This document discusses several neurocutaneous syndromes characterized by abnormalities of both the integument and central nervous system arising from defects in ectoderm differentiation. Some key syndromes covered include neurofibromatosis types 1 and 2, tuberous sclerosis complex, Sturge-Weber syndrome, Von Hippel-Lindau disease, linear nevus sebaceous syndrome, PHACE syndrome, and incontinentia pigmenti. Each syndrome is defined by its clinical features, inheritance, genetic basis when known, diagnostic criteria, management considerations, and associated complications.

1. NEUROCUTANEOUS SYNDROME

2. NEUROCUTANEOUS SYNDROME
• Heterogeneous group of disorders characterized by abnormalities of both the integument and
central nervous system.
• Many of the disorders are hereditary and believed to arise from a defect in differentiation of the
primitive ectoderm (nervous system, eyeball, retina and skin).
• Neurofibromatosis type 1 (NF1)
• Neurofibromatosis type 2 (NF2)
• Tuberous sclerosis complex (TSC)
• Sturge- Weber syndrome (SWS)
• Von Hippel–Lindau disease (VHL)
• PHACE syndrome
• Ataxia-telangiectasia (AT)
• Linear nevus syndrome
• Hypomelanosis of Ito
• Incontinentia pigmenti.

3. NEUROFIBROMATOSES
• Autosomal dominant disorders that cause tumors to grow on nerves and result in other systemic abnormalities.
• There are three types, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis
• NF-1: The disease is clinically diagnosed when any two of the following seven features are present:
(1) six or more café-au-lait macules > 5 mm in greatest diameter in prepubertal individuals and > 15 mm in
greatest diameter in postpubertal individuals
(2) Axillary or inguinal freckling consisting of multiple hyperpigmented areas 2-3 mm in diameter .
(3) Two or more iris Lisch nodules, which are hamartomas located within the iris and are best identified by a
slit-lamp examination
(4) Two or more neurofibromas or one plexiform neurofibroma.
(5) A distinctive osseous lesion such as sphenoid dysplasia (which may cause pulsating exophthalmos) or
cortical thinning of long bones with or without pseudoarthrosis (most often the tibia).
(6) Optic gliomas are present in approximately 15–20% of individuals with NF1
(7) A first-degree relative with NF1 whose diagnosis was based on the aforementioned criteria.

5. • NF2 is a less common disorder than NF1; it is also transmitted in an autosomal dominant manner, with an
incidence of 1 in 25,000 births.
• Typically, NF2 is diagnosed when one of the following four features is present:
(1) bilateral vestibular schwannomas
(2) a parent, sibling, or child with NF2 and either unilateral vestibular schwannoma or any two of the
following: 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; or
(4) multiple meningiomas (two or more) and unilateral vestibular schwannoma or any two of the following:
schwannoma, glioma, neurofibroma, or cataract.
COMPLICATIONS:
1. Symptoms of tinnitus, hearing loss, facial weakness, headache, or unsteadiness
2. Susceptible to neurologic complications and at risk for hypertension, learning disability.
3. Aneurysms and stenosis of cerebral vessels- Moyamoya disease
4. Precocious puberty -presence or absence of lesions of the optic pathway tumors.

6. MRI studies: abnormal hyperintense T2-weighted signals in the optic tracts, brainstem, globus pallidus,
thalamus, internal capsule, and cerebellum.
MANAGEMENT:
• Yearly ophthalmologic examination, neurologic assessment, blood pressure monitoring, and scoliosis
evaluation.
• Neuropsychological and educational testing should be considered
• Imaging studies: all symptomatic cases(visual disturbance, proptosis, increased intracranial pressure)
• Selumetinib, an oral inhibitor of MAPK kinase 1 and 2 for inoperable plexiform neurofibroma
GENETIC COUNSELLING:
Although NF1 is an autosomal dominant disorder, more than half the cases are sporadic, representing de novo
mutations.
• Patients who meet only one of the criteria for clinical diagnosis
• Those with unusually severe disease
• Those seeking prenatal/preimplantation diagnosis.

7. TUBEROUS SCLEROSIS
• Autosomal dominant mode of inheritance and prevalence of 1 in 6,000 to 10,000 newborns.
• Spontaneous genetic mutations occur in 65% of the cases.
• TSC1 gene is located on chromosome 9q34, and the TSC2 gene is on chromosome 16p13.
• The TSC1 gene encodes a protein called hamartin, while the TSC2 gene encodes a protein called tuberin.
• The hallmark of TSC is the involvement of the CNS.
• The characteristic brain lesion is a cortical tuber- Brain MRI.
• Subependymal nodules are lesions found along the wall of the lateral ventricles, where they undergo
calcification and project into the ventricular cavity, producing a candle-dripping appearance.

8. DIAGNOSIS: Two major or one major plus two minor features are present
MAJOR FEATURES
• Cortical dysplasias
• Subependymal nodules
• Subependymal giant cell astrocytoma
• Facial angiofibromas (≥3) or forehead plaque
• Ungual fibromas (≥2)
• Hypomelanotic macules (≥3, ≥ 5 mm in diameter)
• Shagreen patch
• Multiple retinal nodular hamartomas
• Cardiac rhabdomyoma
• Renal angiomyolipoma
• Pulmonary lymphangioleiomyomatosis
MINOR FEATURES
• Dental enamel pits (>3)
• Intraoral fibromas (≥2)
• Retinal achromic patch
• Confetti skin lesions
• Nonrenal hamartomas
• Multiple renal cysts

10. CNS MANIFESTATIONS:
• Epilepsy, cognitive impairment, and autism spectrum disorder.
• TSC may present during infancy with infantile spasms and a hypsarrhythmic electroencephalogram pattern.
• The seizures may be difficult to control, and at a later age, they may develop into focal-onset seizures or generalized
myoclonic seizures
• Vigabatrin is the first-line therapy for infantile spasms, ACTH can be used if treatment with vigabatrin fails.
• Everolimus (adjunctive) -refractory seizures.
• Intellectual disability (45%), autism spectrum disorder (50%), ADHD, anxiety, and depression.
SKIN LESIONS:
• Hypomelanotic macules on the trunk and extremities -Wood ultraviolet lamp
• Facial angiofibromas develop between 4 and 6 years of age.
• Shagreen patch- roughened, raised lesion with an orange-peel consistency located primarily in the lumbosacral region.
• Forehead fibrous plaques usually occur on one side of the forehead.
• During adolescence or later, small fibromas or nodules of skin.
OTHER ORGAN INVOLVEMENT
• Cardiac: Rhabdomyomas (50%)
• Kidney: Angiomyolipomas (75-80%)
• Pulmonary: Lymphangioleiomyomatosis

11. TREATMENT:
RECOMMENDATION:
• 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

12. STURGE-WEBER SYNDROME (SWS)
• Segmental vascular neurocutaneous disorder (1 in 20,000-50,000)
• Characterized by capillary malformation in the face and brain as well as abnormal blood vessels of the eye leading to glaucoma.
• Based on the involvement of the brain and the face, there are three types of SWS in the Roach Scale:
• Type I—Both facial and leptomeningeal angiomas present; may have glaucoma.
• Type II—Facial angioma alone (no CNS involvement); may have glaucoma.
• Type III—Isolated leptomeningeal angiomas; usually no glaucoma.
Portwine birthmark:
• Unilateral and ipsilateral to the brain involvement .
• It may also be evident over the lower face and trunk and in the mucosa of the mouth and pharynx.
Buphthalmos and glaucoma of the ipsilateral eye are common complications.
Neurodevelopment:
• Patients present with seizures, hemiparesis, stroke-like episodes, headaches, and developmental delay.
• Seizures occur in 75–80% of all SWS patients and in over 90% of those with bilateral brain involvement.
• Neurodevelopment -normal in the first year of life,
• Intellectual disability or severe learning disabilities are present in at least 50% of patients in later childhood

14. DIAGNOSIS:
1. Brain MRI with contrast-
• Demonstration of the extension of pial capillary malformation.
• White matter abnormalities are common and are thought to be a result of chronic hypoxia.
• Often, atrophy is noted ipsilateral to the leptomeningeal capillary malformation.
2. CT head: Calcifications can be seen
3. Ophthalmologic evaluation examining for glaucoma
TREATMENT:
• Treatment is aimed at seizure control, relief of headaches, and prevention of stroke-like episodes, as well as
monitoring of glaucoma and laser therapy for the cutaneous capillary malformations.
• If seizures are refractory to anticonvulsant therapy, especially in infancy and the first 1 to 2 year, and arise from
primarily one hemisphere- hemispherectomy.
• Glaucoma-regular measurement of intraocular pressure is indicated.
• Pulsed-dye laser therapy often provides excellent clearing of the PWB, particularly if it is located on the forehead.

15. VON HIPPEL-LINDAU DISEASE 1 in 36,000 newborns
• Affects cerebellum, spinal cord, retina, kidney, pancreas, and epididymis.
• Approximately 80% of individuals have an affected parent, and approximately 20% have a de novo gene mutation.
• The major neurologic features: cerebellar hemangioblastomas and retinal angiomas (retinal capillary hemangioblastomas).
CEREBELLAR HEMANGIOBLASTOMA:
• Present in early adult life
• Symptoms and signs of increased intracranial pressure.
• Hemangioblastoma of the spinal cord: abnormalities of proprioception and 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.
RETINALANGIOMAS:
• 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.
• Treated with photocoagulation and cryocoagulation
• Cystic lesions of the kidneys, pancreas, liver, and epididymis, as well as pheochromocytoma, are frequently associated.
• Renal carcinoma is the most common cause of death, and CNS hemangioblastomas also contribute to morbidity.

16. LINEAR NEVUS SEBACEOUS SYNDROME
• Sporadic condition is characterized by a large facial nevus, neurodevelopmental abnormalities, and systemic defects.
• The nevus is usually located on the forehead and nose and tends to be midline in its distribution.
• It may be quite faint during infancy but later becomes hyperkeratotic, with a yellow-brown appearance.
• Neurologic findings: cortical dysplasia, glial hamartomas, and low-grade gliomas.
• Cerebral and cranial anomalies: hemimegalencephaly and enlargement of the lateral ventricles (72%)
• Epilepsy and intellectual disability
• Focal neurologic signs: hemiparesis and homonymous hemianopia.
• Eyes: strabismus, retinal abnormalities, coloboma, cataracts, corneal revascularization, and ocular hemangiomas),
• Heart: aortic coarctation,
• Kidneys: horseshoe kidney
• Skeleton: fibrous dysplasia, skeletal hypoplasia, and scoliosis/kyphoscoliosis.

17. PHACE SYNDROME:
Posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and other cardiac defects,
and eye abnormalities.
• Posterior fossa malformation: developmental defects, including sternal clefting and/or a supraumbilical raphe.
• Hemangiomas
• Endocrinopathies (such as hypopituitarism, hypothyroidism, growth hormone deficiency, and diabetes insipidus).
• The facial hemangioma is typically ipsilateral to the aortic arch.
• Brain: Dandy-Walker malformation, hypoplasia or agenesis of the cerebellum, cerebellar vermis, corpus callosum,
cerebrum, and septum pellucidum.
• Abnormal neurodevelopment: 44% with language delay, 36% with gross motor delay, and 8% with fine motor
delay.
• The beta-blocker propranolol is emerging as a treatment for infantile hemangiomas associated with PHACE
syndrome.

18. INCONTINENTIA PIGMENTI (IP)
• Rare, heritable, multisystem ectodermal disorder that features dermatologic, dental, ocular, and CNS abnormalities.
1st (bullous) stage:
• Evident at birth or in the first few weeks of life, The 1st stage generally resolves by 4 month of age, Blood eosinophilia as high as 65%.
• Erythematous linear streaks and plaques of vesicles that are most pronounced on the limbs and circumferentially on the trunk.
2nd (verrucous) stage
• Blisters on the distal limbs resolve, they become dry and hyperkeratotic, forming verrucous plaques.
• Involute within 6 months, Epidermal hyperplasia, hyperkeratosis, dyskeratosis, and papillomatosis are characteristic.
3rd (pigmentary) stage- hallmark of incontinentia pigmenti. (The axillae and groin are characteristically affected)
• Begin to appear in the 1st few months of life, Hyperpigmentation is more often apparent on the trunk than the limbs.
• Macular whorls, reticulated patches, flecks, and linear streaks that follow Blaschko lines
• The pigmented lesions, once present, persist throughout childhood, begin to fade by early adolescence and often disappear by age 16 year.
4th (atretic) stage:
• Hairless, anhidrotic, hypopigmented patches or streaks- late manifestation of incontinentia pigmenti
• The lesions develop mainly on the flexor aspect of the lower legs and less often on the arms and trunk.

19. • Alopecia (40%)- scarring and patchy or diffuse, common on the vertex
• Dental anomalies (80%)- late dentition, hypodontia, conical teeth, malocclusion, and impaction.
• CNS manifestations (30%)- seizures, intellectual disability, hemiplegia, hemiparesis, spasticity, microcephaly, and cerebellar ataxia.
• Ocular anomalies (>30%)- retinal neovascularization, microphthalmos, strabismus, optic nerve atrophy, cataracts, retrolenticular masses.
• Less common abnormalities- dystrophy of nails (ridging, pitting), subungual and periungual keratotic tumors, and skeletal defects.
DIAGNOSIS:
• Wood's lamp examination: pigmentary abnormalities.
• Clinical molecular testing is available: 11.7-kb common deletion in IKBKG, (65% of affected females and 16% of affected males)
• Skin biopsy: unclear clinical findings and negative genetic testing.
TREATMENT:
• Dermatology: To characterize the nature of skin lesions, manage extensive skin manifestations
• Medical genetics and genetic counseling: establish a molecular diagnosis, family counseling.
• Ophthalmology: To delineate the presence and extent of retinal neovascularization
• Neurology : Evaluate and treat microcephaly, seizures, and motor abnormalities.
• Dentistry : Teeth implants along with routine care.
• Speech pathologists and nutritionists: If dental abnormalities affect speech or feeding
• Developmental medicine: Recommendations regarding developmental and behavioral concerns.