Roberts syndrome is an extremely rare genetic disorder that is characterized by mild to severe prenatal retardation or disruption of cell division, leading to malformation of the bones in the skull, face, arms, and legs.
The Syndrome is both autosomal, in that there are equal numbers of copies of the gene in both males and females, and recessive, meaning the child must inherit the defective gene from both parents. The mutation causes cell division to occur slowly or unevenly, and the cells with abnormal genetic content die. Roberts syndrome can affect both males and females. Although the disorder is rare, the affected group is diverse. The mortality rate is high in severely affected individuals.
The following is a list of symptoms that have been associated with Roberts syndrome:
- Bilateral Symmetric Tetraphocomelia- a birth defect in which the hands and feet are attached to shortened arms and legs
- Prenatal Growth Retardation
- Hypomelia (Hypoplasia)- the incomplete development of a tissue or organ; less drastic than aplasia, which is no development at all
- Oligodactyly- fewer than normal number of fingers or toes
- Thumb Aplasia- the absence of a thumb
- Syndactyly- condition in which two or more fingers (or toes) are joined together; the joining can involve the bones or just the skin between the fingers
- Clinodactyly- curving of the fifth finger (little finger) towards the fourth finger (ring finger) due to the underdevelopment of the middle bone in the fifth finger
- Elbow/Knee Flexion Contractures- an inability to fully straighten the arm or leg
- Cleft Lip- the presence of one or two vertical fissures in the upper lip; can be on one side (unilateral) or on both sides (bilateral)
- Cleft Palate- opening in the roof of the mouth
- Premaxillary Protrusion- upper part of the mouth sticks out farther than the lower part of the mouth
- Micrognathia- small chin
- Microbrachycephaly- smaller than normal head size
- Malar Hypoplasia- underdevelopment of the cheek bones
- Downslanting Palpebral Fissures- the outer corners of the eyes point downwards
- Ocular Hypertelorism- unusually wide-set eyes
- Exophthalmos- a protruding eyeball
- Corneal Clouding- clouding of the front-most part of the eye
- Hypoplastic Nasal Alae- narrowing of the nostrils that can decrease the width of the nasal base
- Beaked Nose- a nose with a prominent bridge that gives it the appearance of being curved
- Ear Malformations
- Intellectual disability
- Encephalocele (only in severe cases)- rare defect of the neural tube characterized by sac-like protrusions of the brain
Mutations in the ESCO2 gene cause Roberts syndrome. This gene provides instructions for making a protein that is important for proper chromosome separation during cell division. Before cells divide, they must copy all of their chromosomes. The copied DNA from each chromosome is arranged into two identical structures, called sister chromatids. The ESCO2 protein plays an important role in establishing the glue that holds the sister chromatids together until the chromosomes are ready to separate.
A clinical diagnosis of Roberts syndrome is made in individuals with characteristic prenatal growth retardation, limb malformations, and craniofacial abnormalities. The specific characteristics that are looked for in the clinical diagnosis are listed below.
- Prenatal Growth Retardation- low birth length and weight that can range from mild to severe
- Limb Malformations- bilateral symmetric tetraphocomelia, oligodactyly, thumb aplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures
- Craniofacial Abnormalities- bilateral cleft lip and palate, micrognathia, hypertelorism, exophthalmos, down-slanting palpebral fissures, malar hypoplasia, hypoplastic nasal alae, and ear malformations
An official diagnosis of Roberts syndrome relies on cytogenetic testing of the peripheral blood
Cytogenetic preparations that have been stained by either Giemsa or C-banding techniques will show two characteristic chromosomal abnormalities. The first chromosomal abnormality is called premature centromere separation (PCS) and is the most likely pathogenic mechanism for Roberts syndrome. Chromosomes that have PCS will have their centromeres separate during metaphase rather than anaphase (one phase earlier than normal chromosomes). The second chromosomal abnormality is called heterochromatin repulsion (HR). Chromosomes that have HR experience separation of the heterochromatic regions during metaphase. Chromosomes with these two abnormalities will display a "railroad track" appearance because of the absence of primary constriction and repulsion at the heterochromatic regions. The heterochromatic regions are the areas near the centromeres and nucleolar organizers. Carrier status cannot be determined by cytogenetic testing. Other common findings of cytogenetic testing on Roberts syndrome patients are listed below.
- Aneuploidy- the occurrence of one or more extra or missing chromosomes
- Micronucleation- nucleus is smaller than normal
- Multilobulated Nuclei- the nucleus has more than one lobe.
At this point in time, ESCO2 is the only known gene to cause Roberts syndrome mutations. Also, all individuals that have been diagnosed with Roberts syndrome by cytogenetic techniques have also had ESCO2 mutations. Confirmation of a Roberts syndrome diagnosis requires detection of the characteristic chromosomal abnormalities (PCS and HR) or the identification of two ESCO2 mutations that have been linked to Roberts syndrome.
Carrier Testing and Prenatal Diagnosis
Carrier testing for Roberts syndrome requires prior identification of the disease-causing mutation in the family. Carriers for the disorder are heterozygotes due to the autosomal recessive nature of the disease. Carriers are also not at risk for contracting Roberts syndrome themselves. A prenatal diagnosis of Roberts syndrome requires an ultrasound examination paired with cytogenetic testing or prior identification of the disease-causing ESCO2 mutations in the Family.
Genetically Related Disorders
At this time, there are no other phenotypes (observable expressions of a gene) that have been discovered for mutations in the ESCO2 gene.
Mortality is high among those severely affected by Roberts syndrome; however, mildly affected individuals may survive to adulthood.
Treatment of Roberts syndrome is individualized and specifically aimed at improving the quality of life for those afflicted with the disorder. Some of the possible treatments include: surgery for the cleft lip and palate, correction of limb abnormalities (also through surgery), and improvement in prehensile hand grasp development.