Neurocutaneous Markers and Congenital malformations - Dr. S. Srinivasan, Professor of Pediatrics, MGMCRI

Neurocutaneous Markers and Congenital malformations - Dr. S. Srinivasan, Professor of Pediatrics, MGMCRI

1. Neuro-Cutaneous Syndromes in Children ( NCS ) MGMCRI- 8 th & 9 th Semesters MBBS- UG Pediatrics Theory Lecture 31 mar 16 S.Srinivasan Professor of Paediatrics MGMCRI, Pillayarkuppam Puducherry

2. Neurocutaneous Syndromes in Children ( NCS ) Learning Objectives Define the term – “ Neurocutaneus Syndromes” List three common types in NCS Explain the reason of association between Skin and CNS disorders Recognize the cutaneous lesions; Explain or Correlate their presence with the neurological disorders and Diagnose the specific NCSyndrome Tell the mode of genetic inheritance of the NCS Enumerate salient clinical features ( Signs & Symptoms ) of the most common NCS List a few common complications of these conditions Choose appropriate investigative work up Outline briefly the management plan of the common NCS NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

3. Central Nervous System Disorders with concurrent lesions in the Skin, Eye, and possibly other Visceral Organs Neurocutaneous syndromes Refer to a heterogenous group of NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

4. The NeuroCutaneous ( Skin & CNS manifestations are related to the “ COMMON ECTODERMAL ORIGIN ” of these organs Heredofamilial Disorder Defective differentiation of primitive ectoderm Neurocutaneous syndromes Remember the Following 3 Basic POINTS NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

5. Tuberous Sclerosis Neurofibromatosis Sturge - weber Syndrome Incontinentia Pigmenti Hypomelanosis of Ito Ataxia Telangiectasia Von Hippel – Lindau Disease Linear Nevus Syndrome PHACE Syndrome Neurocutaneous syndromes NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

6. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Plexiform Neurofibroma Son and mother having NCS: Eyelid skin Neurofibroma & skin Neurofibromas

7. Tuberous Sclerosis Inherited ( Autosomal Dominant with “ NEAR COMPLETE” penetrance ) Neuro - Cutaneous disorder Characteric pleomorphic features involving many organ systems, including multiple benign neoplasms ( hamartomas ) of the brain, kidney, and skin Nonfamilial cases ( spontaneous mutations or mosaicism ) 2 TS genes- ch 9 & 16 (TSC1 & TSC2 genes) and the other on chromosome 16 (gene) PHYSICAL FINDINGS & CLINICAL NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

8. Dermatologic manifestations : clues to the diagnosis Vogt’s Classic diagnostic triad ( Seizures, mental retardation, & Facial Angiofibromas ) - <50% All clinical features of TS : Not apparent in the first yr of life NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Tuberous Sclerosis – Clinical Features

9. Skin Features in Tuberous Sclerosis NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16   H ypomelanotic ASH LEAF Macules F acial Angiofibromas (Adenoma Sebaceum )   Shagreen's patches F orehead Plaque Ungual Fibromas

10. Dermatologic manifestations in children with Tuberous Sclerosis Easiest and most accessible method of establishing the diagnosis NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

11. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 ADENOMA SEBACEUM (Facial Angiofibromas ) Shagreen’s patches Tuberous Sclerosis

12. ADENOMA SEBACEUM (Facial Angiofibromas ) F orehead Plaque Tuberous Sclerosis

13. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Café – au – lait spots or patches

14. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

15. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

16. Neurologic manifestations in Children with TS Brain hamartomas : - Cortical tubers - Subependymal Nodules - Subependymal Giant Cell Astrocytomas Intractable seizures -90% to 96% of TS Infantile spasms: Most common First epileptic episode in the first 2 yr of life in 85% of children Behavioral and cognitive dysfunction, including autism and mental retardation: 40% to 50% NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Leading cause of morbidity and mortality

17. Involvement of the other Organs in TS Renal Angiomyolipoma Pulmonary (1% to 6%) Lymphangiomyomatosis (LAM), a progressive cystic lung disease Cardiovascular (50 to 60 %) Rhabdomyoma (most common ) - - Primary cardiac tumor in infants and children; 80% to 95% of patients with cardiac rhabdomyomas have TS Ocular ( 40% to 50% ) Retinal Hamartomas NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

18. Early recognition of TS Neuroimaging studies EEG ECG Cardiac, Chest & Renal ultrasonography Chest CT VITAL TO PREVENT SERIOUS CLINICAL CONSEQUENCES. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

19. Neurofibromatosis- (NF) 2 Types: NF-1 & NF-2 Inheritance of both types: Autosomal Dominant Main features: Nerve tumors , Skin changes seen as features/markers with bone deformities NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

20. Axillary Freckling Iris :2 or more Lisch Nodules 2 or more Neurofibromas over the skin or even 1 Plexiform Neurofibroma Sphenoid Dysplasia Neurofibromatosis-1 (NF-1) Classic features NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

21. Commonest of the 2 types Incidence: 1 in 3000 Implicated gene in Ch17 Neurofibromin – Encoded Protein Neurofibromatosis-1 (NF-1) Few Basic known Facts 1) 6 or more Café –au – lait spots 2) Freckling in axillary or inguinal regoin 3) Lisch Nodules -2 or more seen over iris of the eyes 4) 2 or more Neurofibromas over the skin or even 1 Plexiform Neurofibroma 5) Distinctive Bone lesion – Sphenoid Dysplasia 6) Optic Gliomas –Low grade Astrocytomas 7) A first degree relative with NF -1 Diagnosis Presence of 2 / 7 NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

22. Complications in Neurofibromatosis-1 (NF-1) Seizures Macrocephaly Hydrocephalus Learning, Behavioural & Speech Disabilities,ADHD Moya-Moya Disease Precocious Puberty Systemic Hypertension: Fibromuscular Dysplasia, Phaeochromocytoma Malignancies: N.Fibrosarcomas ; Malignant Schwanomas NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

23. Rarer (1 in 25000) NF2 Gene (Merlin or Schwannomin ) Gene: Ch 22q Less common : Café au lait spots & Skin neurofibromas Eyes: 50% - Posterior Subcapsular Cataracts / Lens opacities Neurofibromatosis-Type2 (NF-2) NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

24. Neurofibromatosis-Type2 (NF-2) Diagnosis made – Presence of any one of the following Bilateral vestibular Schwannomas Family ( parent, sibling or child with NF-2) a) unilateral vestibular schwannoma or b)Presence of any two of the following: - Meningiomas , Schwannoma , Glioma , Neurofibroma or Posterior Subcapsular lenticular opacities NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

25. STURGE –WEBER SYNDROME NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

26. Sturge -Weber syndrome (SWS) Sporadic vascular disorder 1 in 50,000 live births Constellation of symptoms and signs Facial port-wine stain capillary malformation Leptomeningeal angioma ( Abnormal blood vessels of the brain ) Abnormal blood vessels of the choroid of the eye → Buphthalmos (Glaucoma) NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

27. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Hyperdense gyriform calcifications in left parieto -occipital lobe with evidence of moderate gyral enhancement  Nevus Flammeus   Lt.Parietal Menin . Haemangioma

28. Sturge -Weber syndrome Port-wine stain involving both V1 V2 dermatomes CT scan- unilateral calcification & atrophy of cerebral hemisphere NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

29. Presenting Symptoms of Sturge –Weber Syndrome ( SWS ) Seizures ( 90% of children with SWS ) Hemiparesis Stroke-like episodes Visual disturbances - Hemianopsia Headaches Developmental and Intellectual delay NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

30. Management of SWS consists of anticonvulsants and surveillance for complications including glaucoma, buphthalmos , and behavioral abnormalities Regular measurement of intraocular pressure AIMS: Seizure control Treatmentof headaches, and Prevention of stroke-like episodes Monitoring of glaucoma and Pulsed-dye L aser therapy for the cutaneous capillary malformation Surgery in selected refractory cases : H emispherectomy . Symptomatic & Multidisciplinary Management

31. von Hippel-Lindau disease 1 in 36,000 newborns Autosomal Dominant Mutation affecting a tumor suppressor gene, VHL Multi organ involvement: Cerebellum , spinal cord, retina, kidney, pancreas, and epididymis NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

32. Major neurologic features Cerebellar & Spinal Cord hemangioblastomas Retinal Angiomas (25%) Cystic lesions: Kidneys , Pancreas , Liver and Epididymis Pheochromocytoma : Common NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

33. Skin : Earliest symptom Skin lesions may follow Blaschko lines and their melanoblasts start to transform into melanocytes after birth 3 or 4 stages :- Vesicular , Verrucous , Hyperpigmented , and sometimes Hypopigmented stagemonths and disappear within 6 months after birth. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Incontinentia Pigmenti (IP ) ( 'Bloch-Sulzberger syndrome' )

34. Incontinentia Pigmenti (IP ) ( 'Bloch-Sulzberger syndrome' ) Rare (1 per 40,000) X-linked genodermatosis Mutation of  NEMO/ IKKr  gene in X-Chromosome O ccurs mostly in female infants (95%)due to its fatality in male in utero NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

35. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

36. MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

37. Other Organs involved in IP Teeth: Delayed eruption of teeth, changes in dental contour (circular or conical shape), and hypodontia Eyes (RETINOPATHY ): Speckled diffuse hypopigmentation in the retina, microphthalmia , lenticular hemorrhage, retrolental fibroplasia , cataract, and atrophy of the optic nerve CNS: seizure, microcephaly , mental retardation, and spastic Paralysis Musculoskeletal , and Cardiovascular anomalies Incontinentia Pigmenti (IP) ('Bloch-Sulzberger syndrome' ) NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16

38. ATAXIA-TELANGIECTASIA NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 Mutation of ATM Gene Ataxia (12-25 months ), Nystagmus , Chorea Ocular Telangiectasia (2-7 years) Chronic Sinopulmonary Infections Vitiligo

39. GTT: abnormal Serum IgA & IgE : Decreased Alpha –Fetoprotein & Carcinoembryogenic Antigen : Elevated Chromosomal Breakages Neuroimaging : Cerebellar Atrophy Predisposition to Lymphoreticular malignancies. NEUROCUTANEOUS SYNDROMES - MGMCRI- 8 th &9 th Semesters MBBS-UG PEDIATRICS Theory Lecture 31 mar 16 ATAXIA-TELANGIECTASIA