Bernier, Anne, Larbrisseau, Albert, and Perreault, Sebastien. Café-au-lait macules and neurofibromatosis type 1: A systematic review of the literature. Pediatric Neurology. In press.
The first sign of neurofibromatosis type 1 (NF1) in a child is often the presence of multiple café-au-lait macules (CALMs). While previous studies reported that almost all patients with multiple CALMs will eventually develop NF1 based on clinical criteria, recent studies and clinical observations suggest that a significant percentage of them do not have NF1.
We conducted the first systematic review of the literature on the prevalence of definitive NF1 among patients referred for isolated CALMs, searching more precisely for the proportion of those patients who do not have NF1. Since we now know that the presence of CALMs and freckling might not distinguish between NF1 and other conditions like Legius syndrome, definitive NF1 was defined as the presence of café-au-lait macules with or without freckling plus one of the followings: Lisch nodules, neurofibroma, plexiform neurofibroma, bone dysplasia, optic pathway glioma or familial history of NF1.
Six articles reported sufficient data to meet our inclusion criteria. Grouping all studies together, we found that 19.5 % to 57.1 % of all patients with isolated CALMs did not have a diagnosis of NF1 after follow-up or genetic testing.
A significant portion of the patients presenting with isolated CALMs at initial consultation might not have NF1. Genetic testing could help guide the follow-up of those patients, but further evidence is needed to make recommendations.
From the article:
The specific question we ought to answer was: "What is the percentage of the patients with six or more CALMs who will not have definitive NF1"? For the purpose of our study, we defined definitive NF1 as the presence of CALMs with or without freckling (because CALMs and freckling cannot distinguish NF1 from Legius syndrome) and the presence of at least one of the following criteria: Lisch nodules, neurofibroma, plexiform neurofibroma, optic pathway glioma, bone dysplasia, familial history of NF1, or genetic confirmation of NF1...
Grouping all studies together, we found that 19.5 % to 57.1 % of all patients did not have NF1 after follow-up or genetic testing, while 19.5% to 64.9 % had a definitive diagnosis of NF1. Some patients could not be classified as having or not having NF1, since they only had CALMs and freckling after follow-up and therefore could have had NF1, Legius syndrome or another condition. Only a small portion (2.5% to 2.7%) of the patients had Legius syndrome when a genetic testing was done....
To our knowledge, this is the first review addressing the important issue of the prevalence or, more precisely, absence of neurofibromatosis type 1 (NF1) among patients with CALMs with or without freckling, even though it is a common reason for referral in NF1 clinics. In fact, a retrospective study conducted in our institution has shown that up to 65.1 % of all the patients presenting for the first time in our NF1 clinic had isolated CALMs. The fact that a significant portion (19.5 % to 57.1 %) of this population does not have NF1 is an important knowledge for physicians caring for children with NF1. This information could be used to optimize follow-up and medical care, and could be an argument to use genetic testing for this population. Hence, patients with definitive NF1 could be followed according to experts’ recommendations, while patients without NF1 could eventually benefit from a less restrictive follow-up if sufficient studies prove they do not develop other complications of NF1. Genetic counselling to families could also be greatly improved by the knowledge of the true presence or absence of NF1 in a child. Another argument to use more frequently genetic testing in the future is that there is now evidence that some specific NF1 mutations can help predict the phenotype. Therefore, future studies will have to address the usefulness of conducting early genetic testing in patient with isolated CALMs.