Neurofibromatosis type 1 & 2 Neurosurgical

1. NEUROFIBROMATOSIS
PRESENTER-
Dr. Akshay Sarraf
1st year Resident
Dept of General Surgery

2. Objectives
• Introduction
• Types
• Genetics
• Clinical presentation
• Menifestations
• Diagnosis

3. Introduction
• A Neurofibromatosis is an A.D. genetically-inherited disorder in
which the nerve tissue grows abnormally to form tumors
(neurofibromas) that may be benign or may cause serious damage by
compressing nerves and other tissues.
• Affects all neural crest cells (Schwann cells, melanocytes and
endoneurial fibroblasts).

4. • Melanocytes also function abnormally in this disease, resulting in
disordered skin pigmentation and café au lait spots.
• Approximately half of cases are due to de novo mutations and no other
affected family members are seen.
• 
It affects males and females equally.

5. • Neurofibromatosis is not a single medical disorder but refers to three
different conditions involving the development of tumors that may
affect the brain, spinal cord, and the nerves that send signals between
the brain and spinal cord and all other parts of the body.
• Neurofibromatosis type 1 (NF1), historically called von
Recklinghausen disease
• Neurofibromatosis type 2 (NF2)
• Schwannomatosis (SWN)

6. Neurfibromatosis Type 1(NF1)
• NF1, previously known as von Recklinghausen disease, is the
most common type of NF.
• It is a multisystem genetic disorder that is characterized by
cutaneous findings, most notably café-au-lait spots and axillary
freckling by skeletal dysplasias, and by the growth of both
benign and malignant nervous system tumors, most notably
benign neurofibromas.

8. • The hallmarks of NF1 are multiple café-au-lait macules and
neurofibromas.
• The condition is called "segmental NF1" when clinical features are
limited to one area of the body due to somatic mosaicism of a
pathogenic variant in the neurofibromin 1 (NF1) gene.

9. Epidemiology
• NF1 is an autosomal dominant genetic disorder with an
incidence of approximately 1:2600 to 1:3000 individuals.(1)
• Approximately one-half of the cases are familial (inherited).
• The de novo mutations occur primarily in paternally derived
chromosomes.(2)
• Mean age at death for persons with NF1 of 54.4 years and
median of 59 years. (4)

10. Pathogenesis
• NF1 is due to pathogenic variants in the NF1 gene, located at
chromosome 17q11.2.
• The protein product, neurofibromin, belongs to a family of guanosine
triphosphate hydrolase (GTPase)-activating proteins (GAPs) that
stimulate intrinsic GTPase activity in the ras p21 family.
• Ras activates a number of signaling pathways that include the stem
cell factor (SCF)/c-kit signaling, mammalian (mechanistic) target of
rapamycin (mTOR), and mitogen-activated protein kinase (MAPK)
pathways.

11. • Results from loss of production or reduced function of protein,
causing the wide spectrum of clinical findings, including NF1-
associated tumors.
• NF1 is highly variable in its expression and has complete
penetrance and functions as a tumor suppressor gene.
• Somatic mutation or loss of heterozygosity at the NF1 locus, in
combination with a germline NF1 mutation, leads to complete
loss of neurofibromin expression that is seen in NF1 lesions such
as pseudoarthrosis and neurofibromas.

12. • Segmental NF1 is caused by somatic mosaicism due to a postzygotic
mutation in the NF1 gene which results in some cells having two fully
functional NF1 genes and other cells containing a pathogenic variant
in one copy of the NF1 gene.
• Persons with segmental NF1 do not have an affected parent.

13. Clinical Menifestations
• Café-au-lait macules — Café-au-lait macules
are flat, uniformly hyperpigmented macules
that appear during the first year after birth and
usually increase in number during early
childhood. Up to 15 percent of the general
population has one to three café-au-lait
macules; however, the presence of six or more
café-au-lait macules is highly suggestive of
NF1. Approximately 95 percent of adults with
NF1 have café-au-lait macules

14. • Freckling — Freckling in the axillary or
inguinal regions (Crowe sign) is a diagnostic
criterion distinct from café-au-lait macules. The
freckles are smaller in size than café-au-lait
macules, appear later, and usually occur in
clusters in skin folds rather than randomly.
Freckling occurs mostly in regions of skin
apposition, especially the axillary and inguinal
areas.
• Lisch nodules — Lisch nodules are raised, tan-
colored hamartomas of the iris and represent a
specific finding for NF1. These lesions are
detected in fewer than 10 percent of affected
children younger than six years of age but are
seen in greater than 90 percent of adults

15. • Tumors-
• NeuroFibromas-
- Neurofibromas are benign peripheral nerve sheath tumors that are composed
of a mixture of Schwann cells, fibroblasts, perineurial cells, and mast cells. It
is in the Schwann cells where loss of both NF1 alleles occurs, indicating that
this is the primary tumor cell of the neurofibroma
- Neurofibromas may appear as focal growths or extend longitudinally along a
nerve and involve multiple fascicles. The latter are referred to as plexiform
neurofibromas. Neurofibromas may be located in the skin (cutaneous
neurofibromas), along peripheral nerves under the skin or deeper inside the
body(Nodular neurofibroma), and along nerve roots adjacent to the spine.

16. Cutaneous Neurofibroma
Plexiform Neurofibroma

17. Nodular Nerofibroma

18. • Optic pathway gliomas — OPGs occur in approximately 15 percent
of children younger than six years of age with NF1. They rarely occur
as new tumors in older children and adults. OPGs are typically low-
grade pilocytic astrocytomas. They can arise anywhere along the
anterior visual pathway to the optic radiations and involve the optic
nerves, chiasm, and postchiasmal optic tracts.

19. • Bone abnormalities — Bone abnormalities in NF1 include
pseudoarthrosis and bone dysplasia, which are part of the United
States National Institutes of Health (NIH) Consensus Conference
criteria for the disease, as well as short stature, scoliosis, nonossifying
fibromas, sphenoid dysplasia, and osteoporosis
• Long bone dysplasia — Long bone dysplasia presents in infants or
young children as anterolateral bowing of the tibia, which progresses
to narrowing of the medullary canal, cortical thickening, and fracture.
• A pseudoarthrosis is a false joint that forms when there is nonunion
of bone fragments at the site of a long bone fracture. It severely
compromises function in the affected limb.

21. Associated conditions
1. Schwann-cell tumors on any nerve (but bilateral V/S are virtually nonexistent)
2. Spinal and/or peripheral nerve neurofibromas
3. Multiple skin neurofibromas
4. Aqueductal stenosis (p.273)
5. Macrocephaly: secondary to aqueductal stenosis and hydrocephalus, increased
cerebral white matter
6. Intracranial tumors: hemispheric astrocytomas are the most common, solitary or
multicentric meningiomas (usually in adults). Gliomas associated with NF1 are
usually pilocytic astrocytomas. Brainstem astrocytomas include both contrast-
enhancing pilocytic lesions and those that are non-enhancing and radiologically
diffuse

22. 7. Unilateral defect in superior orbit → pulsatile exophthalmos
8. Neurologic or cognitive impairment: 30–60% have mild learning disabilities
9. Kyphoscoliosis (seen in 2–10%, often progressive, which then requires surgical
stabilization)
10. Visceral manifestations from involvement of autonomic nerves or ganglia within
the organ. Up to 10% of patients have abnormal gastrointestinal motility/neuronal
intestinal dysplasia related to neuronal hyperplasia within submucosal plexus
11. ≈ 20% develop plexiform neurofibromas: tumors from multiple nerve fascicles
that grow along the length of the nerve. Almost pathognomonic for NF1
12. Syringomyelia
13. Malignant tumors that have increased frequency in NFT: neuroblastoma,
ganglioglioma, sarcoma, leukemia, wilm’s tumor, breast cancer
14. Pheochromocytoma: is occasionally present

23. 15. “unidentified bright objects” (UBOs) on brain or spinal MRI in 53–
79% of patients (bright on T2WI, isointense on T1WI) that may be
hamartomas, heterotopias, foci of abnormal myelination or low grade
tumors. Tend to resolve with age.
16. Severe hypertension — The most common causes of hypertension in
NF1 are essential hypertension, pheochromocytoma, and, in adults <30
years of age, renal artery stenosis.

24. Investigations
• The diagnosis of neurofibromatosis type 1 (NF1) is usually made clinically,
however, molecular testing may be helpful for younger patients with a
single clinical finding, such as multiple café-au-lait spots in the absence of a
positive family history.
• Sequencing of the neurofibromin gene offers the highest detection rate and may
approach 95% in clinically affected individuals.
• 97% of patients with NF1 are expected to meet clinical diagnosis by the age of 8
years. For those not meeting clinical criteria or for those that overlap with Legius
Syndrome, molecular testing can be useful for confirmation.
• Legius Syndrome should be suspected in patients with macrocephaly, café-
au-lait spots and axillary freckling and no NF1 tumors (neurofibromas, lisch
nodules, optic gliomas or plexiform neurofibromas). Given that NF1 is
more common, testing should start with NF1 sequencing and reflex to
SPRED1 if negative.

25. • Neurofibromatosis type 1 (NF1) may be diagnosed by either of
2 methods during the prenatal period.
• In a family with multiple affected members, linkage analysis can track
the NF1 gene through the generations to determine which
chromosome 17 region the fetus received. However, with advances in
molecular diagnosis, family studies are rarely necessary.
• For a parent with NF1 who is the only affected family member, gene
sequencing can be used to identify a specific gene mutation.
Identification of the mutation in the affected parent would permit
prenatal diagnosis via amniocentesis or chorionic villus sample (CVS).
• When a specific mutation is known, preimplantation genetic
diagnosis can also be offered to couples using in vitro fertilization with
selection of unaffected embryos for transfer.

26. • Urinary free catecholamines (norepinephrine and epinephrine) as well
as their metabolites (normetanephrine, metanephrine and vanillyl-
mandelic acid) measured on a 24-hour urine collection are good
biochemical screening tests for a suspected pheochromocytoma.
• Plasma catecholamines may also be measured using liquid
chromatography. Measurement of free plasma metanephrine is more
sensitive in detection of a pheochromocytoma than plasma
catecholamines.

27. Management
1. Optic gliomas
a) Unlike optic gliomas in the absence of NFT, these are rarely chiasmal
(usually involving the nerve), are often multiple, and have a better
prognosis
b) Most are non progressive, and should be followed
ophthalmologically and with serial imaging (MRI or CT)
c) Surgical intervention probably does not alter visual impairment.
Therefore, surgery is reserved for special situations (large disfiguring
tumors, pressure on adjacent structures, high grade gliomas etc)
d) First-line therapy traditionally consists of chemotherapy
with carboplatin, vincristine or vinblastine monotherapy in low grade
and OPGs.

28. 2. Other neural tumors in patients with NF1 should be managed in the
same manner as in the general population
a) Cutaneous and subcutaneous neurofibromas are not removed unless
there is a specific need for removal (eg, pain, bleeding, interference with
function, disfigurement).
b) Focal, resectable, symptomatic lesions should be surgically removed.
c) Intracranial tumors in NF1 may often be unresectable, and in these
cases chemotherapy and/or radiation therapy may be appropriate, with
surgery reserved for cases with increasing ICP.
d) Selumetinib, an oral selective mitogen-activated protein kinase kinase
(MEK) inhibitor that can induced tumor regression is used in plexiform
neurfibromas in patients with symptomatic and inoperable tumors.

29. e) when malignant degeneration is suspected (rare, but incidence of
sarcomas and leukemias is increased), biopsy with or without internal
decompression may be indicated.
f) Malignant peripheral nerve sheath tumors — MPNSTs are staged
and treated as malignant soft tissue sarcomas. Treatment includes
surgical resection and adjunctive radiation therapy

30. Prognosis
• Several studies have highlighted the decreased life expectancy in
persons with NF1, particularly women, compared with the general
population.
• The age at death is reduced for NF1 patients compared with that of the
general population (median 59 versus 74 years, respectively).
- Rasmussen, S. A., Yang, Q., & Friedman, J. M. (2001). Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. American journal
of human genetics, 68(5), 1110–1118.
• Patients with NF1 and CNS tumors are at increased risk for early
mortality, second CNS malignancies, and vascular complications
• OPGs appear to have a more benign course in patients with NF1 than
in those without NF1

31. Surveillance
a) Annual exam by physician familiar with NF1
b) Annual ophthalmologic exam in children, less frequent in adults
c) Regular developmental assessment of children
d) Regular BP monitoring
e) MRI for follow-up of clinically suspected intracranial and other
internal tumors
f) Annual mammography in women starting at age 30 years & consider
annual breast MRI in women age 30–50 years

32. Genetic Counseling
• NF1 has an autosomal-dominant inheritance pattern. Counseling
should be provided for patients and families.
• Should include information on the inheritance of the disorder
(including potential recurrence risk in other offspring), prognosis, and
psychosocial adjustment.
• The progressive nature of the disease and the variability in clinical
presentation should be addressed.

33. • The risk of having this disorder in each offspring of an affected parent
is 50 percent.
• If a couple has one child with NF1 and neither parent meets the
clinical criteria for NF1 the risk of the parents having another child
with NF1 is less than 1 percent.
• When this occurs, it is most often caused by germline mosaicism such
that a proportion of the gonadal tissue contains the mutation.
• The rate of germline mosaicism in NF1 is much lower than in NF2,
osteogenesis imperfecta, and some other dominant disorders

34. Neurofibromatosis Type 2
• NF2-related schwannomatosis (formerly neurofibromatosis type 2).
• AKA MISME syndrome (Multiple Inherited Schwannomas,
Meningiomas, and Ependymomas).
• Is a dominantly inherited syndrome that predisposes individuals to
bilateral vestibular schwannomas as well as multiple other tumors of
the nervous system.
• NF2 is caused by pathogenic variants in the NF2, moesin-ezrin-radixin
like (MERLIN) tumor suppressor (NF2) gene, which produces merlin,
a tumor suppressor.

35. Molecular Pathogenesis
• NF2 is consistently linked with abnormalities of the NF2 gene, which
is located on chromosome 22.
• The NF2 gene produces merlin, also known as schwannomin, a cell
membrane-related protein that acts as a tumor suppressor.
• Individuals with NF2 may inherit an abnormal NF2 allele from a
parent.
• Alternatively, a de novo variant may arise after fertilization, resulting
in a mosaic expression of two cell lines.

36. • Patients with de novo NF2 found that more than 50 percent of such
cases are potentially due to mosaicism.
• The development of schwannomas and other tumors requires
inactivation of both NF2 alleles, since tumors only develop in cells
that have lost function of their normal NF2 allele.
• The "second hit" usually occurs through loss of the entire
healthy NF2 gene and most or all of chromosome 22.

37. • NF2 is fully penetrant.
• Within a family that includes multiple members with NF2, the
phenotypic expression and natural history of the disease are similar.
• Significant differences have been observed among families harboring
different abnormalities of NF2.
• Frameshift or nonsense variants cause truncated protein expression,
which has been associated with more severe manifestations of NF2;
missense or inframe deletions have been associated with milder
manifestations of disease.

38. Clinical Features
• The estimated incidence of NF2 derived from population-based studies
is as high as 1 in 25,000.
• Patients typically present around 20 to 25 years of age.
• NF2 is an autosomal dominant schwannoma predisposition syndrome
that affects the nervous system as well as eyes and skin.
• In addition to schwannomas and other nervous system tumors, most
patients have one or more ophthalmic and cutaneous manifestations.

39. • Neurologic lesions:
 Bilateral vestibular schwannomas, generally develop by 30 years of age – 90
to 95 percent, typically bilateral and cause tinnitus, hearing loss, and balance
dysfunction.
• Schwannomas of other cranial nerves – 24 to 51 percent, occur at an earlier age
(in the 20s) than sporadic (i.e., non-NF2 associated) schwannomas (in the 50s).
 Intracranial meningiomas – 45 to 77 percent, Approximately one-half of
individuals with NF2 have meningiomas, and multiple meningiomas are often
present.
 Spinal tumors (both intramedullary and extramedullary) – 63 to 90 percent,
include schwannoma, meningioma of spinal cord and ependymomas
 Peripheral neuropathy – Up to 66 percent.

40. Coronal postcontrast T1-
weighted MRI showing bilateral
vestibular schwannomas
(arrows) in a patient with NF2-
related schwannomatosis.

41. ●Eye lesions
Cataracts – 60 to 81 percent, manifested as posterior subcapsular lenticular
opacities.
Epiretinal membranes – 12 to 40 percent
Retinal hamartomas – 6 to 22 percent
●Skin lesions
Cutaneous tumors – 59 to 68 percent
Skin plaques – 41 to 48 percent
Subcutaneous tumors – 43 to 48 percent
• Two subtypes:
1. the more common, severe form with younger age of onset (2nd to 3rd decade),
with rapid progression of hearing loss and multiple associated tumors
2. milder form presents later in life, with slower deterioration in hearing and fewer
associated tumors.

42. Diagnosis

43. Genetic Testing
• There is a high frequency of de novo NF2 cases, and patients may present before the
clinical diagnostic criteria are fulfilled.
• Early identification of patients who have NF2 is important to minimize the
complications associated with disease manifestations.
• Ideally, molecular testing for NF2 should start with tumor deoxyribonucleic acid
(DNA) and then targeted testing of blood lymphocytes by sequencing of
any NF2 aberration identified.
• If two tumors are available, identification of an identical NF2 variant in two tumors
that is not present in blood confirms mosaicism.
• LZTR1 should be assessed if individuals meet NF2 criteria with only nonintradermal
schwannoma disease.

44. • Should be done in patients with-
• A first-degree relative with NF2 (ie, affected parent, sibling, or offspring)
• Multiple spinal tumors (schwannomas, meningiomas)
• Cutaneous schwannomas
• An apparently sporadic vestibular schwannoma in an individual younger than
30 years of age
• A solitary meningioma or nonvestibular schwannoma in an individual younger
than 25 years of age
• Two or more anatomically distinct meningiomas in an individual aged 25 to 69
years and three or more meningiomas at any age

45. Management
• The management of patients with NF2 is complex and involves
multiple disciplines to prevent or treat the various complications that
may develop.
Treatment of vestibular schwannomas —
- The goal of treatment for vestibular schwannomas in individuals with NF2 is
preservation of function and maintenance of quality of life
- Although complex, generally managed surgically if treatment is indicated.
- most NF2 patients will become deaf at some time during their life

46. - Chance of preserving hearing is best when the VS is small. Thus, one should
attempt to remove the smaller tumor
- Prior to surgery, one should obtain MRI of cervical spine to R/O intraspinal
tumors that may cause cord injuries during other operations
- If hearing is serviceable in that ear after surgery, then consider removing the
second tumor, otherwise follow the second tumor as long as possible and
perform a subtotal removal in an attempt to prevent total deafness
- Bevacizumab, a monoclonal antibody against vascular endothelial growth
factor (VEGF), can induce both tumor shrinkage and hearing improvement.

47. • Meningioma management —
• Many meningiomas in NF2 grow to a certain size and stop, and do not require
active treatment.
• For rapidly growing meningiomas and those threatening functional loss,
meningiomas are managed surgically when possible.
• Radiation therapy has been used in patients whose tumors are not surgically
accessible or in those in whom only a partial resection is possible
• Risk factors for more rapid growth (eg, ≥2 cm3 per year) are similar to those
for sporadic meningiomas and include large tumor size, peritumoral edema,
absence of calcifications, and isointense or hyperintense T2-weighted MRI
signal

48. • Intramedullary spinal tumors-
• 75 percent of intramedullary spinal tumors are ependymomas.
• Usually grow very slowly without symptoms for a prolonged period.
• If symptoms require intervention, which is relatively uncommon, treatment is
generally surgical resection rather than radiation therapy

49. Tumor surveillance and follow-up
• Annual history and physical examination, including:
• Audiology with measurement of pure-tone thresholds and word recognition
scores
• Ophthalmologic evaluation
• Cutaneous examination
• Brain MRI:
• Annual beginning at 10 years of age.
• If baseline imaging shows no characteristic sites of involvement, frequency
can be reduced to every two years.
• If tumors are detected, brain MRI should be performed twice yearly in the
first year, then annually.

50. • Spinal MRI:
• Every 24 to 36 months beginning at 10 years of age.
• The interval between scans may be reduced to every three to five years if there
is no disease detected on baseline imaging.
• If tumors are detected, imaging should be repeated in six months to evaluate
tumor growth rate.

51. References
• Handbook of Neurosurgery, Mark S. Greenberg, 9th Edition.
• UptoDate.com
• Medscape.com

52. THANK YOU