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More than 200 patients with X-linked alpha thalassemia intellectual disability (ATR-X) syndrome have been reported. Whilst data is limited worldwide, in Japan the prevalence at birth is estimated at 1/60,000-80,000. Males are predominantly affected.

Affected neonates may present with hypotonia and feeding difficulties. The distinctive facial appearance is most readily recognized in early childhood. Facial hypotonia is associated with upswept frontal hair, widely spaced eyes with epicanthic folds, a depressed nasal bridge and a small triangular upturned nose. The upper lip is tented and the lower lip full and everted. The frontal incisors are widely spaced and there is prodigious drooling. Language is usually very limited. Motor milestones may be delayed and some children never walk. Seizures occur in about one third of the cases. While many patients are affectionate with their caregivers, some exhibit autistic-like behavior. Genital abnormalities are observed in 80% of children and range from undescended testes to ambiguous genitalia. Microcephaly and short stature are common. Alpha thalassemia is not always present. Female carriers are usually physically and intellectually normal.

This syndrome is X-linked recessive and results from mutations in the ATRX gene (Xq21.1). This gene encodes the widely expressed ATRX protein. ATRX mutations cause diverse changes in the epigenetic landscape throughout the genome including the pattern of DNA methylation. These are associated with changes in gene expression which are thought to contribute to the clinical phenotype.

The diagnosis can be established by detection of alpha thalassemia, identification of ATRX gene mutations, characteristic changes in DNA methylation, ATRX protein studies in affected males and X-inactivation studies in carrier females.

There is phenotypic overlap with Coffin-Lowry syndrome, Angelman syndrome, Smith-Lemli-Opitz syndrome and Pitt-Hopkins syndrome. There are readily available diagnostic tests for these disorders.

Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

The disorder is an X-linked recessive condition. With the exception of two reported heterozygous females with intellectual disability, female carriers are phenotypically and intellectually normal. Genetic counseling should be offered to mothers and female relatives of affected individuals. For a female who has been identified as a carrier, there is a 50% risk of passing on the disease allele with each pregnancy but, since only males are clinically affected, the risk of having an affected child is 25% for each pregnancy.

Management is multidisciplinary. Young children must be carefully monitored for gastro-esophageal reflux as it may cause death through aspiration. Episodes of unexplained persistent distress may have a gastrointestinal cause with volvulus a known cause. Drooling is frequently seen but, because of reduced gastrointestinal motility, anticholinergics should be used with caution. Constipation is common and initial treatment should be standard. The possibility of cryptorchidism should be assessed in all children. Intra-abdominal testes, which are usually dysgenic, should be removed because of the long-term risk of malignancy. Abnormalities of the renal/urinary system are common, can lead to urinary tract infections, and should be investigated at diagnosis. Alpha thalassemia may be present and give rise to a mild hypochromic, microcytic anemia; this does not require treatment. Iron is not indicated unless the iron stores are low. Asplenia is rare, but if confirmed, antibody prophylaxis and vaccination to prevent pneumococcal and menigococcal infections is recommended. Osteosarcoma has been observed in a small number of affected individuals; painful lesions of the bones should be investigated to exclude osteosarcoma.

A number of individuals with ATR-X are fit and well in their 30s and 40s.