Rubinstein-Tabi syndrome is a genetically heterogeneous (according to recent data) hereditary disease characterized by damage to the central nervous system, deformities of the bones of the skeleton and a number of other malformations. Symptoms of this condition are progressive mental retardation, low growth, dilation of the phalanges of the fingers, polydactyly on the legs, various disorders of the internal organs. The diagnosis of Rubinstein-Tabi syndrome is made on the basis of the data of the patient’s current status, molecular genetic analyses and other studies. There is no specific treatment for this pathology, symptomatic therapy is used depending on the type of defects and disorders.
General information
Rubinstein-Tabi syndrome is a genetic disease that is accompanied by intellectual and physical development disorders, as well as various defects of the skeleton and internal organs. For the first time this pathology was identified in 1963 and described by American pediatricians J. Rubinstein and G. Tabi – the researchers themselves called the disease “the syndrome of the wide first finger of the hands and feet, a specific face and mental retardation.” Further research in the field of genetics confirmed that Rubinstein-Tabi syndrome is an autosomal dominant pathology, but the vast majority of cases occur due to spontaneous mutations of various types. The occurrence is about 1:100,000 – 125,000, boys and girls are affected with approximately the same frequency. A feature of Rubinstein-Tabi syndrome is an increased risk of developing various oncological diseases – mainly some types of leukemia, tumors of the meninges and nerve tissues.
Causes
Rubinstein-Tabi syndrome has a pronounced genetic heterogeneity, however, various types of this disease do not have any clinical features. The most common cause of this pathology is damage to the CREBBP gene, which is located on the 16th chromosome. It encodes the so-called CREB-binding protein, which is an important transcription factor controlling the expression of a huge number of genes. The appearance of various changes in the CREBBP gene (point mutations, translocations, microdeletions in the 16th chromosome) leads either to the formation of a defective protein that is unable to perform its functions, or to a complete blockage of its release. This causes the development of Rubinstein-Tabi syndrome.
In recent years, molecular genetic studies of this pathology have confirmed that mutations of the EP300 gene, which is located on the 22nd chromosome, also play a role in its development. The expression product of this gene is the protein p300, which, like the CREB-binding protein, belongs to the group of transcription factors. According to research data, it is possible to identify the nature of a genetic defect in Rubinstein-Tabi syndrome in 55-60% of cases, about half of patients have CREBBP gene mutations, another 40-45% have deletions and other chromosomal rearrangements affecting the 16th chromosome, and only 3% of patients have EP300 gene mutations. All this points to the possibility of the participation of other genes in the development of this disease.
A defect in the transcription factor protein or its small isolation (due to haplon-sufficiency) leads to numerous disorders caused by insufficient stimulation of a number of other genes. This can be seen by the characteristic clinical picture of Rubinstein-Tabi syndrome. Both transcription factors affect the activity of the formation of new connections between neurons, the formation of long-term memory, stimulation of the immune response, and the development of the reproductive system. The insufficiency of these proteins leads to a whole cascade of pathological processes in the body, which makes up the clinic of Rubinstein-Tabi syndrome. In addition, the above transcription factors also affect the activity of anti-oncogenes, therefore, if they are defective, the risk of developing malignant neoplasms increases significantly.
Symptoms
The symptoms of Rubinstein-Tabi syndrome are characterized by a significant variety in different patients, which affects the severity of the disease and its prognosis. Usually, already at birth, some signs of this pathology can be detected – deformities of the face and skull (micro- or brachycephaly, expansion of the bridge of the nose, epicanthus, beak-shaped nose), a high arched palate, a change in the shape and position of the auricles, enlarged phalanges of the fingers, especially the first ones. Polydactyly is often detected on the legs of patients with Rubinstein-Tabi syndrome. Sometimes, already at birth, signs of malformations of internal organs are determined – pallor or cyanosis (with lung or heart damage), prolonged jaundice of newborns, cryptorchidism.
With the further course of Rubinstein-Tabi syndrome, there is a progressive lag of the child in physical and mental development from healthy peers, difficult development of speech and motor skills. There is also strabismus, myopia. The facial expression of patients is characterized by a grimace resembling a smile, hirsutism occurs, about half of the patients are determined to have a red nevus in the forehead, nape or neck. At an older age, patients with Rubinstein-Tabi syndrome show curvature of the spinal column of various types and low growth (no more than 150-160 centimeters). Chest deformities and (less often) other skeletal anomalies can be determined, cryptorchidism is noted in boys in most cases.
A permanent sign of Rubinstein-Tabi syndrome is mental retardation. As a rule, DSD, oligophrenia, a significant delay in speech development compared to healthy peers are diagnosed. There are violations of concentration of attention, patients are easily distracted by extraneous stimuli when performing any task, sudden mood swings are possible. At the same time, people with Rubinstein-Tabi syndrome are good at making contact, they are easily socialized. Among other neurological symptoms of the disease, poor coordination of movements is often found, convulsive seizures are occasionally observed.
Rubinstein-Tabi syndrome can also manifest itself in various disorders of the internal organs – the brain, heart, kidneys and urinary tract, terminal parts of the digestive system. In addition, such patients significantly increase the risk of cancer, mainly developing at an early age. These include various forms of leukemia, melanoma, and some types of lymphomas. Therefore, before puberty, patients with Rubinstein-Tabi syndrome should periodically undergo examinations by an oncologist for early diagnosis of malignant neoplasms.
Diagnosis and treatment
To identify Rubinstein-Tabi syndrome, data from a general examination of the patient, X-ray examinations and molecular genetic analyses are used, ultrasound and MRI can play an auxiliary role. During the examination, the anomalies of facial development characteristic of this disease are determined (changes in the shape and size of the skull and nose, an anti–mongoloid eye incision), shortening and expansion of the phalanges of the thumbs on the hands and feet, sometimes polydactyly. In adult patients with Rubinstein-Tabi syndrome, a decrease in growth, deep mental retardation, curvature of the spine are also detected. On radiographs, you can see changes in the bones of the phalanges, spine and chest, the bone age is somewhat behind the actual one.
Molecular genetic diagnosis of Rubinstein-Tabi syndrome is performed by a geneticist who can use many methods to determine this disease. Point mutations in the CREBBP and EP300 genes are detected by direct automatic sequencing of the coding sequence. The FISH technique is used when the presence of deletions or translocations on the 16th chromosome is suspected, also leading to the development of Rubinstein-Tabi syndrome. Since it is extremely difficult to determine the possible type of genetic defect based on phenotypic data, several techniques of modern molecular genetics often have to be used at once as part of the diagnosis of this disease.
Auxiliary diagnostic methods make it possible to identify concomitant disorders of internal organs in Rubinstein-Tabi syndrome. Such methods include ultrasound examinations (ultrasound of the kidneys and urinary tract, EchoCG), electrocardiography, magnetic resonance imaging and other techniques. Often, patients with Rubinstein-Tabi syndrome are diagnosed with congenital heart defects (open Botall duct, ventricular septal defect), arrhythmias, kidney abnormalities (doubling, hypoplasia) and urinary tract (atresia in various areas). Also, with this disease, the formation of the corpus callosum of the brain is disrupted, which is determined by magnetic resonance imaging. Some patients with Rubinstein-Tabi syndrome have malformations of the lungs and digestive system.
There is no specific treatment for this pathology at the moment, all therapeutic measures are reduced to the relief of symptoms, correction of anomalies and malformations that threaten the lives of patients. Nootropic drugs, calcium and vitamin D preparations are prescribed, specialized psychological help is recommended to reduce the severity of mental retardation. In some cases, Rubinstein-Tabi syndrome uses surgical methods of treatment – to eliminate heart defects, abnormalities of the rectum and urinary tract, cryptorchidism. It may also require treatment by an ophthalmologist, and if there are signs of the development of a malignant neoplasm, consultation and treatment by an oncologist.
Prognosis and prevention
According to most experts, the prognosis of Rubinstein-Tabi syndrome is often uncertain or unfavorable. This is due to the fact that this disease is characterized by a significant range of various disorders – from relatively safe for life (mild skeletal abnormalities, mental disability) to pronounced ones that can lead to death at an early age (severe malformations of the heart, lungs, kidneys). In addition, the risk of developing oncological pathologies is significantly increased. Therefore, the prognosis of Rubinstein-Tabi syndrome is made strictly individually, based on the specific clinical picture and the general condition of the patient. No specific methods of preventing this disease due to its frequent spontaneous development have been developed to date.