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Alpha Thalassemia X-linked Intellectual Disability Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 2006, 2010

NORD is very grateful to Roger E. Stevenson, MD, Director, Greenwood Genetic Center, JC Self Research Institute of Human Genetics, for assistance in the preparation of this report.

Synonyms of Alpha Thalassemia X-linked Intellectual Disability Syndrome

Disorder Subdivisions

General Discussion

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 mental retardation, characteristic facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia, which is 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. Some researchers prefer use of the name ATR-X syndrome because it is the most widely-recognized term for this disorder.

Symptoms

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. 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). In some cases, affected males do not have the typical facial features or the typical features become less apparent with age.

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).

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 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.

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).

Affected Populations

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

Related Disorders

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 intellectual disability; 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, down-slanting 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 condition. Males are usually more severely affected than females. (For more information on this disorder, choose "Coffin-Lowry 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 intellectual disability; 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 although one family diagnosed with Juberg-Marsidi syndrome had a mutation in XNP the original family has a mutation in a different XLID gene (HUWE1). (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 intellectual disability, 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 condition. One family diagnosed as Smith-Fineman-Myers syndrome had a mutation in XNP, but the original family has not been studied at a molecular level.

Alpha thalassemia/intellectual disability chromosome 16 (ATR-16) syndrome is an extremely rare disorder characterized by intellectual disability, 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.

Standard Therapies

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 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.

Investigational Therapies

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, contact:
www.centerwatch.com

Contact for additional information about alpha thalassemia X-linked intellectual disability syndrome:

Roger E. Stevenson, MD, Director
Greenwood Genetic Center
JC Self Research Institute of Human Genetics
113 Gregor Mendel Circle
Greenwood, SC 29646
864-941-8146 (voice)
864-388-1707 (fax)
res@ggc.org

Organizations related to Alpha Thalassemia X-linked Intellectual Disability Syndrome

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

References

TEXTBOOKS
Abidi FE and Stevenson RE. XLMR-Hypotonic Facies Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:274.

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.

Wada T, Sakakibara M, Fukushima Y, Saitoh S. A novel splicing mutation of the ATRX gene in ATR-X syndrome. Brain Dev. 2006 ;5:322-5.

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.

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:6/3/2010. 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:5/12/10. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301040

Entry No:309580; Last Update:11/13/08. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=309580

Report last updated: 2010/09/15 00:00:00 GMT+0