Features

In the majority of these (96%) 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 Makaton signs. The childrens’ 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.

A number of families with more than one affected child have told us that there is quite a marked difference in the abilities of the boys. The reason for this is unclear. Birth order is not a factor.

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 everted.

Here you see a picture of two unrelated boys with ATR-x Syndrome illustrating the characteristic facial appearance.

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

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

α 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 α thalassaemia is present then some of the red cells, instead of having a uniform blue colour, will appear to be full of blue dots (haemoglobin H inclusions).

This test for alpha thalassaemia is rapid – a few hours – and in most cases (85%) confirms the diagnosis. Genetic testing takes a longer period of time (often weeks) and sometimes it is difficult to know whether changes found in the genetic code are “pathological” or population variants. Testing for the anaemia can often help to solve such a puzzle by confirming the diagnosis and should be a first line test because it is a functional test of the ATRX gene. Finding the genetic cause is of most help when looking to see who might be a carrier in a family and for pre-natal diagnosis.

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. The foreskin may be poorly developed or in part missing. 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.

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.

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.

These are uncommon and sometimes are found incidentally. One of the commonest problems is “reflux”, when on emptying the bladder some of the urine shoots back up towards the kidney. This may predispose to urinary tract infections. In the first few years of life the growing kidneys are very susceptible to damage from infections and it may be necessary for children with this sort of plumbing, to have antibiotics to prevent such infections developing when they are very young.

Early feeding may be problematic due to poor sucking reflex and generalised floppiness. 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).

Frequent regurgitation of food or vomiting are common though this often improves as the child gets older. In a recent study involving a pair of affected non-identical twins, a barium meal revealed that both children had episodic gastric pseudovolvulus. In this condition the stomach does not have the normal system of peritoneal ligaments and has a propensity to twist around itself. This obstructions the normal gastric emptying and the stomach contents are forced back up the oesophagus. A number of children have had surgery to prevent this reflux of food back up the gullet – an operation known as a Nissen’s fundoplication. One family informed us that changing to a macrobiotic diet caused a stop to the regurgitation of food. We would be interested to know of other treatments that have been successful.

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. 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. A few 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 (an ileus in medical terminology). This may be due to abnormalities that have been observed in the nervous system in the gut that is meant to help with coordinating the contraction of the gut. This may also explain why many of the children suffer constipation.

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.

The children are usually described by their parents as content, of a happy disposition and an affectionate nature. They exhibit a wide range of emotions- joy, enthusiasm, excitement, grumpiness, sadness – depending on their circumstances. There have been some reports of apparently unprovoked emotional outbursts with sustained laughing or crying. Sometimes there may be sudden changes of mood from “highs” to “lows”.

Like most children they love attention and play, especially noisy games, rough and tumble, water play and musical toys. Some children exhibit quite repetitive behaviour. They often put their hands into their mouths and may bite their hands. In a few cases the children may push, squeeze or hit their face or neck with a hand. The children usually settle down well at night and sleep.

In two or three reports from parents their children have become very withdrawn and quiet for days on end and often not eating. They may become quite distressed if disturbed. The cause of these episodes, and particularly whether they are associated with illness has not been resolved.

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. A number of parents have reported jerking movements which are not associated with abnormal brain wave activity on EEG.

Because the condition has not long been recognised, 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.