19 February 2016

Behavioural phenotypes are syndromes with a chromosomal or genetic aetiology, comprising both physiological and behaviour manifestations, including a distinctive social, linguistic, cognitive and motor profile.

Gregory O'Brien (UK)

Behavioural phenotypes are syndromes with a chromosomal or genetic aetiology (Skuse, 2002), comprising both physiological and behaviour manifestations, including a distinctive social, linguistic, cognitive and motor profile (O'Brien et al., 2002). The course of the syndrome, both behaviourally and medically, is not stagnant, and the presentation of the syndrome can vary according to level of intellectual disability and input received, and can change with increasing age.

Intellectual disability in behavioural phenotypes
While Down's syndrome is the most common cause of intellectual disability, fragile-X syndrome is the most common inherited cause of learning disability (see Sabaratnam, 2003). The level of intellectual disability can be affected by severity of the phenotypic expression. In a number of syndromes, such as Cornelia de Lange, milder phenotypic expression is associated with less severe intellectual disability. Sex differences can also determine level of intellectual disability; for example, females with fragile-X syndrome have milder phenotypic expression and less severe intellectual disability. Figure 1 shows the typical level of intellectual disability for a range of genetic syndromes.

Owing to the range of intellectual disability exhibited across behavioural phenotypes, it is important to assess cognitive functioning at an early stage, particularly when the level of intellectual disability may be borderline, as in the case of Sotos and Turner syndromes, so that educational intervention can be tailored to meet the individual's needs and maximize the individual's potential (Barnard et al., 2002).

Behavioural phenotypes and aberrant behaviours
Aberrant behaviours such as self-injury, screaming and aggression are common in behavioural phenotypes. This finding is not surprising given that these behaviours are highly prevalent in the population of people with intellectual disabilities, and are more common in people with severe intellectual disability. In a number of syndromes, such as Lesch-Nyhan syndrome, self-injurious behaviour is a primary behavioural feature of the syndrome. Although the underlying origin of these behaviours can sometimes be linked to a biological mechanism, such as a deficiency in the enzyme hypoxanthineguanine phosphoribosyl transferase (HPRT) in Lesch-Nyhan syndrome, in most conditions the pathway from gene to behaviour is less clear.

Reasons for aberrant behaviour
Aberrant behaviours such as self-injury and aggression can be indicative of physical pain. Head-banging is often associated with dental pain or upper respiratory tract infections causing sinusitis or otitis (Clarke, 2002) or gastrointestinal reflux, as commonly occurs in Cornelia de Lange syndrome. Another explanation for behaviours such as temper tantrums and irritability is frustration at being unable to communicate needs. In this instance, alternative ways to promote communication, either through sign language or pictorial representations, depending on the individual's level of ability, should be considered to alleviate the behaviour (see also Joyce, 2003). Speech and language therapy can also be used in order to maximize the individual's verbal ability (Barnard et al., 2002). Behavioural therapies are useful in identifying and alleviating the function of these behaviours. A multidisciplinary approach to treatment is advocated, incorporating pharmacological therapy, physical restraint and behavioural therapy. Fortunately, behaviours such as self-injury often become less prevalent with age.

Psychiatric disorders
In adulthood, the propensity for psychiatric disturbance often increases. Anxiety and depression are frequently cited in the behavioural phenotypes of a number of syndromes (see Figure 2). However, this presents a paradox, as symptoms of a psychiatric disorder may be overshadowed by the behaviour and intellectual disability of affected individuals. Also, the presentation of a psychiatric disorder in people with intellectual disability is often atypical, further confounding diagnosis. If a psychiatric diagnosis is suspected, assessment using a schedule designed for use in intellectual disability is recommended (O'Brien et al., 2001). In spite of the prevalence of autistic-like behaviours in many syndromes, autism is typically associated with a few conditions only, notably tuberous sclerosis.

In syndromes in which there are differences in physical appearance, such as short stature/accelerated growth, facial dysmorphism or delayed sexual development, affected individuals can suffer from low self-esteem and this can often precipitate secondary behavioural difficulties. The prevalence of psychiatric disorders in behavioural phenotypes has directed research towards investigation of a genetic component of psychiatric disorders.

Aberrant behaviours, especially when extreme in severity (such as self-injury) are particularly distressing for both affected individuals and their carers. Practitioners should offer support to both parties, and reassurance and support should also be offered to family members and carers, as they can often perceive themselves to be the cause of the individual's behaviour.

Medical complications
In general, severity of intellectual disability is associated with an increase in associated medical conditions and complications (O'Brien et al., 2002). The relationship between medical complications is complex; they interact with one another, rarely appear in isolation within the same syndrome, and can manifest secondary medical and behavioural complications. Fortunately, preventative measures, such as good diet and physiotherapy, can ameliorate the consequences of medical and behavioural complications. Clinicians should be aware that medical complications associated with the presentation of the behavioural phenotype in childhood can change as the individual reaches adulthood.

Respiratory disorders are a major cause of morbidity and distress in individuals with behavioural phenotypes. Common respiratory disorders include aspiration pneumonia, congenital defects and recurrent respiratory infections. Hypotonia, scoliosis and cardiac anomalies are common causes of respiratory insufficiency. Physiotherapy is a useful intervention for breathing difficulties associated with hypotonia. However, practitioners should be aware that a number of interventions are associated with difficult complications, for example surgical interventions to help alleviate breathing difficulties present a significant anaesthesia risk in a number of syndromes. Tube-feeding for individuals with failure to thrive (both children and adults) can contribute to respiratory infection.

Respiratory complications impact on all aspects of functioning, for example by disturbing sleep. In syndromes characterized by an atypical sleep pattern, such as Sanfilippo syndrome, this can be extremely distressing and can contribute to behavioural disturbances.

Cardiovascular complications: the cardiovascular system is involved in the morbidity and mortality associated with a number of genetic syndromes in which behavioural phenotypes present. Congenital heart defects are common and affect individuals with fragile-X, Down's and Rubenstein-Taybi syndromes (Barnard et al., 2002). Cardiac abnormalities can be associated with muscular and skeletal degeneration. Abnormalities of the cardiovascular system can contribute to secondary complications, such as hypertension in Williams and Turner syndromes. Cardiovascular disease can be secondary to obesity, particularly in Prader-Willi syndrome. In managing these cardiovascular complications, routine ECG screening and promotion of a healthy diet is advocated.

Obesity: in a number of syndromes, such as Angelman and Rubenstein-Taybi syndromes, associated feeding difficulties such as failure to thrive in childhood can manifest into a propensity for obesity in adulthood. Obesity can lead to serious medical problems, such as non-insulin-dependent diabetes mellitus, hypertension and cardiovascular disease. In some syndromes, such as Prader-Willi syndrome, the propensity for obesity is one of the cardinal features, and is potentially life-threatening. Dietary intervention at an early stage can help counteract and minimize secondary medical complications. Intervention techniques such as restricting sources of food (e.g. by locking the refrigerator) and managing calorific intake are effective. Behavioural modification strategies that have an emphasis on self-monitoring and reinforcement, in combination with exercise programmes, can be effective in maintaining a healthy weight.

Epilepsy: associated with behavioural phenotypes can be difficult to manage. The presentation of epilepsy varies according to the syndrome and also with age. For example, in Angelman syndrome seizures are present in infancy but become less frequent with the passage of time. In Rett syndrome, epilepsy is severe in early childhood, but reduces with increasing age and may have ceased by the time affected individuals reach their 20s. For a number of syndromes, the presence of epilepsy can be a diagnostic marker: children with Aicardi and Angelman syndromes have diagnostically distinctive ECG patterns, although less markedly so after puberty.

Epilepsy can be an underlying cause of behavioural disturbance in individuals with a behavioural phenotype. The use of electrophysiological measures in addition to standard behavioural measures can help determine the impact of epilepsy on an individual's behaviour. Routine screening of epilepsy should be performed, particularly in the presence of deteriorating adaptive functioning. Intervention techniques include the use of anti­convulsants to manage and control epilepsy. Surgical intervention may also be considered in some instances, for example in tuberous sclerosis when brain or renal tubers may require removal.

The course of behavioural phenotypes
Behavioural phenotypes associated with a progressive course
Some syndromes have a progressive course, whereas in others such as phenylketonuria (PKU) and galactosaemia, progression of the syndrome is determined by dietary management and elimination from the diet of phenylalanine and lactose respectively, in order to prevent medical and adaptive deterioration. Clinicians should be aware of the nutritional implications of implementing elimination diets, and ensure that essential nutrients lost are substituted with dietary supplements. This can prevent secondary complications such as osteoporosis. These remedial progressive syndromes in addition to progressive and non-progressive syndromes are listed in Figure 3.

At present, there are no cures for many of these progressive degenerative syndromes, but it is important that practitioners are able to anticipate, recognize and treat medical complications at an early stage, in order to increase quality of life and life expectancy. Treatment should be multidisciplinary, incorporating surgery, pharmacotherapy, physiotherapy and the use of mobility aids, and should be aimed at managing symptoms and medical complications, as the following examples show.

  • The myotonia characteristic of congenital myotonic dystrophy can be treated with pharmacological agents and the use of splints.
  • The progressive course of mucopolysaccharide disorders can be slowed down by bone marrow transplantation, in some cases reversing specific symptoms.
  • Physiotherapy and exercise that places low stress on muscles can be beneficial in Duchenne muscular dystrophy and Angelman syndrome (Gilbert, 2000).
  • Corrective surgery can be effective for scoliosis/kyphosis, where it is deemed appropriate, and can alleviate and/or help to prevent compression of the spinal cord.

Emotional and practical support should be offered to both the individual and their family because of the shortened life expectancy of affected individuals, and genetic counselling should be offered to prospective parents. Short-term respite care is also beneficial for families.

Changes in the presentation of behavioural phenotypes with age
Ageing of individuals with behavioural phenotypes is an important issue for clinicians. With recent advances in intervention and treatment techniques, this population are living longer. It is therefore important that clinicians are able to anticipate future medical complications.
The presentation of some of the key features of behavioural phenotypes can change with age. The physical appearance of the individual can change, most notably:

  • facies can become more pronounced or coarse with age, as in Coffin-Lowry syndrome
  • premature ageing (e.g. in Cockayne syndrome premature ageing can make an affected individual appear older than he or she actually is).

The presentation of some of the key features may decline as the individual ages; for example, in hypomelanosis of Ito the characteristic hypopigmentation becomes less prominent in adulthood, and in neurofibromatosis type 1, café-au-lait spots decrease after middle age (Barnard et al., 2002).

Carers and family members should be prepared for and fully informed of the course of the syndrome, in order to anticipate any changes and alert medical professionals. The observations of those closest to the individual are valuable in alerting practitioners to any physical and behavioural changes.

Mortality and morbidity
The cause of mortality and morbidity in genetic syndromes in which behavioural phenotypes occur is often complex. Associated medical complications and abnormalities in conjunction with secondary complications have an interactive and complex relationship. How they interact and how they are managed can impact on life expectancy. In a number of syndromes, such as Cornelia de Lange, early intervention and management of medical complications (e.g. cardiac anomalies, metabolic disorders and severe obesity) can significantly extend longevity. Severity of phenotypic expression can also determine mortality and morbidity. A number of the mucopolysaccharidoses have both mild and severe phenotypic expressions, both of which can determine life expectancy. Figure 4 shows the typical life expectancy and the main cause of death for each syndrome.

Advances in clinical understanding of behavioural phenotypes and the mechanisms that determine the syndrome, paralleled by advances in medical and therapeutic interventions, have increased the quality of life for individuals with behavioural phenotypes, and life expectancy has significantly improved. With increasing age, secondary medical complications that are seen in the general population are becoming more prevalent in this clinical population. Routine procedures, such as regular screening for breast, cervical and prostate cancer, should be offered. Clinicians should be aware that both the physical and behavioural profile of many syndromes changes with age, and should prepare for this. The psychological health of affected individuals should also be monitored throughout adulthood, owing to the increased likelihood of developing psychiatric disorders.

FIGURE 1: Level of intellectual disability

 Level of intellectual disability
Angelman    **
CockayneIntellectual disability is progressive
Coffin-LowryFemales onlyMales only
Coffin-Siris  *** 
Cornelia de Lange   ** 
Cri du chat    * 
Crouzon  **  
Down's  **  
Duchenne muscular dystrophy***   
Fragile-X  **  
Galactosaemia *    
Lesch-Nyhan  **  
Lowe   ** 
Mucopolysaccharidoses  *** 
Myonic dystrophy  **  
Neurofibromatosis type 1 *    
Phenylketonuria (1)   ** 
Prader-Willi **** 
Rett     *
Rubenstein-Taybi  *** 
Smith-Lemli-Opitz *****
Smith-Megenis   *  
Sex aneuploidies: 
- Klinefelter**    
- Turner**    
Sotos **   
Tuberous sclerosis******
Velocardiofacial *    
Williams   *  
Wolf-Hirschhorn    **
(1) If left untreated


FIGURE 3: Syndromes categorized by typical course

Progressive syndromes 
CockayneMucopolysaccharidoses 1
Duchenne muscular dystrophyMyotonic dystrophy
LoweRett syndrome
Non-progressive syndromes 
Angelman Prader-Willi
Coffin-SirisSex aneuploidies 2
Cornelia de LangeSmith-Lemli-Opitz
Cri du chatSmith-Magenis
Down'sTuberous sclerosis
Neurofibromatosis type 1Wolf-Hirschhorn
Remedial progressive syndromes 3 

1 Lysomal storage disorders (for more detailed information see O'Brien et al., 2002)
2 Sex aneuplodies include Turner and Klinefelter syndromes
3 Syndromes in which the course can be determined by dietary intervention



Barnard L, Pearson J, Rippon L, O'Brien G. Behavioural phenotypes of genetic syndromes: summaries including notes on management and therapy. In: O'Brien G, ed. Behavioural Phenotypes in Clinical Practice. London: Mac Keith Press, 2002.
(Provides a comprehensive overview of the major syndromes, including management and treatment interventions.)

Clarke D. Self-injurious and aggressive behaviour. In: O'Brien G, ed. Behavioural Phenotypes in Clinical Practice. London: Mac Keith Press, 2002.
(An excellent overview of aberrant behaviours and management strategies.)

Gilbert P C. A-Z of Syndromes and Inherited Disorders. 3rd edition. Cheltenham: Nelson Thornes, 2000.
(A good reference book that provides simple, straightforward information.)

Joyce T, Functional Analysis and Challenging Behaviour. PSYCHIATRY 2003; 2:8:

O'Brien G, Pearson J, Berney T, Barnard L. Measuring behaviour in developmental disability: a review of existing schedules. Developmental Medicine & Child Neurology 2001; 43: Supplement 87: 1-70.
(Provides information of the most commonly used assessment schedules in learning disability.)

O'Brien G, Barnard L, Pearson J, Rippon L. Physical health and clinical phenotypes. In: Prasher V P, Janicki MP, eds. Physical Health of Adults with Intellectual Disability. Oxford: Blackwell, 2002.
(Reviews the physical health issues implicated in behavioural phenotypes.)

Sarabatnam M, Fragile-X Syndrome. PSYCHIATRY 2003; 2:8:29-33.

Skuse D H. Behavioural phenotypes. PSYCHIATRY 2002;1:7: 98-102.
(A good, comprehensive introduction to the genetic mechanisms implicated in behavioural phenotypes.)

First published in Psychiatry; Volume 2:8 August 2003 and reprinted with the kind permission of The Medicine Publishing Company.