Williams syndrome is a genetic disease characterized by various malformations of the face, cardiovascular system, musculoskeletal system and central nervous system. Symptoms of this condition are a characteristic appearance (“elf face”), muscular hypotension, rather pronounced mental retardation, increased frequency of heart defects and umbilical hernias. Diagnosis of Williams syndrome is carried out on the basis of the data of the patient’s current status and molecular genetic analyses, other studies (ECG, EchoCG) play an auxiliary role. There is no specific treatment for the disease, symptomatic therapy is used, sometimes surgical intervention is performed to eliminate heart defects.
Williams syndrome (Williams-Boyren syndrome, “elf face” syndrome) is a genetic disease caused by the absence of several genes at once, the number of which can range from 25 to 29. This fact is associated with a fairly wide range of clinical manifestations of the condition and differences in their severity. For the first time, this syndrome was described in 1961 by a cardiologist from New Zealand, J. Williams – he identified a number of phenotypically similar children with similar congenital disorders of the cardiovascular system. At the moment, the methods of modern genetics have been able to prove the hereditary nature of Williams syndrome. This disease is more often the result of spontaneous mutation, but can be transmitted by an autosomal dominant mechanism. Its occurrence is quite high relative to other genetic pathologies and is approximately 1 case per 20,000 newborns. The sexual distribution among patients with Williams syndrome has no peculiarities – boys and girls are affected with the same frequency. Despite severe mental retardation, psychological correctional work with such patients can significantly improve their socialization and improve the quality of life.
The cause of Williams syndrome is a chromosomal aberration (chromosomal mutation) – the deletion of the section 7 of the chromosome in the area of its long arm. The length of the remote site is approximately 1.6-1.8 million pairs of nucleotide bases, according to various data, from 25 to 29 genes are located on the site. In fact, deletion of a section of a chromosome is equivalent to simultaneous nonsense mutations of many genes. The greatest role in the development of pathological manifestations in Williams syndrome is played by the absence of genes ELN (elastin protein gene), GTF2I (general transcription factor 2), NCF1 (cytosolic neutrophil factor 1), LIMK1 (the protein encoded by it participates in the formation of the cytoskeleton of neurons), CGRP (calcitonin gene). Such genes as GTF1IRD1, GTF2IRD2, GTF2I, BAZ1B, TFII-1 and a number of others are also located on this section of chromosome 7 – their absence is the cause of carbohydrate metabolism disorders and hypercalcemia in patients with Williams syndrome.
In the vast majority of cases, chromosome damage occurs during meiosis during the formation of germ cells, so Williams syndrome can be considered as a result of spontaneous germinative mutation. Several cases of autosomal dominant inheritance of this pathology have been described. The absence of the ELN gene in one of the chromosomes leads to insufficient formation of elastin, mainly part of the walls of large vessels and heart valves, which is why heart defects and hypertension are quite common in patients with Williams syndrome. According to some data, high blood pressure can also be caused by excessive production of angiotensin 2. Neurological disorders are caused by the combined effect of the absence of LIMK1, GTF2IRD2 and a number of other genes, which leads to pathological changes in neurons and their malnutrition.
The absence of the calcitonin CGRP gene causes the development of hypercalcemia, however, according to modern genetics, in a number of patients with Williams syndrome, its preservation is detected with an increase in the level of calcium in the blood. It is possible that hypercalcemia in this disease is due to other causes or is of a secondary nature. The combination of the above factors – defects of the cardiovascular system, arterial hypertension and hypercalcemia – leads to significant disorders in patients with Williams syndrome. Such disorders include calcification of the walls of blood vessels and heart valves, which over time can cause cardiovascular failure and death of the patient. Other disorders of the nervous system and metabolism further aggravate the course of the disease.
Manifestations of Williams syndrome may sometimes not be determined at the birth of a child – during this period, the presence of the disease can be suspected only by reduced body weight, congenital hip subluxation (not observed in all patients), heart defects. All these factors are quite nonspecific, so most often pathology is detected at an older age. One of the most noticeable symptoms of Williams syndrome is the characteristic appearance of the patients’ face (“elf face”) – a flat bridge of the nose with a rounded nose, an enlarged mouth with upturned corners, plump lips, full cheeks, a small pointed chin. Of the other changes in the face and head area, low-set ears, a protruding nape, and epicanthus are often noted. Patients with Williams syndrome are characterized by a blue eye color with a pronounced pattern on the iris, a bluish tint of the sclera, swelling of the upper and lower eyelids, often strabismus.
Of the pathological changes in Williams syndrome, various heart defects are most often registered, which in some cases can lead to an early fatal outcome. Basically, these violations are reduced to the insufficiency of various valves. Also, patients with Williams syndrome have umbilical and inguinal hernias more often than healthy children. This disease is characterized by generalized muscular hypotension, which causes secondary disorders of the formation of the skeleton – X-shaped legs, scoliosis and other curvatures of the vertebral column, flat feet, deformities of the chest. When examined by a dentist, patients with Williams syndrome reveal long, but rarely located teeth, which are quite often affected by caries and easily destroyed.
Children suffering from Williams syndrome are significantly behind their peers, both in intellectual and physical development. They have a reduced body weight at birth, slowly gain it in the future, their growth stops much earlier, so the manifestation of this disease is also stunting. Body weight after adolescence may increase, there is a risk of developing obesity. Intellectually, patients with Williams syndrome retain signs of imbecility for life (moderate mental retardation, average IQ of 40-80). At the same time, they are quite easy to contact, they usually have a well-developed oral speech, with proper correctional work they are able to perform the simplest household tasks. In some cases, Williams syndrome may experience emotional instability, anxiety, enuresis.
Diagnosis and treatment
The diagnosis of Williams syndrome is made on the basis of the patient’s current status, the results of biochemical blood analysis, cardiological and molecular genetic studies. Upon examination, a characteristic appearance (“elf face”), dental formation disorders and caries, muscle hypotension with concomitant changes in the musculoskeletal system, signs of mental inferiority and lag in physical development are found. The picture of biochemical blood analysis in Williams syndrome is quite diverse, hypercalcemia, an increase in the level of thyroid-stimulating hormone, a slight decrease in the level of neutrophils are almost always determined with this disease. As a rule, the study of the hereditary history of the patient does not make sense, except in cases of the presence of Williams syndrome in one of the parents.
Cardiological studies (EchoCG) can detect congenital heart defects, most often – insufficiency of the aortic or mitral valves, supravalvular stenosis of the aorta and pulmonary trunk. In older patients with Williams syndrome, thickening of the walls of the aorta and other major vessels, pronounced arterial hypertension can be determined. When examined, indirect signs of the disease can serve as umbilical and inguinal hernias, converging strabismus, a hoarse low voice. The most reliable diagnostic method for Williams syndrome is a molecular genetic analysis performed by a geneticist. To detect the absence of a section of chromosome 7, the technique of DNA microchip or fluorescent hybridization (FISH technique) is used, prenatal diagnosis is possible.
There is no specific treatment for Williams syndrome, palliative measures and methods of psychological correction are used. Sometimes surgical intervention is required at an early age to correct congenital heart defects, which in severe cases can lead to death. To reduce the severity of hypertension, traditional drugs are used, mainly from the ACE inhibitor group. Psychocorrective work with Williams syndrome allows patients to master speech, in some cases – reading and writing, reduces the likelihood of developing anxiety and obsessive-compulsive disorder. An important role in reducing the severity of mental retardation is played by a friendly emotional background in the family.
Prognosis and prevention
The prognosis of survival in patients with Williams syndrome is relatively favorable – the greatest threat at an early age is congenital heart defects, but with their mild severity or timely elimination, patients can live to an advanced age. Life expectancy is usually somewhat lower than in healthy people, which is due to a persistent increase in blood pressure, disorders of calcium and carbohydrate metabolism. Although partial social adaptation is possible with Williams syndrome, most patients need careful care and monitoring by relatives. The possibility of any kind of work activity in the presence of this disease is completely excluded. There is no prevention of Williams syndrome, since this disease is usually the result of a spontaneous mutation – only a prenatal definition of this pathology is possible.