Neurocutaneous Syndromes

A pediatric perspective on the diagnosis and management of the various Neurocutaneous Syndromes.

1. NEUROCUTANEOUS SYNDROMES A PEDIATRIC PERSPECTIVE DR NISHANT YADAV RESIDENT PEDIATRICS

2. INTRODUCTION The neurocutaneous syndromes include a heterogeneous group of disorders characterized by abnormalities of both the integument and central nervous system (CNS). Most disorders are familial and believed to arise from a defect in differentiation of the primitive ectoderm.

3. Disorders classified as neurocutaneous syndromes include : Neurofibromatosis Tuberous sclerosis Sturge Weber syndrome von Hippel – Lindau disease PHACE syndrome, Ataxia telangiectasia Linear nevus syndrome, Hypomelanosis of Ito, Incontinentia pigmenti.

4. Neurofibromatoses Neurofibromatoses are autosomal dominant disorders that cause tumors to grow on nerves (Neurofibromas) and result in other abnormalities such as skin changes and bone deformities. 2 types of neurofibromatosis (type 1 and type 2); However, it is recognized that they are clinically and genetically distinct diseases and should be considered separate entities: neurofibromatosis 1 (NF-1) and neurofibromatosis 2 (NF-2).

5. Neurofibroma A benign nerve sheath tumor in the peripheral nervous system Arise from nonmyelinating-type Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein Neurofibromin. Neurofibromin is responsible for regulating the RAS-mediated cell growth signaling pathway. In contrast to Schwannomas, many additional types of cells and structural elements are incorporated in addition to Schwann cells.

6. Types of Neurofibroma Dermal(Cutaneous) and Plexiform Dermal or Cutaneous : Associated with a single peripheral nerve 3 subtypes Discrete cutaneous – Sessile/pedunculated Fleshy Nontender Discrete subcutaneous Bumps on the skin Sometimes tender Deep nodular Involves tissues and organs underneath the dermis Otherwise resembling Cutaneous and Subcutaneous types.

7. Age of onset : Teenage years Onset of puberty Increase in number and size throughout adulthood Complications : Stinging Itching Pain Disfiguration No evidence of malignant transformation

8. Plexiform : Can grow from nerves in the skin or from internal nerve bundles Can be very large Internal plexiform neurofibromas extend through multiple layers of tissues and are difficult to remove. Complications Disfigurement Neurological and other clinical deficits 10% undergo transformation into a Malignant Peripheral Nerve Sheath Tumor (MPNST).

9. NF - 1 Most prevalent Neurocutaneous syndrome. Incidence 1/3,000 Autosomal Dominant Majority of mutations in NF-1 occur in paternal germ line Though , NF-1 is an autosomal dominant disorder, over half the cases are sporadic, representing de novo mutations. The NF1 gene on chromosome region 17q11.2 encodes a protein also known as neurofibromin. Neurofibromin acts as an inhibitor of the oncogene ras.

10. Diagnostic Criteria 2 out of the following 7 signs : Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals. Axillary or inguinal freckling Two or more iris Lisch nodules Two or more neurofibromas or one plexiform neurofibroma

11. Diagnostic Criteria (continued) 5. A distinctive osseous lesion such as Sphenoid dysplasia( which may cause pulsating exophthalmos) Or Cortical thinning of long bones with or without Pseudoarthrosis. 6. Optic gliomas 7. A first-degree relative with NF-1 whose diagnosis was based on aforementioned criteria.

12. Neurofibromas Neurofibromas typically involve the skin, but they may be situated along peripheral nerves and blood vessels and within viscera including the gastrointestinal tract. These lesions appear characteristically during adolescence or pregnancy, suggesting a hormonal influence. They are usually small, rubbery lesions with a slight purplish discoloration of the overlying skin.

13. Plexiform neurofibromas are usually evident at birth and result from diffuse thickening of nerve trunks that are frequently located in the orbital or temporal region of the face. The skin overlying a plexiform neurofi broma may be hyperpigmented to a greater degree than a caf é -au-lait spot. Plexiform neurofibromas may produce overgrowth of an extremity and a deformity of the corresponding bone.

14. Plexiform Neurofibromas on face

15. Café-au-lait spots Café-au-lait spots are the hallmark of neurofibromatosis Present in almost 100% of patients. Present at birth but increase in size, number and pigmentation, especially during the 1 st few years of life. Predilection for trunk and extremities. Facial sparing

16. Other conditions with Café-au-lait macules Neurofibromatosis type 2 Macune albright Syndrome Ataxia telangiectasia Bloom’s syndrome Watsons’s syndrome Familial Café-au-lait macules

17. Other findings in NF-1 Learning disabilities Attention deficit disorders Behavioral and psychosocial problems Abnormalities of speech Seizures – Complex partial and GTCS

18. Other findings (continued) Hydrocephalus secondary to aqueductal stenosis Macrocephaly with normal-sized ventricles Cerebral vessel aneurysms, or stenosis resulting in Moyamoya disease > Transient Ischemic Attacks Precocious puberty Risk of hypertension due to Renal Vascular Stenosis or a Pheochromocytoma

19. Other findings (continued) Higher incidence of Pheochromocytoma , rhabdomyosarcoma,Leukemia and Wilm’s tumor Unusual associations involving Myleoid leukemia, Juvenile xanthogranuloma, and NF-1 Malignant Peripheral Nerve Sheath Tumor (MPNST) Malignant neoplasms Neurofibrosarcoma Malignant schwannomas

20. Other findings (continued) Tumors of the CNS account for significant morbidity and mortality Optic gliomas Meningiomas of the brain and spinal cord Neurofibromas Astrocytomas Neurilemmoma

21. NF-2 Rarer condition Incidence – 1/25,000 The NF2 gene (also known as merlin or schwannomin) is located on chromosome 22q1.11.

22. Diagnostic criteria for NF-2 : 1 of the following 4 features is present: Bilateral vestibular schwannomas A parent, sibling, or child with NF-2 and either unilateral vestibular schwannoma or any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, or posterior subcapsular lenticular opacities Unilateral vestibular schwannoma and any 2 of the following: meningioma, schwannoma, glioma, neurofi broma, or posterior subcapsular lenticular opacities Multiple meningiomas (2 or more) and unilateral vestibular schwannoma or any 2 of the following: schwannoma, glioma, neurofibroma, or cataract.

23. Symptoms Tinnitus Hearing loss Facial weakness Headache Unsteadiness Café-au-lait spots Skin neurofibromas

24. Lesions associated with NF-2

25. Management in a case of Neurofibromatosis

26. Close multidisciplinary follow-up is necessary Regular clinical assessments at least yearly, focusing the history and examination on the potential problems for which they are at increased risk. Yearly ophthalmologic examination, Neurologic assessment, Blood pressure monitoring, Scoliosis evaluation

27. Neuropsychologic and educational testing should be considered as needed. All symptomatic cases (i.e., those with visual disturbance, proptosis , or increased intracranial pressure) must be studied without delay. Cosmetic interventions

28. Genetic Counseling Molecular testing for the NF1 gene is available and can be useful in a number of cases. Scenarios in which genetic testing is helpful include patients who have only 1 of the criteria for clinical diagnosis, those with unusually severe disease, and those seeking prenatal/pre-implantation diagnosis.

29. Tuberous Sclerosis Autosomal dominant Widespread hamartomas – Brain, eyes, skin, kidneys, liver, heart and lungs. Clinical triad Described by Vogt Epi-loi-a Epilepsy Low intelligence Adenoma sebaceum Only in 1/3 rd patients

30. Clinical features May present as Infantile spasms and a hypsarrythmic EEG pattern Later may develop into myoclonic epilepsy Skin lesions Ash leaf macules Sebaceous adenomas Shagreen patch Subungual or Periungual fibromas

31. Periungual fibroma

32. Retinal lesions Mulberry tumors Hamartomas Depigmented areas Brain lesion Cortical tuber – apparent by 3-4 years of age Identified by T2 weighted MRI Undergo calcification and project into ventricular cavity – Candle-dripping appearance Obstructive hydrocephalus Number of tubers is directly related to degree of neurological impairment. Occasionaly differentiates into a malignant Subependymal giant cell astrocytoma

33. CT scan with subependymal calcifi cations characteristic of tuberous sclerosis. MRI demonstrates multiple subependymal nodules in the same patient (arrow).

34. Other features Rhabdomyomas of the heart In 50 % cases At the apex of the left ventricle Can cause Congestive Heart Failure and Arrythmias Slowly resolve spontaneously Angiomyolipomas of kidney In 75-80 % of >10 year old patients Benign Single or multiple renal cysts Lymphangiomyomatosis Classical pulmonary lesion Most common in female patients

35. Management Seizure control Renal imaging every 1-3 year Echocardiogram Chest roentgenogram Brain MRI every 1-3 year Neurodevelopmental testing at the time of beginning 1 st grade.

36. Sturge-Weber Syndrome Sporadic disorder Results from anomalous development of the primordial vascular bed in the early stages of cerebral vascularisation As a result, brain becomes atrophic and calcified, particularly in the molecular layer of the cortex. Clinical manifestations Facial capillary malformation – Port-wine stain Unilateral facial nevus Present at birth Always involves the upper face and eyelid

37. Buphthalmos and glaucoma of the ipsilateral eye Seizures in the 1 st year of life in most patients. Typically focal tonic-clonic and contralateral to the side of nevus. Transient stroke like episodes and persisting visual defects Neurodevelopment appears to be normal in the 1 st year of life Mental retardation or severe learning disabilities in at least 50% in later childhood

38. DIAGNOSIS MRI with contrast is the imaging modality of choice for demonstrating leptomeningeal angioma Skull radiograph Intracranial calcification in the occipitoparietal region Serpentine or Railroad-track appearance CT scan Calcification Unilateral cortical atrophy Ipsilateral dilatation of the lateral ventricle MRI Vascular malformation White matter lesion

39. Gadolinium-enhanced axial T1 FLAIR image of a 15 mo old with Sturge-Weber syndrome shows leptomeningeal enhancement in the left hemisphere.

40. Von Hippel-Lindau Disease Autosomal dominant trait VHL tumor suppressor gene located on 3p25-26 Clinical Features Cerebellar hemangioblastoma – Present with signs of raised Intracranial Tension Total surgical removal is curative Retinal angiomata In peripheral retina – so unaffected vision Retinal detachment -> Visual loss

41. Hemangioblastoma of the spinal cord – Abnormalities of proprioception and gait Bladder sysfunction Cystic lesions of the kidneys, pancreas,liver, and epididymis Pheochromocytoma Most common cause of death – Renal carcinoma Management Regular follow-up Appropriate imaging studies to identify lesions at an early stage

42. PHACE Syndrome Female predominance Consists of Posterior fossa malformation Hemangiomas ipsilateral to the aortic arch Arterial anomalies Coarctation of the aorta,apalsia or hypoplastia of carotid arteries,aneurysmal carotid dilatation, aberrant left subclavian artery Eye abnormalities- glaucoma, cataracts, microphthalmia, optic nerve hypoplasia.

43. Large facial hemangiomas may be associated with Dandy- Walker malformation Interferon- alpha is of value in management of the hemangiomas.

44. Ataxia Telangiectasia Autosomal recessive Chromosome 11 Ataxia begins between 12-15 months of age Telangiectasia appears by 2-7 years on bulbar conjunctiva and skin Abnormal movements Vitilago Abnormal Glucose Tolerance Test

45. Decreased serum IgA Alpha-fetoprotein elevated Sino pulmonary infections Lymphoreticular malignancies Immune deficiency Neuroimaging – Cerebellar atrophy

46. Incontinentia Pigmenti Uncommon genodermatosis of the developing neuroectoderm Vesicular, verrucous and pigmented lesions are associated with developmental defects of eyes, skeletal system and central nervous system. X-linked dominant disorder Mutisystem disorder Skin - Alopecia Neurological – motor and cognitive developmental retardation, seizures, microcephaly,spasticity and paralysis Skeletal Ocular- neovascularization, microphthalmos, strabismus,optic nerve atrophy, cataracts, and retrolenticular masses, Dental – Late dentition, impaction, hypodontia.

47. Manifest at birth or during first few weeks of life 4 stages in the skin – 1. Linear whorled vesicular eruptions along Blaschko’s lines. Acral locations. Peripheral leucocytosis and eosinophilia 2. After 2-6 weeks, vesicular eruptions replaced by verrucous or lichenoid lesions in 30% of the patients. 3.Between 12 th and 20 th week and characterised by hyperpigmented lesions. 4.Fading of lesions leaving behind hypopigmented macules along the Blaschko’s lines.

48. Whorled vesicular phase

49. Management Skin lesions are benign Non cutaneous manifestations need to be managed Genetic counseling

50. REFERENCES NELSON TEXTBOOK OF PEDIATRICS, 20TH EDITION ESSENTIAL PEDIATRICS BY DR O P GHAI, 8TH EDITION WIKIPEDIA

51. Thank You!!