ATR-X is an acronym that stands for Alpha-Thalassemia, mental Retardation, X-linked Syndrome. It is characterized by moderate to severe mental retardation, seizures, hypotonia, microcephaly, midface hypoplasia, genital abnormalities, and alpha-thalassemia.
X-linked Alpha-Thalassemia-Intellectual Disability Syndrome; X-linked Alpha-Thalassemia-Mental Retardation Syndrome.
More than 200 cases have been reported worldwide and the estimated incidence is probably less than 10 in 100,000 live born males.
Inherited in an X-linked dominant fashion and thus only affects males. ATR-X Syndrome is caused by mutations in the ATR-X gene that have been mapped to chromosome Xq21.1. Another form, called ATR-16 Syndrome is a contiguous gene syndrome that is due to mutations in the Hemoglobin H-Related Mental Retardation (HBHR) or ATR1 gene located on chromosome 16pter-p13.3. Inheritance for ATR-16 Syndrome is autosomal dominant and clinically very similar to ATR-X Syndrome, but can also affect females.
It is based on the clinical findings and the presence of hemoglobin H. Genetic and molecular testing are required to confirm the diagnosis.
Patients affected with this disorder present with significant postnatal growth deficiency, delayed bone age, and mental retardation with absent or minimal speech capabilities. The clinical characteristics include short stature, initially feeding difficulties secondary to poor suck and generalized hypotonia (later often changing to spasticity), facial dysmorphism with microcephaly, relative hypertelorism, epicanthal folds, strabismus, midface hypoplasia, low-set and posteriorly rotated ears, a small triangular nose with low bridge and anteverted nares, carp-shaped mouth with dental anomalies (eg, crowded, supernumerary, or hypoplastic teeth), full lips, and a large protruding tongue. Neurologically, in addition to moderate to severe mental retardation, spasticity and seizure activities are the most frequent features. Apneic episodes and cyanotic spells may occur. Lack of bladder and bowel control is common. Neuroimaging (MRI- and/or CT-scans) may reveal mild, nonprogressive cerebral atrophy, partial or complete agenesis of the corpus callosum, hypoplasia or anomalies of the white matter, and abnormal myelination. Defects of the musculoskeletal system may include (occasionally postural) (kypho)scoliosis resulting from hemivertebrae, coxa valga, talipes equinovarus, tapering fingers, and clinodactyly. Excessive salivation, feeding difficulties, gastroesophageal reflux, recurrent vomiting, abdominal pain, and distension and constipation are common. Intestinal malrotation and ultrashort-segment Hirschsprung disease (<4 cm from the anal sphincter) have been described and a high level of suspicion for volvulus and bowel obstruction should be maintained in these patients when they are refusing oral intake. Resulting bowel ischemia was fatal in some cases. Death in early childhood as a result of aspiration or aspiration pneumonia has been reported in a number of patients. Genitourinary abnormalities may consist of hypospadias, small penis, shawl scrotum, cryptorchidism, male pseudohermaphroditism, and inguinal hernias. Hydronephrosis, renal hypoplasia or agenesis, and polycystic kidneys have been described. Cardiac lesions occur in almost ...