Prader-Willi syndrome is a rare genetic disease characterized by gross constitutional disorders, cognitive and mental disorders. The clinical picture is diverse, the main symptoms include obesity, growth retardation and mental retardation. Often there is a decrease in muscle tone, reproductive dysfunction. The final diagnosis is established on the basis of a molecular genetic study. No specific treatment has been developed. Symptomatic therapy is carried out according to the main components of the syndrome: the appointment of a hypocaloric diet and hormonal drugs, individual classes with a defectologist, etc.
ICD 10
Q87.1 Syndromes of congenital anomalies, manifested mainly by dwarfism
General information
Prader-Willi syndrome (hypotension-obesity syndrome) is one of the most pronounced forms of genetically determined obesity. The disease was first described in 1956 by Swiss pediatricians A. Prader and H. Willie. Despite its genetic nature, the disease is sporadic. According to various statistics, the prevalence of the syndrome is 1:15,000 – 1:25,000 newborns. There are no significant gender differences.
Causes
Pathology develops as a result of mutation of chromosome 15 (segment q11.2-q13). There is no direct hereditary transmission of the disease. A chromosomal anomaly occurs at the time of fertilization of an egg, i.e. the exchange of parental genetic materials. In 65-75% of cases, the mutation is due to a defect in the paternal chromosome 15, and in 25-35% – inheritance of both 15 chromosomes from the mother. Risk factors provoking clinical manifestations of chromosomal mutation are unknown.
Pathogenesis
Pathological mechanisms remain poorly investigated. It is known that in this disease there is a pronounced imbalance between the processes of lipolysis and fat synthesis in subcutaneous fat with a shift towards the latter. It is assumed that endocrine dysregulation plays a leading role in obesity and growth retardation in children with Prader-Willi syndrome.
Dysfunction of the nuclei of the hypothalamus leads to a decrease in the production of many hormones, such as somatotropic hormone, gonadotropins, thyroid-stimulating hormone, etc. A drop in the concentration of growth hormone and sex hormones, especially in childhood, contributes to the accumulation of fat depots. It is characterized by an increase in the level of the peptide hormone ghrelin, which is an endogenous appetite stimulant.
In the genesis of neuropsychic disorders, the role of a low level of brain neurotrophic factor involved in the development and differentiation of cells of the central nervous system and their functional activity is considered. Hypopigmentation of the skin and hair is explained by the suppressed function of tyrosinase in hair follicles and melanocytes.
Symptoms
Clinical manifestations begin to manifest already in the period of intrauterine development. There is low fetal mobility, incorrect presentation, prematurity at birth. There is pronounced muscular hypotension. Sucking and swallowing reflexes are significantly weakened. This makes it difficult to feed the baby and leads to insufficient age-related weight gain. In some cases, it is necessary to power through the probe.
A little later, the most characteristic symptom joins – polyphagia (pathologically increased appetite), as a result of which the child begins to gain weight quite quickly, reaching obesity, up to morbid. Fat deposition mainly occurs in the trunk and proximal extremities.
Neuropsychic disorders are expressed. Speech is slowed down, intellectual abilities (memory, concentration, sequential processing of information) are significantly behind the age norm. In adolescence, obsessive-compulsive disorders, sudden mood swings, aggressive behavior are often observed. Due to insufficient saliva production, teeth are quickly affected by caries.
Hypogonadism in boys is manifested by hypoplasia of the scrotum, micropenis, cryptorchidism, in girls – underdevelopment of the labia, late onset of menstruation or their complete absence. Possible coordination disorders, muscle cramps, strabismus. Other constitutional changes include low height, acromicry (reduced size of hands and feet). Typical hypopigmentation of the skin, blonde hair.
Complications
The predominant number of complications of Prader-Willi syndrome is associated with morbid obesity. Excess fat mass contributes to the early development of insulin resistance, metabolic syndrome and type 2 diabetes mellitus. Non-alcoholic fatty liver disease (fatty hepatosis) is often found. A significant accumulation of fat in the neck causes a narrowing of the airway lumen.
As a result, more than half of patients (55-60%) have obstructive sleep apnea syndrome, which in turn dramatically increases the risk of hypertension, stroke, life-threatening arrhythmias. Obesity also causes alveolar hypoventilation and excessive stress on the right parts of the heart, resulting in right ventricular heart failure.
Due to the reduced bone mineral density, any injury can lead to fractures. Almost all patients suffer from primary infertility. There are frequent viral infections of the upper respiratory tract, bronchitis and pneumonia. There is evidence that PV syndrome increases the likelihood of developing leukemia and other oncological diseases.
Diagnostics
Patients suffering from Prader-Willi syndrome are supervised by pediatricians and geneticists. During a general examination, attention is paid to the weakening of muscle tone and tendon reflexes, constitutional changes – obesity, low growth. Additional examination includes the following studies:
- Blood test. Biochemical analysis often reveals an increase in the concentration of glucose and hepatic transaminases (ALT, AST). There is a decrease in the level of gonadotropins (FSH, LH), sex hormones (testosterone, estrogens), somatotropic hormone.
- Densitometry. When conducting double energy X–ray absorptiometry, signs of osteopenia or osteoporosis are determined – bone density indicators are lower than the average value of peak bone mass by more than 2.5 SD.
- Determination of the presence of OSA. Since obstructive apnea poses a threat to health and life, all patients with suspected Prader-Willi syndrome undergo cardiorespiratory monitoring and polysomnographic examination, which show a high index of respiratory disorders and desaturation index.
- Genetic research. Detection of microdeletion 15q11-13 by polymerase chain reaction, karyotyping or fluorescent hybridization is the main verification test that allows a reliable diagnosis.
Differential diagnosis is carried out with diseases that are accompanied by severe muscular hypotension and delayed neuropsychic development – Opitz-Frias syndrome, myopathies, spinal amyotrophy. In addition, PV syndrome differentiates with other hereditary forms of obesity (adiposogenital dystrophy, Lawrence-Moon syndrome).
Treatment
Conservative therapy
Patients are subject to hospitalization in the pediatric department. Effective methods of etiotropic therapy have not been developed, all therapeutic measures are symptomatic. To combat hypotension, massage sessions and physiotherapeutic methods of exposure are prescribed. Classes with a speech therapist, speech pathologist, and psychotherapist are recommended. Other treatments for Prader-Willi syndrome:
- Diet. The main focus is on changes in nutrition. It is necessary to limit foods with a high content of saturated fats and easily digestible carbohydrates. The total daily calorie intake should be 1000-1200 kcal. Appetite suppressant medications are not used, as they have shown low efficacy in patients with PV syndrome.
- Hormone replacement therapy. Subcutaneous administration of recombinant somatotropic hormone is recommended even in early childhood even before the onset of obesity. Gonadotropin-releasing hormone (gozerelin) analogues are used to restore reproductive function.
- SIPAP therapy. For the treatment of obstructive apnea syndrome, the most successful method is the use of a special device for automatic intranasal ventilation of the lungs, which creates a constant positive pressure in the upper respiratory tract.
- Anti-osteoporotic treatment. With low bone density, vitamin D (cholecalciferol), calcium preparations, bisphosphonates (zoledronic acid) are prescribed to avoid pathological fractures.
Surgical treatment
In the presence of certain indications (elongated soft palate, hypertrophy of the tonsils), surgical correction is performed to eliminate OSA – uvulopalatopharyngoplasty, which consists in excision of a part of the soft palate, tonsillectomy, formation of sutures tightening the back wall of the pharynx. The probability of recurrence after surgery is about 50%.
If it is not possible to achieve a reduction in body weight by conservative methods, they resort to bariatric surgery – gastric banding, gastric bypass. The preservation of cryptorchidism by the end of the 1st year of life serves as an indication for the prompt elimination of pathology. Orchipexy is performed – the attachment of the testicle to the scrotum with sutures.
Experimental treatment
New drugs are being developed for the treatment of PV syndrome. There are encouraging results of clinical studies of the use of an oxytocin receptor agonist – carbetocin. It is proposed to influence the intestinal microbiota of sick children with probiotic drugs. In experimental work on laboratory animals, the substance UNC0642, activating genes on the required section of chromosome 15, demonstrated a therapeutic effect.
Prognosis and prevention
The life expectancy of patients suffering from PV syndrome, with timely diagnosis and adequate treatment, reaches 60-70 years. In the absence of preventive measures, death can occur at the age of 4-5 years from cardiopulmonary insufficiency. In 50% of cases, obstructive sleep apnea and cardiovascular catastrophes caused by it become the cause of death.
Less often, patients die from a severe respiratory infection. The only way to prevent the occurrence of the disease is prenatal diagnosis and termination of pregnancy. The main role is assigned to secondary prevention – prevention of complications of the disease, for example, vaccination against influenza and pneumococcal infection.