Cowden disease is a genetic disease, the main manifestation of which is the formation of benign tumors of internal organs, and the incidence of malignant neoplasms is also increased. Multiple hamartomas and cysts are formed in the gastrointestinal tract, mammary gland, organs of the reproductive system. Diagnosis is partly based on the study of the patient’s current status, but the most accurate result is provided by genetic analysis. There is no specific treatment at the moment, only symptomatic therapy is used, including surgical operations to remove benign neoplasms.
Cowden disease (multiple hamartoma syndrome) is a rare hereditary pathology in which the processes of inhibition of pathological tissue growth are disrupted, and because of this, benign tumors arise and there is a risk of developing malignant neoplasms. The syndrome was first described in 1963 by American doctors M. Kennes, L. and M. Dennis, the name contains the surname of the first described patient with this disease. Cowden disease occurs with a frequency of 1:1,000,000 people, with an equal degree of probability affects both men and women. At the same time, in female individuals, the disease is observed in a milder form. A gene whose defect leads to the development of Cowden disease (PTEN) may have other mutations leading to diseases such as Banayan-Riley-Rouvalcaba syndrome, as well as Lermitt-Duclos disease. Therefore, geneticists often combine them into one group – PTEN-associated syndromes of hamartomic tumors.
The main cause of Cowden disease is mutations in the PTEN gene located on the 10th chromosome, it encodes a unique protein-phosphatase. This protein is able to act on proteins and lipids containing phosphates in the inositol ring, splitting off the phosphate group. Many of the substances that are the substrate for PTEN phosphatase are secondary intermediaries in the transmission of information in the cell. This pathway (called PI3K/AKT/mTOR by its main components), among other things, allows the cell to avoid apoptosis even with direct exposure to the corresponding receptors on the membrane. This process is implemented in many types of malignant and benign tumors. The PTEN gene blocks this pathway, thereby showing the activity of a key anti-oncogene, but in the presence of defects in it, various pathologies develop, including Cowden disease.
The transmission of mutations leading to Cowden disease is carried out by an autosomal dominant mechanism, quite often gene disorders are of a germinal nature – they occur in the germ cells of parents during their formation. Due to impaired inhibition of the PI3K/AKT/mTOR pathway, the protective antitumor mechanisms of the body become weakened, resulting in an increased likelihood of the development of numerous neoplasms. In addition, this pathway plays an important role in the functioning of the heart and central nervous system, therefore, intellectual development disorders are often observed in Cowden disease. In addition to the classic picture of the syndrome, there are Cowden-like disorders caused by mutations of other genes. Methods of modern genetics have identified only some of them (for example, SDHD and SDHB), which, as well as the PTEN gene, exhibit anti-oncogenic activity.
The symptoms of the disease can manifest at any age – both in early childhood and in old age. In addition, the very clinical picture of Cowden disease is quite variable and does not always begin with the formation of hamartomas or other types of benign tumors. For example, a pediatrician can diagnose a child with mental retardation, and specific manifestations of a genetic disease can occur only in adulthood. The first symptoms of Cowden disease can also be myopia, disorders of the formation of the maxillofacial region, dental pathology, frequent inflammatory diseases of the upper respiratory tract (sinusitis). All this makes the diagnosis of the disease quite difficult due to the large variability of the first manifestations and the time of their manifestation.
The symptom complex of Cowden disease with the full development of the disease includes lesions of the thyroid gland, the formation of hamartomas in the gastrointestinal tract. The patient’s skin is thin, there is often dryness of the mucous membranes and the formation of leukoplakia on them. In women with Cowden disease, fibrocystic mastopathy is detected at a young age, sometimes cystic hyperplasia, underdevelopment of the milky passages is possible. Hypoplasia of the uterus and instability of the menstrual cycle are often observed, which is reduced to periodic amenorrhea of varying duration. On the part of the central nervous system, in addition to intellectual development delay, there is often a violation of coordination of movements, ataxia. In Cowden disease, speech disorders (dyslalia) are not uncommon, the causes of which, however, are most often caused by defects in the formation of teeth, tongue, and soft palate.
In the oral cavity, in addition to the violation of the formation of teeth, papillomatous formations on the mucous membranes often occur. Premature tooth loss is characteristic, the tongue is enlarged, red in color with a non-uniform surface. In severe cases of Cowden disease, the formation of cysts and tumors in the liver, kidneys, and elements of the musculoskeletal system is possible. The chest is often hollow, asymmetrical, sometimes there is a curvature of the spine. The formation of the external genitalia in Cowden disease occurs without violations, in some cases there is a preservation of the reproductive function. Among the complications of the disease, the greatest threat is malignant neoplasms that occur in various organs primarily or as a result of malignancy of hamart and cysts.
Diagnosis and treatment
It is not always possible to identify Cowden disease when studying the present status of the patient due to the significant variability of its manifestations, which, moreover, can begin to develop at any age. Also, the study of hereditary anamnesis will not always help, since in some cases mutations of the PTEN gene are germinal in nature and are absent from the parents and relatives of the patient. In the presence of multiple gastrointestinal hamartomas, dental formation disorders, fibrocystic mastopathy and other manifestations of Cowden disease, it is necessary to make a genetic diagnosis of the disease. Only sequencing of the PTEN gene sequence can reveal the presence of a mutation and guarantee the presence or absence of Cowden disease. Differential diagnosis is performed with other PTEN-associated syndromes, as well as Clowden-like diseases caused by mutations of other genes.
There is currently no specific treatment for Cowden disease, gene therapy methods that should allow to “replace” the affected PTEN gene are currently being studied in laboratory animals. Symptomatic treatment is carried out by medical specialists of various profiles – the dentist performs dental correction and, if necessary, prosthetics, the surgeon removes hamartomas and other tumor-like formations. When diagnosing Cowden disease at an early age, pediatricians and child psychologists can reduce the severity of mental development disorders. Gynecologists, together with surgeons, treat pathology of the mammary glands and internal female genital organs. Reasonable therapy and constant monitoring of the condition can significantly improve the quality of life of the patient, identify and treat complications in time.
Prognosis and prevention
The prognosis for Cowden disease is uncertain in most cases, since the severity and nature of the symptoms of pathology have significant variability. Intellectual development disorders are observed only in half of the patients, the rest retain a satisfactory level of mental activity. The main danger in Cowden disease is the probability of compression by hamartomas and other benign tumors of important nervous and vascular structures, as well as the risk of developing malignant neoplasms. Therefore, regular monitoring of the patient’s condition by an oncologist and a geneticist is necessary. These precautions will help to identify the complications that have arisen in a timely manner, their treatment at an early stage in most cases can significantly improve the prognosis of the patient’s survival.