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Last updated: 05/17/2023
Years published: 2006, 2010, 2016, 2019, 2023
NORD gratefully acknowledges Roger E. Stevenson, MD, Clinical Geneticist, Equanimitas, Greenwood, SC, for assistance in the preparation of this report.
Summary
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 patient. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition.
Introduction
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 changes (pathogenic variants or 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 person to person. 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 is the most important of the clinical findings, but genital abnormalities, 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 eyesโ 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 infantโs 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), spacing of the teeth 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) and underdevelopment of the scrotum. Rarely, the development of the external genitals will be intermediate between male and female (ambiguous genitalia).
In some patients, 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).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.
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 an abnormal 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 abnormal 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 (pathogenic variants or mutations) in the ATRX gene located on the X chromosome. 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.
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 femaleโs 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 families have been reported by 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. A specific DNA methylation profile is available to help clarify the pathogenicity of alterations of uncertain significance in 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, specialists in treating skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affected childโs 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 is recommended for families of affected individuals.
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: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about alpha thalassemia X-linked intellectual disability syndrome:
Roger E. Stevenson, MD
Equanimitas
105 Wyatt Court
Greenwood, SC 29646
864-992-7562 (voice)
[email protected]
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
JOURNAL ARTICLES
Schwartz CE, Louie RJ, Toutain A, Skinner C, Friez MJ, Stevenson RE. X-linked intellectual disability update 2022. Am J Med Genet A. 2022; online ahead of print.
Aref-Eshghi E, Kerkhof J, Pedro VP, et al. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 mendelian neurodevelopmental disorders. Am J Hum Genet. 2020;109:356-370.
Neri G, Schwartz CE, Lubs HA, Stevenson RE. X-linked intellectual disability update 2017. Am J Med Genet A. 2018;176:1375-88.
Basehore MJ, Michaelson-Cohen R, Levy-Lahad E, et al., Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation โ c.109C>T (p.R37X). Clin Genet. 2015;87:461-6.
Lugtenberg D, de Brouwer AP, Oudakker AR, et al. Xq13.2q21.1 duplication encompassing the ATRX gene in a man with mental retardation, minor facial and genital anomalies, short stature and broad thorax. Am J Med Genet A. 2009;149A(4):760-766. doi:10.1002/ajmg.a.32742
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.
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.
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.
INTERNET
Stevenson RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [Updated 2020 May 28]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1449/ Accessed April 17, 2023.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:301040; Last Update: 12/18/2022. Available at: https://omim.org/entry/301040 Accessed April 17, 2023.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:309580; Last Update: 04/01/2022. Available at: https://omim.org/entry/309580 Accessed April 17, 2023.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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