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

• Coffin-Lowry syndrome
• Juberg-Marsidi syndrome
• Smith-Fineman-Myers syndrome
• Alpha thalassemia/mental retardation chromosome 16 (ATR-16) syndrome

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. In some cases, affected individuals do not walk independently or fail to develop the ability to speak outside of a limited vocabulary. Mental retardation, 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 (midface 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).

In many cases, 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).

In some cases, 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 trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. If they reproduce, males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. 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% to have a son affected with the disease, and a 25% chance to have an unaffected son.

Investigators have determined that ATR-X syndrome occurs due to disruption or changes (mutations) to the X-linked nuclear protein (XNP) 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 XNP 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. The X chromosome carrying the mutated XNP gene is always inactivated (preferential inactivation).

ATR-X syndrome affects males. Female carriers of the mutated gene do not develop symptoms. According to the medical literature more than 150 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.

Symptoms of the following disorders can be similar to those of ATR-X syndrome. Comparisons may be useful for a differential diagnosis.

Coffin-Lowry syndrome is a rare genetic disorder characterized by mental retardation; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RSK2 gene and is inherited as an X-linked dominant genetic trait. Males are usually more severely affected than females. (For more information on this disorder, choose "Coffin Lowy syndrome" as your search term in the Rare Disease Database.)

Juberg-Marsidi syndrome is an extremely rare X-linked inherited disorder that is fully expressed in males only, and is apparent at birth (congenital) or during the first few weeks of life (neonatal period). Affected children exhibit severe mental retardation; delays in reaching developmental milestones (e.g., crawling, walking, etc.); muscle weakness; diminished muscle tone (hypotonia); and/or delayed bone growth as well as growth retardation, resulting in short stature. Affected infants also exhibit hearing loss; underdevelopment of the genitals (microgenitalism); and/or abnormalities of the head and facial (craniofacial) area such as an abnormally small head (microcephaly), a flat (depressed) nasal bridge, eye (ocular) abnormalities, and/or, in some cases, additional physical abnormalities. The range and severity of symptoms may vary from case to case. Juberg-Marsidi syndrome is inherited as an X-linked recessive trait. One family with possible Juberg-Marsidi syndrome has a mutation in XNP. (For more information on this disorder, choose "Juberg Marsidi syndrome" as your search term in the Rare Disease Database.)

Smith-Fineman-Myers syndrome is a rare genetic disorder characterized by mental retardation, diminished muscle tone (hypotonia), characteristic facial features, short stature and additional abnormalities. Common findings include an abnormally small jaw (micrognathia), failure of the testes to descend into the scrotum (cryptorchidism), and delays in reaching developmental milestones. Smith-Fineman-Myers syndrome is inherited as an X-linked recessive genetic trait. One family diagnosed as Smith-Fineman-Myers syndrome has a mutation in XNP.

Alpha thalassemia/mental retardation chromosome 16 (ATR-16) syndrome is an extremely rare disorder characterized by mental retardation, which is milder than in ATR-X syndrome, and alpha thalassemia, which is more severe than in ATR-X syndrome. ATR-16 syndrome occurs due to deletions of genes at the end of chromosome 16.

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., mental retardation, 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 mutation of the XNP 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, 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.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
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TEXTBOOKS
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Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:986-7.

Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:278.

JOURNAL ARTICLES
Guillen-Navarro E, Glover-Lopez G. Monogenic causes of X-linked mental retardation. Rev Neurol. 2006;42:S45-9.

Guilano F, Badens C, Richelme C, Levy N, Lambert JC. ATR-X syndrome: a new mutation in the XNP/ATRX gene near the helicase domain. Arch Pediatr. 2005;12:1372-5.

Wada T, Sakakibara M, Fukushima Y, Saitoh S. A novel splicing mutation of the ATRX gene in ATR-X syndrome. Brain Dev. 2005; [Epub ahead of print].

Borgione E, Sturnio M, Spalletta A, et al., Mutational analysis of the ATRX gene by DGGE: a powerful diagnostic approach for the ATRX syndrome. Hum Mutat. 2003;21:529-34.

Gibbons RJ, Higgs DR. Molecular-clinical spectrum of the ATR-X syndrome. Am J Med Genet. 2000;97:204-12.

Wada T, Kubota T, Fukushima Y, Saitoh S. Molecular genetic study of Japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X). Am J Med Genet. 2000;94:242-8.

Gibbons RJ, McDowell TL, Raman S, et al., Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet. 2000;24:368-71.

Bacho S, Gibbons RJ. Germline and gonosomal mosaicism in the ATR-X syndrome. Eur J Hum Genet. 1999;7:933-6.

Fichera M, Romano C, Castiglia L, et al., New mutations in XNP/ATR-X gene: a further contribution to genotype/phenotype relationship in ATR/X syndrome. Mutations in brief no. 176. Online. Hum Mutat. 1998;12:214.

Picketts DJ, Higgs DR, Bachoo S, et al., ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. Hum Mol Genet. 1996;5:1899-1907.

Gibbons RJ, Suthers GK, Wilkie AO, Buckle VJ, Higgs DR. X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis. Am J Med Genet. 1992;51:1136-49.

FROM THE INTERNET
Stevenson RE. Updated:3/24/2006. Alpha-Thalassemia X-Linked Mental Retardation Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:301040; Last Update:11/23/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301040 Entry No:309580; Last Update: 11/23/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=309580