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Adults with Rubinstein Taybi syndrome.

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CLINICAL REPORT
Adults With Rubinstein–Taybi Syndrome
Cathy A. Stevens,* Jill Pouncey, and Darcy Knowles
Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, Tennessee
Received 30 November 2010; Accepted 23 March 2011
Information in the medical literature regarding adults with
genetic syndromes is limited, making the care of these patients
challenging. We conducted a questionnaire study of adults with
Rubinstein–Taybi syndrome that addressed medical problems,
education, independence, and behavior. The most common
medical problems included short stature, obesity, visual difficulties, keloids, eating problems, spine curvature, and joint
problems. The adults had typically moderate mental retardation,
but most achieved some independence in self-care and communication; many participated in supported work situations. However, approximately one-third were said to have some decreased
abilities over time. Behavior problems were common and often
worsened with age. Very few of the study participants were seeing
a geneticist as an adult. Long-term involvement of geneticists and
education of adult primary care providers may help with many of
the challenges facing adults with RTS and their families.
Ó 2011 Wiley-Liss, Inc.
Key words: Rubinstein–Taybi syndrome; RTS; RSTS; adults with
genetic syndromes
INTRODUCTION
Today more than 90% of individuals with disabilities survive into
adulthood, many of whom have genetic conditions [Blum, 1995].
While this represents marked improvement in medical care, it also
results in several challenges for the provision of health care for these
patients. First, providers of health care for adults tend to be less
knowledgeable regarding genetics and less comfortable taking care
of patients with genetic syndromes [Suther and Goodson, 2003].
Additionally, most clinical geneticists have a background in pediatrics and more experience dealing with young patients with
syndromes. There is limited published information regarding the
management of adults with genetic syndromes and the medical
problems may be much different in adulthood. This is also true for
adults with Rubinstein–Taybi syndrome (RTS or RSTS). First
described in 1963, RTS is characterized by short stature, distinctive
facial appearance, broad thumbs and first toes, and mental retardation [Rubinstein and Taybi, 1963]. RTS is caused by mutations in
the CREBBP gene in approximately 50–70% cases and by EP300
gene mutations in approximately 3% of cases [Bartsch et al., 2005;
Roelfsema et al., 2005]. While there are excellent published reviews
of RTS and recommendations for clinical management [Wiley et al.,
2003; Hennekam, 2010], no studies have focused exclusively on
adults with RTS. In order to address this issue, we conducted a
Ó 2011 Wiley-Liss, Inc.
How to Cite this Article:
Stevens CA, Pouncey J, Knowles D. 2011.
Adults with Rubinstein–Taybi syndrome.
Am J Med Genet Part A 155:1680–1684.
questionnaire study of adults with RTS, which addressed medical
issues, education, independence, and behavior problems.
MATERIALS AND METHODS
Adult participants with RTS were ascertained from a personal
database maintained for over 20 years of patients with RTS who
participated in previous studies over the past several years [Stevens
et al., 1990a, b; Stevens and Bhakta, 1995; Stevens, 1997]. Letters
were mailed to 205 families in this database, and 52 were returned as
undeliverable. Forty-five families completed the questionnaire and
were included in the study. Each of these individuals was diagnosed
by a geneticist and had features typical for RTS by photographs.
Additionally, calls for participants were posted on the RTS list serve
and through the RTS parent support groups. Sixteen patients were
ascertained in this fashion. Twelve of these were diagnosed by a
geneticist while four were diagnosed by other specialists. However,
all had typical photographs and clinical features of RTS. Caregivers
were asked to complete a list of 140 questions regarding medical
problems, education, independence, and behavior. There were
32 males and 29 females ranging in age from 18 to 67 years.
The average age was 28.5 years with 10 subjects being over the
age of 35 years. Ninety percent of participants were from the
United States and all were living at the time of study.
RESULTS
Medical
The average height in the males was 158.5 cm (62.4 inches) and in
females 150.1 cm (59.1 inches). Based on calculation of body mass
*Correspondence to:
Cathy A. Stevens, M.D., Department of Pediatrics, T.C. Thompson
Children’s Hospital, 910 Blackford Street, Chattanooga, TN 37403.
E-mail: cathy.stevens@erlanger.org
Published online 10 June 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.a.34058
1680
STEVENS ET AL.
1681
index (BMI), many subjects were overweight (25%), obese (33%),
or morbidly obese (8%), with slightly more females being obese
than males (72% versus 61%). However, these percentages may not
be significantly different from the rates of overweight/obesity
recently reported for adults in the United States [Flegal et al.,
2010]. Medical problems in the study group are listed in Table I.
The most commonly reported problem-involved vision. This included requiring glasses (80%), strabismus (33%), glaucoma
(11%), and cataracts (7%). Keloids were reported in 57%. More
than one-half of subjects had feeding difficulties including poor
chewing, choking during feeding, and stuffing too much food in the
mouth. Two subjects had eosinophilic esophagitis, which has been
previously reported in RTS [Noble et al., 2007]. Of the 29 who had
spinal curvature, 10 required bracing and/or surgery. Thirteen
participants (22%) reported dislocated patellas, 10 of whom required surgery. Other joint problems included excessive laxity,
arthritis, and stiffness in one or more joints. Hypohidrosis has not
been previously reported in RTS but was noted in 38% of the study
participants. This question was included because of several reports
of decreased ability to sweat noted on the list serve. Of the 18
subjects with hearing loss, five were using hearing aids. Sleep apnea
was reported in 15 persons (25%). Of these, 11 were overweight or
obese. Treatment for this problem included removal of the tonsils
and adenoids (11), continuous positive airway pressure (1), nighttime oxygen (1), and tracheostomy (1).
Nine persons had surgery for congenital heart defects in childhood; seven continue to have structural abnormalities of the heart/
vessels in adulthood (with or without a history of surgery). One
person has congestive heart failure and one person has cardiomyopathy secondary to sleep apnea. Tumors were seen in six persons
(giant cell tumor of the leg, leiomyosarcoma of the thigh, unspecified tumor of the kidney, occipital hamartoma, thyroid cancer, and
pilomatrixomas). Other relatively low-frequency medical problems
included hypertension (10%), seizures (5%), diabetes mellitus
TABLE I. Medical Problems in Adults with RTS
Problem
Visual difficulties
Keloids
Difficulty eating
Spinal curvature
Joint problems
Hypohidrosis
Bladder incontinence
Hearing loss
Chronic nail fungus
Urinary tract infections
Sleep apnea
Patellar dislocation
Heart problems
Frequent infections
Anesthesia complications
Neurologic abnormalities due to tethered cord
Hypothyroidism
Tumor/cancer
Percentage
79
57
53
49
46
38
35
30
30
25
25
22
17
17
14
13
11
10
(5%), hypoglycemia (5%), and kidney stones (5%). The frequency
of diabetes mellitus in this group seems low compared to the high
frequency of obesity. However, this may be due to the relatively
young age of the study group or lack of recognition of a pre-diabetic
condition.
The average age of menarche in females was 14.25 years (range
10–28 years). This compares to 12.5 years on average in the United
States. Two females have experienced non-surgical menopause, one
at 28 years of age and the other in her 30s. Sixteen out of 28 females
use some type of contraception (8 oral contraceptive pills, 3 depoprovera, 3 hysterectomy, 2 tubal ligation). Approximately one-half
use these methods primarily for pregnancy prevention and one-half
primarily for hygiene.
Seventeen percent of families reported difficulty in transitioning
from pediatric to adult medical care. Many reported that adult
providers were uncomfortable taking care of someone with RTS
and were unfamiliar with the associated problems. Most patients
were seeing multiple specialists for care including orthopedics,
gastroenterology, cardiology, endocrinology, and neurology, but
only four (7%) were currently seeing a geneticist.
Dental problems in the study patients are outlined in Table II.
Crowded teeth and extra teeth were commonly reported. Talon
cusps, which are accessory cusp-like structures on the lingual side
of the incisors, were reported in 23%; this prevalence is lower
than that previously reported, perhaps due to under recognition
of their presence by the family or care provider. These cusps may
result in an increase in caries.
Education/Independence
The number of years spent in formal education was widely variable
(9–26 years). Fifty-nine percent received some vocational training,
usually through the school system. One-half of the group has been
employed as adults, and almost all of them received financial
compensation for their work. One-half were employed in the
community and 35% in sheltered workshops. The most common
community work settings were supported work in restaurants,
recycling, and Goodwill facilities. Most subjects are living with
their parents (69%), but others live in group homes (21%) or
supervised apartments (5%). Fifty-eight percent participate in day
programs for handicapped adults. Eighty-two percent are involved
in social activities with other adults and 69% engage in regular
exercise. Only 10% are involved in dating; no individual is married
or has children. Most subjects receive disability payments (93%);
other sources of financial support include parents (61%) and wages
TABLE II. Dental Problems in Adults with RTS
Problem
Crowded teeth
Extra teeth
Talon cusps
Excessive caries
Required braces
Percentage
80
28
23
18
15
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(30%). Seventy-three percent of families arranged for guardianship
after their child reached adulthood.
Eighteen participants reportedly had IQ testing as adults; the
average of the reported IQ scores was 49 with a range of 24 to
approximately 80. Eighteen of 57 (32%) were noted to have a
decrease in abilities over time. In one half of subjects this was
described as a decrease in intellectual abilities such as decreased
social interaction, less interest in books/reading and more limited
speech, while in the other half the worsening was primarily in
physical skills such as stamina and mobility. Seventy percent were
said to be able to read and write to some degree; most were estimated
by the families to have skills at the second to third grade level.
Difficulty with speech was common. Forty-one percent were said to
be conversational, using sentences. Thirty-three percent used short
phrases, 12% signs only, 5% a combination of words/signs, 3%
single words, and 3% used a speech-assist device. Table III lists the
skills that the study subjects were said to perform independently.
Behavior
Behavioral difficulties were very common in the study group. Many
had behaviors suggestive of attention deficit disorder such as short
attention span (72%), distractibility (70%), impulsivity (56%), and
disruptive actions (29%). However, only 17% were diagnosed with
attention deficit disorder or attention deficit/hyperactivity disorder
and only three subjects were on medication for this. Several subjects
had autistic-like behaviors such as needing a strict routine (62%),
intolerance of noise/crowds (62%), difficulty with change in the
environment (62%), and self-stimulation behaviors (61%). Nineteen percent had been diagnosed with autism or autistic behaviors.
Other behavioral characteristics are listed in Table IV. Eighteen
subjects (31%) had been given a psychiatric diagnosis; almost all of
those were obsessive–compulsive disorder, anxiety, or depression.
Of these 18 subjects, 83% were on behavioral medication. Thirtyseven percent of the entire study group was reported by the caregivers to have worsening of behavior over time.
DISCUSSION
Documentation of the phenotype and natural history of genetic
syndromes in adulthood is important for optimal care in these
TABLE III. Skills Achieved in Adults with RTS
Skill
Feeding
Dress
Toilet
Shower
Make bed
Use telephone
Laundry
Prepare food
Use public transportation
Manage money
Percent Achieved
84
72
62
44
43
28
20
11
8
0
TABLE IV. Behavioral Characteristics of Adults with RTS
Behavior
Easily upset
Eats excessively
Difficulty relating to peers
Unaware of common dangers
Inappropriate in public
Odd movements/noises
Overly friendly
Unreasonable fears/anxiety
Self-injury
Difficulty sleeping
Aggressive
Difficulty separating from caregiver
Overly shy
Percentage
60
52
47
47
47
44
43
33
32
28
22
10
9
conditions. The growing interest in this topic is illustrated by the
recent issue of Seminars in Medical Genetics devoted entirely to
adult dysmorphology [Schrander-Stumpel and Williams, 2007].
Studies which focus on adult issues in various syndromes include
Williams syndrome [Morris et al., 1990; Lopez-Rangel et al., 1992],
22q11 deletion syndrome [Cohen et al., 1999], and Down syndrome
[Van Allen et al., 1999]. However, there are no prior studies
specifically evaluating adults with Rubinstein–Taybi syndrome.
There have been several fairly large studies describing the clinical
and/or molecular findings in RTS patients, but none has separated
out adult issues. Partington [1990] conducted a 20-year follow-up
study of 18 patients previously diagnosed with RTS and found that
seven were probably misdiagnosed and three others were deceased.
The eight survivors had moderate to severe mental retardation and
the most frequent medical problems were visual difficulties, keloids,
GI and feeding abnormalities, fractures, and dental caries. The
deceased patients included a 19-year-old who died of aspiration
pneumonia, a 37-year-old who died of sepsis after a fracture and a
52-year-old who died of pneumonia. There are a few studies which
focus on specific medical issues in RTS that include adults. This
includes the paper by Miller and Rubinstein [1995] in which they
described a variety of tumors in RTS including adult patients. The
adult onset tumors included Non-Hogkin lymphoma (2), benign
ovarian teratoma, meningioma (2), pituitary microadenomas,
seminoma, adrenal cortical adenoma, and parathyroid adenoma.
van Genderen et al. [2000] described ocular features in RTS patients
including eleven adults. The eye problems in adults included
strabismus, nystagmus, lacrimal duct abnormalities, cataracts,
refractive abnormalities, and retinal dysfunction.
Levitas and Reid [1998] described seven adults with classic RTS
and six with ‘‘incomplete’’ RTS who had psychological problems;
these were primarily mood disorders and tic/OCD spectrum.
Hennekam et al. [1992] performed psychological and speech
studies in RTS patients including 14 adults, 13 of whom were
institutionalized. The IQ scores ranged from less than 25–48. He
noted a decline in IQ scores with age, particularly the verbal IQ.
However, he thought that this was probably not due to true mental
deterioration but was probably secondary to measurements of
STEVENS ET AL.
different abilities at different ages. In our study, 32% of caregivers
also noticed a decrease in abilities over time; half of these were said
to have intellectual decline and half had a decrease in stamina or
mobility. However, this was strictly based upon subjective observations by the families.
The phenotype of RTS changes over time. As with many other
syndromes, most published photos are of young patients. Figure 1
illustrates the facial features of several of the participants in this
study.
While this study does provide some useful information for
families and health care providers regarding adults with RTS, there
are some limitations to the study. Since this is a rare syndrome (1 in
100,000) we were unable to personally evaluate each patient and,
therefore, a questionnaire design was used. We had to rely on the
parents/caregivers to accurately describe the medical difficulties, IQ
scores, and psychiatric diagnoses. However, the questions were
simple, straightforward, and primarily required ‘yes or no’ answers.
No sophisticated knowledge of medical or psychiatric issues was
required. There could also be some ascertainment bias, particularly
involving those who are members of the list serve and support
groups. This was a fairly small and relatively young study group. A
cohort which includes a greater number of middle aged and elderly
patients would provide important information regarding the natural history of RTS in those age groups. Molecular studies were not
1683
systematically performed. The families were asked if genetic testing
was done; six reported that chromosome studies were normal and
three others stated that a chromosome 16 deletion was detected.
However, none was aware of any molecular studies of the CREBBP
and EP300 genes being done. Since molecular testing has only been
available in the last few years, it is not surprising that most of the
adults have not undergone this testing.
In summary, adults with RTS continue to have significant
medical and dental problems and most become overweight or
obese. While all patients have developmental impairment, most
achieve some independence in self-care, communication, and many
in supported work. Of concern is the report of decreased abilities
over time reported by the caregivers in 32% of participants in this
study. Behavior problems are a significant concern for families and
some worsening of behavior was noted in 37%. Since potential
decline in abilities or behavior could not be objectively documented
in this study with testing of individuals over time, these observations remain tentative. Certainly further studies should be conducted to evaluate whether cognitive or behavioral decline is a valid
concern in adults with RTS. Although behaviors consistent with
ADD/ADHD or autism were commonly described, most subjects
had not been given these diagnoses. Increased recognition of
these behaviors might lead to pharmacological, educational, or
behavioral therapies, which could be of benefit to these individuals.
FIG. 1. Facial appearance of several participants in the study. Note full arched brows, downslanting palpebral fissures, prominent nose with overhanging tip, and nasal septum below the level of the nasal alae.
1684
As we observed, adults with syndromes are often managed by a
multitude of specialists for various medical problems. However,
only 7% of the persons in our study group were seeing a geneticist;
this may be typical for other syndromes as well. Long-term involvement of geneticists as well as education of adult primary care
providers may help with many of the challenges facing adults with
RTS and their families.
ACKNOWLEDGMENTS
The authors sincerely appreciate the assistance of the families
who participated in this study.
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