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Child's Nervous System

, Volume 33, Issue 4, pp 549–560 | Cite as

Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms

  • Martino RuggieriEmail author
  • Andrea D. Praticò
  • Agostino Serra
  • Luigi Maiolino
  • Salvatore Cocuzza
  • Rosario Caltabiano
  • Agata Polizzi
Cover Editorial

Introduction

As in many diseases, exactly which was the first case report of “neurofibromatosis” and who truly deserves the eponymous for credit have been a matter of debate [6, 42, 66]. Certainly, in the past centuries, several renowned “patients” taken from fiction or reality have been labelled as having this condition and, among all, Joseph Merrick also known as the “elephant man” [11, 41, 77, 87] and Quasimodo the “hunchback” of “Notre Dame de Paris” by Victor Hugo [12, 76] are two infamous examples who played an important role in the distorted popular misconception of the disease. The history of neurofibromatosis (in this case neurofibromatosis type 1—NF1), in fact, can be traced to ancient times, if descriptions of grotesque or distorted persons are considered [1, 6, 37, 42, 51, 54, 100].

Similarly, reports of early examples of neurofibromatosis type 2 (NF2) or schwannomatosis sufferers can be traced in descriptions, illustrations or portraits dated as far back as the eighteenth century [1, 6, 42].

In this article, we will review these developments focusing on the most acknowledged descriptions of patients with NF2 in history.

Early history of neurofibromatosis type 1

The earliest examples of individuals having (skin) nodules resembling neurofibromas (or plexiform neurofibromas) [1, 6, 60, 64, 66, 67, 68, 70, 71] can be traced in (a description contained in) the Ebers Papyrus from Ancient Egypt (1.500 bc) [72], in a Hellenistic statuette (Smyrna, 323 bc) [33, 46, 60], in the coinage of the Parthian kings (247 bc) [3, 75, 89], in the manuscript called Cotton Tiberius B.v. (fourth century ad) [66, 100, 101] and in a thirteenth century drawing by a Cistercian monk named Heinricus [51, 54]. Additional descriptions of “grotesque” or distorted individuals (or monsters) are traced in the fifteenth century “Buch der Natur” (Book of Nature) by Konrad von Magenberg [54, 100, 101], in the sixteenth century treatise “Des monstres et prodiges” (“On Monsters and Marvels”) by Ambroise Paré [54, 66] and in a xylograph by José de Ribeira also known as “Lo Spagnoletto” (the Little Spaniard) [66, 100, 101].

The first clinical description of a case is attributed to the Italian physician and naturalist Ulisse Aldrovandi [8, 66, 79, 85], who in the “Monstrorum Historia” (1592 ad) described a man of short stature (homuncio) with a large tumour resembling an isolated plexiform neurofibroma [6, 37, 48, 100] (first possible example of mosaic NF1) [64, 67, 68, 70]. A further example is likely portrayed in a large figure of a head carved in lindenwood, which supports one of the walls under the galleries and balconies of the library of the Cistercian monastery of Waldassen in Germany and known as the (oriental) “curious fool” [25, 60, 61, 66, 100, 101]. Drawings of a child with skin tumours and pigmented lesions can be seen in the eighteenth century “Buffon’s Histoire Naturelle” [37, 48, 66], in the “Wart Man” by Tilesius von Tilenau [88] and in illustrations of pathological studies of NF1 in the “Cruveilhier’s Anatomie Pathologique du Corps Human” [37, 42, 48, 66, 100].

The first English language clinical report is that of Akenside in 1768 [6, 42, 66], followed by a systematic review of clinical cases by the Irish surgeon Robert William Smith in 1849 [1, 47, 72, 78], while Friedrich Daniel von Recklinghausen in 1882 [95] was the first to confirm the origin of skin tumours and to name them neurofibromas [1, 6, 61, 66, 96].

The extraordinary story of Joseph C. Merrick, the so-called elephant man, reported by Frederick Treves in 1884 (P. Ford, 1989, personal communication) [6, 41, 77, 90, 91, 92, 93, 94], played an important role in the development of the perception of “von Recklinghausen’s disease” [41, 42, 66], even though there is now a body of opinion that supports the Proteus syndrome as the diagnosis for Merrick [9, 10, 11, 87]. Other renowned possible “patients” were the Duke Federico of Montefeltro (fifteenth century) and Quasimodo, the hunchback in Notre Dame de Paris by Victor Hugo [12, 76].

Early history of neurofibromatosis type 2 and related conditions

In contrast to the highly visible cutaneous manifestations of NF1 (know in oldest times as “peripheral neurofibromatosis”), the predominantly intracranial variety of neurofibromatosis (i.e. NF2) is considerably subtler in its clinical presentation and thus was not characterised in detail until relatively recently [1, 6, 42].

Earliest descriptions of acoustic neuroma(s)

Early reports of acoustic neuromas do exist [1]. The first description of unilateral acoustic neuromas [73] predated that of bilateral acoustic neuromas by approximately one-half century [97].

Primal development of the term (acoustic) neuroma

The first known mention of acoustic neuroma is attributed to Eduard Sandifort, professor of anatomy at the University of Leiden in the Netherlands (Fig. 1), who in 1777 described such a tumour at autopsy [1, 40, 73].
Fig. 1

Portrait of Sir Eduard Sandifort (1742–1814)

The term “neuroma”, however, is credited to Louis Older (1748–1917), who first coined this name in 1811 because the tumour bears a loose association with nerve neoplasm [1].

The first known detailed description of bilateral acoustic neuromas (i.e., neurofibromatosis type 2, NF2), however, dates back to 1822 when the Scottish surgeon and president of the Royal College of Surgeons of Edinburgh, John H. Wishart, presented an unusual case to the Royal College of Surgeons, in Edinburgh. In his article [97], he described the clinical course and autopsy findings of a patient named Michael Blair, a journeyman baker who died at the age of 21 years. As an infant, he was noted to be blind in one eye and during childhood he tended to fall frequently. He gradually became deaf in both ears (at around age 19 years), became blind and had intractable headaches and vomiting. Toward the end of his life, he had violent paroxysms of pain that were preceded by a disagreeable smell and accompanied by facial twitching [56, 57, 62]. In his terminal event, he became delirious [55, 62] and was attended to by Wishart. An attempt to resect the lesion was unsuccessful and the patient died from a wound infection [1, 97]:

I attempted to bleed him from the arm; but, from his restlessness, the blood could not be made to flow. Calomel and senna tea were ordered; but he appearead to have lost the power of swallowing; and he remained nearly in the same state till about 5 a.m. on the 24th, when he expired.

During his post-mortem examination [1, 97], Wishart opened the skull and observed numerous tumours, some of which were on the (occipital) dura mater (i.e. meningiomas) while others arose from the cranial nerves (i.e. cranial nerve schwannomas). The descriptions of their sizes were based on common household items: a large pin’s head, a split pea, a pea, a small nut, a walnut or a small egg [1]. Wishart described lesions arising from the 5th and 11th nerves as well as from both auditory meati (i.e. schwannomas). The last of these, in retrospect, were almost certainly acoustic neuromas (or acoustic neuromas involving concomitantly the 7th pair) and were believed by Wishart to have originated (solely) from the 7th pair of cranial nerves [1, 97]:

The 7th pair was diseased in the same maner: a tumour of the size of a small nut, and very hard, being attached to each of them, just where they enter the meatus auditorium internum.

Most importantly, Wishart, during examination of the dura mater, observed that [97]:

Its general texture was natural; but a numer of tumours of different sizes and forms were discovered attached to the internal layer of that membrane. Most of them adhered to the falciform process. These tumours, which were from the size of a walnut to that of a pea, were of spongy and fibrous structure, and readily separated from their attachement; and depressions were found in the brain corresponding to each of them.

This critical piece of the puzzle of defining NF2, as a separate clinical disease, was first achieved by Wishart, who associated acoustic neuromas with meningiomas [1, 97].

An adult-onset disease in a child

Wishart’s description of this severely affected (young) patient led to the denomination of Wishart type or Wishart’s variety for NF2 with an early and aggressive clinical course (i.e. childhood-onset NF2) [63, 65, 69]. Thus, a typically (young) adult-onset disease (i.e. NF2) was first reported in a child (who likely had his onset of disease before the age of 1 year: i.e. he likely had a congenital form of NF2) [63, 69].

Further landmarks

In 1835, the renowned French pathologist Jean Cruveilhier (Fig. 2) presented one of the earliest analyses of the intracranial effects of acoustic neuromas [ 15 ]. His account included well-illustrated lithographs of his findings at autopsy in which he described the impact of intracranial masses on the skull and its contents [1, 15].
Fig. 2

Portrait of Professor Jean Cruveilhier (1791–1874)

Knoblauch published a similar early report on bilateral acoustic neuromas, as a dissertation in 1843 [45], only 6 years before Smith’s dissertation on multiple neuromata [82]. In his article, Knoblauch divided neuromatous tumours into those that were the consequence of a “morbid process”, and those that resulted from “an original vice of conformation” [45].

As the reports by Wishart [97] and Knoblach [15] demonstrate, during the first half of the nineteenth century, observations of living and dead tissue were almost uniformly macroscopic, making it nearly impossible to differentiate swelling due to inflammation from cancer in its early stage [1]. Tumours were thought in terms of “coagulated lymph”, part of the blood plasma or derivations of Hippocrates’ concept of the four humours [49]. Great improvements in the optic of the compound microscope in the 1830s combined with improved tissue staining techniques subsequently made the examination of thin sections of tumours and tissue possible. Again, Germany led the way. By the late 1800s, Virchow and his disciples [1, 83] were able to differentiate rapidly growing tumours with the ability to metastasize from benign tumours that were histologically similar to the tissues in which they originated. Virchow grouped these tumours under general categories including fibrous, bony, fatty, neural or vascular tumours [23]. After the reports of Virchow and von Recklinghausen, the understanding of neurofibromatosis and related forms would expand [1, 42, 83], rapidly progressing along four parallel lines of investigation including (1) determination of the histology of acoustic neuromas, (2) recognition of the association of acoustic neuromas with other intracranial tumours, (3) understanding of the familial clustering (i.e. inheritance patterns) of neurofibromatosis and (4) mapping (and cloning) of the chromosomal (genetic) anomalies of the individual diseases [1, 42].

Robert William Smith and his times

In his gigantic book (A Treatise on the Pathology, Diagnosis and Treatment of Neuroma) [82], which measured 48 × 70 cm (“26 ½ inches tall and 18 inches wide”) (thus permitting the inclusion of unusually large illustrations), he was able to collect six examples of what he called “general development of neuromatous tumours” (i.e. neurofibromas) and presented three further cases, suggesting, but unable to prove, that the origin of the tumours was “…. the connective tissue surrounding small nerves….” [23, 26, 42, 82]. Thirty-three years later, in 1882, von Recklinghausen confirmed their origin and named the tumours neurofibromas [42, 47, 61]. Even though nowadays Smith is known for his description of what is today referred to as Smith’s fracture [81] (the fracture of the distal end of the forearm), like many eminent physicians whose names are attached to medical conditions, his contribution to medicine was much greater than just describing one specific entity [47, 78].

Robert William Smith was born and raised in Dublin, Ireland (Fig. 3 and cover figure), and received his medical education primarily at the Richmond Hospital School. It was fortunate for Smith’s training that medicine was in its heyday during this time, which allowed him to work under some of the world’s foremost physicians [1, 78]. After completing his education, Smith taught medical jurisprudence and surgery at the Richmond Hospital School and became a licentiate of the Royal College of Surgeons of Ireland in 1832, fellow in 1844. He received his doctorate at Trinity College in 1842, and in 1847, he was appointed to the first chair of surgery at Trinity College, becoming a member of the Irish Academy in 1849. He was successively surgeon at the hospital for the mentally ill (Lunatic Asylum), founded by Talbot, with Sir Patrick Dun’s and the Richmond Hospital, teaching clinical surgery and forensic medicine at the latter for several years [19]. The excellent museum of the Richmond Hospital was made possible by his efforts. With Abraham Colles (1773–1843), Robert James Graves (1797–1853), Sir Dominic John Corrigan (1802–1880) and William Stokes, Smith founded the Dublin Pathological Society in 1838 [1, 78, 93], was its secretary for 35 years and thus had excellent opportunity to collect pathological preparations. At the time of his death in 1873, for a liver disease, he was vice president of the Royal College of Surgeons of Ireland. A major part of Smith’s work concerned the pathological anatomy of surgical diseases, particularly of knuckles and joints [78, 81]. He took a special interest in rare forms of congenital luxations. It was evident from Smith’s writings that he was a very good linguist and a medical historian [78].
Fig. 3 and cover figure

Portrait of Sir Robert William Smith (1807–1873)

Interestingly, Smith once wrote [78]:

It is, I conceive, the duty of every person who undertakes to write upon a give subject, to make himself, as far as possible, acquainted with, and also to acknowledge the labour of those who may have preceded him in the same field of inquiry [81, 82].

In his book on “neuromas tumours” [82], Smith indicated that such kind of neoplasms could have a spontaneous or a traumatic origin. In the first group, the authors mentioned that rarely the tumours were present “in almost countless numbers throughout the greater part of the nervous system and […] visible in almost every superficial nerve of the body” [82]. This rarity was confirmed by the fact that only six cases of “general development of neuromas tumours” were present in literature, besides the two cases seen personally (the patients John McCann and Michael Lowlor), who came at Smith’s attention at the distance of few weeks, and a third case reported to him by a colleague (Dr. Henry Kennedy). Notably, this (third) case had consulted Dr. Abraham Colles [26] 16 years previously, because of several small painless tumours, which had formed upon his legs and arms: “Mr Colles, although he confessed that he knew not their cause, and was equally ignorant of any mode of treatment by which they could be removed, except by operation, informed him that they were not of a serious nature, or likely to produce any impairment of his general health. He merely recommended a course of tonic medicines, and a strict attention to diet!” [82].

The above description thoroughly reproduces the clinical features and natural history of neurofibromatosis (type 1) in (most) affected individuals [42].

Rediagnosing (the patient) John McCann: neurofibromatosis type 1 vs. neurofibromatosis type 2 vs. schwannomatosis

John McCann, a 35-year-old cattle drover reported as the first case by Smith in his treatise [1, 82], was admitted initially under the care of Dr. Hutton in 1840 because of a large tumour on the right side of the neck thought to be malignant. There was a second tumour sublingually. Operation was not attempted and the patient returned to his occupation. He was readmitted in 1843 in an emaciated state (Fig. 4 and cover figure), and died toward the end of the year “with hepatic symptoms”. An immense tumour had developed at the back of his left thigh, and, when Smith performed a post-mortem examination, he saw that in addition to the three large tumours there were hundreds of others varying in size from that of an almond to a grapestone.
Fig. 4 and cover figure

Plate 1 (from Smith’s original treatise, on the pathology, diagnosis and treatment of neuromas) reproducing patient John McCann when readmitted at hospital in 1843 for the development of an immense tumour at the back of his left thigh

The “neuromata” were examined microscopically at autopsy:

Examined by the aid of the microscope, [he wrote] they were found to be compoused essentialy of a fibro-cellular structure, the fibrous tissue predominating in by far the greater number, the areaolar preponderating in a few; the fibres were arranged in bands or loops, amongst which permanent oval or elongated nuclei became apparent on the addition of acetic acid. In no one instance, out of the numerous specimens examined, was there any trace discovered of nerve-tubes, or any indication whatever of the presence of any of the structures considered by modern pathologists as characteristic of malignant disease [80].

The emaciated state of the unfortunate John McCann, coupled with the progressively enlarging masses (one of which appeared and enlarged over a relatively short time from first to second admission), and the later death would lead to a diagnosis of (a single or multiple) malignant peripheral nerve sheath tumour(s) (MPNST). The gross appearance of the “neuroma of the left sciatic nerve” was that (Plate 2) of a large, globoid, encapsulated tumour, with some attached medium-sized nerves, thus fitting with the diagnosis of MPNST (even though MPNSTs are usually pseudoencapsulated) [7, 44]. Conversely, histopathological examination of the neuromata was (according to the pathology knowledge at Smith’s times) against this hypothesis (“In no one instance ….was there …. any indication whatever of the presence of any of the structures considered by modern pathologists as characteristic of malignant disease”). About half of MPNSTs occur in the clinical setting of neurofibromatosis type 1 (NF1) [44]. In this respect, the cutaneous lesions seen over the trunk and the nodular tumours seen on both upper limbs of Mr. McCann should be regarded as neurofibromas.

The gross appearance of localised (intraneural) neurofibromas (fitting with the diagnosis of NF1) is typically that of a fusiform intraneural mass. Plate 1, however (Fig. 4 and cover figure), illustrates the tumours on the lateral aspect of McCann’s neck, at the back of his thigh and on his upper limbs, in a different way: i.e. as large, globoid (encapsulated), eccentric lesions that deflect the parent nerve over the surface of the tumour, as it occurs in classical schwannomas [7, 44]. In addition to that, (1) at gross pathology, the neuroma of the left sciatic nerve (Plate 2) could also resemble a plexiform schwannoma (rather than a (plexiform) neurofibroma or a MPNST), and (2) at microscopic examination, Smith [23] reported that unlike neurofibromas in “no one instance, out of the numerous specimens examined was there any trace discovered of nerve-tubes”. In classical schwannoma, neurites are generally not demonstrable in the substance of the tumour [7].

Thus, in our opinion, Smith could have reported either the earliest illustrated case of a MPNST in the setting of classical NF1 or the earliest case of neurofibromatosis type 2 (NF2) or of schwannomatosis in the literature. In either the latter occurrences, the small, slightly raised, rounded lesions, appearing over the skin of the trunk, could be interpreted as cutaneous schwannomas (i.e. NF2 plaques) [20, 69] rather than cutaneous neurofibromas. This latter hypothesis (i.e. cutaneous schwannomas vs. neurofibromas) holds true better for NF2 rather than for schwannomatosis. However, even though cutaneous schwannomas are well-recognised stigmata of NF2 [20, 69], these are (increasingly) recognised as additional features of some atypical (but genetically proven) cases of schwannomatosis [4, 59, 80]. In addition to that, if the left sciatic nerve tumour is regarded as a plexiform schwannoma, we must consider that these tumours have been also noted in non-NF2 patients with multiple schwannomas (i.e. in schwannomatosis) [7].

It should be also underlined that at the time of Smith, the neuron theory was as yet unstated, and the pathological anatomy of the nerves, in 1849, was still a great enigma [1, 83]. In addition to that, all three disorders are rare diseases, which still are a challenge for the medical community [74].

Type 2 segmental manifestations of neurofibromatosis or of schwannomatosis

Whatever diagnosis could be considered in John McCann (Fig. 4 and cover figure) (i.e. MPNSTs/NF1, NF2 or schwannomatosis), the degree of involvement (generated by the supposed MPNST or (plexiform) schwannomas in the neck and thigh was very pronounced and superimposed on an ordinary trait (i.e. NF1, NF2 or schwannomatosis), thus resembling the so-called type 2 segmental manifestations of autosomal dominant traits [34, 36] (i.e. a very pronounced (segmental) involvement limited to a restricted area of the body superimposed on the non-segmental phenotype vs. the type 1 segmental manifestations, which are characterised by a true mosaic/localised form of a disease) [35, 64, 67, 68, 70].

The other patient, Micheal Lawlor, a 32-year-old farmer, presented with numerous small tumours beneath the integuments, with the size of peas (Fig. 5), moveable and of firm consistence. Many of similar masses were present in different parts of the body [47, 80]. At the post-mortem examination, thousands of neuromata were disclosed.
Fig. 5

Plate 2 (from Smith’s original treatise, on the pathology, diagnosis and treatment of neuromas) reproducing patient Micheal Lawlor, a 32-year-old man, who presented with numerous small tumours beneath the integuments, with the size of peas, moveable and of firm consistence

In the cases reviewed (see also paragraph on "Robert William Smith and hist times"), Smith reported also on a patient who was observed by Abraham Colles, the famous surgeon who discovered the Colles’ fracture. The patient was a 45-year-old man, who presented multiple small painless tumours in his legs and arms. Colles admitted that he did not know their cause and was ignorant of any mode of treatment, but excluded the severity of their nature [47, 82].

Smith had the worth to recognise the disease as a distinct condition characterised by the development of tumours of the nerves, but did not correlate these with other hallmarks of neurofibromatosis, such as anomalies in pigmentation or involvement of bone. In particular, anomalies of the skin were later strongly correlated with neurofibromas by von Recklinghausen, who described the cutaneous spots as probably being neuromata of the finer nerve plexus of the cutis [47, 95], and the disease is not named after Smith, but after him.

Development of the distinction between (“central”) NF2 and (“peripheral”) NF1

Neurofibromas vs. schwannomas

In 1882, von Recklinghausen (Fig. 6) published his landmark monograph on the disease that would later become known as NF1 [1, 14, 95]. Over the following years, patients with skin and spinal cord tumours were diagnosed with neurofibromatosis and this term came into vogue over multiple neurofibromata during this time, “based upon the repeated observations that the diseases was less of a tumour growth than a widely disseminated fibrosis of the sheaths of the nerves” [1, 86].
Fig. 6

Photograph of Friedrich Daniel von Recklinghausen (1833–1910)

In 1897, Mossé and Cavalié first used the term central neurofibromatosis to denote a variant of “generalised” neurofibromatosis, later called von Recklinghausen disease, that lacked the peripheral manifestations [1, 52, 83]. Further, they recognised that bilateral acoustic neuromas may be accompanied by numerous other cranial nerve neuromas [52].

Based on his histologic studies, Stenberg, at the turn of the century, proposed that the nervous tumours were derived from Schwann cells [83, 84]. Schwann cells had been named in honour of the German pathologist and naturalist Theodor Schwann (1810–1882) who, in “Microscopic Researches Into the Accordance in the Structure and Growth of Animals and Plants” (1839), laid the foundations of the cell theory—later championed by Virchow—by demonstrating that the cell is the basis of all animal and plant tissue [1, 83].

In 1810, Theodor Ambrose Hubert Schwann (Fig. 7) was born the third of ten children in French-occupied Neuss, Germany [83]. He attended the Jesuit College of Cologne for secondary education and went on to the University of Bonn in 1829, where he encountered Johannes Peter Muller, a professor of physiology and anatomy, who at the time was investigating frog spinal nerves. In 1831, Schwann began his medical studies at the University of Würzburg, focusing on pathology and surgery. In 1834, Schwann earned his medical degree, and Muller appointed him as assistant in anatomy. In 1838, Schwann delivered his most important contribution to the scientific world, a unified cell theory, which led to the finding of his eponymous cell. In 1839, Schwann took the position of Chair of Anatomy at the Universite Catholique de Louvain in Belgium, where he championed a thesis illustrating bile’s niche through his study of biliary fistula in canines. Leaving the university in 1848, he created a physiologic apparatus, most importantly, one that allowed for life in oxygen-deficient conditions through an independent, mobile respiratory device [1, 83].
Fig. 7

Portrait of Theodor Ambrose Hubert Schwann (1810–1882)

Schwann was a founding father of the cellular theory and one of the greatest scientists of the nineteenth century [1]. He not only proposed cell theory but also discovered the “secondary” nerve cell and hypothesised its possible function in myelination. It took a century to confirm Schwann’s hypothesis. In 1954, Geren, aided by the electron microscope, demonstrated that the cell of Schwann is responsible for nerve myelination. Concurrently, researchers worked to understand the etiology and pathogenesis of peripheral nerve neoplasms [83].

Central vs. peripheral neurofibromatosis

As early as the beginning of 1900, clinicians began to distinguish (“central”) NF2 from (“peripheral”) NF1. In 1903, Henneberg and Koch described a distinct (intracranial) form of neurofibromatosis that involved the 8th cranial nerves bilaterally but spared the skin [1, 38, 58, 83]. Their paper was most notable both for drawing widespread attention to the finding of bilateral acoustic tumours, which had previously been described only sporadically and incompletely, and for associating them with von Recklinghausen disease. They presented two individuals with bilateral acoustic neuromas, one of whom also had “multiple neurofibromas of the skin, peripheral nerves, extradural and intradural spinal nerves, and the 9th and 10th cranial nerves”. In discussing the acoustic neuromas, they introduced the term cerebellopontine angleKleinhirnbruchenwinkel (from the German Kleinhirn = cerebellum; bruchen = pons or bridge; and winkel = angle)—to denote the location where these tumours were most frequently found. They used the term “central” neurofibromatosis to distinguish these patients from those with the more common “peripheral” neurofibromatosis described by von Recklinghausen [1].

After the seminal report of Henneberg and Koch [38, 83] of bilateral acoustic neuromas, the next two decades saw a multitude of reports describing similar findings: this expanding phenomenon was likely due to the flurry of activity in the emerging field of neurosurgery [1, 83]. After Victor Horsley’s first successful removal of a spinal tumour in 1887 and his subsequent animal experiments and cranial operations in humans, there was a new impetus for the clinical diagnosis of tumours of the central nervous system, as surgical therapy became a viable therapeutic option. Over the turn of the century, a number of neurosurgeons started to attempt surgical removal of cerebellopontine tumours, including Ballance in 1894 (who successfully extirpated a tumour later believed to be a cerebellopontine mass) [18, 83], Annandale in 1895 (who removed a tumour—likely a fibro-sarcoma—causing deafness, vertigo and frontal headache) [1, 31] and Garre in 1903 (who failed to remove a bilateral acoustic neuroma found intraoperatively and recorded, at autopsy, “widespread central neurofibromatosis”) [1, 27, 83]. During that period, Fraenkel and Hunt [1, 24, 83], working at Cornell University in New York, described a patient with bilateral acoustic neuromas and echoed the prevailing sentiment that all neuromatous tumours, central and peripheral, were an expression of the same pathological process. Neurofibromatosis was, at that time, by definition, “the formation of one or more tumours in one or more cerebrospinal or sympathetic nerves” [1]. They noted that acoustic nerves were not immune (as previously thought, paralleling the histology of the 1st and 2nd to the 8th cranial nerves) from the occurrence of neurofibromas and reaffirmed the concept that patients with multiple intracranial tumours were classified under the separate (but related) category of central neurofibromatosis opposed to the syndrome of neurofibromas of the skin, cerebrospinal nerves and sympathetic nerves, which was termed general neurofibromatosis. Individuals with central neurofibromatosis had their peripheral signs “masked” by the occurrence of intracranial tumours. Such explanation was echoed, in one form or another, in all reports during this time and was also coupled to moral characters typically belonging to the spectrum of neurofibromatosis, including mental impairment, imbecility and somatic stigmata of degeneracy (e.g. homosexuality), all suggesting the teratologic nature of the disease [1, 24]. Notably, in the same period, Biggs [5], by reporting the post-mortem examination of a patient with bilateral acoustic neuromas, noted that “the largest acoustic tumour was on the side of the least marked clinical deafness”, thus first introducing the concept of clinical vs. anatomical discrepancy in acoustic neuromas.

The Uruguayan pathologist Jose Juan Verocay (1876–1927) (Fig. 8), in 1910, analysing four isolated acoustic neuromas, first understood that these tumours, differently from von Recklinghausen’s neurofibromas, derived from neoplastic sheaths of undifferentiated neurocytes, capable of giving rise to Schwann cells, with nerve fibres traversing the tumour and essentially corroborated Sternberg’s hypothesis that Schwann cells were intimately involved in neuroma formation: he suggested the controversial name of “neurinoma”, meaning nerve fibre tumour, in contrast to von Recklinghausen’s “neurofibroma” [1, 83].
Fig. 8

Photograph of the Uruguayan pathologist Jose Juan Verocay (1876–1927)

In the following years, researchers who reviewed cases of bilateral vestibular schwannomas found some similarities between the cutaneous features of these patients with the ones of patients affected by NF1 [42]. In his review of the literature of 1915, Henschen reported a series of 245 patients affected by unilateral vestibular schwannomas and 24 by bilateral lesions, finding that 5/245 of the first group and 19/24 of the second group presented signs resembling von Recklinghausen’s disease [39, 42, 83]. This somewhat curious report (most cases of acoustic neuromas do not occur in the presence of peripheral manifestations of neurofibromatosis), credited Henschen with discovering that neuromas of the acoustic nerve originate in the vestibular portion of the nerve lying in the prus acousticus: this was discovered however serendipitously while reconstructing in wax an early acoustic tumour found by chance at autopsy [39, 83].

The first landmark work on schwannomas came from a Swedish physician, Nils Ragnar Eugène Antoni (1887–1968) [83]. Antoni became associate professor and later professor (1931–1954) of neurology at the Karolinska Institute in Solna, Sweden. In 1920, he published his work on spinal cord tumours and neurofibromas titled “Über Rückenmark stumoren und Neurofibrome: Studien zur pathologischen Anatomie und Embryogenese (Mit einem klinischen Anhang)” [2]. Antoni distinguished between two distinct pathologic types of neurofibroma: Antoni A and B subtypes. Antoni subtype A exhibits an orderly placement of cells and nuclei parallel to each other. Subtype B consists of more reticular and disorganised architecture and is prone to mucoid degeneration.

Another work on these tumours came from Pierre Masson (1880–1959), largely regarded as the father of histopathology in Canada [1, 83]. In 1926, he accepted the position of Chairman of the Pathology Department at the University of Montreal. In 1923, his work “Traité de Pathologie Med́icale et de Theŕapeutique Appliqueé / XXVII, Diagnostics de Laboratoire II Tumeurs - Diagnostics Histologiques”, was published, in which he used the terms “schwannomas” and “aneuritic neuromas” [1, 83]. He published the article “Experimental and spontaneous schwannomas (peripheral gliomas)” 9 years later [50, 83]. In this article, Masson discussed the concept of experimental schwannomas, which were studied in detail by his French colleague Jean Nageotte (1866–1948). Nageotte coined the term “peripheral glioma” or “Nageotte’s peripheral glioma” as acknowledged by Masson in his article. In 1912, Nageotte succeeded Ranvier as chair of comparative histology at the Pitié-Salpêtrière Hospital, Paris, France. He experimented extensively on Schwann cells and broadened the concept of peripheral [83].

Harvey Cushing (Fig. 9), America’s prominent neurosurgeon of the early twentieth century, delayed the true distinction between central and peripheral neurofibromatosis into different pathologies by the publication of his classical text “Tumors of the nervus acusticus and the syndrome of the cerebellopontile angle”, in 1917 [83]. In his monograph, he reviewed the existing literature and described 23 cases of acoustic neuromas (even though none of his 23 patients had proven bilateral acoustic neuromas and only two had bilateral symptoms): he writes “when the acoustic tumors are bilateral they are very apt to be merely a local expression of a more widespread process (central or general neurofibromatosis) of the von Recklinghausen type….characterisd by tumefaction of the cerebrospinal and peripheral nerves” [16, 17, 42, 83]. Thus, Cushing recognised a potential significant difference between unilateral and bilateral acoustic neuromas and correctly observed that the solitary acoustic neuroma probably represented a lesion in the transition zone between central neuroglia and the peripheral Schwann sheath. Ten years later, a neurosurgeon at Columbia University, Wilder Penfield, provided histological support for Cushing’s observation and first established histological differences between acoustic neuromas (which contained nerve fibres only in the capsule) and von Recklinghausen’s neurofibromas (where the nerve fibres penetrated the entire tumour). In addition to that, Cushing believed that the incidence of bilateral acoustic neuromas was no more than 1 in 100 unilateral cases. Subsequently, NF2 was seen as manifestation of von Recklinghausen’s disease rather than as an independent entity. Given Cushing’s high reputation, it took almost seven decades for the two diseases to be fully separated again.
Fig. 9

Photograph of Professor Harvey Cushing (1869–1939)

Bilateral acoustic neuromas associated with meningiomas

Wishart achieved the first known association between acoustic neuromas and meningiomas in 1822 (see also above) [1, 97]: more than a century later, bilateral acoustic neuromas associated with meningiomas would characterise the disease with the eponymous “Wishart variety”, which follows a more aggressive course [1, 63, 65, 69].

In 1915, the eminent Swedish pathologist Folker Henschen, in his extensive series mentioned above, included 13 cases of acoustic neuroma accompanied by meningiomas [39]. Thus, by 1917, Cushing was aware of the association of acoustic neuromas with meningeal lesions, which at the time he called endotheliomata. He also recognised that meningeal and acoustic tumours were “of an utterly different pathological character …… the two types of tumour (however) are so frequently associated that there has been a recent tendency to group them together …..”. Cushing later coined the term meningioma that remains widely accepted today [1, 16].

Biggs in 1909, Penfield in 1927 and Gardner and Turner in 1931 were among those to publish significant early reports on acoustic neuromas with meningiomas [1, 5, 30, 42, 83]. Cushing and Eisenhardt reviewed these cases, along with further reports that appeared early in the twentieth century, in their 1938 monograph on meningiomas [16]. These early reports, however, almost uniformly perpetuated the notion that bilateral acoustic neuromas associated with meningiomas were simply “central” manifestations of “von Recklinghausen” disease [in the words of Cushing: “…. even in the absence of any evidence of neurofibromatosis elsewhere, ….. single acoustic tumours, bilateral acoustic tumours, and the generalised involvement of other cranial nerves appear to be …merely gradations of the same malady and do not represent different disorders ….”]. One group, however, led by Worster-Drought in 1937 [98], suggested that bilateral acoustic neuromas associated with meningiomas, which they termed “neurofibroblastomatosis”, should be considered distinct from the purely manifesting von Recklinghausen disease. Even Gardner and Turner, in their 1940 monograph [29], also alluded to the possibility that a single acoustic neuroma associated with one or more meningiomas may be distinct from von Recklinghausen disease, but they ultimately succumbed to the accepted notion that it most likely represented “an incomplete or abortive form of the disease”.

Establishing the familial occurrence of bilateral acoustic neurons

In the following years, after several reports stating that NF2 presented a familial occurrence with autosomal dominant inheritance [1, 22, 28, 29], acoustic neurinomas became accepted as a severe complication of the von Recklinghausen disease. The family reported by Gardiner and Frazier [28], in particular, had 38 affected members over five generations: the affected members had early-onset deafness and balance problems and often died prematurely, and the authors also noted the particularity of the uniform expression of acoustic neuromas and the presence of limited signs of von Recklinghausen disease in these patients. Autopsy was performed on two affected members and revealed bilateral cerebellopontine angle tumours. They observed that approximately 50 % of individuals in their families were at risk of developing the condition, and no evidence of incomplete penetrance or sex specificity was noted [28]. Even if the features of these patients were not so similar to the classical form of the von Recklinghausen disease, the identification of the NF2 as a separate clinical entity was not performed till 1970, being considered as a particular variant of von Recklinghausen’s disease, and studies at that time stated that bilateral acoustic neuromas were present in almost 5 % of all von Recklinghausen patients [13, 42].

Reports of families with members affected by bilateral neuromas became more frequent in the second half of the last century, and the possible presence of a distinct mutation responsible for the disease was suspected [1, 21, 32, 53]. In particular, the study by Moyes focused on four generations of an affected family, suggesting the presence of an entirely different autosomal dominant mutation, because many of the affected members presented a few signs of the classical von Recklinghausen disease but the distinctive bilateral acoustic neuromas [53].

When ultimately Young et al. [99] reported an expanded follow-up on 97 members (Fig. 10) of the index family reported 40 years before by Gardiner and Frazier, [28] NF2 started to be considered as a distinct entity. This report and a subsequent study by the same group [43] covered nine generations of an American family, from the late 1700s to the twentieth century. It was emphasised that the major feature of the affected members was bilateral acoustic neuroma (vestibular schwannomas) and that the cutaneous features, present in some patients, were much less prominent than in NF1: Cafè au lait spots were generally small and solitary and no affected member presented more than two spots. Other NF1 complications were notably absent, and only 2 of 97 had more than one subcutaneous nodule. In addition, they noted that the majority of patients had a relatively mild clinical course [29, 30, 96]: Gardner’s description of a mildly affected family led to the denomination of the Gardner subtype for NF2 with a mild clinical course.
Fig. 10

Genealogic tree of the family reported by Young et al. [99]: several members are affected by NF2 in a span of eight generations

Finally, in 1987, a consensus panel of the National Institutes of Health differentiated the clinical manifestations associated with the classic form of the disease from those of the predominantly intracranial subtype and they were subsequently named as “NF type 1” and “NF type 2”, respectively. In the following years, different genetic origins of the two pathologies have been demonstrated, thus confirming the differentiation in two distinct pathologies [1, 42].

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Martino Ruggieri
    • 1
    Email author
  • Andrea D. Praticò
    • 1
    • 2
  • Agostino Serra
    • 3
  • Luigi Maiolino
    • 3
  • Salvatore Cocuzza
    • 3
  • Rosario Caltabiano
    • 4
  • Agata Polizzi
    • 5
  1. 1.Department of Clinical and Experimental Medicine, Section of Pediatrics and Child NeuropsychiatryUniversity of CataniaCataniaItaly
  2. 2.Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  3. 3.Department of Medical and Surgical Sciences and Advanced Technologies “G. Ingrassia”, Institute of OtorhinolaryngologyUniversity of CataniaCataniaItaly
  4. 4.Department of Medical and Surgical Sciences and Advanced Technologies “G. Ingrassia”, Section of Anatomic PathologyUniversity of CataniaCataniaItaly
  5. 5.National Centre for Rare Diseases, Istituto Superiore di SanitàRomeItaly

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