Neurocutaneous syndromes

Laura Flores-Sarnat MD (Dr. Flores-Sarnat of Alberta Children's Hospital has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released July 29, 2004; last updated April 13, 2016; expires April 13, 2019

This article includes discussion of neurocutaneous syndromes, hereditary hemorrhagic telangiectasia (HHT), and Rendu-Osler-Weber disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Neurocutaneous syndromes are a diverse group of unrelated developmental diseases that affect the nervous system and have cutaneous and subcutaneous lesions. Most have systemic lesions in multiple organ systems, including bone, endocrine glands, eye, kidney, and heart. Neoplasms, both benign and malignant, are frequent in some of the diseases. Primary neurocutaneous syndromes share a common embryological basis as all are disorders of neural crest and, therefore, can be included in the group of neurocristopathies. Autosomal dominant transmission is present in the most common, neurofibromatosis 1 and tuberous sclerosis, and other Mendelian traits are expressed in other neurocristopathies. The majority of neurocutaneous syndromes, however, are probably single gene mutations; hence, patients lack a family history of the disorder, and they are “sporadic” diseases. In several neurocutaneous syndromes, the defective genes have been identified (eg, NF1, TS, and SWS). The most frequent neurocutaneous syndromes are neurofibromatosis 1, tuberous sclerosis, several disorders in the group characterized by angiomas (Sturge-Weber syndrome, Klippel-Trenaunay syndrome, PHACES) epidermal nevus syndromes, and ataxia-telangiectasia. Waardenburg disease, a well-known neurocristopathy, also fulfills the criteria to be considered a primary neurocutaneous syndrome.

Key points

 

• Neurocutaneous syndromes are a group of congenital disorders that have in common the involvement of the ectodermal derivatives nervous system and skin, but also include many mesodermal and endodermal derivatives.

 

• Many lesions are hamartomatous.

 

• Neoplasia can arise from many of the lesions.

 

• Genetic defects are identified in most neurocutaneous syndromes.

 

• Primary neurocutaneous syndromes are neurocristopathies

Historical note and terminology

The association of neurologic disease with cutaneous and retinal lesions was recognized in the 19th century by Van der Hoeve, a Dutch ophthalmologist who coined the term “phakomatosis” (Greek phakos meaning spot, lens) (Van der Hoeve 1920; Van der Hoeve 1932). Initially he included tuberous sclerosis, neurofibromatosis, and von Hippel-Lindau disease. The term “phakomatosis” became inappropriate when Van der Hoeve included Sturge-Weber syndrome, which is not characterized by phakomas or hamartomas. Etymologically, this term also is inadequate to encompass this entire group because it does not include the nervous system. It is still used by some authors but in a more restricted context (Korf 2005). In any case, its use should be reserved to those conditions which manifest retinal hamartomas (“phakomas”), as in the original description, including those with inconstant retinal lesions, such as hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). On the other hand, von Hippel-Lindau disease is a phakomatosis because of the presence of retinal and CNS hemangioblastomas with multisystemic involvement, but it does not correspond to a neurocutaneous disorder because these patients do not have developmental cutaneous lesions.

The term “neurocutaneous syndromes” was introduced by Yakovlev and Guthrie in 1931 to describe this group of disorders as “congenital malformations affecting more or less electively the ectodermal structures, ie, the nervous system, the skin, the retina, the eyeball and its contents; sometimes visceral organs are also involved” (Yakovlev and Guthrie 1931). It has the merit of linking the 2 most obvious manifestations of this group of disorders. However, this term also is not technically correct because cutaneous denotes only the epidermis and dermis, and subcutaneous lesions such as lipomas and subcutaneous neurofibromas also frequently appear in neurocutaneous syndromes. Besides, it is now known that these syndromes involve not only ectoderm derivatives but many other structures than brain and skin. The term “neurocutaneous” has been applied to infectious diseases that affect the skin and nervous system, such as leprosy. Nevertheless, “neurocutaneous syndromes” remains the best terminology, but should be restricted to primary developmental disorders, as described below.

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