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Alpha-Thalassemia X-Linked Intellectual Disability Syndrome.


Stevenson RE.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2000 Jun 19 [updated 2014 Nov 06].



Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies, severe developmental delays, hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the lower lip with coarsening of the facial features over time. Although all affected individuals have a normal 46,XY karyotype, genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Global developmental delays are evident in infancy and some affected individuals never walk independently or develop significant speech.


The diagnosis of ATRX syndrome is established in individuals with somatic abnormalities, intellectual disability, hypotonia, abnormal hemoglobin H production, and a family history consistent with X-linked inheritance. ATRX is the only gene in which mutation causes ATRX syndrome.


Treatment of manifestations: Calorie-dense formula and/or gavage feeding as needed for adequate nutrition; anticholinergics, botulinum toxin type A injection of the salivary glands, and/or surgical redirection of the submandibular ducts for excessive drooling; early intervention programs and special education. Prevention of secondary complications: Antibiotic prophylaxis and vaccination to prevent pneumococcal and meningococcal infection in those with asplenia. Surveillance: Regular assessment of growth in infancy and childhood; regular monitoring of developmental progress. Other: Anemia rarely requires treatment.


ATRX syndrome is inherited in an X-linked manner. The mother of a proband may be a carrier or the affected individual may have a de novo mutation. Carrier women have a 50% chance in each pregnancy of transmitting the ATRX pathogenic variant; offspring with a 46,XY karyotype who inherit the ATRX pathogenic variant will be affected; offspring with a 46,XX karyotype who inherit the pathogenic variant are unaffected female carriers. Affected individuals do not reproduce. Carrier testing for at-risk females and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

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