Different Forms Of Neurofibromatosis Research Articles

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.

The earliest examples of neurofibromatosis (in this case type 1, NF1) can be traced in the Ebers Papyrus (Ancient Egypt, 1.500 B.C.), in a Hellenistic statuette (Smyrna, 323 B.C.), in the coinage of the Parthians kings (247 B.C.) and in some 13th century monks' drawings. These earlier examples are somewhat less well defined as compared to the most recent better defined reports credited as having NF1 including an Inca child mummy (1480-1650 AD), Ulisse Aldrovandi's homuncio ("Monstrorum Historia", 1592 A.D.) with mosaic NF1 or the illustrations seen in the 18th century "Buffon's Histoire Naturelle" and "Cruveilhier's Anatomie Pathologique du Corps Human". The first English language report on NF1 was made by Akenside in 1768 and the first systematic review by Robert William Smith in 1849, while Virchow's pupil, Friedrich Daniel von Recklinghausen, in 1882, was the first to understand the origin of skin tumors and to name them neurofibromas. The touching story of Joseph C. Merrick (the "Elephant man," (who had Proteus syndrome and not NF1), in 1884, played an important role in the later misconception of NF1, as did the novel by Vicotr Hugo on the hunchback Quasimodo. The studies by van der Hoeve (1921), Yakovlev and Guthrie (1931), and Van Bogaert (1935), categorized "von Recklinghausen's" neurofibromatosis among the phakomatoses and the neurocutaneous syndromes. The first known mention of an acoustic neuroma (at autopsy) is attributed to Eduard Sandifort (1777 AD) while John H. Wishart made the earliest autoptic description of neurofibromatosis type 2 (NF2), in 1822, in a 21-year-old man with bilateral acoustic neuromas, who manifested signs since his infancy (Wishart subtype NF2). Smith likely described the first case of schwannomatosis in 1849. Older, Virchow, von Recklinghausen, and Verocay first classified "neuromas" and Masson and Penfield first used the word "schwannoma" taking it from Theodore Schwann's works. In 1903 Henneberg and Koch described NF2 in detail. Young, Eldridge, and Gardner, in the late '70, established NF2 as a distinct familial entity (Gardner subtype NF2). Schwannomatosis, the late entry of the different forms of neurofibromatosis, was credited in the middle '90.

A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features

Neurocutaneous disorders represent a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities, hamartomas or tumors) and the central and peripheral nervous systems. In recent years, besides the well-known neurocutaneous diseases (e.g., the different forms of neurofibromatosis, tuberous sclerosis complex, Sturge-Weber syndrome and mosaic pigmentary/hamartomatous disorders), new distinctive syndromes have been characterized, extending our knowledge on the spectrum of these conditions. The concurrent presence of pigmentary abnormalities (both of the hypo- and hyperpigmented type), and primary microcephaly has not been commonly reported.We report on a 4.5-year-old girl with primary microcephaly, who had in addition moderate to severe developmental delay, behavioral and stereotypic abnormalities and a cutaneous pattern of paired hypo- and hyperpigmented lesions variously distributed over the body, particularly on the trunk. Failure to thrive and mild facial dysmorphic features were also present. To our knowledge, this complex malformation (neurocutaneous) phenotype has not been previously reported.

The different forms of neurofibromatosis.

In the last two decades our knowledge of the natural history, genetics and management of the different forms of neurofibromatosis has changed. Of the numerical classifications of neurofibromatosis proposed in the past, only neurofibromatosis type 1 (Nf1) and neurofibromatosis type 2 (Nf2) have been shown to be distinct at clinical and molecular levels. Mosaicism has been demonstrated both in patients with Nf1 and in patients with Nf2, and features of segmental or mosaic Nf1 and Nf2 have been defined. The outlying phenotypes and the molecular genetics of other, rarer, types of neurofibromatosis have been delineated: these are hereditary spinal neurofibromatosis, Schwannomatosis, familial intestinal neurofibromatosis, autosomal dominant "cafe-au-lait spots alone", autosomal dominant "neurofibromas alone", Watson syndrome, Noonan/neurofibromatosis syndrome and the so-called syndrome of multiple naevi, multiple schwannomas and multiple vaginal leiomyomas. In this article I will review the different forms of neurofibromatosis, focusing on those aspects that most commonly challenge the neurosurgeon.

The neurofibromatoses. An overview

The last two decades have seen clinical and molecular delineation of the different forms of neurofibromatosis. Differentiation of these forms is not just an academic exercise: their natural history, management and genetic counselling are quite different. Of the numerical classifications of neurofibromatosis proposed in the past, only neurofibromatosis type 1 (Nf1) and neurofibromatosis type 2 (Nf2) are now well delineated clinically and have been shown to be distinct at the molecular level. For both forms of neurofibromatosis, patients with clinical generalised disease have been demonstrated to be mosaic at the molecular level, and features of segmental or mosaic Nf1 and Nf2 have been delineated. Other reported forms of neurofibromatosis are rarer; they include Watson syndrome, hereditary spinal neurofibromatosis, familial intestinal neurofibromatosis, autosomal dominant café-au-lait spots alone, autosomal dominant neurofibromas alone, and schwannomatosis, the latter believed to be a variant of Nf2. Further delineation is needed for individuals having overlapping features of Noonan's syndrome and neurofibromatosis (the so-called Noonan/neurofibromatosis syndrome) and the syndrome of "multiple naevi, multiple schwannomas and multiple vaginal leiomyomas". In this article we review the forms of neurofibromatosis which we believe are true clinical entities. Particular attention is given to the neurological manifestations of neurofibromatosis.

What's new in neurofibromatosis?

The last decade has seen major developments in our knowledge of the different forms of neurofibromatosis. Evidence based clinical diagnostic criteria and management guidelines have been developed. The genes for the two major forms, neurofibromatosis type 1 (Nfl) and type 2 (Nf2), have been cloned. This has provided insight into the pathogenesis of these diseases and long-term hope of some form of treatment being developed. In this article we briefly review these developments and try to answer the questions that paediatricians most often ask 'neurofibromatologists'. The term neurofibromatosis or Von Recklinghausen's disease was previously used to describe all patients with variable combinations of caf6 au lait (CAL) spots and tumours of the peripheral and/or central nervous system. As systematic clinical research began in the 1970s it became clear that within this umbrella term there were several distinct diseases. Differentiation of these is not just an academic exercise (and one which clinical geneticists are fond of!), their natural history and management are quite distinct. The other major development in recent years has been the network of support available to families through the UK Neurofibromatosis Association.

Wirbelsäulenveränderungen bei Neurofibromatose im Kindesalter

A systematic radiologic study of the skeletal system of 72 children with different forms of neurofibromatosis (NF) revealed a high proportion of spinal defects. Scoliosis was found in 46%, anomalies of the vertebrae in an even higher percentage, particularly cleft spine in 25%, wedge-shaped vertebrae in 22% and scalloping of vertebrae in 40%. Radiographic examination of children with even minimal signs of NF was helpful in confirming the diagnosis, staging of patients and obtaining additional hints in regard to the long term prognosis of children with neurofibromatosis.

Bilateral dermatomal neurofibromatosis

Neurofibromatosis is a disease seen in several clinical forms. We describe an unusual case of neurofibromatosis involving a bilateral dermatomal area of the trunk. Family history was negative, and extensive evaluation for other signs of neurofibromatosis was unrevealing. The different forms of neurofibromatosis are briefly discussed with particular emphasis on the segmental type.