Psychomotor retardation and central nervous system

Most cases of ATR-X syndrome have global developmental delay. However, even in less severely affected cases, where general performance may be classified as in the moderate level, expressive language is usually very limited.

In early childhood generalised hypotonia is common and all milestones are delayed. More severely affected patients do not walk until later in childhood and some never ambulate. Most have no speech, although an increasing number of individuals are being identified who use a few words or signs. The most severe cases may only have situational understanding, and most are dependent on others for almost all daily activities. More recent reports, however, point to a wider spectrum of intellectual handicap than previously thought. A mutation in the ATRX gene has recently been identified in family originally described by Carpenter and colleagues [1]. All affected males had moderate MR and exhibited expressive language delay, though no psychometric evaluation was available. Guerrini and colleagues reported a mutation in an Italian family with four affected male cousins, one had profound MR, whereas the others had an intellectual quotient (IQ) of 41, 56 and 58 [2]. The basis for this marked variation is unknown.

Generally, affected individuals continue to acquire new skills, though a brief period of neurological deterioration has been reported in three cases. In one report, electroencephalogram (EEG) changes were consistent with encephalitis [3]. The family originally reported by Holmes and Gang [4] was subsequently shown to have an ATRX mutation [5]. The reported family consisted of an infant and two maternal uncles with microcephaly, large fontanel, hypotonic face with short nose and anteverted nares, epicanthus, club foot deformity, and retarded psychomotor development. All three affected males from this family died in childhood and the death of one was attributed to encephalitis.

With age, affected individuals often develop a tendency toward spasticity. One report described a family with an ATRX mutation where affected members had spastic paraplegia from birth [6].

Seizures occur in approximately one third of cases and most frequently are clonic/tonic or myoclonic in nature. A number of parents have reported jerking movements, which are not associated with epileptiform activity on EEG.

Assessment of vision and hearing is difficult. Vision usually appears normal, although two patients have been reported as blind. Optic atrophy or pale discs are commonly noted, as are refractive errors (especially myopia). Sensorineural deafness and alpha thalassaemia were previously considered as features that distinguishes ATR-X syndrome from the allelic condition Juberg-Marsidi syndrome [7]. However, of the 13 cases with a documented sensorineural hearing deficit, seven had alpha thalassaemia suggesting the two conditions are part of a single continuum.

Although the head circumference is usually normal at birth, post-natal microcephaly usually develops. Macrocephaly has not been reported.

Computed tomography (CT) and magnetic resonance imaging (MRI) do not generally reveal remarkable findings, although mild cerebral atrophy may be seen. In two cases, partial or complete agenesis of the corpus callosum was reported. Autopsy reports were available for only three cases. The brain was small in each; in two cases the morphology was normal, but in the remaining case the right temporal gyri were indistinct and there was hypoplasia of the cerebral white matter.

Behavioural phenotype

No systematic study of behaviour has been carried out for ATR-X syndrome. Consequently, most reports of behavioural characteristics are anecdotal. Nevertheless, a thumbnail sketch of the mannerisms of this condition is slowly emerging [8, 9] and may be useful for diagnosis.

The subjects are usually described by their parents as content and of a happy disposition. Affected individuals exhibit a wide range of emotions that are usually appropriate to their circumstances. There have been reports, however, of unprovoked emotional outbursts with sustained laughing or crying. There may be emotional fluctuation with sudden switches between almost manic-like excitement or agitation, and withdrawal and depression. In several instances, the episodes of crying have been thought to be associated with pain, possibly of a gastrointestinal origin (see below).

Whereas many of the individuals are affectionate to their caregivers and appreciate physical contact, some patients exhibit autistic-like behaviour: patients appear to be in a world of their own, show little interest or even recognition of those around them, and avoid eye contact. The latter behaviour may be associated with an unusual and persistent posture.

Affected individuals may be restless, exhibiting choreoathetotic-like movements. Frequently, they put their hands into their mouths and may induce vomiting. Sometimes, they engage in self-injurious behaviour, biting or hitting themselves. They may hit, push or squeeze their neck with their hands to the point of cyanosis, a state they may also achieve through breath-holding. They may exhibit obsessional behaviour such as spinning on one spot while gazing into a light. Repetitive stereotypic movements may be manifest and these may vary from pill-rolling to hand flapping. This characteristic behaviour is reminiscent of Angelman syndrome and may lead to diagnostic confusion.

Facial anomalies

Distinctive facial traits are most readily recognised in early childhood and the gestalt is probably secondary to facial hypotonia (Figure 1). The frontal hair is often upswept, there is telecanthus, epicanthic folds, flat nasal bridge and mid-face hypoplasia, and a small triangular upturned nose with the alae nasi extending below the columella and septum. The upper lip is tented, the lower lip full and everted. The frontal incisors are frequently widely spaced, the tongue protrudes and there is prodigious dribbling. The ears may be simple, slightly low set and posteriorly rotated.

Genital abnormalities

Genital abnormalities are seen in 80% of children. These may be very mild (e.g., undescended testes or deficient prepuce), but the spectrum of abnormality extends through hypospadias and micropenis to ambiguous female external genitalia. The most severely affected children, who are clinically defined as male pseudohermaphrodites, are usually raised as females. In such cases there are no Mullerian structures present, and intra-abdominal, dysgenetic testes or streak gonads have been found [10, 11]. Of particular interest is the finding that these abnormalities breed true within families [12]. Puberty is frequently delayed and, in a few cases, appears to be arrested. Curiously, premature adrenarche has been noted in two children ([13] and unpublished observation).

Skeletal abnormalities

In a series of 45 cases, a wide range of relatively mild skeletal abnormalities were noted, some of which were probably secondary to hypotonia and immobility [14]. Fixed flexion deformities, particularly of the fingers, were common. Other abnormalities of the fingers and toes were also observed: clinodactyly, brachydactyly, tapering of the fingers, drum stick phalanges, cutaneous syndactyly, overlapping of the digits, and a single case with a bifid thumb. Foot deformities occured in 29% of cases and include pes planus, talipes equinovarus and talipes calcaneovalgus. Almost a third of the cases had kyphosis and/or scoliosis, and chest wall deformity was seen in 10 cases. Sacral dimples were present in three cases, radiological spina bifida in two cases and other abnormalities of the vertebrae in five cases. Only a few of the cases had a thorough radiological investigation. In those investigated, the most common findings were delayed bone age and coxa valga. Short stature was seen in two-thirds of cases. Longitudinal data were available for only a few cases. As noted previously, in some patients growth retardation is apparent throughout life, whereas in others it manifests at a later stage, e.g. at the time of the pubertal growth spurt.

Miscellaneous abnormalities

Recurrent vomiting, regurgitation or gastro-oesophageal reflux, particularly in early childhood, are common findings. 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 torsion around itself leading to gastric outlet obstruction and secondary gastro-oesophageal reflux [15]. An apparent reluctance to swallow has been reported by several parents and probably reflects the dyscoordinated swallowing that was observed radiologically in two well-studied cases (unpublished data). The tendency for aspiration is commonly implicated as a cause of death in early childhood. Excessive drooling is very common, as is frequent eructation. Constipation occurs often, and in some individuals is a major management problem. Martucciello et al. [15] demonstrated ultra-short Hirshsprung's disease and colonic hypoganglionosis in two affected children. The authors reviewed 128 cases of ATR-X and found that hospital admissions for recurrent ileus were reported in two cases and that reduced intestinal mobility was observed radiologically in four cases. This may be a consequence of a widespread abnormality in the enteric nervous system, leading to abnormal gut motility. Two of the patients required partial resection of the ileum after developing ischaemia of the small bowel, which in one case was attributed to a volvulus. Volvulus was also reported in an additional case. One child required a right hemicolectomy following an episode of necrotising enterocolitis at 13 days of age (reviewed in [15]).

Evidence suggests that affected individuals are susceptible to peptic ulceration. Oesophagitis, oesophageal stricture and peptic ulcer have observed endoscopically in single cases. In five cases, an upper gastrointestinal bleed was observed, one of which required transfusion (haemoglobin, 5 g/dl) [14, 15]. Pain resulting from peptic ulceration is one possible explanation for the episodes of persistent crying and food refusal reported by a number of parents. A wide range of cardiac abnormalities have been noted: septal defects (10 cases); patent ductus arteriosus (six cases); pulmonary stenosis (three cases); aortic stenosis (two cases); tetralogy of Fallot (two cases) and single cases of transposition of the great arteries, dextracardia with situs solitus and aortic regurgitation ([14] and unpublished data).

Renal abnormalities (hydronephrosis, renal hypoplasia or agenesis, polycystic kidney, vesico-ureteric reflux) may present with recurrent urinary tract infections.

Haematology

Although the presence of alpha thalassaemia was initially one of the defining elements of the syndrome, it is clear that there is considerable variation in the haematological manifestations associated with ATRX mutations. A number of families have been identified in which some or all of the affected members show no signs of alpha thalassaemia [16, 17]. The test for alpha thalassaemia is simple and, when positive, quickly establishes the diagnosis (see diagnostic methods). However, the haematological findings are often surprisingly normal considering the presence of alpha thalassaemia. Neither haemoglobin concentration nor mean cell haemoglobin concentration are as severely affected as in the classical forms of alpha thalassaemia associated with cis-acting mutations in the alpha globin complex. This discrepancy probably reflects the different pathophysiology of the conditions.

Detection of alpha thalassaemia

The most sensitive test uses light microscopy to detect red cells containing HbH inclusions after incubation of venous blood with 1% brilliant cresyl blue in isotonic saline for 4–24 hours at room temperature (Figure 2). HbH is unstable and cells with inclusions may be more difficult to find in older blood samples. When the family history and phenotype are highly indicative of ATR-X syndrome, a careful search for inclusions should be performed in all affected individuals and repeated, if necessary, as inclusions may be very infrequent. It is important to note that, in most cases of ATR-X, the amounts of HbH are too low to be detected by electrophoresis. The haematology is often surprisingly normal considering the presence of alpha thalassaemia.

Mutation detection

The majority of disease-causing mutations are single base changes, most of which are missense mutations. The gene is large and a comprehensive mutation analysis, even of the coding region alone, is a time-consuming and expensive enterprise. However, the missense mutations are clustered: 50%–60% of the identified mutations are located in the ADD domain, 20% have the common 736C>T, R246C mutation and the next most commonly affected region is the helicase domain. A sensible and cost-saving approach is to start by analysing these regions.

Protein studies

Levels of ATRX protein were found to be substantially reduced in a number of patients with missense mutations involving the ADD domain [23, 35]. Analysis of the ATRX protein may also reveal a truncation in the ATRX protein of affected individuals, which allows more directed sequencing.

X inactivation studies

X-chromosome inactivation studies may be used to determine the carrier status of at-risk women. In normal women, one X-chromosome is randomly inactivated in each cell. Most females who are unaffected carriers for ATR-X syndrome display preferential inactivation of the mutant ATRX allele [36]. This phenomenon is referred to as "non-random" or "skewed" X-chromosome inactivation and can be identified by established laboratory techniques. There are, however, exceptions: a child of normal intelligence carrying an ATRX mutation was shown to have a balanced pattern of X inactivation [36]; another female carrier with mild mental retardation also had a non-skewed pattern of X inactivation [37]. This indicates that there may be a risk of false negative results associated with this test. Furthermore, 10% of normal females show skewed X-chromosome inactivation, which could lead to false positives. Finally, in women with certain X-linked conditions, other than ATR-X syndrome, the X chromosome carrying the mutated gene is preferentially inactivated [38]. Since non-random X-chromosome inactivation is not unique to ATR-X syndrome, the test is only supportive, to be used in the context of a suggestive clinical and/or family history.

Development and behaviour

Evaluation of developmental skills from infancy ensures that the appropriate intervention services are introduced as early as possible. Infant stimulation, early intervention and special education are important to optimise abilities. Affected individuals may show improvement in socialisation with one-to-one therapy. Anti-psychotic medication such as prochlorperazine may be effective in treating severe behaviour problems.

Feeding and gastro-intestinal problems

Infantile hypotonia is very common and is associated with considerable difficulty with sucking. Gavage feeding may be required for a number of weeks to assure adequate nutrition.

Recurrent vomiting, regurgitation or gastro-oesophageal reflux, particularly in early childhood, is a common finding and may be secondary to gastric pseudovolvulus. Evaluation of recurrent vomiting should include assessment for gastro-oesophageal reflux and there is a strong case for 24 hr pH monitoring and barium study of the upper gastro-intestinal tract. Initial treatment for gastro-oesophageal reflux should be conservative and standard. Nutrition consultation for assurance of adequate caloric intake may be needed. In severe cases, surgical treatment by fundoplication may be indicated, as well as the introduction of a feeding gastrostomy. If gastric pseudovolvulus is demonstrated this requires surgical correction.

Prolonged periods of food and drink refusal associated with considerable distress are frequently reported by parents. The cause is rarely obvious, but peptic ulceration, oesophagitis or ileus should be considered, as these are well documented in this condition.

Constipation can be a significant management problem and fecal impaction may occur if preventative measures are not undertaken. Adequate hydration is important in preventing constipation, as is the use of bulking agents in the diet and the regular use of osmotic laxatives such as lactulose. If the problem is resistant to conservative management then rectal biopsy should be considered to exclude ultra-short segment Hirshsprung's disease and colonic hypoganglionosis.

Drooling is very common in ATR-X, particularly in young children. Many mothers will describe their sons soaking several bibs during the course of the day. The open mouth associated with facial hypotonia no doubt is an important factor, as is their reluctance to swallow even with a mouth full of saliva. Numerous methods have been tried to control drooling. Feeding by mouth may help encourage the swallowing reflex and this may be supplemented by specialist training by a speech therapist. In other conditions in which there is drooling, anticholinergic drugs are commonly used to reduce production of saliva. However, these drugs cause reduced gastrointestinal motility (which may already be abnormal in ATR-X males) and may exacerbate constipation or provoke ileus. Botulinum toxin type A (Botox) injection of the salivary glands might be tried, but reports are scant and the treatment needs repeating. The surgical options of redirecting the submandibular ducts or removing the glands themselves may be considered.

Neurologic

Spasticity may increase with age. Regular evaluations of the need for physical therapy are needed and ongoing therapy may ameliorate spasticity.

Seizures occur in approximately one third of cases and most frequently are clonic/tonic or myoclonic in nature. In the majority of cases, seizures respond well to standard therapy. Some affected individuals exhibit jerking movements which, though appearing to be seizures, are not associated with epileptiform activity on EEG. Electroencephalogram may need to be carried out with video recording to correlate seizure activity and abnormal movements. Approach to seizure control is standard.

Haematology

In ATR-X syndrome about 90% of cases have alpha thalassaemia. The anaemia, however, is mild and does not require treatment. Iron is not indicated unless iron stores are shown to be low.

Genitourinary

Genital abnormalities are seen in 80% children. The possibility of cryptorchidism should be assessed in all affected children. Orchidopexy should be carried out as required at the standard age. Intra-abdominal testes, which are usually dysgenetic, should be removed because of the long-term risk of malignancy.

Structural abnormalities of the kidneys and ureters are well described and may predispose individuals to urinary tract infections. Renal abnormalities (hydronephrosis, renal hypoplasia or agenesis, polycystic kidney, vesico-ureteric reflux) may present with recurrent urinary tract infections. The urinary system should be imaged with ultrasound at diagnosis. Urine should be cultured when there is symptomatology such as fever or pain on urination. Prophylactic antibiotics are indicated if urinary tract anomalies are present to prevent long-term damage to the kidneys.

Musculoskeletal

A wide range of relatively mild skeletal abnormalities have been noted, some of which are probably secondary to hypotonia and immobility [14]. Foot deformities occur in 29% of cases and include pes planus, talipes equinovarus and talipes calcaneovalgus. Kyphosis and scoliosis are common and increase with age. A careful musculoskeletal exam should be done at diagnosis and throughout childhood. Treatment of musculoskeletal anomalies, when appropriate, is standard.

Hearing and vision

Sensorineural deafness may be present. Standard distraction tests and, if anomalies are suspected, evaluation of auditory evoked responses should be done. Hearing loss should be managed as for any infant.

Refractive abnormalities, in particular myopia, are common. Strabismus may be present. Rarely the children may be blind and this may be associated with optic atrophy. A formal ophthalmologic evaluation is appropriate at diagnosis and regularly thereafter. Ocular problems should be treated as in the general population.