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.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
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