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 May 9, 2018; expires May 9, 2021

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 distinctive developmental diseases that affect the nervous system and the skin and have systemic lesions in multiple organ systems, including bone, endocrine glands, eye, kidney, heart, and lung. Neoplasms, both benign and malignant, are frequent in some of the diseases. In several neurocutaneous syndromes overgrowth is a primary feature. 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 neurofibromatosis 1 and tuberous sclerosis complex, the 2 most frequent neurocutaneous syndromes. Different Mendelian traits are expressed in other neurocutaneous syndromes. 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 all the neurocutaneous syndromes included in this review, the defective genes have been identified. Epidermal nevus syndrome and neurocutaneous melanocytosis are characterized by nevi; other neurocutaneous syndromes are characterized by vascular lesions, such as Sturge-Weber syndrome, Klippel-Trenaunay syndrome, PHACES syndrome, and megalencephaly-capillary malformation syndrome. Waardenburg syndrome, 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.

 

• Overgrowth of many tissues including brain (hemimegalencephaly) occurs in several neurocutaneous syndromes.

 

• 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 or lens “lentil”) (Van der Hoeve 1920; Van der Hoeve 1932). Initially he included tuberous sclerosis, neurofibromatosis, and von Hippel-Lindau disease. The concept of “phakomatosis” lost its original meaning when Van der Hoeve included Sturge-Weber syndrome, which is not characterized by phakomas or hamartomas (Gomez et al 1999). 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, also known as Rendu-Osler-Weber disease (described by Rendu in 1896, Osler in 1901, and Weber in 1907). 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 ectodermal 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.

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