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Detecting Mosaicism Aids Management of NF1, NF2

The authors review the various clinical presentations associated with mosaicism in neurofibromatosis type 1 (NF1) and type 2 (NF2). In mosaicism, an individual resulting from a single fertilization event has two or more genetically distinct cell lines.

In the neurofibromatoses, mosaicism results from a postzygotic NF1 or NF2 gene mutation, so that the embryo has a mixture of normal and mutant cells. As the authors discuss, depending on when the mutation occurs, the mutant cells may be distributed in all tissues, restricted to a region of the body, or confined to the germline. In NF1, mosaicism may occur throughout the body and manifest as standard NF1, although in some cases mosaicism might ameliorate the phenotype severity. Localized mosaicism produces "segmental neurofibromatosis," which may manifest as pigmentary changes (cafe-au-lait macules and skin-fold freckles) alone, neurofibromas alone, or localized occurrences of other NF1 features. Gonadal mosaicism of NF1 has been reported only 3 times in the literature. For NF2, generalized mosaicism may be relatively common and may produce milder disease than nonmosaicism for the same mutation. Localized schwannomas or meningiomas have also been seen in individuals with mosaicism for an NF2 mutation.

Comment: Increasingly, the phenomenon of mosaicism is being recognized as an important component of many genetic disorders. Often, the mosaicism goes undetected because the mutant cell line is either present in small quantities or so widely distributed as to lead to diffuse disease. Mosaicism is particularly identifiable in the neurofibromatoses because many of the features are visible on the skin and the manifestations are typically patchy.

As the reviewers emphasize, mosaicism is important to recognize clinically. Individuals with mosaicism may experience a milder course of disease than might be expected for a given mutation. Individuals with segmental features may receive a misdiagnosis of no neurofibromatosis; this is a problem, because they may be at risk for developing complications or for transmitting the disorder to their offspring. Physicians should be alert to the possibility of mosaicism when diagnosing and managing neurofibromatosis and should realize that this phenomenon occurs in other genetic disorders, such as Duchenne muscular dystrophy.

— BR Korf

Bruce R. Korf, MD, PhD, is Medical Director, Harvard-Partners Center for Genetics and Genomics, Brigham and Women's Hospital and Massachusetts General Hospital, and Associate Professor of Neurology, Harvard Medical School, Boston, MA.

Published in Journal Watch Neurology November 9, 2001

Citation(s):

Ruggieri M and Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 2001 Jun 12 56 1433-1443.

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