Alpha-Thalassemia X-Linked Intellectual Disability Syndrome

Clinical characteristics: Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.

Diagnosis/testing: The diagnosis of ATR-X syndrome is established in a proband with suggestive findings, a 46,XY karyotype, and a hemizygous pathogenic variant in ATRX identified by molecular genetic testing.

Management: Treatment of manifestations: DD/ID, seizures, gastrointestinal manifestations and feeding difficulties, excessive drooling, and genital anomalies are managed per standard of care. Surveillance: Regular assessment of growth and developmental progress in infancy and childhood.

Genetic counseling: ATR-X syndrome is inherited in an X-linked manner. The mother of a proband may be heterozygous (i.e., a carrier) or the affected individual may have a de novo pathogenic variant. If the mother of the proband has an ATRX pathogenic variant, the chance of transmitting it in each pregnancy is 50%: sibs with a 46,XY karyotype who inherit the pathogenic variant will be affected; sibs with a 46,XX karyotype who inherit the pathogenic variant will be heterozygous and will rarely show clinical manifestations. Affected males do not reproduce. Once the ATRX pathogenic variant in the family has been identified, carrier testing for at-risk females, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.