May 17 - World Neurofibromatosis Day

Neurofibromatoses are a group of genetic diseases characterized by the presence of multiple tumors originating from the nerve sheaths of the body. There may be 5 or. 500, they can appear anywhere on the body and inside the body. Anywhere a nerve runs, regardless of its size.

The catalog of potential symptoms is rich. These range from cutaneous macules and subcutaneous nodules to even large tumors found inside the body. These larger ones, as well as those of monstrous size, are called plexiform neurofibromas, and can compress internal organs, large vessels or other important body structures, causing their dysfunction. As they grow from the peripheral nerve sheath, they also compress the nerve's medulla responsible for conducting impulses, causing not only pain, but also unremitting pruritus and sensory disturbances or paresis. Many patients have bone dysplasias. Optic nerve gliomas damage the organ of sight, and brain tumors often require surgery and follow-up therapy in the form of chemotherapy. Children may also have learning problems with associated attention deficit disorder, hyperreflexia and speech development disorders.

There is a high risk of inheriting the disease, passed on to the child by the affected parent. However, almost half of the cases are caused by spontaneous mutations in the Nf1 gene, meaning that there is no gene mutation in the parents, and their extended family is not burdened with NF-1. To date, it is impossible to predict how neurofibromatosis will progress in a given patient. There are adults who find out that they are burdened with neurofibromatosis when they are diagnosed with it in their own child. Then there are those who have suffered pain and suffering and social ostracism due to their appearance since early childhood.

- The peer group rejects such a child. Parents say, "Don't play with him or you'll still get sick." It's cruel and sad at the same time that such a hurtful attitude persists for years. And this also translates into the child functioning less well in society, which exacerbates later educational problems. He feels ashamed, he feels inferior. There is a reluctance to go to school. When the tumors begin to grow, the problems get worse. They not only deform the body, but also cause severe pain. Some of them can become malignant. The patients and their relatives are constantly accompanied by a high sense of anxiety and depressive states. In addition to the ostracization they feel, the fear of it quickly sets in. Patients know that if a tumor appears that significantly deforms the body, their lives and social functioning will be radically affected. Knowing that one is terminally ill, that symptoms may appear that will require complicated treatment or mutilating surgery, and that for the rest of one's life the patient will live in fear of developing another cancer, the so-called "oncological vigilance," is very detrimental to one's well-being. It is also unknown when and if such dramatic disease symptoms will develop at all. Some people have no other symptoms or organ dysfunctions besides an altered body appearance. That's why we treat this disorder as a ticking bomb with a delayed ignition. Unpredictability is the middle name of neurofibromatosis," admits Dorota Korycinska of the Neurofibromatosis Poland Association.

The natural course of the disease is characterized by uncontrolled and progressive growth of skin tumors and areas of multiple organs, which begins in childhood and continues throughout life.

- When parents hear the diagnosis of neurofibromatosis, they are in disbelief, they break down, anger arises. The reactions are very different. This is a disease that the patient will live with for the rest of his life, and as its complications develop, there may be different problems, different symptoms that will manifest themselves in different ways. These patients, like any other patient, should receive very good care," explains Prof. Mariusz Wysocki, a pediatrician, oncologist and pediatric hematologist who was the first doctor in Poland to take care of patients with neurofibromatosis.

The characteristic "cafe au lait" spots do not make it easy to make a definite diagnosis; they can occur in many healthy people, and can also characterize one of more than 80 other "macular diseases." Diagnosis can take years.

- Diagnostic problems arise from the fact that symptoms in the form of milk stains also occur in other diseases, in addition to the fact that 40-60 percent of the general population has single stains and they pose no problem. At least three spots the color of coffee with milk and accompanying other symptoms can be worrisome , and already especially psychomotor developmental disorders, or neurological disorders, but also hematological or any other medical specialty, says Dr. Marek Karwacki, MD, from the Department of Oncology, Pediatric Hematology, Clinical Transplantation and Pediatrics at the Medical University of Warsaw.

In addition to the most common NF-1, the group of neurofibroamptoses includes other diseases, especially neurofibromatosis type 2, with a completely different and distinct course.

- We can estimate that in Poland NF1 has a frequency of 1: 2,500, so on average we have about 12 thousand people with the disease. Far fewer patients suffer from neurofibromatosis type 2. Together we can estimate that several thousand people in Poland suffer from neurofibromatosis," explains Agnieszka Jatczak-Gaca, MD, from the Department of Pediatrics, Hematology and Oncology at the A. Jurasz University Hospital No. 1 in Bydgoszcz.

One of the most severe manifestations of NF-1 is plexiform neurofibroma, which is associated with a significant burden on the health and sometimes the lives of patients. Plexiform neurofibromas are benign tumors of peripheral nerve sheaths, occurring in about 30 percent of NF-1 patients, which can occur anywhere in the body, causing significant discomfort, often due to their size and invasiveness.

NF-1 affects every aspect of the patient's and caregivers' lives, including education, social or work activities.

- In the first year of attending kindergarten, our son was there for the whole year only a few times at a time, and in the second year it was similar. I had to give up my job. Because Kuba's illness involved my frequent absences from work primarily due to long stays in the hospital, which usually extended to two weeks. The hospital is still our second home, in addition to rehabilitation," explains Gabriela Zajączkowska, mother of 6-year-old Kuba, who was diagnosed with neurofibromatosis type 1.

Patients with such tumors in the course of NF-1, especially children, require ongoing care and multispecialty support, including psychological and educational support, as well as comprehensive treatment and coordinated medical care. More recently, the hope for patients is a drug that can stop the symptoms of the disease.

- The world's first therapy for the targeted treatment of plexiform neurofibromas, which has recently emerged, is a kind of insurance policy. Rarely will any patient need to use it, but it's reassuring to know that this policy will be used when tumors begin to grow and threaten life, notes Dorota Korycinska.

The first child in Poland to be treated with a drug that stops the progression of the disease is 6-year-old Kuba. He is currently being treated under emergency access to drug technology - Right now, after the introduction of the treatment, we are in the hospital once every six months. Kuba can finally, like other children, go to kindergarten. When we heard the diagnosis, basically a death sentence, we thought it was the end. Because the doctor said it was a rare genetic disease for which there is no cure. The doctor prepared us for the worst and said that if these tumors started to grow, due to their location and pressure on the surrounding organs, Kubuś would slowly start to die. For me at the time, when I heard this, it was not a diagnosis, but a death sentence. I make no secret of the fact that we broke down after those words. But now, thanks to modern and, so far, the only treatment already available, we have been given a second chance; there is hope that the disease will be halted. Kuba can live, like other children," adds Mrs. Gabriela.

Until recently, treatment available for patients with NF-1 has been very limited. Surgical intervention in many cases is impossible due to the size and location of the tumor (the procedure may lead to mutilation or is infeasible due to severe complications), but also the risk of neurological and local complications, as well as the high risk of recurrence.

The new and only therapy to date, of the worst plexiform neurofibromas, has been recognized by the Ministry of Health as a highly innovative technology and breakthrough. The drug was included in the May 30, 2022 list of highly innovative therapies, but patients are still waiting for reimbursement.

The therapy leads to a halt in the progression of the disease, a clinically significant reduction in tumor volume, a reduction in the pain experienced due to tumor growth, while simultaneously improving, among other things, motor function, resulting in an overall improvement in patients' quality of life.

Coordinated care

A pilot program for coordinated medical care of patients with neurofibromatoses and related RASopathies was introduced in 2020 by a separate decree of the Minister of Health. This program provides patients not only with comprehensive advice from specialists in the treatment of neurofibromatoses and includes assessment of the condition and performance of reasonably planned follow-up examinations along with necessary specialist consultations enabling further diagnostic decisions to be made and determining the patient's pattern of care until the next periodic visit. The novelty of this program is the possibility of permanent access to consultations by the same specialists for parents and other doctors caring for the sick child. In this way, a sense of medical care is provided to patients and their families. The program is being implemented for 3 years in 4 centers designated by the Minister of Health in Poland. At the end of 2023, there will be an evaluation of the pilot program based on data collected by the National Health Service.

- The biggest problem today regarding NF-1 care is the lack of a center for adult patients. In the case of children, it is better, because we have 4 centers, although concentrated in central-northern Poland; there is no such center in southern Poland," explains Dorota Korycinska.

The need to continue the program is also seen by clinicians.

- What is certainly needed is the continuation of the coordinated care program, which is unique. The vast majority of patients appreciate this kind of care, and above all, they feel that when something worrisome happens to their child, they can come to us and get help. It can be said that thanks to the program, we also save the National Health Service funds, which are not spent on unnecessary diagnostic tests and visits to specialists unfamiliar with the course and complications of NF-1. What requires the attention of decision-makers and certainly the patient organization is care for adults with NF-1
and covering them also with coordinated care as is done for children. It would also be important to be able to use the new therapy for plexiform neurofibromas: for many patients this is a chance to live a relatively normal life, to start or return to work or school, to avoid suffering, but also a chance to effectively treat severe pain and neuropathic symptoms that exclude their normal life activities, Dr. Karwacki said.

Professor Mariusz Wysocki recognizes that in the 20 years since he began, dealing with the first patients with neurofibromatosis, much has changed. - There has also been an educational component, as a result of numerous lectures aimed at pediatricians, family physicians and hematooncologists, recognition and awareness of the disease began to increase throughout the country. The pilot program introducing coordinated care is a very big step forward. The pandemic got in the way here, and certainly the development of coordinated care was slowed down. On the other hand, a drug has emerged that can help especially patients with tumors and with deformities that can significantly affect the course of the disease. That is, an organizational structure is slowly being born," said Prof. Wysocki.

Source: press mat.