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 ocular hypertelorism, small nose, tented upper lip, and prominent or everted 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 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. Molecular genetic testing of ATRX, the only gene associated with ATRX syndrome, is clinically available.
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 gene mutation. Carrier women have a 50% chance in each pregnancy of transmitting the ATRX mutation; offspring with a 46,XY karyotype who inherit the ATRX mutation will be affected; offspring with a 46,XX karyotype who inherit the mutation 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 disease-causing mutation in the family is known.