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Background


Rubinstein-Taybi syndrome (RTS) is a genetic disorder characterised by several features:

Facial abnormalities
Broad thumbs
Broad big toes
Mental retardation.

Recently, some patients have demonstrated mutations and alteraation in the CREB binding protein (CREBBP or CBP) gene, localized to chromosome band 16p13.3

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Broad thumbs syndrome
Broad thumb-hallux syndrome
INCIDENCE/
PREVALENCE
 
Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population.

Wallerstein R, Anderson CE, Hay B, Gupta P, Gibas L, Ansari K, Cowchock FS, Weinblatt V, Reid C, Levitas A, Jackson L.

Division of Medical Genetics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

J Med Genet. 1997 Mar;34(3):203-6. Abstract quote  

Rubinstein-Taybi syndrome (RTS) is a well delineated multiple congenital anomaly syndrome characterised by mental retardation, broad thumbs and toes, short stature, and specific facial features. The recent localisation of the disorder to 16p13.3 and subsequent identification of a submicroscopic deletion of this region in RTS patients led us to screen a large cohort of affected subjects using the RT1 probe.

Among 64 patients with clinical evidence of RTS, seven (11%) had a deletion. Another patient had a translocation of the region without evidence of a deletion. The features of coloboma, growth retardation, naevus flammeus, and hypotonia have a positive predictive value for the presence of an RT1 deletion.

Because of the relatively low frequency of deletions in RTS, the RT1 probe is useful in diagnostic confirmation, but has limited use as a screening tool.
AGE  
SEX  
GEOGRAPHY  
EPIDEMIOLOGIC ASSOCIATIONS  

 

DISEASE ASSOCIATIONS CHARACTERIZATION
CHURG-STRAUSS SYNDROME  
Multiple perforating and non perforating pilomatricomas in a patient with Churg-Strauss syndrome and Rubinstein-Taybi syndrome.

Bayle P, Bazex J, Lamant L, Lauque D, Durieu C, Albes B.

Services de Dermatologie, Place du Dr Baylac, Toulouse Cedex, France.
J Eur Acad Dermatol Venereol. 2004 Sep;18(5):607-10. Abstract quote  

We report an unusual association of multiple perforating and non-perforating pilomatricomas with Churg-Strauss syndrome, and a dysmorphic syndrome evocative of Rubinstein-Taybi syndrome.

These syndromes may be independent, but these rare diseases and genetic abnormalities may be linked together.
MENINGIOMA  
Multiple meningiomas in a patient with Rubinstein-Taybi syndrome. Case report.

Verstegen MJ, van den Munckhof P, Troost D, Bouma GJ.

Departments of Neurosurgery and Neuropathology, Academic Medical Center, University of Amsterdam, The Netherlands.
J Neurosurg. 2005 Jan;102(1):167-8 Abstract quote  

The authors report a case of multiple meningiomas in a 37-year-old woman with Rubinstein-Taybi syndrome.

The patient harbored a bifrontal ossifying meningioma and multiple intracranial meningiomas.

She underwent surgery for the frontal ossifying meningioma and a right frontoparietal meningioma.
PILOMATRIXOMA  
Pilomatrixoma of the head and neck.

Chuang CC, Lin HC.

Division of Otolaryngology, Taipei Municipal Yang-Ming Hospital, Taipei, Taiwan, ROC.

J Chin Med Assoc. 2004 Dec;67(12):633-6. Abstract quote  

Pilomatrixoma is a benign skin appendage tumor that commonly occurs as a solitary lesion and is not usually hereditary. There is evidence to suggest that patients with a family history of multiple pilomatrixomas have a high probability of autosomal dominant disorders such as myotonic dystrophy, Gardner syndrome, and Rubinstein-Taybi syndrome.

In January 2004, a case was reported of an 8-year-old girl with 2 progressively enlarged facial masses. One of them was excised and diagnosed as pilomatrixoma. Coincidently, her 13-year-old sister had the same type of tumor when she was 4 years old. We report this unusual case and review the literature. Pilomatrixoma has not been widely reported in the head and neck surgery literature.

This benign tumor may be misdiagnosed as a carcinoma, resulting in unnecessary aggressive therapy. Otolaryngologists should therefore note the clinical and pathologic characteristics of these symptoms.

 

PATHOGENESIS CHARACTERIZATION
CREBBP GENE MUTATIONS  
DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS.

Bartsch O, Schmidt S, Richter M, Morlot S, Seemanova E, Wiebe G, Rasi S.

Institut fur Humangenetik, Klinikum, Universitat Mainz, 55101, Mainz, Germany.


Hum Genet. 2005 Sep;117(5):485-93. Epub 2005 Jul 14. Abstract quote  

Rubinstein-Taybi syndrome (RSTS) is a distinct dominant disorder characterized by short stature, typical face, broad angulated thumbs and halluces, and mental retardation.

The RSTS can be caused by chromosomal microdeletions and molecular mutations in the CREBBP gene; however, relatively few mutations have been reported to date.

Here, we aimed to determine the rate of point mutations and other small molecular lesions in true RSTS and possible mild variants, by using genomic DNA sequencing. A consecutive series of patients including 17 patients from our previous study was investigated.

We identified 19 causative mutations of CREBBP in a total of 45 patients representing three different diagnostic groups: (a) 17 mutations in 30 patients with unequivocal RSTS (detection rate 56.6%), (b) two mutations in eight patients with features suggestive of RSTS ("moderate or incomplete RSTS", detection rate 25%), and (c) no mutation in seven patients with undiagnosed syndromes and isolated features of RSTS. In general, the mutations were distributed without hot spots and most were unique; however, three recurrent mutations (R370X, R1664H, and N1978S) were identified. Furthermore, we detected 15 different intragenic polymorphisms, including two non-synonymous coding polymorphisms, L551I and Q2208H.

We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS. Previous studies have identified cytogenetic deletions in the CREBBP gene in eight to 12% of patients and very recently, Roelfsema et al. reported EP300 gene mutations in three of 92 (3.3%) patients with either true RSTS or different syndromes resembling RSTS.

Our 56.6% detection rate of molecular mutations in CREBBP in patients with unequivocal RSTS supports the new concept that RSTS is a genetically heterogeneous disorder and furthermore, indicates that RSTS may be caused by gene/s other than CREBBP in up to 30% of cases.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
The duplicated longitudinal epiphysis or "kissing delta phalanx": evolution and variation in three different disorders.

Elliott AM, Evans JA, Chudley AE, Reed MH.

Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, R3E 0W3, Canada.
Skeletal Radiol. 2004 Jun;33(6):345-51. Epub 2004 May 6. Abstract quote  

BACKGROUND: The delta phalanx, also known as the delta bone, or longitudinal epiphyseal bracket (LEB), has been described in a variety of syndromes and dysplasias. However, the "kissing delta phalanx" is not as well recognized in the literature; it consists of a duplicated longitudinal bracketed epiphysis, or a complex of two adjacent delta bones, with opposing convex portions facing each other. Magnetic resonance imaging of the kissing delta phalanx has not been previously described.

OBJECTIVE: To describe the evolution, variation and associated osseous anomalies of the kissing delta phalanx in three patients with distinct distal limb malformations using both plain films and magnetic resonance imaging.

RESULTS: Patient 1 had Rubinstein-Taybi syndrome and, in addition to a kissing delta phalanx in both feet, had corresponding delta metatarsals (MT1). Patient 2 had Cenani-Lenz syndactyly with distinct variation of the kissing delta phalanx in each hand. He had a disorganized appearance to the phalanges, metacarpal fusions and carpal coalitions. Patient 3 had an isolated oligosyndactyly of the left hand with metacarpal fusions and carpal coalitions. All three patients were followed over time. We describe two types of kissing delta phalanges: separated (without fusion of the corresponding epiphyseal brackets) and nonseparated (with fusion of the corresponding epiphyseal brackets). Both types can be seen in the same patient and are a reflection of the relative degree of segmentation of the two delta bones.

CONCLUSION: The appearance of this rare osseous abnormality changes with time and can be found in a limited number of uncommon disorders. It can also be found in association with other osseous anomalies of the distal extremities; therefore magnetic resonance imaging early in life can greatly assist in surgical planning. Recognition of the kissing delta phalanx may be an important radiological clue to diagnosis of these rare disorders.
LABORATORY MARKERS  
GENETIC ANALYSIS  
Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.

Petrij F, Dauwerse HG, Blough RI, Giles RH, van der Smagt JJ, Wallerstein R, Maaswinkel-Mooy PD, van Karnebeek CD, van Ommen GJ, van Haeringen A, Rubinstein JH, Saal HM, Hennekam RC, Peters DJ, Breuning MH.

Departments of Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.

J Med Genet. 2000 Mar;37(3):168-76. Abstract quote  

Rubinstein-Taybi syndrome (RTS) is a malformation syndrome characterised by facial abnormalities, broad thumbs, broad big toes, and mental retardation. In a subset of RTS patients, microdeletions, translocations, and inversions involving chromosome band 16p13.3 can be detected.

We have previously shown that disruption of the human CREB binding protein (CREBBP or CBP) gene, either by these gross chromosomal rearrangements or by point mutations, leads to RTS. CBP is a large nuclear protein involved in transcription regulation, chromatin remodelling, and the integration of several different signal transduction pathways.

Here we report diagnostic analysis of CBP in 194 RTS patients, divided into several subsets. In one case the mother is also suspect of having RTS. Analyses of the entire CBP gene by the protein truncation test showed 4/37 truncating mutations. Two point mutations, one 11 bp deletion, and one mutation affecting the splicing of the second exon were detected by subsequent sequencing. Screening the CBP gene for larger deletions, by using different cosmid probes in FISH, showed 14/171 microdeletions.

Using five cosmid probes that contain the entire gene, we found 8/89 microdeletions of which 4/8 were 5' or interstitial. This last subset of microdeletions would not have been detected using the commonly used 3' probe RT1, showing the necessity of using all five probes.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits.

Cantani A, Gagliesi D.

Department of Pediatrics, Medical School, University La Sapienza, Rome, Italy.

Eur Rev Med Pharmacol Sci. 1998 Mar-Apr;2(2):81-7. Abstract quote  

In 1963 Rubinstein and Taybi described a new syndrome characterized by broad thumbs and toes, facial abnormalities and mental retardation.

The syndrome can be observed in the neonatal period by typical thumbs, halluces and facial abnormalities. The prevalence in the general population is unknown, however the disorder is not rare and is present in about 1:600 patients in mental retardation clinics.

At the present time there is no definite inheritance pattern and recurrence is very unlikely. 18 different chromosomal anomalies have been identified in some patients with this syndrome.

In this paper we identify a typical case and review the symptoms and signs of the RT syndrome and meta-analyze 732 cases.
VARIANTS  
CERVICAL VERTEBRAE ANOMALY  

Congenital anomaly of cervical vertebrae is a major complication of Rubinstein-Taybi syndrome.

Yamamoto T, Kurosawa K, Masuno M, Okuzumi S, Kondo S, Miyama S, Okamoto N, Aida N, Nishimura G.

Department of Medical Genetics, Clinical Research Institute, Kanagawa Children's Medical Center (KCMC), Yokohama, Japan.
Am J Med Genet A. 2005 Jun 1;135(2):130-3. Abstract quote  

Rubinstein-Taybi syndrome (RTS; MIM# 180849) is a well-known malformation syndrome, characterized by broad thumbs and halluces, a characteristic facies, short stature, and mental retardation.

RTS is accompanied by a variety of morbid complications, particularly of the skeleton. Based on the experience of five RTS patients with malformation of the craniovertebral junction, we draw attention to previously unrecognized life-threatening complications of RTS, including instability of C1-C2, os odontoideum, hypoplasia of the dens, and fusion of the cervical vertebrae. One patient developed severe cervical myelopathy.

Malformation of the cervical spine may be a common syndromic constituent of RTS, to which special attention should be paid to prevent its neurologic sequelae.
EYE  

Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature.

van Genderen MM, Kinds GF, Riemslag FC, Hennekam RC.

Institute for the Visually Handicapped "Bartimeus", Zeist, Netherlands.


Br J Ophthalmol. 2000 Oct;84(10):1177-84. Abstract quote  

AIMS: To delineate the nature and frequency of ocular pathology in Rubinstein-Taybi syndrome (RTs).

METHODS: Literature was searched for reports describing ocular symptoms in patients with RTs. 24 RTs patients (out of a total of 73 Dutch known RTs individuals) were selected for ophthalmological and electrophysiological examination, selection being based only on the distance between a patient's residence and the place of investigation.

RESULTS: Most frequently reported eye anomalies in the literature were lacrimal duct obstruction, corneal abnormalities, congenital glaucoma, congenital cataract, and colobomata. Abnormalities of almost any eye segment have been published in case reports. Ophthalmological examination of 24 Dutch RTs patients showed a visual acuity </=0.3 in five patients. The most frequently found eye anomalies were nasolacrimal duct problems (six patients), cataract (six patients, four congenital), and retinal abnormalities (18 patients). VEPs showed an abnormal waveform in 15 patients. It was possible to perform an ERG in 18 patients, of whom 14 were abnormal (eight showed cone dysfunction, six cone-rod dysfunction).

CONCLUSIONS: Ocular abnormalities occur in the majority of RTs patients and can be remarkably diverse. The high frequency of retinal dysfunction (78%) has not been described before. With age, retinal as well as electrophysiological abnormalities occur more frequently. In four patients no signs of retinal dysfunction were observed, indicating phenotypic heterogeneity. Further cytogenetic and molecular examination of the patients is needed before it becomes clear if this also represents genetic heterogeneity. Because of the high frequency of ocular abnormalities, visual function tests and electrophysiological investigations should be performed in every RTs patient at regular intervals.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
PILOMATRIXOMA  

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  
ELECTRON MICROSCOPY  

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
GENERAL  
A case with some clinical findings overlapping to Rubinstein-Taybi, Rubinstein-Taybi-like syndrome or multiple pterygium syndrome: coincidental findings or a new entity?

Kargi AE, Balci S, Akoz T, Kargi S, Erdogan B.

Department of Plastic and Reconstructive Surgery, Ankara Numune Community Hospital, Turkey.

Turk J Pediatr. 2001 Apr-Jun;43(2):166-71. Abstract quote  

We report a case with broad, deviated thumb and big, duplicated, deviated toes resembling Rubinstein-Taybi syndrome. But the patient did not have severe mental retardation as in Rubinstein-Taybi syndrome and had no microdeletions on chromosome 16 by FISH-based assay.

This patient had mild webbing as seen in multiple pterygium syndrome, but broad-deviated thumb has not been reported in this syndrome.

We discuss whether these are coincidental or overlapping findings or whether this is a possible new clinical entity.

 

PROGNOSIS CHARACTERIZATION
GENERAL  
Rubinstein-Taybi syndrome (RTS) with postaxial polydactyly of the foot: 4-year follow-up until improvement of dysbasia.

Muneuchi G, Kogure T, Sano N, Hamamoto Y, Kishikawa Y, Tamai M, Igawa HH.

Department of Plastic and Reconstructive Surgery, Kagawa University, Kagawa 761-0793, Japan.
Congenit Anom (Kyoto). 2005 Jun;45(2):65-6. Abstract quote  

Rubinstein-Taybi syndrome (RTS), also known as 'broad thumbs syndrome' or 'broad thumb-hallux syndrome', is a malformation syndrome characterized by the triad of broad thumbs or first toes, a peculiar facial expression called 'comical face' and mental retardation. Although various malformations are combined with the triad, polydactyly is rare.

We treated a male patient with RTS complicated by postaxial polydactyly of the foot. His clinical course was different from typical patients with polydactyly, especially in the aspect of walking development.

Osteoplasty-combined surgery, which was ideal for anatomical reconstruction, was performed on the patient at 2 years and 11 months of age. A 4-year follow-up period was required until there was an improvement of dysbasia.

 

TREATMENT CHARACTERIZATION
GENERAL  
Rubinstein-Taybi syndrome medical guidelines.

Wiley S, Swayne S, Rubinstein JH, Lanphear NE, Stevens CA.

Children's Hospital Medical Center, Division of Developmental Disabilities, 3333 Burnet Ave., Cincinnati, Ohio 45229, USA.
Am J Med Genet A. 2003 Jun 1;119(2):101-10. Abstract quote  

Children and adults with Rubinstein-Taybi Syndrome have specific medical conditions that occur with greater frequency than the general population.

Based on the available information from the literature and clinical experience, recommendations for specific surveillance and interventions are made to guide those clinicians caring for individuals with Rubinstein-Taybi Syndrome. This is a first attempt at medical guidelines for individuals with RTS in the United States.

On-going research is needed in many areas to guide decisions in medical care and allow for refinement of these medical guidelines.

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Last Updated September 20, 2005

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