Information on the following diseases can be found in the Related Disorders section of this report:

• Thrombocytopenia-Absent Radius (TAR) Syndrome

The symptoms associated with Roberts syndrome vary widely from case to case even among members of the same family. Most infants experience growth deficiencies and have abnormalities of the limbs and craniofacial region. Infants with Roberts syndrome often experience life-threatening complications early in infancy.

Affected infants may experience growth deficiencies before and after birth (pre- and postnatally). Mental retardation is a variable finding that occurs in approximately 50 percent of cases.

Limb abnormalities are common in infants with Roberts syndrome and may range from underdeveloped bones in the arms and legs (hypomelia) to complete absence of all four limbs (tetraphocomelia). The arms are usually more severely affected than the legs.

Additional abnormalities may affect the arms and legs including permanent fixation (contracture) of various joints, especially the knees and elbows. The number of fingers and/or toes may be reduced and the fifth fingers may be in a fixed laterally deviated position (clinodactyly). Webbing of the finger and toes (syndactyly) may also be present. Infants with Roberts syndrome may also have a form of club foot where the heel of the foot may be elevated and turned outward away from the body (talipes equinovalgus).

Infants with Roberts Syndrome also have a variety of craniofacial abnormalities including a small, broad head (microbrachycephaly); an abnormal groove in the upper lip (cleft lip) with or without incomplete closure of the roof of the mouth (cleft palate); a flattened nose with small wings; an abnormally small jaw (micrognathia); sparse, silvery hair; and malformed, low-set ears that often lack lobes. Some infants may experience premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). Affected infants may have eye (ocular) abnormalities including widely spaced eyes (hypertelorism); unusually small eyes (microphthalmia); cloudy corneas; and bulging or prominent eyes (proptosis) due to shallow eye cavities (orbits). In some cases, the whites of the eyes may be blue (blue sclera) and increased pressure within the eyeball (glaucoma) may also be present.

Some infants with Roberts syndrome may have one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries).

Infants with Roberts syndrome often have abnormalities affecting the genitourinary system. Males may have the urinary opening located on the underside of the penis (hypospadias) and the testicles may fail to descend into the scrotum (cryptorchidism). Females may have a malformed uterus with horn-like branches (bicornuate uterus).

Less common symptoms associated with Roberts syndrome include malformed kidneys, an abnormal increase in cerebrospinal fluid resulting in enlargement of the skull (hydrocephalus), paralysis of cranial nerves, seizures, heart defects and a decreased number of blood platelets (thrombocytopenia).

Roberts syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Some cases of Roberts syndrome have had parents who were related by blood (consanguineous). All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Investigators have determined that Roberts syndrome is caused by disruptions or changes of the ESCO2 (establishment of cohesion 1 homolog 2) gene located on the short arm (p) of chromosome 8 (8p21.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes, which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further subdivided into many bands that are numbered. For example, "chromosome 8p21.1" refers to band 21.1 on the short arm of chromosome 8. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Researchers also determined that certain complex chromosomal abnormalities play a role in the development of Roberts syndrome. Most affected individuals experience premature centromere separation in miotic cells of various chromosomes, especially chromosomes 1, 9, and 16, a phenomenon often referred to as "puffing." The centromere is the center of a chromosome located between the long and short arms of a chromosome. Researchers believe that the characteristic "puffing" abnormality occurs during mitosis, the process in which a cell divides ultimately forming two cells identical to the original.

Roberts syndrome affects males and females in equal numbers. The incidence of Roberts syndrome is unknown.

Symptoms of the following disorders can be similar to those of Roberts syndrome. Comparisons may be useful for a differential diagnosis:

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhaging) primarily during infancy. Other characteristic findings include absence (aplasia) of the bones on the thumb side of the forearms (radii) and underdevelopment (hypoplasia) or absence of the bones on the "pinky" side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or mental retardation that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "TAR syndrome" as your search term in the Rare Disease Database.)

Baller-Gerold syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In infants with Baller-Gerold syndrome, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Affected infants may also have a prominent forehead; downslanting eyelid folds (palpebral fissures); small, malformed (dysplastic), low-set ears; and/or other craniofacial abnormalities. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the thumb side of the forearms (radii). In addition, the bone on the "pinky" side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. In some cases, additional physical abnormalities and/or mental retardation may also be present. Baller-Gerold syndrome is thought to be inherited as an autosomal recessive trait. (For more information on this disorder, choose "Baller Gerold" as your search term in the Rare Disease Database.)

Holt-Oram syndrome (HOS), also known as Cardiac-Limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic) or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper and/or lower chambers of the heart (atrial and/or ventricular septal defects), or abnormal transmission of electrical impulses that coordinate the heart's muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited as an autosomal dominant trait or appear to occur spontaneously due to new genetic mutations. (For further information, choose "Holt Oram" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of Roberts syndrome is suspected based upon a thorough clinical evaluation, detailed patient history and identification of characteristic abnormalities. A diagnosis may be confirmed by chromosomal analysis that detects characteristic premature centromere separation (puffing) on various chromosomes. Absence of puffing does not exclude the diagnosis, as it was reported to be absent in some clinically diagnosed cases.

In some cases, it is possible that a diagnosis of Roberts syndrome may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis, chorionic villus sampling (CVS), or ultrasonography. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such fluid or tissue samples may reveal premature centromere separation (puffing) in miotic cells. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain developmental abnormalities suggestive Roberts syndrome (e.g., limb abnormalities).

Treatment
The treatment of Roberts syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, neurologists, eye specialists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Individuals with Roberts Syndrome may benefit from surgery for facial and limb defects. Prosthetic devices can also reduce problems associated with missing limbs.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Dr. Uta Francke of the Stanford University School of Medicine is conducting a study of Roberts Syndrome and is in need of more patients, their brothers and sisters who do not show symptoms of the syndrome, and their parents to participate in the study. If you are interested, please contact:

Uta Francke, M.D.
Department of Genetics
Stanford University School of Medicine
Beckman Center for Molecular and Genetic Medicine B203
Stanford, CA 94305-5323
(650) 725-8089
ufrancke@stanford.edu

TEXTBOOKS
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Jones KL., ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:298.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:735-8.

JOURNAL ARTICLES
Schule B, Oviedo A, Johnston K, Pai S, Francke U. Inactivating mutations in ESCO2 cause SC Phocomelia and Roberts syndrome: no phenotype-genotype correlation. Am J Med Genet. 2005;117-28.

Hwang K, et al. Roberts syndrome, normal cell division, and normal intelligence. J Craniofacial Surg. 2002;13:390-4.

Maheshwari A, et al. Roberts-SC phocomelia syndrome. Indian J Pediatr. 2001;68:557-9.

McDaniel LD, et al. Novel assay for Roberts syndrome assigns variable phenotypes to one complementation group. Am J Med Genet. 2000;93:223-9.

Camlibel T, et al. Roberts SC phocomelia with isolated cleft palate, thrombocytopenia, and eosinophilia. Genet Couns. 1999;10:157-61.

Petrikovsky BM, et al. Prenatal diagnosis of pseudothalidomide syndrome in consecutive pregnancies of a consanguineous couple. Ultrasound Obstet Gynecol. 1997;10:425-8.

Concolino D, et al. A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of upper limbs. Clin Genet. 1996;49:274-6.

Van den Berg DJ, Francke U. Roberts syndrome: a review of 100 cases and a new rating system for severity. Am J Med Genet. 1993;15:1104-23.

Van den Berg DJ, Francke U. Sensitivity of Roberts syndrome cells to gamma radiation, mitomycin C, and protein synthesis inhibitors. Somat Cell Mol Genet. 1993;19:377-92.

Holden KR, Jabs EW, Sponseller PD. Roberts/pseudothalidomide syndrome and normal intelligence: approaches to diagnosis and management. Dev Med Child Neurol. 1992;34:534-9.

Sherer DM, et al. Prenatal sonographic features and management of a fetus with Roberts-SC phocomelia syndrome (pseudothalidomide syndrome) and pulmonary hypoplasia. Am J Perinatol. 1991;8:259-62.

Keppen LD, et al. Roberts syndrome with normal cell division. Am J Med Genet. 1991;38:21-4.

Romke C, et al. Roberts syndrome and SC phocomelia. A single genetic entity. Clin Genet. 1987;31:170-7.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:268300; Last Update:3/17/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=268300 Accessed on: 9/15/2004.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:269000; Last Update:4/16/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=269000 Accessed on: 9/15/2004.