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. 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.
Wishart described lesions arising from the 5th and 11th nerves as well as from both auditory meati i. 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 ]. Thus, a typically young adult-onset disease i. NF2 was first reported in a child who likely had his onset of disease before the age of 1 year: i. In , the renowned French pathologist Jean Cruveilhier Fig. 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 ].
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 ]. Great improvements in the optic of the compound microscope in the s 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 s, 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. Thirty-three years later, in , von Recklinghausen confirmed their origin and named the tumours neurofibromas [ 42 , 47 , 61 ].
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 , fellow in He received his doctorate at Trinity College in , and in , he was appointed to the first chair of surgery at Trinity College, becoming a member of the Irish Academy in The excellent museum of the Richmond Hospital was made possible by his efforts.
With Abraham Colles — , Robert James Graves — , Sir Dominic John Corrigan — and William Stokes, Smith founded the Dublin Pathological Society in [ 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 , for a liver disease, he was vice president of the Royal College of Surgeons of Ireland. He took a special interest in rare forms of congenital luxations. 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 ].
Henry Kennedy. Notably, this third case had consulted Dr. He merely recommended a course of tonic medicines, and a strict attention to diet! The above description thoroughly reproduces the clinical features and natural history of neurofibromatosis type 1 in most affected individuals [ 42 ].
John McCann, a 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 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 in an emaciated state Fig. 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.
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.
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. 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.
NF2 plaques [ 20 , 69 ] rather than cutaneous neurofibromas. This latter hypothesis i. 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.
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 , 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 ]. Whatever diagnosis could be considered in John McCann Fig.
NF1, NF2 or schwannomatosis , thus resembling the so-called type 2 segmental manifestations of autosomal dominant traits [ 34 , 36 ] i. The other patient, Micheal Lawlor, a year-old farmer, presented with numerous small tumours beneath the integuments, with the size of peas Fig.
Many of similar masses were present in different parts of the body [ 47 , 80 ]. At the post-mortem examination, thousands of neuromata were disclosed. The patient was a 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.
In , von Recklinghausen Fig. 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 ]. He attended the Jesuit College of Cologne for secondary education and went on to the University of Bonn in , where he encountered Johannes Peter Muller, a professor of physiology and anatomy, who at the time was investigating frog spinal nerves.
In , Schwann earned his medical degree, and Muller appointed him as assistant in anatomy. In , Schwann delivered his most important contribution to the scientific world, a unified cell theory, which led to the finding of his eponymous cell. Leaving the university in , he created a physiologic apparatus, most importantly, one that allowed for life in oxygen-deficient conditions through an independent, mobile respiratory device [ 1 , 83 ]. Schwann was a founding father of the cellular theory and one of the greatest scientists of the nineteenth century [ 1 ].
In , 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 ]. In , 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.
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 ].
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. 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.
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.
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 ].
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 ].
Antoni became associate professor and later professor — of neurology at the Karolinska Institute in Solna, Sweden. 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 — , largely regarded as the father of histopathology in Canada [ 1 , 83 ].
In , he accepted the position of Chairman of the Pathology Department at the University of Montreal. In this article, Masson discussed the concept of experimental schwannomas, which were studied in detail by his French colleague Jean Nageotte — He experimented extensively on Schwann cells and broadened the concept of peripheral [ 83 ].
Harvey Cushing Fig. 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.
In addition to that, Cushing believed that the incidence of bilateral acoustic neuromas was no more than 1 in unilateral cases. In , the eminent Swedish pathologist Folker Henschen, in his extensive series mentioned above, included 13 cases of acoustic neuroma accompanied by meningiomas [ 39 ].
Thus, by , Cushing was aware of the association of acoustic neuromas with meningeal lesions, which at the time he called endotheliomata. Cushing later coined the term meningioma that remains widely accepted today [ 1 , 16 ]. Biggs in , Penfield in and Gardner and Turner in 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 monograph on meningiomas [ 16 ]. 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. 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. This report and a subsequent study by the same group [ 43 ] covered nine generations of an American family, from the late s to the twentieth century.
Other NF1 complications were notably absent, and only 2 of 97 had more than one subcutaneous nodule. Genealogic tree of the family reported by Young et al. In the following years, different genetic origins of the two pathologies have been demonstrated, thus confirming the differentiation in two distinct pathologies [ 1 , 42 ]. Evolution of the concept of neurofibromatosis type 2.
Arch Otolaryngol Head Neck — Healthy children with NF1 are usually examined at six or month intervals. Adults with NF1 generally have standard physical evaluations and an examination of the skin for growths, spots, scoliosis, blood pressure, vision and screening for hearing loss. Physicians should also be on the lookout for any new or enlarging mass or any new symptoms in general. Adults with NF1, who are otherwise healthy, usually have annual checkups. Patients with NF2 should have similar routine examinations and care.
Known growths are often imaged with periodic surveillance scans with treatment reserved for enlarging or symptomatic growths. There is no known treatment or cure for neurofibromatosis or schwannomatosis. Medication can be prescribed to help with pain. In some cases, growths may be removed surgically or reduced with radiation therapy. Although surgery in these areas can cause further injury to nerves and additional neurological problems, it is usually well tolerated.
The benefits of surgery should always be weighed against its risks. Likewise, in situations where radiation treatment is an option, the risks and benefits must be carefully considered.
The AANS does not endorse any treatments, procedures, products or physicians referenced in these patient fact sheets. This information is provided as an educational service and is not intended to serve as medical advice. Joint Providership. Incidence and Prevalence. Other Names. Neurofibromatosis 1 NF1 is usually diagnosed during childhood. Signs are often noticeable at birth or shortly afterward and almost always by age Signs and symptoms are often mild to moderate, but can vary in severity.
Neurofibromatosis 2 NF2 is much less common than NF1. Signs and symptoms of NF2 usually result from the development of benign, slow-growing tumors in both ears acoustic neuromas , which can cause hearing loss. Also known as vestibular schwannomas, these tumors grow on the nerve that carries sound and balance information from the inner ear to the brain.
Signs and symptoms generally appear during the late teen and early adult years, and can vary in severity. Signs and symptoms can include:. Sometimes NF2 can lead to the growth of schwannomas in other nerves, including the cranial, spinal, visual optic and peripheral nerves.
People who have NF2 may also develop other benign tumors. This rare type of neurofibromatosis usually affects people after age Symptoms usually appear between ages 25 and Schwannomatosis causes tumors to develop on the cranial, spinal and peripheral nerves — but rarely on the nerve that carries sound and balance information from the inner ear to the brain.
Tumors don't usually grow on both hearing nerves, so people who have schwannomatosis don't experience the same hearing loss as people who have NF2. See your doctor if you or your child develop signs or symptoms of neurofibromatosis. The tumors associated with neurofibromatosis are often benign and slow growing. Neurofibromatosis is caused by genetic defects mutations that either are passed on by a parent or occur spontaneously at conception.
The specific genes involved depend on the type of neurofibromatosis:. In an autosomal dominant disorder, the mutated gene is a dominant gene located on one of the nonsex chromosomes autosomes. You need only one mutated gene to be affected by this type of disorder. The biggest risk factor for neurofibromatosis is a family history of the disorder.
About half of people who have NF1 and NF2 inherited the disease from an affected parent. People who have NF1 and NF2 and whose relatives aren't affected are likely to have a new gene mutation. The inheritance pattern for schwannomatosis is less clear. Complications of neurofibromatosis vary, even within the same family. Generally, complications result from tumors that affect nerve tissue or press on internal organs.
The pain caused by schwannomatosis can be debilitating and may require surgical treatment or management by a pain specialist. Neurofibromatosis care at Mayo Clinic. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. This content does not have an English version.
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