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Neurocutaneous Syndromes
The document provides an overview of several neurocutaneous syndromes from a pediatric perspective. It discusses the defining features and management of neurofibromatosis types 1 and 2, tuberous sclerosis complex, and Sturge-Weber syndrome. Key points include: neurofibromatosis type 1 is characterized by café-au-lait spots and neurofibromas; neurofibromatosis type 2 features tumors of the cranial and spinal nerves; tuberous sclerosis complex causes non-cancerous tumors in many organs and features epilepsy and intellectual disability; and Sturge-Weber syndrome is identified by a port-wine stain on the face and glaucoma of the ipsilateral eye. Close multidisciplinary monitoring
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Neurocutaneous Syndromes
- 1. NEUROCUTANEOUS SYNDROMES A PEDIATRIC PERSPECTIVE DRNISHANT YADAV RESIDENT PEDIATRICS
- 2. INTRODUCTION • The neurocutaneoussyndromes 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 asneurocutaneous 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 areautosomal 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 benignnerve 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 1. 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 ofonset : • Teenage years • Onset of puberty • Increase in number and size throughout adulthood • Complications : • Stinging • Itching • Pain • Disfiguration • No evidence of malignant transformation
- 8. 2. 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 • 2out of the following 7 signs : 1. 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. 2. Axillary or inguinal freckling 3. Two or more iris Lisch nodules 4. 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 typicallyinvolve 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 neurofibromasare 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.
- 15. Café-au-lait spots • Café-au-laitspots are the hallmark of neurofibromatosis • Present in almost 100% of patients. • Present at birth but increase in size, number and pigmentation, especially during the 1st few years of life. • Predilection for trunk and extremities. • Facial sparing
- 17. Other conditions withCafé-au-lait macules • Neurofibromatosis type 2 • Macune albright Syndrome • Ataxia telangiectasia • Bloom’s syndrome • Watsons’s syndrome • Familial Café-au-lait macules
- 18. Other findings inNF-1 • Learning disabilities • Attention deficit disorders • Behavioral and psychosocial problems • Abnormalities of speech • Seizures – Complex partial and GTCS
- 19. 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
- 20. 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
- 21. 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
- 22. NF-2 • Rarer condition •Incidence – 1/25,000 • The NF2 gene (also known as merlin or schwannomin) is located on chromosome 22q1.11.
- 23. Diagnostic criteria forNF-2 : • 1 of the following 4 features is present: 1. Bilateral vestibular schwannomas 2. 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 3. Unilateral vestibular schwannoma and any 2 of the following: meningioma, schwannoma, glioma, neurofi broma, or posterior subcapsular lenticular opacities 4. Multiple meningiomas (2 or more) and unilateral vestibular schwannoma or any 2 of the following: schwannoma, glioma, neurofibroma, or cataract.
- 24. • Symptoms • Tinnitus •Hearing loss • Facial weakness • Headache • Unsteadiness • Café-au-lait spots • Skin neurofibromas
- 25.
- 26. Management in acase of Neurofibromatosis
- 27. • Close multidisciplinaryfollow-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
- 28. • Neuropsychologic andeducational 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
- 29. Genetic Counseling • Moleculartesting 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.
- 30. Tuberous Sclerosis • Autosomaldominant • 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 1/3rd patients
- 32. • 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
- 34.
- 35. • 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
- 36. CT scan with subependymalcalcifi cations characteristic of tuberous sclerosis. MRI demonstrates multiple subependymal nodules in the same patient (arrow).
- 37. • 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
- 38. • Management • Seizurecontrol • Renal imaging every 1-3 year • Echocardiogram • Chest roentgenogram • Brain MRI every 1-3 year • Neurodevelopmental testing at the time of beginning 1st grade.
- 39. Sturge-Weber Syndrome • Sporadicdisorder • 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
- 40. • Buphthalmos andglaucoma of the ipsilateral eye • Seizures in the 1st 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 1st year of life • Mental retardation or severe learning disabilities in at least 50% in later childhood
- 41. DIAGNOSIS • MRI withcontrast 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
- 42. Gadolinium-enhanced axial T1 FLAIRimage of a 15 mo old with Sturge-Weber syndrome shows leptomeningeal enhancement in the left hemisphere.
- 43. VonHippel-LindauDisease • Autosomal dominanttrait • 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
- 44. • Hemangioblastoma ofthe 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
- 45. PHACE Syndrome • Femalepredominance • 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.
- 46. • Large facialhemangiomas may be associated with Dandy- Walker malformation • Interferon- alpha is of value in management of the hemangiomas.
- 47. Ataxia Telangiectasia • Autosomalrecessive • 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
- 48. • Decreased serumIgA • Alpha-fetoprotein elevated • Sino pulmonary infections • Lymphoreticular malignancies • Immune deficiency • Neuroimaging – Cerebellar atrophy
- 49. Incontinentia Pigmenti • Uncommongenodermatosis 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.
- 50. • Manifest atbirth 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 12th and 20th week and characterised by hyperpigmented lesions. • 4.Fading of lesions leaving behind hypopigmented macules along the Blaschko’s lines.
- 51. • Whorled vesicularphase
- 52. • Management • Skinlesions are benign • Non cutaneous manifestations need to be managed • Genetic counseling
- 53. REFERENCES • NELSON TEXTBOOKOF PEDIATRICS, 20TH EDITION • ESSENTIAL PEDIATRICS BY DR O P GHAI, 8TH EDITION • WIKIPEDIA
- 54.