Skip to main content
NCBI home page
Deutsches Ärzteblatt International logoLink to Deutsches Ärzteblatt International
. 2025 Feb 7;122(3):71–76. doi: 10.3238/arztebl.m2024.0257

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

Said Farschtschi 1,*, Pia Vaassen 2, Lan Kluwe 1, Tabea Hartung 1, Johannes Salamon 3, Thorsten Rosenbaum 2
PMCID: PMC12434714  PMID: 39773869

Abstract

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.

Information about this CME

This article has been certified by the North Rhine Academy for Continuing Medical Education.

The questions may be found at http://daebl.de/RY95. The closing date for entries is February 6, 2026.

Participation is possible at cme.aerztebatt.de

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 (1–7), 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.

Figure

Open in a new tab

Age-dependent development of selected NF1 manifestations and their incidence

The increased risks for some manifestations are given in comparison with the general population. The first line contains an age scale in years. The manifestations are listed in the order of incidence which is provided in square brackets. The references are provided as numbers in brackets. The color gradient correlates with the appearance of the symptoms.

*Various manifestations are grouped together here, for example moyamoya angiopathy, cerebral vasculopathy, vascular stenoses, strokes, so no incidence can be provided.

yrs, years; GIST, gastrointestinal stroma tumor; NF, neurofibroma; MPNST, malignant peripheral nerve sheath tumor; PNF, plexiform neurofibroma

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

1 • ≥ 6 typically configured café-au-lait (CAL) spots
 before puberty: >0.5 cm in diameter
 after puberty: >1.5 cm in diameter*2
2 • freckling in skin folds (axillary or inguinal)*2
3 • neurofibromas
 ≥ 2 cutaneous/subcutaneous neurofibromas OR
 ≥ 1 plexiform neurofibroma
4 • optic pathway glioma (OPG)
5 • Lisch nodules or choroidal abnormalities (OCT/NIR)
6 • distinctive bone dysplasia (sphenoid wing dysplasia*3, anterolateral bowing of the tibia, pseudarthrosis of long tubular bones)
7 • presence of heterozygous pathogenic NF1 variants with an allele frequency of around 50% in non-affected tissue (blood leukocytes or buccal mucosa)
Open in a new tab

*1 The child of a parent who already meets the criteria only needs to meet one of the criteria to be diagnosed with NF1.

*2 If only CAL and freckling are evident, then the diagnosis of NF1 is probable, although in exceptional cases patients may have a different diagnosis, such as Legius syndrome. In any case, one of the pigmentation abnormalities must occur on both sides.

*3 Sphenoid wing dysplasia is not a separate diagnostic criterion in cases with a plexiform neurofibroma of the orbit on the same side.

NIR, near-infrared reflectance imaging; OCT, optical coherence tomography.

eFigure 1.

eFigure 1

Open in a new tab

Café au lait spots

are characterized as follows:

– milk-coffee colored, circumscribed, sharply demarcated

– oval-shaped

– congenital or conatal

– prepubertal: >5 mm in diameter

– post-pubertal: ≥ 15 mm in diameter

eFigure 8.

eFigure 8

Open in a new tab

Optic nerve gliomas

Optic nerve gliomas are also diagnostic criteria for NF1. The term “optic pathway glioma” is more appropriate since the tumor can develop along the entire visual pathway (left image, T2 hyperintense tumor of the left optic nerve just before the optic chiasm, to the right of the image, presentation of the contrast enhancement on the T1 image). NF1-associated optic nerve gliomas show significantly different dynamics as compared with sporadic OPG. The tumors are almost exclusively WHO grade 1 pilocytic astrocytomas, become symptomatic in very few cases, but then respond better to chemotherapy than their sporadic counterparts.

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, 13–15). 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.

Table 2

Open in a new tab

Basic clinical investigations and radiological diagnostic assessment

*1 Children with NF1 have lower body height and higher ratio of head circumference to body height (34). A percentile-crossing for growth of head circumference may be associated with an aqueduct stenosis-related obstructive hydrocephalus (in around 2% of NF1 cases) (35).

*2 Focal neurologic signs and symptoms, severe persistent headache, epileptic seizures, neuro-cognitive alterations

*3 Support from partners, parents, families

*4 Rapidly growing/painful nodules, new neurologic deficits, changes of consistency (e.g., new nodules within a soft neurofibroma)

*5 Changes in digestion, continuous abdominal pain, unintended loss of weight. NF1-associated GIST are often KIT-negative. Surgical treatment without subsequent chemotherapy is therefore of primary importance (12).

*6 The incidence of renal artery stenosis in childhood is about 2% in patients with NF1 (36–38). The risk of a pheochromocytoma or paraganglioma is increased by up to 5.7%, primarily in adulthood (33).

*7 Patients at risk of developing MPNST: atypical PNF, high internal tumor burden, large/multiple PNFs, after radiotherapy, a relative with NF1-MPNST, large NF1 gene deletion (19, 20), or missense variant at codons 844–848.

*8 OPG occurs primarily in the first decade of life (38). Further clarification required using funduscopy in the event of abnormal findings.

*9 The sensitivity of a FDG-PET/CT scan for NF1-associated MPNST is 89–95%, their specificity is 72–95% (39).

*10 The risk of breast cancer in women with NF1 is increased fivefold (24, 25).

CALS, café-au-lait spots; CT, computed tomography; DXA, dual-energy X-ray absorptiometry; GIST, gastrointestinal stroma tumor; KIT, tyrosine kinase KIT or CD117; MRI, magnetic resonance imaging; MPNST, malignant peripheral nerve sheath tumor; NF, neurofibromas; NF1, neurofibromatosis type 1; OPG, optic nerve gliomas; PET, positron emission tomography; PNF, plexiform neurofibroma; CNS tumor, tumor of the central nervous system, such as pilocytic astrocytoma

Table 3.

Table 3

Open in a new tab

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

*1 The examination is difficult in infants under the age of six and requires a high degree of pediatric ophthalmologic expertise. Children with confirmed OPG in particular should be assessed half-yearly. Deterioration of vision is an indication for treatment. MRI is not absolutely necessary without obvious clinical progression.

*2 Also general tumor boards, such as pediatric-oncology boards, neuro-oncology tumor boards, and sarcoma conferences.

*3 The possible impact of high-dose estrogens or other hormone preparations on neurofibroma growth should be pointed out; on the other hand, there are currently no proven contraindications to oral contraception (40).

ADHD, attention-deficit/hyperactivity disorder; CMMRD, constitutional mismatch repair deficiency; JMML, juvenile myelomonocytic leukemia; MPNST, malignant peripheral nerve sheath tumor; NF1, neurofibromatosis type 1; NF, neurofibroma; OPG, optic nerve glioma; OCT, optical coherence tomography; PNF, plexiform neurofibroma

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 (feedbacknf1@bv-nf.de). The overarching goal is to ensure the best and most efficient care and management possible for NF1 patients in Germany.

eFigure 2.

eFigure 2

Open in a new tab

Freckling

Typical freckling (freckle-like ephelides in axillary, inguinal, or submammary areas of skin not exposed to the sun). Freckling is considered a diagnostic criterion if it occurs bilaterally in the axillae and/or groins.

eFigure 3.

eFigure 3

Open in a new tab

Cutaneous neurofibromas

Cutaneous neurofibromas do not usually develop in early childhood but tend to occur in prepuberty or puberty. These are obligatory benign cutaneous nerve sheath tumors which can range in size from a few millimeters to several centimeters. Manifestation severity varies enormously within NF1, even with identical genetic variants. Cutaneous neurofibromas may be absent in some very few genetic subtypes (familial spinal neurofibromatosis), as can Lisch nodules and café-au-lait spots.

eFigure 4.

eFigure 4

Open in a new tab

Lisch nodules

Lisch nodules are benign, hamartomatous collections of melanocytes on the iris of no pathological value. As they usually appear earlier than cutaneous neurofibromas, they are an important diagnostic feature, especially when differentiating from Legius syndrome.

eFigure 5.

eFigure 5

Open in a new tab

Plexiform neurofibroma

In adulthood, a significantly larger proportion of NF1-associated plexiform neurofibromas (PNF) are symptomatic. The growth behavior of plexiform neurofibromas is complex and can only be anticipated to a certain extent. Close clinical monitoring and MRI examinations form the basis for risk stratification and designing an appropriate treatment plan. Apart from predominantly very small cutaneous neurofibromas (a, arrows), an extensive PNF of the neck and shoulder region (b, asterisk) is evident in this case. Dystrophic scoliosis (c, arrow heads) has also developed together with the tumor manifestations. The MRI image clearly demonstrates the infiltrative growth pattern of the PNF (d, asterisk) which is compromising the surrounding structures.

eFigure 6.

eFigure 6

Open in a new tab

Plexiform neurofibroma

Superficial facial, cervical, and thoracic plexiform neurofibromas on the right side of an adult with NF1

eFigure 7.

eFigure 7

Open in a new tab

Nonunion

An osseous malformation typical of neurofibromatosis type 1 in addition to the diagnostic characteristics of tibial bowing (left), tibial pseudarthrosis (middle, multiple previous operations), and sphenoid wing dysplasia (right; the left temporal pole is prolapsing into the orbit, see arrow)

eFigure 9.

eFigure 9

Open in a new tab

Whole-body MRI in a case of NF1

A large plexiform neurofibroma extends from the lumbar region across the pelvis to the left lower leg, manifesting as elephantiasis. The tumor masses appear on MRI as distinct inhomogeneities and distinguishable nodular lesions (asterisk). The PET/CT scan shows significant enhancement (SUVmax 4.6) of retroperitoneal lesions on the left side (arrowhead). A malignant peripheral nerve sheath tumor must be excluded here.

left: T2-weighted STIR SSH coronal; 3T MRI.

right: coronal reformation ([18F] FDG-PET/CT).

Questions on the article in issue 3/2025:

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

The submission deadline is 6 February 2026. Only one answer is possible for each question.

Please select the answer that is most appropriate.

Question 1

How high is the reported incidence of neurofibromatosis type 1 (NF1) in Germany?

  1. 1 in 10 000 neonates

  2. 1 in 5 000 neonates

  3. 1 in 3 000 neonates

  4. 1 in 1 000 neonates

  5. 1 in 300 neonates

Question 2

What is the pattern of inheritance of NF1?

  1. X-linked dominant inheritance

  2. autosomal-dominant

  3. autosomal-recessive

  4. X-linked recessive inheritance

  5. Y-linked inheritance

Question 3

Which examination is considered appropriate after establishing a diagnosis?

  1. One-off lung scintigraphy

  2. One-off bone scan

  3. Two computed tomography scans (with and without contrast) of the whole body

  4. One-off magnetic resonance imaging of the whole body

  5. One-off chest X-ray

Question 4

Genetic analysis is important for excluding the differential diagnoses for NF1. Which of the following disorders is not one of the differential diagnoses mentioned in the article?

  1. Schwannomatosis

  2. Legius syndrome

  3. Marfan syndrome

  4. McCune-Albright syndrome

  5. Incontinentia pigmenti (Bloch-Sulzberger syndrome)

Question 5

Which of the following nutritional deficiencies frequently occurs in patients with NF1?

  1. vitamin B12 deficiency

  2. magnesium deficiency

  3. iron deficiency

  4. folate deficiency

  5. vitamin D3 deficiency

Question 6

Which of the following laboratory parameters can indicate pheochromocytoma?

  1. elevated metanephrines

  2. low lactate levels

  3. elevated levels of troponin

  4. elevated C-reactive protein levels

  5. low blood sugar levels

Question 7

Which of the following criteria is not a diagnostic criterion for type 1 neurofibromatosis?

  1. Lisch nodules

  2. café-au-lait spots

  3. freckling in skin folds

  4. neurofibromas

  5. vitiligo

Question 8

In NF1, which precursor develops into a malignant peripheral nerve sheath tumor as a result of malignant transformation?

  1. non-ossifying fibroma (NOF)

  2. cutaneous neurofibroma

  3. plexiform neurofibroma

  4. intradermal neuroma

  5. schwannoma

Question 9

What is a typical manifestation of neurofibromatosis type 1 in the eye which also occurs predominantly in childhood?

  1. pigment dispersion syndrome

  2. optic nerve glioma

  3. iris coloboma

  4. optic neuritis

  5. heterochromia

Question 10

What is the primary pathomechanism underlying the predisposition of patients with neurofibromatosis type 1 to develop tumors?

  1. inactivation of the tumor suppressor protein p53

  2. overactivation of phospholipase C

  3. inhibition of the serine threonine kinase mTOR

  4. overactivation of the MAP kinase signal pathway

  5. overactivation of Janus kinase 2 (JAK2)

Acknowledgments

Acknowledgments

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

Translated from the original German by Dr. Grahame Larkin

References

1. Huson SM, et al.: J Med Genet 1989; 26: 704–11.

2. Farschtschi S, et al.: Dtsch Arztebl Int 2020; 117: 354–60.

3. Hirbe AC, et al.: Lancet Neurol 2014; 13: 834–43.

4. DeBella K, et al.: Pediatrics 2000; 105: 608–14.

5. Legius E, et al.: Genet Med 2021; 23: 1506–13.

6. Bergqvist C, et al.: Orphanet J Rare Dis 2020; 15: 37.

7. Tucker T, et al.: J Med Genet 2009; 46: 259–65.

8. Heimgärtner M, et al.: Int J Pediatr 2019; 2019: 9493837.

9. Uusitalo E, et al.: J Clin Oncol 2016; 34: 1978–86.

10. Evans DGR, et al.: J Med Genet 2002; 39: 311–4.

11. Lammert M, et al.: Arch Dermatol 2005; 141: 71–4.

12. Carton C, et al.: EClinicalMedicine 2023; 56: 101818.

13. Ferner RE, et al.: J Med Genet 2007; 44: 81–8.

14. Miller DT et al.: Pediatrics 2019; 143: e20190660.

15. Stewart DR, et al.: Genet Med 2018; 20: 671–82.

16. Azizi AA, et al.: Monatsschr Kinderheilkd 2024. doi.org/10.1007/s00112–024–01955–3.

17. Sunder-Plassmann V, et al.: Wien Klin Wochenschr 2024; doi:10.1007/s00508–024–02443–0.

18. Kluwe L, et al.: Hum Mutat 2004; 23: 111–6.

19. Well L, et al.: PLoS Genet 2021; 17: e1009517.

20. Pasmant E, et al.: Hum Mutat 2010; 31: E1506–18.

21. Schnabel C, et al.: Clin Biochem 2014; 47: 560–3.

22. Charoenngam N, et al.: Calcif Tissue Int 2023; 113: 166–74.

23. Al-Sharefi A, et al.: Eur Endocrinol 2019; 15: 95–100.

24. Sharif S, et al.: J Med Genet 2007; 44: 481–4.

25. Evans DGR, et al.: Genet Med 2020; 22: 398–406.

26. Barreto-Duarte B, et al.: PLoS One 2021; 16: e0241096.

27. Sellmer L, et al.: Orphanet J Rare Dis 2017; 12: 34.

28. Agaimy A, et al.: Int J Clin Exp Pathol 2012; 5: 852–62.

29. Schulz A, et al.: Exp Neurol 2018; 299: 334–44.

30. Ferner RE, et al.: J Med Genet 2004; 41: 837–41.

31. Bergqvist C, et al.: Orphanet J Rare Dis 2021; 16: 230.

32. Niemeyer CM, et al.: J Blood 2019; 133: 1060–70.

33. Sung L, et al.: J Pediatr 2004; 144: 666–8.

34. Bizzarri C, et al.: Horm Res Paediatr 2015; 83: 232–41.

35. Glombova M, et al.: Brain Dev 2019; 41: 678–90.

36. Oderich GS, et al.: J Vasc Surg 2007; 46: 475–84.

37. Srinivasan A, et al.: Pediatr Radiol 2011; 41: 308–16.

38. Celik B, et al.: Eur J Pediatr 2021; 180: 3477–82.

39. Ahlawat S, et al.: Skeletal Radiol 2020; 49: 199–219.

40. Lammert M, et al: BMC Cancer 2005; 5: 16.

Footnotes

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.

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;26:704–711. doi: 10.1136/jmg.26.11.704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Farschtschi S, Mautner VF, Lawson McLean AC, Schulz A, Friedrich RE, Rosahl SK. The neurofibromatoses. Dtsch Arztebl Int. 2020;117:354–360. doi: 10.3238/arztebl.2020.0354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13:834–843. doi: 10.1016/S1474-4422(14)70063-8. [DOI] [PubMed] [Google Scholar]
  • 4.DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105:608–614. doi: 10.1542/peds.105.3.608. [DOI] [PubMed] [Google Scholar]
  • 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;23:1506–1513. doi: 10.1038/s41436-021-01170-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1186/s13023-020-1310-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Tucker T, Schnabel C, Hartmann M, et al. Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1) J Med Genet. 2009;46:259–265. doi: 10.1136/jmg.2008.061895. [DOI] [PubMed] [Google Scholar]
  • 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 doi: 10.1155/2019/9493837. 9493837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Uusitalo E, Rantanen M, Kallionpää RA, et al. Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol. 2016;34:1978–1986. doi: 10.1200/JCO.2015.65.3576. [DOI] [PubMed] [Google Scholar]
  • 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;39:311–314. doi: 10.1136/jmg.39.5.311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol. 2005;141:71–74. doi: 10.1001/archderm.141.1.71. [DOI] [PubMed] [Google Scholar]
  • 12.Carton C, Evans DG, Blanco I, et al. ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1. EClinicalMedicine. 2023;56 doi: 10.1016/j.eclinm.2022.101818. 101818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44:81–88. doi: 10.1136/jmg.2006.045906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR. Health supervision for children with neurofibromatosis Type 1. Pediatrics. 2019;143 doi: 10.1542/peds.2019-0660. e20190660. [DOI] [PubMed] [Google Scholar]
  • 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;20:671–682. doi: 10.1038/gim.2018.28. [DOI] [PubMed] [Google Scholar]
  • 16.Azizi AA, Baumgartner AC, Seidel M, et al. Neurofibromatose Typ 1: Vorsorgebogen für Kinder und Jugendliche in Österreich. Monatsschr Kinderheilkd www.doi.org/10.1007/s00112-024-01955-3. 2024 [Google Scholar]
  • 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. doi: 10.1007/s00508-024-02443-0. Online ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kluwe L, Siebert R, Gesk S, et al. Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat. 2004;23:111–116. doi: 10.1002/humu.10299. [DOI] [PubMed] [Google Scholar]
  • 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 doi: 10.1371/journal.pgen.1009517. e1009517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Pasmant E, Sabbagh A, Spurlock G, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 2010;31:E1506–E1518. doi: 10.1002/humu.21271. [DOI] [PubMed] [Google Scholar]
  • 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;47:560–563. doi: 10.1016/j.clinbiochem.2014.02.020. [DOI] [PubMed] [Google Scholar]
  • 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;113:166–174. doi: 10.1007/s00223-023-01094-z. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.17925/EE.2019.15.2.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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;44:481–484. doi: 10.1136/jmg.2007.049346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/s41436-019-0651-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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 doi: 10.1371/journal.pone.0241096. e0241096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1186/s13023-017-0588-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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;5:852–862. [PMC free article] [PubMed] [Google Scholar]
  • 29.Schulz A, Grafe P, Hagel C, et al. Neuropathies in the setting of neurofibromatosis tumor syndromes: complexities and opportunities. Exp Neurol. 2018;299:334–344. doi: 10.1016/j.expneurol.2017.06.006. [DOI] [PubMed] [Google Scholar]
  • 30.Ferner RE, Hughes RA, Hall SM, Upadhyaya M, Johnson MR. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1) J Med Genet. 2004;41:837–841. doi: 10.1136/jmg.2004.021683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1186/s13023-021-01856-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Niemeyer CM, Flotho C. Juvenile myelomonocytic leukemia: who‘s the driver at the wheel? Blood. 2019;133:1060–1070. doi: 10.1182/blood-2018-11-844688. [DOI] [PubMed] [Google Scholar]
  • 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;144:666–668. doi: 10.1016/j.jpeds.2004.02.026. [DOI] [PubMed] [Google Scholar]
  • 34.Bizzarri C, Bottaro G. Endocrine implications of neurofibromatosis 1 in childhood. Horm Res Paediatr. 2015;83:232–241. doi: 10.1159/000369802. [DOI] [PubMed] [Google Scholar]
  • 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;41:678–690. doi: 10.1016/j.braindev.2019.04.003. [DOI] [PubMed] [Google Scholar]
  • 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;46:475–484. doi: 10.1016/j.jvs.2007.03.055. [DOI] [PubMed] [Google Scholar]
  • 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;41:308–316. doi: 10.1007/s00247-010-1854-9. [DOI] [PubMed] [Google Scholar]
  • 38.Celik B, Aksoy OY, Bastug F, Poyrazoglu HG. Renal manifestations in children with neurofibromatosis type 1. Eur J Pediatr. 2021;180:3477–3482. doi: 10.1007/s00431-021-04144-6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s00256-019-03290-1. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1186/1471-2407-5-16. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Deutsches Ärzteblatt International are provided here courtesy of Deutscher Arzte-Verlag GmbH

RESOURCES