Phakomatoses and syndrome-specific surveillance

Neurocutaneous Syndromes (The Phakomatoses)

The phakomatoses (derived from the Greek phakos, meaning "lentil" or "birthmark") encompass a group of congenital neuro-oculo-cutaneous disorders characterized by widespread hamartoma formation involving tissues of ectodermal and mesodermal origin (central nervous system, retina, skin, and visceral organs). Master-level differentiation of these conditions is a consistent testing pillar in the EBOD examination.

1. Neurofibromatosis Type 1 (NF1 / von Recklinghausen Disease)

Genetics & Pathophysiology

• Inheritance: Autosomal dominant (AD) with $100\%$ penetrance but highly variable expressivity; approximately $50\%$ of cases arise from de novo spontaneous mutations.
• Gene & Locus: NF1 gene located on chromosome 17q11.2, encoding neurofibromin.
• Function: Neurofibromin functions as a GTPase-activating protein (Ras-GAP) that accelerates the hydrolysis of active Ras-GTP into inactive Ras-GDP, negatively regulating the p21-Ras proto-oncogene signaling pathway. Loss of neurofibromin leads to uncontrolled cellular proliferation and tumorogenesis.

Current NF1 Criteria

The 2021 revised criteria require two qualifying features in a person without an affected parent. They include characteristic pigmentary findings, neurofibromas/plexiform neurofibroma, optic-pathway glioma, characteristic bone lesions, two Lisch nodules or two choroidal abnormalities on appropriate imaging, and a heterozygous pathogenic NF1 variant in unaffected tissue. With an affected parent, one qualifying feature can establish the clinical diagnosis. Lisch and choroidal signs are alternatives within one criterion, not two independent points. Pigment-only children require differentiation from Legius syndrome and other conditions. See the international consensus.

2. Neurofibromatosis Type 2 (NF2 / Schwannomatosis-NF2)

Genetics & Hallmarks

• Inheritance: Autosomal dominant (AD); chromosome 22q12.2; NF2 tumor suppressor gene encoding merlin (also known as schwannomin), a cytoskeletal protein regulating contact-dependent cell growth inhibition.
• Hallmark: Bilateral vestibular schwannomas (acoustic neuromas, arising from cranial nerve VIII), presenting in early adulthood with progressive sensorineural hearing loss, tinnitus, and unsteadiness.

Ocular Manifestations (Vital Differentials vs. NF1)

• Absence of Lisch Nodules: Lisch nodules are absent in NF2. This is a critical clinical discriminator.
• Juvenile Posterior Subcapsular or Cortical Wedge Cataracts: Present in $>60-80\%$ of NF2 patients before age 30. Often subtle, appearing as posterior subcapsular or radial cortical opacities.
• Combined Hamartoma of the Retina and RPE (CHRRE): A slightly elevated, hyperpigmented, vascularised glial-pigmentary lesion occurring at the optic disc or posterior pole, frequently causing early-onset vitreoretinal traction, epiretinal membrane, and macular distortion.
• Epiretinal Membranes (ERMs): Idiopathic ERMs developing in children or young adults should prompt an immediate neuro-ophthalmic workup for NF2.
• Cranial Nerve Palsies: Secondary to multiple intracranial schwannomas or meningiomas (e.g., CN III, IV, VI, VII palsy).

3. Tuberous Sclerosis Complex (Bourneville Disease)

Genetics & Pathophysiology

• Inheritance: Autosomal dominant (AD); high spontaneous mutation rate ($60-70\%$).
• Genes: TSC1 on chromosome 9q34 (encoding hamartin) and TSC2 on chromosome 16p13.3 (encoding tuberin). Hamartin and tuberin form an intracellular heterodimer that acts as a GTPase-activating protein for Rheb, exerting a tonic inhibitory effect on the mammalian target of rapamycin complex 1 (mTORC1). Inactivating mutations cause constitutive mTOR hyperactivation, driving widespread benign hamartoma development.

Ocular Hallmarks

• Retinal Astrocytic Hamartomas (50% of patients): Arise from the retinal nerve fiber layer. Two morphologic varieties:
  • Type 1 (Non-calcified): Flat, smooth, translucent, non-calcified, grey-white circular lesions with feathered margins, most often located in the mid-periphery.
  • Type 2 (Calcified / Classic Mulberry Lesion): Highly elevated, opaque, multinodular, yellow-white "mulberry-like" lesions located at or adjacent to the optic nerve head. Autofluorescent on fundus autofluorescence (FAF) due to dense calcium deposition. Usually benign and static; rarely produce vitreous hemorrhage or tractional retinal detachment.
• Other Ocular Signs: Depigmented iris sectors, iris colobomas, chorioretinal depigmentation ("punched-out" chorioretinal lesions).

Systemic Triad & Organ Involvement

• Dermatological: Hypomelanotic macules ("ash-leaf spots", $\ge 3$, illuminated under Wood's UV lamp); facial angiofibromas (adenoma sebaceum, butterfly distribution over the malar bridge and nasolabial folds); Shagreen patch (connective tissue plaque in lumbosacral region); periungual fibromas (Koenen tumours).
• Central Nervous System: Cortical tubers, subependymal glial nodules ("candle wax drippings" lining the lateral ventricles), subependymal giant cell astrocytomas (SEGA) near the foramen of Monro (risk of obstructive hydrocephalus; treated with oral mTOR inhibitors such as everolimus), and infantile spasms (traditionally treated with vigabatrin).
• Visceral Organs: Bilateral renal angiomyolipomas (AMLs; risk of massive retroperitoneal bleeding if $>4\text{ cm}$), cardiac rhabdomyomas (present in infancy, frequently undergo spontaneous involution), and pulmonary lymphangioleiomyomatosis (LAM).

4. Von Hippel-Lindau Disease (VHL)

Genetics & Molecular Mechanism

• Inheritance: Autosomal dominant (AD); chromosome 3p25; VHL tumour suppressor gene.
• Molecular Biology: The pVHL protein forms a complex that ubiquitinates the alpha subunit of hypoxia-inducible factor (HIF-1$\alpha$), targeting it for rapid proteasomal degradation under normoxic conditions. Inactivating mutations prevent HIF-1$\alpha$ breakdown. Constitutively stabilized HIF-1$\alpha$ translocates to the nucleus, driving massive, unregulated transcription of angiogenic growth factors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

Ocular Hallmark: Retinal Capillary Haemangioblastomas (Retinal Angiomatosis)

• Occurs in $50-70\%$ of VHL patients; often the earliest clinical manifestation.
• Biomicroscopic Appearance: A discrete, round, elevated, bright orange-red vascular nodule supplied by a markedly dilated, tortuous feeding retinal artery and drained by an engorged, dusky draining vein spanning from the optic disc to the periphery.
• Complications: Progressive transudation produces marked lipid exudation (circinate rings, macular star), subretinal fluid accumulation, tractional or exudative retinal detachment, vitreous hemorrhage, and secondary neovascular glaucoma.
• Management: Small peripheral lesions ($<1.5\text{ mm}$) respond excellently to argon laser photocoagulation applied directly to the tumor and feeding arterioles. Anterior peripheral lesions are treated with transscleral cryotherapy. Vitrectomy is indicated for non-clearing vitreous hemorrhage or tractional detachment. Anti-VEGF agents serve as valuable adjuvants to reduce vascular permeability and exudation.

Systemic Tumors (Mandatory Screening)

• CNS Haemangioblastomas: Infratentorial lesions predominantly located in the cerebellum ($60-70\%$) and spinal cord, presenting with ataxia and obstructive hydrocephalus.
• Renal cancer: A major VHL complication. Surveillance includes renal imaging under an age- and organ-specific specialist programme; an identical annual ultrasound/MRI schedule is not appropriate for every patient.
• Pheochromocytomas: Occur in the adrenal medulla or sympathetic paraganglia; present with paroxysmal hypertension, palpitations, and headache. Screened via urinary/plasma fractionated metanephrines.

5. Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis)

Genetics & Etiology

• Sporadic & Non-inherited: Congenital vascular malformation syndrome arising from a somatic mosaic activating mutation in the GNAQ gene (chromosome 9q21, encoding the G-protein subunit alpha-q, $G\alpha_q$).

Clinical Triad

1. Facial Port-Wine Stain (Naevus Flammeus): A congenital cutaneous capillary-venous malformation present at birth. While it can involve any part of the face, forehead and upper-eyelid distribution raises concern for ocular and leptomeningeal involvement. This follows developmental vascular territory rather than a strict trigeminal V1 dermatome; arrange syndrome-specific assessment rather than assigning a fixed risk from the stain alone.
2. Ocular Manifestations:
   • Glaucoma (50-60%): Develops ipsilateral to the port-wine stain. Exhibits a bimodal onset:
     • Infantile onset (60%): Secondary to congenital anterior chamber angle dysgenesis and trabeculodysgenesis.
     • Juvenile / Adult onset (40%): Secondary to elevated episcleral venous pressure (EVP) driven by arteriovenous shunting within episcleral hemangiomas.
     • Surgical Warning: Filtration surgery carries an exceptionally high risk of ciliochoroidal effusion, severe intraoperative hypotony, and expulsive suprachoroidal haemorrhage due to the sudden decompression of an engorged uveal bed.
   • Diffuse Choroidal Haemangioma (50%): A diffuse, cavernous vascular malformation of the choroid, giving the fundus an intensely fiery red, saturated appearance compared to the normal fellow eye, classically termed the "tomato-ketchup fundus". B-scan ultrasound demonstrates diffuse, smooth choroidal thickening with high, regular internal acoustic reflectivity. Complications include progressive hyperopic shift and bullous exudative retinal detachment.
3. Neurological Manifestations: Ipsilateral leptomeningeal angiomatosis (pial vascular malformation) leading to cerebral cortical ischemia, progressive neuronal loss, and cerebral hemiatrophy. Classically displays gyriform "tram-track" cortical calcifications on skull radiographs or non-contrast brain CT. Patients suffer from medically refractory focal motor seizures, contralateral hemiparesis, and cognitive delay.