Update : 11 November 2001

About ATR-x

(information provided by Mr. R. Gibbons)

What is a syndrome Anemia -  a thalassaemia  
The features in ATR-X syndrome Genital abnormalities  
Learning difficulties  Skeletal problems    
Facial appearance    


X-linked  a thalassaemia/mental retardation syndrome, or ATR-X syndrome for short, is one of many genetic conditions that can cause learning difficulties.  It is the purpose of this article to describe what is known about the condition, its pattern  of inheritance and the implications for the family.  ATR-X syndrome has only been recognized in the last few years, and information about it is continually evolving and nothing, as yet, is set in stone.  Each affected child is different and what may be true for one child may not be true of another. Top

 What is a syndrome? 

A syndrome is a condition which has a constellation of apparently unrelated features, for example in a particular syndrome an affected child may have limb abnormalities associated with heart problems.  Rather than arising independently, it is thought that the features have a common cause.  It is believed that in many cases this common cause is genetic,  that is loss or damage to the inherited instructions (genes) which are the blue print for normal development. 

Syndromes are recognized by particular  combinations of clinical features.  The features themselves are rarely unique to a particular syndrome and may be seen in many different syndromes.  Some of these features clearly are abnormal whereas some, such as incurved fingers and often called soft signs, fall within the spectrum of normal development.  Diagnosis of syndromes is difficult and the degree of confidence in a particular diagnosis may vary.  In some cases additional support can be provided by laboratory tests.Top

The features in ATR-X syndrome 

There are 3 principal features in the ATR-X syndrome:  learning difficulties;  a characteristic facial appearance and an unusual form of anemia known as  alpha thalassaemia.  Other features such as abnormal genital development may also be present and these are discussed below.  The anemia can be detected by a specific blood test and this forms the basis of a laboratory test for this condition.  Table 1 shows the frequency with which these features are encountered in ATR-X syndrome.  The table, however, does not indicate the subtlety with which these features may be present.  It should be noted that even the 'principal' features may be absent.Top

Learning difficulties

Over 100 affected children are known and in the majority of these (97%) the learning difficulties are classified as severe. 

At birth, the children are usually floppy and it is often apparent in the first 6-9 months that the baby's development is delayed.  The "motor milestones", such as sitting unsupported, are delayed.  Some never crawl, and those that do eventually walk may not start till late in childhood.  Most remain in nappies, though occasionally, with training, a degree of bowel and bladder control may be achieved.  Many children will learn to drink from a cup or beaker and will finger feed or use a spoon.

Speech is usually absent though some learn a few words and a small repertoire of Mankato signs.  The children's' comprehension is also affected.  Some are restricted to recognition of the family and awareness of their surroundings, and may be upset by a change to their daily routine.  Others understand more, such as learning where a biscuit tin is kept, learning to turn on the TV and obeying simple commands.  The boys may continue to acquire new skills for many years.  Although physical illness may set the children back, it is not usual for them to regress developmentally or lose skills. 

Until recently all the affected children have been classified as having severe learning difficulties.  However, our recent experience with one family indicates that milder degrees of learning difficulties may exist.  In this one family with 4 affected cousins, one lad is severely affected, whereas one has moderate learning difficulties and two mild learning difficulties.  The latter two talk in sentences and have achieved a degree of independence in tasks of daily living.  It is not clear if this family is unique or whether the spectrum of severity in ATR-X syndrome is broader than previously thought.   Top

Facial appearance 

Many syndromes, for example Downs, are associated with a recognizable facial appearance.  This is true also of ATR-X syndrome, though the characteristic facial appearance is easier to recognize in early childhood.  The head size is often small (microcephaly), the eyes widely spaced, the bridge of the nose rather broad and flat, the nose itself is small, triangular and upturned at the end.  The upper lip has a tented appearance and the lower lip is full and averted. Top

Anemia -  a thalassaemia

Hemoglobin is the oxygen carrying molecule in the blood and is packaged in the red blood cells.  If the level of hemoglobin is reduced the patient is described as having anemia.  If the level is very low then the patient will look "anemic", and the skin and especially the lips, eyelids and tongue will be   pale.  In ATR-X syndrome the reduction in hemoglobin is usually very mild and only apparent on blood testing.

There are many causes of anemia but in ATR-X it is due to a reduction in the manufacture of one of the proteins,  a globin, that makes up hemoglobin.  This form of anemia is called  a thalassaemia.  The term 'thalassaemia' comes from the Greek for sea and the name derives from the fact that this type of anemia is common in the Mediterranean.  Although the anemia in ATR-X shares the same name it has little else in common with the Mediterranean variety and this will be discussed further below.

Alpha Thalassaemia can be diagnosed with a simple blood test.  A drop of blood is mixed with a blue dye and left to incubate for a few hours.  A spot of this blood is then spread on a slide and looked at under the microscope.  If  alpha thalassaemia is present then some of the red cells, instead of having a uniform blue colour, will appear to be full of blue dots (hemoglobin H inclusions).  Hemoglobin is normally made up of 2 proteins,  a-globin and  b-globin.  In  alpha thalassaemia there is a reduction in the amount of  a-globin and consequently a relative excess of b-globin.  Some of this excess b-globin combines on its own to form an abnormal protein called hemoglobin H which forms the blue dots when the cells are dyed.

It is a quick and useful test,  but like all medical tests it is not foolproof.  If the inclusions are plentiful then there is little doubt the test is positive and it is likely that the diagnosis of ATR-X is correct.  Sometimes rare cells with inclusions may be seen in normal individuals and so if only occasional cells are seen in a patient it is not possible to say that this is ATR-X.  If inclusions are not present, ATR-X is less likely to be the correct diagnosis.  Nevertheless, it does not exclude ATR-X because we know of some cases in whom the genetic tests have established the diagnosis of ATR-X although hemoglobin H inclusions are absent.

In our experience the anemia itself is usually very mild, does not lead to any problems and does not require any treatment.  In particular, there is no benefit in taking extra iron. Top

Other features:

Genital abnormalities

These vary enormously.  At the mildest end of the spectrum the testicles may be undescended.  The penis may be small and the scrotum poorly developed.  Sometimes "hypospadias" is present, when the exit for the urine is not at the end of the penis but along the shaft.  In a few children, the appearance of the genitalia makes the child's gender unclear or else appears to be female.  The children do not have wombs or ovaries but small poorly formed testes may be found during exploratory surgery.  The development of the genitalia depends on the presence of the male sex hormones which are principally made by the testes.  The problems of genital development seen in ATR-X syndrome are probably due to inadequate amounts of male hormones and this may also be the reason for some of the children not passing through puberty normally.  Paradoxically, in a few children,  sparse public hair may be present in early childhood and the cause of this is unclear. Top

Skeletal problems

These are rather diverse and may become apparent as the children grow.  Occasionally a child may be born with a club-foot deformity.  Some joints especially the fingers may be in a fixed, flexed position.  Curvature of the spine can occur with age and should be checked for. Top

Heart problems

A few children are born with abnormalities of the heart.  These may involve holes between the chambers of the heart, or abnormalities in the heart valves.  Some, but not all of these, require surgical correction. Top

Kidney problems

These are uncommon and sometimes are found incidentally.  They may predispose to urinary tract infections. Top

Digestive systems

Early feeding may be problematic due to poor sucking reflex.  Frequent regurgitation of food or vomiting are common though this often improves as the child gets older.   Swallowing may be  rather uncoordinated in ATR-X syndrome - some of the children show an apparent reluctance to swallow the food in their mouths and not infrequently it "goes down the wrong way" causing episodes of choking.  Many burp prodigiously and the copious dribbling that is so commonly seen in this condition may be related to incoordinated swallowing.  One or two children have had episodes when the gut appears to have "gone on strike" and stopped the normal contractions that propel the contents along the length of the gut.  Most of the children suffer constipation.

Feeding via a tube passed into the stomach may be required during the early months.  Very occasionally, especially if feeding difficulties are prolonged in childhood, a feeding tube has been used which passes through the abdominal wall into the stomach (feeding gastrostomy).  In one or two cases ducts from the salivary glands have been repositioned to further back in the mouth in an attempt to reduce dribbling.  Drug treatments to reduce the production of saliva are sometimes used, but these can reduce the muscular contractions of the gut and the boys may be particularly sensitive to this effect. Top


Many of the children have short stature and their growth is consistently behind that of others of a similar age.  In a few, growth is within the normal range in childhood but they fall behind during the growth spurt of the early teens. Top


In the main, the children have a happy disposition and an affectionate nature.  Like most children they love attention and play, especially noisy games, rough and tumble, water play and musical toys.  They usually settle down well at night and sleep.  Episodes of apparently unprovoked laughter or crying been mentioned by one or two parents.  Repetitive behavior has also been reported. Top


About a third of boys have epileptic seizures.  In the main they can be well controlled with drug therapy.  Some children who have fits in early childhood appear to grow out of them. Top

Life expectation

Because the condition has not long been recognized, the group of affected boys has not been followed for sufficiently long to know much about life expectation.  Some adults are healthy into their thirties.  We do not have post-mortem information to know the cause of death in older cases. A number of children perish under the age of five years. Pneumonia is frequently the cause.  Repeated chest infections are possibly related to episodes of vomiting and food going down the 'wrong way' into the lungs. Top


The gene associated with ATR-X syndrome lies on the X chromosome.  Males only have one X chromosome and this is always inherited from their mothers.  Females have two X chromosomes and, therefore, two copies of the ATR-X gene.  If they are carriers and have one damaged copy, the other, normal  copy fully compensates.  This explains why female carriers avoid being affected themselves.  When carriers have children there is a 50 : 50 chance of passing on the affected gene.  If a male inherits the damaged gene he will be affected; if a female inherits the damage gene she will be a carrier like her mother.  If a female carrier passes on the normal copy of the gene, a son would be unaffected and a daughter would not be a carrier.  The risk of a carrier passing on the gene is the same for each pregnancy and the outcome is as random as tossing a coin.

ATR-X like many genetic conditions can run in a family or arise anew, out of the blue.  If a mother has one affected child there are two possibilities:  she may be a carrier or else the damage to the gene may have arisen in the egg or developing embryo and in this case the mother would not be a carrier.  In the former case other female members of the family may be at risk of carrying the condition;   in the latter case, they would not be at risk. Top


What tests are available?

The gold standard is to identify the underlying genetic change in an affected child and look for this in female relatives.  Unfortunately, it sometimes takes a considerable time to identify this change in a new case - it is like looking for a needle in a haystack.  Until it is found, another method has to be employed.

When we know that the condition has been passed down through a family, we can use DNA markers that lie close to the gene to track the damaged copy (see Figure 1).  In smaller families and especially if there is just one affected boy in a family, this technique is less helpful because it does not take into account the possibility that the genetic change has arisen anew in some generation.  It is important to discuss with a clinical geneticist the specific circumstances in a family and the most appropriate form of testing that is available.

For couples wanting prenatal diagnosis this may be feasible and again advice should be sought from a clinical geneticist.  Such testing can be performed from about 11 wks of pregnancy.  A sample of the placenta that is made by the developing foetus is obtained under local anesthetic by passing a needle, under ultrasound guidance, through the mother's abdominal wall and into the womb.  The laboratory analysis then takes 1-2 weeks.  Initially the sex of the baby is determined:  if female, no further testing is performed;  if male, the sample is checked to determine whether or not the baby has inherited the damaged ATRX gene. Top

Research work at Oxford

In the UK, ATR-X research takes place in the labs of Doug Higgs and Richard Gibbons.  Doug and Richard have worked together on this condition for over 9 years.  The group, which is now seven strong, has been involved in describing the clinical features, identifying the gene involved and the nature of the defect in affected individuals.  Our present work is focusing on the following areas:

        -       how common ATR-X syndrome is

        -       how varied the clinical manifestations are

        -       development of new diagnostic tests for the condition

        -       determining the function of the ATRX gene product and how it  controls the activity of other genes

        -       how the clinical features in ATR-X syndrome arise.


Richard Gibbons

Nuffield Department Clinical Biochemistry

John Radcliffe Hospital


Oxford OX3 9DU


Summary of the major clinical manifestations of the ATR-X syndrome






# out of
Severe MR 108 110 98  
Normal birth weight 65 72 90  
Neonatal hypotonia 59 68 87  
Seizures     36 104 35  
Characteristic face 86 96 90  
Microcephaly   67 88 76  
Genital abnormalities 83 94 88
Skeletal abnormalities 83 91 91  
Cardiac defects  21 98 21  
Renal/urinary abnormalities 16 98 16  
Short stature 51 74 69  
Gut dysmotility  66 86 77