(information provided by Mr. R. Gibbons)
|What is a syndrome||Anemia - a thalassaemia|
|The features in ATR-X syndrome||Genital abnormalities|
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
Over 100 affected children are known and in the majority of these (97%) the learning difficulties are classified as severe.
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
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.
- a thalassaemia
- a thalassaemia
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.
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.
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.
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.
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.
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.
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.
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.
are uncommon and sometimes are found incidentally.
They may predispose to urinary tract infections.
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.
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.
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.
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.
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
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.
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.
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.
tests are available?
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.
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
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.
work at Oxford
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.
Nuffield Department Clinical Biochemistry
John Radcliffe Hospital
Oxford OX3 9DU
of the major clinical manifestations of the ATR-X syndrome
|Normal birth weight||65||72||90