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Pathology of Neurocutaneous Syndromes

Definition

Neurocutaneous syndromes or phakomatoses from the Greek phacos = lens, spot; phaos = light, literally meaning “tumor of lenses” after the retinal hamartomas that would eventually be recognized as part of constellation of findings now recognized as tuberous sclerosis complex. Neurocutaneous syndromes represent a group of central nervous system disorders with concurrent lesions in the skin, eye, and possibly other visceral organs.
The neurocutaneous manifestations are related to the common ectodermal origin of these organs. They include tuberous sclerosis complex, Sturge-Weber syndrome, von Hippel-Lindau disease, and neurofibromatosis. The definition can be expanded to include other entities such as ataxia telangiectasia, incontinentia pigmenti, nevoid basal cell carcinoma syndrome (Gorlin syndrome), among others.

Tuberous sclerosis complex

Originally known as Bourneville’s disease after the French neurologist, Désiré-Magloire Bourneville, tuberous sclerosis complex (TSC, which is the preferred abbreviation, to distinguish this entity from Tourette syndrome [TS]) is a genetically determined neurocutaneous syndrome—one of the most common—characterized clinically by variable neuropsychiatric manifestations that range from intractable epilepsy (including infantile spasms, which occur in as many as 20-30% of TSC infants) to mental retardation and autism and are often the defining and/or presenting feature of the illness.

Clinicopathologic features of tuberous sclerosis complex have been recognized since the late 1880s. This disease involves multiple organ systems throughout the body, especially the heart, lungs, skin, and kidneys in addition to the central nervous system (CNS). Visceral manifestations of tuberous sclerosis complex include cardiac rhabdomyomas, renal angiomyolipomas, and pulmonary lymphangiomyomatosis, whereas its cutaneous signs include facial angiofibromas, subungual fibromas, Shagreen patches, and hypomelanotic macules.

Because of its variable manifestations, tuberous sclerosis complex is clinically diagnosed by attention (in a given patient) to a combination of major and minor diagnostic criteria. The major criteria include the above-mentioned cutaneous lesions, as well as cortical tubers (cortical growth abnormalities), subependymal nodules (SENs), subependymal giant-cell tumors (SGCTs; formerly subependymal giant cell astrocytoma [SEGA]), cardiac rhabdomyomas, renal angiomyolipomas, multiple retinal nodular hamartomas and pulmonary lymphangiomyomatosis (LAM). (Pulmonary LAM is a disorder resulting from abnormal proliferation of smooth muscle cells within the lungs.)

Minor criteria include pitting of dental enamel, gingival fibromas, hamartomatous rectal polyps, radiographic evidence of bone cysts, multiple renal cysts, “confetti” skin lesions among other features. For a clinical diagnosis of definite tuberous sclerosis complex, either 2 major features or 1 major feature and 2 minor features are required, whereas, for the diagnosis of probable tuberous sclerosis complex, only 1 major and 1 minor criteria are required.

Sporadic glioneuronal hamartomas

In practice, sporadic glioneuronal hamartoma is a diagnosis rarely made in cortical resections for epilepsy—at least at the authors’ center. A much more common diagnosis (the most common diagnosis in infants with intractable seizures, including infantile spasm seizures [ISS]) is that of “cortical dysplasia,” a malformation of cortical development (MCD) which, in its extreme form, shows features almost identical to those of a tuber of tuberous sclerosis complex. Glioneuronal hamartomas are occasionally found at autopsy in noncortical regions, where they are not associated with the “epileptic ” phenotype and are often discovered in entirely asymptomatic individuals.

Sturge-Weber Syndrome (encephalotrigeminal angiomatosis)

First described in 1879, Sturge-Weber syndrome (SWS; sometimes described as Sturge-Weber-Dimitri syndrome or by the more descriptive name encephalotrigeminal angiomatosis) is a sporadic neurocutaneous syndrome, with no known genetic cause. It is the third most common neurocutaneous disorder (after NF and TSC).
SWS manifests with the hallmark of a cutaneous nevus flammeus (port-wine stain) in the region of the first branch of the trigeminal nerve with an associated ipsilateral leptomeningeal (venous) angioma, which may lead to seizures and/or neurologic deficits. The ipsilateral eye is also commonly involved by some pathology, glaucoma or vascular abnormality. “Classic” Sturge-Webber syndrome manifests within the cranial vault, on the skin and in the eye as a facial angioma, leptomeningeal angioma, and glaucoma.

Von Hippel-Lindau Syndrome

Von Hippel-Lindau (VHL) disease is an inherited syndrome which manifests with neoplasia in a variety of organs with marked variability of expression of disease. It is inherited in an autosomal dominant fashion and has variable penetrance. This constellation of findings that occur in VHL was first described in a brother and sister in 1894. VHL is named after Eugen von Hippel, a German ophthalmologist, who described patients to have what we now know to be VHL disease; and Arvind Lindau, a Swedish neuropathologist who pieced together the systemic character and hereditary nature of the disease.
von Hippel-Lindau disease was first used as a name to designate this disorder in 1936. The disease is characterized by multiple tumors in multiple different organs. Most commonly these are hemangioblastomas, clear cell renal cell carcinoma, pheochromocytomas, endolymphatic sac tumors, neuroendocrine neoplasms of the pancreas as well pancreatic and renal cysts.

Neurofibromatosis

Neurofibromatosis consists of two separate and different inherited autosomal dominant disorders, named neurofibromatosis 1 (NF1) (also known eponymously as von Recklinghausen disease) and neurofibromatosis 2 (NF2). These disorders are characterized broadly by the development of multiple tumors of the nervous system expressing themselves in the skin and peripheral and central nervous system. These tumors are usually benign but some may harbor malignant potential. The most common tumor present in an NF1 patients are neurofibromas, while in NF2 patients schwannomas are most common.

NF1 is characterized by multiple café-au-lait spots, multiple cutaneous neurofibromas, inguinal and axillary lentigines, and Lisch nodules (melanocytic hamartomas of the iris). These findings are often readily visible on the patient in childhood, leading to early recognition of the disease presence.

NF2 (formerly known as central NF) has the characteristic finding of bilateral vestibular schwannomas.

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