Review ArticleIs it time to change the neurofibromatosis 1 diagnostic criteria?
Introduction
Neurofibromatosis 1 (OMIM #162200) is a complex inherited neurocutaneous disease that has an incidence of about 1 in 3500 live births and requires a multidisciplinary management approach because of its clinical impact on the nervous system, skin, eyes and bones. Its diagnosis is currently based on the clinical criteria encoded by National Institute of Health Consensus Conference statement organised in 1988 in the United States [1]. However, over the last 26 years, our understanding of this disease has naturally improved, and some clinicians have acquired considerable clinical experience as a result of the creation of dedicated diagnostic and follow-up centres. Moreover, increasingly precise molecular analyses have provided a new objective means of confirming a diagnosis in about 95% of patients [2].
Diagnostic communication to patients and their parents is difficult because the clinical presentation of the disease can vary from exclusively cutaneous involvement to the complete expression of various signs in different organs, thus making its evolution unpredictable, and its inter- and intra-familial prognosis uncertain. As it is now easy to access more or less official medical websites that often describe neurofibromatosis 1 in its worst presentation, patients and their families understandably become anxious about its prognosis, and interpret the cautious attitude of the clinicians as a lack of transparency. On the other hand, correct communication is only possible if physicians are perfectly aware of the characteristics of the disease, and its evolution and prognosis but, with the exception of clinicians working in dedicated diagnostic centres, there seems to be considerable confusion.
The aims of this review are to discuss the current clinical diagnostic criteria and suggest some new aspects that should be considered in patients with suspected neurofibromatosis 1. To this end, we analyse the literature published over the last twenty years, concentrating on the critical phases of the diagnostic process.
Section snippets
Clinical and genetic diagnosis
Table 1 shows the “classical” USA National Institute of Health neurofibromatosis 1 diagnostic criteria. Just a few years after their publication, the gene for neurofibromatosis 1 was cloned on chromosome 17q11.2 [3], thus leading to a better understanding of the disease's underlying pathogenic mechanisms. The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of neurofibromatosis 1 cases arise as a result of spontaneous mutations. However, a number of
Cutaneous signs
The onset of many features of the neurofibromatosis 1 is age dependent. The usual order of the appearance of the clinical signs listed in the USA National Institute of Health criteria is café-au-lait macules, freckling, Lisch nodules, and neurofibromas [8]. It has been observed that about 95% of neurofibromatosis 1 patients meet the current diagnostic criteria by the age of eight years, and all do so by the age of 20 years, which often leads to a late diagnosis and follow-up [8].
The first of the
Extra-cutaneous signs
Among the extra-cutaneous signs of neurofibromatosis 1, only Lisch nodules, optic pathway gliomas and bone anomalies are included in the USA National Institute of Health criteria. Lisch nodules are benign melanocytic hamartomas, that can be detected by means of a slit-lamp. Over 90% of adults affected by neurofibromatosis 1 presents Lisch nodules but it seems that they are often undetectable in early childhood [20], [21]. Consequently, the recently described ophthalmological sign of choroidal
Diagnostic and prognostic crossroads: the healthcare transition challenges
As already emphasized, the onset of many features of neurofibromatosis 1 is age dependent, with about 95% of neurofibromatosis 1 patients meeting the current diagnostic criteria by the age of eight years, and all doing so by the age of 20 years. In adolescent age, the patients that did not develop the typical complications of this condition often give up the periodic medical screening, on the one hand due to the lack of guidelines in national healthcare programmes on how to transition
Conclusions
All of the findings described above would undoubtedly help clinicians make an early diagnosis of neurofibromatosis 1 and decide on the most appropriate follow-up. Table 2 shows the laboratory data and cutaneous and extra-cutaneous signs that we believe should be added to the “classic” diagnostic criteria when evaluating patients with neurofibromatosis 1. The established diagnostic criteria may be very specific, but they are not so sensitive because some of them are not present in infancy, thus
Learning points
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In most cases, the current diagnostic criteria of neurofibromatosis 1 do not allow an early diagnosis.
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Over the last 26 years, medical understanding of neurofibromatosis 1 has naturally improved, and molecular analyses are now available that confirm the diagnosis in about 95% of patients.
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New clinical clues related to neurofibromatosis 1 have been reported, including cutaneous signs (anaemic nevi, juvenile xanthogranulomas, mixed vascular hamartomas and cherry angiomas, hypochromic macules, “soft
Conflict of interests
The authors declare that they have no conflict of interest.
Acknowledgements
This review was supported by a grant from the Italian Ministry of Health (Ricerca Corrente 2014 850/01) to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. The authors thank the Associazione Neurofibromatosi ONLUS (ANF) for supporting this study.
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