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Neurofibromatosis
  1. J M S Pearce
  1. 304 Beverley Road, Anlaby, Hull HU10 7BG, UK; jmspearce{at}freenet.co.uk

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    Friedrich Daniel von Recklinghausen (1833–1910) was born in Gütersloh, Westphalia, and graduated in Berlin in 1855. In 1881, as a tribute to Rudolf Virchow’s 25th year Jubilee, he wrote his classical article on neurofibromatosis.1 The first patient, a 55 year old woman who was admitted because of lung haemorrhages, died a few hours after admission to the hospital and was autopsied. Skin tumours had been present since the age of 3. At autopsy the following findings were noted:

    “Innumerable nodules, almost over the entire outer skin layer (Plate 1), for the most part on stalks, while others sat on broad bases and were mostly simple spheres in all possible sizes. The larger ones, however, were especially polypous, up to 5 cm long and 4 cm thick, all covered with completely intact, almost smooth skin; although on the sacrum there was a flatly pressed, mushroom-shaped nodule, lightly ulcerated on its surface, while another small ulcerated nodule appeared on the left side of the trunk …

    In general, the skin of the entire body had a dirty brown colour; closer examination revealed the existence in many places, particularly on the trunk and throat, of innumerable brown pigmentation spots …

    On the left side, on the femoral nerve, in the middle of the thigh below the origin of the saphenous nerve, there was a spindle-shaped tumour 32 mm long, 7 mm thick, running along the posterior side of the nerve. At the knee was another small tumour on the saphenous nerve. There were small tumours on the muscle rami of the femoral nerve. The lateral cutaneous (femorocutaneous) nerve exhibited two tumours, one below the branching point on the upper ramus, the other a hand-width above it … The spinal cord and brain were unremarkable, even under microscopic examination. Death resulted from pulmonary haemorrhage from a pulmonary artery aneurysm.”

    The autopsy report was followed by a histological description: there were no signs of nerve fibre neoplasia or “fatty degeneration”. Even in larger neurinomas, the nerve fibres could be distinguished. Although still myelinated, some fibres showed an increase of connective tissue.

    The second case history was a 47 year old man with unaffected relatives; he had observed the number of skin tumours had increased since he was 15. Von Recklinghausen found enlargement of the peripheral nerves he could distinguish from skin fibromas. With his colleague, Friedrich Jolly, he noted normal sensibility for pain as well as the irritability of the muscle by electric stimulus of the median nerve. Four small nodules examined microscopically disclosed the same findings as in the first case. He decided that “fibromas formed in the greater trunks in layers, but at first started in primitive nerve fibres.”

    An earlier account of generalised neurofibromatosis is contained in a monograph by RW Smith (1849),2 who refers to many prior examples, but Von Recklinghausen first provided the necessary histological detail and demonstrated a hereditary disease characterised by café au lait spots combined with multiple peripheral nerve tumours and other dysplastic abnormalities of the skin, nervous system, bones, endocrine organs, and blood vessels.3

    We now know that the neurofibroma is the hallmark lesion of NF1, whereas the schwannoma is the typical peripheral nerve tumour of NF2. The NF1 gene product is neurofibromin, a negative regulator of signal transduction; this suggests possible approaches for treatment. Von Recklinghausen is remembered for three distinct discoveries:

    1. multiple neurofibromatosis;

    2. osteitis fibrosa cystica (hyperparathyroidism);

    3. Haemochromatosis.

    He was assistant to Virchow for 6 years, then became Professor of Pathology, first at Königsberg, next Wurzburg, and in 1872 at Strasburg, where he remained an active teacher and researcher until his death. Trousseau gave the `first description’ of haemochromatosis, in 1865,4 but von Recklinghausen in 1889 provided the name with a full description.5 In 1862, while still Virchow’s assistant, he published two important papers, one showing that connective tissue contained spaces, which were drained by lymphatics6 and in which cells were present: `von Recklinghausen’s canals’. He showed these cells had amoeboid movements and identified them as leukocytes. He identified granular cells in the mesentery of the frog, later named mast cells by Ehrlich (1879).

    He established the method of using silver to stain the lines cell junctions and his work led to Cohnheim’s studies on leukocyte migration and inflammation. Cohnheim was an assistant in the laboratory at that time.

    He was a typical histopathologist of his time but even though he had made vital contributions to the early understanding of inflammation he was resistant to certain changes such as the introduction of the microtome. He trained many leaders in German pathology, including Friedlander Zahn and Aschoff. A colourful personality, he was an industrious enthusiast, but strangely opposed Koch’s concept that the tubercle bacillus was the cause of tuberculosis. He was considered second only to Virchow in an era of great German pathologists.

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