Neurocutaneous Syndromes. Phakomatoses

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1 Neurocutaneous Syndromes Phakomatoses

2 Financial Disclosures I have NO SIGNIFICANT FINANCIAL, GENERAL, OR OBLIGATION INTERESTS TO REPORT

3 Neurocutaneous Syndomes Definition Entities Diagnosis/ Presentation Genetics Pathology

4 Definition Phakomatoses are a group of neuroocular or neurocutaneous disorders that involve the embryologic ectoderm. - Phakos = spot, mark, lens

5 Neurocutaneous Syndromes Neurofibromatosis type 1 (von Recklinghausen s) Neurofibromatosis type 2 (central) Tuberous Sclerosis Von Hippel-Lindau disease All autosomal dominant Sturge-Weber disease Sporadic

6 VON RECKLINGHAUSEN'S DISEASE (NF-1) 1 in 3,000-4,000 Autosomal dominant Chromosome 17 ( neurofibromin ) Multiple peripheral nerve tumors Café-au lait spots Optic nerve gliomas Other tumors

7 Clinical diagnosis of NF1 can be made if a patient has 2 or more of the following: Six or more café-au-lait spots or hyperpigmented macules > 5 mm in diameter in children younger than 10 years and > 15 mm in adults Two or more neurofibromas of any type, or one plexiform neurofibroma Freckles in the axillary or inguinal regions Sphenoid wing dysplasia or congenital bowing of long bone cortex. Optic nerve glioma >2 pigmented nodules (Lisch nodules) on the iris A first-degree relative with NF1

8 Peripheral nerve tumors may be solitary or multiple

9 The tumors may be schwannomas or neurofibromas, as shown here.

10 Schwannoma Neurofibroma Schwannomas displace the adjacent nerve fibers, while neurofibromas infiltrate through the nerve, and may not be removed without sacrificing the nerve

11 Plexiform Neurofibroma Virtually pathognomonic for NF-1. Infiltrating tumor cells enlarge and distort the nerve bundles, forming a characteristic tangle said to resemble a bag of worms. Microscopically, there are typical wavy spindle cells and collagen fibers that are said to resemble shredded carrots.

12 Café-au-lait spots

13 Café-au-lait spot increased amount of pigment in basal epidermis; no increased number of melanocytes

14 Macromelanosomes in café-au-lait spot

15 Usually begin to appear in childhood; may be the only skin manifestation in an unaffected relative Axillary freckles

16 Lisch Nodules Melanocytic hamartomas of the iris in NF-1

17 Prevalence of Lisch Nodules (Solid Bars) and Neurofibromas (Hatched Bars) in 167 Patients with Neurofibromatosis 1, According to Age. Lubs ME et al. N Engl J Med 1991;324:

18 Optic Nerve Astrocytoma

19 Optic Nerve Astrocytoma Bilateral = NF1

20 1 in 50,000 Neurofibromatosis 2 ( Central ) Tumor suppressor gene on Chromosome 22 ( merlin ); Autosomal dominant; estimated 50% new mutations Bilateral acoustic schwannomas- Diagnostic Multiple meningiomas Schwannomas, Neurofibromas Gliomas, ependymoma

21 Acoustic Schwannoma

22 Bilateral Acoustic Schwannoma

23 Multiple Meningiomas

24 Nerve root schwannomas

25 Glial Hamartomas or Hamartia microscopic nodular collections of glial cells in cerebral cortex What is a hamartoma?

26 Tuberous Sclerosis 1 in 10,000 Two chromosomes: 9 ( hamartin ) 16 ( tuberin ) Seizures Mental Retardation Skin Lesions Hamartomas

27 Depigmented Nevi ( Hypomelanotic patches, ash-leaf spots ) May be the earliest finding

28 Adenoma Sebaceum

29 Subungual fibroma Angiofibroma

30 Angiofibroma In Tuberous sclerosis= Adenoma Sebaceum

31 Shagreen patches Resemble rough, untanned leather

32 Haphazard bundles of collagen in Shagreen patch

33 Cortical Tubers Enlarged, distorted, firm cortical area that resembles a potato

34 Cortical Tubers Distorted cortical lamination due to haphazard arrangement of neurons and glia Tuber Normal

35 Cortical Tubers Enlarged cells with abundant cytoplasm; many cells resemble both neurons and glia

36 Subependymal Nodules Resemble candle gutterings; Cellularity similar to tubers; many calcifications

37 Tuber and subependymal nodules in same specimen

38 Subependymal Giant Cell Astrocytoma (SEGA)

39 Subependymal Giant Cell Astrocytoma Cellularity similar to tubers and subependymal nodules

40 Heart - Rhabdomyoma May mechanically interfere with cardiac function leading to death

41 Kidneys - Angiomyolipomas

42 Angiomyolipoma

43 Angiomyo- lipoma

44 Intestinal Smooth Muscle hamartoma

45 Bronchial/lymphatic smooth muscle hamartoma

46 How do these things happen? (and can we do something about it?) Normal Hamartin (chromosome 9) and Tuberin (chromosome 16) bind together, forming a heterodimer complex which inhibits the mtor (mammalian target of rapamycin) cascade. mtor is a kinase which increases cell growth and proliferation and is known to control cell size.

47 NEJM Nov 4, 2010

48 Von Hippel-Lindau Disease (Retino-cerebral angiomatosis) 1 in 39,000 Chromosome 3 Hemangioblastomas of retina, cerebellum, spinal cord Renal cell carcinoma Cysts in kidneys, pancreas, liver Pheochromocytoma

49 Retina in VH-L

50 Cerebellar hemangioma in VH-L

51 Cerebellar hemangioma in VH-L

52 VH-L Hemangioblastoma

53 Other lesions in Von Hippel-Lindau disease Spinal cord angioma Clear Cell Renal carcinoma

54 Pancreas in VH-L T 2 Pancreatic lesions include simple cysts, cystadenomas and islet cell tumors (NET)

55 How do these things happen? (and can we do something about it?) The VHL gene codes for a protein (pvhl) that normally down-regulates VEGF, erythropoietin, and other hypoxia-inducible growth factors. Mutation of the VHL gene leads to increased activity of these growth factors, with the expression of vascular neoplasms, polycythemia and other lesions, particularly highly vascular renal cell carcinomas. Clinical trials are testing anti-angiogenic drugs Mab s or inhibitors of the growth factors or their receptors, transmembrane tyrosine kinases. (J Clin Endocrinol Metab 94: , 2009)

56 Sturge Weber Disease (Encephalofacial angiomatosis) Three major features: Port wine stain birthmark Leptomeningeal angiomas Increased intraocular pressure (glaucoma) Also, seizure, headache, paralysis, learning disabilities Frequency: 1:20,000-50,000 Not inherited- somatic mosaic mutations in the GNAQ gene (long arm of chromosome 9)

57 Angiomas in Trigeminal Distribution Mikhail Gorbachev Port wine stain or nevus flammeus Thin walled capillaries of skin

58 Sturge - Weber Leptomeningeal angioma

59 Tram-track Calcification Calcification in outer cortex Linear calcific deposits beneath cortical surface produce parallel lines on X-ray

60 NEJM May 8, 2013

61 Objectives 1. Describe the inheritance patterns of these diseases. 2. Define and describe the important features of NF-1, NF- 2, tuberous sclerosis, von Hippel- Lindau disease and Sturge Weber syndrome including: 1. Characteristic and/or pathognomonic lesions 2. Pathogenesis 3. Types of tumors encountered 4. Types of skin lesions 5. Associated visceral lesions and clinical significance