Roberts Syndrome Research Articles

Femorotibial Ankylosis in a Child With Roberts Syndrome

Roberts syndrome is a rare autosomal recessive disorder affecting many organs. The marked disabilities are mainly due to extreme short stature and severe limb deformities. Treatment in children who survive focuses on surgical correction of facial and limb defects. Z.B., a 9.5-year-old girl, was diagnosed at birth with Roberts syndrome. She gradually achieved gross and fine motor developmental milestones and spontaneously ambulated by "walking" on her knees. Her primary obstacle to further improvement was the severe fixed flexion deformities of the knees. At age 5 years and 9 months, she underwent surgery which involved quadriceps splitting, exposure, and then excision of the bony ankylosis. Stable fixation was achieved with crossed Kirschner wires. Quadriceps reefing was then performed, and long-leg casts applied. Currently, she walks independently without orthoses and functions as well as her height permits. Knee ankylosis is a very rare entity, and the affected patients are usually treated nonoperatively. Careful evaluation and appropriate surgery afforded our patient a better quality of life and should be considered in other patients.

SCE Frequency Measurement Could Be Useful in the Prenatal Diagnosis of Roberts Syndrome

In a previously published article (Resta et al., 2006) on Robert's syndrome in prenatal diagnosis, a case of a 36-year-old woman and her 36-year-old, nonconsanguineous husband were presented. Our findings suggest the existence of nonsense mediated decay (NMD) variability which could account for the varying severity reported in carriers of identical mutations. Furthermore, fetal cells were used to evaluate the influence of premature centromere separation (PCS) on the sister chromatid exchange (SCE) and micronucleus (MN) frequency. Given the similar variation observed in the SCE frequencies, dependent on tissue/cell type (amniotic fluid sample, chorionic villus sampling) and duration of in vitro cultures (48 hours or 72 hours), the idea was that this new piece of information could be interesting. It seems that the SCE frequency increased proportionally to the cell cycle increasing (1 degrees < 2 degrees < 3 degrees ... n). Obviously, our observations are too scarce to draw conclusions, but further investigation could be useful to corroborate or dispute these results, considering that the two techniques, (MN and SCE), are simple to perform and do not require expensive laboratory equipment.

A clinical algorithm of prenatal diagnosis of Radial Ray Defects with two and three dimensional ultrasound

To review the antenatal diagnosis of Radial Ray Defects (RRD) in a tertiary referral fetal medicine unit & to set out a clinical algorithm to aid assessment and management. All cases of RRD isolated or associated with other anomalies notified to NorCAS between 2000 and 2005 were identified. Outcome information was obtained from paediatric records and histopathology and cytogenetics in cases of pregnancy interruption. Thirty five cases were referred, 17 cases were excluded including skeletal dysplasia (16). An antenatal diagnosis was made in 61% (11/18) - isolated limb reduction defects, Trisomy 18, TAR, fetal valproate syndrome, Roberts syndrome. Of the rest, 3 had a cordocentesis with normal chromosome fragility tests (VACTERL association, Goldenhar syndrome and Acrofacial dysostosis) and 4 declined testing (2 TOP with Cornelia de Lange, 2 ongoing pregnancies diagnosed postpartum with Fanconi anaemia and VACTERL association). The challenge of radial ray anomalies is to combine clinical and ultrasound expertise with input from clinical genetics, ultrasound and molecular testing. Our clinical algorithm encourages targeted sonography including 3D views for subtle face, ear and hand anomalies, providing a useful tool to diagnose the underlying condition, crucial for appropriate obstetric management and prognosticating for future pregnancies.

Norman–Roberts syndrome: characterization of the phenotype in early fetal life

Our purpose is to describe the prenatal manifestation of Norman-Roberts syndrome and to expand the knowledge of the fetal phenotype of this rare condition. The recurrence in two sibs might contribute to the hypothesis of a recessive condition. Three cases are presented in which the diagnosis was suggested by a prenatal ultrasound examination and confirmed by pathology of the fetuses, after termination of pregnancy. The major sign was the ultrasound detection of microcephaly at the 22nd and 23rd week of gestation. Fetal Magnetic Nuclear Resonance, the pathological examination with histological studies, was applied to arrive at the diagnosis of Norman-Roberts syndrome. To the best of our knowledge, this is the second description of prenatal cases of Norman-Roberts syndrome. The combined clinical and pathological data is a contribution that might help to increase the identification of this rare condition and to correctly define the risk of its recurrence.

Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia de Lange Syndrome with Predominant Mental Retardation

Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.

Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia–Absent Radius Syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).

A homozygous frameshift mutation in the ESCO2 gene: Evidence of intertissue and interindividual variation in Nmd efficiency

Roberts syndrome (RS) is a rare disorder characterized by tetraphocomelia and several other clinical features. Cells from RS patients exhibit characteristic premature separation of heterochromatic region of many chromosomes and abnormalities in cell cycle. Mutations in the ESCO2 gene have recently been identified in 20 RS families. We performed mutational analysis of the ESCO2 gene in two fetuses diagnosed with RS and their normal parents. In both fetuses, we identified homozygosity for the c. 745_746delGT mutation, while the non-consanguineous parents were both heterozygous for the same mutation. Considering the position of the mutation identified, we carried out qualitative and quantitative real-time ESCO2 cDNA analysis on RNA isolated from CVS-stromal cells in one fetus, amniocytes in the second fetus, and lymphocytes from the heterozygous parents. The results of this analysis showed that despite the presence of a premature termination codon (PTC) 112 nucleotides upstream of the next exon3-exon4 junction, the mutant ESCO2 mRNA was present in both fetuses, albeit at low levels, indicating a partial resistance to nonsense mediated decay (NMD). Interestingly, when cells derived from the two fetuses were treated with an inhibitor of translation, they revealed the presence of tissue and individual variability in NMD efficiency, despite the identical mutational status. The existence of such a variation in the NMD efficiency could explain the broad intrafamilial and interfamilial variability in the clinical presentation of RS patients, and in other genetic diseases where nonsense mutations are responsible for most of the mutation load. Moreover, considering that a mutated full length mRNA was produced in both fetuses, we used Western blot analysis to demonstrate the absence of the ESCO2-truncated protein in cells derived from both fetuses and in a lymphoblastoid cell line derived from the parents.

Twin pregnancy with Roberts syndrome in one fetus and trisomy 18 in the other

We report a case of a 26-year-old multigravida pregnant woman with a history of 3 stillbirths with hydrops fetalis who presented with 17 weeks menstrual age. Sonographic examination revealed twin gestation. Twin 1 showed subcutaneous edema, pleural effusion, and mesomelic limb shortening, suggestive of lethal skeletal dysplasia (Roberts syndrome). Twin 2 corresponded to 17 weeks menstrual age with no major malformations. Karyotyping of the fetuses showed normal karyotype in twin 1 and trisomy 18 in twin 2. Fetal autopsy confirmed the sonographic findings. The occurrence of trisomy 18 in the fetus may be due to chance, but it raises the possibility that the heterozygotes of Roberts syndrome may be at higher risk of nondisjunction and aneuploidy in the fetus. Furthermore, this case illustrates that karyotyping of both fetuses is warranted when 1 of the twins is found to have major malformations.

Inactivating Mutations in ESCO2 Cause SC Phocomelia and Roberts Syndrome: No Phenotype-Genotype Correlation

The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3-8 of ESCO2. In two families, affected individuals were homozygous--for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR.

Mullerian Agenesis and Thrombocytopenia Absent Radius Syndrome: A Case Report and Review of Syndromes Associated With Mullerian Agenesis

Mullerian agenesis, commonly referred to as Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS), is a congenital defect that is most commonly associated with renal and spinal malformations. It is very rare for Mullerian agenesis to be accompanied by malformations of the extremities. In this report, we describe a 22-year-old woman with Mullerian agenesis and thrombocytopenia absent radius syndrome (TARS). We also review rare syndromes associated with Mullerian anomalies, including Mullerian hypoplasia/aplasia-renal agenesis-cervicothoracic somite dysplasia (MURCS), Roberts syndrome, Bardet-Biedl syndrome (BBS), McKusick-Kaufman syndrome (MKS), Wolf-Hirschhorn syndrome, and others. The pathogenesis of these complex malformation syndromes is not well understood as a result of their sporadic occurrence. However, some of these syndromes do follow a pattern of inheritance, suggesting that they could provide insights into our understanding of their origins. Obstetricians & Gynecologists, Family Physicians After completion of this article, the reader should be able to review the rare congenital defects associated with Mullerian agenesis, to determine the genetic etiologies of the associated syndromes with Mullerian agenesis, and to discuss information for parental counseling related to inheritance patterns and growth and development of the affected child.

Mapping of a Single Locus Capable of Complementing the Defective Heterochromatin Phenotype of Roberts Syndrome Cells

Roberts syndrome (RS) is a developmental disorder characterized by tetraphocomelia and a broad spectrum of additional clinical features. Most patients with RS exhibit characteristic cytogenetic phenotypes, which include an abnormal appearance of pericentromeric heterochromatin on metaphase chromosomes, referred to as "heterochromatic repulsion." In the present study, we use complementation of this abnormal cytogenetic phenotype as a means to identify a specific region of the normal human genome capable of rendering phenotypic correction. We screened the entire human genome, using a transient chromosome-transfer assay, 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. The results are consistent with the notion that the single gene defect responsible for heterochromatic splaying and developmental abnormalities maps to chromosome 8p21.

Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion

Roberts syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts syndrome in 15 kindreds. 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.

Recapitulation of the Roberts syndrome cellular phenotype by inhibition of INCENP, ZWINT-1 and ZW10 genes

Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reduction of all limbs and growth retardation. Patients have been reported to have premature separation of heterochromatin regions of many chromosomes and abnormalities in cell cycle. Given the rarity of the syndrome, the linkage analysis approach is not suitable to identify the responsible gene. In this work, a cell line derived from a patient affected by Roberts syndrome was characterized by cell biology and molecular cytogenetics, including comparative genomic hybridization and spectral karyotype. No recurrent chromosomal rearrangements were identified. Thereafter, based on the fact that premature chromatide separation is a reliable marker of the disease, we used antisense oligonucleotide technologies to inhibit six genes involved in various steps of the correct chromosome segregation, such as chromosome cohesion, kinetochore assembling, spindle checkpoint and spindle formation. We found that the inhibition of INCENP, ZWINT-1, ZW10 genes results in the appearance of mitotic cells characterised by centromere separation, chromosome aneuploidy and micronuclei formation. In addition, INCENP, ZWINT-1, ZW10 antisense-treated chromosome morphology was very similar to that of Roberts chromosome when analysed by atomic force microscopy. We concluded that INCENP, ZWINT-1, ZW10 gene inhibition results in cellular phenocopies of Roberts syndrome. Taken together, these findings support a possible role of these genes in the pathogenesis of Roberts syndrome.

Genetically determined long bones deficiency – Roberts syndrome, a case report

Roberts syndrome, a genetically determined long bones deficiency inherited in an autosomal recessive way, was first described as phocomelia with cleft palate in 1919. Because of the similarity in clinical picture, Roberts syndrome is also called pseudo-thalidomide syndrome. In 40% of cases the consanguinity of the parents has been stated.

Antenatal Detection of Skeletal Dysplasias

To assess the accuracy of the prenatal diagnosis of skeletal dysplasias. All antenatally detected anomalies are coded in our ultrasound database, which is linked with a genetics database that includes outcomes. A final diagnosis is sought on the basis of radiographic studies, molecular testing, or both. Our ultrasound and genetics databases were queried for "skeletal dysplasias." All cases were reviewed specifically for the degree of bone shortening and other distinguishing characteristics on antenatal sonography. Thirty-seven cases of skeletal dysplasia were antenatally diagnosed over an 8-year period. Complete follow-up was available in 31 cases. The mean gestational age at diagnosis was 22.7 weeks (range, 14-32.3 weeks). Twenty-one cases were diagnosed before 24 weeks. A final diagnosis was obtained in 80% of cases. The antenatal diagnosis was correct in 20 (65%) of 31 cases. There were 2 false-positive diagnoses. Specific final diagnoses included thanatophoric dysplasia (8), osteogenesis imperfecta (6), Roberts syndrome (2), achondroplasia (3), Ellis-van Creveld syndrome (1), metaphyseal dysplasia (1), spondyloepiphyseal dysplasia (1), distal arthrogryposis (1), caudal regression (1), and glycogen storage disorder (1). The condition was correctly thought to be lethal in 16 of the fetuses on the basis of early severe long bone shortening (13), femur length-abdominal circumference ratio of less than 0.16 (12), hypoplastic thorax (10), marked bowing or fractures (4), short ribs (4), caudal regression (1), and cloverleaf skull (1). The ability to predict lethality was 100%. There were no false-positive findings with respect to lethality. Accurate antenatal diagnosis of skeletal dysplasias is problematic; in this series, only 20 of 31 cases were correctly diagnosed. However, the antenatal prediction of lethality was highly accurate. The most common predictors of lethal skeletal dysplasias included early and severe shortening of the long bones, femur length-abdominal circumference ratio of less than 0.16, hypoplastic thorax, and certain distinguishing characteristics.

Unusual chromosome cleavage dynamic in rodent neonatal germ cells.

At the metaphase/anaphase transition in the mouse and rat male germ lines during the perinatal period, sister centromeres separate before sister chromatids. This gives the chromosomes an unusual appearance that resembles the premature centromere division described in some human pathological conditions such as Roberts syndrome. At the same period, there is also an unusual pattern of DNA methylation, with strongly demethylated heterochromatin and methylated euchromatin. This suggests that chromosome DNA methylation may modulate chromatid and centromere splitting, without altering normal chromosome segregation.

Autopsy on a case of Roberts syndrome reported in 1672: the earliest description?

In 1672, François Bouchard reported the autopsy of a male infant discovered on public exhibition at Leiden. The findings of tetraphocomelia more severe in the upper limbs with reduction in the number and length of digits, hydrocephalus, bilateral cleft lip, micrognathia, and cryptorchidism are consistent with a diagnosis of Roberts syndrome. Bouchard did not find internal abnormalities other than hydrocephalus, which he attempted to demonstrate by showing decreased specific gravity of the brain. Death was due to umbilical vein hemorrhage following birth trauma.

Femur-fibula-ulna (FFU) complex in the 33rd week of gestation: ultrasonography, radiology, pathology and differential diagnosis. Case report

We present a case of a 27 year old I. gravida, I. para. Despite of regular ultrasonographic examination the diagnosis of skeletal malformation at the fetus was not before 33. weeks of gestation. It was the rare type of a bothside femur-fibula-ulna (FFU) complex. The FFU-complex is a no lethal malformation with typical unilateral combination from defects of femur and fibula, with contralateral defect of ulna. Dependent to involvement of malformated limbs the FFU-complex is classifiable in four groups. Only in 10 % all limbs are affected. Our case (type IV) showed a peromelia of both upper limbs with stumps of humeri, bothside aplasia of fibula and missing from 4. and 5. toes. There fetus were without nonlimb congenital abnormalities. The etiology of FFU-complex is unknown, the occurrence sporadic. There are never found genetic abnormalities. Familial recurrence is not described. There is no maternal or paternal age effect on FFU-complex. The differential diagnosis must include malformations with reduction anomalies of extremities, like thalidomide syndrome, splenogonadal fusion with limb malformations, Roberts syndrome, oroacral complex or acheiropodia. Mark off are amniotic band too.

Norman–Roberts syndrome: prenatal diagnosis and autopsy findings

Norman–Roberts syndrome: prenatal diagnosis and autopsy findings

Norman–Roberts syndrome: prenatal diagnosis and autopsy findings

We report on the autopsy findings of a male fetus in the 27th week of gestation with Norman-Roberts syndrome. The unaffected parents are first cousins and have a five-year-old child with a low, sloping forehead, broad and prominent nasal bridge, widely set eyes, severe psychomotor retardation, and an agyric cortex. Prenatal diagnosis showed a small head at the 25th week of gestation. At this time, a slowing-down of the growth of the sonographic measurements of the biparietal diameter and head circumference was found. Both the biparietal diameter (57 mm, <5th percentile) and the head circumference (207 mm, <5th percentile) showed a delay of at least two weeks in comparison with other non-cephalic somatometric parameters, that were normal for the gestational age (femur length: 46 mm=median value). After termination of pregnancy, post-mortem examination showed a normotrophic fetus with microcrania and marked microcephaly (brain weight: 50 g), low, sloping forehead, broad and prominent nasal bridge, and widely set eyes. The cerebral hemispheres displayed an almost completely smooth surface with poorly defined sylvian fissures and failure of operculization of the insula. Microscopic examination showed a predominantly four-layered cortex (lissencephaly type I). Karyotype was normal and in situ hybridization did not show any deletion in the Miller-Dieker/isolated lissencephaly critical region on 17p13.3. The syndromes with lissencephaly are reviewed.