Comprehensive genetic research abstract concerning Rubinstein-Taybi Syndrome. Topics addressed include, but are not limited to: molecular genetic analysis, etiology, expressivity manifestations, phenotype observations, and lifespan prognosis

1. Rubinstein-Taybi Syndrome
(Genetic Disorder Abstract – Final Draft)
David B. Johnson
Human Genetics
November 7, 2003

2. The earliest documented report concerning Rubinstein-Taybi Syndrome (RSTS) dates back to
1957, written by Dr. Michail et al, and at that time it was called Broad Thumb-Hallux
Syndrome (Wardlow, 2003). Later, in 1963, Drs. Jack Rubinstein and Hooshang Taybi
submitted the first research publication detailing the syndrome. They had recognized a specific
and broad ranging set of physical features and developmental delays that occurred in a number
of unrelated children (Rubinstein and Taybi 1963). By the mid-1970’s the medical community
had dubbed the condition its current name based on Rubinstein’s and Taybi’s work.
The history of the etiological search for RSTS is a fascinating one whose timeline has been
governed by medical technological advances. Although the cause is still not conclusively
known, the current theory is that sub-microscopic interstitial deletions at 16p13.3 is the
underlying causative agent (Bartsch et al, 1999). This hypothesis was first posed in 1999. In
some cases, translocations and inversions have been observed, as well as varying sizes of
deletions. This is probably the reason for the widely varying expressivity of the syndrome signs
and symptoms. In 1992-93, the cause was suspected to be located on gene 16p13.3 (Lacombe
et al, 1992). In 1990, geneticists were investigating 2p13.3 and favored an autosomal dominant
explanation (Hennekam et al, 1990). In 1987, geneticists surmised that a microdeletion
somewhere was responsible, but they were unable to identify the location (Berry 1987). In
1968 a leading theory was multifactorial inheritance (Roy et al, 1968). This was quickly ruled
out due to the rarity of the disease. Finally, the very first published record of etiological
reference was in 1967 when Giroux and Miller postulated a chromosomal abnormality (Giroux
and Miller 1967).
As stated earlier, the symptoms of RSTS cover a very wide spectrum. Not all patients exhibit
all of the symptoms, nor do all patients exhibit the symptoms to the same degree. The total list
of all recorded clinical features is three full pages. For brevity’s sake, only the major category
and features seen in at least 50% of patients are listed: 1) Neonatal – Respiratory distress 78%,
feeding difficulties 77%, constipation 54% (all due to hypotonicity); 2) Neurological –
Developmental delay (motor, language, social) 99%, IQ < 50 (most in mild to moderate range)
74%, hyperactive deep tendon reflexes 53%; 3) Facial – Beaked nose 93%, high-arched palate
93%, downward slanting palbebral fissures 90%, broad nasal bridge 86%, hypertelorism 83%;
4) Musculoskeletal – broad, short thumbs and/or halluces 100%, microcephaly 95%, short
stature 93%, stiff gait 87%, broad terminal phlanges 73%; 5) Ophthalomologic – Strabismus
71%, refractive error 56%; 6) Cutaneous – Hirsutism 75%, capillary hemangiomata 61%, deep
plantar crease 56%. Additionally, respiratory, cardiovascular, and genitourinary complications
are common (Gandy, 2003).
The rate of occurrence for RSTS is a very problematic variable to quantify due to the rarity of
the syndrome. Presently there are only approximately 600 cases documented worldwide
(Gandy, 2003), and from what is known, the syndrome does not favor one race or ethnic group.
Cases have been reported predominately in Japan, North America, Europe, India, and South
Africa. There are probably far more cases existing than are actually reported due to a lack of
available diagnostic care and reporting in less industrialized nations. The condition strikes
males and females with equal frequency, and one estimate is that one in 300,000 persons has
RSTS. This number, however, is only a guess and, on the surface, seems to be too high by as
much as a factor of 10 (Wardlow, 2003).

3. As a result of the rarity of RSTS, mode of inheritance has not been established, as yet.
Multifactorial inheritance has conclusively been ruled out. Genetic tests have been performed
on parents of RSTS children and in every case the parents have been normal. The only
documented cases of siblings with RSTS have been two cases of monozygotic twins. Pedigree
studies have revealed no familial histories of RSTS (Breuning et al, 1993). In short, no definite
genetic pattern has been identified.
Current etiogenetic theory holds that RSTS is caused by varying degrees of microdeletion of
16p13.3. This deletion has been found in 25% of reported cases, and it is believed that a far
greater percentage of microdeletions would be found if genetic testing was performed in a
more standardized and thorough manner. Of the microdeletions discovered, the detections were
made by FISH and cosmic probes, which has become the state-of-the-art objective
confirmation of clinical diagnosis in new patients (Breuning et al, 1993).
The gene located at 16p13.3 is responsible for coding the CBP binding proteins. This is a large
nuclear protein involved in transcription regulation, chromatin modification, and the
integration of several different signal transduction pathways (Petrij et al, 2000). More
specifically, CBP is a histone acetyl transferase responsible for acetylation of histones H3 and
H4, a precursor to transcription. At the molecular level, RSTS is most likely a
haploinsufficiency of CBP function, since 20% of mutations are deletions or microdeletions or
protein-truncating mutations (Hendrick and Bickmore, 2001). The pervasive use of CBP in
most areas of human growth and development explains why the clinical features presenting
with RSTS are so extensive. Further, the degree of deletions present along with inversions and
translocations explains why the penetrances of certain symptoms are of varied degree.
Although RSTS could really be categorized as a chromatin disorder of unknown etiogenetic
origin, it is inherited in a manner resembling an autosomal dominant disorder.
The average age of diagnosis for RSTS is 15.2 months of age. Usually the patient is referred to
a genetic expert by a pediatrician or a neonatologist, and in almost all cases, the diagnosis is
made on the basis of a physical exam. The exam is then followed or confirmed by a
karyotyping and 2-color fluorescence in situ hybridization with cosmid probes (Breuning et al,
1993). In utero testing is not performed primarily because of the infrequency of RSTS.
Rubinstein-Taybi children are like the rest of the population with respect to personality. Each
individual is unique. However, family members of RSTS individuals generally describe them
as: loving, friendly, and happy. One constant seems to be that they all have a profound interest
in music. Behaviors that have been reported in 90% of cases include: rocking, spinning, and
hand-flapping. This behavioral trait seems to abate by the late teen years. For the most part,
RSTS persons are sociable and are easily integrated into typical social settings such as school
(Wardlow, 2003).
The prognosis for RSTS individuals is that they will live a normal life span. In adult years they
are not capable of totally independent living, but function well in group homes (with a “group
parent”) or in supervised apartment settings. Most are definitely able to hold jobs in sheltered
workshops with a dedicated supervisor/job coach (Gandy, 2003).

4. References
Bartsch, O.; Wagner, A.; Hinkel, G.K.; Krebs, P.; Stumm, M.; Schmalenberger, Bohm. S.;
Balci, S.; Majewski, F.: FISH studies in 45 patients with Rubinstein-Taybi
syndrome:deletions associated with polysplenia, hypoplastic left heart and death in
infancy. European Journal of Human Genetics: 748-56, 1999 Oct-Nov.
Berry, A.C.: Rubinstein-Taybi syndrome. Journal of Medical Genetics, 24, 562-566, 1987.
Breuning, M.H.; Dauwerse, H.G.; Fugazza, G.; Saris, J.J.; Spruit, L.; Wijnen, H.; Tommerup,
N.; van der Hagen, C. B.; Imaizumi, K.; Kuroki, Y.; van der Boogaard, M-J.; de Pater, J.M.;
Mariman, E.C.M.; Hamel, B.C.J.; Himmelbauer, H.; Frischauf, A.M.; Stallings, R.L.;
Beverstock, G.C.; van Ommen, G.J.B.; Hennekam, R.C.M.: Rubinstein-Taybi syndrome
caused by submicroscopic deletions within 16p13.3. American Journal of Human Genetics,
52: 249-254, 1993.
Gandy, A: Rubinstein-Taybi Syndrome:
www.icondata.com/health/pedbase/files/RUBINSTE.HTM: accessed on 08/28/2003: Pediatric
Database of University of Western Ontario.
Giroux, J.; Miller, J.R.: Dermatoglyphics of the broad thumb and great toe syndrome.
American Journal of Disabled Children. 113; 207-209; 1967.
Hendrick, B.; Bickmore, W.: Human disease with underlying defects in chromatin
structure modification. Human Molecular Genetics: 2233-42; Oct. 1, 2001.
Hennekam, R.C.M.; van der Boogaard, M.-J.; Sibbler, B.J.; van Spijker, H.G.: Rubinstein-
Taybi syndrome in the Netherlands. American Journal of Medical Genetics, Suppl. 6: 17-29,
1990.
Lacombe, D.; Saura, R.; Taine, L.; Battin, J.: Confirmation of assignment of a locus for
Rubinstein-Taybi syndrome to gene 16p13.3. American Journal of Medical Genetics. 44:
126-128, 1992.
Petrij, F; Dauwerse, H.G.; Blough, R.I.; Giles, R.H.; van der Smagt, J.J.; Wallerstein, R.;
Maaswinkel –Mooy, P.D.; van Karnebeek, C.D.; van Ommen, G.-J.B.; van Haeringen, A.;
Rubinstein, J.H.; Saal, H.M.; Hennekam, R.C.M.; Peters, D.J.M.; Breuning, M.H.: Diagnostic
analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for
microdeletion detection and low number of protein truncating mutations. Journal of
Medical Genetics. 37: 168-176, 2000.

5. Roy, F.H.; Summitt, R.L.; Hiatt, R.L.; Hughes, J.G.: Ocular manifestations of Rubinstein-
Taybi syndrome:case report and review of the literature. Arch. Ophthal. 79: 272-278,
1968.
Rubinstein, J.H.; Taybi, H.: Broad thumbs and toes and facial abnormalities. American
Journal of Disabled Children 105: 588-608, 1963.
Wardlow, D: Book For Families: www.rubinstein-taybi.org/html: accessed on 08/28/2003:
United States RTS Association.