Neurocutaneous Disorders

1

What are the two main forms of neurofibromatosis?

Neurofibromatosis type 1 (NF-1 or von Recklinghausen's disease) and neurofibromatosis type 2 (NF-2). NF-1 accounts for 90% of all cases of neurofibromatosis and affects approximately 1 in 2600–3000 individuals. NF-2 is a genetically distinct entity with a prevalence of 1 in 25,000. Both conditions have autosomal dominant inheritance with 50% of cases representing sporadic (de novo) mutations.

2

Where is the gene for NF-1 located? What protein does it encode? What is the function of this protein?

The NF-1 gene is a large gene mapping to chromosome 17q11.2. It encodes a protein called neurofibromin, which functions as a tumor suppressor by inhibiting the Ras signal. Ras promotes mitogen-activated protein kinase (MAPK) pathways, which contribute to cell survival and proliferation. Mutations in neurofibromin remove the inhibition of the Ras-MAPK pathway promoting tumor growth.

Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type I—mutations in NF1 gene as a cause of disease. Dev Period Med . 2014;18:297–306.

3

What is the earliest manifestation of NF-1?

Café-au-lait macules (CALMs) and axillary/inguinal freckling are the earliest cutaneous sign of NF-1. These sharply defined, light brown patches may be present at birth but more commonly appear by the first year of life ( Fig. 5.1 ). They are noted initially by 4 years or less in all affected children and within the first year in 82% of cases. Osseous dysplasia, such as sphenoid wing dysplasia, and plexiform neurofibormas may be present at birth or arise earlier than CALMs but can go undetected until later in life.

Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol. 2009;61:1–14.

4

What is Crowe's sign? When does it develop?

Crowe's sign is freckling of the axillae or other body folds. It develops in 90% of NF-1 patients, usually by age 3 to 5 years. These lesions are not really freckles, but multiple small café-au-lait macules.

5

When do neurofibromas appear in NF-1?

Neurofibromas usually start to develop just before or during puberty but increase in size and number in early adult life. They are soft, pink, or skin-colored papules, nodules, or tumors distributed mainly over the trunk and limbs ( Fig. 5.2 ). They increase in size and number with age and can range from a few to thousands, with the highest density occurring over the trunk.

6

What is a plexiform neurofibroma?

Plexiform neurofibromas are neurofibromas that grow longitudinally along a nerve involving multiple fascicles. Lesions are usually congenital and can grow rapidly in childhood. They can be deep or superficial and present with overlying skin hypertrophy, hyperpigmentation, and hypertrichosis. They are a major cause of morbidity and are often disfiguring ( Fig. 5.3 ).

7

Why is it necessary to follow patients with plexiform neurofibroma(s)?

Studies examining the behavior of plexiform neurofibromas have found a rate of malignant degeneration between 3% and 15%. The sudden onset of rapid growth, acute pain, or neurologic deficit in an associated plexiform neurofibroma may be a sign of malignant transformation into a malignant peripheral nerve sheath tumor (MPNST).

8

What are Lisch nodules?

Melanocytic hamartomas of the iris. When multiple, these lesions are pathognomonic of NF-1, occurring in more than 90% of patients by the second decade. They are best seen on slit lamp examination ( Fig. 5.4 ).

9

What is the most common central nervous system (CNS) tumor occurring in NF-1?

Optic pathway gliomas, which are typically low-grade astrocytomas, occur in 15% of patients before 6 years of age. They can occur anywhere on the optic pathway, and a majority are asymptomatic. A minority of children become symptomatic with visual disturbance, but advanced tumors involving the hypothalamus can present with precocious or delayed puberty which can alert the clinician to their presence.

Guillamo JS, Creange A, Kalifa C, et al. Progrnostic factors of CNS tumours in neurofibromatosis 1 (NF-1): a retrospective study of 104 patients. Brain 2003;126:152.Lewis RA, Gerson LP, Axelson KA, et al. Von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology. 1984;91:929.

10

What are the most common skeletal abnormalities in NF-1?

Scoliosis and macrocephaly are the most common skeletal abnormalities in NF-1. Pseudoarthrosis, or false joint formation following nonunion of bone following fracture, is a highly suggestive finding of NF-1. NF-1 is the most common cause of pseudoarthrosis, accounting for up to 50%–80% of cases. Long bone and sphenoid wing dysplasia are less common and are usually present at birth.

Elefteriou F, Kolanczyk M, Schindeler A, et al. Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am J Med Gen A. 2009;149A:2327–2338.

11

What is segmental NF?

Formerly known as NF-5, segmental NF is due to a post-zygotic mutation in the NF-1 gene leading to somatic mosaicism. It can present with CALMs and neurofibromas involving a block-like or blaschkolinear pattern with midline demarcation, and in 30% of patients, there may be extra-cutaneous systemic manifestations.

Garcia-Romero MT, Parkin P, Lara-Corrales I. Mosaic neurofibromatosis type 1: a systematic review. Pediatr Dermatol. 2016;33:9–17.

12

How frequently should patients with NF-1 be assessed? What should this assessment include?

An annual assessment is usually sufficient. The clinical examination should include a blood pressure measurement (hypertension occurs in 6% due to renovascular stenosis or pheochromocytoma) and a full neurologic examination. Children should receive an annual eye exam until the age of 10; surveillance for scoliosis, precocious puberty, and hypogonadism; and regular developmental assessments. Additional investigations should be guided by symptoms or physical signs. Lifelong follow-up is recommended for the surveillance of MPNSTs.

Drappier J-C, Khosrotehrani K, Zeller J, et al. Medical management of neurofibromatosis 1: a cross sectional study of 383 patients. J Am Acad Dermatol. 2003;49:440–444.

13

What are the diagnostic criteria for NF-2?

The diagnostic criteria are met by an individual who has:

• Bilateral vestibular schwannomas before age 70 or unilateral vestibular schwannomas and first-degree relative with NF-2

• First-degree relative with NF-2 or unilateral eighth nerve mass and any two of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity.

14

Where is the gene for NF-2? What is the gene product?

The NF-2 gene is located on chromosome 22q12.1. It encodes a cytoskeletal protein, merlin (also called schwannomin), which acts as a tumor suppressor.