Rare Neurocutaneous Disorders: State of the Art and Update

Neurocutaneous disorders are a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities and/or cutaneous tumors) and the central and peripheral nervous systems (with congenital abnormalities and/or tumors).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] This striking association has long attracted the attention of physicians,[12] [13] [14] and in particular in the past decades, many associations have been recognized and well characterized.[12]

Aside from the (more) common forms including the different forms of neurofibromatosis, tuberous sclerosis complex, and Sturge–Weber syndrome, the great majority of neurocutaneous disorders are relatively rare but, collectively, they account for a significant proportion of the neurological disorders, especially in children.[9] [10] Their clinical manifestations are polymorphous, they may involve many other organs or systems besides the skin and nervous system (e.g., eyes, heart, lungs, kidneys, blood vessels, and bones), and they may be difficult to diagnose.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

The ectodermal origin of the skin and nervous system appeared to justify a common categorization of these disorders under the umbrella term of phacomatoses,[15] [16] [17] neurocutaneous diseases,[18] or neuroectodermal dysplasias,[19] [20] even if, recent studies revealed that the concept that the skin and nervous system are entirely derived from the ectoderm should be revised, as mesoderm and endoderm are also involved.[12] More recently, the molecular genetic and cellular bases of an increasing number of neurocutaneous disorders have been found, shedding light on the interplays between common intra- and extraneuronal signaling pathways encompassing receptor–protein and protein–protein cascades (e.g., RAS, MAPK, mTOR, PI3K/AKT, and GNAQ pathways), which are responsible for the phenotypic appearance and distribution of cutaneous and extracutaneous features.[12] In view of these recent acquisitions, this group of conditions has expanded enormously, especially as a result of the recent additional development in neuroimaging and genomics, and it is now difficult to find an overall synthetic view of the complexities of this spectrum of disorders.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

For these reasons, the general panorama of the (common and rare) neurocutaneous diseases is rapidly changing and currently there is no universal agreement on a definition of these disorders: new conditions are increasingly recognized and the respective frequencies of the various types have changed with recent studies.[10] The domain has considerably grown to include many other conditions in which variable amounts of cutaneous and neurological abnormalities tend to occur in persons with one same condition but not necessarily in the same person and most often with relatively independent involvement of various systems and organs.

The clinical presentation of these conditions is extremely variable and even major features may be missing in many accepted cases. In addition, extraneurological and extracutaneous anomalies have been increasingly recognized and, in some cases, can represent the dominant clinical abnormalities. In several of these disorders, the skin abnormalities can assume a mosaic patterning (usually arranged in archetypical patterns):[12] [21] alternating segments of affected and unaffected skin or segmentally arranged patterns of abnormal skin often mirror similar phenomena occurring in extracutaneous organs/tissues (e.g., eye, bone, heart/vessels, lung, kidney, and gut).[12] [21] In some neurocutaneous syndromes, the abnormal mosaic/segmental patterning involves mainly the skin and the nervous system configuring a (true) mosaic neurocutaneous disorder;[12] [20] [21] [22] [23] or an ordinary trait of a neurocutaneous disorder is sometimes superimposed by a pronounced linear or otherwise segmental involvement; or, lastly, a neurocutaneous disorder can occur solely in a mosaic pattern. Such heterogeneity further complicates the issue of classification and diagnosis.

Things have recently changed also with respect to the diagnostic workup and management requirements of affected individuals by neurocutaneous disorders given the rarity and complexity of some of these conditions.[10] [12] [22] [23] [24] Many centers are currently offering a team approach to challenging and/or rarer cases, with multidisciplinary units or specialized clinics devoted to neurocutaneous disorders and linked to specialized laboratory and imaging facilities as no single physician can endeavor both the diagnosis and management requirements of all patients.[25] [26] [27]

This special issue will focus on the rare neurocutaneous disorders, to offer to pediatric neurologists and pediatricians detailed update on such (not always so uncommon) syndromes. It includes review articles on pigmentary mosaicism of the Ito type, cutis tricolor, mixed vascular nevus syndrome, blue rubber bleb nevus syndrome, Wyburn–Mason syndrome, phacomatosis pigmentovascularis and pigmentokeratotica, microcephaly–capillary malformation, megalencephaly–capillary malformation, speckled lentiginous syndrome, nevus sebaceous syndrome, Becker's nevus syndrome, Gomez-Lopez-Hernandez syndrome, and encephalocraniocutaneous lipomatosis.

• References

• 1 Gomez MR. Neurocutaneous Diseases. A Practical Approach. Boston: Butterworths; 1987
• 2 Moss C, Savin J. Dermatology and the New Genetics. Oxford: Blackwell Science; 1995
• 3 Harper J. Inherited Skin Disorders. The Genodermatoses. Oxford: Butterworth Heinemann; 1996
• 4 Spitz JL. Genodermatoses. A Full-Color Guide to Genetic Skin Disorders. Baltimore: Williams & Wilkins; 1996
• 5 Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997
• 6 Cohen MM, Neri G, Weksberg R. Overgrowth Syndromes. New York: Oxford University Press; 2002
• 7 Roach ES, Miller VS. Neurocutaneous Disorders. Cambridge: Cambridge University Press; 2004
• 8 Spitz JL. Genodermatoses. A Full-Color Guide to Genetic Skin Disorders. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005
• 9 Curatolo P, Riva D. Neurocutaneous Syndromes in Children. Montrouge: John Libbey Eurotext; 2006
• 10 Ruggieri M, Pascual-Castroviejo I, Di Rocco C. Neurocutaneous Disorders: Phakomatoses and Hamartoneoplastic Syndromes. New York/Wien: Springer-Verlag; 2008
• 11 Islam MP, Roach ES. Neurocutaneous syndromes. In: Handbook of Clinical Neurology. 3rd Series. Vol. 132. Edinburgh: Elsevier; 2015
• 12 Ruggieri M, Praticò AD. Mosaic neurocutaneous disorders and their causes. Semin Pediatr Neurol 2015; 22 (04) 207-233
• 13 Beighton P, Beighton G. The Man Behind the Syndromes. Berlin: Springer-Verlag; 1986
• 14 Beighton G. The Person Behind the Syndromes. Berlin: Springer-Verlag; 1996
• 15 Van der Hoeve J. Eye symptoms in tuberous sclerosis of the brain. Trans Ophthalmol Soc 1920; 20: 329-334
• 16 Van der Hoeve J. Eye symptoms in phakomatoses (The Doyle Memorial Lecture). Trans Ophthalmol Soc 1932; 52: 380-401
• 17 Van der Hoeve J. Les phakomatoses de Bourneville, de Recklinghausen et de von Hippel-Lindau. J Belge Neurol Psychiatr 1933; 33: 752-762
• 18 Yakovlev PI, Guthrie RH. Congenital ectodermoses (neurocutaneous syndromes) in epileptic patients. Bourneville tuberous sclerosis (epiloia). Arch Neurol Psychiatry 1931; 26: 1145-1194
• 19 Van Bogaert L. Les dysplasies neuroectodermiques congenitales. Rev Neurol (Paris) 1935; 63: 354-398
• 20 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: first descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. Am J Med Genet A 2018; 176 (03) 515-550
• 21 Happle R. Mosaicism in Human Skin Disorders. Berlin: Springer; 2014
• 22 Ruggieri M, Polizzi A. From Aldrovandi's “Homuncio” (1592) to Buffon's girl (1749) and the “Wart Man” of Tilesius (1793): antique illustrations of mosaicism in neurofibromatosis?. J Med Genet 2003; 40 (03) 227-232
• 23 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
• 24 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Rediagnosing one of Smith's patients (John McCann) with “neuromas tumours” (1849). Neurol Sci 2017; 38 (03) 493-499
• 25 Polizzi A, Balsamo A, Bal MO, Taruscio D. Rare diseases research and practice. Endocr Dev 2014; 27: 234-256
• 26 Taruscio D, Agresta L, Amato A. , et al. The Italian National Centre for Rare Diseases: where research and public health translate into action. Blood Transfus 2014; 12 (12) (Suppl. 03) s591-s605
• 27 Luzzatto L, Hollak CE, Cox TM. , et al. Rare diseases and effective treatments: are we delivering?. Lancet 2015; 385 (9970): 750-752