NEUROCUTANEOUS SYNDROME

Moderators: Dr. Jimoh/Dr. Nepyil

PRESENTERS

TABLE OF CONTENTS

01

02

03

04

INTRODUCTION

NEUROFIBROMATOSIS

STURGE-WEBER SYNDROME

TUBERCULOSIS SCLEROSIS

VON-HIPPEL LINGUA

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ATAXIA TALENGIECTASIA

05

06

TABLE OF CONTENTS

07

08

09

10

LINEAR EPIDERMAL NERVUS SYNDROME

HYPOMELANOSIS OF ITO

CONCLUSION & REFERENCE

INCONTINENTIA PIGMENTI

INTRODUCTION

• Neurocutaneous syndromes are a heterogenous group of disorders .

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•These diseases have many features in

common.

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• Most are hereditary.

INTRODUCTION

-Involvement of organs of ectodermal

origin (nervous system,eyeball, retina

and skin)

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-Tendency to form hermatomas

(benign tumor-like formations due to

maldevelopment) and a disposition to

fatal malignant disposition.

INTRODUCTION

Disorders classified as neurocutaneous syndromes

include:

• Neurofibromatosis

• Tuberous sclerosis

• Sturge Weber syndrome

• Von Hippel - Lindau disease

• Ataxia telangiectasia

• Linear nevus syndrome,

• Hypomelanosis of Ito,

• Incontinentia pigmenti.

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Neurofibromatosis

01

and other neural crest derivative disease

Symptoms

There are two types of neurofibromatosis, each

with different signs and symptoms.

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Neurofibromatosis 1

Neurofibromatosis 1 (NF1) is usually diagnosed

during childhood. Signs are often noticeable at birth

or shortly afterward and almost always by age 10.

Symptoms

Flat, light brown spots on

the skin (cafe au lait

spots)

These harmless spots are common in many people.

Having more than six cafe au lait spots suggests NF1.

They are usually present at birth or appear during the first years of life. After childhood, new spots stop appearing

Symptoms

Freckling in the

armpits or groin area

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Freckling usually appears by ages 3 to 5. Freckles are smaller than cafe au lait spots and tend to occur in clusters in skin folds.

Symptoms

Tiny bumps on the iris

of the eye (Lisch

nodules)

These harmless nodules can't easily be seen and don't affect vision.

Symptoms

Soft, pea-sized bumps on or under the skin (neurofibromas)

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These harmless nodules can't easily be seen and don't affect vision.

Symptoms

Bone deformities

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Abnormal bone development and a deficiency in bone mineral density can cause bone deformities such as a curved spine (scoliosis) or a bowed lower leg

Symptoms

Tumor on the optic nerve

(optic glioma)

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These tumors usually appear by

age 3, rarely in late childhood

and adolescence, and almost

never in adults

Symptoms

Learning disabilities. Impaired thinking skills are

common in children who have NF1 but are usually mild.

Often there is a specific learning disability, such as a

problem with reading or mathematics.

Attention-deficit/hyperactivity disorder (ADHD) and speech

delay also are common.

Larger than average head size. Children with NF1 tend

to have a larger than average head size due to increased

brain volume.

Short stature. Children who have NF1 often are below

average in height

Neurofibromatosis 2 (NF2) is much less common than

NF1. Signs and symptoms of NF2 usually result from the

development of benign, slow-growing tumors in both ears

(acoustic neuromas), which can cause hearing loss. Also

known as vestibular schwannomas, these tumors grow

on the nerve that carries sound and balance information

from the inner ear to the brain.

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Signs and symptoms generally appear during the late teen and early adult years, and can vary in severity

Signs and symptoms can include:

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• Gradual hearing loss
• Ringing in the ears
• Poor balance
• Headaches

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Sometimes NF2 can lead to the growth of schwannomas

in other nerves, including the cranial, spinal, visual (optic)

and peripheral nerves. People who have NF2 may also

develop other benign tumors.

Signs and symptoms of these tumors can

include:

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• Numbness and weakness in the arms or legs
• Pain
• Balance difficulties
• Facial drop
• Vision problems or cataracts
• Seizures
• Headache

Diagnosis

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Eye examination. Lisch nodules, cataracts and visual loss

can be detected

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Hearing and balance examination. A test that measures hearing (audiometry), a test that uses electrodes to record your eye movements (electronystagmography) and a test that measures the electrical messages that carry sound from the inner ear to the brain (brainstem auditory evoked response) can help assess hearing and balance problems in people who have NF2

X-rays, CT scans or MRIs can help identify bone abnormalities, tumors in the brain or spinal cord, and very small tumors. MRI can be used to diagnose optic gliomas.

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Genetic tests. Tests to identify NF1 and NF2 are available and can be done in pregnancy before a baby is born.

TUBEROUS SCLEROSIS

02

Sturge-Weber Syndrome (SWS)

03

(Encephalotrigerminal Angiomatosis)

INTRODUCTION

Inheritance

• Non-inherited

Pathophysiology

• Somatic mutation of GNAQ gene (sporadic)

Triad of SWS (PEN)

Clinical Manifestations

• Hemiparesis
• Hemisensory deficit
• Buphthalmos and glaucoma
• Transient stroke like episodes/visual defects
• Epilepsy(Contralateral to the side Of the facial capillary Malformation)
• MR or severe learning disabilities 50% in later childhood.

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Diagnosis

• Eye Exam: IOP measurement to ruleout glaucoma
• EEG: To detect seizure activity

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• Imaging:MRI (GS)

RAIL-ROAD TRACK CALCIFICATION

UNILATERAL CORTICAL �ATROPHY

Investigations

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• CSF Analysis - Elevated Proteins
• Angiography - Aberrant tortuous vessels, Non - filling dural sinuses
• CT Scan - Tram-Track appearance, Calcifications,
• Enlarged Choroid plexus, Aberrant vessels Blood brain barrier breakdown(during seizures)

Treatment Modalities

• Pulsed Dye Laser Tx.
• Laser Photocoagulation
• Anti-convulsants for seizures
• Prophylactic treatment for headache
• Drugs to reduce IOP for Glaucoma
• Ca inhibitors
• Beta agonists
• Adrenergics

Von Hippel-Lindua Disease

04

Introduction

Von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, is a rare genetic disorder characterized by visceral cysts and benign tumors in multiple organ systems that have subsequent potential for malignant change

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Clinical hallmarks of VHL include the development of:

1. Retinal and CNS hemangioblastomas
2. Multiple cysts in the kidneys and pancreas
3. Increased risk of transformation of renal cysts in renal cell carcinoma

The wide age range and pleiotropic manner in which VHL disease presents complicates diagnosis and treatment in affected individuals, as well as their at-risk relatives

Epidemiology

• Autosomal-dominant
• Worldwide incidence is 1:32,000 live births
• Males and females are equally affected
• Age at diagnosis varies from infancy to age 60-70, average age 26

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Pathophysiology

Mutation in the Von Hippel-Lindau (VHL) gene located on the short (p) arm of chromosome 3 which encodes Von Hippel-Lindau protein is the only known cause of VHL disease

Von Hippel-Lindau protein has many functions including:

1. Polyubiquitination
2. Regulation of transcription factors: HIF1a and HIF2a
3. Regulation of other hypoxia-inducible genes
4. Interaction with the extracellular matrix
5. Cell cycle control

Molecular genetic testing of VHL gene detects mutations in 90%-100% of affected individuals

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Tumorigenesis

How the loss of pVHL function causes tumorigenesis is not fully known. The VHL gene may act as a classic tumor suppressor gene as originally described by Knudson in his 2-hit theory of carcinogenesis

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When this theory is applied to an individual with VHL disease, the person inherits a germline mutation that renders one VHL allele inactive and an acquired "second hit" to the other VHL allele in a somatic cell leaves that cell without tumor suppressor ability

Clinical Findings

Hemangiomas

• VHL disease is characterized by retinal capillary hemangiomas. Diagnosed in 50% of patients with VHL disease, these hemangiomas are composed of endothelial cells and pericytes
• Complications such as glaucoma or permanent vision loss

Renal lesions

• The primary cause of morbidity and mortality in VHL disease, as well as the most serious sequela of the condition, involves the malignant degeneration of renal cysts
• Approximately 40% of patients with VHL disease develop malignant transformation. Other renal lesions, such as hemangiomas and benign adenomas can occur

CNS hemangioblastomas

• CNS hemangioblastomas are the second most common cause of morbidity and mortality in patients with VHL disease.

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• Approximately 70% of patients with VHL disease develop these tumors

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• Although hemangioblastomas are usually benign, enlargement of these tumors within the confines of the CNS can cause neurologic compromise.

Retinal hemangioblastomas

Patients with retinal hemangioblastomas are usually asymptomatic, but these benign ocular tumors can lead to considerable morbidity through retinal detachment or vision loss from an enlarging lesion

Others include;

• Pancreatic lesions
• Pheochromocytomas
• Epididymal papillary cystadenomas

Diagnostic criteria

1. A single hemangioblastoma in the CNS or retina, plus a visceral manifestation (multiple renal, pancreatic, or hepatic cysts; pheochromocytoma; renal cancer)
2. More than one hemangioblastoma in the CNS (brain, spinal cord) or eye
3. Mutation in the VHL gene
4. Positive family history plus any one of the above clinical manifestations

Investigations

1. Imaging studies
2. Ophthalmic ultrasonography
3. Abdominal/genitourinary ultrasonography: Renal and pancreatic lesions, cysts of the epididymis and broad ligament
4. Abdominal CT scanning without and with contrast: Renal, pancreatic, and adrenal gland lesions
5. Abdominal MRI: Renal, pancreatic, and adrenal gland lesions
6. Brain CT scan with and without contrast
7. CNS MRI with and without contrast

Investigations

Biochemical analysis

1. Complete blood count: is used to look for evidence of polycythemia vera due to EPO expression by renal cysts and cerebellar hemangioblastomas.
2. Electrolytes and renal function (BUN and creatine) are used for electrolyte measurement and renal baseline function.
3. Measurement of plasma catecholamines and urinary catecholamine metabolites is performed to detect pheochromocytomas

Treatment

Medical care and treatment approaches for patients with von Hippel-Lindau (VHL) disease are determined by the specific complications present. Most therapies for complications of VHL disease are surgical (eg, excision of tumors in the CNS, adrenal gland tissue, or kidneys)

Diet and lifestyle

Dietary guidelines for patients with VHL disease have been recommended by the VHL Family Alliance. These Include:

• Increase consumption of phytochemicals, such as grains, cruciferous and other vegetables, fruits, and spices
• Decrease consumption of protein from fish, poultry, and meat
• Limit alcohol intake
• Avoid tobacco products because of their risk associated with renal cancer
• Avoid chemicals and industrial toxins known to affect VHL-involved organs

Differentials

• Multiple endocrine neoplasia, type 2 (MEN type 2)
• Multiple paraganglioma syndrome
• Neurofibromatosis
• Pheochromocytoma
• Autosomal dominant polycystic kidney disease (ADPKD)
• Birt-Hogg-Dube (BHD) syndrome
• Tuberous sclerosis complex (TSC)
• Choroidal mass (tumor/metastasis)
• Retinal telangiectasia
• Retinal macroaneurysm

Prognosis

• The morbidity of VHL disease varies depending on the particular organ system involved and the extent of the organ-system insult.
• The average life expectancy in affected individuals is 49 year
• Diligent surveillance enabling early treatment interventions can increase life expectancy.

The potential for malignancy require a lifelong strategy of surveillance (particularly for the neurologic, ocular and renal systems) to enable early detection and treatment of complications

ATAXIA TELANGIECTASIA

05

Introduction

• Also known as louis-bar syndrome,it is a rare neurodenegerative autosomal recessive disease characterized by progressive neurological impairement and cerebellar ataxia . It affects multiple systems in the body but primarily the nervous system and the immune system .it affects both genders equally and affects all race. The incidence is 1 in 100,000 births.
• Syllaba and Henner first published descriptions of patients with ataxia telangiectasia in 1926 , they observed progressive choreoathetosis and ocular telangiectasia .

ETIOLOGY

It is caused by the genetic mutation in the ATM gene on chromosome 11q(22-23) tBecause of this defect, cell response to different pathogenic triggers, such as ionizing radiation and alkylating agents, is impaired

PATHOPHYSIOLOGY

• The defect in the gene causes loss of the ataxia telangiectasia mutated serine threonine kinase protein , a key protein involved in the activation of the DNA damage checkpoint impairing DNA damage and apoptosis signals. This protein activates other proteins like tumor suppressor p53 and BRCA 1 by phosphyration , failure to activate apoptosis in specific neural regions causes progressive spinocerebellar granular neural cell damage and purkinje cell degeneration , damage to p53 and BRCA1 causes impaired signaling of downstream cell cycle with increased disposition to cancer

CLINICAL FEATURES

1.Ataxia, telangiectasia

2.Difficulty in walking

3.Choreoathethosis

4.Wasted face

5.Slurred speech

6.Oculomotor Apraxia

Neuropathy

INVESTIGATIONS

1.Alpha feto protein assay

2.Chromosomal analysis

3.Immunoglobulin assay

4.MRI scan

Treatment

Theres is currently no cure for AT and it mainly focuses on managing the symptoms and complications

1.Give immunoglobulin supplements

2.Antibiotics

3.Beta adrenergic blockers

Surveillance in cases of cancer

COMPLICATIONS

1.Chronic lung infections

2.Cognitive impairment

3.Recurrent infections

4.Neurologic deficts

5.Speech and swallowing difficulties

6.Growth delay

Linear Epidermal Nevus Syndrome

06

(LENS)

Introduction

Linear Epidermal Nevus Syndrome (LENS) is a rare neurocutaneous disorder characterized by the presence of linear epidermal nevi, which are raised, warty, or verrucous skin lesions arranged in a linear pattern.

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This condition not only poses cosmetic concerns but often coincides with various neurological, ocular, and musculoskeletal manifestations.

Etiology

It is sporadic and arises from postzygotic mutations during embryonic development. These mutations affecLENS t specific genes, leading to the formation of epidermal nevi and other associated abnormalities. The exact genetic mutations can vary among affected individuals, contributing to the heterogeneity of this condition.

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Pathogenesis

The pathogenesis of LENS is primarily related to somatic mosaic mutations in the genes responsible for skin development. These mutations lead to abnormal keratinocyte proliferation, resulting in the formation of epidermal nevi. The mosaic nature of these genetic changes explains the linear pattern of skin lesions and the absence of familial inheritance.

Clinical Manifestations

�The hallmark of LENS is the presence of linear epidermal nevi, which often appear at birth or in early childhood. These nevi are typically raised and can vary in color and texture. They are most commonly found on the limbs and trunk, but they can extend to other body regions.�Alongside the cutaneous findings, LENS can be associated with a range of clinical manifestations:

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Neurological Abnormalities: These may include developmental delay, seizures, and intellectual disability. Epilepsy is a common neurological feature.

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Ocular Abnormalities: Some individuals may exhibit ophthalmic issues such as strabismus, cataracts, or colobomas.

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Musculoskeletal Anomalies: Skeletal abnormalities like limb length discrepancies or hemiatrophy may be present.

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Diagnosis�Diagnosis of LENS is clinical and based on the characteristic linear epidermal nevi, as well as the presence of associated clinical findings. Molecular genetic testing may be performed to identify specific mutations, but these tests are not always required for diagnosis.

Investigations and Their Findings

Imaging studies, such as brain MRI, may be indicated to assess neurological manifestations. Findings may include the presence of structural abnormalities in the brain, especially in individuals with seizures or developmental delays.

Ophthalmic evaluations may reveal the presence of cataracts, colobomas, or other eye abnormalities. X-rays or other imaging modalities may be used to detect musculoskeletal issues, particularly when limb length discrepancies or skeletal deformities are present.

Management and Treatment

The management of LENS typically requires a multidisciplinary approach. Treatment primarily addresses the cosmetic and functional concerns associated with epidermal nevi. Management strategies may include:

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Surgical Excision: Surgical removal or reduction of epidermal nevi can be considered for cosmetic improvement, but it may not completely eliminate skin lesions.

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Laser Therapy: Laser treatment can help to reduce the size and thickness of epidermal nevi.

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Neurological, ophthalmic, and musculoskeletal issues associated with LENS may require specialized care. For example, epilepsy in individuals with LENS may be managed with antiepileptic medications. Ophthalmic abnormalities may necessitate surgical correction.

Hypomelanosis of Ito

07

INTRODUCTION

-Hypomelanosis of Ito is a pigmentary mosaicism characterized by a clone of skin cells with decreased ability to produce pigment.

-characterized by hypopigmented streaks and whorls running along the lines of Blaschko, characteristically involving more than 2 body segments. -one fifth of patients have a patchy presentation without a specific distribution pattern.

-Various terms have been used to describe this mosaicism, including Blaschkoid dyspigmentation, linear and whorled nevoid hypermelanosis, pigmentary mosaicism of the hypopigmented type, and incontinentia pigmenti achromians

EPIDEMIOLOGY

-prevalence of 1 case per 7,540 births -the third most common neurocutaneous syndrome

-No clear racial predilection

-more common in women than in men

-Skin lesions may become more pigmented over time and blend well with normally pigmented skin.

ETIOLOGY

• Chromosomal mosaicism and sporadic mutations are the causes of hypomelanosis of Ito.
• There is no firm evidence for genetic transmission

PATHOPHYSIOLOGY

• The affected areas seen in hypomelanosis of Ito result from postzygotic mutations in a variety of pigmentation-associated genes, resulting in a clone of skin cells with reduced capacity to produce pigment.
• Structural or numerical chromosomal aberrations present in these clones of cells have been linked with this entity. Around 90% of these chromosomal aberrations are present in the locations of genes involved in pigmentation

SIGNS & SYMPTOMS

• Small 0.5- to 1-cm hypopigmented macules coalesce to form reticulated patches along the lines of Blaschko, usually stopping at the midline.
• They are most often seen on the trunk and limbs.
• The macules/patches cover more than 2 dermatomes and are often on both sides of the body.

DIAGNOSIS

• A Wood lamp enhances the pattern, especially in White patients.

Clinical diagnosis

• Histologic findings include a decreased amount of melanin present in keratinocytes and melanocytes along the basal layer of the epidermis

Prognosis

The prognosis is determined by any associated abnormalities

Differential Diagnosis

• Fourth stage of incontinentia pigmenti

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• Lichen Striatus

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• Linear and whorled nevoid hypermelanosis

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• Linear leukoderma

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• Nevus depigmentus

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• Pigmentary demarcation lines

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• Vitiligo Segmental

INCONTINENTIA PIGMENTI

08

INTRODUCTION

• Heritable, x-linked dominant
• Multisystem ectodermal disorder features dermatologic, dental, and ocular abnormalities
• The phenotype is produced by functional mosaicism
• Random x-inactivation of an x-linked dominant gene that is lethal in males (ikk-gamma/NEMO gene)
• The paucity of affected males
• The occurrence of female-to-female transmission,
• An increased frequency of spontaneous abortions in carrier females support this supposition.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

This disease has 4 phases, not all of which may occur

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The 1st phase is evident at birth or in the 1st few weeks of life

• Consists of erythematous linear streaks and plaques of vesicles
• Most pronounced on the limbs and circumferentially on the trunk.
• The lesions may be confused with those of herpes simplex, bullous impetigo, or mastocytosis, but the linear configuration is unique
• Histopathologically, epidermal edema and eosinophil-filled intraepidermal vesicles
• Eosinophils also infiltrate the adjacent epidermis and dermis.
• Blood eosinophilia as high as 65% of WBC count

CLINICAL MANIFESTATIONS AND DIAGNOSIS

In the 2nd phase, as blisters on the distal limbs resolve, they become dry and hyperkeratotic, forming verrucous plaques

• The verrucous plaques rarely affect the trunk or face and generally involute within 6 mo
• Epidermal hyperplasia,
• Hyperkeratosis
• Papillomatosis are characteristic.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

The 3rd or pigmentary stage is the hallmark of IP

• It generally develops over weeks to months
• May overlap the earlier phases, be evident at birth, or, more commonly, begin to appear in the 1st few weeks of life
• Hyperpigmentation is on the trunk > the limbs
• Distributed in macular whorls, reticulated patches, flecks, and linear streaks that follow blaschko lines
• The axillae and groin are invariably affected

CLINICAL MANIFESTATIONS AND DIAGNOSIS

In the 4th stage, hairless, anhidrotic, hypopigmented patches or streaks occur

• late manifestation of IP o they may develop, however, before the hyperpigmentation of stage 3 has resolved
• The lesions develop mainly on the flexor aspect of the lower legs and less often on the arms and trunk.

DIAGNOSIS OF INCONTINENTIA PIGMENTI

• Although major and minor criteria have been established
• Wood lamp examination - highlight pigmentary abnormalities
• Clinical molecular testing is available
• 80% of the affected patients a deletion that removes exons 4 through 10 of NEMO can be detected.
• D/D - hypomelanosis of Ito, which presents with similar skin manifestations and is often associated with chromosomal mosaicism.

MANAGEMENT

• The choice of investigative studies and the plan of management depend on the occurrence of particular noncutaneous abnormalities since the skin lesions are benign
• The high incidence of associated major anomalies warrants genetic counseling.

CONCLUSION

• Neurocutaneous syndromes are a group of genetic disorders affecting the nervous system and skin.

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• These conditions often require lifelong managment & care.

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• Early diagnosis and intervention are crucial to improve the quality of life for individuals with these syndromes

Reference

• www.Slideshare.com
• http://emedicine.medscape.com/article/1177523-overview
• http://www.sturge-weber.org/medical-matters/sturge-weber-
• http://www.nlm.nih.gov/medlineplus/ency/article/001426.htm