63  Neurocutaneous Syndromes

63.1 Introduction

Neurocutaneous syndromes, also known as phakomatoses, are a diverse group of congenital disorders characterised by abnormalities of the skin and nervous system, often involving other organs such as the eyes, bones, and endocrine glands. They result primarily from genetic mutations that affect the development and differentiation of tissues derived from the ectoderm. Because both the skin and the nervous system originate from the ectodermal layer during embryogenesis, a developmental insult to this germ layer can explain the frequent coexistence of neurological and cutaneous manifestations.

Recognition of these disorders is crucial in paediatrics, as cutaneous findings may serve as visible markers of significant underlying neurological disease. Early diagnosis allows for timely surveillance, prevention of complications, and genetic counselling for families. The most common and well-studied neurocutaneous syndromes include Neurofibromatosis type 1 and 2, Tuberous sclerosis complex, Sturge–Weber syndrome, and Von Hippel–Lindau disease. Other less frequent syndromes include Ataxia telangiectasia, Incontinentia pigmenti, and Hypomelanosis of Ito.

63.2 Embryological and Pathophysiological Basis

During the third to fourth week of embryonic development, the ectoderm differentiates into two main tissues: the neural ectoderm, which forms the nervous system, and the surface ectoderm, which gives rise to the skin and its appendages. Genetic defects that disrupt the proliferation or migration of neural crest cells, progenitors for melanocytes, Schwann cells, meninges, and components of the peripheral nervous system, underlie most neurocutaneous disorders.

These mutations often affect genes involved in tumour suppression, cell growth regulation, and signal transduction pathways, such as the RAS/MAPK and mTOR pathways. The result is dysregulated cell proliferation, hamartoma formation, and predisposition to both benign and malignant tumours.

The underlying pathophysiological mechanisms therefore include:

• Hamartomatous growths in skin, brain, and other organs
• Vascular malformations
• Abnormal neuronal migration
• Predisposition to neoplasia

63.3 General Clinical Features

Neurocutaneous syndromes present variably, but some general features include:

• Cutaneous findings: café-au-lait macules, hypopigmented macules, angiofibromas, shagreen patches, or port-wine stains.
• Neurological manifestations: seizures, developmental delay, learning disability, and focal neurological deficits.
• Ocular features: retinal hamartomas, optic gliomas, and choroidal angiomas.
• Skeletal anomalies: scoliosis, pseudoarthrosis, and bone cysts.
• Endocrine abnormalities: precocious puberty or adrenal lesions in certain syndromes.

Diagnosis relies on recognizing these characteristic associations, supported by neuroimaging and genetic testing.

63.4 Major Neurocutaneous Syndromes

63.4.1 Neurofibromatosis Type 1 (NF1)

NF1, also known as von Recklinghausen disease, is the most common neurocutaneous disorder, occurring in about 1 in 3,000 live births. It is caused by mutations in the NF1 gene on chromosome 17, which encodes neurofibromin, a tumour suppressor that regulates the RAS pathway.

Key clinical features:

• ≥6 café-au-lait macules (>5 mm prepubertal, >15 mm postpubertal)
• Axillary or inguinal freckling
• ≥2 neurofibromas or one plexiform neurofibroma
• Lisch nodules (iris hamartomas)
• Optic pathway glioma
• Bony lesions (e.g., sphenoid dysplasia, pseudoarthrosis)
• A first-degree relative with NF1

Neurological features: learning difficulties, attention deficit, seizures, and risk of intracranial tumours.
Complications: hypertension due to renal artery stenosis or pheochromocytoma, malignant peripheral nerve sheath tumours, and scoliosis.

Management: multidisciplinary, dermatologic surveillance, annual ophthalmology, developmental assessment, and blood pressure monitoring.

63.4.2 Neurofibromatosis Type 2 (NF2)

NF2 results from mutations in the NF2 gene on chromosome 22, which encodes merlin (schwannomin), another tumour suppressor. It is rarer (1 in 25,000 births) and typically presents in adolescence or early adulthood.

Hallmark features:

• Bilateral vestibular schwannomas causing hearing loss and imbalance
• Meningiomas, spinal schwannomas, and ependymomas
• Posterior subcapsular cataracts in children

Cutaneous findings are less prominent than in NF1.
Management: MRI surveillance, hearing monitoring, and neurosurgical intervention when necessary.

63.4.3 Tuberous Sclerosis Complex (TSC)

TSC is an autosomal dominant disorder due to mutations in TSC1 (hamartin) or TSC2 (tuberin) genes, which regulate the mTOR signalling pathway. It affects about 1 in 6,000 births.

Cutaneous features:

• Hypomelanotic macules (“ash leaf” spots)
• Facial angiofibromas (adenoma sebaceum)
• Shagreen patch (connective tissue nevus)
• Periungual fibromas

Neurological manifestations:

• Cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs)
• Epilepsy (infantile spasms common)
• Cognitive impairment and autism spectrum disorder

Other organ involvement:

• Cardiac rhabdomyomas (often regress spontaneously)
• Renal angiomyolipomas and cysts
• Pulmonary lymphangioleiomyomatosis (especially in females)

Management:

• mTOR inhibitors (everolimus, sirolimus) for SEGA or renal angiomyolipomas
• Antiepileptic therapy
• Developmental and genetic counselling

63.4.4 Sturge–Weber Syndrome (SWS)

SWS is a sporadic neurocutaneous disorder caused by somatic mutations in the GNAQ gene. It is characterized by vascular malformations involving the leptomeninges and facial skin.

Clinical features:

• Facial port-wine stain (nevus flammeus) along the ophthalmic branch of the trigeminal nerve
• Leptomeningeal angioma causing seizures, stroke-like episodes, and hemiparesis
• Glaucoma and visual impairment

Neuroimaging: CT shows “tram-track” calcifications; MRI reveals leptomeningeal enhancement.
Management: seizure control, ophthalmologic follow-up, and laser therapy for port-wine stains.

63.4.5 Von Hippel–Lindau Disease (VHL)

An autosomal dominant disorder caused by mutations in the VHL tumour suppressor gene on chromosome 3.

Major features:

• Retinal and cerebellar hemangioblastomas
• Renal cell carcinoma and pancreatic cysts
• Pheochromocytoma

Pediatric significance: retinal angiomas may present in adolescence.
Management: regular MRI screening and surgical or laser intervention for tumours.

63.4.6 Ataxia Telangiectasia (AT)

AT is an autosomal recessive disorder due to mutations in the ATM gene, which regulates DNA repair.

Key features:

• Progressive cerebellar ataxia beginning in early childhood
• Oculocutaneous telangiectasias (especially conjunctivae)
• Immunodeficiency (low IgA and IgE)
• High risk of malignancy, particularly lymphoma and leukemia

Management: supportive care, physiotherapy, infection prophylaxis, and avoidance of ionizing radiation.

63.4.7 Incontinentia Pigmenti (IP)

An X-linked dominant disorder lethal in males, caused by IKBKG gene mutations affecting NF-κB signalling.

Stages of skin lesions:

1. Vesicular stage (blistering rash in neonates)
2. Verrucous stage (wart-like lesions)
3. Hyperpigmented streaks along Blaschko’s lines
4. Hypopigmented atrophic patches in adolescence/adulthood

Associated findings: seizures, intellectual disability, dental anomalies, and ocular defects.

63.4.8 Hypomelanosis of Ito

Characterized by whorled or streaked hypopigmented lesions along Blaschko’s lines. It represents chromosomal mosaicism rather than a single gene defect.

Associated features: developmental delay, seizures, scoliosis, and ocular anomalies.
Diagnosis is clinical; management is supportive.

63.5 Investigations

Diagnostic evaluation depends on the suspected syndrome but generally includes:

• Neuroimaging (MRI brain/spine): for intracranial lesions, calcifications, or tumours
• Dermatological examination: Wood’s lamp for hypopigmented lesions
• Ophthalmological assessment: slit-lamp and retinal evaluation
• Genetic testing: confirmation of specific mutations
• Renal ultrasound: in NF1 and TSC for cysts or angiomyolipomas
• EEG: in children with seizures
• Audiometry: in NF2 for vestibular schwannoma detection

63.6 Management Principles

Management is multidisciplinary, involving paediatric neurologists, dermatologists, ophthalmologists, geneticists, and surgeons. The principles include:

• Early recognition through skin examination
• Regular surveillance for neurological, renal, and ocular complications
• Seizure management using appropriate antiepileptics
• Surgical intervention for accessible tumours or disfiguring lesions
• Use of targeted therapies (e.g., mTOR inhibitors in TSC)
• Genetic counselling and screening of at-risk family members

63.7 Prognosis

Prognosis varies widely depending on the syndrome and severity of organ involvement. For example:

• NF1 and TSC are compatible with long survival but carry risks of malignancy.
• Sturge–Weber and AT have more guarded outcomes due to neurological decline.
• Early diagnosis and targeted interventions have improved life expectancy and quality of life.

63.8 Public Health Importance

In Ghana and other low-resource settings, recognition of neurocutaneous syndromes is often delayed due to limited access to dermatology and genetic services. Raising awareness among healthcare providers is essential for early identification and referral. Establishing registries and integrating genetic counselling into paediatric services will improve outcomes and guide family planning.