How is this condition inherited, and why does it almost exclusively affect males?

This disorder follows an X-linked recessive inheritance pattern. Males have one X and one Y chromosome, so a single mutation on their X chromosome causes the condition. Females have two X chromosomes, so they are typically carriers and usually do not show symptoms unless they have a rare chromosomal abnormality. A mother who is a carrier has a 50 percent chance of passing the mutated gene to a son, who will be affected, and a 50 percent chance of passing it to a daughter, who will be a carrier. What are the typical developmental milestones that are delayed in children with this syndrome?::Children with this syndrome often experience significant delays in motor and speech development. Due to low muscle tone (hypotonia), many children take longer to sit up or walk, and some may never walk independently. Speech and language development are also frequently delayed; while some individuals learn to speak or sign a few words, many remain non-verbal throughout their lives. Parents should monitor for these delays and seek early intervention services for physical and occupational therapy. Does the blood disorder associated with this syndrome require medical treatment?::In most cases, the alpha thalassemia component is mild and does not require specific blood-related treatment. However, individuals should be monitored by a hematologist to check for anemia or other red blood cell abnormalities. If anemia develops, it may need to be managed with iron supplements or other therapies, but the primary medical focus for this syndrome is usually on managing the intellectual disability, seizures, and physical health rather than the blood condition itself. What are the distinctive physical features that help clinicians identify this syndrome in early childhood?::Clinicians often look for a specific set of facial features that are most apparent in early childhood. These include widely spaced eyes, a small nose with upturned nostrils, low-set ears, and a prominent lower lip. The upper lip often has a characteristic upside-down V shape. While these features may become less distinct as the individual ages, they are key diagnostic clues alongside the genetic testing results and developmental history.

Alpha thalassemia X-linked intellectual disability syndrome

Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder primarily affecting males, characterized by intellectual disabilities, red blood cell abnormalities, and distinctive physical features.

Overview

Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder that affects intellectual functioning, red blood cells, and other body systems. This condition occurs almost exclusively in males.

Individuals with alpha thalassemia X-linked intellectual disability syndrome have intellectual disabilities and certain aspects of their development may be delayed. These can include speech and language development, and some affected individuals never speak or sign more than a few words. Most affected children have weak muscle tone (hypotonia), which contributes to the characteristic facial features and delays the development of motor skills such as sitting and walking. Some people with this disorder are never able to walk independently. Individuals with this condition have seizures, although this is less common.

About 75 percent of individuals with alpha thalassemia X-linked intellectual disability syndrome have mild signs of a blood disorder called alpha thalassemia. This disorder reduces the production of hemoglobin, which is the protein in red blood cells that carries oxygen to cells throughout the body. Without sufficient hemoglobin, not enough oxygen can reach the body's tissues. In rare cases, affected individuals also have a shortage of red blood cells (anemia).

Almost everyone with alpha thalassemia X-linked intellectual disability syndrome has distinctive facial features, including widely spaced eyes, a small nose with upturned nostrils, and low-set ears. The upper lip is shaped like an upside-down "V," and the lower lip tends to be prominent. These facial characteristics are most apparent in early childhood. Over time, the face may appear flatter or the nose can become shorter.

Additional features of alpha thalassemia X-linked intellectual disability syndrome can include an unusually small head size (microcephaly) and short stature. Some people with this condition have skeletal abnormalities that affect the spine, hands, or feet. Many affected individuals have problems with the digestive system, such as a backflow of stomach acids into the esophagus (gastroesophageal reflux) and chronic constipation. Genital abnormalities are also common; affected males may have undescended testes and the opening of the urethra may be on the underside of the penis (hypospadias). In some cases, the external genitalia do not look clearly male or female.

Frequency

Alpha thalassemia X-linked intellectual disability syndrome appears to be a rare condition, although its exact prevalence is unknown. More than 200 affected individuals have been reported in the scientific literature. Because the signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome overlap with those of many other conditions, it can be challenging to diagnose.

Causes & Risk Factors

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the ATRX gene cause alpha thalassemia X-linked intellectual disability syndrome. The ATRX gene provides instructions for making a protein that plays an essential role in normal development. The ATRX protein has many functions, such as helping to repair DNA damage and regulating the activity (expression) of other genes. Two of the genes that the ATRX protein helps regulate are HBA1 and HBA2, which are necessary for normal hemoglobin production.

Pathogenic variants in the ATRX gene lead to changes in the ATRX protein, which likely impair its ability to regulate gene expression. Reduced activity of the HBA1 and HBA2 genes causes alpha thalassemia. The lack of functioning ATRX proteins likely affects the expression of other genes as well, leading to the intellectual disabilities, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome.

Associated Genes

ATRX

Inheritance Pattern

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), a pathogenic variant in the only copy of the gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. It is estimated that 80 to 90 percent of males with alpha thalassemia X-linked intellectual disability syndrome inherit the ATRX gene variant from their mother. The remaining cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's mother or in early embryonic development.

In females (who have two copies of the X chromosome), a pathogenic variant in one copy of the ATRX gene typically does not cause the health problems that are associated with alpha thalassemia X-linked intellectual disability syndrome. In rare cases, these females may have intellectual disabilities and other signs and symptoms.

Other Names

Alpha thalassemia/intellectual disability syndrome X-linked
Alpha-thalassemia/impaired intellectual development syndrome
ATR-X syndrome
ATRX syndrome
XLMR-hypotonic face syndrome

Additional Information & Resources

Genetic Testing Information

Genetic Testing Registry: Alpha thalassemia-X-linked intellectual disability syndrome

Genetic and Rare Diseases Information Center

Alpha-thalassemia-X-linked intellectual disability syndrome

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED; ATRX

Scientific Articles

PubMed

References

Gibbons R. Alpha thalassaemia-mental retardation, X linked. Orphanet J Rare Dis. 2006 May 4;1:15. doi: 10.1186/1750-1172-1-15. Citation on PubMed or Free article on PubMed Central
Leon NY, Harley VR. ATR-X syndrome: genetics, clinical spectrum, and management. Hum Genet. 2021 Dec;140(12):1625-1634. doi: 10.1007/s00439-021-02361-5. Epub 2021 Sep 15. Citation on PubMed
Noordhuis-Zijderveld A, Festen DAM, Kharl A, van Gastel M, Hartman M, Bruggenwirth HT, Zeidler S, Valstar MJ. Clinical variability in individuals with ATR-X syndrome in the Netherlands. Eur J Med Genet. 2025 Aug;76:105026. doi: 10.1016/j.ejmg.2025.105026. Epub 2025 Jun 6. Citation on PubMed
Palaniappan C, Ramalingam R. Deciphering the Molecular Effects of Mutations on ATRX Cause ATRX Syndrome: A Molecular Dynamics Study. J Cell Biochem. 2017 Oct;118(10):3318-3327. doi: 10.1002/jcb.25984. Epub 2017 May 3. Citation on PubMed
Stevenson RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [updated 2020 May 28]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1449/ Citation on PubMed

Medical Encyclopedia

Ambiguous genitalia
Genetics
Hypospadias

Understanding Genetics

What is the prognosis of a genetic condition?
How can gene variants affect health and development?
What does it mean if a disorder seems to run in my family?
What are the different ways a genetic condition can be inherited?
How are genetic conditions treated or managed?