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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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (2)

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CREBBP 16p13.3 CBP, RSTS, KAT3A, RSTS1 -CREBBP mutation in Rubinstein-Taybi Syndrome
EP300 22q13.2 p300, KAT3B, MKHK2, 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).


Merk DJ, Ohli J, Merk ND, et al.
Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma.
Dev Cell. 2018; 44(6):709-724.e6 [PubMed] Related Publications
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.

Yagi Y, Kuwatsuka Y, Asai M, et al.
Coexistence of keloids and pilomatricoma in a patient with Rubinstein-Taybi syndrome.
Dermatol Online J. 2018; 24(1) [PubMed] Related Publications
Rubinstein-Taybi syndrome (RTS) is an autosomaldominant hereditary disease, which contains many skeletal and organ anomalies as well as mental retardation. Although high incidence of keloids in RTS is known, it is difficult to find a detailed report on the clinical features of keloids. In the following letter, we report an RTS patient fulfilling diagnostic criteria whosuffered from both keloids and pilomatricoma. We also performed a literature search, which identified the possible involvement of the Wnt/β-catenin signaling pathway in the pathogenesis of these two skin lesions.

Boot MV, van Belzen MJ, Overbeek LI, et al.
Benign and malignant tumors in Rubinstein-Taybi syndrome.
Am J Med Genet A. 2018; 176(3):597-608 [PubMed] Free Access to Full Article Related Publications
Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomalies syndrome associated with mutations in CREBBP (70%) and EP300 (5-10%). Previous reports have suggested an increased incidence of specific benign and possibly also malignant tumors. We identified all known individuals diagnosed with RSTS in the Netherlands until 2015 (n = 87) and studied the incidence and character of neoplastic tumors in relation to their CREBBP/EP300 alterations. The population-based Dutch RSTS data are compared to similar data of the Dutch general population and to an overview of case reports and series of all RSTS individuals with tumors reported in the literature to date. Using the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA Foundation), 35 benign and malignant tumors were observed in 26/87 individuals. Meningiomas and pilomatricomas were the most frequent benign tumors and their incidence was significantly elevated in comparison to the general Dutch population. Five malignant tumors were observed in four persons with RSTS (medulloblastoma; diffuse large-cell B-cell lymphoma; breast cancer; non-small cell lung carcinoma; colon carcinoma). No clear genotype-phenotype correlation became evident. The Dutch population-based data and reported case studies underscore the increased incidence of meningiomas and pilomatricomas in individuals with RSTS. There is no supporting evidence for an increased risk for malignant tumors in individuals with RSTS, however, due to the small numbers this risk may not be fully dismissed.

Romaniouk I, Romero A, Runza P, et al.
Management of neuroendocrine tumor in a patient with Rubinstein-Taybi syndrome in chronic hemodialysis.
Nefrologia. 2018 Jul - Aug; 38(4):446-448 [PubMed] Related Publications

Sy C, Henry J, Kura B, et al.
Primary Diffuse Large B-Cell Lymphoma in a Patient with Rubinstein-Taybi Syndrome: Case Report and Review of the Literature.
World Neurosurg. 2018; 109:342-346 [PubMed] Related Publications
BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare, congenital syndrome that is known to be associated with neoplasms of various organ systems. Evaluation and treatment of such patients is challenging, given the cognitive delay and heterogeneity of pathologic presentations that define this syndrome.
CASE DESCRIPTION: Presented here is a case of a patient with RSTS, diagnosed at birth, who presented with subtle symptoms of lethargy and a change in behavior. He was found to have a large (7.0-cm × 4.7-cm), right-sided brain mass that was eventually diagnosed as a primary central nervous system lymphoma.
CONCLUSIONS: To the best of our knowledge, this is the first reported case of a primary central nervous system lymphoma presenting in a patient with RSTS. This was confirmed through microscopic and histologic studies. The large size attained by this mass in our patient highlights the increased scrutiny and surveillance needed to provide the best care for these patients. A multidisciplinary team approach is ideal as successful treatment of our patient using surgical debulking, appropriate chemotherapy, and close postoperative follow-up has resulted in an excellent clinical outcome.

Villani A, Greer MC, Kalish JM, et al.
Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk.
Clin Cancer Res. 2017; 23(12):e83-e90 [PubMed] Related Publications
In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific

Rokunohe D, Nakano H, Akasaka E, et al.
Rubinstein-Taybi syndrome with multiple pilomatricomas: The first case diagnosed by CREBBP mutation analysis.
J Dermatol Sci. 2016; 83(3):240-2 [PubMed] Related Publications

Butler GH, Boyle M, Lynch SA, et al.
One to Watch: A Germ Cell Tumor Arising in an Undescended Testicle in Rubinstein-Taybi Syndrome.
J Pediatr Hematol Oncol. 2016; 38(6):e191-2 [PubMed] Related Publications
A male preterm infant was born with dysmorphic features consistent with Rubinstein-Taybi syndrome (RTS). An undescended right testicle was noted on examination. At 5 months of age he developed a palpable right-sided abdominal mass and an elevated alpha-fetoprotein. Histology revealed a malignant germ cell neoplasm arising within the undescended testis. This is the first reported case of a germ cell tumor occurring in a pediatric patient with RTS. Urologic abnormalities occur in approximately 52% of RTS patients, of which cryptorchidism is the commonest. Given the frequency of undescended testes in this population, closer screening may be warranted.

Mar N, Digiuseppe JA, Dailey ME
Rubinstein-Taybi syndrome - a window into follicular lymphoma biology.
Leuk Lymphoma. 2016; 57(12):2908-2910 [PubMed] Related Publications

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

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