Neurocutaneous syndromes in art and antiquities

Abstract Neurocutaneous syndromes are a group of genetic disorders affecting the skin, the central and peripheral nervous system, and the eye with congenital abnormalities and/or tumors. Manifestations may also involve the heart, vessels, lungs, kidneys, endocrine glands and bones. When people with these disorders are portrayed in works of art, physicians have speculated on possible diagnoses. In particular, many figures have been labeled as possibly having a neurocutaneous disorder, sometimes distorting the popular conception of these diseases. We review numerous documents, drawings, prints, lithographs, xylographs, and portraits which span the ages from antiquity to the era of the pioneers behind the eponyms, depicting a large spectrum of neurocutaneous disorders.


| Definition of the neurocutaneous syndromes
In their current definition, neurocutaneous syndromes/disorders (or phacomatoses) are a heterogeneous group of genetic diseases affecting the skin, the eye, and the central and peripheral nervous systems.
Nowadays, the most commonly used terms remain neurocutaneous syndromes and phacomatoses, which are used interchangeably.
The synonym "neurocutaneous syndromes" came from the studies of the American neurologist Paul Ivan Yakovlev and the American psychiatrist Riley H. Guthrie. They established the key phenotypic and diagnostic roles of nervous system and skin in the complex medical conditions affecting some individuals seen at the Monson State Hospital for Epileptics in Massachusetts (Ashwal, 1990;Yakovlev & Guthrie, 1931). They named these disorders the neurocutaneous syndromes, or ectodermatoses, to explain the pathogenesis due to a common embryological origin from the neuroectodermal layer. The Belgian pathologist Ludo van Bogaert came to similar conclusions (Van Bogaert, 1935), but called them neuroectodermal dysplasias (Ashwal, 1990).
The Dutch pathologist Sylvan E. Moolten (Moolten, 1942) named Bourneville tuberous sclerosis "tuberous sclerosis complex", thus recognizing its multi-organ nature. He first introduced the terms hamartial, hamartoma, and hamartoblastoma, derived from the Greek verb hamart anein, which means "to miss the mark" or "to err" or "to fail." Later, the American pediatric neurologist Manuel R. Gomez changed definitively the former concept of "phakoma/phakomata" into the more modern definition of "hamartia/hamartoma" (Gomez, 1987).
Genodermatoses and neurocristopathies have been and still are sometimes used as alternative terms in the scientific literature .

| THE NEUROFIBROMATOSES
Three forms have been recognized under the umbrella term of neurofibromatosis, including neurofibromatosis Type 1 (NF1) (Von Recklinghausen, 1882), neurofibromatosis Type 2 (NF2) (Gardner & Turner, 1940;Wishart, 1822) and schwannomatosis (MacCollin, Woodfin, Kronn, & Short, 1996). These are autosomal dominant conditions caused by different genes, which share common clinical features, including hyperpigmented birthmarks of the skin, congenital anomalies (e.g., bone and/or vascular dysplasias), and a predisposition to develop benign and, less frequently, malignant tumors of the central and peripheral nervous system but also of other organs and systems (Ferner et al.,   healthy male with trunk and part of limbs is partially covered with multiple smooth, sessile nodules, resembling cutaneous neurofibromas. Some authors have suggested that it could have been a medical teaching aid while others hypothesized that it was more probably a decorative figure, maybe a satyr or a humanoid being, possibly a votive offer to the divinity (Gourevitch & Grmek, 1994;Linden, 1994;Ragge & Munier, 1994 Much of the knowledge on the aspects of the kings of Parthia arises from the coins (Daryaee, 2017;Faghfoury, 2020). Centuries before, Alexander the Great had established the typical pattern of the empire's coin: a right-facing profile of a divinity on the obverse and a full-length deity on the reverse (Faghfoury, 2020). This pattern changed after the third century BC, when the rulers' own portraits started to appear in their left facing profile (Selwood, 1971). The first Parthian king to start issuing coins was Mithridates I [171-138 BC] (Selwood, 1971;Todman, 2008). The kings' representations in the coins are characteristic and realistic and it is possible to identify changes in the hairstyles and beards (Faghfoury, 2020;Selwood, 1971;Widengren, 1983 (Figure 2b,c) (Ashrafian, 2011;Selwood, 1971;Todman, 2008).
The presence of these nodules in many generations suggests a possible hereditary trait, like neurofibromas in NF1 (Ashrafian, 2011;Selwood, 1971;Todman, 2008). Other hypotheses include common warts, trichoepitelioma (Hart, 1966), or basal cell carcinomas in the case of Mithridates II (Ashrafian, 2011). 3.1.3 | A large mass in von Megenberg's "Buch der Natur"  Konrad von Magenberg [1309-1374] was a Bavarian scholar and philosopher who wrote more than 30 treatises on theological, astronomical, physical, historical, and political issues. His Buch der Natur, the first book of natural history in the German language, was extremely popular and was printed seven times, in several editions, in the 15th century alone (Baltrusaitis, 1960;Lattis, 2007;Pfeiffer, 2012).
In the 12th Tome of the Ausgburg edition [1475 AD], in addition to various types of imaginative figures including the mythological single large-footed sciapod, the headless monster with six arms, the cynocephalus and the Cyclops, one can observe a woman ( Figure 3) who, according to Choulant (1963), has a large goiter. According to Zanca andZanca (1977, 1980) she has NF1 and to Ruggieri and Polizzi (2003) she bears an isolated plexiform neurofibroma shaped like an elongated sack fitting with the diagnosis of mosaic NF1.

| Federico da Montefeltro's facial lesions and dysplasia by Piero della Francesca [1472]
The Duke Federico III da Montefeltro [1422-1480 AD] was one of the most famous Italian Condottieri (military chieftains) of the Renaissance and Lord of Urbino. He was said to have lost his right eye during a tournament, carrying for the rest of his life a vast and disfiguring scar, so that it was necessary to portray him only on his "good" side: that is, the left profile (Roeck & Tonnesmann, 2009;Stevenson, 2021;Tommasoli, 1978; http://www.gallerianazionalemarche.it/palazzoducale/storia-della-famiglia-montefeltro/). Om and Om (2018) hypothesize, based on the portrait by Piero della Francesca (Figure 4) (https://www.uffizi.it/opere/i-duchi-diurbino-federico-da-montefeltro-e-battista-sforza), that Montefeltro had several benign intradermal nevi, in the form of dome-shaped, skincolored papules. These lesions, however, could also be attributed to small dermal neurofibromas, and the fact that he lost his right eye in a tournament has also been questioned, as he could have undergone surgical removal of an optic glioma and associated plexiform neurofibroma and dysplasia of the orbits. Notably, disruption of the orbit, either by trauma or surgery, may have invaded the root of the nose, whose shape is quite unusual (Ruggieri, Praticò, Caltabiano, & Polizzi, 2018).  (Céard, 1971;Hambry, 1967).
Among the various figures in his book Des monstres et prodiges (On Monsters and Marvels) (Pallister, 1995) is an infant born near Turin, Italy (Figure 5a) (Zanca & Zanca, 1977, 1980. The face "…was wellproportioned in every way, but there were five horn-like growths on the head and a long, fleshy mass hanging down from the head along the back "like a woman's hat…another double fleshy mass like a shirt collar was visible around the neck". This fleshy mass hanging down along the back was diagnosed as a solitary plexiform neurofibroma (i.e., mosaic NF1) (Ruggieri & Polizzi, 2003, Ruggieri & Praticò, 2015. However, this severe anomaly is likely exaggerated and certainly inaccurate. Paré did not observe the case first-hand, but obtained this drawing from a 1,578 pamphlet in Chambery (Pallister, 1995). Notably, Paré's sketch of this infant, with the less than believable claw-like digits and horns, represents a fairly standard view of the relationship between human disorders and the conception of "monsters" during the 16th century (Brosius, 2010;Céard, 1971;Ruggieri & Polizzi, 2003;Ruggieri, Praticò, Caltabiano, & Polizzi, 2018 (Caprotti, 1980;Simili, 2001;Tega, 2002).
He was the driving force behind the construction of Bologna's botanical garden, one of the first in Europe, and of a most spectacular cabinet of curiosities, illuminating natural history and comprising some 18,000 "different examples of natural things," and 7,000 "specimens of dried plants," representing the "diversità di cose naturali" ("diversity of natural things") (Simili, 2001;Tega, 2002, Wittkower, 1942.  (Aldrovandi, 1642). Some Italian Authors (Zanca, 1975;Zanca andZanca, 1977, 1980;Zanca & Tagliavini, 1980) inferred that this misshapen man may represent a case of NF1, based on: (a) the appearance of the masses, which look like plexiform neurofibromas covered with hair, similar to the hairy nevi seen over plexiform neurofibromas in NF1; and (b) the short stature of the subject, a minor NF1 feature (Morse, 1999;Mulvhill, 1988). Madigan and Masello (1989) added a third NF1 feature, that is, macrodactyly of the left second toe and leg asymmetry secondary to scoliosis. Ruggieri and Polizzi (2003) proposed that the diagnosis of the homuncio would fit better with mosaic NF1 (Ruggieri & Praticò, 2015) rather than classical NF1 as the large fleshy mass (i.e., the plexiform  (Huson, 1994;Ruggieri & Polizzi, 2003). An alternative diagnosis is an epidermal sebaceous nevus with satellite lesions (Ruggieri, Praticò, Caltabiano, & Polizzi, 2018 on the skin, café-au-lait spots, macrocephaly, and scoliosis." In a color reproduction (Figure 6b) of the original illustration accompanying the case presentation one can note a fleshy mass hanging forward toward the abdomen. The latter might be a pedunculated F I G U R E 5 (a) The imaginative "infant of Chieri" by Ambroise Paré: the fleshy mass hanging down along the back was interpreted as a plexiform neurofibroma. Copyright © Wellcome Library London, UK; (b) Aldrovandi's "homuncio," with enormous, flabby masses of flesh, hanging from his right side, likely representing a plexiform neurofibroma in mosaic neurofibromatosis type 1 (NF1). Copyright © Biblioteca Universitaria di Bologna, Italy diffuse cutaneous plexiform neurofibroma (Ruggieri, Praticò, Caltabiano, & Polizzi, 2018).
Drawings and portraits of women ( Figure 7b) and men ( Figure 7c) represented with facial angiofibromas [at that time known as "adenoma sebaceum" as it was believed that the sebaceous glands were the source of the problem] (Balzer & Ménétrier, 1885;Curatolo, 2003;Gomez, 1995;Hallopeau & Leredde, 1885;Jay, 1999;Pringle, 1890) were common at the turn of the 19th century.

| "Sclerotic islands and tumors" in the lithographs by Eduard Brissaud [1880]
The French physician, neurologist, neuropathologist and later Paris councilman and Deputy member of the French Parliament, Desiré Magloire Bourneville  provided the first (Bourneville, 1880(Bourneville, -1881 and second (Bourneville & Brissaud, 1881) detailed clinical and neuropathological description of tuberous sclerosis in two children, Marie and George. The 15-year-old Marie, hospitalized in Paris at La Pitié Salpetrière since the age of 3 years and who had died secondary to the complications of status epilepticus, had the typical skin lesions of tuberous sclerosis and a history of severe psychomotor delay, learning and language difficulties, behavioral stereotypies, spastic hemiplegia and recurrent episodes of status epilepticus since the age of 2 years and was eventually declared a" hopeless case." At postmortem examination, her brain revealed various whitish, opaque, dense, hypertrophic sclerotic islands (i.e., cortical tubers) alongside small sclerous clusters of tumors in the external walls of the lateral ventricles (i.e., subependymal nodules) (Brigo et al., 2018;Gomez, 1995). To describe the peculiarity of this cerebral pathology F I G U R E 6 (a) Lithograph depicting Maria Herig with multiple dark leaf-shaped areas of hyper pigmentation of the skin (likely café-au-lait spots) in the limbs and in the trunk and a large, raised "pigskin" encircling lesion over her trunk (likely a cutaneous plexiform neurofibroma or an epidermal nevus). Copyright © Wellcome Library London, UK; (b) von Tilenau's "Wart Man".© Authors' personal collection Bourneville coined the term "Sclérose tubéreuse des circonvolutions cérébrales" (tuberous sclerosis of the cerebral circonvolutions) and asked his friend and colleague Eduard Brissaud  to depict Marie's brain findings (Figure 7d).
These disorders have been collectively named "pigmentary mosaicism"; however, some individuals with hypopigmented abnormalities along the lines of Blaschko, may also have additional associated systemic involvement affecting principally the eyes, the musculoskeletal and nervous systems, thus configuring a complex neurocutaneous syndrome known as hypomelanosis of Ito (Ito, 1952), whose manifestations are cataracts, scoliosis, seizures, cognitive deficits, speech/ language deficits, hypotonia, or abnormal EEGs (Ruggieri & Pavone, 2000;.
5.1 | Alfred Blaschko and his system of lines: A precursor of "mosaicism" Alfred Blaschko [1858-1922 was a private practitioner of dermatology in Berlin whose interests ranged from leprosy to occupational skin diseases (Bolognia et al., 1994 (b,c) two 20th century prints depicting facial "adenoma sebaceum" (i.e., the old term used for the facial angiofibromas): Copyright © Wellcome Library, London, UK; (d) Drawings of the brain of the 15-year-old Marie: note the "sclerotic" cortical "tubers" and the "subependymal tumors" (nodules) of the lateral walls of the ventricles: Copyright transposed the pattern in each patient onto dolls and statues used for illustrating his 1901 book ( Figure 8a) (Blaschko, 1901). A composite diagram of these distribution patterns was then drawn that has subsequently been referred to as the Lines of Blaschko and applied in the liberty style cover of Blaschko's posthumous book ( Figure 8b) (Happle, 1993 (Levy & Massey, 2015;. 6.1 | Cranial protuberances in a 20th century medical treatise [1910] A lithograph from a 20th century bookTreatise of Medicine shows an illustration (Figure 8c) of the head and face of a man with large, rounded masses protruding from his head, supposedly consisting of multiple lipomas within the context of encephalocraniocutaneous lipomatosis.

| CONCLUSION
Neurocutaneous syndromes have been observed in numerous types of artworks through the millennia. We hope that readers will appreciate the art itself and the way of depicting and looking at these medical entities across the centuries and, ultimately, to view the humanity of the persons portrayed rather than their disorder, seen in the past as a "medical curiosity."

CONFLICT OF INTEREST
None.

DATA AVAILABILITY STATEMENT
Data are available upon request to the author.