Neurocutaneous syndromes final powepoint

neurocutaneous syndromes are vital part of cns disorders which are extensively studied

1. Neurocutaneous syndromes Presenter: Dr Ira K.C. Moderator: Dr Anamika Mahato

2. Introduction Heterogenous group of disorders characterised by abnormalities of both the Integument and Central Nervous System of variable severity Arise due to defect in the differentiation of primitive ectoderm (nervous system, eyeball, retina and skin) Mostly familial Includes: Neurofibromatosis Tuberous Sclerosis Sturge Weber Syndrome Complex Von Hippel-Lindau Disease PHACE (Posterior fossa malformations, hemangiomas , Arterial anomalies, Cardiac Defects, Eye abnormalities) Ataxia Telangiectasia Hypomelanosis of Ito Incontinentia pigmenti Linear Nevus Syndrome

3. neurofibromatosis Autosomal dominant 3 types: Neurofibromatosis Type 1 (Von Recklinghausen disease) Neurofibromatosis Type II (Bilateral Acoustic Neurofibromatosis ) Schwannomatosis Cellular elements derived from the neural crest (i.e., Schwann cells, melanocytes, and endoneurial fibroblasts, the natural components of skin and nerves) proliferate excessively in multiple foci

4. Neurofibromatosis type I Most prevalent 50% Autosomal Dominant inheritance and 50% sporadic mutation Due to loss of function mutation in NF1 gene located on chromosome 17q11.2 that encodes for a protein called Neurofibromin Neurofibromin acts as an inhibitor of RAS oncogene

5. DIAGNOSTIC CRITERIA OF NF TYPE 1 Diagnosed when any 2 or more of the following 7 features are present: 1. Six or more Cafe-au-lait macules (macules >5 mm in prepubertal patients and >15 mm in postpubertal patients ) 2. Axillary or inguinal freckling 3. Two or more iris Lisch nodules 4. Two or more neurofibromas or 1 plexiform neurofibroma 5. A distinctive osseous lesion such as Sphenoid dysplasia , thinning long bone cortex with pseudoarthrosis 6. Optic gliomas, low-grade astrocytomas 7. A first-degree relative with NF- 1

6. Cafe-au-lait macules Hallmark of neurofibromatosis Present in almost 100% of patients Present at birth but increase in size, number, and pigmentation, especially during first few years of life Predilection for the trunk and extremities but spares the face Axillary or inguinal freckling Multiple hyperpigmented areas 2-3 mm in diameter Skinfold freckling usually appears between 3 and 5 years of age Frequency greater than 80% by 6 year of age High correlation with neurofibromatosis when six or more freckles are present in the axilla.( Crowe sign)

7. Iris Lisch nodules Pigmented hamartomatous nevus (type of benign tumor ) affecting iris Best identified by a slit-lamp examination Present in >74% Prevalence increases with age Neurofibromas Benign tumors arising from Peripheral nerve Small, rubbery lesions with a slight purplish discoloration of overlying skin 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 Plexiform neurofibromas may produce overgrowth of an extremity and a deformity of the corresponding bone 5-13% risk of malignant transformation

8. A distinctive osseous lesion such as sphenoid dysplasia (which may cause pulsating exophthalmos) or cortical thinning of long bones (e.g. of the tibia) with or without pseudoarthrosis. Optic gliomas present in approximately 15-20% of patients and represent mostly low-grade astrocytomas . CNS tumor with a marked increased frequency in NF-1. When they progress, visual symptoms occur because the tumors enlarge and put pressure on the optic nerves and chiasm resulting in impaired visual acuity and visual fields.

9. Neurofibromatosis type ii Less common Incidence of 1/25,000 live births NF2 gene (also known as merlin or Schwannomin ), located on chromosome 22q1.11 Posterior subcapsular lens opacities are identified In about 50% of patients with NF-2 Bilateral acoustic neuromas - most distinctive feature (In contrast with NF-1 – optic gliomas).

10. Diagnostic criteria of nf type ii May be diagnosed when 1 of the following 4 features is present: Bilateral vestibular schwannomas First degree relative with NF-2 and either unilateral vestibular schwannoma or any two of the associated lesions: meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular lenticular opacities Unilateral Vestibular schwannoma and any two of the following: meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular lenticular opacities Multiple meningiomas (two or more) and unilateral vestibular schwannoma or any two of the following: schwannoma, glioma, neurofibroma or cataract

11. diagnosis Clinical Diagnosis LABORATORY TESTS: Genetic testing is available. Results can only tell if an individual is affected but cannot predict the severity of the disease. IMAGING STUDIES: MRI with gadolinium is the imaging study of choice in both NF1 and NF2 patients. MRI increases detection of optic gliomas, tumors of the spine, acoustic neuromas, and “bright spots”

12. MANAGEMENT Yearly ophthalmologic examination, neurologic assessment, blood pressure monitoring, and scoliosis evaluation. Yearly, focusing the history and examination on the potential problems for which they are at increased risk. All symptomatic cases (i.e. those with visual disturbance, proptosis, or increased intracranial pressure) must be studied without delay. Selumetinib : an oral inhibitor of MAPK kinase 1 and 2, has been demonstrated, in preliminary trials in children with NF1-related inoperable plexiform neurofibromas. Genetic counseling : Patients who have only 1 of the criteria for clinical diagnosis, those with unusually severe disease, and those seeking prenatal/pre-implantation diagnosis. Surgery or irradiation Neurofibromas that cause severe symptoms may require surgical removal or irradiation, although surgery may obliterate function of the involved nerve. Optic gliomas that have become malignant may be treated with radiation therapy or chemotherapy.

13. Tuberous sclerosis TSC is an extremely heterogeneous disease with a wide clinical spectrum varying from severe mental retardation and incapacitating seizures to normal intelligence and a lack of seizures, often within the same family Disease affects many organ systems other than skin and brain, including heart, Kidney, eyes, lungs, and bone Autosomal Dominant Due to mutation in either TSC1 gene (hamartin) or TSC2 (tuberin) “Classic triad” of symptoms in TSC: Seizures, Mental retardation, Adenoma sebaceum ( angiofibromas ).

14. diagnosis Major features Hypomelanotic macules (≥3, at ≥5 mm in diameter) Facial angiofibromas (≥3) or fibrous cephalic plaque Ungual fibromas (≥2) Shagreen patch Multiple retinal hamartomas Cortical dysplasias / tubers Subependymal nodules Subependymal giant cell astrocytoma Cardiac rhabdomyoma Pulmonary Lymphangioleiomyomatosis Renal Angiomyolipoma Minor features “Confetti” skin lesions Dental enamel pits (>3) Intraoral fibromas (≥2) Retinal achromic patch Multiple renal cysts Nonrenal hamartomas Definite TSC: 2 major or 1 major and 2 minor features Possible TCS: 1 major or two or more minor features

15. management Medical: mTOr kinase Inhibitors: Sirolimus, Everolimus , Temsirolimus Antiepileptic medications: Vigabatrin, Topiramate, Lamotrigine Surgical: Focal Cortical resection/ thermal ablation Corpus Callosotomy Vagus nerve stimulation

16. FOLLOW UP: Brain MRI every 1-3 year Renal imaging using ultrasound, CT or MRI every 1-3 year Echocardiogram every 1-3 year in patients with cardiac rhabdomyomas Electrocardiogram every 3-5 year High resolution chest CT every 5-10 year in females older than 18 year Dental examination twice a year Skin examinations once a year Detailed ophthalmic examination once a year in patients with vision concerns or retinal lesions (sooner if they are receiving treatment with vigabatrin) Neurodevelopmental testing at the time of beginning 1st grade Screening for TAND at each clinic visit.

17. Sturge weber syndrome Segmental vascular neurocutaneous disorder with constellation of signs and symptoms characterized by capillary malformations in the face (port wine stain) and brain (leptomeninges) as well as abnormal blood vessels of the eye leading to glaucoma Due to mosaic mutation in GNAQ gene in chromosome 9q21  abnormal cell proliferation through activation of Extracellular signal regulated kinase pathway

18. Clinical features Cutaneous: Nevus (port-wine birthmark): Involves the forehead and upper eyelid Usually obvious at birth Reactive hypertrophy of adjacent bone and connective tissue Only 10% to 20% of children with a port-wine nevus of the forehead have leptomeningeal angioma, Which is typically ipsilateral to a unilateral facial nevus Ophthalmic: Buphthalmos , Amblyopia Glaucoma, Choroid angiomas or heterochromasia of the iris ipsilateral to the nevus Neurologic: Epileptic seizures- develop in 72% to 80% of patients with unilateral lesions and in 93% of patients with bihemispheric involvement Focal motor seizures or generalized tonic- clonic seizures, infantile spasms, myoclonic seizures, and atonic seizures Intellectual disability - Only 8% of the patients with bilateral brain involvement are intellectually normal Focal neurological deficits- Transient stroke-like episodes or visual defects

19. Diagnosis CT head: calcifications with unilateral cortical atrophy and ipsilateral dilatation of the lateral ventricle Brain MRI with contrast: extension of pial capillary malformations White matter abnormalities due to chronic hypoxia is common. Atrophy is noted ipsilateral to the leptomeningeal capillary malformation. PET Scan using 18F-deoxyglucose: reduced metabolism of the brain adjacent to the leptomeningeal lesion SPECT- reduced perfusion of the affected brain Opthalmologic evaluation: to monitor glaucoma

20. management Symptomatic and multidisciplinary Treatment aimed at: Seizure control: AEDs or Hemispherectomy Relief of headaches Prevention of stroke like episodes: Aspirin Monitoring of Glaucoma Pulse dye laser therapy for cutaneous capillary malformations

21. ATAXIA TELANGIECTASIA Autosomal recessive disorder Characterised by progressive cerebellar degeneration, oculocutaneous telangiectasia, immunodeficiency, and susceptibility to cancer as well as radiation toxicity Due to pathogenic variants in the ATM(Ataxia telangiectasia mutated) gene located in chromosome 11q22

22. Clinical features Neurologic: Ataxia: earliest neurologic manifestation Appear healthy for the first year of life and begin walking at normal age Walk on an unusually narrow base, prefer to walk fast or run Gross and fine motor skills deteriorate in the early school age period By second decade, most rely on wheelchairs for mobility Eye movement abnormalities: Voluntary and involuntary saccades lost Delay in initiating eye movements Inability to coordinate head and eye movements

23. Oculocutaneous: Telangiectasia: over bulbur conjunctiva and exposed areas of skin like pinnae, nose, face and neck First appears when child reaches 3-6 years of age Café au lait macules Hypopigmented macules Melanocytic nevi Immunedeficiency : Affects both cellular and humoral immunity Recurrent sinopulmonary infections, bronchiectasis Malignancy: Hematologic manifestations like lymphoma and leukemia

24. DIAGNOSIS α- fetoprotein level elevated in all patients with AT screening diagnostic test. Approximately 80% have decreased serum immunoglobulin— IgA, IgE , or IgG, especially the IgG2 subclass Karyotype: high incidence of chromosomal breaks, especially on chromosome 14 Fibroblasts can be screened in vitro for x-ray sensitivity and radioresistant DNA synthesis Brain imaging - cerebellar atrophy

25. treatment Supportive, no effective treatment to date Surveillance for infections and neoplasms Infections should be treated vigorously IVIG Minimize radiation as may induce further chromosomal damage and lead to neoplasms PROGNOSIS 67% of children die by age 20, typically from infection or neoplasm

26. Von hippel lindau disease Von Hippel–Lindau disease affects cerebellum, spinal cord, retina, kidney, pancreas, and epididymis. Autosomal dominant mutation affecting a tumor suppressor gene, VHL. Approximately 80% of individuals have an affected parent, and 20% have a de novo gene mutation. Major neurologic features: cerebellar hemangioblastomas and retinal angiomas. Cerebellar hemangioblastoma: Present in early adult life with symptoms and signs of increased intracranial pressure. Hemangioblastoma of spinal cord-abnormalities of proprioception, disturbances of gait and bladder function. Brain CT or MRI scan- cystic cerebellar lesion with a vascular mural nodule. Total surgical removal of the tumor is curative. Retinal angiomas: Small masses of thin walled capillaries that are fed by large and tortuous arterioles and venules. Located in the peripheral retina so that vision is unaffected. Exudation in the region of the angiomas may lead to retinal detachment and visual loss. Retinal angiomas are treated with photocoagulation and cryocoagulation .

27. Incontinentia pigmenti Rare X-linked dominant condition affecting the skin, eyes, and CNS Female >>male produced by functional mosaicism caused by random X-inactivation of an X-linked dominant gene that is lethal in males ( IKK-gamma/NEMO gene) CLINICAL FEATURES: 1 st stage: Bullous stage 2 nd stage: Verrucos stage 3 rd stage: Pigmentary stage 4 th stage: Atretic stage

28. Alopecia ,scarring and patchy or diffuse, is most common on the vertex and occurs in up to 40% of patients. Hair may be lusterless, wiry, and coarse Dental anomalies, 80% of patients: late dentition, hypodontia, conical teeth, malocclusion and impaction CNS manifestations: motor and cognitive developmental retardation, seizures, microcephaly, spasticity, and paralysis, are found in up to two third of affected children Ocular anomalies , such as neovascularization, microphthalmos, strabismus, optic nerve atrophy, cataracts, and retrolenticular masses, occur in >30% of children Less common abnormalities: dystrophy of nails (ridging, pitting) and skeletal defects. MANAGEMENT Because IP is a multi-faceted condition, dermatologic, genetic, ophthalmic, neurologic, and dental consultations should be obtained. Generally, brain imaging should be obtained (MRI) to investigate the occlusive consequences of IP in the brain. EEG should be obtained if seizures are present. Developmental therapy may be needed. Skin lesions should be managed symptomatically to avoid infection or excessive scarring.

29. Purpose This study aimed to analyze the therapeutic effect of sirolimus on seizures in pediatric patients with tuberous sclerosis. Methods We first compared the efficacy of controlling seizures in all patients after they had taken sirolimus for one year, and then we performed a subgroup analysis based on whether the administered antiepileptic drugs were changed to determine whether the efficacy was associated with changes of antiepileptic drugs. Results A total of 91 eligible children were enrolled. The response rate was 78.0 % (71/91), and 47.2 % (43/91) of all patients were became seizure-free. The improvement in seizure control before and after treatment with sirolimus was significant ( p  < 0.001). In the AEDs unaltered group, 34 were responders (34/45, 75.6 %, 95 % CI 17.4–88.3), of which 24 were seizure-free (24/34, 70.6 %). In the AEDs-altered group, 37 were responders (37/46, 80.4 %, 95 % CI 56.7–88.1), of which 19 were seizure-free (19/37, 51.4 %). There was no significant difference between the two groups for reductions in rate of seizure frequency ( p  = 0.308). In the patients with refractory epilepsy, treatment with sirolimus was also effective ( p  = 0.01). Logistic regression analysis showed that age was an important factor affecting outcome of epilepsy ( p  = 0.003, 95 % CI 2.05–38.31). No Grade 3 or 4 adverse events were noted during the follow-up. Conclusions Sirolimus has a significant effect on seizures associated with tuberous sclerosis complex (TSC), with no or only moderate adverse events after long-term administration. Sirolimus could be used as the first-line medication for pediatric patients with TSC-associated epilepsy. Sirolimus improves seizure control in pediatric patients with tuberous sclerosis: A prospective cohort study Department of Pediatrics , The First Medical Center of Chinese, PLA General Hospital, China Center for Brain Disorders Research, Capital Medical University, Beijing Institute for Brain Disorders, China

30. REFERENCES Nelson Textbook of Pediatrics , 21 st Edition Uptodate 2023 Elsevier, Volume 79, July 2020

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