Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia, a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin), is not seen in every case. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition.
Some researchers have suggested the name XLID-hypotonic face syndrome be used to designate several disorders formerly considered separate entities including ATR-X syndrome, Carpenter-Waziri syndrome, Chudley-Lowry syndrome, Holmes-Gang syndrome, and X-linked intellectual disability-arch fingerprints-hypotonia syndrome. All of these syndromes occur due to mutations of the same gene on the X chromosome. The name ATR-X syndrome is the most widely-recognized term for this disorder.
Causes
ATR-X syndrome is inherited as an X-linked recessive genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
If a male with X-linked disorders can reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. No male with ATR-X is known to have reproduced.
ATR-X syndrome occurs due to disruption or changes (mutations) to the ATRX gene located on the long arm (q) of the X chromosome (Xq13.3). 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 sub-divided into many bands that are numbered. For example, “chromosome Xq13.3” refers to band 13.3 on the long arm of the X chromosome. The numbered bands specify the location of the hundreds of genes that are present on each chromosome.
Females who carry the mutated ATRX gene are intellectually normal and do not have clinical symptoms because of a process known as marked skewing of X chromosome inactivation. In this process, early during fetal development, one of a female’s two X chromosomes is inactivated. With rare exceptions, the X chromosome carrying the mutated ATRX gene is inactivated (preferential inactivation).
Diagnosis
ATR-X syndrome may be suspected at birth or during infancy based upon a thorough clinical evaluation and identification of characteristic findings (e.g., intellectual disability, distinctive facial features, genitourinary abnormalities). Blood tests (e.g., brilliant cresyl blue stain) that demonstrate the presence of hemoglobin H inclusion bodies in red blood cells may assist in diagnosis. However, HbH is a variable finding in ATR-X syndrome and failure to detect HbH inclusion bodies does not rule out ATR-X syndrome. A diagnosis of ATR-X syndrome may be confirmed by molecular genetic testing that identifies a mutation of the ATRX gene.
Treatment
The treatment of ATR-X 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, dental specialists, speech pathologists, eye specialists, specialists in treating skeletal disorders (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Early developmental intervention is important in ensuring that affected children with ATR-X syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services.
Genetic counseling will be of benefit to the families of affected individuals. Another treatment for ATR-X syndrome is symptomatic and supportive.
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