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

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.

Figure

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 2

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 (–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

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

eFigure 1

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 2

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

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

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

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

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

eFigure 7

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 8

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.

eFigure 9

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).