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:
1. Neurofibromatosis
2. Tuberous Sclerosis
3. Sturge Weber Syndrome Complex
4. Von Hippel-Lindau Disease
5. PHACE (Posterior fossa malformations, hemangiomas, Arterial anomalies, Cardiac Defects, Eye
abnormalities)
6. Ataxia Telangiectasia
7. Hypomelanosis of Ito
8. Incontinentia pigmenti
9. Linear Nevus Syndrome
3. NEUROFIBROMATOSIS
• Autosomal dominant
• 3 types:
1. Neurofibromatosis Type 1 (Von Recklinghausen disease)
2. Neurofibromatosis Type II (Bilateral Acoustic Neurofibromatosis )
3. 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:
1. Bilateral vestibular schwannomas
2. 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
3. Unilateral Vestibular schwannoma and any two of the following: meningioma, schwannoma, glioma,
neurofibroma or posterior subcapsular lenticular opacities
4. 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
1. Hypomelanotic macules (≥3, at ≥5 mm in diameter)
2. Facial angiofibromas (≥3) or fibrous cephalic plaque
3. Ungual fibromas (≥2)
4. Shagreen patch
5. Multiple retinal hamartomas
6. Cortical dysplasias
7. Subependymal nodules
8. Subependymal giant cell astrocytoma
9. Cardiac rhabdomyoma
10. Pulmonary Lymphangioleiomyomatosis
11. Renal Angiomyolipoma
Minor features
1. “Confetti” skin lesions
2. Dental enamel pits (>3)
3. Intraoral fibromas (≥2)
4. Retinal achromic patch
5. Multiple renal cysts
6. Nonrenal hamartomas
Definite TSC: 2 major or 1 major and 2
minor features
Possible TCS: 1 major or two or more
minor features
17. 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.
18. 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
19. 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
20. 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
• SPEC- reduced perfusion of the affected brain
• Opthalmologic evaluation: to monitor glaucoma
21. 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
22. 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
23. 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
24. 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
Recuurent sinopulmonary infections, bronchiectasis
Malignancy:
Hematologic manifestations like lymphoma and leukemia
25. 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
26. 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
27. 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.
28. 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:
1st stage: Bullous stage
2nd stage: Verrucos stage
3rd stage: Pigmentary stage
4th stage: Atretic stage
29. • 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.
30. 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
