Rubinstein-Taybi Syndrome


Rubinstein-Taybi Syndrome (RTS) ia an autosomal dominant chromosomal disorder characterized by broad thumbs, webbing of fingers and toes, mental retardation, beaked nose, short upper lip, pouting lower lip. Individuals with RTS have an increased risk of brain tumors and occasionally other tumours. Approximately 5 % of RTS patients develop a malignancy or a benign tumor. (FaCD)

Literature Analysis

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  • Differential Diagnosis
  • Infant
  • Histones
  • Medulloblastoma
  • Histone Deacetylases
  • Mutation
  • Neuroblastoma
  • Rubinstein-Taybi Syndrome
  • Adolescents
  • CREB-Binding Protein
  • Acetylation
  • Rett Syndrome
  • X-Ray Computed Tomography
  • Pilomatrixoma
  • Wnt Proteins
  • Transcription
  • Trans-Activators
  • Hair Diseases
  • Scalp
  • Transcription Factors
  • Acetyltransferases
  • Newborns
  • Coffin-Lowry Syndrome
  • Skin Cancer
  • Chromatin
  • Liver Cancer
  • EP300
  • Multiple Abnormalities
  • Cell Cycle Proteins
  • DNA Methylation
  • Nuclear Proteins
  • Childhood Cancer
  • Neoplasm Recurrence, Local
  • Translocation
  • Protein Processing, Post-Translational
  • Hemangioma
  • p300-CBP Transcription Factors
  • Histone Acetyltransferases
  • Epigenetics
  • alpha-Thalassemia
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (2)

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CREBBP 16p13.3 CBP, RSTS, KAT3A -CREBBP mutation in Rubinstein-Taybi Syndrome
EP300 22q13.2 p300, KAT3B, RSTS2 -EP300 mutation in Rubinstein-Taybi Syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).


Milani D, Bonarrigo FA, Menni F, et al.
Hepatoblastoma in Rubinstein-Taybi Syndrome: A Case Report.
Pediatr Blood Cancer. 2016; 63(3):572-3 [PubMed] Related Publications

Papathemeli D, Schulzendorff N, Kohlhase J, et al.
Pilomatricomas in Rubinstein-Taybi syndrome.
J Dtsch Dermatol Ges. 2015; 13(3):240-2 [PubMed] Related Publications

Johannesen EJ, Williams T, Miller DC, Tuller E
Synchronous ovarian and endometrial carcinomas in a patient with Rubinstein-Taybi syndrome: a case report and literature review.
Int J Gynecol Pathol. 2015; 34(2):132-5 [PubMed] Related Publications
Rubinstein-Taybi syndrome is characterized by distinctive facial and limb features and is associated with several types of tumors. A 29-yr-old woman with this syndrome presented with a large, complex ovarian mass. She was subsequently diagnosed with a low-grade serous carcinoma of the ovary and an endometrioid adenocarcinoma of the uterus. Rubinstein-Taybi syndrome is an autosomal dominant, multiple congenital anomalies-mental retardation syndrome. Two genes, CREBBP and EP300, have been found to be associated with this disorder, although some cases do not have an identifiable cause. These genes code for proteins that acetylate histone tails, an epigenetic modification that serves to control transcription. They also serve as cofactors to several transcription factors and modulate p53. Although these patients have a predisposition to benign and malignant neoplasms, no malignant gynecologic neoplasm has been described thus far. Although no significant evidence linking CREBBP and EP300 to gynecologic malignancies has yet been found, some studies have suggested that hypoacetylation of histones may be involved in endometrial and ovarian carcinomas.

de Kort E, Conneman N, Diderich K
A case of Rubinstein-Taybi syndrome and congenital neuroblastoma.
Am J Med Genet A. 2014; 164A(5):1332-3 [PubMed] Related Publications

Bourdeaut F, Miquel C, Richer W, et al.
Rubinstein-Taybi syndrome predisposing to non-WNT, non-SHH, group 3 medulloblastoma.
Pediatr Blood Cancer. 2014; 61(2):383-6 [PubMed] Related Publications
Medulloblastomas (MB) are classified in four subgroups: the well defined WNT and Sonic Hedgehog (SHH) subgroups, and the less defined groups 3 and 4. They occasionally occur in the context of a cancer predisposition syndrome. While germline APC mutations predispose to WNT MB, germline mutations in SUFU, PTCH1, and TP53 predispose to SHH tumors. We report on a child with a Rubinstein-Taybi syndrome (RTS) due to a germline deletion in CREBBP, who developed a MB. Biological profilings demonstrate that this tumor belongs to the group 3. RTS may therefore be the first predisposition syndrome identified for non-WNT/non-SHH MB.

Huidobro C, Fernandez AF, Fraga MF
The role of genetics in the establishment and maintenance of the epigenome.
Cell Mol Life Sci. 2013; 70(9):1543-73 [PubMed] Related Publications
Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine-N-methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein-Taybi syndrome, Coffin-Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease.

Sahiner UM, Senel S, Erkek N, et al.
Rubinstein Taybi syndrome with hepatic hemangioma.
Med Princ Pract. 2009; 18(2):162-4 [PubMed] Related Publications
OBJECTIVE: It was the aim of our study to present a case of Rubinstein Taybi syndome (RTS) associated with hepatic hemangioma.
CLINICAL PRESENTATION AND INTERVENTION: A 6.5-year-old boy was diagnosed with RTS. He had large areas of cutaneous capillary hemangiomas. Radiological examination revealed a hepatic hemangioma. A multidisciplinary follow-up program was commenced and hepatic ultrasound examinations were performed periodically. No progression and complication have since occurred.
CONCLUSION: This case shows an association between RTS and hepatic hemangioma, and hence, we recommend regular hepatic ultrasound examination when RTS is suspected or diagnosed.

Pogrzebielski A, Piwowarczyk A, Kohylarz J, Romanowska-Dixon B
Lacrimal caruncle nevus associated with Rubinstein-Taybi syndrome.
Klin Oczna. 2007; 109(7-9):330-2 [PubMed] Related Publications
We present a 28-year-old man with diagnosed Rubinstein-Taybi syndrome (RSTS), known as "Broad thumb-Hallux syndrome" with co-existing lacrimal caruncle tumor. Because of the documented enlargement of the lacrimal caruncle mass and known increased risk to develop malignancies in RSTS patients we decided to perform excisional biopsy, which revealed caruncle nevus. To our knowledge this is the first description of such an association.

Roelfsema JH, Peters DJ
Rubinstein-Taybi syndrome: clinical and molecular overview.
Expert Rev Mol Med. 2007; 9(23):1-16 [PubMed] Related Publications
Rubinstein-Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100,000 newborns. Mutations in two genes - CREBBP and EP300 - have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein-Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein-Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.

Swaminathan V, Reddy BA, Ruthrotha Selvi B, et al.
Small molecule modulators in epigenetics: implications in gene expression and therapeutics.
Subcell Biochem. 2007; 41:397-428 [PubMed] Related Publications
Altered gene expression resulting from changes in the post-translational modification patterns of the histones and DNA is collectively termed epigenetics. Such changes are inherited albeit there are no alterations in the DNA sequence. Epigenetic regulation of gene expression is implemented by a wide repertoire of histone and DNA modifying enzymes including the acetyltransferases and deacetylases, the methyltransferases and kinases among others. Therefore, a regulation of these enzyme activities affords a tighter regulation of gene expression. Conversely, aberrant enzymatic activities lead to unregulated gene expression, resulting in several diseases such as RTS (loss of CBP HAT activity) and Spinal and Bulbar muscular atrophy (HATs and HMTases), apart from several forms of cancers, particularly myeloid leukemia (RAR-PML or RAR-PLZF fusion proteins resulting in the mistargeting of HDACs). Thus these enzymes have emerged as novel targets for the design of therapeutics. In this direction, several small molecule modulators (activators and inhibitors) of HATs, HDACs and HMTases are being reported in literature. This chapter introduces the different histone modifying enzymes involved in gene regulation, their connection to disease manifestation and focuses on the role of small molecule modulators in understanding enzyme function and also the design and the evolution of chromatin therapeutics

Van Beekum O, Kalkhoven E
Aberrant forms of histone acetyltransferases in human disease.
Subcell Biochem. 2007; 41:233-62 [PubMed] Related Publications
One of the major mechanisms through which eukaryotic cells respond to developmental and environmental signals is by changing their gene expression patterns. This complex and tightly regulated process is largely regulated at the level of RNA polymerase II-mediated transcription. Within this process an important class of transcriptional regulators are the histone acetyltransferases (HATs), proteins that acetylate histones and non-histone substrates. While hyperacetylation of histones is generally associated with active genes, the effect of acetylation of nonhistone proteins varies between substrates resulting in for example alterations in (sub-nuclear) protein localization or protein stability. Given the central role of HATs in transcriptional regulation and other cellular processes, it may not be surprising that genetic alterations in the genes encoding HATs, resulting in aberrant forms of these regulatory proteins, have been linked with various human diseases, including congenital developmental disorders and various forms of cancer, including leukaemia. Here we will review mutations found in genes encoding human HATs and discuss the (putative) functional consequences on the function of these proteins. So far the lessons learned from naturally occurring mutations in humans have proven to be invaluable and recapitulating such genetic alterations in various experimental systems will extend our knowledge even further. This seems particularly relevant given the wide range of diseases in which acetyltransferases have been implicated and may help to open up new therapeutic avenues.

Verstegen MJ, van den Munckhof P, Troost D, Bouma GJ
Multiple meningiomas in a patient with Rubinstein-Taybi syndrome. Case report.
J Neurosurg. 2005; 102(1):167-8 [PubMed] Related Publications
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.

Bayle P, Bazex J, Lamant L, et al.
Multiple perforating and non perforating pilomatricomas in a patient with Churg-Strauss syndrome and Rubinstein-Taybi syndrome.
J Eur Acad Dermatol Venereol. 2004; 18(5):607-10 [PubMed] Related Publications
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.

Altintas F, Cakmakkaya S
Anesthetic management of a child with Rubinstein-Taybi syndrome.
Paediatr Anaesth. 2004; 14(7):610-1 [PubMed] Related Publications

Iyer NG, Ozdag H, Caldas C
p300/CBP and cancer.
Oncogene. 2004; 23(24):4225-31 [PubMed] Related Publications
p300 and cyclic AMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a number of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematological disorders. p300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in critical protein domains, and these are often associated with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematological tumor formation. The involvement of these proteins in critical tumorigenic pathways (including TGF-beta, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.

Weeber EJ, Levenson JM, Sweatt JD
Molecular genetics of human cognition.
Mol Interv. 2002; 2(6):376-91, 339 [PubMed] Related Publications
Our understanding of the molecular underpinnings of human cognition has been greatly aided by the convergent synergy of clinical, genetic, and signaling research. By identifying the mutated genes that give rise to syndromes of mental retardation or cognitive defects in patients, and by placing the associated gene products within signaling networks, researchers are piecing together how learning occurs and how memories are formed and sustained.

Kurosawa K, Fukutani K, Masuno M, et al.
Gonadal sex cord stromal tumor in a patient with Rubinstein-Taybi syndrome.
Pediatr Int. 2002; 44(3):330-2 [PubMed] Related Publications

Harth W, Linse R
[Dermatological stigmata in Rubinstein-Taybi syndrome].
Hautarzt. 2001; 52(10 Pt 2):977-9 [PubMed] Related Publications
The clinical features of the Rubinstein-Taybi syndrome include mental deficiency and broad thumbs and toes. Typical dermatological findings are capillary hemangioma of the forehead and hypertrichosis. Rubinstein-Taybi syndrome patients also seem to be prone to develop keloids. We present a case of a one year old girl with Rubinstein-Taybi syndrome and the typical dermatological features.

Schepis C, Greco D, Siragusa M, et al.
Rubinstein-Taybi syndrome with epidermal nevus: a case report.
Pediatr Dermatol. 2001 Jan-Feb; 18(1):34-7 [PubMed] Related Publications
We describe an 8-year-old boy with Rubinstein-Taybi syndrome, a multiple congenital anomaly/mental retardation syndrome characterized by broad thumbs and great toes, peculiar facies, and mental retardation caused by mutations in the transcriptional coactivator CREB binding protein (CBP). He had on his right side yellowish papular lesions organized in narrow bands according to Blaschko lines, later confirmed by histology as an epidermal nevus. Epidermal nevus syndrome has been ruled out because the patient failed to meet the criteria for inclusion under this designation. This association may be coincidental.

Ishii S
[Transcriptional co-activator CBP and co-repressor Ski/Sno].
Tanpakushitsu Kakusan Koso. 2000; 45(9 Suppl):1418-26 [PubMed] Related Publications

Cribier B
[Diseases associated with adnexal tumors. I--Follicular tumors].
Ann Dermatol Venereol. 1999; 126(3):270-9 [PubMed] Related Publications

Ihara K, Kuromaru R, Takemoto M, Hara T
Rubinstein-Taybi syndrome: a girl with a history of neuroblastoma and premature thelarche.
Am J Med Genet. 1999; 83(5):365-6 [PubMed] Related Publications
A 7-year-old girl with Rubinstein-Taybi syndrome (RTS) who had a history of neuroblastoma and premature thelarche is reported. The neuroblastoma was detected at age 6 months on a nation-wide neuroblastoma screening program, surgically removed, and took a favorable clinical course with minimal therapy. She developed isolated breasts at age 6 years, had normal plasma levels of estradiol, follicular-stimulating hormone (FSH), and luteinizing hormone (LH), and showed a FSH-predominant pattern on the LH-releasing hormone stimulation test. In view of these findings, she was diagnosed to have premature thelarche. Premature thelarche may not be uncommon in girls with RTS.

Masuno M, Imaizumi K, Ishii T, et al.
Pilomatrixomas in Rubinstein-Taybi syndrome.
Am J Med Genet. 1998; 77(1):81-2 [PubMed] Related Publications

Burton BJ, Kumar VG, Bradford R
Granular cell tumour of the spinal cord in a patient with Rubenstein-Taybi syndrome.
Br J Neurosurg. 1997; 11(3):257-9 [PubMed] Related Publications
A case of cervical spinal cord granular cell tumour in a patient with Rubenstein-Taybi syndrome is described. A granular cell tumour arising from the spinal cord itself has never been previously described. Complete excision of the tumour could not be achieved owing to its location. It subsequently recurred and was treated with radiotherapy. The patient made a complete recovery with no further recurrence after 2 years of follow-up.

Giles RH, Petrij F, Dauwerse HG, et al.
Construction of a 1.2-Mb contig surrounding, and molecular analysis of, the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3.
Genomics. 1997; 42(1):96-114 [PubMed] Related Publications
In the interest of cloning and analyzing the genes responsible for two very different diseases, the Rubinstein-Taybi syndrome (RTS) and acute myeloid leukemia (AML) associated with the somatic translocation t(8;16)(p11;p13.3), we constructed a high-resolution restriction map of contiguous cosmids (contig) covering 1.2 Mb of chromosome 16p13.3. By fluorescence in situ hybridization and Southern blot analysis, we assigned all tested RTS and t(8;16) translocation breakpoints to a 100-kb region. We have previously reported exact physical locations of these 16p breakpoints, which all disrupt one gene we mapped to this interval: the CREB-binding protein (CBP or CREBBP) gene. Intriguingly, mutations in the CBP gene are responsible for RTS as well as the t(8;16)-associated AML. CBP functions as an integrator in the assembly of various multiprotein regulatory complexes and is thus necessary for transcription in a broad range of transduction pathways. We report here the cloning, physical mapping, characterization, and full cDNA nucleotide sequence of the human CBP gene.

Skousen GJ, Wardinsky T, Chenaille P
Medulloblastoma in patient with Rubinstein-Taybi syndrome.
Am J Med Genet. 1996; 66(3):367 [PubMed] Related Publications

Miller RW, Rubinstein JH
Tumors in Rubinstein-Taybi syndrome.
Am J Med Genet. 1995; 56(1):112-5 [PubMed] Related Publications
The 14 tumors reported in Rubinstein-Taybi syndrome since 1989, when added to the 22 previously reported, are beginning to show a pattern of neural and developmental tumors, especially of the head, which is malformed in the syndrome. Among the neoplasms were 12 of the nervous system: 2 each of oligodendroglioma, medulloblastoma, neuroblastoma, and benign meningioma, a pheochromocytoma, and 3 other benign tumors; 2 of nasopharyngeal rhabdomyosarcoma; and 1 each of leiomyosarcoma, seminoma, and embryonal carcinoma. Among the other benign tumors were an odontoma, a choristoma, a dermoid cyst, and 2 pilomatrixomas.

Chahidi N
A case of Proteus syndrome.
J Hand Surg Br. 1994; 19(2):263-4 [PubMed] Related Publications

Cambiaghi S, Ermacora E, Brusasco A, et al.
Multiple pilomatricomas in Rubinstein-Taybi syndrome: a case report.
Pediatr Dermatol. 1994; 11(1):21-5 [PubMed] Related Publications
Rubinstein-Taybi syndrome is a multisystem developmental disorder due to an autosomal dominant mutation. It is clinically defined by the presence of peculiar facies, mental retardation, and broad thumbs and first toes. Important dermatologic findings include hirsutism, keloids, hemangiomas, and dermatoglyphic abnormalities. We report a 12-year-old girl with the typical phenotype of Rubinstein-Taybi syndrome, associated with numerous pilomatricomas. These are benign epithelial neoplasms with hair cell differentiation that may have a familial transmission. Pilomatricomas have not been reported in patients with Rubinstein-Taybi syndrome, although their association with myotonic dystrophy, another autosomal dominant disorder, is well known. Possibilities to explain the association include contiguous gene syndrome, the action of a pleiotropic gene, predisposition to malformations, and mere coincidence.

Bonioli E, Bellini C
Rubinstein-Taybi syndrome and pheochromocytoma.
Am J Med Genet. 1992; 44(3):386 [PubMed] Related Publications

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