Roberts-SC Phocomelia Research Articles

Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.

Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene. Cardinal clinical manifestations are pre- and postnatal growth retardation and craniofacial and limb malformations. Here, we report RBS in a Chinese adolescent with novel biallelic ESCO2 variations and complex cerebrovascular diseases. Medical history, neurological examinations, neuroimaging, and pathology were collected in the proband and the family. Whole exome sequencing (WES) with copy number variation analysis was performed to screen for genetic variations. The clinical features of the proband were craniofacial and limb malformations together with complex cerebrovascular diseases. She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old. Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts. Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy. Whole exome sequencing (WES) identified novel biallelic variations in the ESCO2 gene (c.1220A>T, p.H407L and c.1562delC, p.A521fs). We describe complex cerebrovascular diseases in Roberts syndrome caused by novel ESCO2 biallelic variations. This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts.

A multimodal genetic testing approach to a diagnosis of Roberts-SC phocomelia syndrome, an ESCO2 spectrum disorder

Abstract Diagnosis of a genetic syndrome has traditionally relied upon the identification of characteristic phenotypic findings, followed by targeted laboratory testing. Shared clinical manifestations between genetically distinct syndromes and variable expressivity of findings within a single syndrome can complicate the diagnosis. Multiple testing modalities may be necessary, even when the putative gene(s) is known. We describe the multi-pronged genetic testing applied to a patient with a suspected diagnosis of Roberts- SC phocomelia syndrome (RBS). RBS is an autosomal recessive developmental disorder (OMIM 268300) caused by pathogenic variants in the “establishment of sister chromatid cohesion N-acetyltransferase” (ESCO2 ) gene mapped to chromosome 8p21.1. The ESCO2 enzyme product is a conserved protein with acetyltransferase activity required for formation of the cohesin complex, which, among other activities, maintains sister chromatid association during S-phase of the cell cycle. Because of the defective cohesin complex, RBS joins other syndromes referred to as cohesinopathies. The patient, a newborn male, was small for gestational age, with hypertelorism, cleft lip and palate, shortened forearms, absence of the radius and thumbs, and bilateral clubbed feet. All of these findings are established characteristics of RBS. Targeted Next Generation Sequencing revealed a single variant in exon 10 of ESCO2 (c.1654C>T, p.Arg552*) predicted to result in a loss of function. Chromosomal microarray was also performed and showed an estimated 15 Mb region of homozygosity (ROH) extending from 8p11.21 to 8p21.2, which spans ESCO2. The finding of this ROH supported the interpretation of homozygosity for the variant, as did a family history of consanguinity. Additional cytogenetic analysis documented premature sister chromatid separation and repulsion of heterochromatin chromosomal regions characteristic of RBS. These chromosomal findings served as a functional assay supporting pathogenicity of the ESCO2 variant. Interestingly, the only report of an identical variant within exon 10 of ESCO2 was described for two brothers diagnosed with Juberg-Hayward syndrome. Juberg-Hayward was considered allelic to, but a distinct entity from RBS. In contrast, our findings support the conclusion that RBS and Juberg-Hayward are not distinct syndromes, but rather represent variability within an ESCO2 syndrome spectrum. Such unification of diagnoses based on genomic findings has influenced numerous other clinical disorders. Further, our findings demonstrate the contributions of each of the genetic testing modalities, which may be applied, selectively or collectively, based on integration with clinical and family history data.

Esco2 promotes neuronal differentiation by repressing Notch signaling

Esco2 is an acetyltransferase that is required for the establishment of sister chromatid cohesion. Roberts–SC phocomelia (RBS) syndrome caused by the mutations of Esco2 gene, is an autosomal recessive development disorder characterized by growth retardation, limb reduction and craniofacial abnormalities including cleft lip and palate. Here, we show that Esco2 protein co-immunoprecipitates with Notch but not with CBF1. Esco2 represses the transactivational activity of Notch protein in an acetyltransferase-independent manner. Chromatin immunoprecipitation experiments suggest that Esco2 might regulate the activity of NICD–CBF1 via attenuating NICD binding to CBF1 on the promoter of Hes1, the downstream target gene of Notch. Furthermore, we demonstrate that the overexpression of Esco2 promotes the neuronal differentiation of P19 embryonic carcinoma cells and C17.2 neural progenitor cells and the knockdown of Esco2 by siRNA blocks the differentiation. The inhibitory effects of Notch protein on neuronal differentiation of P19 cells was suppressed by Esco2 overexpression. Taken together, our study suggests that Esco2 may play an important role in neurogenesis by attenuating Notch signaling to promote neuronal differentiation.

Tetra-amelia with lung hypoplasia and facial clefts, Roberts-SC syndrome: report of two cases

Although limb anomalies are a common clinical problem, they are rarely studied. The spectrum of limb anomalies ranges from very mild disorders such as syndactyly to very severe forms such as absent limb (amelia). Tetra-amelia is a rare anomaly with complete or partial deficiency of all four limbs. It may be isolated or associated with other anomalies. Roberts-SC phocomelia syndrome comprises four limb deficiencies, lung hypoplasia, facial clefts and other anomalies. We describe two cases that presented to us.

Heterochromatin and the cohesion of sister chromatids

Heterochromatin, once thought to be the useless junk of chromosomes, is now known to play significant roles in biology. Underlying much of this newfound fame are links between the repressive chromatin structure and cohesin, the protein complex that mediates sister chromatid cohesion. Heterochromatin-mediated recruitment and retention of cohesin to domains flanking centromeres promotes proper attachment of chromosomes to the mitotic and meiotic spindles. Heterochromatin assembled periodically between convergently transcribed genes also recruits cohesin, which promotes a novel form of transcription termination. Heterochromatin-like structures in budding yeast also recruit cohesin. Here the complex appears to regulate transcriptional silencing and recombination between repeated DNA sequences. The link between heterochromatin and cohesin is particularly relevant to human health. In Roberts-SC phocomelia syndrome, heterochromatic cohesion is selectively lost due to mutation of the acetyltransferase responsible for cohesin activation. In this review I discuss recent work that relates to these relationships between heterochromatin and cohesin.

Cohesin and Human Disease

Cornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein subunits and more than 25 additional proteins involved in its regulation. The discovery that this complex also has a fundamental role in long-range regulation of transcription in Drosophila has shed light on the mechanism likely responsible for its role in development. In addition to the three cohesin proteins involved in CdLS, a second multisystem, recessively inherited, developmental disorder, Roberts-SC phocomelia, is caused by mutations in another regulator of the cohesin complex, ESCO2. Here we review the phenotypes of these disorders, collectively termed cohesinopathies, as well as the mechanism by which cohesin disruption likely causes these diseases.

Roles of the sister chromatid cohesion apparatus in gene expression, development, and human syndromes

The sister chromatid cohesion apparatus mediates physical pairing of duplicated chromosomes. This pairing is essential for appropriate distribution of chromosomes into the daughter cells upon cell division. Recent evidence shows that the cohesion apparatus, which is a significant structural component of chromosomes during interphase, also affects gene expression and development. The Cornelia de Lange (CdLS) and Roberts/SC phocomelia (RBS/SC) genetic syndromes in humans are caused by mutations affecting components of the cohesion apparatus. Studies in Drosophila suggest that effects on gene expression are most likely responsible for developmental alterations in CdLS. Effects on chromatid cohesion are apparent in RBS/SC syndrome, but data from yeast and Drosophila point to the likelihood that changes in expression of genes located in heterochromatin could contribute to the developmental deficits.

Limb/pelvis hypoplasia/aplasia with skull defect (Schinzel phocomelia): Distinctive features and prenatal detection

Schinzel phocomelia syndrome is characterized by limb/pelvis hypoplasia/aplasia: specifically, intercalary limb deficiencies and absent or hypoplastic pelvic bones. The phenotype is similar to that described in a related multiple malformation syndrome known as Al-Awadi/Raas-Rothschild syndrome. The additional important feature of large parietooccipital skull defects without meningocele, encephalocele, or other brain malformation has thus far been reported only in children with Schinzel phocomelia syndrome. We recently evaluated a boy affected with Schinzel phocomelia born to nonconsanguineous healthy parents of Mexican origin. A third-trimester fetal ultrasound scan showed severe limb deficiencies and an absent pelvis. The infant died shortly after birth. Dysmorphology examination, radiographs, and autopsy revealed quadrilateral intercalary limb deficiencies with preaxial toe polydactyly; an absent pelvis and a 7 x 3-cm skull defect; and extraskeletal anomalies including microtia, telecanthus, micropenis with cryptorchidism, renal cysts, stenosis of the colon, and a cleft alveolar ridge. A normal 46,XY karyotype was demonstrated, and autosomal recessive inheritance was presumed on the basis of previously reported families. This case report emphasizes the importance of recognizing severe pelvic and skull deficiencies (either post- or prenatally) in differentiating infants with Schinzel phocomelia from other multiple malformation syndromes that feature intercalary limb defects, including thalidomide embryopathy and Roberts-SC phocomelia.

Roberts‐SC phocomelia syndrome: a case with additional anomalies

Roberts-SC phocomelia syndrome (RS) is an autosomal recessive disorder with symmetric limb defects, craniofacial abnormalities, pre- and postnatal growth retardation and mental retardation. Patients with RS were reported to have premature separation of heterochromatin of many chromosomes. We report an infant whose clinical, radiologic and chromosomal findings resemble those of RS, with rudimentary gallbladder and accessory spleen. This patient may represent a variant of RS.

Prenatal Sonographic Features and management of a Fetus with Roberts-SC Phocomelia Syndrome (Pseudothalidomide Syndrome) and Pulmonary Hypoplasia

The Roberts-SC phocomelia syndrome (pseudothalidomide syndrome) is a rare, usually lethal condition involving short limbs and occasional hydrocephalus. Presented is a case in which prenatal sonographic findings were highly suggestive of this syndrome, although not definite. In this fetus, findings of hydrocephalus, short limbs, and probable pulmonary hypoplasia changed the intrapartum management. The findings, correlated with the postmortem radiography, led to diagnosis of probable Roberts-SC syndrome.

Roberts syndrome with normal cell division

Roberts-SC phocomelia syndrome (RS) is an autosomal recessive disorder of symmetric limb defects, craniofacial abnormalities, pre- and postnatal growth retardation, and mental retardation. Patients with RS have been reported to have premature separation of heterochromatin of many chromosomes and abnormalities in the cell-division cycle. We report an infant whose clinical and radiologic findings resemble those of RS but who lacks the cytogenetic and cell division abnormalities reported in RS. This patient may represent a variant of RS or a new syndrome.