Neurofibromatosis Type 1

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Neurofibromatosis Type 1

Neurofibromatosis Type 1 is an autosomal dominant neurocutaneous disorder caused by mutations in the tumor suppressor gene neurofibromin, which negatively regulates RAS signaling. It accounts for approximately 90% of neurofibromatosis cases and is also known as von Recklinghausen disease. Diagnostic criteria require 2 or more specific features including 6 or more café au lait macules, intertriginous freckling, 2 or more neurofibromas or 1 plexiform neurofibroma, 2 or more Lisch nodules, optic glioma, distinctive osseous lesions such as sphenoid wing dysplasia or congenital tibial pseudoarthrosis, or an affected first degree relative. Cutaneous neurofibromas demonstrate buttonholing, and plexiform neurofibromas have a bag of worms texture with a 10% risk of malignant peripheral nerve sheath tumor transformation, often associated with p53 mutations. Ocular Lisch nodules are iris hamartomas seen in more than 90% of patients by age 10. Additional manifestations include ADHD, optic pathway gliomas, renovascular hypertension in children secondary to fibromuscular dysplasia, essential hypertension in adults, pheochromocytoma, nevus anemicus, and painful glomus tumors characterized by tenderness, cold sensitivity, and paroxysmal pain. NF1 is associated with a triple association of juvenile xanthogranuloma and juvenile chronic myelogenous leukemia. Pulmonic stenosis in the setting of NF1 is referred to as Watson syndrome.

Neurofibromatosis Type 1

Core Identity

  • Gun = NF1
  • #1 Foam Finger = NF1 Is The Most Common Type
  • Neurofibroom = Neurofibromin Tumor Suppressor Gene
  • Rat = RAS Activation Negatively Regulated By Neurofibromin

Cutaneous Manifestations

  • Button = Neurofibroma With Buttonholing
  • Bag Of Worms = Plexiform Neurofibromas
  • Spilled Coffee = Café Au Lait Macules
  • #6 = At Least 6 Café Au Lait Macules
  • Crow Pecking At Armpits And Groin = Intertriginous Freckling Crowe Sign

Ocular Manifestations

  • Black Hole Painting With Brown Planets = Lisch Nodules

Skeletal Manifestations

  • Butterfly Spreading Wings = Sphenoid Wing Dysplasia
  • Table With Bowed Legs = Congenital Tibial Pseudoarthrosis

Neurologic Manifestations

  • HD TV = ADHD
  • Optic Camera With Black Shield = Optic Gliomas

Diagnostic Criteria

  • Family Portrait = Affected First Degree Relative

Cardiovascular And Endocrine

  • Feet Chrome Spa = Pheochromocytoma
  • High Pressure Kettle = Hypertension From Renal Vascular Stenosis In Children
  • Child Flexing Muscles = Fibromuscular Dysplasia
  • Smiling Adult Customer = Essential Hypertension

Additional Cutaneous Associations

  • White Patch On The Wall = Nevus Anemicus
  • Globe Light = Glomus Tumors

Malignant Transformation

  • Take 53 Clapper Board = p53 Mutation

Triple Association

  • Triple Musketeer Chocolate Bar = NF1 Juvenile Xanthogranuloma Juvenile Chronic Myelogenous Leukemia
  • Yellow And Red Tomatoes = Juvenile Xanthogranuloma
  • Puppy Named Milo = Juvenile Chronic Myelogenous Leukemia

Syndromic Association

  • Lung Vest = Pulmonic Stenosis
  • Wooden Vest = Watson Syndrome

Quiz

Question 1
Neurofibromatosis type 1 is caused by mutation in which gene?
A. TP53
B. NF1 (neurofibromin)
C. RET
D. PTEN

Question 2
What is the inheritance pattern of NF1?
A. Autosomal recessive
B. X-linked dominant
C. Autosomal dominant
D. Mitochondrial

Question 3
Neurofibromin primarily functions to regulate which pathway?
A. JAK-STAT pathway
B. RAS signaling pathway
C. Hedgehog pathway
D. MAPK only

Question 4
How many café au lait macules are required as part of diagnostic criteria?
A. 2 or more
B. 4 or more
C. 6 or more
D. 10 or more

Question 5
Which clinical sign describes axillary or inguinal freckling?
A. Darier sign
B. Crowe sign
C. Nikolsky sign
D. Koebner phenomenon

Question 6
Which tumor type demonstrates “buttonholing” on physical exam?
A. Lipoma
B. Neurofibroma
C. Schwannoma
D. Fibroma

Question 7
Which neurofibroma subtype has a “bag of worms” texture and risk of malignancy?
A. Cutaneous neurofibroma
B. Plexiform neurofibroma
C. Intradermal nevus
D. Lipoma

Question 8
Which ocular finding is highly characteristic of NF1?
A. Kayser-Fleischer rings
B. Lisch nodules
C. Cherry red spot
D. Retinal detachment

Question 9
Which malignancy can arise from plexiform neurofibromas?
A. Basal cell carcinoma
B. Malignant peripheral nerve sheath tumor
C. Melanoma
D. Squamous cell carcinoma

Question 10
Which of the following is NOT commonly associated with NF1?
A. Optic glioma
B. Pheochromocytoma
C. Glomus tumors
D. Hyperextensible skin

Answers:
1 B. NF1 (neurofibromin)
2 C. Autosomal dominant
3 B. RAS signaling pathway
4 C. 6 or more
5 B. Crowe sign
6 B. Neurofibroma
7 B. Plexiform neurofibroma
8 B. Lisch nodules
9 B. Malignant peripheral nerve sheath tumor
10 D. Hyperextensible skin