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NORD gratefully acknowledges Uta Francke, MD, Department of Genetics, Stanford University School of Medicine, for assistance in the preparation of this report.
ESCO2 spectrum disorder includes conditions caused by changes (variants or mutations) in the ESCO2 gene that range from Roberts syndrome at the severe end to SC phocomelia at the milder end. Roberts syndrome is the best known and most widely studied condition in this group. These conditions are inherited in an autosomal recessive pattern.
Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth, malformations of the arms and legs, and distinctive abnormalities of the skull and facial (craniofacial) region. Intellectual disability occurs in about half of affected children. In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities), however, such limb defects are usually symmetrical which are distinct from the asymmetrical limb defects in Cornelia de Lange syndrome (CdLS). Such abnormalities may range from absence of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of certain bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or on the outside of the lower legs (fibulae). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); abnormal grooves on either side of the upper lip (bilateral cleft lip); incomplete development of the roof of the mouth (cleft palate); thin, small wings of the nose (hypoplastic nasal alae) and/or low-set, malformed (dysplastic) ears. Additional abnormalities are often present.
Initially, researchers believed that Roberts syndrome and SC phocomelia syndrome were separate disorders. However, researchers now believe that the two disorders are different expressions of one distinct disorder because different changes in the same gene are the underlying cause for both conditions. Juberg-Hayward syndrome is a malformation syndrome characterized by cleft lip/palate, microcephaly, drooping upper eye lids (ptosis), short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction.
The symptoms associated with Roberts syndrome vary widely from person to person 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. Intellectual disability is a variable finding that occurs in approximately 50 percent of affected children.
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 children, 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).
The ESCO2 spectrum disorders, including Roberts syndrome, are caused by changes (variants or mutations) in the ESCO2 gene.
Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. There are certain complex chromosomal abnormalities which are distinguishing features of ESCO2 spectrum disorders. Cells from affected individuals show premature centromere separation 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. The characteristic “puffing” abnormality is apparent in mitosis, the process in which a cell divides ultimately forming two cells identical to the original.
ESCO2 spectrum disorders, including Roberts syndrome, are inherited in an autosomal recessive pattern. Genetic diseases of this type are determined by two abnormal genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
It is also possible that a new mutation in an autosomal dominant gene could be the cause of Roberts syndrome in some families. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
ESCO2 spectrum disorders affect males and females in equal numbers. Affected children often have parents who are blood relatives. Patients have been reported from all over the world. The two families with Juberg-Hayward syndrome were identified in a tribe in Thailand with the identical ESCO gene mutation.
A diagnosis of ESCO2 spectrum disorders, including Roberts syndrome, is suspected based upon a thorough clinical evaluation, detailed patient history and identification of characteristic abnormalities. A diagnosis may be supported by chromosomal analysis that detects characteristic premature centromere separation (puffing) on various chromosomes. The diagnosis is confirmed by molecular testing for ESCO2 gene mutations. The presence of mutations in this gene is strictly correlated with the centromere puffing phenomenon.
In some children, it is possible that a diagnosis of ESCO spectrum disorder 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. In families with high risk where both parents are carriers, DNA sequencing of fetal samples can detect an ESCO2 mutation. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain developmental abnormalities suggestive of the diagnosis (e.g., cleft lip/palate, limb abnormalities).
The treatment of ESCO spectrum disorder 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 plan an affected child’s treatment systematically and comprehensively.
Patients may benefit from surgery for facial and limb defects. Prosthetic devices can also reduce problems associated with missing limbs.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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