Abstract
Neurofibromatosis type 1 and type 2 both occur in mosaic forms. Mosaicism results from somatic mutations. Early somatic mutations cause generalized disease, clinically indistinguishable from nonmosaic forms. Later somatic mutation gives rise to localized disease often described as segmental. In individuals with mosaic or localized manifestations of neurofibromatosis type 1 (segmental neurofibromatosis type 1), disease features are limited to the affected area, which varies from a narrow strip to one quadrant and occasionally to one half of the body. Distribution is usually unilateral but can be bilateral, either in a symmetric or asymmetrical arrangement. Patients with localized neurofibromatosis type 2 have disease-related tumors localized to one part of the nervous system; for example a unilateral vestibular schwannoma with ipsilateral meningiomas or multiple schwannomas in one part of the peripheral nervous system. The recognition of mosaic phenotypes is important. Individuals with the mosaic form, even with a generalized phenotype, are less likely to have severe disease. They also have lower offspring recurrence risk than individuals with the nonmosaic form. The mosaic forms of neurofibromatosis provide a good example of the effects of somatic mutation. It is increasingly recognized that mild and unusual forms of many dominantly inherited disorders are caused by the same mechanism.
In this article we review the current concepts of mosaicism and localized phenotypes in dominant single-gene disorders, using the neurofibromatoses as an example. The relevant literature and our own clinical experience are summarized.
The neurofibromatoses.
There are two main forms of neurofibromatosis: type 1 (NF1) and type 2 (NF2).1,2⇓ Both are autosomal dominant disorders in which approximately half the patients are the first affected persons in their families. The genes for both forms have been cloned.3,4⇓ Mutation analysis is not straightforward because of the large size of the genes and lack of mutation hot spots. In clinical practice, diagnosis is made using internationally agreed diagnostic criteria.1
NF1.
NF1 is the most common form of neurofibromatosis, with an estimated birth incidence of 1/2,500 and a disease prevalence of approximately 1/4,500.5,6⇓ The clinical features are usefully divided into three groups.5,7⇓
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1. Major features (present in the vast majority of affected individuals and forming the basis of the diagnostic criteria, other than complications very specific for NF1). These include café-au-lait spots (six or more), freckling in specific places, peripheral neurofibromas, and iris Lisch nodules.1
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2. Minor disease features (present in a significant proportion of patients but not sufficient to be used as diagnostic criteria; their documentation may be a helpful aid in predicting the diagnosis of NF1 in years to come). These include macrocephaly, short stature, hypertelorism, and thorax abnormalities (eg, pectus excavatum).6,7⇓
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3. Complications (any condition occurring at an increased frequency in individuals with NF1 compared with the general population). These include learning difficulties; plexiform neurofibromas; neurologic, orthopedic and ophthalmologic complications; and an increased risk of specific malignancies.2,5⇓
NF2 and related conditions.
NF2 is much less common than NF1, with an estimated birth incidence of approximately 1 in 33,000 and a symptomatic prevalence of 1 in 210,000.8 Affected individuals develop vestibular schwannomas, other tumors of the CNS (meningiomas, ependymomas, and astrocytomas), and schwannomas of the peripheral nervous system. Many patients have associated eye changes, particularly asymptomatic posterior lens opacities. The clinical overlap with NF1 lies in the similar appearance of some of the peripheral nerve tumors and the fact that café-au-lait spots, but not skin fold freckling, are also seen, although in much smaller numbers than in NF1. Until the 1980s, the distinct nature of the two conditions was not widely recognized. Even today, children with the severe form of NF2 may initially present with skin stigmata that provoke consideration of a diagnosis of NF1. The finding of distinctive NF2 skin plaques in these children leads to a request for appropriate neuroimaging and a correct diagnosis.9,10⇓
Two clinically overlapping phenotypes that appear to be distinct genetically from NF2 are autosomal dominant inherited multiple meningiomas (or meningiomatosis)11 and sporadic and autosomal dominant schwannomatosis.12-14⇓⇓ The relative frequency of these conditions was recently reported in a Finish population study.15
Mosaicism./TITLE>
Mosaicism describes the situation in which an individual who arose from a single genetically homogeneous zygote has more than one genetically distinct cell-line.16,17⇓ Mosaicism is caused in females through the process of X inactivation (Lyonization)16,17⇓ and in both sexes through mutational errors arising during somatic or germ cell division.16,18⇓ In the present paper, we examine mosaicism in dominant single-gene disorders using neurofibromatosis as an example. In this context, the term is used to describe a person with a mixture of cells, some of which have normal copies of the gene and others, an abnormal copy.
Somatic mutation occurs due to miscopying events during cell division with clonal expansion of the mutated viable cells. Major errors at mitosis, such as nondisjunction, cause chromosomal mosaicism. Mitotic error at the DNA copying level can give rise to mutation in single human disease genes. The clinical effect of somatic mosaicism arising through mutation depends on when and in what cell type the change occurs.16,17⇓ If a mutation occurs very early in a growing and developing embryo (before tissue differentiation) the clinical phenotype will be generalized. Mutations occurring in a late-stage differentiated cell give rise to a phenotype confined to a single region or organ.
The majority of mosaics arise by gene mutation occurring in a genetically normal population. The term revertant mosaicism is used to describe the situation in which a gene mutation reverts to normal and gives rise to a clone of normal cells in an individual with a genetic abnormality.17,19⇓
The clinical recognition of mosaicism.
The clinical phenotype reflects the timing of and tissues involved in the somatic mutation. We find it useful to reflect this by dividing patients into three groups.
Mild generalized disease.
Individuals with mild generalized disease cannot be reliably distinguished clinically from patients with an inherited mutation. Clinical awareness of their existence is important because of issues related to genetic counseling that we explore fully in the section on NF2.
Localized or segmental disease.
The disease in individuals with localized or segmental disease is caused by a later somatic mutation.17,20,21⇓⇓ The clinical effect of the disease depends on the timing of the mutation (early versus late embryonic development) and the embryonic cell line(s) affected by the mutation. Patients with some forms of localized disease have been reported to have children with the full-blown disorder, indicating gonadal involvement; such patients are referred to as gonosomalmosaics.16-18⇓⇓ Segmental or localized disease has been most studied in dermatologic conditions as they are most easily recognized clinically.17,20,22,23⇓⇓⇓
Mosaic phenomena have been reported in other body organs.24 For example, carriers of X-linked ocular albinism are asymptomatic but may exhibit mottled or streaky areas of hypopigmentation in the periphery of the retina or radial translucencies of the iris.24 Carriers of X-linked cataract may have segmental lens opacities. Similar phenomenon are also seen in X-linked diseases affecting teeth and bone.24 The advent of body imaging allows us to observe mosaicism in relation to internal organs: for example, localized development of schwannomas and meningiomas in mosaic NF2 and partial symmetric streak myelinization defects on MRI of females with incontinentia pigmenti.8,24⇓
Mosaicism in the neurofibromatoses.
In both NF1 and NF2 approximately half the patients seen are the first affected person in their families.5,6⇓ Although many of these patients with sporadic disease have a clinical phenotype indistinguishable from that seen in familial cases, there is increasing evidence that a small but significant proportion of these cases arise through somatic mutation of the NF1 or NF2 genes. On the other hand, pure gonadal mosaicism is rare.26
Mosaicism in NF1.
Mosaicism presenting as generalized disease.
The NF1 gene has one of the highest new mutation rates in humans.3 The majority of these mutations are of paternal origin, without a significant paternal age effect.27 This led to speculation that a significant proportion of patients with NF1 who are apparent new mutations would be somatic mosaics.28 The high mutation rate was explained by the fact that there was a high frequency of both somatic and germ-line mutation.
Somatic mosaicism for the NF1 gene in patients with sporadic generalized NF1 has been demonstrated in five published cases.29-33⇓⇓⇓⇓ In all five the mutation was a large gene deletion: three patients had whole gene deletions demonstrated by fluorescent in situ hybridization29-31⇓⇓ and two were analyzed with DNA markers only (in one patient the deletion extended from at least exon 4 to intron 3932 and in the other from at least exon 5 to intron 4133). It seems unlikely that all patients with somatic mosaicism will have large gene deletions. The reported cases probably reflect the fact that whole gene deletions are much easier to detect. In a recent study two possible cases of somatic mosaicism with other types of NF1 mutation were reported.34 The genomic DNA direct sequencing chromatograms of two patients suggested that the mutant and wild-type sequence were not present in equal amounts.
Two of the three reported patients who were mosaic for whole NF1 gene deletions were ascertained through severely affected children. The parental phenotype was noted to be significantly milder. The third patient was a child who was reported not to have the dysmorphic features usually seen in nonmosaic cases with whole gene deletions. Of the other two patients, in one the disease severity was not specifically commented on and in the other, the slightly unusual feature was that the neurofibromas had not developed until the relatively late age of 26 years.
Clinical family studies show that few sporadic cases can be somatic mutants or other mosaics in which the gonad is spared.35 The studies found no evidence that patients with sporadic disease were more mildly affected than those with familial disease, or of abnormal disease segregation in children of patients with sporadic disease. Only one study has reported mutation detection rates in patients with familial and sporadic NF1.34 Mutations were found in 29/29 patients with familial but only 35/38 patients with sporadic disease, so it is difficult to know if this is a significant difference. This is in contrast to NF2, in which, as we will see, there is both clinical and molecular evidence that somatic mosaicism is not an uncommon cause of sporadic disease and that this has implications for genetic counseling.36 The fact that later somatic mutation of the NF1 gene, presenting as localized or segmental disease, is not uncommon suggests that somatic mutation can occur at all stages of embryogenesis. One possibility for the lack of evidence of somatic mosaicism in generalized disease is that patients with very mild generalized disease, who do not have affected children, may never come to medical attention. In patients with NF2 however, tumor-related symptoms are likely to lead to diagnosis even in the mildest cases.
Mosaic localized (segmental) NF1.
This condition is under-diagnosed, as it occurs with a clinical picture that, due to absence of symptoms and complications in most affected patients, can be ignored by the patient (who assumes it is an odd birthmark or a harmless nodule) and passes unnoticed by the physician.
Classification.
The first case of segmental NF1 was reported in 1931.37 Somatic mosaicism of the NF1 gene as the likely cause was suggested in 1952.38 In 1977 the term segmental neurofibromatosis was proposed and has become widely used.39 In the first classification of neurofibromatosis into seven different types, segmental neurofibromatosis was classified as NF type 540 and defined as the “occurrence of café-au-lait spots (and/or freckling) and accompanying neurofibroma(s) restricted to a single side of the body, with no crossing of the midline.” In 1987 it was reported that even within segmental neurofibromatosis, different clinical subtypes were emerging41 and not all cases were unilateral.
These subdivisions were based on clinical observation but in retrospect reflect the timing of the mutational event.40,41⇓ A further classification was proposed in 1994 to reflect the “somatic mutation hypothesis.”42 It was concluded that the clinical picture is determined by 1) the timing of the mutation (early versus late embryonic development) and 2) the source of tissue affected by the mutation. Taken to its extreme, the somatic mutation hypothesis means that the reported patients with generalized NF1 who are mosaic at the molecular level represent mutations occurring very early in embryonic development, the extreme of which would be mutation in the zygote. At the other end of the spectrum, in individuals with isolated café-au-lait spots or neurofibromas and no other disease features, the lesions represent somatic mutation in terminally differentiated cells.
With the recognition of mosaicism in NF243 it has become important to specify the type of mosaic NF. In 1997, the term mosaic NF1 was suggested to reflect the probable disease pathogenesis and to enable the inclusion of patients who had mild generalized NF1 clinically but who were mosaic at the molecular level.1 We prefer to use the terms mosaic generalized NF1 and mosaic localized NF1, because the health implications and recurrence risks to offspring in the former group are likely to be more significant.
Epidemiology.
Mosaic localized NF1 has a prevalence in our regions (Oxford, UK, and Catania, Italy) of 1 in 36,000 to 40,000 individuals in the general population, or 0.002%.44 Other authors have estimated its frequency as 0.0014%45 and 0.0018%.46
Clinical features.
We have clinically assessed 124 patients with mosaic localized NF1. The mean age was 17.4 years (range, 4 to 70); 66 were male and 58 female. The majority of patients were asymptomatic. They sought medical opinion because of the unusual appearance of the affected area. The exception to this are patients with spinal neurofibromas or lesions on major peripheral nerves (figure 1) who present most commonly with pain or neurologic deficit. It is this group of patients who are most often seen by neurologists.
Figure 1. Patient with mosaic localized neurofibromatosis type 1, with nodular neurofibromas alone. Coronal T2-weighted (relaxation time, 2080 msec; echo time, 180 msec) MRI of the pelvis shows multiple nodular neurofibromas involving the left lumbar plexus in the buttock region. This 34-year-old man had had pain and paraesthesia for 6 months prior to MRI scan. There was no cutaneous involvement.
Area of involvement.
The area of involvement is variable (figure 2, A and B). In the majority of patients it is unilateral. The affected area varies from a narrow strip (see figure 2B) to one quadrant (see figures 2A, 3, 4A, and 5) and, occasionally, one half of the body. Some patients may have more than one segment involved on both sides of the midline, either in a symmetric (figure 6, B and C) or asymmetric arrangement (figures 5 and 6⇓A), thus reflecting the patterns of skin mosaicism proposed by Happle.20,23⇓ In patients with pigmentary involvement, the borders appear to follow the lines of Blaschko in most cases. In patients with neurofibromas alone, the lesions are usually dermatomal or involve a major peripheral nerve or nerve plexus.
Figure 2. Patients with mosaic localized neurofibromatosis type 1 with variation in area of involvement. (A) A 12-year-old boy shows a segment of café-au-lait macules and freckling in his left trunk and arm as his only clinical features. Note the sharp midline cut-off, the darker background, and the more intense freckling in the involved area. (B) Cutaneous neurofibromas in a dermatomal distribution in an otherwise healthy 40-year-old man.
Figure 3. Natural history of development of pigmentary changes in a patient with mosaic localized neurofibromatosis type 1. (A) The right lower quadrant of the abdomen and right thigh shows a hyperpigmented background area with a sharp midline cut-off easily seen above the horizontal plane passing through the umbilicus in this 2-year-old boy. Within this area are three café-au-lait spots and early freckling in the right groin. (B) Same patient at age 8 years. Note the increase in number of café-au-lait spots and the appearance of freckling.
Figure 4. Patients with mosaic localized neurofibromatosis type 1 showing pigmentary changes only. (A) Segment of café-au-lait spots and freckles localized to the trunk in an 8-year-old boy. The dark pigmented nevus in the lower part of the trunk is a coincidental lesion. (B) Close up of the involved area in the patient shown in figure 2A.
Disease features.
Any division of patients with mosaicism on clinical grounds is to some extent arbitrary. We present our patients in four groups. Three groups are categorized according to the presence or absence of pigmentary changes or neurofibromas, or both (table 1), whereas the fourth are patients with isolated plexiform neurofibromas only. The clinical significance of this categorization is that the groups tend to present at different ages and to different specialists. The disease features develop at the same time as in generalized NF1: pigmentary features and plexiform neurofibromas in childhood and neurofibromas in adulthood. What is different is that not all patients with pigmentary changes develop neurofibromas in the affected area as adults. This presumably reflects the cell lineage in which the mutation took place.
Clinical features of 116 individuals with mosaic localized (segmental) neurofibromatosis type 1
In other mosaic dermatologic phenotypes, attention has been drawn to the fact that the disease manifestation may be more florid in an affected area. We observed this in many of our patients. It has been proposed that this may reflect areas in which the second copy of the gene has mutated.47
Pigmentary changes alone.
In patients with pigmentary changes alone, medical opinion is usually sought because of the appearance of café-au-lait spots in the first year or two of life (figure 3, A and B). They are often noticed after the child’s first significant sun exposure. Some of these patients are initially diagnosed with generalized NF1, depending on the number of macules and the proportion of skin involved. Others patients who have very limited areas of involvement may initially be regarded as a variation of normal and only return for reassessment after the appearance of more café-au-lait spots or freckles in the affected area. A number of patients are initially misdiagnosed as having other dermatological entities; for example, speckled lentiginous segmental eruption, zosteriform freckling, or nevus spillus-like lesions.48 In our opinion, the majority of reported patients with these conditions have mosaic localized NF1.
Figure 5. Patient with mosaic localized neurofibromatosis type 1 (NF1), with neurofibromas alone. Cutaneous and nodular neurofibromas circumscribed to the left arm in a 70-year-old man who transmitted mosaic localized NF1 to his daughter (see text). The cutaneous neurofibromas first appeared at around age 35 and progressively increased in number. There was also an area involved in the left groin and over the left upper shoulder.
The natural history of mosaic localized NF1 is similar to generalized NF1. The café-au-lait spots develop first (figure 3A), then the freckling (figure 3B). If freckling is present it is often very intense and develops in parts of the body not usually associated with dense freckling in the generalized disease (figure 2A and figure 4A). Some of the children we have seen may develop neurofibromas as adults. However, 16 of our patients were older than 18 years, and in nonmosaic generalized NF1 one would have expected them to have already developed at least some dermal neurofibromas. All patients with specific NF1 complications were in this group (see table 1).
Figure 6. Patients with mosaic localized neurofibromatosis type 1 (NF1) showing a combination of pigmentary lesions and cutaneous neurofibromas. (A) A 47-year-old woman with pigmentary lesions and neurofibromas in several areas (the lumbar area bilaterally, the right flank, shoulder, and neck, and the anterior aspect of the upper chest bilaterally). This patient had been diagnosed as having full-blown NF1. Anterior (B) and posterior (C) views of the lower trunk in a 45-year-old woman who had all her NF1 lesions (café-au-lait spots, freckling, cutaneous and nodular neurofibromas) confined to the buttocks. Note the hyperpigmented background with a sharp cut-off.
One of the most striking features seen in 83 of our 86 patients was that the area of skin involved had a darker background. This effect is well illustrated by figure 3A. The darker background is a useful diagnostic sign. Sometimes it only becomes apparent on examination with an ultraviolet light. The café-au-lait spots and freckles are all within this background pigmented area (figure 3, A and B and figure 4, A and B). In some of our patients, referring physicians have described these areas as huge café-au-lait spots. We interpret the background pigmentation as suggesting that even in the heterozygous state the NF1 gene has an effect on skin color.
Because of our interest in mosaic NF1, a number of patients who have segments of evenly pigmented skin but no other abnormality are referred to us. The differential diagnosis then becomes much wider and includes disorders such as McCune–Albright syndrome.48 When referred patients who have just a segment of pigmented skin in the first year of life it is our practice to follow-up the children, because the differential diagnosis includes a number of neurocutaneous disorders with long-term developmental or neurologic implications.48 By observing them we also pick up the patients who are going to go on to develop café-au-lait spots or freckling within this area. However, once the children have reached the age of 5 years, if this is the only finding and they are developmentally normal with no other problems, then we are reassured about the health implications of these areas. Genetic counseling is more complex for such patients, as these areas may simply reflect NF1 mosaicism without café-au-lait spots or freckles, or somatic mosaicism of another pigmentary gene.
Neurofibromas alone.
Neurofibroma as the sole manifestation in mosaic localized NF1 is the form most frequently reported in the literature (84/150 patients; 56%).44 Our excess of children with a pigmentary phenotype reflects ascertainment bias, because one of us is a pediatric neurologist.
The appearance of the individual neurofibromas is exactly the same as when they occur in the generalized disease (see figure 2B). In our description of neurofibromas we use the term cutaneous for the common dermal neurofibroma.5 These lie within the dermis and epidermis, and move passively with the skin. The majority are discrete nodules and have a characteristic violaceous color (see figures 2B and 5⇑). They vary in size from 0.1 cm to several centimeters in diameter. Some become papillomatous when they grow. These lesions may itch and worry the patient cosmetically, but hardly ever cause other symptoms. The term nodular neurofibroma is used to describe tumors on major peripheral nerve trunks5 (see figure 1).
It is patients with localized nodular neurofibromas who most frequently present to a neurologist. The presentation varies depending on which nerve is involved. Neurofibromas on relatively superficial nerves present as subcutaneous nodules (see figure 5) that are often only painful when touched. Those on deeper nerves (see figure 1) usually present with pain only, with the lesions identified on scan. Histologically, the neurofibromas from the affected areas are usually plexiform neurofibromas. Some neurofibromatosis experts may regard these patients as having a form of plexiform neurofibroma. This is because the nerve between lesions is abnormal. Patients with nodular neurofibromas have severe recurrent tumor associated problems and are at risk of malignant change.49
Neurofibromas and pigmentary changes.
Patients may have both disease features in a circumscribed area (see figure 6, A through C), often in association with a darker background area in the affected part of the body (see figure 6,B and C). These patients are frequently diagnosed as having full-blown NF1, especially if the areas involved are multiple or widely distributed (see figure 6A). Recognition of these patients is not just of academic interest, because they have a much lower risk of disease complications and offspring involvement.
Solitary plexiform neurofibromas.
Eight of our 124 patients had only plexiform neurofibromas. Their mean age was 24.3 years (range, 8 to 61). Seven of these patients had head or neck lesions, and in one the PNF was localized to the shoulder. None had affected children. We included these patients because their lesions presumably arose by mosaicism of NF1 or a related gene. The appearance and natural history of these lesions is the same as when they occur as a complication in generalized NF1 (figure 7).
Figure 7. Patient with mosaic localized neurofibromatosis type 1 with isolated plexiform neurofibroma. A solitary plexiform diffuse neurofibroma is seen on the left temporal area of the scalp.
Other NF1 features in mosaic localized disease.
Lisch nodules are rarely seen (see table 1).44 One study reported a higher prevalence of short stature and macrocephaly,50 but we did not find this (see table 1). One patient in whom the involved left upper quadrant was smaller than the right side was recently reported. The authors speculated that the mild hypoplasia might be related to the regional affect of the NF1 gene mutation because body height is often reduced in generalized NF1.51 One of our patients showed a similar phenomenon.
Seven of our 124 patients (5.6%) had specific NF1 complications. They included learning difficulties, plexiform neurofibromas, optic pathway gliomas, and pseudarthrosis (see table 1). The area of cutaneous involvement was more extensive in those with learning difficulties. The complications did not always arise in the segment of skin involvement. One patient with pseudarthrosis of the left tibia and fibula had freckles and café-au-lait spots in a segment extending from the right armpit across the upper chest.
Genetic basis.
All authors reporting cases of localized NF1 have agreed they reflect somatic mosaicism,38 but this has only recently been proven at the molecular level.51 A patient with freckles and café-au-lait spots localized to the left upper trunk and forearm was shown to have a whole gene deletion by FISH analysis in a percentage of fibroblasts from a café-au-lait spot in the affected skin but not from unaffected skin or blood lymphocytes. The importance of further analysis of mosaic phenotypes is that it may provide further insight into which cell types are critical for particular disease features. Molecular studies in our own patients are just beginning.
The majority of reported patients with mosaic localized NF1 have no affected relatives with the disease. There are a handful of reported instances in which parents with localized NF1 had had children with full-blown disease (reviewed in references 44 and 52); it is assumed these patients are gonosomal mosaics, with involvement of both somatic and gonadal tissue.52 Five of our patients were ascertained through children with NF1; four had a diagnostic combination of café-au-lait spots and freckling and the fifth had a unilateral segment of hyperpigmented skin extending from midline posteriorly to midline anteriorly. It is important to note that in these patients the affected area can be anywhere, ie, does not necessarily overlie the gonads.
More difficult to explain pathogenically are the cases of vertical transmission of localized NF1.53,54⇓ In the two reported families a father with localized neurofibromas had a daughter with a localized disease. We have seen three further families with vertical transmission of localized NF1 in our centers44 (figure 4). The occurrence of mosaic localized NF1 in successive generations is difficult to explain on the basis of gonosomal mosaicism. Various possibilities exist: perhaps the NF1 gene in these families has variable expression within the same individual analogous to positional-effect variegation.55 Alternatively, perhaps an inherited premutation became a full mutation only in certain body areas or there was a partial correction of a germ-line mutation in the offspring after somatic mutation in the parent, as seen in revertant mosaicism.19 Mutation analysis in these families is ongoing.
Management and genetic counseling.
There is no management specific for mosaic localized NF1. Patients need to be advised they do not have generalized NF1 and are at a low risk of developing any disease-associated complications. Those considering children need to be aware of the small risk of having a child with generalized NF1. The exact risk is not definable but, based on animal work, is proportional to the percentage of body area involved.56 It is important to note that risk does not depend on the affected area of skin overlying the gonads. Conversely, when a patient with apparently isolated NF1 presents, it is important to examine the skin and eyes of the parents.
Gonadal mosaicism in NF1.
There are only three examples of gonadal mosaicism in the literature.5,26⇓ In one, mosaicism was confirmed by mutation analysis.26 When a child is newly diagnosed with NF1, we do full cutaneous and slit-lamp examination in the parents. If these are normal, a very low recurrence rate for the parents’ future offspring can be expected (much less than 1%).
Mosaicism in NF2.
Mosaicism presenting as generalized disease.
Recent molecular genetic studies of patients with NF2 has drawn attention to the importance of this phenomenon. The first case was reported in 1993.57 The same mutation was identified in two unrelated individuals with NF2, one with the severe and the other with the mild NF2 phenotype. Analysis of different tissues from the mildly affected individual demonstrated somatic mosaicism. An additional family was reported58 in which the affected parent was found to be a somatic mosaic when clinical and linkage data gave conflicting results for her children. Some studies36,59⇓ have looked at the frequency of somatic mosaicism in large series of NF2 patients who fulfilled the revised NIH diagnostic criteria.1 Both groups concluded that a significant proportion of patients with sporadic disease are somatic mosaics—an estimated 15% based on UK data.36
These findings have important clinical implications. NF2 is thought to show a fairly consistent phenotype within a family. Caution must now be expressed when counseling mildly affected patients with sporadic disease. In patients with mosaicism, the risk to offspring may not be as high as 50%: in the UK study, only 1/9 children of three patients with mosaic disease inherited the condition.36 As with all cases of mosaicism however, it is impossible to define an exact recurrence risk for patients with somatic NF2 mosaicism. Finally, the finding of somatic mosaicism should also influence our requests for molecular genetic testing in families with NF2. It is unwise to rely purely on linkage analysis for prediction in the children of a sporadic index patient in whom no mutation was identified.58 Other reports have identified mutations in significantly fewer patients with sporadic than familial disease.36,59⇓ Therefore, if one requests mutation testing and two generations of a family are available, affected children should be initially analyzed.
Mosaic localized (segmental) NF2.
Until the advent of CT and MRI imaging it was almost impossible to identify patients with mosaic localized NF2. Cases have only been reported in the literature since 1992.8 Just as in localized NF1, these patients are recognized clinically by disease localized to one part of the nervous system.
Epidemiology.
No reports on the frequency of the mosaic localized NF2 phenotype have been published. The experience of the Oxford NF2 clinic is summarized in table 2. The data are derived from the patients seen during the first 5 years of operation of the clinic (1995 to 1999), who were still alive at the time of writing and living in the Oxford region (population 2.9 million).
Frequency of neurofibromatosis type 2 and related phenotypes in the Oxford clinic population
Clinical presentation.
The most obvious cases of mosaic localized NF2 are those with unilateral acoustic neuromas and ipsilateral meningiomas (figure 8, A through C;table 2). Other presentations include multiple schwannomas localized to one part of the peripheral nervous system (e.g., peripheral nerve or nerve plexus in a single extremity or unilateral involvement of spinal nerve roots). Our own studies are based on clinical observation only, but other authors have confirmed somatic mosaicism for the NF2 gene in some of their patients.12,60⇓
Figure 8. Patient with mosaic localized neurofibromatosis type 2. Axial T2-weighted (relaxation time, 2,080 msec; echo time, 180 msec) MRI of the brain shows multiple right-sided meningiomas (left and center) and ipsilateral vestibular schwannoma (right) in a patient who presented with decreased hearing in the right ear at age 44 years.
Management and genetic counseling.
As in the case of mosaic localized NF1, there is no specific management for mosaic localized NF2. Patients need to be advised that they do not have generalized NF2 and therefore the disease burden may not be as severe. We conclude that someone has localized NF2 only after a full clinical assessment, including cutaneous and ophthalmologic examination and full CNS imaging. We request NF2 mutation analysis on lymphocyte DNA (but this has been uniformly negative to date) and offer clinical assessment and CNS imaging to at-risk children, as we would for patients with generalized NF2. When such patients have tumors removed, molecular genetic analysis of the tumors can lead to identification of a mutation that could subsequently be used for presymptomatic diagnosis in the children (providing the same mutation has been identified in two or more tumors).
Mosaic localized (segmental) schwannomatosis and meningiomatosis.
Several of our patients might provide examples of mosaic localized schwannomatosis or meningiomatosis. However, it is equally probable that they are mosaic for the mutations in NF2 gene at the molecular level, as demonstrated in other series of patients with localized schwannomatosis.60 The underlying pathogenesis does not alter clinical management of the patient, which is dictated by monitoring the tumors in the affected area. For genetic counseling purposes we follow the same protocol described for patients with localized NF2.
Gonadal mosaicism in NF2.
There has only been one report of possible gonadal mosaicism in NF2.61 The parents of two affected boys were asymptomatic and no lesions were found on full-brain and spinal MRI. In the clinical setting, by the time a child presents with NF2 the parents have often completed their family and so recurrence risks are much less of an issue than in patients with NF1. If more children are planned, we would fully evaluate the parents (cutaneous and ophthalmologic examination, head and spine MRI). If these are normal, the recurrence risk is very low (<1%).
Acknowledgments
Acknowledgment
The authors thank Dr. J. Byrne for figure 8 and Jenny Wright for her secretarial assistance.
- Received May 30, 2000.
- Accepted February 15, 2001.
References
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