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RUBINSTEIN-TAYBI SYNDROME

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RUBINSTEIN-TAYBI SYNDROME Powered By Docstoc
					From: Management of Genetic Syndromes

       Allanson J, Cassidy S
       3rd Edition, 2010



RUBINSTEIN-TAYBI SYNDROME



Raoul C.M. Hennekam, MD, PhD

Professor of Clinical Genetics and Dysmorphology

University College London

Institute of Child Health

Great Ormond Street Hospital for Children

London

United Kingdom

Professor of Pediatrics and of Clinical Genetics

University of Amsterdam

Academic Medical Center

Department of Pediatrics and Institute of Human Genetics

Amsterdam

The Netherlands




Keywords : Rubinstein-Taybi syndrome; CBP gene; p300 gene; feeding problems; growth

retardation; retinal dysplasia; keloid; neoplasia; sleep apnea; obsessive behavior
Abstract

The Rubinstein-Taybi syndrome is a multiple congenital anomaly syndrome that is mainly

characterized by an unusual face, broad thumbs, broad big toes, short stature, and mental

retardation. The facial appearance is striking, in part due to the morphology, but also due to the

facial expression. The syndrome shows a pleiotrophy of features, of which the behavior,

orthopedic problems, keloid formation, and increased tumor risk are especially important. The

syndrome is caused by de novo heterozygous constitutional deletions or mutations of the CREB-

binding protein (CBP) gene or of the p300 gene. Management is supportive.
INTRODUCTION



Rubinstein-Taybi syndrome is a multiple congenital anomaly syndrome that is mainly

characterized by a particular face, broad thumbs, broad big toes and mental retardation. It was

first described in 1957 by three Greek orthopedic surgeons in a French orthopedic journal as "a

new case of congenital malformations of the thumbs absolutely symmetrical" (Michail et al.,

1957). In that same year Jack Rubinstein, a pediatrician from Cincinnati, investigated a girl with

similar findings. Together with Hooshang Taybi, a pediatric radiologist from Oklahoma, he was

able to collect 6 other cases, which were published in 1963 (Rubinstein and Taybi, 1963). The

name Rubinstein-Taybi syndrome was suggested by Coffin (1964) and Job et al. (1964) and

definitively chosen by Warkany (1974).



Rubinstein-Taybi syndrome can be considered one of the archetypal syndromes in clinical

genetics: first recognized clinically, followed by numerous reported individuals that delineated

the full clinical spectrum, gradual recognition of the behavioral characteristics and increased

cancer risk, discovery of the syndrome localization in the genome through a small number of

affected individuals with a chromosome anomaly, cloning of the gene through advanced

molecular work, building of animal models, functional studies leading to discovery of a second

gene involved, cooperation between clinicians and basic scientists to explain the phenotype by

studying different gene functions, and recent increased interest in the natural history.



Incidence
Many of the older studies on the incidence of Rubinstein-Taybi syndrome are difficult to

interpret due to uncertainty about the clinical diagnosis. One example is the often quoted

frequency of 1 case per 300 institutionalized persons in Canada, which would have indicated a

population frequency of about 1 in 300,000 (Simpson and Brissenden, 1973). Careful follow-up

showed that many of these individuals, in fact, did not have the syndrome (Partington, 1990). In

the Netherlands, a long running register has sought to locate all affected individuals nationwide.

Through this registry the birth prevalence was found to be 1/100,000 – 1/125,000 in the 1980s

(Hennekam et al., 1990a), and this has proven to be correct for the period 1988-2007 as well.

Rubinstein-Taybi syndrome occurs in both males and females with equal frequency, and has

been described in populations of many different ancestries. However the number of reports of

non-Caucasians is low. This probably represents socio-economic or publication bias, or (less

likely) a true lower incidence.



Diagnostic Criteria



There are no defined diagnostic criteria for the Rubinstein-Taybi syndrome, but the cardinal

features are well delineated. These include abnormalities of the face, broad and angulated

thumbs and big toes, growth retardation, mental retardation, and behavioral problems

(Rubinstein, 1990; Stevens et al., 1990a; Hennekam et al., 1990b).



The facial appearance of a child with Rubinstein-Taybi syndrome is striking. This is, in part, due

to the dysmorphic features: microcephaly, prominent forehead, downslanting palpebral fissures,

broad nasal bridge, convex nose profile with the nasal septum extending well below the nasal
alae, highly arched palate, everted lower lip, mild micrognathia, and minor anomalies in shape,

position or rotation of the ears (Figure 47.1). Of equal importance, however, is facial expression:

the grimacing or unusual smile with nearly complete closing of the eyes is almost universal. The

facial features show considerable change with time (Figure 47.2) (Allanson, 1990; Hennekam,

1993). Newborns often show a full, edematous face, unusual dark hair, upward slanting of the

palpebral fissures, a nose without the low hanging columella, a full lower lip, and slight

micrognathia. With time, the face elongates, the palpebral fissures slant downward due to the

relative lesser growth of the zygoma, the nose profile becomes more convex, the columella hangs

low, and the lower lip becomes more everted. Ears can be simple and small. Pits may be present

on the posterior side of the helix.



Broad thumbs and broad great toes are present in almost all affected individuals (Figure 47.3). In

about one-third of affected individuals the thumbs and halluces are also angulated, either in

valgus or varus positions. Radiologically, broadening or partial duplication of the first

metacarpals, metatarsals, and proximal or distal phalanges of the first ray can be found, but

complete preaxial polydactyly has not been reported. Postaxial polydactyly of the feet does

occur, as does (partial) syndactyly of the second and third toes or third and fourth fingers. The

terminal phalanges of the fingers tend to be broad, and persistent fetal fingertip pads are

common.



Growth retardation is common but not invariable (Stevens et al., 1990b). Abnormal ossification

may be evident in the large and slowly closing anterior fontanel. Infrequent parietal foramina,

delayed bone age, and increased fracture frequency are reported. Other skeletal symptoms
include pectus deformity, scoliosis and hyperkyphosis, spina bifida at various levels, generalized

lax ligaments (Robson et al., 1980; Rubinstein, 1990; Hennekam et al., 1990b), slipped capital

femoral epiphyses (Bonioli et al., 1993), and patellar dislocations (Hennekam et al., 1990b;

Moran et al., 1993; Stevens, 1997).



There is a wealth of less frequent skeletal findings and anomalies of internal organs and skin.

These have been reviewed elsewhere (Rubinstein, 1990; Hennekam et al., 1990b; Gorlin et al.,

2001).



Etiology, Pathogenesis, and Genetics



Rubinstein-Taybi syndrome is generally a sporadically occurring entity. For a couple with a

previous affected child, the empiric recurrence risk was found to be as low as 0.1% (Hennekam

et al., 1990a). If a person with Rubinstein-Taybi syndrome is able to reproduce, however, the

recurrence risk is probably as high as 50%. Three cases are described in the literature in which

women who are likely affected with Rubinstein-Taybi syndrome have had a child with the

syndrome (Hennekam et al., 1989; Marion et al., 1993; Petrij et al., 2000). In all three cases, the

children had more pronounced physical features and were more mentally retarded than their

mothers, and the diagnosis in the mothers would have been difficult without the more

pronounced phenotype in their children. All three mothers had at least one unaffected child.



In 1991, Imaizumi and Kuroki (1991), and shortly thereafter Tommerup et al. (1992) and

Lacombe et al. (1992), described individuals with de novo reciprocal translocations that were
consistent for a breakpoint at 16p13.3. This prompted a group of Dutch researchers to analyze 24

affected individuals with fluorescence in situ hybridization (FISH) using a series of probes from

the region. A signal was missing from one chromosome 16 in 6 of them (Breuning et al., 1993;

Hennekam et al., 1993). In the available families, no parent showed a microdeletion, indicating a

de novo rearrangement. Using molecular markers, a copy of chromosome 16 from both parents

was found in 19 others, excluding uniparental disomy as a frequent causative mechanism

(Hennekam et al., 1993). In combining the results of all microdeletion studies published so far,

the actual 16p microdeletion frequency in Rubinstein-Taybi syndrome is approximately 10% (41

of the 454 studied individuals to date). Clinical features in those with or without detectable

deletions are essentially the same, with the possible exception of microcephaly, angulation of

thumbs and halluces, and partial duplication of halluces, which are more common in those with

16p deletion (Hennekam et al., 1993).



Continuing research eventually led to the demonstration of mutations in the causative CBP gene

(Petrij et al., 1995). Cyclic-AMC-regulated enhancer (CRE) binding binding protein, or CREB

binding protein, is generally referred to as CBP. CBP has a homolog, p300, located at

chromosome 22q13, that shows a striking resemblance in primary structure and in function: both

act as transcriptional co-activators and act also as potent histone acetyltransferases by making the

DNA accessible to transcription factors. They are mediators of signaling pathways and

participants in basic cellular functions such as DNA repair, cell growth, cell differentiation,

apoptosis, and tumor suppression (reviewed by Goodman and Smolik, 2000). Combining the

results of larger studies (Coupry et al., 2002; Kalkhoven et al., 2003, Hennekam, 2006), a CBP

mutation was found in 63 of 155 patients (41%). Subsequent studies showed mutations in p300
in a limited number of individuals (Roelfsema et al., 2005). The true frequency of p300

mutations remains uncertain. At present it remains uncertain whether there is yet another cause

of Rubinstein-Taybi syndrome.



Diagnostic Testing



The diagnosis of Rubinstein-Taybi syndrome is still made clinically and rests on recognition of

the characteristic features. Karyotyping should be performed in every person suspected to be

affected. FISH studies for a chromosome 16p13.3 microdeletion are now widely available, and

can be performed using five different cosmids dispersed over the total CBP gene (Petrij et al.,

2000). Molecular studies to detect mutations in the CBP gene are only available on a research

basis in a few labs in the US and Europe. Combined cytogenetic and molecular studies will allow

detection of an abnormality in 50-55% of cases.



Differential Diagnosis



As the combination of features in Rubinstein-Taybi syndrome is usually distinctive, the

diagnosis can often be made clinically without difficulty. The diagnosis is most difficult in older

infants and young children, due to milder facial features, but becomes more easy with time.

Many of the components of the syndrome may occur as isolated findings. Other syndromic

entities that may give confusion are Saethre-Chotzen syndrome (Lowry, 1990), Cornelia de

Lange syndrome (Kroth, 1966)(Chapter 15), and trisomy 13 (Chapter 54). The facial features

also show resemblance to Floating-Harbor syndrome and Gorlin-Chaudry-Moss syndrome
(Gorlin et al., 2001). Broad thumbs may be observed in Apert syndrome and Pfeiffer syndrome,

and short thumbs and fingers are seen in type D brachydactyly and Greig syndrome (Chapter 41).

A number of case-reports of individuals or families with features overlapping those found in

Rubinstein-Taybi syndrome can be distinguished on the basis of several missing features or the

presence of findings not described in typical Rubinstein-Taybe syndrome (Gorlin et al., 2001).



MANIFESTATIONS AND MANAGEMENT



Growth and Feeding



In the first year of life 80% of the children with Rubinstein-Taybi syndrome have feeding

problems, which are mainly caused by generalized hypotonia, gastroesophageal reflux, and

recurrent upper respiratory infections. Frequently nasogastric tube feeding is needed for several

months, and some infants benefit from a gastrostomy. Most feeding problems resolve after a

period of one year (Grunow, 1982; Hennekam et al., 1990b). Reflux does occur thereafter, but is

not often a serious problem. Some affected individuals develop a voracious appetite in late

childhood, early adolescence or adulthood (Stevens et al., 1990b) that may even resemble the

appetite of children with Prader-Willi syndrome. In adulthood, feeding problems are rare,

although choking remains common.



At birth, length (average 49 cm; range 43.9-53.3 cm), weight (mean 3.1 kg; range 2.05-4.28 kg),

and head circumference (34.2 cm in males; 32.2 cm in females) are between the 25th and 50th

centiles, although the head circumference of males tends to be somewhat lower than females
(Rubinstein, 1990; Stevens et al., 1990b). Poor weight gain during infancy is common. In the

first few months all growth curves decline: length to the 5th percentile, weight below the 5th

percentile and head circumference to the 2nd centile. During the preschool and early school

years, height continues to follow these centiles. Weight gain can be considerable in boys during

these years: their average weight is in the 25-50th centile, indicating that weight-to-height ratio is

often above the 95th centile. Excess weight is mainly visible around the abdomen, buttocks and

thighs. By adolescence, weight drops again to below the 5th centile. The weight excess in

females starts somewhat later, between 5 and 10 years of age. It is more likely to remain a

problem throughout life (Hennekam et al., 1990b). Neither boys nor girls experience a pubertal

growth spurt, which contributes to their short stature as adults. Final height is 153.1 cm for males

and 146.7 cm for females. Growth hormone studies have not been published thus far. A small but

detailed pilot study in the Netherlands (n=5) did not show any abnormalities (L Soors D’Ancona

et al., personal communication).



Evaluation



   Measurements of head circumference, length, and weight should be performed at birth and

    every 6-12 month thereafter throughout childhood, using both the regular and syndrome-

    specific growth charts (Stevens et al. 1990b). Growth velocity should also be monitored

    during puberty.

   If growth deficiency is noted, nutritional status should be evaluated and chronic illness ruled

    out. If no explanation is found, growth hormone testing should be performed using standard

    methods (growth hormone response to L-DOPA or clonidine).
   Close monitoring of weight centiles and height-to-weight ratio in later childhood, puberty

    and adolescence is strongly recommended.



Treatment



   In infants, as long as weight centile is appropriate for length centile, no direct intervention is

    necessary, due to the self-limiting character of the feeding problems. If not taken orally,

    adequate caloric intake should be ensured through nasogastric feeding, with consideration of

    gastrostomy in the more serious cases. Involvement of a dietician may be useful.

   The diagnosis of Rubinstein-Taybi syndrome alone, without abnormality demonstrable in

    growth hormone testing, is not an indication for growth hormone supplementation. Growth

    hormone supplementation in the absence of demonstrable growth hormone deficiency has

    uncertain value at this time, and should only be used in a closely monitored research trial.

   There is no specific medication available to control appetite. Therefore decreased intake

    through a low-calorie and well balanced diet, and a regular exercise program (30 minutes of

    physical activity a day) are often required both for boys during childhood and for girls from

    early adolescence onward.

   If obesity gives rise to complications, these should be treated as in the general population.



Development and Behavior



The general psychomotor development of people with Rubinstein-Taybi syndrome is delayed.

Most parents describe affected individuals as easy-going and loving babies. Table 47.1 gives an
overview of the motor developmental milestones found among those with the syndrome

(Hennekam et al., 1992).



First words are usually spoken at about age two years, while two or three word sentences take as

long as four years and sometimes even seven years to be acquired. Between 4 and 5 years of age

many children gradually start to make much more use of language. Despite the abnormalities in

oral anatomy and speech delay, speech mechanisms and articulation appear normal in most.

Some children have nasal speech. The voice can also be high pitched. Many individuals have a

rapid or staccato speech rhythm. Despite a frequently limited vocabulary (corresponding to IQ)

communication abilities are often remarkably good. A not insignificant number of children never

learn to speak, and they require sign language or other systems to communicate.



The average IQ has been reported as 36 (range 25-79) in one study (Hennekam et al., 1992) and

as 51 (range 33-72) in another study (Stevens et al., 1990a). Performance IQ is generally higher

than verbal IQ. At an older age, the full-scale IQ decreases due to measurement of different

abilities at different ages: for example at an older age, concept formation and more complex

language tasks carry more weight in the tests. The IQ decline is not caused by mental

deterioration or regression.



Children with Rubinstein-Taybi syndrome are generally friendly, happy, and easy going.

Nevertheless 25% of the parents report behavioral problems often characterized by short

attention span, stubbornness, lack of persistence, a need for continuous attention from their

parents, and sudden mood changes (Hennekam et al., 1992). With increasing age, behavior can
become more difficult, and develops an obsessive-compulsive character. Social abilities are

usually a strength. There are, however, some affected individuals who display genuinely autistic

behavior. More commonly, older children and adults like to be on their own, avoiding crowds

and excessive noise.



Evaluation



   Each child should be tested at regular intervals of 2 to 3 years with a systematic

    developmental assessment starting at age 3 to 4 years, to ensure adequate educational support

    compatible with the child’s potential.

   Each child should be checked for hearing loss or diminished vision every 3 years. In adults

    ophthalmological evaluation every 5 years is useful (see Ophthalmology).

   Assessment of family support and psychological/emotional needs will assist adequate care

    for the whole family.



Treatment



   Most children need some degree of individualized educational programming, whether in

    specialized or inclusive settings.

   Affected children will benefit from speech therapy, physical therapy, and educational

    guidance.

   Sign language or other communication techniques should be introduced for non-verbal

    children.
   Sensory disturbances should be treated as in the general population.

   A change in behavior should prompt evaluation for common medical problems such as

    gastroesophageal reflux or toothache.

   Long-standing behavior problems may be improved with behavior modification techniques,

    usually through instruction by a psychologist or developmental specialist.

   Pharmaceutical treatment of behavior can be helpful in individual cases. The treatment

    should be adapted to the individual needs, as no specific psychoactive medication is known

    to have a particular benefit. Medication choice is no different from in the general population.

   For adults leaving their family home, an adequate living situation should be sought. This is

    usually a group home or other supervised setting for the mentally retarded.



Ophthalmology



Children with Rubinstein-Taybi syndrome frequently have lacrimal duct obstruction (43%

bilateral, 7% unilateral), which often leads to recurrent conjunctivitis. Other frequent ocular

problems are ptosis, strabismus (58%), and refractive errors (41%) (van Genderen et al., 2000).

Cataract, glaucoma and coloboma occur less frequently (less than 10%). Correction of refractive

errors becomes more important in the second half of the first year. The majority of children have

myopia, but hypermetropia and astigmatism also occur. About half of affected individuals are

photophobic.



Van Genderen and co-workers (2000) described a high frequency of retinal dysfunction (78%) in

children and adults with Rubinstein-Taybi syndrome. Electroretinogram showed cone or cone-
rod dysfunction in 58% and visual evoked potentials showed an abnormal wave form in 63% of

the 24 individuals investigated. With age, retinal as well as electrophysiological abnormalities

occurred more frequently. Below 15 years of age only minor abnormalities were found.



Evaluation



   The high frequency of ocular abnormalities makes ophthalmologic assessment in the first six

    months of life important. The assessment should include visual function tests. Vision should

    be evaluated thereafter every 3 years.

   Because of the frequent retinal dysfunction in older children and adults, electrophysiological

    investigations should be performed in every individual with Rubinstein-Taybi every 5 years

    after 16 years of age. This information is helpful in vocational and residential planning.



Treatment



   Surgical intervention for lacrimal duct stenosis may be necessary if the problems do not

    resolve. In some cases, placement of glass tear ducts is required, but usually this is not

    performed until the individual has reached adulthood.

   In some individuals surgery is required to correct ptosis or strabismus. This should follow the

    guidelines used in the general population.

   During the first two years of life correction of refractory errors is seldom needed, but

    thereafter many need corrective lenses.
   There is no good treatment known for photophobia. Protection using a hat or sunglasses is

    appreciated by some of the children and adults.



Respiratory



Obstructive sleep apnea may be a considerable problem in a small number of individuals with

Rubinstein-Taybi syndrome (Hennekam et al., 1990b; Zucconi et al., 1993). It may be caused by

the combination of a narrow palate, micrognathia, hypotonia, obesity, and easy collapsibility of

the laryngeal walls (Hennekam et al., 1990b). Rarely, a tracheostomy may be required.

Intubation may be difficult because of enhanced collapsibility of the laryngeal wall. Clues to the

presence of obstructive sleep apnea are snoring, a particular sleeping posture (with the head

between the knees), light sleep at night, and excessive sleepiness during the day. Without more

daytime sleep, mood changes, excitability and irritability can occur. Long term obstructed

respiration can lead to pulmonary hypertension, which in turn can cause right ventricular

hypertrophy and ultimately lead to decompensation.



Evaluation



   During regular health visits specific attention should be paid to possible symptoms of sleep

    apnea.

   If sleep apnea is suspected, a sleep study (polysomnography) should be performed.
Treatment



   If sleep apnea is present, the simplest solution is optimal positioning in sleep (Hennekam et

    al., 1990b; Zucconi et al., 1993). Continuous Positive Airway Pressure (CPAP) is usually

    successful but may not be accepted by individuals with Rubinstein-Taybi syndrome.

   Adenotomy and/or tonsillectomy May be helpful in individuals with a clear enlargement of

    these lymph nodes, but is not advocated in the other individuals

   If present, treatment of pulmonary hypertension is standard.

   If surgery is required for any reason, the anesthesiologist should be aware of easy

    collapsibility of the laryngeal wall, and the child should be intubated earlier and extubated

    later than other children.



Dental



Timing of the eruption of deciduous and permanent dentition is normal in Rubinstein-Taybi

syndrome. Marked caries can be found in about one-third of affected people, probably caused by

problems in dental care due to the small opening of the mouth, malpositioning and malformation

of the teeth, and non-cooperation. Hypodontia, hyperdontia, and natal teeth can be manifestations

of the syndrome. The most important dental feature in Rubinstein-Taybi syndrome is the very

high incidence of talon cusps in the permanent dentition (92%). They can be present in the

deciduous dentition (9%) or sometimes can be detected in the jaws by orthopanthogram. Talon

cusps are accessory cusp-like structures on the lingual side of the incisors, in the main. Two or

more talon cusps are rarely found in the general population or in other syndromes, and this
finding strongly supports the diagnosis (Hennekam et al., 1990c). Talon cusps increase the

likelihood of caries because food remains behind them.



Evaluation



   Regular, routine semiannual dental examinations and dental prophylaxis are indicated.

    Usually first visits to the dentists are at 2 to 3 years, to allow the child to get used to oral

    exams. A dentist experienced in treating children and adults with developmental delay can be

    of great assistance.



Treatment



   Emphasis should be placed on good dental hygiene as in any other child. Tooth brushing is

    often more effective with an electric device than by hand.

   Normal standard dental care should be provided. Some individuals with Rubinstein-Taybi

    syndrome have an increased fear of dental care and treatment is only possible with general

    anesthesia. The anesthesiologist should be aware of easy collapsibility of the laryngeal wall,

    and the child should be intubated earlier and extubated later than other children.

   It is possible to grind off the tips of the talon cusps or fill up the space between the cusps and

    the teeth.

   Malpositioned and crowded teeth will respond to standard orthodontic intervention.
Cardiovascular



About one third of people with Rubinstein-Taybi syndrome has a congenital heart malformation.

In 65% this is a single defect (patent ductus arteriosus, septal defect, coarctation or pulmonic

stenosis) while 35% have two or more defects or a complex malformation. The symptoms do not

differ from those in other children.



Evaluation



   All individuals with Rubinstein-Taybi syndrome should have a cardiac assessment, including

    an echocardiography, at the time of diagnosis.

   Subsequent management and follow-up are dictated by these investigations and the clinical

    course.



Treatment



   Any child with a cardiac defect should be referred to a pediatric cardiologist.

   In half of the cases with a single defect, surgery is needed, as compared to 80% of the more

    complex cases.

   The indications for and methods of surgical interventions are the same as in the general

    population.

   Antibiotic prophylaxis should be considered before and during any procedure that induces

    (transient) bacteremia, such as dental treatments, as in the general population.
Dermatologic



Keloid formation can be a major problem in adolescents and adults with the syndrome. Keloids

have been described in 22%; and hypertrophic scarring in 16% (Rohlfing et al., 1971;

Goodfellow et al., 1980; Selmanowitz et al., 1981; Sammartino et al., 1986; Hennekam et al.,

1990b; Stevens et al., 1990a). They can cause pain and extreme itchiness. Keloids occur where

keloids are usually located in persons without Rubinstein-Taybi syndrome as well (chest; upper

part of back; upper arms). Sometimes only minimal trauma such as a bee sting or even the

rubbing of clothes can initiate the keloid formation. Molecularly one finds loss of heterozygosity

at the 16p13.3 region in cells from keloid biopsies, which may be the explanation for difficulties

in adequate treatment.



Evaluation



   Physical examnination is usually sufficient to diagnose keloid formation. A biopsy can be

    difficult due to the extreme firmness of the tissue and should only be taken when the

    diagnosis is in doubt.



Treatment
   Keloids are very therapy resistant. Oral antihistamines, local corticosteroids, or laser therapy

    are often ineffective, and sometimes cause more damage than improvement. Occasionally

    patients have been treated by local radiation with good results.

   It is important to prevent skin trauma when possible.



Genitourinary



Almost all boys with Rubinstein-Taybi syndrome have incomplete or delayed descent of the

testicles. Hypospadias is seen in 11% of boys. Renal anomalies are present in about 50% and

may increase the likelihood of urinary tract infection.



The timing of puberty is normal and secondary sex characteristics develop normally. Girls often

have hypermenorrhagia or metrorrhagia. Fertility in woman with the syndrome is probably

normal. No adult male is known to have fathered a child.



Evaluation



   Every male with the syndrome should be checked for cryptorchidism and hypospadias at

    diagnosis.

   Renal ultrasound is recommended at diagnosis.



Treatment
   Treatment of cryptorchidism is standard.

   Surgery for hypospadias should be considered only if the hypospadias is severe or where

    there is recurrent infection.

   Hypermenorrhagia or hypermetrorrhagia often responds to treatment with an oral

    contraceptive. No contraindications to this treatment are known.

   Some of the adolescents and adults of either sex are sexually active, thus contraception and

    sex education need to be adequately addressed with the affected individuals, their parents and

    other caregivers.



Musculoskeletal



Individuals with significant angulation of their thumbs should be considered for surgical repair

prior to age two years because such angulations can have serious consequences for functional

dexterity of the hands (Wood et al., 1987). Surgery on angulated great toes is performed only

when they hinder walking or wearing footwear.



Hypermobility of joints is seldom a problem at a young age, but, once walking begins,

generalized hypotonia and hyperextensibility of joints due to lax ligaments can become

problematic. This is especially the case if there is a concomitant weight problem. The gait is

commonly stiff and sometimes waddling.



Children with Rubinstein-Taybi syndrome have an increased risk for dislocation of the radial

head and the patella, which, when present, may persist into adulthood. Patellar dislocation can be
particularly burdensome and have great consequences for mobility. If not treated in time, patellar

dislocation can lead to complications such as genu valgum, tibial torsion, and flexion contracture

at the knee. At about 10 years of age children with Rubinstein-Taybi syndrome may develop

kyphosis, lordosis, and scoliosis. Several older children and adolescents have severe and

prolonged aseptic hip joint inflammation (Perthes-like). In general this problem resolves in one

or two years without intervention, but symptomatic treatment might be necessary because of

pain. Slipped capital femoral epiphysis, which usually occurs in adolescence, can become a

major problem. Initially it is often silent, and once there are symptoms the radiographic changes

are often already severe. Pain or a change in gait should always be carefully evaluated in any

child with Rubinstein-Taybi syndrome.



Evaluation



   Annual clinical assessment of the chest cage, spine, and walking pattern is recommended.

   Physical therapy may be useful for any young child with walking difficulties.

   A change in gait should prompt careful analysis of hip function and anatomy, and search for

    a patellar dislocation.



Treatment



   Scoliosis may require bracing or surgery, as in the general population.
   Surgical correction of angulated thumbs should be considered if it will improve dexterity. It

    should optimally be performed before the age of 2 years by a surgeon familiar with this

    procedure in Rubinstein-Taybi syndrome.

   Aseptic hip joint inflammation should be treated with rest, including the use of a wheelchair.

    With prolonged duration or in cases with pain, surgery may be helpful.

   Treatment of slipped capital epiphysis is standard.



Neoplasia



An increased tumor risk has been recognized in Rubinstein-Taybi syndrome (Miller et al., 1995).

Exact figures are not available. Personal experience in the Netherlands indicates that the

frequency is about 10%. The majority of tumors are neural crest derivatives, and include

nasopharyngeal rhabdomyosarcoma (Sobel et al., 1981), intraspinal neurilemmoma (Russell et

al., 1971), pheochromocytoma (Bonioli et al., 1992), meningioma (Bilir et al., 1990; Hennekam

et al., 1990b), other brain tumors (Hennekam et al., 1990a; Lannering et al., 1990; D'Cruz et al.,

1993; Evans et al., 1993; Skousen et al., 1996), pilomatrixoma (Cambiaghi et al., 1994; Masuno

et al., 1998), and acute leukemia (Jonas et al., 1978). About half of the tumors are malignant.

Tumors are generally manifest before the age of 15 years (86%) (Miller et al., 1995). However,

meningiomas are more likely to occur around 40 years of age. Molecular studies have shown that

there can be loss of heterozygosity for the 16p13.3 region in tumor cells.



Evaluation
   If a child with the syndrome develops unusual symptoms before the age of 15 years, one

    should always consider the possibility of a tumor.

   No standard tumor surveillance regimens are suggested as most tumors will lead to easily

    recognizable symptoms and screening has not improved outcome.



Treatment



   Treatment is the same as in the general population. One should take into account that there is

    an increased risk for multiple primary tumors.



RESOURCES



Brochures and Newsletters



USA support group: “The Rubinstein-Taybi book” (1997)

UK support group: “Rubinstein-Taybi syndrome: An information booklet” (2002)

Dutch support group: “Rubinstein-Taybi syndroom: informatie voor ouders” (2003)



Internet

Brazil support group: www.artsbrasil.org.br

ARTS

Rua Harmonia 722/81

CEP 05435-000
São Paulo-SP

Brasil

+55 11 4153 3211

Canadian support group: www.rtscanada.org

Dutch support group: www.rtsyndroom.nl

French support group: www.afsrt.com

Association Francaise du Syndrome de Rubinstein-Taybi

5 Rue des Corvees

Cidex 8571 Jarday

41000 Villerbon

France

Phone +33 2 54 78 10 53

Spanish support group: www.rubinstein-taybi.portalsolidario.net

UK support group: www.rtsuk.org

USA support group: www.rubinstein-taybi.orgGarry and Lorrie Baxter

P.O. Box 146

Smith Center, Kansas 66967

USA

Phone +1 888 447 2989



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TABLE 47.1. Developmental milestones of children with Rubinstein-Taybi syndrome

compared to children in the general population




Milestone   Rubinstein-Taybi syndrome            Normal children

            Average age (months)        Range    Average age (months)   Range

Laughing    2.5                         2-6      2                      2

Roll over   10                          4-18     6                      5-7

Sit         16                          9-24     7                      6-8

Crawl       19                          12-36    9                      8-10

Stand       29                          11-80    9                      8-10

Walk        35                          18-54    14                     12-15

				
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