NORD gratefully acknowledges Roger E. Stevenson, MD, Senior Clinical Geneticist, Greenwood Genetic Center, JC Self Research Institute of Human Genetics, for assistance in the preparation of this report.
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.
The specific signs and symptoms present and their severity vary greatly from case to case. Many of the signs associated with ATR-X syndrome are apparent during infancy. Affected infants may exhibit diminished muscle tone (hypotonia), feeding difficulties and significant delays in reaching developmental milestones especially speaking or walking. Some affected individuals do not walk independently or fail to develop the ability to speak outside of a limited vocabulary. Intellectual disability, seizures, and stiff movements of the legs also occur. Growth deficiency occurs after birth (postnatally), but may not become apparent until adolescence. Ultimately, growth deficiency may result in short stature.
Individuals with ATR-X syndrome have characteristic facial features including an abnormally large space between the eyes (hypertelorism), vertical skin folds (epicanthal folds) that may cover the eyes’ inner corners, underdevelopment of the middle portion of the face (mid-face hypoplasia), an abnormally flat bridge of the nose, and a small triangular nose. Most infants also have microcephaly, a finding that indicates that the head circumference is smaller than would be expected for an infant’s age and sex. Additional features include an abnormally large, protruding tongue, improper positioning of the teeth of the upper jaw in relation to those of the lower jaw (malocclusion), and abnormal configuration of the outer, visible portions of the ears (pinnae). Some affected males do not have the typical facial features or the typical features become less apparent with age.
Many affected individuals have abnormalities of the genitourinary tract including failure of the testes to descend into the scrotum (cryptorchidism), unusual placement of the urinary opening (meatus) on the underside of the penis (hypospadias), an abnormal fold of skin extending around the base of the penis (shawl scrotum), and underdevelopment of the scrotum. In rare cases, the development of the external genitals will be intermediate between male and female (ambiguous genitalia).
Some affected individuals may have alpha thalassemia, a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin). The form of alpha-thalassemia associated with ATR-X syndrome is called hemoglobin H (HbH) disease, which may result in low levels of circulating red blood cells (anemia). This is usually not symptomatic or clinically significant.
In some cases, anomalies of the skeletal system may be present including shortening of the fingers and toes (brachydactyly), permanent fixation of certain fingers in a bent position (clinodactyly), joint contractures, and abnormal side-to-side and front-to-back curvature of the spine (kyphoscoliosis).
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 is able to 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).
ATR-X syndrome affects males. More than 200 cases have been reported to laboratories conducting molecular genetic testing. However, because this disorder is underdiagnosed it is difficult to determine its true frequency in the general population. Female carriers of the mutated gene do not usually develop any manifestations.
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.
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, and 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. Other treatment for ATR-X syndrome is symptomatic and supportive.
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Contact for additional information about alpha thalassemia X-linked intellectual disability syndrome:
Roger E. Stevenson, MD, Senior Clinical Geneticist
Greenwood Genetic Center
JC Self Research Institute of Human Genetics
113 Gregor Mendel Circle
Greenwood, SC 29646
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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