Alpha-thalassemia x-linked intellectual disability syndrome

Other Names: Alpha thalassemia intellectual disability syndrome, nondeletion type, X-linked; ATRX syndrome; ATR, nondeletion type; XLMR hypotonic face syndrome; X-linked alpha-thalassemia/intellectual disability syndrome

Alpha-thalassemia x-linked intellectual disability (ATRX) syndrome is a genetic condition that causes intellectual disability, muscle weakness (hypotonia), short height, a particular facial appearance, genital abnormalities, and possibly other symptoms. This condition occurs almost exclusively in males.

Epidemiology

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.

Cause

Alpha thalassemia X-linked intellectual disability syndrome results from mutations in the ATRX gene. This gene provides instructions for making a protein that plays an essential role in normal development. Although the exact function of the ATRX protein is unknown, studies suggest that it helps regulate the activity (expression) of other genes. Among these genes are HBA1 and HBA2, which are necessary for normal hemoglobin production.

Mutations in the ATRX gene change the structure of the ATRX protein, which likely prevents it from effectively regulating gene expression. Reduced activity of the HBA1 and HBA2 genes causes alpha thalassemia. Abnormal expression of other genes, which have not been identified, probably causes developmental delay, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked recessive pattern. The ATRX gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), one working copy of the ATRX gene can usually compensate for the mutated copy. Therefore, females who carry a single mutated ATRX gene almost never have signs of alpha thalassemia X-linked intellectual disability syndrome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Signs and symptoms

Males with alpha thalassemia X-linked intellectual disability syndrome have intellectual disability and delayed development. Their speech is significantly delayed, and most never speak or sign more than a few words. Most affected children have weak muscle tone (hypotonia), which delays motor skills such as sitting, standing, and walking. Some people with this disorder are never able to walk independently.

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 facial features become coarser, including a flatter face with a shortened nose.

Most affected individuals 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. A reduction in the amount of hemoglobin prevents enough oxygen from reaching the body's tissues. Rarely, affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, and fatigue.

Additional features of alpha thalassemia X-linked intellectual disability syndrome include an unusually small head size (microcephaly), short stature, and skeletal abnormalities. 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 on the underside of the penis (hypospadias). In more severe cases, the external genitalia do not look clearly male or female (ambiguous genitalia).

Diagnosis

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome should be suspected in individuals with the following clinical findings, hematologic findings, and family history.

Clinical findings A recognizable pattern of craniofacial findings including small head circumference, upsweep of the frontal hair, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, thick or everted lower lip, and open mouth. Irregular anatomy of the pinnae, widely spaced teeth, and protruding tongue are supplemental findings, the latter two adding to a coarseness of the facial appearance, particularly after the first few years of life.

Growth impairment including microcephaly and short stature, usually present at birth Genital anomalies (in an individual with a 46,XY karyotype) that can range from hypospadias and undescended testes to ambiguous genitalia to normal external female genitalia Developmental delay / intellectual disability, typically in the severe-to-profound range

Hematologic findings: Hematologic studies show evidence of alpha-thalassemia in approximately 75% of males with ATR-X syndrome .

HbH inclusions (β-globin tetramers) in erythrocytes can be demonstrated following incubation of fresh blood smears with 1% brilliant cresyl blue. The proportion of cells with HbH inclusions ranges from 0.01% to 30% . HbH inclusions may be demonstrated readily in some individuals, found only in an occasional erythrocyte in some, or observed only after repeated testing in others. The absence of HbH inclusions in one fourth of affected individuals and the rarity of inclusions (≤1% of erythrocytes) in an additional 40% of affected individuals diminish the utility of this testing in most clinical settings. Red blood cell indices. A microcytic hypochromic anemia characteristic of alpha-thalassemia may be seen in some affected individuals, but many have red cell indices in the normal range .

Newborn screening: In rare instances, ATR-X syndrome has been identified through the detection of HgH on newborn screening for hemoglobinopathies. Family history consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Treatment

Treatment includes regular visits to the doctor to monitor growth and intellectual development, early intervention and special education programs, and special formula to help with feeding and nutrition.

NIH genetic and rare disease info

• NIH info on Alpha-thalassemia x-linked intellectual disability syndrome

Alpha-thalassemia x-linked intellectual disability syndrome is a rare disease.

Alpha-thalassemia x-linked intellectual disability syndrome Resources
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