: No published guidelines to evaluate the clinical manifestations contributing to morbidity and mortality exist. The recommendations given are based on the literature and the experience of medical geneticists.Treatment of ManifestationsIt has been suggested that most individuals with RBS are stillborn or die in infancy. However, it is important to emphasize that, because it is possible for individuals to have normal intelligence and a healthy psychological adjustment, even with all of the stigmata of RBS, such individuals should be managed in a way that allows each to improve their quality of life and to reach their full potential.Individuals with severe RBS who survive the newborn period face a number of medical problems, and management of these individuals usually requires more than one medical specialist; experts in pediatrics, genetics, ophthalmology, cardiology, nephrology, neurology, child development, rehabilitation, general surgery, orthopedics, or dentistry may be involved. Comprehensive medical intervention is suggested, as is complete and clear parental counseling when discussing the possible outcome for these individuals [Karabulut et al 2001].Treatment is based upon the affected individual’s specific needs and may include the following:Surgical treatments including cosmetic or reconstructive surgery for clefts of the lip and/or palate and for limb abnormalities (several surgeries are usually required). Hand surgery improves early and proper development of the prehensile grasp.ProsthesesSpeech assessment and therapy and aggressive treatment of otitis media if cleft palate is presentIntervention and/or special education if developmental delays are detectedStandard treatment for specific cardiac defects and renal dysfunctionSurveillanceThe following are appropriate:Periodic follow-up to monitor mental and physical growth and to determine if frequent infections are an issueRegular follow-up for assessment of speech and ear infections/hearing loss if cleft lip and palate are presentAnnual screening for developmental delays or learning disordersMonitoring as per specific ophthalmologic, cardiac, or renal anomaliesEvaluation of Relatives at RiskSee 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. Roberts Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDESCO28p21.1N-acetyltransferase ESCO2Establishment of Cohesion 1 homolog 2 (ESCO2) @ LOVDESCO2Data 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 Roberts Syndrome (View All in OMIM) View in own window 268300ROBERTS SYNDROME; RBS 269000SC PHOCOMELIA SYNDROME 609353ESTABLISHMENT OF COHESION 1, S. CEREVISIAE, HOMOLOG OF, 2; ESCO2Normal allelic variants. ESCO2 comprises 11 exons distributed over 30.3 kb, transcribed into a 3,376 nucleotide mRNA with an open reading frame of 1,806 nucleotides [Vega et al 2005]. The normal variant p.Ala80Val in exon 3 has a heterozygosity of 0.235, but its functional significance is not known. Pathologic allelic variants. The mutations in ESCO2 are highly variable. Different mutations in ESCO2 have been reported in families with Roberts syndrome (RBS) (Table 2). All but one are frameshift or nonsense mutations that lead to protein truncation or nonsense-mediated decay. The single missense mutation leads to an amino acid substitution of one highly conserved amino acid in the acetyltransferase domain. Table 2. Selected ESCO2 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Exon or IVS 2Reference SequencesNormalc.239C>Tp.Ala80Val3NM_001017420.2 NP_001017420.1 rs4732748Pathologicc.252_253delAT 3p.Ser85Phefs*6 (p.V84fs*7)3NM_001017420.2 NP_001017420.1 c.294_297delGAGA 4p.Arg99Serfs*2 (p.E98fs*2)3c.307_311delAAAGA (c.307_311delAGAAA) 5p.Lys103Glufs*2 (p.I102fs*1)3c.308_309delAA 4p.Lys103Argfs*3 (p.K103fs*3)3c.417dupA (c.411_412insA) 3p.Pro140Thrfs*8 (p.K138fs*10)3c.505C>T 3p.Arg169X3c.604C>T 5p.Gln 202X3c.745_746delGT 6p.Val249Glnfs*13c.751dupG (c.750_751insG) 3p.Glu251Glyfs*30 (p.E251fs*30)3c.760dupA (c.751_752insA) 4, 5p.Thr254Asnfs*27 (p.K253fs*26)3c.760delA (c.752delA) 4, 5p.Thr254Leufs*13 (p.K253fs*12)3c.764_765delTT 4p.Phe255Cysfs*25 (p.F255fs*25)3c.875_878delACAG 4p.Asp292Glufs*48 (p.D292fs*47)4c.879_880delAG (c.877_888delAG) 3, 4, 7p.Arg293Serfs*7 (p.R293fs*7)4c.955+2_+5delTAAG 4--IVS4c.1111dupA (c.1104_1105insA) 3p.Thr371Asnfs*32 (p.K369fs*34)6c.1111_1112insG 4p.Thr371Serfs*32 (p.T371fs*32)6c.1131+1G>A 2, 5--IVS6c.1132-7A>G 2, 5--IVS6c.1263+1G>C 5--IVS7c.1269G>A 2p.Trp423X8c.1354-18G>A 5--IVS8c.1461_1462delAG (c.1457_1458delAG) 3p.Arg487Serfs*19 (p.K486fs*20)9c.1597_1598dupT (c.1597_1598insT) 5p.Cys533Leufs*5 (p.L533fs*5)10c.1615T>G 3p.Trp539Gly10c.1674-2A>G 5--IVS10See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions 2. IVS = intervening sequence or intron 3. Vega et al [2005]4. Gordillo et al [2008]5. Schüle et al [2005]6. Resta et al [2006]7. Schulz et al [2008]Normal gene product. Translation of the mRNA results in a protein of 601 amino acids with two different domains, the C-terminal portion with acetyltransferase activity and the N-terminal end, which binds to chromatin [Hou & Zou 2005, Vega et al 2005]. The acetyltransferase domain is homologous to Drosophila deco and S cerevisiae eco1, which are proposed to play a role in establishing sister chromatid cohesion during S phase after DNA replication [Skibbens et al 1999, Toth et al 1999, Williams et al 2003].Abnormal gene product. The abnormalities reported in ESCO2 are predicted to lead to loss of function, truncation in the protein, or single amino acid changes [Schüle et al 2005, Vega et al 2005, Gordillo et al 2008]. Table 2 shows the amino acid changes. The c.1615T>G (pTrp539Gly) missense mutation results in loss of in vitro acetyltransferase activity [Gordillo et al 2008]. The cellular phenotype resulting from this missense mutation is equivalent to the one produced by nonsense and frameshift mutations, indicating that the RBS molecular mechanism involves loss of acetyltransferase activity [Gordillo et al 2008]. Alterations in ESCO2 function result in lack of cohesion at heterochromatic regions, which may lead to activation of the mitotic spindle checkpoint with the subsequent mitotic delay and the impaired cell proliferation observed in RBS cells. The clinical manifestations of RBS may result from the loss of progenitor cells during embryogenesis of structures affected in RBS.