Lhermitte-Duclos disease is a genetic pathology that leads to the development of a slow–growing tumor of the cerebellum, which can appear at any age of the patient. The main manifestations of the disease, in addition to the symptoms of damage to the cerebellum, are also hydro- and megalocephaly, skeletal malformations and gum hyperplasia. Diagnosis is based on the study of the brain (CT, MRI), neurological symptoms, as well as genetic studies. There is no specific treatment for Lhermitte-Duclos disease, but timely surgical removal of the tumor can significantly prolong the patient’s life.
General information
Lhermitte-Duclos disease (hereditary dysplastic gangliocytoma of the cerebellum) is a rare genetic disease belonging to the group of PTEN-associated syndromes of hamartomic tumors. In addition to this pathology, Cowden disease and Banayan-Riley-Ruwalcaba syndrome belong to this class. For the first time, Lhermitte-Duclos disease was described in 1920, after which about 220 cases of the disease have been registered to date. Because of this, it is very difficult to reliably determine the occurrence, most researchers assume that it is about 1:1000000. An additional factor complicating the study of the frequency of pathology is the discovery in 1969 of an asymptomatic carrier of Lhermitte-Duclos disease. The disease affects both men and women with equal probability, in neurology it is considered almost the only cause of dysplastic gangliocytoma of the cerebellum – more than 90% of patients with this tumor have genetic mutations characteristic of the syndrome.
Causes
The direct cause of Lhermitte-Duclos disease is a mutation of the PTEN gene located on the 10th chromosome – it encodes the enzyme phosphatase, the substrate of which can be both proteins and lipids. The latter contain phosphates in the inositol ring, which are cleaved off by phosphatase. In this case, the so-called PI3K/AKT/mTOR is blocked-the pathway of information transmission in the cell, which allows, in some cases, to bypass the process of apoptosis. For this reason, PTEN acts as one of the key anti-oncogenes, and its mutations cause diseases characterized by the development of tumors and hamart in the body. One of the pathologies of this plan is the disease of Lhermitte-Duclos. Modern genetics knows several more syndromes associated with a violation of the structure of this gene, and all of them are accompanied by certain neoplasms, which confirms the anti-oncogenic role of PTEN. The mutation that causes the disease is inherited by an autosomal dominant mechanism, and germinal damage to the PTEN gene that occurs in germ cells during their formation is also possible. However, the pathogenesis of cerebellar tumor development in Lhermitte-Duclos disease remains unknown today.
Symptoms
Manifestations of the disease can occur at any age, the history describes cases of detection of symptoms of Lhermitte-Duclos disease both in early childhood and in elderly patients. However, neurologists most often identify the characteristic signs of cerebellar gangliocytoma in adolescence or in the third decade of the patient’s life. Indirect signs of pathology are congenital anomalies of development – hydrocephalus, megalocephaly, skeletal anomalies of the hands (poly- and syndactyly). Possible skeletal asymmetry of the face, the appearance of rashes on the tongue and gum hyperplasia. As the tumor develops, symptoms of increased intracranial pressure and impaired circulation of the cerebrospinal fluid are added – headaches that worsen in the morning, nausea and vomiting, fainting.
In the absence of treatment, the above manifestations of Lhermitte-Duclos disease are joined by symptoms of damage to the cerebellum and cranial nerves – cerebellar ataxia and paralysis. Speech disorders (dysarthria), hearing disorders are often observed, nystagmus occurs, memory loss and disorientation. Patients subsequently fall into a comatose state and, without regaining consciousness, die. At the same time, an asymptomatic course of Lhermitte-Duclos disease is also possible, which can manifest itself only with minor congenital malformations. Dysplastic gangliocytoma of the cerebellum in such patients is detected accidentally on MRI and CT scans performed for another reason or at autopsy. Some researchers believe that in this case we are not talking about an asymptomatic, but a slowly progressing form of Lhermitte-Duclos disease, and it will still lead to a characteristic clinical picture in the future.
Diagnosis and treatment
Diagnosis of Lhermitte-Duclos disease is performed by identifying characteristic formations in the cerebellum using computer and magnetic resonance imaging. A CT scan of the brain reveals a voluminous hyperdensive formation with blurred and fuzzy edges, which can be located both on the surface and in the depth of the cerebellum. MRI of the brain is best performed with intravenous contrast, since it is this method that will best study the structure and vascular network of the neoplasm. In the absence of the technical possibility of conducting these studies, X–ray ventriculography can be done – as a rule, it shows a decrease or displacement of the fourth ventricle and the aqueduct. However, with an insignificant gangliocytoma size, such changes may not occur, therefore ventriculography is not considered the main method of diagnosing Lhermitte-Duclos disease.
In addition, if possible (for example, if the tumor is located on the surface relative to the cerebellum), a biopsy of the formation is performed with subsequent histological examination. Similar studies in recent years have revealed that gangliocytoma of the cerebellum in Lhermitte-Duclos disease is a hamartoma. In its structure, there is an expansion of the molecular layer and its filling with ganglion cells. Geneticists also perform sequencing of the PTEN gene sequence, which reveals the presence or absence of mutations in it. A study of the hereditary history can also help in the diagnosis of Lhermitte-Duclos disease – at the same time, it is worth paying attention to indirect signs of the disease, given the possibility of an asymptomatic course. These include the presence of poly- and syndactyly, megalocephaly, and gum hyperplasia in the closest relatives.
There is no specific treatment for Lhermitte-Duclos disease today, but patients often undergo palliative surgery to remove cerebellar gangliocytoma. This is a technically difficult operation, since there is no clear boundary and transition layer between normal tissues and hamartoma. In addition, in some cases, the tumor may be located deep in the cerebellum, which makes it inaccessible for complete removal. However, even partial resection of a gangliocytoma can significantly alleviate the patient’s condition and prolong his life for several years. Other methods of tumor control (for example, radiation therapy) for Lhermitte-Duclos disease are most often ineffective.
Prognosis and prevention
The prognosis for Lhermitte-Duclos disease is often uncertain, as it depends on a number of circumstances – the severity of concomitant malformations, the rate of progression of gangliocytoma, its location in the cerebellum. All these factors are very variable, which leads to such differences in the clinical picture and duration of the disease – from an asymptomatic course to a fatal outcome in childhood. Complete removal of the cerebellar tumor in Lhermitte-Duclos disease, especially if the operation was performed at the age of 30-40, often has favorable prospects – the new formation simply does not have time to develop again until the end of life. In cases where a full-fledged operation is technically impossible, partial resection can prolong the patient’s life.