- Excerpt from Chapter 3, Behavioral Phenotype of Genetic
Disorders, by Andrew Levitas, M.D., Elizabeth Dykens, Ph.D.,
Brenda Finucane, M.S., and Wendy R. Kates, Ph.D.
The phenotype of a genetic syndrome is the set of physical
characteristics produced by a genetic abnormality, or genotype.
The most widely known example is the easily recognized face of a
person with Down syndrome. Smith’s “Recognizable Patterns
of Human Malformation”, the standard text in the field, contains
photographs of many currently known syndromes, with descriptions of
other aspects of their respective phenotypes, including laboratory
and X-ray findings.
The phrase behavioral phenotype was coined by Nyhan. The
Society for the Study of Behavioural Phenotype (SSBP),
http://www.ssbp.co.uk, has proposed a consensus definition:
A characteristic pattern of motor, cognitive, linguistic and/or
social abnormalities which is consistently associated with a
biological disorder.
Dykens proposed a clinical definition of behavioral phenotype:
. . . a heightened probability that people with a given syndrome will
exhibit behavioral or developmental sequelae relative to others
without the syndrome.
Theoretically, if there were no connection between genetic syndromes
and mental disorders, any mental disorder should occur in individuals
with any genetic syndrome, in the same frequency from one syndrome to
another and in the same frequency as in the general population.
Dykens’s definition implies that, with respect to genetic
syndromes, behavioral and personality traits, neuropsychiatric
abilities and deficits, and mental disorders are distributed
nonrandomly. Phenotypes of all kinds—behavioral
phenotypes, perhaps especially—can be the final common pathway
of multiple causes. The broader the phenotype, the more likely it
will be that there are multiple causes. Also, syndromes with multiple
molecular causes (phenocopies) may have subtly different behavioral
phenotypes. It is to be hoped that the association between a given
genetic syndrome and a given mental disorder might be a clue to the
underlying mechanisms of both, but for the moment the concept of
behavioral phenotype is mostly of clinical utility. Mental health
professionals working with individuals with developmental
disabilities need to be aware of the contribution of behavioral
phenotype to diagnosis and treatment. To offer just two examples,
they should be aware that a person with Down syndrome who is
hallucinating is far more likely to have Major Depressive Disorder,
Severe With Psychotic Features, than to have Schizophrenia or
Dementia of the Alzheimer’s Type, and that a cause might be
hypothyroidism. Similarly, mental health professionals should be able
to recognize Rubinstein-Taybi syndrome and avoid the use of older
antipsychotic medications because of the high rate of Neuroleptic
Malignant Syndrome in people with this genetic disorder.
The remainder of this chapter is devoted to capsule descriptions of
the behavioral phenotypes of 12 ID syndromes. Wherever they exist,
Internet resources are included. The following are four important
general resources for the clinician:
Jones, K. L. (Ed.). (1997). Smith’s Recognizable Patterns of
Human Malformations (5th ed.). Philadelphia: W. B. Saunders.
OMIM (sometimes simply said as a word, “Omim”)
is the acronym for the online version of McKusick’s
comprehensive text Mendelian Inheritance in Man. Maintained by
the National Center for Biotechnology Information at the National
Library of Medicine, constantly updated as new information becomes
available, the database is searchable by name of syndrome or by
location of chromosome abnormality. Other sites and references often
refer to a syndrome’s “OMIM number.”
The URL (Internet address) is: http://www3.ncbi.nlm.nih.gov/OMIM/. Note:
The site cannot be accessed from some networks. When this is the
case, a link to an alternate or mirror site is offered. http://www.geneclinics.org
contains reviews of 175 conditions. This is now the resource of
choice among geneticists and genetic counselors, more so than OMIM.
It also has a search engine to enable users to locate the nearest
medical genetics center in their area.
The Alliance of Genetic Support Groups is an
organization made up of groups devoted to each particular syndrome.
It can be reached it at 202-966-5557, through its Web page at
http://www.geneticalliance.org/. There is a searchable database of
support groups and informational newsletters, valuable in locating
groups involved with especially rare syndromes. It is worth
remembering in this connection that a person with ID can have a
genetic syndrome unconnected with the ID, just as he or she can have
any other disorder.
Proposed Behavioral Phenotypes of 12 ID Syndromes
This section describes behavioral phenotypes for the following 12 ID syndromes:
q Angelman syndrome
q Cri-du-chat (5p–) syndrome
q Down syndrome
q Fetal alcohol syndrome
q Fragile-X syndrome
q Phenylketonuria and other hyperphenylalaninemias
q Prader-Willi syndrome
q Rubenstein-Taybi syndrome
q Smith-Magenis syndrome
q Tuberous sclerosis complex
q Velocardiofacial syndrome
q Williams syndrome
Each of the subsections on these syndromes includes information on
physical findings, diagnosis, cognition, behavioral and associated
mental health disorders, and a table comparing the physical
and laboratory phenotype features with childhood and adulthood manifestations.
Angelman Syndrome
(OMIM # 105830)
Physical Findings: Although Prader-Willi syndrome (PWS)
and Angelman syndrome (AS) are genetically related “sister
syndromes,” they are as different as one can imagine in their
associated features. People with AS have microcephaly, as well as
ataxic movements; seizures; bouts of frequent laughter; stereotypies;
hypermotoroic behavior; absent or limited expressive language; and
Severe or Profound ID. EEG findings are typically abnormal, showing
large amplitude, slow-spike waves. Seizures generally begin in
early childhood, and they might have a severe onset and then wax and
wane in severity or frequency, or they might become less severe and
more easily managed over time. Seizures notwithstanding, adults
generally show good health, with risks of scoliosis and decreased
motility in the older years.
Whereas PWS is due to a lack of paternally derived imprinted
information, AS is associated with a lack of maternally derived
imprinted information to the q11–q13 region of chromosome
15. AS is due to the inactivation or absence of a gene, UBE3A,
located in the AS critical region and involved in the complex protein
pathways that are found in all cells. Approximately 70% of people
with AS have maternal deletions that include UBE3A. A small
percentage (2–3%) have paternal uniparental disomy (UPD), the
situation when UBE3A is silenced and both chromosome 15s are
inherited from the father instead of the usual situation, wherein one
chromosome 15 is inherited from each parent. With UPD, the
chromosomes themselves are normal, but the inheritance pattern is
amiss. Some people with AS have mutations in UBE3A, while still
others have imprinting center defects that are believed to disrupt
the regulation of UBE3A. In about 15% of cases that meet clinical
criteria, the genetic cause cannot be determined. Subtle behavioral
differences are seen across some of these genetic classes of AS.
Diagnosis: In people with clinical features of AS,
fluorescence in-situ hybridization (FISH) testing will detect
deletions. DNA methylation testing can detect deletions, as well as
paternal UPD or defects in the imprinting center. High-resolution
chromosome analysis can assist in ruling out other conditions.
Although most people with AS can be diagnosed with a combination of
these tests, a small percentage of individuals show abnormalities
upon additional testing of the UBE3A gene.
Cognition: People with AS generally have severe
levels of cognitive delay. Some individuals show unfocused,
non-goal-related actions and limited communicative intent, especially
individuals with more severe seizures or ataxia. More commonly,
individuals with AS show interests in others, and they might use a
few words expressively, engage in gestures or signs, and show
relatively well-developed receptive language abilities. Individuals
with AS due to paternal UPD fare slightly better, showing less
frequent or severe seizures or ataxia, and they show an increased
ability to use signs or gestures.
Behavioral and Associated Mental Health Disorders: Beginning
with Angelman’s initial observations, the behavioral
descriptions of people with AS have remained remarkably consistent.
People with AS typically show speech delay; smiling or bouts of
laughter that are unrelated to context; mouthing objects; problems
falling or staying asleep; motoric hyperactivity and inattention;
seizures; and stereotypies, such as hand-flapping or twirling.
Tantrums and irritability are occasionally present, but they are
secondary to the “happy demeanor” suggested by smiling and
laughter. Many individuals with AS have an attraction to water and
shiny objects. Adults might show less motoric hyperactivity than do
children, as well as less sleep disturbance and excitability. The
unsteady gait and bouts of laughter appear to persist over time.
Symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) are often
present in children, and many children with AS are misdiagnosed as
having Autistic Disorder.
Cri-du-Chat (5p–) Syndrome
(OMIM # 123450)
Physical Findings: Cri-du-chat syndrome, now more
commonly referred to as 5p– syndrome, was initially named for
one of its cardinal features—a high-pitched, infantile catlike
cry. Although the cry appears to dissipate over time, older children
might have a high-pitched voice. Almost all babies with the syndrome
have hypotonia, and about half develop hypertonia and limited range
of motion in their later years. Other common concerns include feeding
problems, a poor suck, regurgitation, and frequent respiratory and
ear infections. Older individuals might show severe constipation,
dental malocclusion, and ocular problems.
Most cases of 5p– syndrome are associated with a deletion on the
tip of the short arm of chromosome 5, specifically at 5p15. People
with deletions that encompass a portion of 5p15.2 generally show the
syndrome’s characteristic features of Severe or Profound ID, a
distinct round face with epicanthal folds, down slanting palpebral
fissures, microcephaly, and low-set malformed ears. A small number of
individuals, however, have the characteristic high-pitched cry, but
not ID, and these individuals have deletions at 5p15.3. A cat cry in
a newborn might be significant for very different outcomes, depending
on which areas of the 5p15 region are deleted.
Diagnosis: Diagnostic tools exist that enable the
differentiation between individuals with the classic 5p–
syndrome, which encompasses both the 5p15.2 and 5p15.3 critical
regions, and those with just the cat cry, which involve a deletion
only at 5p15.3. Approximately 80% of individuals have deletions,
whereas 10% might have rare chromosomal anomalies, and another 10%
might have unbalanced translocations. The 5p– syndrome appears
to be one of the most common human deletion syndromes, with an
incidence varying between 1 in 20,000 to 1 in 50,000 births. The
frequency in populations of patients with Profound ID (with an IQ
less than 20) is approximately 1%.
Cognition: On average, individuals with 5p–
syndrome function in the Moderate to Severe range of ID. A cognitive
profile has been consistently found in which receptive language
abilities exceed expressive language. Furthermore, many individuals
use sign language, even those that have some expressive language.
Individuals with unbalanced translocations generally function at
lower cognitive and adaptive levels than do those with deletions.
Most individuals are mobile and actively participate in their
adaptive care routines. Several high-functioning individuals have
been reported, with well-developed language, social, and cognitive
skills; their level of functioning appears unrelated to deletion size.
Behavioral and Associated Mental Health Disorders: Many
children and adults with 5p– syndrome have pronounced
inattention and hyperactivity, even compared with others with similar
levels of delay. Temper tantrums have been noted, but they do not
generally involve severe outbursts or aggression. Self-stimulatory
and repetitive behaviors are often seen, with some self-injury as
well. Stereotypies and self-injury are more apt to be seen in those
individuals with lower cognitive-adaptive levels. Social skills are
strengths relative to other adaptive areas—with the majority of
individuals showing an awareness of family members versus others,
being responsive to praise, being oriented to peers, acting engaged,
and showing imitation skills. Such strengths debunk the myth that all
people with 5p– syndrome are socially withdrawn or are prone to
Autistic Disorder. Nonetheless, compared with those with deletions,
individuals with translocations are more apt to be withdrawn,
uncommunicative, and unresponsive to others.
