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Roberts Syndrome

Synonyms: Roberts-SC Phocomelia Syndrome, Pseudothalidomide Syndrome, Roberts-SC (Pseudothalidomide), SC-Phocomelia Syndrome

, PhD, , MD, PhD, and , MD.

Author Information
, PhD
Department of Surgery
Weill Cornell Medical College
New York, New York
, MD, PhD
National Human Genome Research Institute
Undiagnosed Diseases Program
National Institutes of Health
Bethesda, Maryland
Division of Biology and Medicine
Alpert Medical School
Brown University
Providence, Rhode Island
hugo_vega@nih.gov
, MD
Department of Genetics and Genomic Sciences
Mount Sinai School of Medicine
New York, New York

Initial Posting: ; Last Update: November 14, 2013.

Summary

Disease characteristics. Roberts syndrome (RBS) is characterized by prenatal growth retardation (ranging from mild to severe), craniofacial findings (including microcephaly and cleft lip and/or palate) and 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 include cleft lip and/or cleft palate, premaxillary prominence, micrognathia, microbrachycephaly, malar flattening, downslanted palpebral fissures, widely spaced eyes, exophthalmos resulting from shallow orbits, corneal clouding, underdeveloped ala nasi, beaked nose, and ear malformations. Intellectual disability is reported in the majority of affected individuals. Mortality is high among severely affected pregnancies and newborns. Mildly affected individuals may survive to adulthood.

Diagnosis/testing. The diagnosis of RBS relies on cytogenetic 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 named heterochromatin repulsion, HR) in most chromosomes in all metaphases. ESCO2 is the only gene in which mutations are known to cause RBS.

Management. Treatment of manifestations: Individualized treatment aimed to improve quality of life; surgery for cleft lip and/or palate, for correction of limb abnormalities, and to improve proper development of the prehensile hand grasp. Prostheses, speech assessment and therapy, aggressive treatment of otitis media, special education for developmental delays, and standard treatment for ophthalmologic, cardiac, and renal abnormalities may be indicated.

Surveillance: Periodic follow up of psychomotor development and physical growth; follow-up assessment of speech development and hearing if cleft lip and palate are present; screening for developmental delays or learning disorders; monitoring for specific ophthalmologic, cardiac, or renal anomalies.

Genetic counseling. RBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members is possible if the mutations have been identified in the family. Prenatal testing for pregnancies at increased risk is possible by a combination of ultrasound examination and cytogenetic testing, or by molecular genetic testing if the mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

The 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, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformation.

The diagnosis of RBS relies on cytogenetic testing in peripheral blood of individuals with suggestive clinical findings.

Testing

Cytogenetic 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).

Figure 1

Figure

Figure 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 Testing

Gene. ESCO2 is the only gene in which mutations are known to cause RBS [Vega et al 2005].

Clinical testing

Table 1. Summary Molecular Genetic Testing Used in Roberts Syndrome

Gene 1Test Method Mutations Detected 2Mutation Detection Frequency by Test Method 3
ESCO2Sequence analysisSequence variants 4100% of reported mutations 5
Deletion/duplication analysis 6Exonic or whole-gene deletion/duplicationUnknown, none reported 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. To date, all individuals with a cytogenetic diagnosis of RBS also have mutations in ESCO2.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. No deletions or duplications involving ESCO2 have been reported to cause RBS.

Testing Strategy

To confirm/establish 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.

Clinical Description

Natural History

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].

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 prominence, micrognathia, microbrachycephaly, midfacial capillary hemangioma, malar flattening, downslanted palpebral fissures, widely spaced eyes, exophthalmos resulting from shallow orbits, corneal clouding, underdeveloped ala nasi, 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 arteriosus
  • Kidneys. Polycystic kidney, horseshoe kidney
  • Male genitalia. Enlarged penis, relatively large appearance in relation to the reduced limbs; cryptorchidism
  • Female genitalia. Enlarged clitoris
  • Hair. Sparse hair, silvery blonde scalp hair
  • Cranial 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].

Genotype-Phenotype Correlations

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.

Nomenclature

In 1919, John B Roberts reported phocomelia, bilateral cleft lip and cleft palate, and protrusion of the intermaxillary region in three affected sibs of an Italian couple who were first cousins [Roberts 1919].

In 1969, J Herrmann and colleagues described a syndrome of intrauterine and postnatal growth retardation; mild symmetric reduction of the limbs; flexion contractures of various joints; multiple minor anomalies including: capillary hemangiomas of the face, cloudy corneas, hypoplastic cartilages of the ears and nose, micrognathia, and scanty, silvery-blond hair; and autosomal recessive inheritance. They named this condition the pseudothalidomide or SC syndrome (for the initials of the surnames of the two families described) [Herrmann et al 1969].

Controversy existed as to whether SC phocomelia syndrome was the same entity as RBS. After reports of unrelated families with a high degree of phenotypic variation between sibs, some with RBS and others with SC phocomelia syndrome, these two syndromes are now considered clinical variants of the same disorder [Van Den Berg & Francke 1993, Schüle et al 2005].

Other synonyms used for RBS in the past are Appelt-Gerken-Lenz syndrome, hypomelia-hypotrichosis-facial hemangioma syndrome, and tetraphocomelia-cleft palate syndrome.

Prevalence

RBS is rare; no accurate estimates of prevalence have been published. Approximately 150 individuals of diverse racial and ethnic backgrounds have been reported.

Parental consanguinity is common.

Carrier frequency for RBS is unknown.

Differential Diagnosis

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.

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 prominent 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 and later found 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 on 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 at least 15 genes, which are responsible for the known FA complementation groups (A, B, C, D1 [BRCA2], D2, E, F, G, I, J [BRIP1], L, M, N [PALB2], O [RAD51C], and P [SLX4]). The latter two genes are still thought of as tentative as they do not fall within a very easily characterized compartment biologically and have very few representative individuals. If the relevant complementation group is identified, molecular genetic testing can be directed to the appropriate gene.

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 with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur. The presence of cleft lip and palate associated with skeletal changes such as absent radius suggests RBS rather than TAR syndrome. TAR syndrome is inherited in an autosomal recessive manner and results from compound heterozygosity of RBM8A mutations.
  • 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 syndrome, characterized by the (complete) absence of all four limbs and anomalies involving the cranium and the face (cleft lip/cleft palate, micrognathia, microtia, single naris, choanal atresia, absence of nose); eyes (microphthalmia, microcornea, cataract, coloboma, palpebral fusion); urogenital system (renal agenesis, persistence of cloaca, absence of external genitalia, atresia of vagina); anus (atresia); heart; lungs (hypoplasia/aplasia), skeleton (hypoplasia/absence of pelvic bones, absence of ribs, absence of vertebrae), and central nervous system (agenesis of olfactory nerves, agenesis of optic nerves, agenesis of corpus callosum, hydrocephalus). 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) 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. More than 70% of individuals who meet strict diagnostic criteria have an identifiable mutation in TBX5.This syndrome can be excluded in individuals with congenital malformations involving the following structures or organ systems: ulnar ray only, 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 nose with anteverted nares, small widely spaced teeth, and microcephaly. Frequent findings include: cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, 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 approximately 60%of affected individuals; mutations in SMC1A and SMC3 are identified in a small percentage of affected individuals [Borck et al 2004, Gillis et al 2004, Tonkin et al 2004, Bhuiyan et al 2006, Musio et al 2006, Yan et al 2006, Borck et al 2007, Deardorff et al 2007, Selicorni 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Roberts syndrome (RBS), the following evaluations are recommended:

  • Radiographic documentation of the craniofacial, limb, and hand anomalies
  • Orofacial and limb malformation assessment to determine the need for management and plastic surgery
  • Ophthalmologic evaluation
  • Echocardiogram or evaluation by cardiologist to assess for structural heart defects
  • Ultrasound evaluation of the kidneys for cysts
  • Multidisciplinary evaluation including psychological assessment and formal, age-appropriate developmental assessment
  • Medical genetics consultation

Note: 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 Manifestations

It 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 on 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.
  • Prostheses
  • Speech assessment and therapy and aggressive treatment of otitis media if cleft palate is present
  • Intervention and/or special education if developmental delays are detected
  • Standard treatment for specific ophthalmologic problems, cardiac defects and renal dysfunction

Surveillance

The following are appropriate:

  • Periodic follow up to monitor mental and physical growth and to determine if frequent infections are an issue
  • Regular follow up for assessment of speech and ear infections/hearing loss if cleft lip and palate are present
  • Annual screening for developmental delays or learning disorders
  • Monitoring as per specific ophthalmologic, cardiac, or renal anomalies

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Roberts syndrome (RBS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • Pregnancies in individuals with RBS are rare; two have been reported, one resulting in an unaffected girl and the other resulting in a second-trimester miscarriage [Parry et al 1986].
  • The offspring of an individual with RBS are obligate heterozygotes (carriers) for a disease-causing mutation in ESCO2.

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

Carrier Detection

Carrier status cannot be determined by cytogenetic analysis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Ultrasound examination combined with cytogenetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by cytogenetic testing of fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). These findings in conjunction with ultrasound examination to follow growth and to evaluate the limbs, heart, palate, and other organs or structures affected in RBS are used for prenatal diagnosis of the syndrome [Kennelly & Moran 2007].

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • Reach: The Association for Children with Hand or Arm Deficiency
    PO Box 54
    Helston Cornwall TR13 8WD
    United Kingdom
    Phone: +44 0845 1306 225
    Fax: +44 0845 1300 262
    Email: reach@reach.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Roberts Syndrome: Genes and Databases

Data 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)

268300ROBERTS SYNDROME; RBS
269000SC PHOCOMELIA SYNDROME
609353ESTABLISHMENT OF COHESION 1, S. CEREVISIAE, HOMOLOG OF, 2; ESCO2

Normal 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.

Pathogenic 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 two are frameshift or nonsense mutations that lead to protein truncation or nonsense-mediated decay. The two missense mutations lead to amino acid substitutions of highly conserved amino acids in the acetyltransferase domain. Exonic or whole gene deletions or duplications have not been reported.

Table 2. Selected ESCO2 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Exon or IVS 2Reference Sequences
Normalc.239C>Tp.Ala80Val3NM_001017420​.2
NP_001017420​.1
rs4732748
Pathogenicc.252_253delAT 3p.Ser85PhefsTer6
(p.V84fs*7)
3NM_001017420​.2
NP_001017420​.1
c.294_297delGAGA 4p.Arg99SerfsTer2
(p.E98fs*2)
3
c.307_311delAAAGA
(c.307_311delAGAAA) 5
p.Lys103GlufsTer2
(p.I102fs*1)
3
c.308_309delAA 4p.Lys103ArgfsTer3
(p.K103fs*3)
3
c.417dupA
(c.411_412insA) 3
p.Pro140ThrfsTer8
(p.K138fs*10)
3
c.505C>T 3p.Arg169Ter3
c.604C>T 5p.Gln202Ter3
c.745_746delGT 6p.Val249GlnfsTer13
c.751dupG
(c.750_751insG) 3
p.Glu251GlyfsTer30
(p.E251fs*30)
3
c.760dupA
(c.751_752insA) 4, 5
p.Thr254AsnfsTer27
(p.K253fs*26)
3
c.760delA
(c.752delA) 4, 5
p.Thr254LeufsTer13
(p.K253fs*12)
3
c.764_765delTT 4p.Phe255CysfsTer25
(p.F255fs*25)
3
c.875_878delACAG 4p.Asp292GlufsTer48
(p.D292fs*47)
4
c.879_880delAG
(c.877_888delAG) 3, 4, 7
p.Arg293SerfsTer7
(p.R293fs*7)
4
c.955+2_+5delTAAG 4--IVS4
c.1111dupA
(c.1104_1105insA) 3
p.Thr371AsnfsTer32
(p.K369fs*34)
6
c.1111_1112insG0 4p.Thr371SerfsTer32
(p.T371fs*32)
6
c.1131+1G>A 2, 5--IVS6
c.1132-7A>G 2, 5--IVS6
c.1263+1G>C 5--IVS7
c.1269G>A 2p.Trp423Ter8
c.1354-18G>A 5--IVS8
c.1461_1462delAG
(c.1457_1458delAG) 3
p.Arg487SerfsTer19
(p.K486fs*20)
9
c.1597_1598dupT
(c.1597_1598insT) 5
p.Cys533LeufsTer5
(p.L533fs*5)
10
c.1615T>G 3p.Trp539Gly10
c.1674-2A>G 5--IVS10
c.1741G>C 8p.Gly581ArgExon 11

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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]

8. Vega et al [2010]

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 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.

References

Literature Cited

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Suggested Reading

  1. Gordillo M, Vega H, Jabs EW. ESCO2 and Roberts syndrome. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2 ed. Chap 111. New York, NY: Oxford University Press; 2008:1011-9.

Chapter Notes

Revision History

  • 14 November 2013 (me) Comprehensive update posted live
  • 14 April 2009 (cd) Revision: sequence analysis and prenatal testing available for ESCO2 mutations
  • 2 October 2008 (me) Comprehensive update posted live
  • 18 April 2006 (me) Review posted to live Web site
  • 2 December 2005 (ewj) Original submission
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