Sotos syndrome is a rare genetic disease that manifests itself in various disorders of skeletal formation, mental retardation, abnormal facial features and disproportionality of body development. Symptoms of Sotos syndrome are high growth, increased size of the skull, feet and hands, macroglossia, delayed psychomotor development with a sharp acceleration of growth during puberty. The diagnosis of Sotos syndrome is made on the basis of anthropometric data, the results of X-ray studies, magnetic resonance tomography, electroencephalography and molecular genetic analyses. There is no specific treatment for this condition, symptomatic therapy and psychological corrective measures are used.
Sotos syndrome (cerebral gigantism syndrome) is a rare genetic disease, most often the result of spontaneous mutations, leading to a violation of the development of the skeleton and the central nervous system. For the first time this pathology was described by the American pediatrician Juan Sotos in 1964, since then the disease has been named after him. Sotos syndrome is an extremely rare autosomal dominant disease, about 120 cases have been described throughout history, for this reason it is not possible to reliably establish its occurrence. The rarity of this condition caused its rather slow study – the molecular genetic mechanisms of pathology development were discovered only at the beginning of the XXI century. It was possible not only to identify the genes whose mutations lead to the development of Sotos syndrome, but also to establish the fact that usually such mutations are the result of spontaneous genetic defects. This disease affects boys more often, but the causes of sexual distribution are currently unknown.
Causes and classification
According to modern genetics, Sotos syndrome is a heterogeneous disease, since defects in various genes can lead to its development. On this basis, the classification of this pathology is built, at the moment two types of it are known, which are practically indistinguishable from each other in their clinical manifestations. Sotos syndrome of the first type is caused by mutations of the NSD1 gene, which is located on the 5th chromosome and encodes the sequence of one of the transcription factors. The cause of the disease can be both point mutations of the gene and chromosomal abnormalities (deletions) at the locus where NSD1 is located, which leads to a sharp inhibition of protein expression or even the absence of its isolation. At the same time, the mutation must be in a heterozygous state (there is a phenomenon of haplon–sufficiency) – according to some data, the presence of a defect in both alleles does not lead to Sotos syndrome, but is a lethal mutation.
Sotos syndrome of the second type is caused by damage to the NFIX gene, which is localized on the 19th chromosome. This type of pathology is considered a rarer variant of the disease. As in the previous case, it is inherited by an autosomal dominant mechanism or (much more often) occurs as a result of sporadic mutations. The product of the expression of the NFIX gene is also a transcription factor (nuclear transcription factor 1), which controls the activity of a number of other genes involved in the development of the central nervous system and other parts of the body. In addition to this disease, damage to the NFIX gene leads to a pathology such as Marshall-Smith syndrome. As mentioned above, it is not possible to differentiate the different types of Sotos syndrome according to the clinical course, only molecular genetic analysis is able to identify which gene was damaged.
The molecular basis of pathogenesis in various variants of Sotos syndrome is also very similar. The transcription factors expressed by the NSD1 and NFIX genes regulate the activity of a number of other genes, many of which are actively involved in embryogenesis, the development of various organs and systems. In the presence of a mutation in a heterozygous state, the activity of these factors becomes insufficient, which disrupts the work of controlled genes and leads to the emergence of Sotos syndrome. It was found out that the form of the disease of the first type is also accompanied by a violation of the activity of androgen receptors, and of the second type – estrogen.
Many manifestations of Sotos syndrome can be detected already at the birth of a child, which makes it possible to suspect the presence of this genetic disease. As a rule, the physical indicators of newborns (body length, head circumference, weight) are slightly higher than average values. Almost always with Sotos syndrome, anomalies of the development of the face and head are revealed – hypertelorism, antimongoloid incision of the eyes, macrodolichocephaly, the presence of brow bumps, prognathism. A constant sign of the disease is macroglossia, which can significantly complicate the process of feeding a child. Also, newborns with Sotos syndrome may have a high arched palate, in extremely rare cases, its cleavage occurs, signs of congenital heart defects are possible.
The growth of children with Sotos syndrome is sharply accelerated – physical indicators increase especially intensively in the period of 3-4 years, while the motor and psychological development of patients lags behind the age norm. Children with this pathology later than their peers begin to lift their heads, walk, the development of speech and motor skills is quite delayed. As a rule, during puberty, the growth of the body is sharply accelerated again, but this acceleration is short-lived, so patients with Sotos syndrome eventually have physical indicators on the verge of the upper limit of the norm. Quite often, with this disease, there is an increase in the relative size of the hands and feet (acromegaly), syndactyly is sometimes determined on the legs.
Adult patients with Sotos syndrome are characterized by high growth, slight disproportion of the body, increased size of the head and lower jaw. They can also be diagnosed with curvature of the spinal column, flat feet, curvature of the legs, but these manifestations are quite rare. Mental development in Sotos syndrome is significantly reduced, people with this disease begin to speak late, in the future they remain closed, taciturn. The emotional sphere of such patients is quite unstable, in some cases they are overly excitable, quickly change their mood, sometimes they may show signs of aggression, including unmotivated.
Diagnosis and treatment
Due to the significant range of disorders and anomalies in Sotos syndrome, a large number of various diagnostic techniques are used to determine this disease. These include general examination of patients, radiography of skeletal bones, magnetic resonance imaging of the brain, electroencephalography, molecular genetic analyses. Neurological and psychological studies are used to assess the neuropsychiatric development of children and adults with this pathology. In addition, tests to determine the level of pituitary hormones in the blood, cardiological studies, abdominal ultrasound can play an auxiliary role in the diagnosis of Sotos syndrome. During the examination, violations characteristic of this disease are revealed – disproportionality of addition, excess of age norms of physical indicators, changes in the face.
The radiographs determine the advance of bone age relative to the actual one, the curvature of the vertebral column and deformities of some other bones may also be detected. Magnetic resonance imaging with Sotos syndrome in some cases confirms the underdevelopment of the corpus callosum, sometimes pronounced anatomical changes in the brain are not detected. At the same time, electroencephalography always indicates a decrease in the background activity of the nervous system, there are EEG signs of a violation of the relationship between the cortex and subcortical structures. Molecular genetic diagnosis of Sotos syndrome is carried out by a geneticist and is reduced to the detection of mutations in NSD1 or NFIX genes by direct automatic sequencing. Sometimes, to determine this disease, a search for deletions on the 5th chromosome is performed using FISH technology.
To exclude other pathologies accompanied by an increase in physical indicators or mental retardation, tests are prescribed to determine the level of pituitary or adrenal hormones – with Sotos syndrome, these indicators remain within the normal range. Electrocardiogram and ultrasound examinations can reveal abnormalities in the development of the heart and other internal organs, which often occurs with this disease. There is no specific treatment for Sotos syndrome, symptomatic therapy is used. Correction of heart defects, anomalies of internal organs is carried out. The curvature of the spinal column and deformities of the bones can be corrected by traditional orthopedic techniques. In some cases, neuropsychological correction and (due to mental retardation) specialized training of patients with Sotos syndrome are required.
Prognosis and prevention
As a rule, the prognosis of Sotos syndrome is relatively favorable, since, despite mental retardation and changes in the skeleton, nothing threatens the lives of patients. With timely adequate psychotherapeutic assistance and specialized training, persons with this disease can serve themselves. The prognosis of Sotos syndrome may be worsened by the presence of concomitant disorders on the part of internal organs – mainly congenital heart defects. According to some reports, there is also an increased risk of developing some oncological diseases with this pathology. In extremely rare cases, patients with Sotos syndrome are aggressive, which requires their short-term isolation in specialized institutions and the appointment of sedatives. Prevention of this disease due to the spontaneity of its development has not been developed at the moment.