Age-Adapted Diagnostic Evaluation and Treatment of Patients With Type 1 Neurofibromatosis in Germany

Background: Neurofibromatosis type 1 (NF1) is a rare genetic disorder affecting multiple bodily systems that predisposes to the development of tumors. It affects approximately 1 in 3000 newborns in Germany. Its clinical manifestations are diverse and complex, and its diagnostic and therapeutic management call for specialized knowledge and experience. The lack of nationwide guidelines and recommendations further increases the difficulty of establishing an appropriate standardized and interdisciplinary approach.

Methods: The suggestions presented here are based on a selective literature review, international guidelines, and our own clinical experience over many years.

Results: We propose an age-adapted diagnostic and therapeutic approach to patients with NF1, subdivided into four main areas. We suggest follow-up examinations every one to two years to address typical course of the disease as well as administrative aspects, such as care by pediatricians. Whole-body magnetic resonance imaging (MRI) should be performed when the diagnosis is made. MRI and ultrasonography of particular body regions should be performed where appropriate. The NF1 gene should be sequenced to determine the causative pathogenic variant and as an aid to genetic counseling. If this fails to reveal a pathogenic variant, the NF1 gene should also be sequenced in tumor tissue. The vitamin D3 and sex hormone status are also relevant, as are serum metanephrines. Further specialist consultations may be necessary, and their findings should be discussed in an interdisciplinary framework.

Conclusion: These recommendations are intended to serve as a guide to a standardized interdisciplinary approach to the management of patients with NF1 in Germany, based on an up-to-date scientific understanding of the disease. This approach should improve care overall, both by enabling better care and by eliminating unnecessary diagnostic studies.

Cite this as: Farschtschi S, Vaassen P, Kluwe L, Hartung T, Salamon J, Rosenbaum T: Age-adapted diagnostic evaluation and treatment of patients with type I neurofibromatosis in Germany. Dtsch Arztebl Int 2025; 122: 71–6. DOI: 10.3238/arztebl.m2024.0257

Neurofibromatosis type 1 (NF1) is a multisystem disorder with tumor predisposition being its primary characteristic. Apart from malformations and NF1 manifestations affecting multiple organ systems (1, 2, 3, 4, 5, 6, 7), neuropsychological deficits are also a common feature (8). Life expectancy is reduced by around 15 years due to the increased risk of malignancies as well as cardiovascular and cerebrovascular events (9, 10).

The etiology of NF1 is based on heterozygous inactivating variants in the NF1 gene located on chromosome 17. More than half of the patients did not actually inherit these changes which have in fact developed spontaneously. Genetic mosaicism should be considered a possibility in these patients, can present clinically as a segmental form, and is statistically associated with milder manifestations. Genetic analysis can confirm the presence of mosaicism.

The NF1 gene is a tumor suppressor gene, the biallelic inactivation of which is the precondition for tumor development. This mechanism is comparable with that of the well-known tumor suppressor gene RB1. The loss of function of the NF1 gene product neurofibromin is known to result in overactivation of the MAP kinase signal pathway (6). Haploinsufficiency of the NF1 gene also results in various manifestations, of which NF1-associated neuropsychological deficits are an example. The exact pathophysiology, however, is largely unexplained.

One of our own studies involving more than 150 000 unselected children aged six years during routine medical examinations at elementary school enrolment revealed an estimated incidence of NF1 in Germany of 1 in 2600 to 1 in 3000 affected newborns (11). The pattern of inheritance of NF1 is autosomal dominant with a penetrance of 100%, yet the disease course demonstrates wide phenotypic variability ranging from very mild to severe impairments (6). The different genetic variants and mosaicism contribute to some extent to the high degree of variability. Epigenetic factors (for example, hormones) also play an important role but have not yet been researched to any great extent. The Figure provides an overview with a selection of symptoms, their chronological appearance, and estimated incidence. The diagnosis of NF1 is established using the revised international consensus recommendations of 2021 (5), listed in Table 1. eFigures 1–8 show characteristic manifestations of NF1.

Figure

Age-dependent development of selected NF1 manifestations and their incidence

Table 1

Diagnostic criteria for neurofibromatosis type 1 (≥ 2 of the characteristics must be met to confirm the diagnosis*¹)

eFigure 1

Café au lait spots

eFigure 2

Freckling

eFigure 3

Cutaneous neurofibromas

eFigure 4

Lisch nodules

eFigure 5

Plexiform neurofibroma

eFigure 6

Plexiform neurofibroma

eFigure 7

Nonunion

eFigure 8

Optic nerve gliomas

eFigure 9

Whole-body MRI in a case of NF1

European practice guidelines

In 2023, the guideline of the European Reference Network for Genetic Tumor Risk Syndromes (ERN GENTURIS) published for the first time standardized measures for the management of tumors associated with NF1, without addressing the non-oncological manifestations of NF1, however (12). Furthermore, the guideline cannot be applied without restriction because local healthcare structures within Europe vary considerably from region to region. Some countries, for example, France, the United Kingdom, and the USA, have their own country-specific guidelines (6, 13, 14, 15). Surveillance forms for NF1 patients were also published in Austria in April 2024 (16, 17). So far, there are no recommendations for action for the German healthcare system.

Care of NF1 patients in Germany

NF1 is a rare disorder with very complex, variable, and broad clinical manifestations. For some of these NF1-manifestations, the degree of expression is age-dependent (Figure). For example, optical pathway glioma (OPG) occurs predominantly in childhood. Consequently, without specialized knowledge and experience, diagnosis and management becomes very challenging. In 2009, the German Ministry of Health already implemented measures to improve the healthcare situation of patients with rare disorders in Germany. These measures explicitly address the situation faced by patients with NF1 and problems encountered in the standard care setting, in specialized healthcare structures, and in networking between centers. However, actual implementation of this program is still pending. Furthermore, specialized centers are rare, and their capacities are limited. The waiting time for new patients is usually more than a year, which reflects the desperate gap in care. Moreover, many patients (often together with their family) have to travel far to be able to receive adequate specialist care. The training of experts and the development of healthcare structures for NF1 are therefore urgently needed. In addition, treatment options in non-specialized facilities for less complex and already diagnosed cases would be desirable.

Aim of the suggestions

We, the authors of the present article, are physicians and researchers from three different centers who have been offering specialist care to NF1 patients in Germany for decades. Our experience has made us aware of the urgency to achieve standardized professional healthcare for NF1 in Germany based on current scientific knowledge. With this in mind, we would like to share our expertise and experience and taking the initiative to propose a plan of approach with age-adapted suggestions for measures. This plan is tailored to the German health system and can be applied in routine care. Our proposals are intended to provide some orientation as to which age-dependent measures are required and beneficial for NF1 patients. They are for all physicians in Germany treating patients with NF1. The aim is to enable, facilitate, and optimize NF1 care or partial care at various levels and in all relevant areas, also for facilities which are not specializing in NF1. Establishing more specialized healthcare facilities would also be desirable. In this respect, the suggestions could form the basis for working on a national guideline for the management of NF1 in Germany.

Structure of the suggestions

The suggestions are based on the latest expert knowledge, current international guidelines, especially the ERN GENTURIS guidelines (12), and our own clinical experience. The proposals are subdivided into four main areas:

• basic clinical investigations, screenings, and intervals
• radiological diagnostics: When? What? Why?
• human genetic diagnostics and appropriate laboratory tests
• other specialized examinations.

The suggestions for action are listed in Table 2 and Table 3 and arranged in order of frequency and importance. An age scale is also indicated. Certain points are discussed below and explained in the footnotes of the tables.

Table 2

Basic clinical investigations and radiological diagnostic assessment

Table 3

Human genetic testing, appropriate laboratory studies, and other specialist investigations

Basic clinical examinations, screenings, and intervals / radiological diagnostics

Structure of the diagnostic investigations

Suggestions are made for a basic structure and timeline for NF1-related clinical and radiological examinations (Table 2). The general care and diagnostic examinations for indications unrelated to NF1 should be conducted independently of, or in combination with, the suggestions. Special cases will need appropriate adaptation, for example additional examinations when new symptoms develop or when clinical deterioration is encountered. The list of suggestions is extensive due to the very high variability of NF1. The measures do not, however, apply to all patients to an equal extent but are often indication-based. The basic clinical investigations can usually be performed by primary care physicians, including those specializing in general medicine and pediatrics, or also those working in institutions with specialized healthcare facilities for NF1.

Classification by age and investigation intervals

Classification by age and investigation intervals are based on biological stages of development (for example, puberty) and administrative aspects (care up to and including the age of 18 is usually provided by pediatricians). Furthermore, the known course of the disorder (Figure) and international guidelines, as well as personal experience, also play a role. The relatively short investigation intervals are due to the fact that the disorder does not follow a linear course and can change unexpectedly and quickly. A typical example is the transformation of plexiform neurofibroma to malignant peripheral nerve sheath tumor, where early detection is decisive to the survival of the patients.

Contact with specialized centers and care on site

It is recommended that patients have access to an institution with specialized care for NF1. Once the diagnosis has been confirmed, less complex cases can be managed locally by appropriate primary care doctors. Unfortunately, a structure of centers of excellence for NF1 has not yet been established in Germany. Creation of a list of institutions offering specialist services is currently under discussion. Questions regarding which time intervals for follow-up by a specialist institution or (future) center would be appropriate still needs to be discussed and developed. The following contact details of patient organizations can be passed on to patients:

• German lay organization Bundesverband Neurofibromatose (Germany), www.bv-nf.de
• Children’s Tumor Foundation (USA, international), www.ctf.org

Whole-body and local magnetic resonance imaging

Since NF1 is a disorder predisposing to multiple tumors which can develop in all areas of the body, a whole-body MRI scan is advisable once the diagnosis has been established. This enables the (internal) tumor burden of the entire body to be assessed. Any possible scoliosis can also be detected.

A whole-body MRI scan also has economic advantages over multiple local examinations. Furthermore, representation by diffusion-weighted MRI sequences (DWI/ADC mapping) allows characterization of the tumors at the same time. After the initial screening scan, monitoring of the individual tumor manifestations can be accomplished by appropriate local MRI or local ultrasound.

Human genetic diagnostics and other examinations

Genetic testing

• The NF1 gene should be sequenced to identify any pathogenic variants. The test can be performed in laboratories specializing in NF1 or in human genetics laboratories (Table 3).
• Genetic mosaicism is possible in NF1 and can be confirmed by genetic analysis. For this purpose, it is important to examine several tumors because, in the event of mosaicism, the pathogenic change is often not present in blood leukocytes. If a pathogenic variant is detected in two unrelated tumors, then that variant can be defined as the constitutional pathogenic variant. Statistically, mosaic formations are associated with milder clinical courses and a reduced risk for transmission to the next generation.
• Around ten percent of the inactivating genetic alterations of the NF1 gene are due to the deletion of the entire NF1 gene, with loss of a few flanking genes such as SUZ12 (18). Compared with smaller changes within the gene, large deletions are associated with a severe clinical course and a higher risk of malignancy (19, 20).
• Genetic testing is essential for diagnosing or ruling out different diseases such as the Legius syndrome (pathogenic variant in the SPRED1 gene), tumor manifestations not typical for NF1, schwannomatosis, Noonan spectrum disorders, and McCune-Albright and Bloch-Sulzberger syndromes (the latter being also known as incontinentia pigmenti).

NF1-specific laboratory parameters

• Hormonal deviations can affect the development and growth of neurofibromas.
• Vitamin D3 deficiency is common in NF1 patients (21).
• From the age of 50 onwards, 50% of NF1 patients develop osteopenia or osteoporosis (22).
• Elevated metanephrine levels (degradation products of catecholamines) can be the result of a pheochromocytoma with subsequent cardiovascular complications (23).

Other specialist investigations

Should additional specialist investigations be necessary, then patients can be referred to the appropriate department. The examination results should be interpreted and assessed on an interdisciplinary basis in order to be able to develop additional care concepts.

Closing words and outlook

The presented suggestions for measures are intended to contribute towards standardizing diagnosis, monitoring, and management of patients with NF1 in Germany. They are supposed to help those treating NF1 patients to take appropriate and age-adapted measures in order to ensure quality of care on the one hand and avoid excessive diagnostics and inadequate management on the other.

These suggestions are currently being developed further to produce recommendations and guidelines. We would welcome, and are grateful for, any feedback and interest regarding the creation of further developments ([e-mail]). The overarching goal is to ensure the best and most efficient care and management possible for NF1 patients in Germany.

Acknowledgments

We would like to thank our patients and families for their trust in our medical care.

Funding

Some wording and the formatting of the manuscript were supported by the co.faktor company (Berlin, Germany). The costs incurred were financed by Alexion Pharma Germany (Munich, Germany). The content of the manuscript was compiled exclusively by the authors. Its revision, including the wording and formatting, was completed exclusively by the authors themselves. The authors received no fees, either directly or indirectly, in this respect.

Conflict of interest statement
SF has received funding from Alexion Pharma Germany for medical writing. Research funding from the Federal Association Neurofibromatosis and the charities “Nothing is forever” and Hamburg macht Kinder gesund e.V.. Funds for consulting activities and lectures from Alexion Pharma and funds for lecture activities from Astra Zeneca. He received reimbursement of traveling expenses and payment of conference fees from Alexion Pharma. He is unpaid honorary chairman of the Federal Association Neurofibromatosis, member of the steering committee European NF Group, representative of the European Reference Network (ERN) and, in this capacity, European lead of the European Lead Thematic Group 1 (NF).

LK received financing from Alexion Pharma Germany for medical writing and fees for research funding from the Federal Association Neurofibromatosis and the charities “Nothing is forever” and “Hamburg makes children healthy”.

TR received consulting fees from Alexion Pharma Germany and Alexion Pharmaceuticals. He was remunerated for continuing education events by Alexion Pharma Germany and Alexion Pharmaceuticals, Astra Zeneca, and Taiwan Society for Pediatric Neurosurgery. He received travel expense support and reimbursement of congress fees from Alexion Pharma Germany, Alexion Pharmaceuticals, and Astra Zeneca India. He is a member of the Advisory Board of Alexion Pharma. He is also chairman of the NF steering committee of Alexion Pharmaceuticals and board member of the German Society for Neuropediatrics.

PV received fees for lectures and for serving on advisory boards of Alexion Pharma Germany and Merck and reimbursement of traveling expenses.

JMS received consulting fees, reimbursement of traveling expenses, and fees for lectures and serving on advisory boards of Alexion Pharma.

TH declares that she has no conflicts of interests.

Manuscript received August 09, 2024, revised version accepted on December 18, 2024

Translated from the original German by Dr. Grahame Larkin

Corresponding author
PD Dr. med. Said Farschtschi
Neurofibromatose-Ambulanz

Klinik und Poliklinik für Neurologie

Universitätsklinikum Hamburg-Eppendorf
Martinistrasse 52
20246 Hamburg

References

1. Huson SM, Compston DA, Clark P, Harper PS: A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet 1989; 26: 704–11

2. Farschtschi S, Mautner VF, Lawson McLean AC, Schulz A, Friedrich RE, Rosahl SK: The neurofibromatoses. Dtsch Arztebl Int 2020; 117: 354–60

3. Hirbe AC, Gutmann DH: Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43

4. DeBella K, Szudek J, Friedman JM: Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000; 105: 608–14

5. Legius E, Messiaen L, Wolkenstein P, et al.: Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med 2021; 23: 1506–13

6. Bergqvist C, Servy A, Valeyrie-Allanore L, Ferkal S, Combemale P, Wolkenstein P: Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis 2020; 15: 37

7. Tucker T, Schnabel C, Hartmann M, et al.: Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1). J Med Genet 2009; 46: 259–65

8. Heimgärtner M, Granström S, Haas-Lude K, Leark RA, Mautner VF, Lidzba K: Attention deficit predicts intellectual functioning in children with neurofibromatosis type 1. Int J Pediatr 2019; 2019: 9493837

9. Uusitalo E, Rantanen M, Kallionpää RA, et al.: Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol 2016; 34: 1978–86

10. Evans DGR, Baser ME, McGaughran J, Sharif S, Howard E, Moran A: Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002; 39: 311–4

11. Lammert M, Friedman JM, Kluwe L, Mautner VF: Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 2005; 141: 71–4

12. Carton C, Evans DG, Blanco I, et al.: ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1. EClinicalMedicine 2023; 56: 101818

13. Ferner RE, Huson SM, Thomas N, et al.: Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007; 44: 81–8

14. Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR: Health supervision for children with neurofibromatosis Type 1. Pediatrics 2019; 143: e20190660

15. Stewart DR, Korf BR, Nathanson KL, Stevenson DA, 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 2018; 20: 671–82

16. Azizi AA, Baumgartner AC, Seidel M, et al.: Neurofibromatose Typ 1: Vorsorgebogen für Kinder und Jugendliche in Österreich. Monatsschr Kinderheilkd 2024. www.doi.org/10.1007/s00112–024–01955–3

17. Sunder-Plassmann V, Azizi AA, Farschtschi S, et al.: Neurofibromatosis type 1 adult surveillance form for Austria. Wien Klin Wochenschr 2024; doi: 10.1007/s00508–024–02443–0. Online ahead of print

18. Kluwe L, Siebert R, Gesk S, et al.: Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 2004; 23: 111–6

19. Well L, Döbel K, Kluwe L, et al.: Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth. PLoS Genet 2021; 17: e1009517

20. Pasmant E, Sabbagh A, Spurlock G, et al.: NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat 2010; 31: E1506–18

21. Schnabel C, Dahm S, Streichert T, Thierfelder W, Kluwe L, Mautner VF: Differences of 25-hydroxyvitamin D3 concentrations in children and adults with neurofibromatosis type 1. Clin Biochem 2014; 47: 560–3

22. Charoenngam N, Wattanachayakul P, Jaroenlapnopparat A, Ungprasert P, Chenbhanich J: Bone mineral density in neurofibromatosis type 1: a systematic review and meta-analysis. Calcif Tissue Int 2023; 113: 166–74

23. Al-Sharefi A, Javaid U, Perros P, et al.: Clinical presentation and outcomes of phaeochromocytomas/paragangliomas in neurofibromatosis type 1. Eur Endocrinol 2019; 15: 95–100

24. Sharif S, Moran A, Huson SM, et al.: Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 2007; 44: 481–4

25. Evans DGR, Kallionpää RA, Clementi M, 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

26. Barreto-Duarte B, Andrade-Gomes FH, Arriaga MB, Araújo-Pereira M, Cubillos-Angulo JM, Andrade BB: Association between neurofibromatosis type 1 and cerebrovascular diseases in children: a systematic review. PLoS One 2021; 16: e0241096

27. Sellmer L, Farschtschi S, Marangoni M, et al.: Non-optic glioma in adults and children with neurofibromatosis 1. Orphanet J Rare Dis 2017; 12: 34

28. Agaimy A, Vassos N, Croner RS: Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen‘s disease): clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol 2012; 5: 852–62.

29. Schulz A, Grafe P, Hagel C, et al.: Neuropathies in the setting of neurofibromatosis tumor syndromes: complexities and opportunities. Exp Neurol 2018; 299: 334–44

30. Ferner RE, Hughes RA, Hall SM, Upadhyaya M, Johnson MR: Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet 2004; 41: 837–41

31. Bergqvist C, Hemery F, Jannic A, Ferkal S, Wolkenstein P: Lymphoproliferative malignancies in patients with neurofibromatosis 1. Orphanet J Rare Dis 2021; 16: 230

32. Niemeyer CM, Flotho C: Juvenile myelomonocytic leukemia: who‘s the driver at the wheel? Blood 2019; 133: 1060–70

33. Sung L, Anderson JR, Arndt C, Raney RB, Meyer WH, Pappo AS: Neurofibromatosis in children with rhabdomyosarcoma: a report from the intergroup rhabdomyosarcoma study IV. J Pediatr 2004; 144: 666–8

34. Bizzarri C, Bottaro G: Endocrine implications of neurofibromatosis 1 in childhood. Horm Res Paediatr 2015; 83: 232–41

35. Glombova M, Petrak B, Lisy J, Zamecnik J, Sumerauer D, Liby P: Brain gliomas, hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1. Brain Dev 2019; 41: 678–90

36. Oderich GS, Sullivan TM, Bower TC, et al.: Vascular abnormalities in patients with neurofibromatosis syndrome type I: clinical spectrum, management, and results. J Vasc Surg 2007; 46: 475–84

37. Srinivasan A, Krishnamurthy G, Fontalvo-Herazo L, et al.: Spectrum of renal findings in pediatric fibromuscular dysplasia and neurofibromatosis type 1. Pediatr Radiol 2011; 41: 308–16

38. Celik B, Aksoy OY, Bastug F, Poyrazoglu HG: Renal manifestations in children with neurofibromatosis type 1. Eur J Pediatr 2021; 180: 3477–82

39. Ahlawat S, Blakeley JO, Langmead S, Belzberg AJ, Fayad LM: Current status and recommendations for imaging in neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Skeletal Radiol 2020; 49: 199–219

40. Lammert M, Mautner VF, Kluwe L: Do hormonal contraceptives stimulate growth of neurofibromas? A survey on 59 NF1 patients. BMC Cancer 2005; 5: 16