Neurofibromatosis type 1 (NF-1) is an inherited neoplastic syndrome. Adults affected by NF-1 in Poland are mostly unaware of the disease-related risk of cancer. During a year since the Ministry of Health settled a national coordinated medical care program for NF-1 children, 388 NF-1 patients up to 30 years of age were admitted to our Center and 187 had an affected parent (48.1% of familial cases). Only 18 NF-1 parents (9.6%) had any knowledge concerning the risk of malignancy, yet 22 (11.7%) were informed about their primary diagnosis for the first time simultaneously with their child. Asymptomatic tumors were revealed in 3 (1.6%) individuals who underwent preventive ultrasonography recommended during the first visit in the Center: abdominal pheochromocytoma in 2 (a 36-year-old man and a 33-year-old woman) and 1b breast cancer in 1 (a 32-year-old woman) case. Concluding, the early successful prevention of malignancy in professionally counselled NF-1 patients, proven currently, necessitates the urgent extension of prophylaxis and coordinated medical care program to the whole NF-1 population, not only in Poland, but worldwide. Precise knowledge concerning the disease-related medical risks should become a subject of the training of medical professionals regardless of their specialty.
Research Article
Coordinated medical care program for neurofibromatosis type 1 children and adolescents in Poland influences the future of their affected parents: a single academic reference center experience and national program description.
https://doi.org/10.21203/rs.3.rs-3600570/v1
This work is licensed under a CC BY 4.0 License
Version 1
posted
You are reading this latest preprint version
neurofibromatosis type 1
NF-1
risk of malignancy
coordinated medical care program
Neurofibromatosis type 1 (NF-1; ORPHA 636; OMIM #162200) is a primary neo-plastic syndrome, yet with a higher than populational risk of malignancy [1, 2]. It is one of the most common monogenic diseases worldwide, with an estimated prevalence of 1:2.5 thousand live births [3]. The primary phenotypic presentation of NF-1 includes the so-called “cafe au lait” spots (CALs) observed on the skin of every NF-1 patient in varying, but usually high numbers. Multiple neurofibromas (NFM) of two different kinds, which represent the benign peripheral nerve sheath tumors of various clinical significance are the second hallmark of the disease (Table 1).
The multisystem anomalous phenotype of NF-1 patients results from pathogenic Nf1 gene variants and is inherited as an autosomal dominant trait [3, 4, 5, 6]. In NF-1 patients, the mutated gene is not only responsible for oncogenesis, but especially for connective tissue anomalies (mostly bone dysplasia and joint hypermobility [7], mild cardiac anomalies characteristic of a RASopathy group of disorders and multiple aneurysms [8]) as well as behavioral and learning disability (attention deficit and hyperactivity syndromes, learning difficulties and suchlike [9]). However, the endocrine and reproductive systems are involved in NF-1 pathogenesis as well. The outstanding characteristic of NF-1 among other genetic syndromes comprises: (1) 100% penetrance of gene mutation, (2) a high number of spontaneous mutations, reaching 50%, and (3) outstandingly age-dependent and extremely variable phenotypic expression (Fig. 1) without anticipation. The last item means that the spectrum of symptoms differs in every patient even in one family and regardless of the generation (offspring may suffer less than the parent).
All the features of NF-1 listed above significantly complicate not only genetic counselling but the clinical diagnosis in early childhood as well. Contrary to toddlers, a correct clinical diagnosis of NF-1 based on phenotypic manifestations may be established in > 90% of children at the age of 6 years [10, 11, 12] (Table 1) and in adulthood. Although the diagnostic criteria allowing the accurate clinical diagnosis of NF-1 have been revised recently [13], the phenotypic presentation of the disease in adults is striking. Therefore, every physician regardless of the medical specialty should be able to recognize NF-1 in a given patient usually presenting with at least multiple CALs and NFMs. Regrettably, despite the certainty of NF-1 diagnosis in adults, the proper diagnosis is still neglected among the physicians not only in Poland [14], but also elsewhere [1, 3, 5]. As a consequence, the majority of NF-1 patients do not receive preventive measures to minimize NF-1-related threats, which additionally creates specific problems for national healthcare systems. Particularly, the awareness of Polish medical professionals concerning an increased risk of cancer in such a population of patients is scant [14]. Moreover, no global recommendations are available for the prevention and treatment of NF-1-related cancer and patients with NF-1 in an organized manner. Thus, specialists in the field had postulated the institution of medical coordination centers for NF-1 patients in Poland for years. Overall, the idea diffused across the whole world as well, as legally organized NF-1 centers are unavailable in most countries, except Great Britain, the USA, France, Germany and some others. As demonstrated in our previous paper, the awareness of the NF-1-related breast cancer risk was declared by only 30% of Polish women suffering from NF-1 and only 21% of them received this important information from medical professionals [14]. Regrettably, there are no other studies concerning the awareness of NF-1-related risks in this group of patients, and especially adults suffering from the disease.
For years the increased prevalence of carcinogenesis in general, and concerning specific cancer types in NF-1 patients has become obvious worldwide [15, 16, 17, 18, 19]. The scope of knowledge changed when a new important discovery was made in this matter [16].
The Nf1 gene belongs to the important regulators in the RAS-MAP-Kinase family of tumor suppressor genes [4]. Under physiological conditions, it is specifically responsible for disabling the activated RAS oncogene, which results in control of the division, growth and function of different cells. The important pathophysiological function of Nf1 became obvious when cancer genetic trials revealed a significant number of different malignancies (both cancers and sarcomas) in otherwise healthy individuals without NF-1, presenting with somatic homozygous mutation deactivating the Nf1 gene in numerous tumors. The biallelic mutational deactivation of the Nf1 in malignant cells added up to carcinogenesis and became a critical driver in multiple cancers, especially in breast, colorectal, urothelial, lung, ovarian and skin cancers (including melanoma), as well as in brain and neuroendocrine neoplasia, sarcomas of different types, and leukemias [20]. Currently, it is assumed that the Nf1 biallelic mutation may induce therapeutic resistance to chemotherapy, as well as endocrine and targeted therapies in different malignancies [21].
Germinal Nf1 mutation responsible for NF-1 favors a mutational drive leading to oncogenesis. However, unique and specific neoplasia is more prevalent in NF-1 patients than in the general population (Table 2) [16].
|
Type of tumors and malignancies more common in patients with NF-1 regardless of the age |
Type of both benign and malignant tumors occurring at a younger age in NF-1 patients than in the general population |
Type of malignancy appearing to be more fatal in NF-1 patients than in the general population |
|---|---|---|
|
• Glioma (low- and high-grade) • Sarcoma (many types) • Breast cancer • Endocrine cancers (including pheochromocytoma and neuroendocrine tumors) • Melanoma • Acute lymphoblastic leukemia • Ovarian cancer • Prostate cancer • Meningioma |
• Low-grade glioma • High-grade glioma • Malignant peripheral nerve sheath tumors • Breast cancer |
• Undifferentiated pleomorphic sarcoma • High-grade glioma • Malignant peripheral nerve sheath tumors • Ovarian cancer • Melanoma |
Apart from cutaneous NFMs that do not become malignant and are observed in almost 100% of adult NF-1 patients, clinically and histologically distinct plexiform neurofibromas (PNF) are present in more than one half of them as well. This kind of tumors may arise not only in the skin, but also in other body structures and may become malignant. The risk of the malignant transformation of PNF into malignant peripheral nerve sheath tumor (MPNST) is assumed at 8–15%. MPNSTs become the most common and the most life-threatening malignancy in NF-1 [14, 17]. Apart from peripheral ones, other common neurogenic tumors associated with NF-1 arise in the central nervous system (CNS):
-
relatively frequent optic pathway gliomas occurred in approximately 40% of patients, predominantly in toddlers (the prevalence of 11.1% [16]),
-
rarely occurring intracranial low-grade gliomas (pilocytic astrocytomas; the prevalence of 16.6% [16]) found in approximately 20% of patients with NF-1 and, likewise, detected in childhood [19, 21],
-
high-grade CNS tumors, mostly gliomas, are diagnosed rarely; the overall prevalence is 1.7%, whereas the prevalence of glioblastoma multiforme is 1.1% [19].
The aggravation of high-grade CNS tumors and aggressive sarcomas (except MPNST) or cancers (especially colon cancer), in patients presenting with the “typical” NF-1 phenotype must raise suspicion of constitutional mismatch repair deficiency syn-drome (CMMRD) which may be misdiagnosed as NF-1 [22].
In addition to tumors originating from the peripheral and central nervous system, breast cancer, gastrointestinal stromal tumors, and pheochromocytoma were other neoplasms in NF-1 patients which appeared to be more prevalent than in the general population [14]. Furthermore, leukemias (especially acute lymphoblastic leukemia) and melanoma, as well as soft tissue sarcomas, were acknowledged as NF-1-associated malignancies [17, 23]. Biallelic somatic mutation of the Nf-1 gene occurs in 10 to 15% of juvenile myelomonocytic leukemia (JMML) cells [24], but JMML rarely arises in NF-1 children [25]. The latest results of population studies showed an increased number of both benign and malignant tumors other than previously described in those patients [19, 26]. They comprised embryonal rhabdomyosarcoma (ERMS), neuroendocrine tumors (NETs) other than pheochromocytoma (PhCC), squamous cell lung carcinoma, papillary thyroid carcinoma, and meningioma (commonly assumed as pathognomonic for NF-2) [19, 27]. As published recently by Landry et al. [16], the prevalence of non-neurofibromatic neoplasia was 41.4% and it usually presented as a single entity (the prevalence of 34.2%, whereas the prevalence of multiple neoplasia was 7.2%). According to the authors, the most important risk of non-neurofibromatic carcinogenesis encompassed:
-
breast cancer (BRCA) with a NF-1-related prevalence of 2.9% and the median age at diagnosis of 44.2 years (range 23.4–70.9), whereas general populational prevalence was assumed as 0.7% and the median age at diagnosis was 62.0 y.,
-
gastrointestinal stromal tumor (GIST) and pheochromocytoma with the prevalence of 1.2% for each (populational – 0.004% and 0.02%, respectively),
-
melanoma with the prevalence of 0.9% (populational 0.24%), and
-
embryonal rhabdomyosarcoma (ERMS) with the prevalence of 0.8% (vs. 0.002% in the general population).
The significant risk of BRCA in NF-1 patients (possibly in men as well) has been recently revealed, following a leading publication of Uusitalo and coresearchers [28]. The results were also confirmed by other authors [29–32].
All of the facts described above together with:
(1) the prevalence resulting from the high birth incidence of NF-1 (currently assumed as 1 in 2,500 births [33], and
(2) insignificantly reduced life expectancy, as compared to other tumor predisposition syndromes of childhood (assessed as 8-15-year reduction with reference to the life expectancy of the general population [34, 35])
contribute to significant morbidity and necessitate the specific systemic organization of multispecialty care for patients suffering from NF-1 which is focused on the age-related characteristics of their health problems.
The piloting of comprehensive coordinated medical care program for patients with neurofibromatoses and related RASopathies was introduced to the National Health System in Poland by the Decree of the Polish Minister of Health (MOH) in June 2020 [36].
The purposes of the 3-year pilot program lasting until 2024 were:
- the official settlement of 4 Centers of Coordinated Medical Care for NF/RAS Patients (NF/RAS CMCCtrl) in Poland each of which had provided specialized care for NF-1 patients previously, but differed in disease- and patient-oriented care experience,
- the evaluation of program effectiveness with regard to general health system cost reduction and improvement of disease recognition and the prevention of its complications
- the final analysis of the program is expected in 2024 and the results will be presented as the levelized and averaged data of the total cost of the coordinated care per patient, including medical and health-related extra-medical costs (e.g., lost working and school days, costs of traveling) in comparison with the cost of care of the same patient in a period pre-ceding program implementation (mostly multiple unnecessary imaging and consultations),
- enhancement of the coordinated medical care for the whole population of NF-1 patients, if the pilot program meets the expectations of healthcare system authorities
- until the end of program evaluation, the piloting is directed to the population of NF-1 patients from birth up to 30 years of age (see further).
The mainstay of the program is multispecialty supervision of the patients’ health complaints based on the regular once-yearly visits at the Center and all year-round health surveillance based on telemedical contact (see graphical scheme presented on the Figure 2). It comprises the necessary imaging as well as physical examinations and, if required, specialist consultations to address current or longitudinal patient’s complaints. In case of emerging symptoms dis-covered either by the patient or caregiver or the patient’s physician(s), the NF/RAS CMCCtrl is obliged to organize an urgent visit or hospitalization and implement necessary examinations and consultations. Thus, NF-1 patients included into the program are protected against unnecessary and frequently repeated consultations and imaging, but receive adequate and comprehensive care instead. Apart from the main goals of the pro-gram (i.e., the improvement of prophylactic measure efficacy and general health status, and care for NF-1 population in Poland), one of the secondary cardinal aims of the patient-oriented, coordinated care is to avoid the so called “diagnostic odyssey” of the patients and to free them from costly and unnecessary, usually repeated examinations and medical consultations, and sometimes harmful medical procedures as well [37]. The prevention of unnecessary “over-diagnosing” improves the sense of well-being and psycho-logical status of the patients and their families, allowing them to release from the feeling of disability as well. The program was settled in accordance with the Polish standards of care for NF-1 patients [37].
Regrettably, the major limitation of the program is the age of patients having access to the coordinated medical care program, which is limited to young people aged up to 30. It results from the character of the centers set up by the regulation, all of which belong to pediatric oncology departments. Moreover, this limitation is a consequence of the fact that till 2022 no specialized care has been dedicated to adult NF-1 patients older than 30 in Poland. The situation is currently changing. Overall, beside current, but isolated, initiatives undertaken mostly by adult clinical oncologists [38], neither specialized care for adult patients with NF-1 has been established in Poland so far, nor adult patients have been properly informed about the possible risk of health- or life-threatening symptoms related to the Nf1 gene mutation [14]. The standard of care for adult patients suffering from NF-1 (e.g., described by Stewart et al. [39]) is still an enigma in Poland. Thus, the obligatory responsibility of each NF/RAS CMCCtrl includes mandatory counselling provided to every symptomatic parent of a child burdened with NF-1 concerning the precise information about the disease-related risks of genuine malignancy and hormonal disturbances. Such counselling is particularly important in case of NF-1 women in case of menopause, which may be accelerated. In such women Hormone Replacement Therapy is contraindicated because of an increased risk of BRCA. They are also advised on the necessary examinations required to reveal possible NF-1 complications which mostly unveil in adulthood:
- breast and abdominal ultrasound screening (an increased risk of BRCA, aneurysms, GIST, pheochromocytoma and ERMS) on a regular yearly basis (or on demand, if necessary),
- ultrasound of unusual and/or symptomatic skin lumps or subcutaneous tumors (pain, symptoms of neuropathy, itching including generalized one), especially when they present with an accelerated growth or a new clinical characteristic,
- yearly multiparametric complete blood count with reticulocyte count, or on demand (risk of leukemias),
- dermoscopy of superficial melanoma,
- urgent (but not routine) CNS MRI in case of sudden, severe cephalgia or unexpected and significant intensification or change in the patient’s migraine symptomatology or a distinct change in the patient’s behavior (CNS tumor or aneurysm, or thrombosis complicate NF-1-related blood vessel anomalies, like Moya-moya disease),
- others, necessary to establish the reason for unusual patient complaints.
The information is spread both via internet communicators established exclusively for NF-1 families (e.g., Facebook platform and world wide web page of parental organization and task force group, NF/RAS CMCCtrl Facebook platform and others) and during annual country joint parental educational meeting with the participation of NF-1 professionals.
A total of 388 patients aged up to 30 with the confirmed NF-1 diagnosis were included into the coordinated medical care program in the NF/RAS CMCCtrl of the Medical University of Warsaw (MUW) during one year out of the 3-year pilot program (between October 1st, 2020 when the official Agreement between the Polish NHF and our Center was assigned, and September 30th, 2021). Patient characteristics are summarized in Fig. 3.
As regards the patient group, 201 of them (201/388; 51.8%) were diagnosed as a sporadic mutation case and 24 (24/388; 6.1%) were older than 18 years of age. A total of 187 patients had an affected parent (187/388; 48.2% of familial cases). In 22 families (22/187; 11.7%), a full-blown affected parent was informed about the definite diagnosis for the first time in our Center when the diagnosis was established and confirmed in his/her child. Surprisingly, but not unexpectedly, it was in accordance with our previously published observation [14 11]. Noteworthy, amid those 187 affected parents, only 18 (18/187; 9.6%) had any knowledge concerning the risk of malignancy and the methods of possible cancer risk screening and prevention. As described above, all those newly diagnosed patients (i.e., parents) were recommended to undergo all necessary examinations: regular screening or in case of an unexpected or significant intensification of existing symptoms com-plicating NF-1 course, or serious medical issues arising “de novo”. All but 13 (13/187; 6.9%) accepted the information provided by the Center’s physician and declared that they would apply advised preventive modalities. The results obtained due to this procedure were striking. As a consequence, 3 affected parents (3/187; 1.6%; one man and 2 women) were operated immediately after they underwent the so-called preventive ultrasound recommended during the first visit in our NF/RAS CMCCtrl, which revealed a de novo tu-mor in the examined region. Abdominal pheochromocytomas were confirmed histologically and removed radically in presymptomatic period in 2 patients (a man, 36, and a woman, 33 years old). The surgical procedure ended the treatment process entirely. One of them had the primary diagnosis of NF-1 established simultaneously with her child’s diagnosis (the parent lived 33 years not being aware of the disease). The third woman (32 years old) with a breast lump finally diagnosed as 1b breast cancer received adequate care in a dedicated regional BRCA Department.
The research confirming the unawareness of an increased BRCA risk among Polish women suffering from NF-1 is currently a published fact [14]: 68% of surveyed women had not received such information at all, whereas only 23% had received professional counselling which was mostly provided by NF center physicians. The oldest, previously ignorant, woman received the precise diagnosis of NF-1 from oncologists during the 62nd year of her life. At the same time, she was informed about the BRCA diagnosis. This publication indirectly confirmed that the awareness of Polish adult NF-1 patients concerning their inherited disease is limited, and that their knowledge with respect to the necessity of active medical supervision regarding the primary disease health complication is a must. Despite the definite limitation of the Polish National Health Fund [14], the patients’ self-responsibility for their well-being should drive them to seek medical consultation not only in case of fatal complications, but in advance, as a prophylactic measure. Regardless of the mild or insignificant intellectual limitations which may sometimes play a role in case of NF-1, the knowledge concerning the possible complications of NF-1 course is currently easily available due to wide internet access and various possibilities of information exchange. However, the awareness of the precise basic diagnosis constitutes the funda-mental basis for such active patient’s self-care. Albeit, it is limited in Poland, as some physicians, including general practitioners, disregard even striking symptoms of NF-1 in patients [14]. The ignorance of the NF-1-related risks may result in prolonging the precise diagnosis and prolonged maltreatment. The author was unable to retrieve any other than presented [14] literature publications concerning health problems resulting from the un-awareness of NF-1-related complications. However, the problem was discussed widely in medical fora, especially during parental organization meetings held not only in Poland, but also in other countries.
Therefore, the lack of an established and comprehensive program of care for adults suffering from NF-1 is our national challenge, and all initiatives taken currently by “adult medicine specialists” [38] are welcome both by the patients and the non-governmental organization representing their interests in Poland. As described above, the fundamental age-related restriction limiting the access of adult NF-1 patients to coordinated medical care program is related to the fact, that all four centers responsible for NF/RAS comprehensive program in Poland were established on a pediatric academic oncology department basis. Fortunately, 3 of them are a part of the multispecialty structure of Medical University Clinical Centers, gathering highly specialized medical academic departments for children AND adults. Thus, the parent Medical Universities in Poland registered NF/RAS Centers in their structures are being able to provide the highest standards of care for NF-1 patients (and other neurofibromatoses) regardless of the age. Hence, the only action advice for the Polish MOH (and generally – healthcare system authorities) is to spread the legal responsibility of NF/RAS CMCCtrl from pediatric-only to pediatric and adult care for NF-1 patients. The idea may be widened and include other healthcare systems without appropriate care for NF-1 and, more widely, other rare disorders in general.
As described above and in the previous publication [14], during the anamneses the MUW NF/RAS CMCCtrl staff frequently noted the ignorance of the health risks related to NF-1. It may be due to the common belief of medical professionals that NF-1 is a disease slightly limiting life expectancy [23, 34, 39]. The life expectancy limitation of 8 to 15 years in comparison with the general population determined by the quoted epidemiology studies seems to justify this general belief. Regrettably, NF-1 is still a disorder of a significantly in-creased risk of various health complications related to the tissue and organ consequences of Nf1 mutation. In our practice, which is a mainstay of the MUW NF/RAS CMCCtrl activity, the affected parents of primarily diagnosed children always receive written information concerning the NF-1-related complications occurring particularly in adulthood and the screening modalities necessary to diagnose them, during the first admission to the Center or at the time of disease confirmation in the child (or/and the affected parent) at the latest. In this context, the negligible percentage of NF-1 adults aware of their disease hazards is relevant (less than 10% as disclosed above), and necessitates further action to im-prove adult NF-1 care in Poland. It may be applicable to other countries all over the world as well, where the access of all patients to NF-1 screening program is still limited.
Finally, with reference to the title of the present paper, the clinical significance of the “unexpected immediate result” of the coordinated care program limited to children and youths only is difficult to prove, as, particularly in Poland, no NF-1 patient registry has been developed yet. The only measurable epidemiological data available in Poland refer to the incidence and mortality related to BRCA, but not to pheochromocytoma. Despite favorable mortality trends since the 1990’s in Europe [40], Poland is the only country where the BRCA mortality rate is currently increasing [41]. The disease progresses to an advanced stage in 30% of women with BRCA in Poland, and in 5–10% of patients it is diagnosed when it has already metastasized to other organs [42]. It results mostly from the fact that Polish women disregard the need of preventive examinations ([43] and recent not published data of the Polish National Health Fund discussed in [44]) and the fact, that the Population Program for Early Detection of Breast Cancer targets women aged 50 to 69 and women with proven genetic predispositions to BRCA. The test assessing the genetic pre-disposition to BRCA in Poland does not include the Nf1 gene, which is against the widely accepted recommendations [45]. As regards other rare tumors (e.g., pheochromocytoma), no preventive measures or activity have been performed in Poland at all. In this respect, the 3 young patients with NF-1 referred for preventive ultrasonography after MUW NF/RAS CMCCtrl counselling, would not have the growing tumor diagnosed at the pre-symptomatic stage of the disease, early enough to protect the patient’s health or even life. The published results constitute indirect, but significant, evidence, that precise information provided to the persons at risk is the responsibility of NF-1 care programs, especially in countries with a limited access to NF-1 patient-oriented care.
The immediate but unexpected result of the implementation of coordinated medical care program for NF-1 patients in Poland is worth being propagated not only in the country, but worldwide. Early successful prevention of malignancy or its complications in professionally counselled NF-1 patients, as demonstrated in the presented 3 cases pro-vided with adequate knowledge at a right time, requires the urgent extension of the prophylaxis and coordinated medical care program for the whole NF-1 population. Finally, it is advised that with regard to NF-1 and its high prevalence among rare diseases, precise knowledge concerning the possible cancer as well as other disease-related medical risks should become a subject of training of medical professionals regardless of their specialty.
BRCA: breast cancer; CNS: central nervous system; ERMS: embryonal rhabdomyosarcoma; GIST: gastrointestinal stromal tumors; MRI: magnetic resonance imaging; MUW: Medical University of Warsaw; NF-1: neurofibromatosis type 1 or von Recklinghausen disease; NFLS: NF-like syndrome or Legius syndrome; NFM: neurofibroma; NHS: National Health Service; MOH: Ministry of Health; MPNST: malignant peripheral nerve sheath tumor; O(MIM): Online Mendelian Inheritance in Man; ORPHA code: Orphanet’s unique, time-stable and non-reusable numerical identifier of disease; ORPHANET: Orphanet is a multi-stakeholder, global network of 41 countries, coordinated by the Orphanet Coordi-nating team at the French National Institute of Health and Medical Research in Paris; PNF: plexiform neurofibroma
- Ethics approval and consent to participate: Ethics approval was not required for this kind of researcg and publication according to Polish Law.
- Consent for publication: Not applicable. All participants with neurofibromatosis type 1 provided consent/assent to participate in the focus group of patients in our Institution.
- Availability of data and materials: Not applicable. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
- Competing interests: The author declares no conflict of interest. However, in the field of neurofibromatoses author keeps a position of the Principal Investigator in Astra Zeneca’s and Fosun’s Commercial Clinical Trials of I/II phases dedicated to NF-1 patients, as well as in noncommercial 2a phase of clinical trial recruiting Schwannomatosis related to Nf2 gene mutation patients. Occasionally author has been granted by Astra Zeneca to participate in country and international symposia as well as received financial gratitude for lectures concerning NFs.
- Funding: This research received no external funding. The publication fee was covered by the Foundation supporting our MUW’s Department of Pediatric Hematology and Oncology, Transplantation Medicine and Pediatrics (Fundacja na rzecz Katedry i Kliniki Pediatrii, Hematologii i Onkologii Warszawskiego Uniwersytetu Medycznego w Warszawie)
- Authors' contributions: Not applicable. Single author manuscript.
- Acknowledgements: I sincerely would like to thank Dr. Ewa Celi, my kind colleague and co-worker for her substantial support in the preparation of this article and the hard work for NF-1 patient community. Yet, I would like to express my gratitude to Prof. Michał Matysiak, the former Head of the MUW Department, my close friend, as well as a medical and scientific tutor for years, and Prof. Pawel Laguna, the actual Department’s Head, whose profound assistance resulted in establishing the institution of NF/RAS Center in the Medical University of Warsaw with theirs further support.
Authors' information (optional): Marek W. Karwacki, M.D., Ph.D. currently keeps the position of Assistant Professor in the Department of Pediatric Hematology and Oncology, Transplantation Medicine and Pediatrics, Medical University of Warsaw and a Coordinator of the Coordinated Medical Care Center for NF/RAS Patients, Pediatric Teaching Hospital of Medical University of Warsaw University Clinical Center. He graduated from the Medical University of Warsaw, Poland. He is a practicing specialist in Pediatrics and Pediatric Hematology and Oncology with Ph.D. Diploma in Clinical Genetics. His professional and scientific career started during medical studies and finally resulted in up-to-date 72 published scientific articles, 69 chapters in Polish and international medical monographies and textbooks as well as the authorship and editorial of scientific monography published in Poland and more than 350 congress reports. His scientific interest focuses on the medical issues related to rare disorders: mostly in the field of pediatric hematology and oncology as well as pediatric palliative care and medical law, and bioethics. He is a member of EHA, SIOP-E and national scientific societies of pediatrics, pediatric hematology/oncology and palliative care.
- Riccardi V.M. Von Recklinghausen neurofibromatosis. N Engl J Med. 1981; 305:1617–1627.
- Uusitalo E.; Rantanen M.; Kallionpää R.A.; Pöyhönen M.; Leppävirta J.; Ylä-Outinen H.; Riccardi V.M.; Pukkala E.; Pitkäniemi J.; Peltonen S.; et al. Distinctive Cancer Associations in Patients with Neurofibromatosis Type 1. J Clin Oncol. 2016; 34:1978-86.
- Boyd K.P.; Korf B.R.; Theos A. Neurofibromatosis type 1. J Am Acad Dermatol. 2009; 61:1–14.
- Pasmant E.; Vidaud M.; Vidaud D.; Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet. 2012; 49:483–9.
- Castle B.; Baser M.E.; Huson S.M.; Cooper D.N.; Upadhyaya M. Evaluation of genotype-phenotype correlations in neurofibromatosis type 1. J Med Genet. 2003; 40e:109.
- Sabbagh A.; Pasmant E.; Imbard A.; Luscan A.; Soares M.; Blanché H.; Laurendeau I.; Ferkal S.; Vidaud M.; Pin-son S.; et al. NF-1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013; 34:1510–8.
- Karwacki M.W.; Wozniak W. The Skeleton Abnormalities in Patients with Neurofibromatosis Type 1: Important Consequences of Abnormal Gene Function. In Osteoporosis, 1st ed.; Dionyssiotis Y., Ed.; Publisher: InTech, Rijeka, Croatia, 2012, pp. 323-342.
- Tedesco M.A.; Di Salvo G.; Natale F.; Pergola V.; Calabrese E.; Grassia C.; Ratti G.; Iarussi D.; Iacono A.; Calabrò R.; Lama G. The heart in neurofibromatosis type 1: an echocardiographic study. Am Heart J. 2002; 143:883-8.
- Smith T.F.; Kaczorowski J.A.; Acosta M.T. An executive functioning perspective in neurofibromatosis type 1: from ADHD and autism spectrum disorder to research domains. Childs Nerv Syst. 2020; 36:2321-2332.
- Legius E.; Messiaen L.; Wolkenstein P.; Pancza P.; Avery R.A.; Berman Y.; Blakeley J.; Babovic-Vuksanovic D.; Cunha K.S.; Ferner R.; et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an in-ternational consensus recommendation. Genet Med 2021; 23:1506–1513.
- Karwacki M.W. Breast cancer risk (un)awareness among women suffering from neurofibromatosis type 1 in Poland. Contemp Oncol (Pozn). 2020; 24:140-144.
- Sørensen S.A.; Mulvihill J.J.; Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. 1986; 314:1010–1015.
- Imaizumi Y. Mortality of neurofibromatosis in Japan.; 1968-1992. J Dermatol 1995; 22:191–195.
- Zöller M.; Rembeck B.; Akesson H.O.; Angervall L. Life expectancy, mortality and prognostic factors in neu-rofi-bromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg, Sweden. Acta Derm Ve-nereol 1995; 75:136–140.
- McGaughran J.M.; Harris D.I.; Donnai D.; Teare D.; MacLeod R.; Westerbeek R.; Kingston H.; Super M.; Harris R.; Evans D.G. A clinical study of type 1 neurofibromatosis in north west England. J Med Genet. 1999; 36:197–203.
- Landry J.P.; Schertz K.L.; Chiang Y.J.; Bhalla A.D.; Yi M.; Keung E.Z.; Scally C.P.; Feig B.W.; Hunt K.K.; Roland C.L.; et al. Comparison of Cancer Prevalence in Patients with Neurofibromatosis Type 1 at an Academic Cancer Center vs in the General Population From 1985 to 2020. JAMA Netw Open. 2021; 4:e210945.
- Philpott C.; Tovell H.; Frayling I.M.; Cooper D.N.; Upadhyaya M. The NF-1 somatic mutational landscape in spo-radic human cancers. Hum Genomics. 2017; 11:13.
- Tao J.; Sun D.; Dong L.; Zhu H.; Hou H. Advancement in research and therapy of NF-1 mutant malignant tu-mors. Cancer Cell Int 2020; 20:492.
- Perez-Valencia, J.A., Gallon, R., Chen, Y. Koch J., Keller M., Oberhuber K., Gomes A., Zschocke J., Burn J., Jackson M.S., et al. Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1. Genet Med 22, 2081–2088 (2020).].
- Bergqvist C.; Servy A.; Valeyrie-Allanore L.; Ferkal S.; Combemale P.; Wolkenstein P. NF France Network. Neu-ro-fibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis. 2020; 15:37.
- Online Mendelian Inheritance in Man: # 607785 JMML
- Liy-Wong C, Mohammed J, Carleton A, Pope E, Parkin P, Lara-Corrales I. The relationship between neurofibroma-tosis type 1, juvenile xanthogranuloma, and malignancy: A retrospective case-control study. J Am Acad Dermatol. 2017 Jun;76(6):1084-1087
- Well L.; Döbel K.; Kluwe L.; Bannas P.; Farschtschi S.; Adam G.; Mautner VF.; Salamon J. Genotype-phenotype cor-relation in neurofibromatosis type-1: NF-1 whole gene deletions lead to high tumor-burden and increased tu-mor-growth. PLoS Genet. 2021; 17:e1009517.
- Alkhayyat M.; Saleh MA.; Coronado W.; Abureesh M.; Zmaili M.; Qapaja T.; Almomani A.; Khoudari G.; Man-soor E.; Cooper G. Epidemiology of neuroendocrine tumors of the appendix in the USA: a population-based na-tional study (2014-2019). Ann Gastroenterol. 2021; 34:713-720.
- Stewart D.R.; Korf B.R.; Nathanson K.L.; Stevenson D.A.; Yohay K. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018l; 20:671-682.
- Wilding A.; Ingham S.L.; Lalloo F.; Clancy T.; Huson S.M.; Moran A.; Evans D.G. Life expectancy in hereditary can-cer predisposing diseases: an observational study. J Med Genet. 2012; 49:264-9.
- Bergqvist C.; Hemery F.; Jannic A.; Ferkal S.; Wolkenstein P. Lymphoproliferative malignancies in patients with neurofibromatosis 1. Orphanet J Rare Dis. 2021; 16:230.
- Uusitalo E.; Kallionpää RA.; Kurki S.; Rantanen M.; Pitkäniemi J.; Kronqvist P.; Härkönen P.; Huovinen R.; Carpen O.; Pöyhönen M.; et al. Breast cancer in neurofibromatosis type 1: overrepresentation of unfavorable prognostic fac-tors. Br J Cancer. 2017; 116:211-217.
- Frayling I.M.; Mautner V.F.; van Minkelen R.; Kallionpaa R.A.; Aktaş S.; Baralle D.; Ben-Shachar S.; Callaway A.; Cox H.; Eccles D.M.; et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of Nf1 gene muta-tion: a new genotype-phenotype correlation. J Med Genet. 2019; 56:209-219.
- Evans D.G.R.; Kallionpää R.A.; Clementi M.; Trevisson E.; Mautner V.F.; Howell S.J.; Lewis L.; Zehou O.; Pel-tonen S.; Brunello A.; et al. Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five-country cohort study. Genet Med. 2020; 22:398-406
- Gensini F.; Sestini R.; De Luca A.; Pinna V.; Daniele P.; Orzalesi L.; Petrella M.C.; Porfirio B.; Papi L. Early-onset ma-lignant phyllodes breast tumor in a patient with germline pathogenic variants in Nf1 and BRCA1 genes. Fam Can-cer. 2021; 20:195-199.
- Crook A.; Kwa R.; Ephraums S.; Wilding M.; Thiyagarajan L.; Fleming J.; Moore K.; Berman Y. The psychological impact and experience of breast cancer screening in young women with an increased risk of breast cancer due to neurofibromatosis type 1. Fam Cancer. 2021; 8:1-13.
- Evans DG.; Howard E.; Giblin C.; Clancy T.; Spencer H.; Huson SM.; Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service Am J Med Genet A. 2010; 152A:327–332.
- Karwacki M.W.; Wysocki M.; Perek-Polnik M.; Jatczak-Gaca A. Coordinated medical care for children with neu-rofibromatosis type 1 and related RASopathies in Poland. Arch Med Sci 2021; 17:1221–1231.
- Rozporządzenie Ministra Zdrowia z dnia 15 czerwca 2020 r. w sprawie programu pilotażowego w zakresie koor-dynowanej opieki medycznej nad chorymi z neurofibromatozami oraz pokrewnymi im rasopatiami. Dzi-ennik Ustaw RP nr 2020.1185 [Journal of Laws of the Republic of Poland.; Decree of Ministry of Health no. 2020.1185].
- Nunley K.S.; Gao F.; Albers A.C.; Bayliss S.J.; Gutmann D.H. Predictive value of café au lait macules at initial con-sultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol 2009; 145:883-7.
- Ben-Shachar S.; Dubov T.; Toledano-Alhadef H.; Mashiah J.; Sprecher E.; Constantini S.; Leshno M.; Messiaen LM. Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules. J Am Acad Dermatol. 2017; 76:1077-83.e3.
- Gibbs N.F.; Hanspaul S.; Makkar H.S. Disorders of Hyperpigmentation and Melanocytes. In: Neonatal Der-ma-tology (Second Edition). Eichenfield L.F., Frieden I.J., Esterly N.B., Eds.; Publisher: W.B. Saunders, Philadelphia, USA, 2008. pp. 397-421.
- Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, La Vecchia C. Trends and predictions to 2020 in breast cancer mortality in Europe. Breast 2017; 36: 89-95.
- Malvezzi M, Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C, Negri E. European cancer mortality predic-tions for the year 2019 with focus on breast cancer. Ann Oncol 2019; 30: 781-787.
- Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A, Bray F. Estimating the glob-al cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019; 144: 1941-1953.
- Jasiura A., Dera I., Szlachcic K., Gorzel M., Zmonarska J. Breast cancer screening programs in selected European countries and Poland. Journal of Education, Health and Sport. 2021;11(7):11-21.
- https://www.euractiv.com/section/diabetes-cancer-hepatitis/news/fighting-metastatic-breast-cancer-is-a-race-against-time-in-poland/
- Hu C., Hart S.N., Gnanaolivu R., Huang H., Lee K.Y., Na J., Gao C., Lilyquist J., Yadav S., Boddicker N.J., et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med. 2021 Feb 4;384(5):440-451.