Alpha-thalassemia/mental retardation syndrome, x-linked

Symptoms

What are the main symptoms of alpha-thalassemia X-linked intellectual disability syndrome?

One of the main features of alpha-thalassemia X-linked intellectual disability syndrome is that it almost exclusively affects males and has so far been described in only one female (as of March 2016). Females with a genetic mutation in ATRX typically do not show any signs of this disorder; however, all males with a genetic mutation in ATRX are expected to have some of the main symptoms, which include: intellectual disability, hypotonia (low muscle tone), specific facial features, abnormal genitalia, and alpha-thalassemia.

All affected males have intellectual disability and global developmental impairment, which can range from moderate to profound. The ability to speak is typically significantly delayed, with some individuals never able to speak more than a few words.

Hypotonia, or low muscle tone, is also present in affected males during childhood. This leads to problems achieving many childhood milestones such as sitting, standing, and walking. Although most affected males do learn to walk, some severely affected males are never able to walk independently.

Although most affected males have a normal birth weight, they tend to grow more slowly after birth. This growth deficiency may not be noticeable until adolescence. Final adult height in most males with this condition is shorter than average.

There is also a specific set of facial features common to affected males. These features are seen in almost all males with alpha-thalassemia X-linked intellectual disability syndrome. The head tends to be smaller than average ("microcephaly"), the eyes tend to be widely spaced ("hypertelorism"), the nose is small with the tip turned up and the bridge flattened, and the ears are set low set on the head. The middle of the upper lip is pointed upwards toward the nose and the lower lip is often full. These features are often most noticeable in childhood, changing and sometimes lessening over time.

Most males with this disorder have abnormal development of the genitalia. These abnormalities can include incorrect placement on the penis of the opening to the urethra ("hypospadias") and/or undescended testes ("cryptorchidism") . In more severe cases, the external genitalia may not look clearly male or female ("ambiguous genitalia"), or may even look clearly female.

The last common feature of this disorder is a mild blood disorder known as alpha-thalassemia, which results in reduced production of hemoglobin. Hemoglobin is a protein in red blood cells that is responsible for carrying iron and oxygen throughout the body. Hemoglobin is made up of alpha- and beta- building blocks. Individuals with alpha-thalassemia X-linked intellectual disability syndrome have a problem making the right kind of alpha-subunit, leading to lower than average amounts of hemoglobin. This leads to a type of mild anemia ("hemoglobin H disease") that can cause pale skin and easy tiring, but is most often not significant enough to cause medical problems or need treatment.

The majority of affected males also have gastrointestinal symptoms such as reflux and constipation. In addition, seizures have been reported in approximately one-third of affected males. Individual patients have been reported to have other physical symptoms, including ocular coloboma (notch or gap in part of the eye), cleft palate (split or opening in the roof of the mouth), abnormalities of the heart, inguinal hernia (tissue that bulges through a weak spot in the groin muscle), and asplenia (lack of development of the spleen).

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If you have alpha-thalassemia X-linked intellectual disability syndrome will you always show symptoms?

What health problems should my doctor be watching for in alpha-thalassemia X-linked intellectual disability syndrome?

Are there any other diseases that look like alpha-thalassemia X-linked intellectual disability syndrome?

If you have alpha-thalassemia X-linked intellectual disability syndrome will you always show symptoms?

To the best of our knowledge, all males with changes in the ATRX gene that cause abnormal ATRX protein function have alpha-thalassemia X-linked intellectual disability syndrome. There is a range of severity from mild to severe; therefore, some males with this disorder may have subtle enough symptoms that they have not yet been diagnosed. Females with causative changes in the ATRX gene almost never show signs of the disorder. In fact, there is only one reported case of a female with a change in this gene having enough signs of alpha-thalassemia X-linked intellectual disability syndrome to be diagnosed with this condition.

What health problems should my doctor be watching for in alpha-thalassemia X-linked intellectual disability syndrome?

Most individuals with alpha-thalassemia X-linked intellectual disability syndrome have good general physical health. Nonetheless, there are some medical problems more common in people with this disorder for which they should be watched. Infants with this disorder often have low muscle tone which can contribute to feeding issues, leading to poor nutrition. Therefore, the growth of these infants should be monitored closely, at least throughout childhood. Because digestive problems are also common in affected individuals, doctors should monitor for signs of swallowing problems, reflux, and/or recurrent vomiting. These problems can also affect nutrition and growth. Major anatomic structural problems are not typically associated with alpha-thalassemia X-linked intellectual disability syndrome; however, there have been rare reports of affected individuals having cleft palates, heart defects, and/or absent spleens ("asplenia"). Therefore, careful physical examination for signs of these problems is warranted. Eye problems have also been reported as a feature associated with this disorder, so doctors should routinely check affected individuals for structural eye defects and vision problems. Although a mild form of anemia known as hemoglobin H disease is seen in many individuals with this syndrome, it is typically not clinically significant.

Are there any other diseases that look like alpha-thalassemia X-linked intellectual disability syndrome?

There are other diseases that share similar symptoms with alpha-thalassemia X-linked intellectual disability syndrome. Coffin-Lowry syndrome is also inherited in an X-linked fashion and is associated with severe to profound intellectual disability in affected males. One difference in Coffin-Lowry syndrome is that females can be affected as well. Although there are typical facial features associated with Coffin-Lowry syndrome, they are different than those seen in alpha-thalassemia X-linked intellectual disability syndrome. Finally, individuals with Coffin-Lowry syndrome have distinctive looking hands and fingers.

Another disorder that shares features with alpha-thalassemia X-linked intellectual disability syndrome is MECP2 duplication syndrome. This disorder is X-linked as well, but again, can affect both females and males, with half of affected males dying by early adulthood. The facial features are more subtle in this condition than in alpha-thalassemia X-linked intellectual disability syndrome and small head size ("microcephaly") is not a common feature. Seizures are more common in this condition than in alpha-thalassemia X-linked intellectual disability syndrome.

Isolated Alpha-thalassemia, where anemia is seen without intellectual disability, is typically due to changes in the genes for alpha-hemoglobin. Isolated alpha-thalassemia is not an X-linked condition and affects males and females equally. It is inherited in an autosomal recessive manner and is more common in individuals of Southeast Asian, African, or Mediterranean descent. Alpha-thalassemia X-linked intellectual disability syndrome is pan-ethnic, meaning it is not more or less common in individuals of any particular ethnicity.

Another condition that is separate from ATRX syndrome but is also associated with alpha-thalassemia and intellectual disability is called alpha-thalassemia mental retardation chromosome 16 syndrome (ATR-16). ATR-16 happens when an individual is missing a large piece of chromosome 16 where the alpha-globin gene and other important genes for global development are located. Depending on the size of this missing piece of chromosome 16, or chromosome 16 deletion, the features of the condition will vary. Although individuals affected with ATR-16 share many similar features as those with ATRX syndrome, individuals with ATR-16 are more likely to have clubfoot, where the foot or feet are rotated in an abnormal position. Furthermore, ATR-16 affects both males and females equally, whereas ATRX affects males.

Juberg-Marsidi syndrome is a very rare disorder which, like alpha-thalassemia X-linked intellectual disability syndrome, is only seen in males and causes similar intellectual and developmental disabilities, low muscle tone, short stature and other features. Initially, Juberg-Marsidi syndrome was thought to be caused by changes in ATRX; however, a subsequent study has identified changes in a different gene that suggests it is a distinct disorder from alpha-thalassemia X-linked intellectual disability syndrome.

Smith-Fineman-Myers syndrome is a condition which may or may not be distinct from alpha-thalassemia X-linked intellectual disability syndrome. It is extremely rare and it is unclear whether it is caused by changes in ATRX or a different gene. The features are very similar to those with alpha-thalassemia X-linked intellectual disability syndrome. Further studies are needed to determine whether these are the same condition or distinct from one another.

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