Phakomatosis

Phakomatoses, also known as neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes.

[4] This term later became imprecise when van der Hoeve also used it to include those with Sturge-Weber syndrome as they do not have similar lesions on the skin.

The term neurocutaneous syndrome was subsequently defined by the Russian-American neurologist Paul Ivan Yakovlev and psychiatrist Riley H. Guthrie and it is currently more commonly used.

[2] The first clinical description was made in “Monstrorum Historia” by an Italian physician and naturalist named Ulisse Aldrovandi who described a patient with probable neurofibromatosis type I in 1592.

[2] However, there are artistic or descriptive representations which have been speculated to depict individuals with phakomatoses as far back as the Hellenistic period and ancient Egypt.

In most instances, neurofibromatosis type 1 can be diagnosed clinically according to consensus criteria and genetic testing is only used in atypical presentations or for family planning decisions.

On the contrary, plexiform neurofibromas arise from multiple nerve fascicles and malignant transformation occurs in approximately 10% of cases.

[14] They may result in significant morbidity as they may cause organ compression, vascular occlusions, bone destruction, pain and cosmetic issues.

Common findings include sphenoid wing dysplasia, osteopenia, osteoporosis, anterior chest wall deformities as well as scoliosis.

[25] Relative to the general population, meningiomas in NF2 tend to occur at a younger age, are more likely to be multiple and are associated with increased mortality.

[25] Other potential manifestations include focal amyotrophy, mononeuropathy multiplex or a severe generalized polyneuropathy in 3-5% of patients.

Tuberous sclerosis complex (TSC) is a multisystemic disorder due to autosomal dominant mutations in either TSC1 or TSC2 which results in the impaired inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway.

[39] Dermatological manifestations occur in almost all patients and may include facial angiofibromas, confetti skin lesions, ungual fibromas, shagreen patches, hypomelanotic macules and fibrous cephalic plaques.

[40] Sturge-Weber syndrome occurs in approximately 1 in 20,000-50,000 live births and is caused by a somatic activating mutation in GNAQ.

[42] It is classically characterized by a facial port-wine stain in the ophthalmic division of the trigeminal nerve, glaucoma and leptomeningeal angioma.

[41] However, the clinical presentation can vary significantly depending on the timing of the somatic mutation ranging from an isolated port-wine stain to complete Sturge-Weber syndrome.

Over time, port-wine stains can develop soft tissue or bone hypertrophy, proliferative nodules, and progressive ectasia which can lead to significant disfigurement.

[53] Neurological impairment can accrue gradually over time and may occur in the context of stroke-like episodes which may be triggered by seizures or head injuries.

[50] In addition, patients with Sturge-Weber syndrome have an increased prevalence of depression, endocrinological abnormalities, headaches with migraine-like features, ADHD and behavioral problems.

[54] Cortically mediated visual field defects and hemiparesis occur in approximately one-third and one-half of patients, respectively.

Life expectancy is reduced for individuals with this condition and one study found a median age of death at 52 years.

[74] Many neurocutaneous syndromes have established diagnostic criteria which may facilitate a diagnosis without necessarily requiring genetic testing.

For instance, neurofibromatosis types 1 and 2, tuberous sclerosis complex and incontinentia pigmenti have formal diagnostic criteria.

For some neurocutaneous syndromes such as neurofibromatosis 1 and tuberous sclerosis complex there are guidelines with recommendations for surveillance and management.

Surveillance is a necessity for many neurocutaneous syndromes because new manifestations may develop over time which may only be detected with specific and focused testing.

Thus, patients may be advised to obtain particular evaluations (e.g., MRI, ophthalmologic or dermatological examinations) within recommended intervals over time with the aim of detecting new manifestations of the syndrome early on.

There are currently significant efforts underway to develop additional treatments that address the underlying causes of neurocutaneous syndromes.

[80] Neurocutaneous syndromes are complex, lifelong conditions that have the potential to affect many different organ systems over time.

Integrated, multidisciplinary clinics have developed in an effort to optimize the long-term care for patients with neurocutaneous syndromes.

[81] Specialties represented at these clinics may include genetics, neurology, ophthalmology, hematology-oncology, neurosurgery, psychiatry, dermatology and more.