Velo-cardio-facial syndrome is a congenital (sometimes hereditary) disease characterized by multiple malformations and a disorder of cognitive functions. Its main symptoms are defects of the hard palate (obvious and hidden crevices), cardiovascular disorders, mental retardation, characteristic facial features. Diagnosis is made on the basis of the present status of the patient (including during the examination of newborns) and data from cytogenetic studies. There is no specific treatment for the disease, symptomatic therapy is used, including surgical techniques.
Velo-cardio-facial syndrome is a genetic disease, the basis of which lies in the violation of the intrauterine development of many organs and systems of the body. There are several similar phenotypes with similar manifestations (for example, Di Giorgi and Sprintzen syndromes), which, moreover, are due to similar genetic causes. Therefore, some researchers in the field of genetics combine all these conditions into the group “velocardiofacial syndrome”, while others believe that these are still different nosological units. For example, the difference between Di Giorgi’s disease is immunological disorders, which are weakly expressed in velo-cardio-facial syndrome. The occurrence is about one case per 3000-4000 births, develops with equal probability in both boys and girls, in most cases the pathology occurs spontaneously and is not present in the parents or close relatives of the child. Only in some cases has the hereditary transmission of velo-cardio-facial syndrome by autosomal dominant mechanism been reliably proven.
The direct cause of the development of velocardiofacial syndrome is a violation of the structure of the long arm of the 22nd chromosome – locus q11.2. Such defects occur during meiosis during the formation of germ cells, after which they are transmitted to offspring. Most often these are microdeletions, which are reduced to the absence of a small section of the chromosome, while important genes, in particular TBX1, disappear from the patient’s genome. The role of this gene in the development of velo-cardio-facial syndrome is proved by the fact that in some forms of the disease there is no deletion of the 22nd chromosome site, but point mutations in TBX1 are detected. This gene is one of the transcription regulation factors most actively involved in the processes of embryonic development.
A violation of the structure of TBX1, or even more so the absence in the genome as a result of deletion, leads to pathologies of embryogenesis, which causes congenital malformations. In particular, cell migration processes in the area of the fourth gill pocket and neural crest are disrupted. For this reason, in the case of velo-cardio-facial syndrome, it is those structures that develop from these embryonic rudiments that are affected. This is most strongly reflected in the face, cardiovascular, nervous and endocrine systems. Patients with velo-cardio-facial syndrome have numerous disorders in the above-mentioned organ systems that require long-term and sometimes surgical treatment. Sometimes other structures that are not related to these embryonic rudiments are also affected – the kidneys, ureters and bladder, sex glands (cryptorchidism). Such manifestations are caused either by secondary processes, or by the fact that other genes besides TBX1 can be damaged during deletion.
Deletion of the long arm of the 22nd chromosome or mutations of the TBX1 gene often occur in the germ cells of parents, that is, they do not occur in the patient’s relatives. However, cases with an autosomal dominant inheritance mechanism have been described, for this reason, if one of the parents suffers from velo-cardio-facial syndrome, then the probability of having a child with this pathology is 50%. It has been noted that Di Giorgi and Sprintzen syndromes similar to this disease often do not occur spontaneously, but are inherited. And in this case, the mechanism of transmission of disorders is autosomal dominant.
Manifestations can be detected immediately at the birth of a child, but this does not always allow such a diagnosis to be made immediately. Firstly, this is due to the similarity of the manifestations of the disease with other similar syndromes (Di Giorgi, Sprintzen), and secondly, some of the symptoms begin to manifest with age and are not registered in infancy. One of the most obvious manifestations of velocardiofacial syndrome is the characteristic type of face – the retraction of the lower jaw back, the small size of the nose and mouth, the expansion of the bridge of the nose are revealed. Deformities of the cartilage of the nose and auricles may be observed. Cleft of the hard palate is present in all patients, but the severity of this disorder can be different – from sharply obvious to almost imperceptible, detected only with instrumental studies.
In addition, even in infancy, seizures may occur due to low levels of calcium in the blood due to hypofunction of the parathyroid glands. They need to be differentiated from convulsive seizures caused by central nervous system damage, which can also occur with velo-cardio-facial syndrome – however, they most often occur much later in life. Other neurological disorders may include mental retardation, mental illness. Speech disorders can have both a neurological nature and be caused by malformations of the palate and facial skeleton. Almost a quarter of patients have a shortage of body weight in the thoracic period, with age, almost all patients have a lag in physical development of one degree or another.
Signs of damage to the cardiovascular system are detected in almost two thirds of patients. Their nature and severity are different – anomalies of the location of arterial vessels (common arterial trunk, right-sided aorta, carotid artery dystopia), tetrad of Fallot, ventricular septal defect. The symptoms in this case depend on the nature and severity of the cardiovascular abnormality – cyanosis, shortness of breath, weakness, tachycardia may be detected. In particularly rare cases of velo-cardio-facial syndrome, dextrocardia may be observed – the right-sided location of the heart. In some cases, some cardiovascular abnormalities can progress over time, which requires regular monitoring by a cardiologist. Among other manifestations of velo-cardio-facial syndrome, signs of damage to the urinary system, reduced resistance of the body to infectious agents may be detected.
Diagnosis of velo-cardio-facial syndrome is based on the data of the patient’s current status, the study of the cardiovascular, endocrine and nervous systems, as well as genetic studies. At the same time, it may take several years of observation to confirm the diagnosis without the participation of a geneticist, since many of the symptoms are nonspecific, and some manifest themselves only when patients reach a certain age. When examining a newborn, a cleft palate of varying severity is revealed, sometimes it is accompanied by splitting of the upper lip. In patients with velo-cardio-facial syndrome, a characteristic appearance is also determined – a wide bridge of the nose, a protruding nose, a small mouth, short stature. Infants often have a shortage of body weight, and in the future – a lag in physical development from their peers. With palpation, muscle hypotension, inhibition of reflexes can be determined.
The study of the functions of the cardiovascular system with the help of EchoCG in almost 70% of cases reveals certain developmental anomalies that are associated with this disease. These may be defects of the interventricular septum, tetrad of Fallot, an unusual arrangement of arterial vessels. In rare cases, a condition such as destrocardium may be detected. Patients need regular follow-up by a cardiologist, as a number of disorders may occur or progress over time. With the development of seizures, it is necessary to conduct a blood test to determine the level of calcium and parathyroid hormone – both of these indicators can be significantly reduced. Changes in the functions of other endocrine glands, as a rule, are not determined.
An important aspect of the diagnosis and treatment of velocardiofacial syndrome is the observation of the psychophysical development of the child. In most cases, in early childhood, sick children lag significantly behind their peers, grow slower, start talking later, have difficulty assimilating new information. This can have both primary neurological causes and be caused by secondary circumstances – cleft of the hard palate (feeding of newborns and speech in older children is difficult), muscle hypotension, problems with the cardiovascular system (chronic oxygen starvation of tissues). However, with timely correction of disorders, the developmental delay in cycling cardiofacial syndrome decreases by school age.
The genetic diagnosis includes the identification of microdeletion sites on the long arm of chromosome 22 and the search for point mutations in the TBX1 gene. Since deletions are statistically more common, the genetic confirmation of the disease begins with their detection. For this purpose, various variants of multiplex polymerase chain reaction are most often used. In relation to the TBX1 gene, a direct sequence sequencing method is used to determine defective sites. Differential diagnosis of velo-cardio-facial syndrome is performed with other pathologies caused by microdeletions of the 22nd chromosome (Di Giorgi and Sprintzen syndromes) and the “cat’s cry” syndrome.
There is no specific treatment for velo-cardio-facial syndrome, only symptomatic treatment and correction of anomalies in the development of the palate, face, and cardiovascular system are possible. The most common palliative surgery for this disease is the correction of the cleft of the hard palate – it is often performed even in infancy, since this defect significantly complicates the nutrition of the child. Seizures caused by hypocalcemia are eliminated by the appointment of calcium preparations – in most cases, this allows you to completely stop this manifestation of the velocardiofacial syndrome. In some cases, surgical correction of heart and vascular abnormalities is necessary, which can be performed by cardiac surgeons at different ages, depending on the nature, severity and other circumstances.
An important aspect of the treatment of velocardiofacial syndrome is assistance in the psychophysical development of the child. With hypotension of muscles from an early age, physiotherapy and physical therapy are indicated to improve coordination of movements and activity of muscle tissues. A special problem is the development of the patient’s speech – it is impaired both due to neurological disorders and due to the presence of a cleft of the hard palate. Therefore, surgical removal of this defect and work with a speech therapist are necessary for further socialization of the child. In some cases, work with a psychologist, a correctional teacher and auxiliary training is required, some children may eventually attend regular schools and classes. In some patients with this syndrome, attention deficit hyperactivity disorder (ADHD) is detected, which requires the use of additional medicinal and psychotherapeutic measures.
The prognosis of the disease is often uncertain due to a wide range of symptoms – especially abnormalities in the development of the cardiovascular system. In severe forms of this pathology, malformations of the heart and blood vessels can lead to the death of the patient at an early age. However, in most cases, timely surgical correction and symptomatic treatment significantly increase both patient survival and quality of life. Since this pathology is complex, the help of many medical specialists is needed to control its course and eliminate violations. Regular visits to a cardiologist, work with a psychologist and a speech therapist, physical therapy are necessary – all this will significantly reduce the severity of the manifestations of velo-cardio-facial syndrome.