Roberts syndrome (RS) is a rare autosomal recessive cohesinopathy caused by biallelic mutations in ESCO2, essential for sister chromatid cohesion and genomic stability. Clinically, RS manifests as severe pre- and postnatal growth restriction, tetraphocomelia, craniofacial anomalies, and variable visceral organ malformations. Prenatal suspicion is often raised by ultrasonographic evidence of limb reduction and fetal hypotrophy. However, diagnosis remains elusive without molecular confirmation. This case underscores the diagnostic and prognostic value of next-generation sequencing in suspected RS, particularly within consanguineous populations where autosomal recessive conditions are more prevalent. A four-month-old male infant, born to consanguineous parents, was referred for evaluation of multiple congenital anomalies. Prenatal ultrasonography demonstrated significant intrauterine growth restriction, bilateral upper limb absence of radius and ulna at 22 weeks, and unilateral renal pelvis dilation at 38 weeks. Postnatal findings included bilateral phocomelia, thumb aplasia, and flexion contractures at the elbows and knees. Physical examination revealed features consistent with cohesinopathy. Whole exome sequencing identified a homozygous pathogenic variant in ESCO2, confirming RS. Multisystemic involvement warranted early multidisciplinary coordination and genetic counseling for recurrence risk. This case supports redefining isolated limb anomalies as early indicators warranting targeted prenatal genetic screening for cohesinopathies like RS.

ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening of the upper and/or lower limbs), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia), flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations), and ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities). Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected infants; mildly affected individuals may survive to adulthood. The diagnosis of ESCO2 spectrum disorder is established in a proband with suggestive clinical findings and either biallelic pathogenic variants in ESCO2 identified by molecular genetic testing or premature centromere separation identified by cytogenetic testing. Treatment of manifestations: Individualized treatment to improve quality of life; feeding and nutrition support; management of limb malformations through a multidisciplinary neuromuscular clinic including orthopedics, physical medicine, and physical and occupational therapy with adaptative devices, prostheses, therapy, stretching, night splints, and casts as needed; hand surgery as needed to facilitate early development of prehensile grasp and improve motor function; specialized bottle and surgery for cleft lip and/or palate; surgical treatment for craniosynostosis and micrognathia; treatment of ocular issues per ophthalmologist; developmental and educational support including speech therapy; standard treatment for ophthalmologic, cardiac, urogenital, and kidney abnormalities; prompt treatment of infection with management per infectious disease specialist; treatment of stroke per neurologist; treatment of malignancy per oncologist; family and social support. Surveillance: Assess growth, limb mobility and function, development and educational needs, blood pressure, frequency of infections, and home adaptation needs at each visit; assessment of feeding, speech development, and hearing (in those with cleft lip and palate) per craniofacial team; kidney function tests annually; follow up for ophthalmologic and cardiac anomalies per treating physicians; physical examination including full skin and neurologic examination for evidence of malignancy annually; referral to neurologist including brain imaging for vascular anomalies and aneurysms in those with intellectual disability, corneal opacities, and/or heart defects; assess for clinical manifestations of aneurysms and vascular malformations annually starting in adolescence; serum immunoglobulin levels in infancy. ESCO2 spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ESCO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ESCO2 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. Prenatal testing for pregnancies at increased risk is also possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling in conjunction with ultrasound examination.

The cohesin complex is composed of core ring proteins (Smc1, Smc3 and Mcd1) and associated factors (Pds5, Scc3, and Rad61) that bind via Mcd1. Extrusion (looping from within a single DNA molecule) and cohesion (the tethering together of two different DNA molecules) underlie the many roles that cohesins play in chromosome segregation, gene transcription, DNA repair, chromosome condensation, replication fork progression, and genome organization. While cohesin functions flank the activities of critical cell checkpoints (including spindle assembly and DNA damage checkpoints), the extent to which checkpoints directly target cohesins, in response to aberrant cohesin function, remains unknown. Based on prior evidence that cells mutated for cohesin contain reduced Mcd1 protein, we tested whether loss of Mcd1 is based simply on cohesin instability or integrity. The results show that Mcd1 loss persists even in rad61 cells, which contain elevated levels of stable chromosome-bound cohesins, and also in scc2-4, which do not affect cohesin complex integrity. In fact, re-elevating Mcd1 levels suppresses the temperature-sensitive growth defects of all cohesin alleles tested, revealing that Mcd1 loss is a fundamental mechanism through which cohesins are inactivated to promote cell lethality. Our findings further reveal that cells that exhibit aberrant cohesin function employ E3 ligases (such as San1) to target Mcd1 for degradation. This mechanism of degradation appears unique in that Mcd1 is reduced during S phase, when Mcd1 levels typically peak and despite a dramatic upregulation in MCD1 transcription. We infer from these latter findings that cells contain a negative feedback mechanism used to maintain Mcd1 homeostasis.

The cohesin protein complex plays a very important role in chromosome segregation, transcription, DNA replication and chromosome condensation. Mutations in cohesin proteins give rise to a disease collectively referred to as Cohesinopathies. The major cause of cohesinopathies arise due to defects associated with gene expression, that give rise to developmental disorders. We have used Saccharomyces cerevisiae to mimic the cohesinopathy disorder Roberts syndrome with mutations (eco1W216G) homologous to that of humans (esco2). Our data suggests that polyol sugars like sorbitol, can repair misfolded proteins and reduce ER and proteostatic stress. We have used sorbitol as a chemical chaperone, to check how it can restore chromosome segregation, gene expression, misregulation, protein misfolding, autophagy and translational defects in the cohesin mutant of the Roberts' phenotype. Molecular docking has helped us identify the possible sites on Eco1, which could possibly alter the phenotypic traits.

Cerebellofaciodental syndrome (CFDS) (OMIM# 616202) is an autosomal recessive neurodevelopmental disorder with an incidence of one in 10 000 000. To date, only 15 cases have been reported in the literature. It is characterized by dysmorphic features, microcephaly, short stature, intellectual disability, and central nervous system anomalies. Here, we describe a case presenting with short long bones, restricted limb movements, and growth restriction during the antenatal period. After birth, the infant exhibited facial dysmorphism, microcephaly, a bell-shaped thorax, short extremities, brachydactyly, clinodactyly, and a short penis. The clinical features were suggestive of skeletal dysplasia or BRF1-related syndromes. Whole exome sequencing identified a homozygous pathogenic missense variant, c.875C>G (p.Pro292Arg), in the BRF1 gene (NM_001519.4), confirming a diagnosis of CFDS. This case highlights the phenotypic overlap between CFDS and Roberts syndrome, emphasizing the need for a better delineation of the disease's genotypic and phenotypic spectrum. It also underscores that growth failure can be evident before the onset of neurodevelopmental abnormalities and characteristic facial features.