Neurocutaneous Syndromes

1. Neurocutaneous Syndromes Dr. Lamyaa Jad FRCPC Pediatric Neurologist King Fahad Medical City

2. Definition Referred to as neurocutaneous syndromes because of frequent involvement of the skin in addition to the nervous system Other name phakomatosis- phakos= greek for lentil or birth mark Notable for their dysplastic nature and tendency to form tumors in various tissues

4. Neurocutaneous Disorders Neurofibromatosis I/II Tuberous Sclerosis Sturge-Weber Von Hippel-Lindau Ataxia Teleangiectesia PHACES Syndrome Linear Nevus Syndrome Hypomelanosis of Ito Incontinentia Pigmenti

5. Neurofibromatosis Autosomal dominant disorders Affects nervous system, skin, bone, and soft tissue Type I &Type II 3rd segmental NF=disease limited to single body region may be related to mosaicism or segmental hyperexpression of the condition

6. NF-1 NF-1 Most prevalent Incidence 1/4000 M=F Autosomal dominant Chromosome 17q11.2 Protein product Neurofibromin ;tumour suppressor Signs can range from benign cutaneous manifestations to profound disfigurement.

7. First degree Relative with NF-1 Chromosome 17q11.2

9. Features of NF1 Pigmentary Features Caf�-au lait macules Skinfold freckling Hyperpigmented iris hamartomas (Lisch nodules) Optic Pathway Gliomas Neurofibromas Bony Abnormalities Learning Disabilities and T2 Hyperintensities

10. Caf� -au-lait macules Trunk and extremities, spares face

11. NF-1 Caf�-au-lait Macules Flat ,homogenous hyperpigmentation with smooth regular borders Numbers increase in 1st 2yrs of life Do not evolve into tumors May fade in adults

12. Skin fold freckling ;multiple hyperpigmented areas 2-3 mm in diameter

13. NF-1 Skinfold Freckling Freckling in non-sun-exposed regions, such as the axilla and inguinal regions Occur in 80% by age 6 Also observed under the neck and breasts where skinfolds exist

14. Optic Glioma

15. NF-1 Optic Pathway Gliomas Most common CNS tumor in NF1 15-20% Grade I glioma (pilocytic astrocytomas) Mean age of presentation= 4.2 years Arise anywhere along the optic pathway Frequently involve the optic nerve, chiasm, or hypothalamus. May cause visual loss ,proptosis & precocious puberty Annual ophthalmologic examinations recommended during 1st 10 yrs of life

16. NF-1 Lisch Nodules Hyperpigmented iris hamartomas Found in~30% of individuals with NF1 by age 6 Do not cause visual impairment or other clinical sequelae Slit lamp necessary for accurate detection of Lisch nodules

17. identified with slit lamp Hamartomas located within the iris. >74% patients with NF-I, two or more increases with age-

18. NF-1 Dermal Neurofibroma Most common tumor in adults with NF1 A benign peripheral nerve sheath tumor composed of Schwann cells, fibroblasts, and mast cells Do not appear until puberty and increase with age & are present in nearly all adults with NF1 No risk of malignant transformation, but carry a major cosmetic burden

19. Two or more -Small, rubbery, purplish skin Skin, peripheral nerves, GI tract During adolescence and pregnancy.

20. NF-1 Plexiform Neurofibromas Found in 1/3rd of NF1 Diffuse neurofibroma involving multiple nerve fascicles May involve multiple tissues, including skin, fascia, muscle, bone, and internal organs May arise from deep structures, remain silent until later in life May stimulate underlying bone growth, causing leg length discrepancies, scoliosis, or sphenoid wing dysplasia Cross tissue planes ,highly vascular so, extremely difficult to resect

21. Plexiform Neurofibromas 10% lifetime risk of malignant transformation can evolve into a malignant peripheral nerve sheath tumor. Malignant peripheral nerve sheath tumors are highly aggressive, lethal tumors that frequently metastasize and rarely do not respond to chemotherapy and radiation Pain and neurologic deficit are the two most reliable indicators of malignant transformation

22. Malignant Peripheral Nerve Sheath Tumor PET studies useful in distinguishing benign from malignant peripheral nerve sheath tumors Standard treatment of malignant peripheral nerve sheath tumor ;wide surgical excision followed by local radiotherapy Treatment delays local recurrence, but does not improve long-term survival

23. Sphenoid Dysplasia.

24. NF-1 Bony Abnormalities Skeletal dysplasias ; sphenoid wing dysplasia ,scoliosis & tibial pseudarthrosis Scoliosis affects 10-20% Cortical thinning of long bones or dysplastic bony changes lead to repeated pathologic fractures with incomplete healing resulting in pseudarthrosis Tibial pseudarthrosis typically presents in early infancy Short in stature 13% of NF1 height <than 2 std deviations below the mean. Macrocephaly; 24% of NF1 head circumference >2 S.D. above the mean

25. Scoliosis most common bony manifestation Pseudoarthrosis.

26. NF-1 T2 Hyperintensities Areas of signal hyperintensity on T2 MRI observed in 60-70% of children with NF1; termed unidentified bright objects(UBO�s) UBO�s are found in ;brainstem, basal ganglia, thalamus & cerebellum. The relationship between unidentified bright objects and cognitive dysfunction in NF1 is controversial

27. NF-1 Learning Disabilities Specific learning disabilities 30-65% Learning deficits involve visual spatial and visual motor integration skills & language-based skills ;reading & spelling ADHD IQ 89 -94. All children with NF1 should undergo comprehensive cognitive evaluation to identify specific cognitive deficits

28. The Clinical Manifestations of NF1 are Age Dependent 

29. Diagnostic Criteria for NF-1 The diagnostic criteria are met if >2 of below are present Caf� au lait macules Prepubertal ; Six or more > 5 mm Postpubertal : Six or more >15 mm Neurofibromas >2 of any type or 1 plexiform neurofibroma Axillary /inguinal freckling Optic glioma Lisch nodules >2 =(iris hamartomas ( Osseous lesions; such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis 1st degree relative with NF-1 according to the above criteria

30. Complications learning disabilities, ADHD, Speech disorder Seizures Hydrocephalus Macrocephaly Moya-moya Disease Precocious puberty Hypertension. Fibromuscular dysplasia Pheochromocytoma Malignancy Neurofibrosarcoma Malignant Schwanoma Abnormal signals in the globus pallidus, thalamus and internal capsule 30

31. Neurofibromatosis II Bilateral Acoustic Neuromas Hearing loss Unsteadiness Headache Facial weakness common in 2nd -3rd decade Chromosome 22q1.11 protein product merlin (or schwannomin)= tumor supressor

32. Subcapsular opacity- 50% of NF-II 32 Neurofibromatosis II

33. Neurofibromatosis II 33 Ependymomas (80%)in spinal cord. Spinal Schwannomas (70%) intradural extramedullary

34. Tumor Types in NF II Vestibular schwannomas Schwannomas on other cranial nerves ;CN1 , CNIII , CNIV Meningioma Pilocytic astrocytomas Ependymomas

36. Management of NF1 ,NII Genetic counseling 50 % sporadic mutation Prenatal diagnosis in familial cases. Annual evaluation ; Hearing language development Blood pressure spine eye exam change in neurofibroma 36

37. Tuberous Scelrosis 1/6000 Ch. 9q34-TSC1-Hamartin Ch. 16p13-TSC2-Tuberin 50% sporadic Wide clinical spectrum 37

38. TS Dermatologic Features� 95 % of TS patients have 1 characteristic skin lesion Ash-leaf spots; elliptic hypopigmented macules Angiofibromas; involve malar regions of face Shagreen patches ;over lower trunk Fibrous forehead brown plaques; infants & neonates Periungual and ungual fibromas; adolescence or adulthood

39. TSOphthalmic Features� Retinal hamartomas Flat, translucent lesion 70 % Multilobular mulberry lesion 55% Transitional lesion 9% Chorioretinal depigmentation Angiofibromas of the eyelids Nonparalytic strabismus Colobomas Sector iris depigmentation

40. Central nervous system Manifestation of Tuberous Sclerosis  Cortical tubers White matter heterotopias Subependymal nodules Subependymal giant cell tumors (Subependymal giant cell astrcytoma) Relative risk of malignancy in TS 18-fold higher Risk of invasive cancer higher in TSC2 than TSC1 mutations

41. Cardiac Rhabdomyomas Develop in utero detected on prenatal ultrasound Benign mainly asymptomatic, some symptomatic in perinatal period Spontaneous regression in 1st few yrs of life Other cardiovascular manifestations� Coarctation of the aorta Renal artery stenosis Aortic aneurysm

42. Renal Manifestation of TS Angiomyolipomas most common Benign cysts Lymphangiomas Renal cell carcinoma 1 - 2 % of adults

43. Pulmonary Manifestations Lymphangioleiomyomatosis+/- with renal angiomyofibromas Some women have this combination as an isolated finding with no other features of TS and no identifiable germline mutation in TSC1 or TSC2 genes

44. Hypopigmented in 90% of patients Enhanced by wood�s lamp examination 44

45. Retinal Lesions Mulberry Tumors Retina nerve fiber and undifferentiated glial tissue 30-50% Ts Can be found in normal persons. 45

46. Facial Angiofibroma Forehead Plaque 46

47. Shagreen patch at lower back. 47

48. Confetti lesions 48

49. Candle Dripping Tubers 49

50. Cardiac Rhabdomyoma 50

52. Diagnosis of TS Definite :2 major features or 1 major feature +2 minor features. Probable : 1 major +1 minor feature. Possible : 1 major feature or >2 minor features.

53. Major Features of TS Facial angiofibromas or forehead plaque Nontraumatic ungual or periungual fibromas Hypomelanotic macules 3 (>3) Shagreen patch (connective tissue nevus Multiple retinal nodular hamartomas Cortical tuber Subependymal nodule Subependymal giant cell astrocytoma Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosis Renal angiomyolipoma

54. Minor Features of TS Multiple randomly distributed pits in dental enamel Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Gingival fibromas Nonrenal hamartoma Retinal achromic patch Confetti skin lesions Multiple renal cysts

55. Management of TS CT/MRI brain Cardiac Echo Renal Ultrasound .adolescence renal ultrasonography every 1 - 3 yrs Seizure control-ACTH for infantile spasm Symptomatic tumor treatment. Cosmetic treatments 55

56. Sturge-Weber Syndrome Etiology-Anomalous development of primordial vascular bed. 1/50,000 Hypothesis : somatic mutations in fetal ectodermal tissues cause inappropriate control /maturation of capillary blood vessel formation NOT a heritable disorder, recurrence is unlikely

57. Sturge-Weber Syndrome Facial (port-wine stain) Leptomeningeal angioma Vascular malformations associated with ocular and neurologic abnormalities

58. Sturge Weber Syndrome Portwine Stain 58

59. Sturge Weber Syndrome Cutaneous Port Wine Stain Small % of children with port-wine stains have SWS Present on forehead & upper eyelid , distribution of 1st /2nd divisions of trigeminal Leptomeningeal angioma ;90 % when port wine stain involves both upper & lower eyelids vs 10 % with 1 eyelid affected Extension of skin lesion to both sides of face , trunk & extremities common Treated by selective photothermolysis using pulsed dye laser

60. Sturge Weber Syndrome Leptomeningeal Angioma Occurs in 10 -20 % with a facial port wine stain Found ipsilateral to port wine stain Commonly affects parietal & occipital areas Pathology ; thickening & discoloration of leptomeninges caused by the increased vascularity Angiomatous tissue fills the subarachnoid space in the sulci, & large tortuous venous structures drain superficially into the deep venous system. The underlying parenchyma may be atrophic with intraparenchymal calcification 2nd ry chronic tissue hypoxia caused by venous stasis.

61. Sturge Weber Syndrome Ocular Features Glaucoma in 30 - 70 % Risk highest in 1st decade Congenital glaucoma in 50% (buphthalmos) Treatment usually surgical Vascular malformations of conjunctiva, episclera, choroid, and retina � Iris Heterochromia ; darker iris ipsilateral to facial angioma Visual field defects; common when occipital cortex affected

62. Sturge Weber Syndrome Neurologic Features Seizures� Hemiparesis Hemiatrophy Mental retardation� Behavior problems� Homonymous hemianopia Hydrocephalus

63. � Sturge Weber Syndrome Seizures  80 % of SWS More common with bilateral port-wine stains Can develop at any age May be associated with acute hemiparesis Onset < 1 year & poor response to anticonvulsant associated with cognitive impairment Adequate control accomplished with AED in 40 % In refractory cases, hemispherectomy or limited surgical resection of epileptogenic tissue

64. Sturge Weber Syndrome Hemiparesis Develops acutely in conjunction with onset of seizures Deficit contralateral to intracranial lesions Affected extremity grows at slower rate ? hemiatrophy Possible mechanisms ; cumulative effect of repeated thrombotic events in leptomeningeal angioma or chronic disturbance of blood flow and O2�delivery to brain

65. Sturge Weber Syndrome Diagnosis� Neuroimaging MRI with contrast � By 1 yr of age, -ve brain MRI with gadolinium can exclude leptomeningeal angioma CCT = intraparynchymal calcification It is reasonable to perform imaging in infancy only if ocular & neurologic abnormalities (glaucoma, seizures, or hemiparesis) present

66. Sturge Weber Syndrome prognosis depends on; Extent of leptomeningeal angioma & cerebral cortex perfusion Severity of ocular involvement. Age of onset of seizures Ability to control seizures

67. Buphthalmos 67

68. Gyriform Pattern of Cortical Calcification 68

69. Unilateral cortical atrophy 69

70. Treatment Seizures-medications hemispherectomy or lobectomy Physical Therapy and Rehabilitation Ophthalmic evaluations periodically Port Wine Stain- Laser Aspirin controversial 70

71. Ataxia-Telangiectasia Autosomal recessive disorder Defective DNA repair mechanisms Incidence 1 in 20,000 -100,000 live births 1.4 - 2.0 % of Caucasians in US carry 1 defective AT gene

72. Ataxia-Telangiectasia Pathology Central & peripheral nervous systems involved CNS abnormalities more severe; cerebellar atrophy with loss of Purkinje cells Peripheral nerves have malformed Schwann cells nuclei Thymus hypoplastic, with few lymphocytes & absent Hassall corpuscles consistent with the associated immune deficiency

74. Ataxia-Telangiectasia Clinical Features Progressive cerebellar ataxia Abnormal eye movement Oculocutaneous telangiectasias Immune deficiency Increased incidence of malignancy Radiation sensitivity Diabetes mellitus caused by insulin resistance.

75. Ataxia-Telangiectasia  Neurologic Abnormalities Progressive cerebellar ataxia Gross & fine motor skills deteriorate Oculomotor apraxia; Abnormality with voluntary and involuntary saccades & smooth pursuit Nystagmus Extrapyramidal abnormalities; dystonia, chorea Peripheral axonal neuropathy Anterior horn cell degeneration

76. Ataxia-Telangiectasia Telangiectasias Bulbar conjunctivae Exposed areas of the skin;pinnae, nose, face, and neck Usually appear at 3-5yrs of age. Delayed appearance of telangiectasia results in delayed diagnosis

77. Ataxia-Telangiectasia

78. Ataxia-Telangiectasia Immune deficiency� Cellular and humoral immunity 70% Recurrent sinopulmonary infections Progressive pulmonary disease a major cause of morbidity and mortality

79. Ataxia-Telangiectasia Laboratory abnormalities� Elevation of serum alpha-fetoprotein Absence or marked reduction of IgA, IgG2, and other IgG subclasses Inability to produce antibodies to polysaccharide antigens Oligoclonal gammopathy Lymphopenia

80. Ataxia-Telangiectasia Malignancy� After 10 yrs, the incidence of cancer is 1 %/yr 10- 20 % develop malignancy 85 % lymphomas and acute leukemias Predisposition to breast cancer & others AT cells susceptible to damage by ionizing radiation, or chemotherapeutic agents causing double-stranded breaks in DNA.

81. Ataxia-Telangiectasia

82. Von-Hippel-Lindau Disease Chromosome 3q25 Variable penetrance and delayed expression Cerebellar hemagioblastomas and retinal angiomata. Affects many organ systems-Cerebellum, spinal cord, medulla, retina, kidney, pancreas, and epididymis.

83. Cerebellar Hemangioblastoma Raised intracranial pressure Cystic cerebellar lesion with vascular mural nodule- erythropoietin like protein. Spinal Cord-abnormalities of proprioception, disturbances of bladder control & gait impairment

84. Retinal Angioma Peripheral-Initially vision unaffected Grow, bleed, leave serous fluid-retinal detachment Small-Laser photocoagulation Large-Freezing probe from outside globe. 25% of retinal angioma patients have extraocular manifestation 60% with nonocular manifestations have retinal angioma

85. Von-Hippel-Lindau Disease Cystic lesions of kidneys, pancreas, liver and epididymis Pheochromocytomas. Renal carcinoma is most common cause of death.

86. Linear Sebaceous Nevus 86

87. Linear Nevus Syndrome 84%-Face 50%-Scalp, Neck and face Scalp lesions devoid of hair Seizures 75% Infantile spasm Generalized Tonic Tonic Clonic Neurological Deficits Cranial Nerve palsies VI, VII Cortical Blindness Hemiparesis (hemimegalencephaly) Mental Retardation-i70% 87

88. PHACE Syndrome.

89. PHACE Syndrome Posterior fossa malformations Hemangiomas Arterial anomalies Coaractation of the aorta Eye abnormalities

90. Incontententia PigmentaStage I Erythematous linear streaks and plaques of vesicles DD-Herpes, bullous impetigo, mastocytosis eosinophilic spongiosis Resolve by 4 mo

91. Incontententia PigmentaStage II Verrucous plaques Dry & hyperkeratotic Involute in 6 months

92. Incontententia PigmentaStage III Hyperpigmentation Hallmark Macular whorls, linear streaks Lines of Blaschko. Sites are not necessorily same. Invariably affects axilla and groin Fade by early adolescence.

93. Incontententia PigmentaStage IV Hypopigmented Hairless Anhydrotic Usually lower legs. 93

94. Incontententia PigmentaOther Manifestations CNS (33%) Motor and cognitive developmental retardation Seizures Microcephaly Spasticity paralysis Dental(80%) Late dentition Hypodontia Conical teeth Impaction Ocular(30%) Neovascularization Microphthalmos Strabismus Optic Nerve atrophy Cataracts Retrolenticular masses. 94

95. Incontententia Pigmenta Genetics Functional mosaicism Random X-inactivation of an X-linked dominant Gene Lethal in Males Xq28 Increased frequency of spontaneous abortions. 95

96. Hypomelanosis of Ito Mosaicism-Family history is rare Neurological Association Mental retardation (70%) Seizures (40%) Microcephaly(25%) Developmental delay Deafness Visual problems Headache Tooth or mouth problems 96

97. Hypomelanosis of Ito