Noonan syndrome is a genetic pathology characterized by the development in patients of a symptom complex similar to Shereshevsky–Turner disease, but it occurs in persons of both sexes and is not accompanied by a change in the number of chromosomes. Symptoms of this pathology are small stature, hypertelorism, pterygoid folds on the neck, malformations of the genitourinary and cardiovascular systems, infertility in men. Diagnosis is based on the data of the patient’s current status, the study of his hereditary history, molecular genetic and cytological studies. There is no specific treatment of pathology, symptomatic and supportive therapy is used.
General information
Noonan syndrome (turner syndrome with a normal karyotype) is a hereditary disease that is accompanied by the development in patients of both sexes of the clinical picture of the Shereshevsky–Turner syndrome while maintaining a normal karyotype. This disease was first described in 1962 by pediatric cardiologist Jacqueline Noonan, who drew attention to the combination of heart defects with stunting, the presence of pterygoid folds on the neck and other disorders. Currently, the genetic nature of Noonan syndrome has been clarified – this is a disease with an autosomal dominant type of inheritance, but mostly transmission is through the maternal line. A significant part of cases of pathology is caused by spontaneous mutations. The cause of maternal transmission is the presence in men of pronounced abnormalities of the development of the genitourinary system up to infertility. The prevalence of Noonan syndrome according to various data ranges from 1:1000 to 1:16 000 newborns. This disease is on average more common in girls and occurs in them somewhat easier than in boys. Genetic defects in Noonan syndrome are found in about half of patients, so geneticists continue to study this disease in order to more accurately determine its causes.
Causes
According to modern genetics, Noonan syndrome is caused by mutations of the PTPN11 gene located on chromosome 12. It encodes the sequence of one of the regulatory proteins of the cellular response to a variety of external influences. Other defects of this gene cause the development of diseases such as juvenile myelomonocytic leukemia, metachondromatosis and some hereditary malformations of the cardiovascular system. Currently, several dozen mutations of the PTPN11 gene have been described, mainly defects are located on exons 3, 7 and 13. Protein domains are encoded at these sites, the structure of which determines the transition of the signal protein to the active state. A change in the amino acid sequence dramatically reduces the activity and disrupts the work of this compound, which leads to the development of Noonan syndrome.
Defects in the PTPN11 gene are responsible for only half of the cases of Noonan syndrome, in other cases, the etiology of the disease remains unknown. Mutations are inherited by an autosomal dominant mechanism, but most new cases of the disease are caused by spontaneous germinative genetic defects. Family variants of Noonan syndrome are usually characterized by transmission through the maternal line, since in sick women, unlike men, fertility and the ability to conceive a child are preserved. Violation of the cellular response to various influences leads to the formation of defects of the cardiovascular, urinary and partly musculoskeletal system. Intellectual development in Noonan syndrome suffers to varying degrees – from severe mental retardation to slightly reduced or normal intelligence.
Symptoms
The clinical picture of Noonan syndrome is characterized by significant similarity with the Shereshevsky-Turner syndrome – low height (the highest limit is about 150-160 centimeters), the presence of pterygoid folds on the neck, deformity of the elbow joints. In patients, characteristic facial features are revealed – a wide bridge of the nose with hypertelorism, ptosis (lowering of the corners of the mouth downwards), an anti-mongoloid incision of the eyes, a low location of the auricles, often accompanied by their deformation. The face is often asymmetrical. The neck of patients with Noonan syndrome is short, the chest is sunken, the fingers on the hands are shortened. Disorders of the lymphatic system are also observed – lymphatic edema of the lower extremities and (less often) of the hands are possible.
On the part of internal organs with Noonan syndrome, various heart defects are most often found – this may be pulmonary trunk stenosis, ventricular septal defect and other disorders. Pathologies of the urinary system are not uncommon. Such patients often have hydronephrosis, hypoplasia of the kidneys or even agenesis of one of them, at an older age all this can lead to chronic renal failure. Sexual development in Noonan syndrome is particularly affected in male patients – they often develop testicular hypoplasia, cryptorchidism, oligo- or azoospermia, in 90% of cases such patients remain infertile. In girls with this disease, the underdevelopment of the reproductive system is less pronounced, mainly hypoplasia of the external genitalia and the later onset of menstruation are observed, but fertility can be preserved.
Mental development in Noonan syndrome is usually somewhat reduced compared to healthy peers, sometimes various degrees of mental retardation are detected. Among other disorders in this disease, increased bleeding, easier development of hypertrophic and keloid scars are noted. In some cases, there is a decrease in the level of immunity and flat feet. As a rule, patients with Noonan syndrome retain a level of mental and physical development that allows them to perform certain work – in other words, disability of such patients does not always occur.
Diagnostics
To identify Noonan syndrome, a general examination method is used, a study of the patient’s hereditary history, cardiological studies, genetic and cytogenetic analyses. An auxiliary role in the diagnosis of this disease is played by tests for the level of sex and other hormones, the study of the functioning of the urinary and reproductive systems of patients. When examining girls with Noonan syndrome, changes are determined that often lead to the diagnosis of Shereshevsky-Turner syndrome – low height, pterygoid folds, a characteristic type of face. However, the assumption of the presence of this disease is refuted by the results of studying the karyotype of patients – they have a normal number of chromosomes (46 XX in girls and 46 XY in boys). Thus, cytogenetic analysis is the main method of differential diagnosis of Noonan and Shereshevsky-Turner syndromes.
When conducting cardiological studies (electrocardiography, echocardiography, and others) with Noonan syndrome, a variety of congenital heart defects are detected in 80% of cases – pulmonary trunk stenosis, ventricular septal defect, open Botall duct. Hypertrophy of various parts of the myocardium may be registered in older patients. Quite often, patients with Noonan syndrome, during ultrasound examination, abnormalities of kidney development are determined – from hydronephrosis and hypoplasia to the complete absence (agenesis) of one of them. Male patients often have cryptorchidism, which should be differentiated with complete testicular agenesis, which can also occur in this condition. The spermogram detects azoospermia or a decrease in the number of active spermatozoa. When performing ultrasound in girls with Noonan syndrome, reduced dimensions of the uterus and ovaries are revealed, but severe malformations of the internal genitalia are often absent.
Blood test for various hormones in boys with Noonan syndrome usually confirms a decrease in testosterone levels of varying degrees – from the lower limit of the norm to a pronounced deficiency. At the same time, the level of pituitary gonadotropin increases quite significantly in patients of both sexes. The concentration of growth hormone, despite the shortness of patients with Noonan syndrome, is within the normal range or even slightly increased. Molecular genetic analysis in this disease is reduced to sequencing the PTPN11 gene in order to identify mutations. The absence of mutations is not a full–fledged criterion for excluding Noonan syndrome – according to recent data, PTPN11 defects occur in only half of such patients. Currently, the main reason for the diagnosis is the presence of a characteristic clinical picture against the background of a normal karyotype of patients.
Treatment
There is no specific treatment for Noonan syndrome today, a variety of symptomatic measures are used, including surgical ones. Most often, the help of surgeons is required at an early age to correct congenital heart defects characteristic of this disease. In boys, long-term cryptorchidism can be determined, therefore, to reduce the risk of malignant degeneration of testicular tissues, this defect is corrected operationally. In addition, with Noonan syndrome, surgical intervention may be required in the case of pronounced disorders of the formation of the urinary system or pronounced lymphostasis of the lower extremities. When performing operations, it is necessary to take into account the increased propensity of such patients to develop bleeding.
Conservative treatment in boys with Noonan syndrome usually includes androgen replacement therapy – this reduces the manifestations of hypogonadism. With impaired functions of the urinary system and the development of chronic renal failure, regular hemodialysis is indicated. In severe cases, the question of kidney transplantation is raised, but with Noonan syndrome, the need for this occurs quite rarely. If a patient with this syndrome is carrying a child, careful patronage control over the course of pregnancy and supportive treatment with vitamin and mineral complexes is required.
Prognosis and prevention
The prognosis of Noonan syndrome regarding the patient’s life is quite favorable, especially with correctly and timely symptomatic measures – correction of heart defects, cryptorchidism and other disorders. Patients should undergo regular examination by specialists of various profiles, mainly by a cardiologist, urologist or andrologist. This makes it possible to identify possible complications of Noonan syndrome at an early stage and begin their timely therapy. There are no other methods of preventing this condition at the moment, with the exception of prenatal diagnosis. It should be borne in mind that in the presence of a disease in the expectant mother, the probability of developing Noonan syndrome in a child (with a genetically healthy father) is 50%.