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Fitzpatrick's Dermatology, 9th Edition (Chapter-based Decks) > 135: Neurofibromatosis > Flashcards

135: Neurofibromatosis Flashcards

1
Q

What are the five distinct clinical syndromes associated with neurofibromatosis?

A
  1. NF-1 (Von-Recklinghausen disease)
  2. NF-2
  3. Segmental/Mosaic NF-1
  4. Legius syndrome
  5. Schwannomatosis
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2
Q

What is the inheritance pattern of Neurofibromatosis type 1 (NF-1)?

A

NF-1 is inherited in an autosomal dominant manner with 100% penetrance.

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3
Q

What are the genotype-phenotype correlations associated with NF-1?

A
  1. Deletion of entire gene:
    • Increased risk of facial dysmorphism, intellectual disability, early appearance of neurofibromas, and presence of plexiform neurofibromas.
  2. Specific 3 base pair-in frame deletion in exon 17 of NF-1:
    • Associated with CALM, IF, Lisch nodules but does not develop cutaneous or plexiform neurofibromas.
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4
Q

What is the significance of the NF1 gene in neurofibromatosis?

A

NF1 is located on the long arm of chromosome 17 and encodes for neurofibromin.

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5
Q

How does the severity of NF-1 inheritance differ between maternal and paternal lines?

A

The severity of NF-1 is greater with maternal inheritance compared to paternal inheritance.

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6
Q

What is the outcome of a homozygous NF-1 mutation?

A

A homozygous NF-1 mutation is considered lethal.

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7
Q

What is the incidence of neurofibromatosis in live births?

A

1 in 3000 live births.

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8
Q

What are cutaneous neurofibromas and how do they differ from subcutaneous neurofibromas?

A

Cutaneous neurofibromas are softer and protrude just above the skin surface, while subcutaneous neurofibromas arise from peripheral nerves and are generally harder.

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9
Q

What are plexiform neurofibromas and their potential complications?

A

Plexiform neurofibromas may lead to disfigurement, blindness, or organ dysfunction due to compression of vital structures.

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10
Q

What is the significance of loss of heterozygosity of NF-1 in somatic cells?

A

Loss of heterozygosity of NF-1 leads to the inactivation of the normal NF-1 allele, responsible for tumorigenesis and development of discrete and plexiform dermal neurofibromas.

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11
Q

What role does neurofibromin play in cellular function?

A

Neurofibromin acts as a negative regulator of RAS, particularly K-RAS, favoring the inactive state (GDP).

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12
Q

What are Café au Lait spots and their clinical significance in NF-1?

A

Café au Lait spots (CALM) are flat pigmented macules that are often the first manifestation of NF-1, present at birth.

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13
Q

What is intertriginous freckling and its association with NF-1?

A

Intertriginous freckling (IF) refers to CALM spots that are less than 5mm in size, found in areas such as the axillae, inguinal region, and under the breast.

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14
Q

What are discrete neurofibromas and their relevance in NF-1?

A

Discrete neurofibromas are benign tumors that can develop in individuals with NF-1.

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15
Q

What initiates tumorigenesis in NF-1?

A

Tumorigenesis is initiated when both copies of the NF-1 gene cease functioning normally.

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16
Q

What is the function of neurofibromin?

A

Neurofibromin is a negative regulator of RAS, particularly K-RAS, favoring the inactive state (GDP).

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17
Q

What happens to neurofibromin levels in NF-1 gene mutation?

A

There are reduced intracellular levels of neurofibromin.

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18
Q

What is the significance of the size and shape of Café au Lait spots in diagnosing NF-1?

A

The size, shape, and contour of CALM are of no diagnostic significance.

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19
Q

What are the characteristics of cutaneous neurofibromas in NF-1?

A
  • Softer than surrounding tissue
  • Positive Buttonhole sign
  • Protrudes just above the skin surface or lies just under the skin with a violaceous hue.
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20
Q

What is the significance of the ‘Giant café au lait spot’ in relation to plexiform neurofibromas?

A

The ‘Giant café au lait spot’ is associated with plexiform neurofibromas and indicates overlying hyperpigmentation or hypertrichosis.

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21
Q

What are the symptoms and detection methods for malignant peripheral nerve sheath tumors arising from plexiform neurofibromas?

A

Symptoms include:
- Pain
- Rapid growth
- Focal neurologic dysfunction
Detection methods:
1. Biopsy
2. F-FDG PET/CT scan

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22
Q

What percentage of children with NF-1 will develop optic pathway tumors (OPT) and how many will become symptomatic?

A

15% of children with NF-1 will have optic pathway tumors (OPT), but less than half of these will become symptomatic.

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23
Q

What is the typical treatment for neurofibroma-associated pruritus?

A

Treatment with antihistamines.

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24
Q

What is the relationship between NF-1 and malignant peripheral nerve sheath tumors?

A

Malignant peripheral nerve sheath tumors arise from plexiform neurofibromas.

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25
Q

A patient with NF-1 has a rapidly growing, painful mass in a deep plexiform neurofibroma. What is the most likely complication?

A

The most likely complication is the development of a malignant peripheral nerve sheath tumor.

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26
Q

A child with NF-1 has a café au lait macule with overlying hyperpigmentation and hypertrichosis. What is the underlying lesion?

A

The underlying lesion is a plexiform neurofibroma.

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27
Q

What is the most likely complication of a painful mass in a deep plexiform neurofibroma?

A

The most likely complication is the development of a malignant peripheral nerve sheath tumor.

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28
Q

How can a malignant peripheral nerve sheath tumor be diagnosed?

A

Diagnosis can be made using F-FDG PET/CT scan or biopsy.

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29
Q

What is the underlying lesion in a child with NF-1 who has a café au lait macule with overlying hyperpigmentation and hypertrichosis?

A

The underlying lesion is a plexiform neurofibroma.

It may lead to disfigurement, blindness, or loss of limb function depending on its location.

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30
Q

What is the diagnostic sign associated with a soft cutaneous neurofibroma that protrudes above the skin surface?

A

The diagnostic sign is the buttonhole sign, where the lesion feels softer than the surrounding tissue.

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31
Q

What genetic mutation is associated with the transformation of benign to malignant neurofibromas in NF-1?

A

The transformation is associated with RAS mutation.

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32
Q

What are the potential complications of a thoracic plexiform neurofibroma?

A

Thoracic plexiform neurofibromas may invade or compress vital structures such as the ureters, bowel, or spinal cord.

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33
Q

What does a ‘wormy’ sensation on palpation of a plexiform neurofibroma indicate?

A

The ‘wormy’ sensation indicates the involvement of multiple nerve fascicles in the plexiform neurofibroma.

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34
Q

What is a plexiform neurofibroma with overlying hypertrichosis commonly referred to as?

A

This lesion is commonly referred to as a ‘giant café au lait spot.’

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35
Q

What is the characteristic feel of a subcutaneous neurofibroma on the neck?

A

The lesion has a ‘bead necklace’ feel.

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36
Q

What is the recommended imaging modality for detecting malignant transformation in a plexiform neurofibroma?

A

The recommended imaging modality is F-FDG PET/CT scan.

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37
Q

What does a plexiform neurofibroma with a period of rapid growth followed by quiescence indicate?

A

Plexiform neurofibromas have a highly variable growth pattern with periods of rapid growth alternating with periods of quiescence.

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38
Q

What is the clinical term for a plexiform neurofibroma with overlying hyperpigmentation?

A

The clinical term for this presentation is a ‘giant café au lait spot.’

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39
Q

What is the period of greatest risk for the development of symptomatic optic pathway tumors (OPT) in children with NF-1?

A

The first 6 years of life is the period of greatest risk for the development of symptomatic OPT; development after 6 years is unusual.

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40
Q

What are the common ophthalmologic signs associated with symptomatic optic pathway tumors (OPT) in NF-1?

A

Common ophthalmologic signs include:
- Afferent pupillary defect
- Optic nerve atrophy
- Papilledema
- Strabismus
- Defect in color vision

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41
Q

What are Lisch nodules and their significance in NF-1?

A

Lisch nodules are slightly raised, well circumscribed melanocytic hamartomas of the iris that are virtually pathognomonic of NF-1 and do not cause functional impairment of vision.

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42
Q

What is sphenoid wing dysplasia and its consequences in NF-1?

A

Sphenoid wing dysplasia is a congenital mesodermal dysplasia causing poor formation of the wall and/or floor of the orbit, leading to proptosis or enophthalmos.

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43
Q

What is the most commonly affected bone in long bone dysplasia associated with NF-1?

A

The most commonly affected bone in long bone dysplasia associated with NF-1 is the tibia.

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44
Q

What is pseudarthrosis in the context of long bone dysplasia in NF-1?

A

Pseudarthrosis, or ‘False joint’, refers to the failure of primary union following a fracture, which can occur in children with long bone dysplasia associated with NF-1.

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45
Q

What is the risk percentage for developing symptomatic optic pathway tumors (OPT) in the first 6 years of life?

A

30% rapid onset of proptosis, moderate to severe visual loss.

46
Q

What are the common ophthalmologic signs associated with NF-1?

A

Afferent pupillary defect, optic nerve atrophy, papilledema, strabismus, defect in color vision.

47
Q

What is the significance of Lisch nodules in NF-1?

A

They are virtually pathognomonic of NF-1 and do not cause functional impairment of vision.

48
Q

What is the frequency of Lisch nodules in adults with NF-1?

A

> 90% of adults with NF-1.

49
Q

What is the clinical manifestation of chiasmal tumors in NF-1?

A

They manifest as precocious puberty, characterized by accelerated linear growth and development of secondary sexual characteristics.

50
Q

What is the likely diagnosis for a 4-year-old child with NF-1 presenting with proptosis and moderate visual loss?

A

The likely diagnosis is an optic pathway tumor (OPT). The period of greatest risk for symptomatic OPT is the first 6 years of life.

51
Q

What are the clinical manifestations of sphenoid wing dysplasia in NF-1?

A

Sphenoid wing dysplasia can lead to proptosis due to herniation of meninges/brain into the orbit or enophthalmos.

52
Q

What is the most commonly affected bone in long bone dysplasia associated with NF-1 and what complication can arise?

A

The most commonly affected bone is the tibia. A complication that can arise is pseudarthrosis or a ‘false joint.’

53
Q

What is the primary method for diagnosing Neurofibromatosis Type 1 (NF-1)?

A

Diagnosis is primarily clinical, with specific diagnostic criteria that must be met.

54
Q

When is laboratory confirmation necessary for NF-1 diagnosis?

A

Only for presymptomatic individuals or prenatal diagnosis when a mutation has been identified in an affected parent.

55
Q

What is the purpose of a biopsy of a plexiform neurofibroma?

A

It is reserved only for exclusion of malignancy; otherwise, biopsy of cutaneous masses is unnecessary.

56
Q

What genetic mutation is associated with Neurofibromatosis Type 2?

A

Merlin gene mutation on chromosome 22.

57
Q

What are common clinical features of Neurofibromatosis Type 2?

A

Bilateral vestibular schwannomas, meningiomas, and optic nerve sheath schwannomas.

58
Q

How does the morbidity of Neurofibromatosis Type 2 compare to NF-1?

A

It is less common than NF-1 but has greater morbidity, including deafness and paralysis.

59
Q

What are the cutaneous findings associated with Neurofibromatosis Type 2?

A

Characteristic cutaneous schwannoma, which is a plaque-like lesion with a faint violaceous hue, occasionally with hair.

60
Q

What are the ophthalmologic findings associated with Neurofibromatosis Type 2?

A

Juvenile posterior subcapsular cataracts, retinal hamartomas, and optic nerve sheath meningiomas.

61
Q

What are the manifestations of Mosaic Neurofibromatosis type 1?

A

Manifestations of NF-1 include café-au-lait macules (CALM), neurofibromas, and are limited to one area of the body.

62
Q

What is the genetic mutation associated with Neurofibromatosis type 1-Noonan syndrome?

A

Neurofibromatosis type 1-Noonan syndrome is associated with a mutation in the PTPN11 gene.

63
Q

What are the common physical features of individuals with Neurofibromatosis type 1-Noonan syndrome?

A

Common features include hypertelorism, ptosis, down slanting palpebral fissures, posteriorly rotated ears, webbed neck, pectus deformities, and short stature.

64
Q

What is the primary risk associated with Mosaic Neurofibromatosis type 1?

A

Individuals with Mosaic Neurofibromatosis type 1 have a high risk for developing complications of NF-1 in the affected area, particularly neurofibromas.

65
Q

What is the inheritance pattern of Legius syndrome?

A

Legius syndrome is inherited in an autosomal dominant manner and is associated with a SPRED-1 mutation.

66
Q

What are the diagnostic criteria for Schannomatosis in patients over 30 years old?

A

The diagnostic criteria for Schannomatosis in patients over 30 years old include:
1. More than 2 intradermal schwannomas with at least 1 histologic confirmation
2. NF2 diagnostic criteria not fulfilled
3. No evidence of vestibular schwannomas on MRI
4. No first-degree relatives with NF-2
5. No germline mutation of NF-2.

67
Q

What characterizes Schannomatosis?

A

Multiple schwannomas without developing other manifestations of NF-2.

68
Q

What is a key diagnostic criterion for Schannomatosis in patients over 30 years old?

A

More than 2 intradermal schwannomas with at least 1 histologic confirmation.

69
Q

What is the significance of genetic testing in Schannomatosis?

A

To exclude the possibility of NF-2 by looking for vestibular schwannomas.

70
Q

What is the diagnosis for a patient with NF-1 who has multiple intradermal schwannomas but no vestibular schwannomas?

A

The diagnosis is schwannomatosis. It is confirmed by genetic testing and MRI to exclude vestibular schwannomas.

71
Q

What are the general management strategies for NF-1 patients regarding family history and regular check-ups?

A
  • First degree relatives should undergo cutaneous examination and slitlamp examination at the first visit.
  • Patients should have yearly visits to identify NF-1 complications.
  • Children under 10 years should have yearly complete ophthalmologic exams to look for signs of optic pathway tumors (OPT), with frequency reduced for children over 10.
  • Yearly measurements of weight and height should be taken to assess for precocious puberty.
  • Blood pressure measurements are necessary to document renovascular hypertension.
  • A spine assessment should be conducted to check for scoliosis.
72
Q

What treatments are available for cutaneous neurofibromas in NF-1 patients?

A
  • Discrete cutaneous neurofibromas are typically removed surgically.
  • Deeper neurofibromas may require surgical removal if they push on vital structures.
  • Complications of surgery can include regrowth of the original tumor and nerve damage.
  • For pruritus, antihistamines and ketotifen can be used to prevent rapid growth of new fibromas.
  • Other treatments include CO2 laser under general anesthesia and Er:YAG laser ablation for the removal of hundreds of cutaneous neurofibromas.
73
Q

What are the challenges and treatment options for plexiform neurofibromas in NF-1?

A
  • Surgical debulking may be performed to improve cosmesis or prevent loss of function, but complete resection is often impossible due to the infiltrative nature of the tumor.
  • Nontraditional chemotherapy is not commonly used due to:
    1. Lack of growth following treatment may be part of the tumor’s natural history.
    2. Tumor burden is difficult to quantify radiographically.
    3. Plexiform neurofibromas may spread along nerve roots, complicating treatment.
  • Biologics such as Pirfenidone, Sirolimus, and Imatinib have been explored, with Imatinib showing a 70% reduction in size of neurofibromas during treatment.
74
Q

How do optic pathway tumors in NF-1 patients compare to those in non-NF-1 patients?

A
  • Brainstem tumors in both children and adults with NF-1 are generally more indolent than their non-NF-1 counterparts.
  • This suggests that routine screening for these tumors in NF-1 patients may not be beneficial.
75
Q

What is the effect of Imatinib on neurofibromas?

A

Imatinib shows a 70% reduction in size of neurofibromas during treatment.

76
Q

How do optic pathway tumors in NF-1 patients compare to those in non-NF-1 patients?

A

Brainstem tumors in both children and adults with NF-1 are generally more indolent than their non-NF-1 counterparts.

77
Q

What is the recommended management for first-degree relatives of NF-1 patients during their first visit?

A

A cutaneous examination and slitlamp examination.

78
Q

How often should children under 10 years with NF-1 have complete ophthalmologic exams?

A

Yearly.

79
Q

What is the purpose of yearly measurements of weight and height in NF-1 management?

A

To assess for precocious puberty.

80
Q

What type of laser is used for the treatment of Café-au-lait macules (CALMs) in NF-1?

A

Copper vapor laser and QS 755nm Alexandrite laser.

81
Q

What is the surgical approach for discrete cutaneous neurofibromas in NF-1?

A

They are removed surgically.

82
Q

What is a common complication of surgery for deeper neurofibromas?

A

Regrowth of the original tumor and nerve damage.

83
Q

What is the role of sirolimus in the treatment of plexiform neurofibromas?

A

It is an inhibitor of rapamycin that prolongs time to progression by only 4 months in patients with progressive plexiform neurofibromas.

84
Q

Why is routine screening for optic pathway tumors in NF-1 patients not considered beneficial?

A

Because brainstem tumors in both children and adults with NF-1 are generally more indolent than non-NF-1 counterparts.

85
Q

What is the treatment approach for pruritus associated with neurofibromas in NF-1?

A

Antihistamines and ketotifen to prevent rapid growth of new fibromas.

86
Q

What is the significance of BP measurements in NF-1 management?

A

To document renovascular hypertension.

87
Q

What is the primary goal of treatment for vision issues in NF-1 patients?

A

The primary goal of treatment is preservation of vision with minimization of side effects of therapy.

88
Q

What are the two types of scoliosis associated with NF-1 and how do they differ?

A

Type | Description | Treatment |
|—————|—————————————————————————–|——————————-|
| Dystrophic | Result of primary bone dysplasia, characterized by a sharply angulated curve and extreme rotation. | Surgery |
| Non-Dystrophic| More common, similar to idiopathic scoliosis in adolescents. | Expectant management or Bracing|

89
Q

What is the most common cancer associated with NF-1 in women under 40 years old?

A

The most common cancer associated with NF-1 in women under 40 years old is Breast Cancer.

90
Q

What is the significance of malignant peripheral nerve sheath tumors in NF-1 patients?

A

Malignant peripheral nerve sheath tumors almost exclusively arise from preexisting plexiform neurofibromas, and the outcome of therapy is poor.

91
Q

What is the mean age of presentation for pheochromocytoma in NF-1 patients?

A

The mean age of presentation for pheochromocytoma in NF-1 patients is 42 years old.

92
Q

What types of leukemia are children with NF-1 at increased risk for?

A

Children with NF-1 are at increased risk for Juvenile Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL).

93
Q

What is the most common skeletal manifestation of NF-1?

A

Scoliosis (10-30%).

94
Q

What is the recommended management for non-dystrophic scoliosis in adolescents with NF-1?

A

Expectant management or bracing.

95
Q

What is the treatment for dystrophic scoliosis in NF-1?

A

Surgery.

96
Q

What percentage of pheochromocytoma cases in NF-1 patients present with catecholamine associated symptoms and hypertension?

A

61%.

97
Q

What is the common clinical feature of renal artery vasculopathy in patients with neurofibromatosis type 1 (NF-1)?

A

Renal artery vasculopathy is characterized by renovascular hypertension that is not easily controlled with single antihypertensive medication.

98
Q

What are the typical findings associated with cerebral artery vasculopathy in NF-1?

A

Cerebral artery vasculopathy leads to post-stenotic proliferation of small capillaries (Moyamoya), resulting in recurrent bleeding and stroke.

99
Q

What are unidentified bright objects (UBOs) and their significance in NF-1?

A

UBOs are regions of increased signal intensity in T2 weighted images, found in areas like the internal capsule and basal ganglia. They correspond to areas of myelin vacuolization and are present in 60% of children with NF-1.

100
Q

What is the relationship between learning disabilities and intelligence in patients with NF-1?

A

Learning disabilities in NF-1 are common and lifelong, affecting 30-60% of patients.

101
Q

What is the treatment approach for renovascular hypertension due to renal artery vasculopathy in NF-1?

A

The treatment for renovascular hypertension involves percutaneous transluminal angioplasty if the condition is uncontrollable using oral antihypertensives.

102
Q

What is the common association of juvenile xanthogranulomas?

A

NF-1, Juvenile XG, Myeloid leukemia.

103
Q

What is the main characteristic of renal artery vasculopathy in NF-1?

A

Renovascular hypertension that is not easily controlled with single antihypertensive medication.

104
Q

What diagnostic method confirms renal artery vasculopathy?

A

Aortography with selective angiography.

105
Q

What is the treatment for uncontrollable renovascular hypertension in NF-1?

A

Percutaneous transluminal angioplasty.

106
Q

What percentage of children with NF-1 present with unidentified bright objects (UBOs)?

A

60%.

107
Q

What is the mean IQ difference of patients with NF-1 compared to the general population?

A

5-10 points lower.

108
Q

What learning disabilities are common in patients with NF-1?

A

Discrepancies between ability (intellect) and performance.

109
Q

What effect do stimulant medications have on patients with NF-1?

A

They may have a profound beneficial effect.

110
Q

A patient with NF-1 has hypertension that is not controlled with a single antihypertensive medication. What is the most likely cause, and how is it diagnosed?

A

The most likely cause is renovascular hypertension due to renal artery vasculopathy. Diagnosis is confirmed with aortography and selective angiography.

111
Q

A patient with NF-1 has multiple yellowish papules on the head and trunk. What is the diagnosis, and what is the unusual association with NF-1?

A

The diagnosis is juvenile xanthogranulomas. There is an unusual association of NF-1 with juvenile xanthogranulomas and myeloid leukemia.

Fitzpatrick's Dermatology, 9th Edition (Chapter-based Decks) (48 decks)

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