Neurocutaneous Syndromes (Phakomatoses)

The phakomatoses are disorders in which the skin, eye and nervous system are affected together, because these tissues share developmental pathways. Most are tumour-predisposition syndromes: a germline variant in a tumour-suppressor gene leaves every cell with one working copy, and a second hit produces hamartomas or tumours. Sturge-Weber syndrome is the exception — it is a sporadic vascular malformation caused by a mosaic somatic variant, not an inherited disorder.

Neurofibromatosis type 1 is the most common of the hamartoma-neoplastic syndromes and is autosomal dominant: an affected parent has a 50% chance of passing it to each child. The NF1 gene on chromosome 17 encodes neurofibromin, a GTPase-activating protein that normally inhibits the RAS pathway. Neurofibromas develop when both NF1 alleles are lost in Schwann-lineage cells.

The revised diagnostic criteria published in 2021 require two or more of the following in a person without a parent with NF1. A child of an affected parent needs only one.

• Six or more café-au-lait macules — over 5 mm before puberty, over 15 mm after puberty.
• Freckling in the axillary or inguinal region (Crowe sign).
• Two or more neurofibromas of any type, or one plexiform neurofibroma.
• Optic pathway glioma.
• Two or more iris Lisch nodules, or two or more choroidal abnormalities.
• A distinctive osseous lesion — sphenoid dysplasia, bowing of the tibia or pseudarthrosis of a long bone.
• A pathogenic NF1 variant on genetic testing.

Café-au-lait macules, axillary or inguinal freckling, Lisch nodules and neurofibromas are the first features to appear. Café-au-lait macules increase in size and number during the first decade. Freckling is seen in around 70% and appears 3 to 5 years after the macules. Lisch nodules are present in over 90% of affected adults. Osseous dysplasia and optic glioma usually appear between 1 and 3 years of age.

Tumour risk is increased throughout life: optic nerve glioma (about 15% of children under six with NF1), malignant peripheral nerve sheath tumour, leukaemia, gastrointestinal stromal tumour, phaeochromocytoma, breast cancer and melanoma. Selumetinib, an oral targeted drug, is approved for children aged three years and older with symptomatic plexiform neurofibromas that cannot be removed surgically.

NF2 — now renamed NF2-related schwannomatosis — results from pathogenic variants in the NF2 gene on 22q12.2, which encodes the tumour suppressor merlin. It was previously called MISME syndrome: multiple inherited schwannomas, meningiomas and ependymomas. Its incidence is roughly 1 in 25,000 to 1 in 40,000 live births, with nearly complete penetrance by 60 years.

Symptoms usually start around 20 years of age with hearing loss, tinnitus and imbalance from vestibular schwannomas. The characteristic eye finding is early-onset posterior subcapsular or cortical cataract, present in about 67% and often appearing before neurological symptoms. Bevacizumab is the most established systemic therapy, used off-label to shrink vestibular schwannomas and preserve hearing.

Tuberous sclerosis complex arises from mutations in TSC1 (9q34, hamartin) or TSC2 (16p13.3, tuberin). Loss of the inhibitory TSC protein complex allows aberrant activation of mTOR, which drives hamartomas in the brain, skin, heart, kidney and lung. Inheritance is autosomal dominant, but most cases are sporadic. About 90% have neurological symptoms — epilepsy and neurocognitive problems — and infantile spasms treated with vigabatrin are especially common.

A definite diagnosis needs two major features, or one major plus two or more minor features. One major feature, or two minor features alone, gives a possible diagnosis.

• Hypomelanotic (ash-leaf) macules — the most common skin sign, present in about 90%; may be present at birth and are best seen under a Wood's lamp.
• Facial angiofibromas — in about 75%, across the cheeks and nose in a butterfly distribution, usually from 3 to 10 years; historically mislabelled adenoma sebaceum.
• Shagreen patch — an orange-peel connective-tissue naevus, usually on the lower back, in over 50%.
• Ungual (Koenen) fibromas — periungual growths that appear near puberty.
• Brain — cortical tubers, subependymal nodules in 80% to 90% and subependymal giant cell astrocytoma (SEGA) in 10% to 20%.
• Heart, kidney, lung — cardiac rhabdomyomas can be seen prenatally; renal angiomyolipomas in up to 75%; lymphangioleiomyomatosis in women around age 35.

mTOR inhibitors (everolimus, sirolimus) are used for asymptomatic SEGA and are considered first-line for renal angiomyolipoma, preferred over surgery. Angiomyolipomas larger than 3.5 cm may be embolised to avoid nephrectomy.

Sturge-Weber syndrome combines a facial port-wine birthmark, leptomeningeal angiomatosis and ocular vascular involvement. It is sporadic and caused by a somatic mosaic GNAQ variant (most often R183Q) on chromosome 9q21. Port-wine birthmarks occur in 3 of every 1,000 births, but only a minority have brain involvement; a birthmark in the ophthalmic (V1) distribution carries a 20% to 50% risk of brain involvement.

• Seizures — the most common presenting neurological symptom, median onset about 6 months, often becoming drug-resistant and followed by hemiparesis.
• Stroke-like episodes, migraine-type headaches, hemiparesis and intellectual disability.
• Glaucoma — very common and almost always ipsilateral to the birthmark; congenital in about 60% of affected patients; the risk rises when both upper and lower lids are involved.
• Imaging — CT is best for calcification; MRI shows leptomeningeal enhancement and cortical atrophy on the side of the birthmark.

Von Hippel-Lindau syndrome is an autosomal dominant tumour syndrome caused by variants in the VHL gene at 3p25.3. About 80% inherit it from an affected parent and about 20% have a de novo variant. The exam focus is its tumour list.

Pathogenic VHL variants fail to downregulate hypoxia-inducible factor alpha, leading to overexpression of effectors such as VEGF that drive these vascular tumours. Belzutifan, a HIF-2α inhibitor, is approved in many countries for adults with VHL-associated renal cell carcinoma, CNS haemangioblastomas or pancreatic neuroendocrine tumours not needing immediate surgery.

Klippel-Trenaunay syndrome (KTS) is a vascular malformation syndrome with a neurocutaneous flavour: a capillary malformation (port-wine stain), venous and lymphatic malformations and soft-tissue and bone hypertrophy of a limb, usually the lower limb. The diagnosis is clinical — at least 2 of the 3 classic findings: cutaneous capillary malformation, venous abnormality and limb hypertrophy. It is linked to somatic PIK3CA mutations and sits within the PIK3CA-related overgrowth spectrum (PROS).

• Port-wine stain is seen in about 90–100% of cases and is usually present at birth; venous malformations (varicosities, persistent embryonic veins) in 70–100%.
• Complications include venous stasis, recurrent deep vein thrombosis and pulmonary embolism, and gastrointestinal bleeding from colonic venous malformations.
• Arteriovenous malformations define the distinct Parkes Weber syndrome, so the old name Klippel-Trenaunay-Weber is now avoided.
• Do not confuse with Sturge-Weber syndrome, where the facial port-wine stain is accompanied by leptomeningeal angiomatosis and glaucoma.