Neurofibromatosis by Dr. Basil Tumaini, presented at Muhimbili National Hospital in Dar es Salaam Tanzania

1. NEUROFIBROMATOSIS (NF)
Dr. Basil Tumaini
Resident, Internal Medicine (MUHAS)
07 December 2016

2. PRESENTATION OUTLINE
• A (sample) case report from the internet
• Discussion and review of literature:
epidemiology, pathogenesis, clinical
manifestations, Diagnosis,Treatment, Prognosis
• Take home message
• References
Basil Tumaini, Resident Int. Med. (MUHAS) 2

3. History
• Demographics: 52 years old, male, Bulgaria
• Chief complaints:
 Multiple hyperpigmented skin lesions – since
childhood
 Skin growths – 6 years ago
• The disease started in childhood with the
appearance of multiple hyperpigmented
lesions
• At the age of 46, a lot of skin growths
appeared all over the body surface especially
on the left eyelid
Basil Tumaini, Resident Int. Med. (MUHAS) 3

4. History ...
• The patient is mentally retarded
• He had not consulted a doctor since then
• A growth appeared on the upper eyelid of LE
• It caused visual difficulties making him to seek
care
Basil Tumaini, Resident Int. Med. (MUHAS) 4

5. Dermatology:
Numerous soft cutaneous nodules of variable sizes, most
numerous on the trunk and limbs, ranging from a few
millimeters to several centimeters in diameter
On examination
Basil Tumaini, Resident Int. Med. (MUHAS) 5

6. Some of them were pedunculated
Basil Tumaini, Resident Int. Med. (MUHAS) 6

7. Had multiple café-au-lait spots with diameter > 1.5 cm
Basil Tumaini, Resident Int. Med. (MUHAS) 7

8. Axillary, as well as inguinal, freckling was present
The mucous membranes were not affected
Basil Tumaini, Resident Int. Med. (MUHAS) 8

9. Ophthalmological status:
Multiple cutaneous nodules
of different sizes on eyelids of
both eyes without
inflammation
There was a 1.5 cm nodule
that affected the edge of
eyelid and spread
approximately 1 cm to the
eyelid margin on the lateral
part of the left upper eyelid
The upper eyelid had partial
secondary ptosis
Basil Tumaini, Resident Int. Med. (MUHAS) 9

10. Lisch’s nodules on the iris of both eyes were
without clinical visual involvement
Basil Tumaini, Resident Int. Med. (MUHAS) 10

11. • No other alterations in the central or
peripheral nervous system were detected
• The vestibulocochlear nerve was also intact
Basil Tumaini, Resident Int. Med. (MUHAS) 11

12. Investigations
• The standard laboratory tests values were in
the normal range.
• X-ray and CT are were normal
• The histological result confirmed the diagnosis
of neurofibromatosis
Basil Tumaini, Resident Int. Med. (MUHAS) 12

13. Diagnosis
• Neurofibromatosis type 1 (NF-1)
Basil Tumaini, Resident Int. Med. (MUHAS) 13

14. Treatment
• Excision of the eyelid tumor
Basil Tumaini, Resident Int. Med. (MUHAS) 14

15. Outcome
• A good cosmetic result was achieved.
• The excised material was sent for histological
examination.
• After the excision, the configuration of upper
eyelid was restored and peripheral vision of
left eye - which was the main complaint of the
patient – improved
Basil Tumaini, Resident Int. Med. (MUHAS) 15

16. Discussion and Literature review
• The neurofibromatoses are a group of three
genetically distinct disorders that cause
tumors to grow in the nervous system
• Tumors begin in the supporting cells that
make up the nerve and the myelin sheath
Basil Tumaini, Resident Int. Med. (MUHAS) 16

17. Classification
1. Neurofibromatosis type 1 (NF1, also called
von Recklinghausen disease),
2. Neurofibromatosis type 2 (NF2)
3. Schwannomatosis
Basil Tumaini, Resident Int. Med. (MUHAS) 17

18. Epidemiology (1)
• Incidence of NF-1 is approximately 1 in 2600
to 3000 individuals (in US)
• Approximately 1/2 of the cases are familial.
The remainder result from de novo (sporadic)
mutations
• No sex predilection
• De novo mutations occur primarily in
paternally derived chromosomes, the
likelihood of which increases with advanced
paternal age
Basil Tumaini, Resident Int. Med. (MUHAS) 18

19. Epidemiology (2)
• The incidence of NF-2 may be as high as 1 in
25,000
• More than 1/2 of cases represent de novo
mutations and occur in the absence of a
positive family history
• Schwannomatosis is an uncommon disorder,
with an annual incidence estimated at 0.58
cases per 1,000,000 persons; mostly sporadic
Basil Tumaini, Resident Int. Med. (MUHAS) 19

20. Epidemiology (3)
• In a 5-year-period, 23 cases of PN tumours were seen
at the pathology department of Muhimbili Medical
Cente.
• Nine of these had von-Recklinghausen's disease
(neurofibromatosis).
• One of these patients developed malignant
schwannomas at two different sites simultaneously
• Patients with malignant disease in Tanzania as in other
sub-Saharan African countries usually get to the large
referral hospitals late in the course of their disease
Basil Tumaini, Resident Int. Med. (MUHAS) 20

21. Pathogenesis (1)
NF-1 NF-2 Schwannomatosis
Mutation mutations in
the NF1 gene,
located at
chromosome
17q11.2
abnormalities of the
NF2 gene, which is
located on
chromosome 22
mutations in the
SMARCB1 on
chromosome
22q11.23; INI1;
LZTR1 is located on
chromosome
22q11.21
Inheritance autosomal
dominant
autosomal
dominant
AD in about 15%
Protein product Neurofibromin
expressed in many
tissues including
brain, kidney,
spleen, and thymus
merlin, a cell
membrane-related
protein that acts as
a tumor suppressor
Penetrance
Expression
Complete
Variable
Complete
Variable
Reduced
Variable
©Basil Tumaini, 2016
Basil Tumaini, Resident Int. Med. (MUHAS) 21

22. Pathogenesis (2)
• 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 includes the stem cell factor (SCF)/c-
kit signaling, mechanistic target of rapamycin
(mTOR), and mitogen-activated protein
kinase (MAPK) pathways
Basil Tumaini, Resident Int. Med. (MUHAS) 22

23. Pathogenesis (3)
• Mutations in the NF1 gene result in reduced
amounts of functional protein, causing the
wide spectrum of clinical findings, including
NF1-associated tumors
Basil Tumaini, Resident Int. Med. (MUHAS) 23

24. Clinical manifestations of NF-1 in typical order of
appearance
• Café-au-lait macules
• Axillary and/or inguinal freckling
• Lisch nodules (iris hamartomas)
• Neurofibromas
• Osseous lesions, if present, usually appear during the patient's
1st year after birth
• Symptomatic optic pathway glioma (OPG) usually occurs by the
time the patient is 3 years of age
• Other tumors and neurologic complications typically begin to
appear after the 1st year of life.
• Hypertension may occur in childhood.
• Malignant transformation of tumors may also occur in
childhood, but more often occurs in adolescence and adulthoodBasil Tumaini, Resident Int. Med. (MUHAS) 24

25. Café-au-lait macules
•Flat, uniformly
hyperpigmented macules that
appear during the first year
after birth and usually
increase in number during
early childhood
•The number of café-au-lait
macules then stabilizes over
time
•Up to 15 percent of the
normal population has one to
three café-au-lait macules
•The presence of six or more
café-au-lait macules is highly
suggestive of NF1
Basil Tumaini, Resident Int. Med. (MUHAS) 25

26. Freckling
•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
intertriginous areas: axillary,
inguinal and inframammary
areas (in women)
•Usually is not apparent at
birth, but often appears by age
3 - 5 years, typically first in the
inguinal region
•The presence of a café-au-lait
macule in a skin fold does not
constitute a skin-fold freckle.
Basil Tumaini, Resident Int. Med. (MUHAS) 26

27. Lisch nodules
•Raised, tan-colored hamartomas of
the iris
•Represent a specific finding for
NF1
•Do not affect vision in any manner
•Useful both in establishing a
diagnosis of NF1 in a child and
determining whether a parent is
affected
•Detected in < 10 % of affected
children younger than 6 years of
age, but are seen in >90 percent of
adults
•May be seen with a direct
ophthalmoscope, if the nodules are
large or numerous and the iris is
light
•Best seen thorough slit-lamp
examination by an ophthalmologist
to detect the lesions and to
distinguish them from iris nevi
Basil Tumaini, Resident Int. Med. (MUHAS) 27

28. Tumors
• Patients with NF1 develop both benign and
malignant tumors at increased frequency
throughout life
• Neurofibromas are the most common type of
benign tumor that develops in patients with NF1
• OPGs are the predominant type of intracranial
neoplasms
• Overall risk of malignancy in NF1 is increased
2.5- to 4-fold higher than that of the general
population
Basil Tumaini, Resident Int. Med. (MUHAS) 28

29. Bone abnormalities
• Bony abnormalities in NF1 include
pseudoarthrosis and bone dysplasia as well as
short stature, scoliosis, and osteoporosis
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30. Neurologic abnormalities
• Cognitive deficits and learning disabilities
• Seizures
• Gross and fine motor developmental delays
are also seen
• Macrocephaly is a common feature
• Peripheral neuropathy is much less common
in NF1 than in NF2
Basil Tumaini, Resident Int. Med. (MUHAS) 30

31. Hypertension
• Hypertension is a frequent finding in adults with NF1
• May develop during childhood
• Hypertension is considered essential in most cases,
but vascular lesions producing renovascular
hypertension are more frequent in NF1 patients. Thus,
evaluation for renovascular causes should be initiated
in children with NF1 and hypertension
• A much less common cause of hypertension in NF1 is
pheochromocytoma, which has been clinically
identified in 0.1 to 5.7 percent of patients
Basil Tumaini, Resident Int. Med. (MUHAS) 31

32. Other manifestations
• Very rarely, patients may develop cardiovascular
complaints or airway compromise due to mediastinal
neurofibromas or MPNST metastases to the heart and
lung
• Pulmonary hypertension, pulmonary artery stenosis,
ILD, and bullous lung disease have also been reported.
• Pulmonary embolism and AMI have occurred in
patients with both NF1 and pheochromocytoma
• Other vascular lesions may cause stenosis of major
vessels, including the internal carotid, resulting in
moyamoya syndrome. In rare instances, arterial
dissection can occur, sometimes leading to life-
threatening hemorrhage
Basil Tumaini, Resident Int. Med. (MUHAS) 32

33. Segmental NF1
• Due to mosaicism for an NF1 gene mutation
• The presentation of segmental and generalized NF1 is
mostly similar with regard to the age of appearance of the
specific features
• In segmental NF1, pigmentary features and plexiform
neurofibromas tend to present in children, while dermal
neurofibromas develop in adults. Lisch nodules may be
present in one or both eyes.
• In most patients, the affected area is limited to one side,
with involvement ranging from a narrow strip to one-half
of the body
• More serious complications of NF1, such as OPGs,
pseudoarthrosis, plexiform neurofibromas, and learning
difficulties, are uncommon in patients with segmental NF1,
occurring in 5.6 percent in one series of 124 patients
Basil Tumaini, Resident Int. Med. (MUHAS) 33

34. Clinical manifestations of NF-2
 Patients typically present around 20 years of age
 The most frequent clinical features include:
Neurologic lesions
Bilateral vestibular schwannomas, generally
developing by 30 years of age – 90 to 95 %
Schwannomas of other cranial nerve – 24 to 51 %
Intracranial meningiomas 45 - 77 %
Spinal tumors (both intramedullary and
extramedullary) 63 - 90 %
Peripheral neuropathy – Up to 66 %
Basil Tumaini, Resident Int. Med. (MUHAS) 34

35. Clinical manifestations of NF-2 ...
Eye lesions
 Cataracts – 60 to 81 %
 Epiretinal membranes – 12 to 40 %
 Retinal hamartomas – 6 to 22 %
Skin lesions
 Cutaneous tumors – 59 to 68 %
 Skin plaques – 41 to 48 %
 Subcutaneous tumors – 43 to 48 %
Basil Tumaini, Resident Int. Med. (MUHAS) 35

36. Clinical features of Schwannomatosis
• Most patients with schwannomatosis present
in adulthood with one or more symptomatic
schwannomas and pain that may or may not
localize to known tumors
• The average age of symptom onset is 25 - 30
years
• Multiple schwannomas are the hallmark
feature of schwannomatosis
Basil Tumaini, Resident Int. Med. (MUHAS) 36

37. Diagnosis
• History
• Physical examination
Diagnostic criteria
± Genetic testing
± Imaging and other investigations
Basil Tumaini, Resident Int. Med. (MUHAS) 37

38. Diagnosis ...History
• History should be obtained regarding
symptoms associated with the disorder, such
as pain, visual complaints, weakness or
neurologic deficits, headaches, and seizures
• The developmental history and school
progress should be reviewed
• A detailed family history should also be
obtained
Basil Tumaini, Resident Int. Med. (MUHAS) 38

39. Diagnosis ... Physical examination
• Examine skin: (new) peripheral neurofibromas,
signs of plexiform neurofibromas, or progression
of existing lesions
• Check blood pressure for signs of hypertension
• Evaluate growth measurements including height,
weight, and head circumference
• Evaluate for skeletal changes, including scoliosis,
vertebral changes, and limb abnormalities,
particularly tibial dysplasia in young patients
• A formal ophthalmologic examination, including
visual screening
Basil Tumaini, Resident Int. Med. (MUHAS) 39

40. Diagnosis ... Physical examination
• Assessment for precocious puberty – Evaluate older
children for early development of secondary sexual
characteristics or abnormal growth acceleration that
may be associated with lesions of the pituitary from
optic glioma involving the chiasm
• Developmental assessment – Evaluate
neurodevelopmental progress and evidence for
attention-deficit disorder
• Monitoring of plexiform neurofibromas – (Patients
should be questioned, particularly in adolescence,
about any change in pain or growth pattern associated
with a preexisting plexiform neurofibroma and, if
found) should be evaluated for possible malignant
transformation of the neurofibroma
Basil Tumaini, Resident Int. Med. (MUHAS) 40

41. Diagnosis ...
Basil Tumaini, Resident Int. Med. (MUHAS) 41

42. Diagnosis ...
Genetic testing
• Often not required to make the diagnosis
• Can be helpful in confirming the diagnosis for
children who do not meet diagnostic criteria
or only demonstrate café-au-lait macules and
axillary freckling
Basil Tumaini, Resident Int. Med. (MUHAS) 42

43. Diagnosis of NF-2:presence of ONE of the following
criteria
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44. Diagnosis of schwannomatosis
Basil Tumaini, Resident Int. Med. (MUHAS) 44

45. Diagnosis of schwannomatosis ...
Basil Tumaini, Resident Int. Med. (MUHAS) 45

46. Diagnosis of schwannomatosis ...
Basil Tumaini, Resident Int. Med. (MUHAS) 46

47. Imaging and other investigations
• The decision to obtain testing such as imaging studies
depends upon the history and physical findings
• Clinical evaluation appears to be more useful to detect
complications than are screening investigations in
asymptomatic patients
Basil Tumaini, Resident Int. Med. (MUHAS) 47

48. An axial T2 weighted MRI
Diffuse high
signal intensity
of a large left
intra-orbital
optic nerve
glioma seen
Basil Tumaini, Resident Int. Med. (MUHAS) 48

49. Coronal T2 weighted
MRI
Diffuse high
signal intensity
of a large left
intra-orbital
optic nerve
glioma seen
Basil Tumaini, Resident Int. Med. (MUHAS) 49

50. Axial T1 weighted
MRI following
gadolinium
shows
diffuse,
intense
enhancemen
t of the
tumor
(arrow)
Basil Tumaini, Resident Int. Med. (MUHAS) 50

51. MRI of a patient
with NF2
The hallmark of
the condition is
bilateral
vestibular
schwannomas
(seen as rounded
white structures
in the center of
the figure).
Basil Tumaini, Resident Int. Med. (MUHAS) 51

52. DDx of NF-1
• Legius syndrome
clinical features are a subset of those of NF1
multiple café-au-lait macules, axillary freckling, and
macrocephaly
lack neurofibromas and central nervous system (CNS)
tumors
• Constitutional mismatch repair-deficiency
(CMMR-D) syndrome
hematologic malignancies typically develop in infancy
to early childhood
brain tumors (primarily glioblastoma) in mid-
childhood
CRC in adolescence to young adulthood
Basil Tumaini, Resident Int. Med. (MUHAS) 52

53. DDx of NF-1
• Noonan syndrome
short stature, webbed neck, characteristic facial
features, and pulmonic stenosis
Affected individuals may have café-au-lait spots,
sometimes > 6 that are larger than 5 mm (which
fulfills a diagnostic criterion for NF1 in children)
• Neurofibromatosis type 2
Basil Tumaini, Resident Int. Med. (MUHAS) 53

54. Key differences between NF1 and NF2
 Café-au-lait macules are much less frequent in NF2,
and Lisch nodules are not seen.
 The schwannomas associated with NF2 rarely undergo
malignant transformation into a malignant peripheral
nerve sheath tumor (MPNST).
 The spinal root tumors that are seen with both NF2
and NF1 are schwannomas in NF2 and neurofibromas
in NF1.
 NF2 is not associated with the cognitive impairment
that is often seen with NF1.
 NF2 is associated with a very high prevalence of
bilateral acoustic schwannomas
Basil Tumaini, Resident Int. Med. (MUHAS) 54

55. DDx of NF-2
 Sporadic vestibular schwannomas: unilateral
 Neurofibromatosis type 1
 Schwannomatosis: can develop intracranial
and peripheral schwannomas involving spinal
roots, plexuses, and peripheral nerves but
sparing the vestibular nerve
 Familial meningioma: not associated with
abnormalities of the NF2 gene
Basil Tumaini, Resident Int. Med. (MUHAS) 55

56. DDx of Schwannomatosis
NF-2
• presence of bilateral vestibular schwannomas,
which are a key clinical feature of NF2 and
incompatible with a diagnosis of
schwannomatosis
• absence of bilateral vestibular schwannomas
on a high-resolution brain MRI is particularly
reliable for ruling out NF2 in patients over the
age of 30 years
NF-1
Basil Tumaini, Resident Int. Med. (MUHAS) 56

57. Treatment of NF1
There is no one overall treatment for NF1, nor
are there any therapeutic agents specifically
approved for patients with NF1
Individual manifestations are treated as they
arise
Multidisciplinary team approach is important
Basil Tumaini, Resident Int. Med. (MUHAS) 57

58. Treatment of NF1 ...
 Longitudinal care for individuals with NF1
 The approach to treatment of the various
tumors associated with NF1
 Neurologic disorders
 Orthopedic intervention: long bone dysplasia
and scoliosis
 Counseling should be provided for patients
and families
Basil Tumaini, Resident Int. Med. (MUHAS) 58

59. Longitudinal care for individuals with NF1
• Aims at the early detection and symptomatic
treatment of complications as they occur
• In providing medical supervision to children with
NF1, the frequency of follow-up visits should
increase to address disease complications as they
arise
• The decision to obtain diagnostic studies
depends upon the history and physical findings.
Clinical evaluation appears to be more useful to
detect complications than are screening
investigations in asymptomatic patients
Basil Tumaini, Resident Int. Med. (MUHAS) 59

60. Treatment of the various tumors
• Depends upon the type of tumor, its effect on
adjacent tissues, and related complications
• No specific medical treatment for
neurofibromas exists
• Surgical treatment and pain management of
plexiform neurofibromas can be challenging
• Surgical resection often is limited to debulking
of a specific area of a large lesion
Basil Tumaini, Resident Int. Med. (MUHAS) 60

61. Neurologic disorders that may require
specific management
• Cognitive deficits
• Learning disabilities
• Seizures
• Peripheral neuropathy
Basil Tumaini, Resident Int. Med. (MUHAS) 61

62. 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
• Identification of a tumor per se is not an indication for
treatment and the potential benefits must be
balanced against the risks of active intervention.
• Treatment is generally indicated when there is a risk
of brainstem compression, deterioration of
hearing, and/or facial nerve dysfunction
• If treatment is required in patients with NF2,
vestibular schwannomas are generally managed
surgically
Basil Tumaini, Resident Int. Med. (MUHAS) 62

63. Treatment of vestibular schwannomas ...
• Stereotactic radiosurgery and stereotactic radiotherapy
have become important modalities in the treatment of
appropriately selected patients with sporadic vestibular
schwannomas
• The role of radiation therapy in managing vestibular
schwannomas in patients with NF2 is less clear with
reports showing variable outcomes
• For patients with severe hearing impairment, strategies
such as cochlear or brainstem implants may offer some
benefit
• Targeted therapies are an area of active investigation
Basil Tumaini, Resident Int. Med. (MUHAS) 63

64. Treatment of schwannomatosis
• Primarily symptomatic
• No established medical therapies that target
the underlying disease at the present time
• Multidisciplinary team
• Pain management
one of the most common symptoms of
schwannomatosis
Severity of pain varies widely between patients and can
often be severe and incapacitating
Pharmacologic & non pharmacologic management
Basil Tumaini, Resident Int. Med. (MUHAS) 64

65. Pain management: Pharmacologic therapy
• Treatment with gabapentin or pregabalin and
use of short acting opioids and/or NSAIDs for
breakthrough pain can be successful for many
patients
• Additional agents, including TCAs such
as amitriptyline, serotonin-norepinephrine
reuptake inhibitors such as duloxetine, or
antiepileptics such as topiramate or
acarbamazepine, as adjuncts or independently
Basil Tumaini, Resident Int. Med. (MUHAS) 65

66. Nonpharmacologic therapy
• Meditation, yoga and mindfulness-based
stress reduction (MBSR) techniques can help
with relaxation, stress reduction, dealing with
difficult emotions, examining thoughts and
beliefs about pain, and training the mind to be
less reactive to painful sensations
Basil Tumaini, Resident Int. Med. (MUHAS) 66

67. Surgery
• Medically refractory local pain, spinal cord
compression, or impingement of other organs
• highly individualized and is dependent on the
size, location and complexity of tumors, the
need for pathologic conformation for
diagnosis, the presence and/or progression of
neurologic or systemic symptoms, and pain
Basil Tumaini, Resident Int. Med. (MUHAS) 67

68. Surgery
• Surgical resection of these tumors is often complex and
may put patients at risk of additional neurologic
compromise.
• The goals of surgery should be explicitly discussed with
the patient.
• In general, the goal of surgery is to prevent progression
of symptoms as neurologic dysfunction is unlikely to be
reversed by tumor resection
• If pain is the primary indication, patients should be
counseled that, though surgery may relieve pain, it is
also possible that it will be ineffective or could even
worsen pain
Basil Tumaini, Resident Int. Med. (MUHAS) 68

69. Prognosis
• Information about the effect of NF1 on mortality
is limited, although life expectancy appears to be
shortened
• Malignant neoplasms, particularly malignant
peripheral nerve sheath tumors (MPNST), are the
primary cause of decreased survival
• Mean 54.5 versus 70.1 years and median 59
versus 74 years
• NF1 patients were more likely to have a
malignant neoplasm listed on their death
certificates, especially if death occurred before
they reached 30 years of age
Basil Tumaini, Resident Int. Med. (MUHAS) 69

70. Takehome message
• Management of neurofibromatosis requires
multidisciplinary team approach
• The decision to obtain testing such as imaging
studies should be based upon the history and
physical findings
Basil Tumaini, Resident Int. Med. (MUHAS) 70

71. Reference
• UpToDate
Basil Tumaini, Resident Int. Med. (MUHAS) 71