Robert syndrome
Robert syndrome is a rare autosomal recessive developmental disorder characterized by various congenital anomalies, particularly affecting limb and facial development. It arises due to mutations in the ESCO2 gene, which plays a crucial role in cell division and chromatid cohesion. Individuals with Robert syndrome often present with hypomelia, cleft lip and palate, prenatal growth deficiencies, and possible intellectual disabilities. The condition is diagnosed through chromosome analysis, which reveals specific cytogenetic features, alongside molecular genetic testing for ESCO2 mutations.
As Robert syndrome is extremely rare, with approximately 150 cases reported across diverse ethnic backgrounds, the risk of occurrence is heightened in consanguineous couples or those with a family history of the syndrome. Treatment is tailored to individual needs, potentially involving surgical interventions and supportive therapies to address developmental challenges. Prognosis varies significantly; while many severely affected pregnancies may end in stillbirth or early death, some mildly affected individuals may lead fulfilling lives into adulthood. Genetic counseling is recommended for families impacted by this syndrome to better understand risks and management options.
Robert syndrome
ALSO KNOWN AS: Roberts syndrome; Roberts-SC phocomelia syndrome; pseudothalidomide syndrome; SC-phocomelia syndrome; Appelt-Gerken-Lenz syndrome; hypomelia hypotrichosis facial hemangioma syndrome; RBS; SC syndrome; tetraphocomelia-cleft palate syndrome
DEFINITION Robert syndrome is a developmental disorder that affects multiple organ systems, prenatal and postnatal growth, and mental development. It is an autosomal recessive condition caused by mutations in the gene ESCO2.
Risk Factors
Since Robert syndrome is an extremely rare condition, carrier frequency and prevalence are unknown. Approximately 150 cases have been reported in individuals of a variety of ethnic backgrounds. Couples who are consanguineous or have a family history of Robert syndrome are at increased risk for having an affected child.
Etiology and Genetics
Robert syndrome is an autosomal recessive genetic condition. When both parents are carriers of a single mutation ESCO2, there is a 25 percent chance in each pregnancy that the child will inherit both mutation and will be affected with Robert syndrome.
In individuals with Robert syndrome, cytogenetic abnormalities have been noted in the process of cell division. Typically, during metaphase the two sister chromatids of each chromosome are bound closely together. The proteins that bind them together are broken down during anaphase and the sister chromatids separate into sister chromosomes. In individuals with Robert syndrome, the centromeres of the sister chromatids separate during metaphase rather than in anaphase, which is referred to as premature centromere separation. This gives the chromosomes in a metaphase spread a “railroad track” appearance due to the absence of the primary constriction at the centromere. In addition, there is a lack of cohesion in the heterochromatic (dense, genetically inactive) regions of the sister chromatids. This results in “heterochromatin repulsion” or “puffing” around the centromere and in heterochromatic regions, such as in the acrocentric chromosomes and the long arm of the Y chromosome.
Premature centromere separation and separation of the heterochromatic regions are thought to trigger activation of the mitotic spindle checkpoint in metaphase, which delays mitosis and impairs cell proliferation. This impaired proliferation is thought to cause the growth failure associated with Robert syndrome. The congenital anomalies characteristic of Robert syndrome may result from the loss of progenitor cells during embryogenesis.
The gene ESCO2 (Establishment of Cohesion 1 homolog 2) is located at 8p21.1. It codes for the protein N-acetyltransferase ESCO2. This enzyme has been found to have autoacetylation activity in vitro. Most of the ESCO2 mutations that have been described in families with Robert syndrome create a premature stop codon that would result in a truncated protein or instability in mRNA. However, a point mutation that disrupts autoacetylation activity has also been described in an affected individual. Therefore, the inability of this protein to transfer acetyl groups from one compound to another in affected individuals is thought to be involved in the pathogenesis of Robert syndrome. It is thought that ESCO2 is involved in regulating the establishment of sister chromatid cohesion during the S phase of the cell cycle.
Symptoms
Robert syndrome commonly affects the growth and development of the limbs and midface. Affected individuals are born with hypomelia, or incomplete development of the limbs, which is typically more severe in the upper limbs. They may also have cleft lip with or without cleft palate, prenatal onset growth deficiency, intellectual disability, and other congenital anomalies.
Screening and Diagnosis
A diagnosis of Robert syndrome can be made with a routine chromosome analysis using Giemsa or C-banding. Chromosomes have a characteristic appearance due to premature centromere separation and separation of the heterochromatic regions.
In addition, molecular genetic testing for Robert syndrome is available. Sequence analysis of ESCO2 can confirm a diagnosis in an affected individual. Since carrier status cannot be determined from cytogenetic testing, molecular genetic testing must be used for carrier testing. Prenatal diagnosis can be performed on an amniocentesis or chorionic villus sampling with either molecular genetic testing or cytogenetic testing.
Treatment and Therapy
Following an initial diagnosis, evaluations may include X rays and assessments of the limbs, hands, and face; ophthalmologic evaluation; cardiac evaluation; renal ultrasound; and developmental assessment. Treatment would be based on an individual’s specific needs. Limb abnormalities may require reconstructive surgery or prostheses. Facial clefting may require multiple surgeries, speech therapy, and management of recurrent ear infections. Developmental delays may result in a need for special education. Growth and development should be closely monitored.
Prevention and Outcomes
The prognosis for an affected individual depends of the severity of the condition. Many severely affected pregnancies result in stillbirth or early infant death. Mildly affected individuals may survive to adulthood. Although prenatal diagnosis is available for pregnancies at risk based on ultrasound findings or family history, there is no effective means of preventing Robert syndrome. Genetic counseling should be made available to the families of affected individuals.
Bibliography
Canepa, G., Pierre Maroteaux, and V. Pietrogrande. Dysmorphic Syndromes and Constitutional Disease of the Skeleton. Padova: Piccin, 2001. Print.
"ESCO2 Spectrum Disorder." National Organization for Rare Disorders, 8 June 2023, rarediseases.org/rare-diseases/roberts-syndrome/. Accessed 10 Sept. 2024.
Gardner, R. J. McKinlay, Grant R. Sutherland, and Lisa G. Shaffer. Chromosome Abnormalities and Genetic Counseling. 4th ed. New York: Oxford UP, 2012. Print.
Gorlin, Robert J., Michael M. Cohen, Jr., and Raoul C. M. Hennekam. Syndromes of the Head and Neck. 4th ed. New York: Oxford UP, 2001. Print.
Jones, Kenneth Lyons. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Philadelphia: Elsevier, 2013. Print.
Vega, Hugo, Miriam Gordillo, and Ethylin Wang Jabs. “ESCO2 Spectrum Disorder.” GeneReviews, 26 Mar. 2020, www.ncbi.nlm.nih.gov/books/NBK1153/.