Neurocutaneous Syndromes (Phakomatoses)

• Definition: A heterogeneous group of congenital disorders characterized by the presence of lesions involving structures derived from the embryonic ectoderm (Skin and Central Nervous System).
• Pathogenesis: Most are caused by defects in tumor suppressor genes, leading to hamartomas or neoplasms.
• Inheritance: Majority are Autosomal Dominant (NF1, NF2, TSC, VHL), though spontaneous mutations are common. Some are Autosomal Recessive (Ataxia Telangiectasia) or Sporadic (Sturge-Weber).

I. Neurofibromatosis Type 1 (Von Recklinghausen Disease)

The most common neurocutaneous syndrome (1:3000).

1. Genetics

• Gene: NF1 tumor suppressor gene on Chromosome 17q11.2.
• Protein: Neurofibromin (regulates RAS-MAPK pathway).
• Inheritance: Autosomal Dominant (50% are de novo mutations).

2. Diagnostic Criteria (NIH Consensus)
Diagnosis requires $\ge$ 2 of the following 7 features:

1. Café-au-lait (CAL) Macules: $\ge$ 6 spots. (Prepubertal: >5mm; Postpubertal: >15mm).
2. Axillary or Inguinal Freckling: (Crowe’s sign).
3. Neurofibromas: $\ge$ 2 of any type or 1 Plexiform Neurofibroma.
4. Optic Glioma: Tumor of the optic pathway (often asymptomatic).
5. Lisch Nodules: $\ge$ 2 iris hamartomas (seen on slit-lamp exam).
6. Bone Lesions: Distinctive osseous lesion (sphenoid dysplasia or tibial pseudarthrosis).
7. Family History: First-degree relative with NF1.

3. Systemic Complications

• Neurologic: Learning disabilities (40–60%), ADHD, seizures (rare), unidentified bright objects (UBOs) on MRI.
• Malignancy: Malignant Peripheral Nerve Sheath Tumor (MPNST), Pheochromocytoma, Leukemia (JMML).
• Orthopedic: Scoliosis, short stature.
• Vascular: Renal artery stenosis (Hypertension), Moyamoya syndrome.

II. Tuberous Sclerosis Complex (TSC)

Second most common; characterized by hamartomas in multiple organs.

1. Genetics

• Genes: TSC1 (Ch 9q34, Hamartin) or TSC2 (Ch 16p13, Tuberin).
• Mechanism: Failure to inhibit the mTOR pathway $\to$ uncontrolled cell growth.
• Inheritance: Autosomal Dominant (2/3 sporadic).

2. Clinical Features (Vogt’s Triad: Epilepsy, ID, Adenoma Sebaceum)

• Dermatologic (Major Criteria):
  • Hypomelanotic Macules (Ash-Leaf Spots): Earliest sign; seen with Wood's lamp.
  • Facial Angiofibromas: Malar rash (butterfly distribution); appear age 4–6 yrs.
  • Shagreen Patch: Leathery connective tissue nevus (lumbosacral).
  • Ungual Fibromas: Koenen tumors.
• Neurologic:
  • Epilepsy (>90%): Infantile Spasms (West syndrome) are classic. Focal seizures later.
  • Pathology: Cortical Tubers, Subependymal Nodules (SEN).
  • SEGA (Subependymal Giant Cell Astrocytoma): Can cause obstructive hydrocephalus.
• Systemic:
  • Cardiac: Rhabdomyomas (often regress spontaneously).
  • Renal: Angiomyolipomas (bleed risk).
  • Pulmonary: Lymphangioleiomyomatosis (LAM) in adult females.

3. Management

• Seizures: Vigabatrin (Drug of choice for Infantile Spasms in TSC).
• mTOR Inhibitors: Everolimus/Sirolimus for SEGA and large renal AMLs.

III. Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis)

A vascular neurocutaneous syndrome.

1. Genetics

• Mutation: Somatic activating mutation in GNAQ gene.
• Inheritance: Sporadic (Not inherited).

2. Clinical Features

• Cutaneous: Port-Wine Stain (Nevus Flammeus). Capillary malformation in the distribution of CN V1 (Ophthalmic branch).
• Neurologic:
  • Leptomeningeal Angioma: Ipsilateral to skin lesion.
  • Seizures: Focal motor seizures (contralateral) starting in infancy; often refractory.
  • Calcification: "Tram-track" cortical calcifications (gyriform) on CT/X-ray.
  • Deficits: Contralateral hemiparesis, hemianopia, intellectual disability.
• Ocular: Glaucoma (Buphthalmos) in ~50% (ipsilateral).

3. Management

• Seizures: Aggressive control (sometimes requires hemispherectomy).
• Skin: Pulsed dye laser.
• Eye: Annual screening for intraocular pressure.

IV. Neurofibromatosis Type 2 (NF2)

"MISME" Syndrome (Multiple Inherited Schwannomas, Meningiomas, and Ependymomas).

• Gene: NF2 on Chromosome 22q12. Protein: Merlin (Schwannomin).
• Hallmark: Bilateral Vestibular Schwannomas (Acoustic Neuromas).
• Presentation: Hearing loss, tinnitus, balance issues (adolescence/young adult).
• Skin: Fewer CAL spots than NF1; skin plaques.

V. Ataxia Telangiectasia

A combined neurocutaneous and immunodeficiency disorder.

• Genetics: ATM gene on Ch 11q22 (DNA repair defect). Autosomal Recessive.
• Clinical Features:
  • Ataxia: Cerebellar ataxia begins when walking starts (1–2 yrs).
  • Telangiectasia: Ocular (bulbar conjunctiva) appears age 3–6 yrs.
  • Immunity: T-cell and B-cell deficiency (low IgA/IgE) $\to$ sinopulmonary infections.
  • Sensitivity: Extreme sensitivity to ionizing radiation (avoid X-rays).
• Markers: Elevated Alpha-Fetoprotein (AFP).

VI. Other Rare Syndromes

VII. Approach to a Child with Neurocutaneous Markers

1. Detailed Skin Exam: Wood's lamp for hypopigmented macules; measurement of CAL spots; check axilla/groin.
2. Ophthalmology Referral: Essential for all (Lisch nodules, optic glioma, retinal hamartomas, glaucoma).
3. Neuroimaging (MRI):
   • NF1: If symptomatic (vision loss, seizures, rapid head growth).
   • TSC: Baseline MRI brain and abdomen (renal) upon diagnosis.
   • SWS: MRI with contrast to visualize angioma.
4. Genetic Counseling: Crucial for family planning (AD inheritance patterns).