Rubinstein-Taybi syndrome is a rare genetic disease characterized by mental and growth retardation and occurs as a result of chromosomal deletions and point mutations. Because the genes that are affected are involved in the development of numerous organs and tissues, the clinical presentation includes heart, skin, facial and digital anomalies, and the diagnosis is made clinically and by karyotypic analysis. Treatment involves managing symptoms and accompanying comorbidities.
The clinical presentation of Rubinstein-Taybi syndrome involves several organs, but the most prominent features are exhibited in the facial region and the distal extremities. Prominent and beaked nose, hypoplasia of the maxilla, low-set ears, micrognathia, enamel hypoplasia, talon cusps, highly arched eyebrows and long eyelashes are the most common facial abnormalities in these patients  . Broad and angulated thumbs, fingers, and great toes are observed in practically all patients, while clinodactyly is seen in some patients as well.
Growth retardation and postnatal growth failure are present in the majority of patients. Infants often fall below the fifth percentile in terms of weight, height, and head circumference, and failure to thrive is frequently reported . Feeding difficulties and dysphagia occur commonly in patients with recurrent respiratory tract infections, and short stature is often established during the physical examination. Microcephaly is also frequently reported.
Severe mental retardation, cognitive impairment, short attention span, sudden mood changes and speech difficulties are readily observed. Defects in motor skills and coordination, sometimes accompanied with hypotonia and hyperreflexia may be seen.
Findings that are somewhat less prevalent in these patients include:
This syndrome presents with a complex clinical symptomatology, but the distinct facial and digital features, together with findings related to other systems should be indicative of this disease, and the initial diagnosis is made clinically. Once this syndrome is suspected, a full diagnostic workup should be performed, to establish all accompanying findings in these patients. Imaging studies, including X-rays, computed tomography (CT scan) or magnetic resonance imaging (MRI) should be done to evaluate the change in the skeletal system, while echocardiography is indicated to rule out the presence of congenital heart disease. Ophthalmoscopy, ENT examination, ultrasound of the abdomen and lung studies should be performed as well. With supporting evidence obtained from diagnostic procedures, genetic testing can be performed. Karyotype analysis, and in situ hybridization can detect mutations and microdeletions in CREBBP gene and the 16p13.3 segment, respectively. However, CREBBP mutations are established in only 55% of patients , which does not exclude the diagnosis, while EP300 gene mutations are established in less than 10% of individuals.
It is important to mention that patients with Rubinstein-Taybi syndrome are prone to develop malignant diseases, including tumors of the nervous system (oligodendroglioma, medulloblastoma, meningioma), as well as lymphomas and leukemias.
Treatment of patients with Rubinstein-Taybi syndrome requires a multidisciplinary approach and consists of rehabilitation and supportive therapy together with management of accompanying comorbidities and findings . Mental retardation open link and cognitive difficulties require special forms of education, speech and behavioral therapy, and various other measures of mental rehabilitation, which can present a significant challenge. Growth should be closely monitored, and correction of other findings is necessary. Physical therapy and exercise are indicated in all patients, with an attempt to reduce musculoskeletal changes that may impair the normal functioning of patients.
Congenital heart disease, cryptorchidism, and presence of either benign or malignant tumors, are all indications for surgical treatment, but patients with this syndrome are quite prone to laryngeal and tracheal wall collapse, which can significantly complicate the process of anesthesia and intubation . Management of other findings, such as renal, ocular, and skin manifestations should be done accordingly, and a long-term follow-up of patients is necessary for ensuring a good quality of life.
Overall survival rates are good, patients frequently reach adulthood, but accompanying comorbidities may reduce life expectancy that is estimated to be normal in these patients. Growth and mental retardation present as a significant burden to the patient and the family, and congenital heart disease, recurrent respiratory infections, and other severe complications of this disease can significantly contribute to morbidity and mortality. Additionally, it is established that patients have an increased risk of developing malignant diseases, including lymphomas, leukemias, and tumors of the brain, such as meningioma and medulloblastoma, which can carry a poor prognosis if not diagnosed early .
The cause of Rubinstein-Taybi syndrome involves the chromosomal segment 16p13.3, and point mutations, translocations, or microdeletions of CREBBP, and the E1A-binding protein p300 (also known as EP300) . The proteins of these genes act as co-activators of the process of transcription, and their roles are bridging of RNA polymerase II and DNA-binding transcription factors, chromatin rearrangements through performing the function of histone acetyltransferases, and other processes in gene expression. EP300 mutations and deletions have been established in patients with malformations of the skeletal system, such as broadening and angulation of fingers and toes, as well as facial abnormalities, which are the hallmarks of this disease . It is understood that because these proteins are present in numerous cells, and perform some of the most important functions in the process of gene expression, several organs may be affected, including the heart, lungs, kidneys, the skin, testes, and the eyes.
The estimated prevalence for Rubinstein-Taybi syndrome vary, and is somewhere between 1 per 100,000-125,000 live births . The majority of cases occur sporadically. Familial cases are extremely rare, and neither gender nor ethnic predilection has been documented.
It is not completely understood why the changes in the 16p13.3 segment and involvement of CREBBP and EP300 genes occur. It is assumed that the majority of mutations, microdeletions, or simple translocations occur de novo, while familial occurrence is extremely rare. As a result, defects in these regions lead to dysfunctional transcription process, because the proteins derived from these genes are co-activator of this process.
It is established that patients with Rubinstein-Taybi syndrome have some form of immune deficiency, which could be the primary reason why about 75% of patients have recurrent respiratory infections .
Although mutations that are presumed to be responsible for Rubinstein-Taybi syndrome have been identified, prevention of this syndrome is currently not possible. It is important to establish the diagnosis as early as possible, so that the development of complications, which can be life-threatening, can be reduced to a minimum. Proper therapy may significantly improve the life of the patient, and reduce the burden that this disease carries.
Rubinstein-Taybi syndrome is a very rare genetic disorder which includes several congenital anomalies such as mental retardation, growth abnormalities, broad and angulated thumbs and toes, and a variety of other symptoms. It was initially described in the 1960s , and the cause is presumed to be microdeletions, point mutations, or other types of changes in the chromosome 16p13.3 and cyclic adenosine-monophosphate-response element binding protein (CBP or CREBBP). This protein is active in numerous cells and organs and is involved in various metabolic and proliferative processes, such as chromatin remodeling, signal transduction pathway integration, and regulation of transcription . As a result, its mutations lead to significant impairment of normal cellular functioning, leading to diverse symptoms involving multiple organs. The majority of cases are sporadic, but reports of Rubinstein-Taybi syndrome in monozygotic twins have been documented . The prevalence of this genetic disease is estimated to be 1 per 100,000-125,000 live births, and the most prominent features of this syndrome include mental and growth retardation. Intellectual disability, short stature, feeding problems during the first months and years of life as well as growth failure are essential components of this syndrome and can be quite debilitating for the patient and the family. Facial and digital abnormalities are also characteristic features of this syndrome, including malformations of the ears, nose, lips, and other parts as well; abnormally broad and angulated fingers and toes are some of the most commonly encountered features. Other organs may be involved, including the testes, skin, heart, the skeletal system, and the kidneys, while more than 70% of patients experience recurrent respiratory infections, presumably because of defects in the immune response. The diagnosis is made by clinical criteria, and molecular analysis is shown to reveal mutations in approximately 55% of cases, which does not exclude the diagnosis. Goals of treatment are to reduce the burden of the disease by managing symptoms individually, through physical and mental rehabilitation, genetic counseling, and correction of accompanying findings, such as congenital heart disease, recurrent respiratory infections, and cryptorchidism.
Rubinstein-Taybi syndrome is a rare genetic disease that involves various organs, but primarily exhibits changes in the face and fingers, and virtually all patients have growth retardation and intellectual disability. It occurs in approximately 1 individual per 100,000, and it caused by mutations in genes and parts of chromosomes that are involved in the process of gene expression. These mutations are in extremely rare cases hereditary, and occur spontaneously in the vast majority of patients, for unknown reasons. These mutations lead to defective cellular functioning in numerous organs and systems, and the most prominent pathological findings include growth failure in infants and severe intellectual disability, which presents as a significant burden to patients and their families. Various facial features, such as the underdeveloped jaw, beaked nose, low-set ears, and long eyelashes, are accompanied with broadening and angulation of thumbs, big toes, and other fingers. Additionally, patients may have congenital heart disease, which is diagnosed in a significant number of patients, as well as recurrent respiratory and urinary infections, vision problems, and various other changes. The diagnosis is primarily made upon clinical examination, and mutations of the involved genes are detected in about 50% of patients, which does not exclude the diagnosis. Treatment of patients with Rubinstein-Taybi syndrome is complex and necessitates both mental and physical rehabilitation, but also the management of accompanying comorbidities that may significantly influence the quality and duration of the patients' life. Special education, speech therapy, and physical rehabilitation are indicated for all patients, while surgery may be necessary to correct other defects. Patients with this syndrome carry a good prognosis in general, but significant intellectual disability, as well as the presence of other comorbidities, require long-term monitoring, which is a significant challenge.