The association between NF1 and nevus anemicus (NA) was suggested by Naegeli in 1915,1 but there are hardly any literature reports on the topic until 2013.2–5 NAs are pale irregularly shaped macules whose size varies between a few millimeters and several centimeters; clinically they are not readily detected, and become apparent after mild rubbing of the area (Fig. 1). Lesions can be single or multiple and are located on any area of the body, although they are more frequent on the presternal region.3,5 Although the published series reflect a high prevalence in children, the exact time of onset of the lesions is not known, as parents often have not noticed the presence of NAs until they are detected by a dermatologist in the clinic. In our series, patients with NAs were present in at least 50% of patients with confirmed NF1.5 Possibly, the difference in prevalence in the different studies, which ranges from 8.8% to 51%,3 is a result of the retrospective or prospective study design as these lesions are difficult to diagnose unless sought systematically. To detect such lesions, we routinely ask the parents if they have seen any transient whitish lesions during bathing, fever, crying, or exercise. We then rub the entire presternal area in babies and young children to highlight the lesions. NAs appear to be due to the absence of focal response to the action of catecholamines, and histologically they are indistinguishable from normal skin.

Figure 1.

Presternal nevus anemicus on an 8-year-old patient. The lesion can hardly be discerned before rubbing the area (A). After rubbing, a pale irregular macule can be seen surrounded by an erythematous halo (B).

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Although NAs can appear in healthy individuals, in particular, in proximity to capillary malformations, an association of these lesions and CaLS with other genodermatoses or segmental neurofibromatosis has not been reported. In line with other authors,2–4 we believe that NAs are a distinctive finding in NF1 and that the presence of these lesions is of important predictive value in NF1.5

Juvenile xanthogranulomas (JXGs) are the most common form of Langerhans cell histiocytosis, and a relatively frequent finding in NF1 (Fig. 2).6 The lesions disappear spontaneously after a few years, and it is rare to find them in late childhood and early adulthood.7 Their estimated prevalence in patients with NF1 ranges from 0.7% in adults8 to 37.5% in children,7 and these lesions are particularly common in children aged less than 9 years.4,7 In our series, the prevalence of JXGs in pediatric patients with definite diagnosis of NF1 was 6.2%,5 a figure that approximates the 8.5% reported by other authors.3 In any case, it cannot be denied that JXG is a significant finding in patients with NF1, and it can be of particular importance in cases with no definitive diagnosis. A study found that 8 out of 10 patients with NF1 who only had CaLS at the first visit and who on physical examination had JXGs or NA, subsequently developed the disease,4 and another study found that NF1 was subsequently confirmed in children with JXGs and CaLS.7 Therefore, considering that JXG is the most frequent tumor in NF1, it is probable that the coexistence of CaLS and JXGs in small children should not be considered a casual finding but rather one highly indicative of the disease. Their presence has also been associated with a greater risk of childhood leukemia in patients with NF1, in particular juvenile myelomonocytic leukemia (JMML).9 However, this association is not supported by the findings of other studies, and has been questioned by some authors,10–12 in particular in the dermatology literature. Although there are several case reports of such an association,13–16 a greater incidence of JMML has not been observed in larger series of patients with NF1 who presented with JXGs, including our series.4,5,7 Therefore, the suspicion of JMML in a patient with NF1 who develops JXGs should be directed by clinical symptoms and physical exploration, and not by the mere finding itself.11

Figure 2.

Juvenile xanthogranulomas on the eyebrow tail and the medial angle of the right eye, and nevus anemicus in the left clavicular region in a patient aged 15 months.

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The association of NF1 with glomus tumors was suspected since 1938,17 but it was not until 2009 when this association was definitively confirmed when NF1 mutations on both alleles was demonstrated in glomus cells.18 Glomus tumors are benign vascular lesions that originate in the glomus body, a neuro-myo-arterial structure specialized in the regulation of vascular flow. The lesions are usually located in acral regions, particularly below the nails, and they are characterized by paroxysmal pain on applying pressure and with temperature changes. In patients with NF1, these lesions are usually multiple and recurring.19 They are rare in children, with an estimated prevalence of 5% in adult patients with NF1.20 Although they can appear in healthy individuals, around 30% of patients with glomus tumors have NF1.19,20 From the histological point of view, they are characterized by the presence of fine-walled vessels surrounded by uniform cells with rounded and dark nuclei. Unlike in sporadic cases, these cells do not express neurofibromin in individuals with NF1.19

Pruritus, generalized hyperpigmentation, presence of hypochromic macules, and soft skin are findings that can be readily detected in patients with NF1.

Pruritus affects 20% of patients with NF1 and considerably impacts their quality of life.21 The itching has been attributed to increased mastocytes in the skin, but there do not appear to be any differences in plasma levels of histamine in patients with itching compared to the general population.22 Many patients do, however, have pruritus localized in the neurofibromas, where elevated mastocytes have been detected; administration of ketotifen can suppress the itching.23 We should bear in mind that localized itching can be a warning for the development of medullary tumors or tumors of the central nervous system,24,25 and so it is a relevant symptom in patients with NF1.

Patients with NF1 have diffuse generalized hyperpigmentation that becomes evident on comparing the tone of their skin with that of unaffected family members, and this explains the underlying hyperpigmentation often seen in segmental forms of NF1. Recently, in vitro studies have shown that melanocytes with a mutation in the NF1 gene reproduce this hyperpigmentation, which is attributed to overexpression of microphthalmia-associated transcription factor, tyrosinase, and dopachrome tautomerase, all agents involved in melanogenesis.26

Just as CaLS are observed in tuberous sclerosis, in children with NF1, hypopigmented macules can be found relatively frequently (Fig. 3),27 but to date, there are no studies that have characterized their prevalence, number, and morphology. Finally, skin softness in patients with NF1 is a subjective perception that is also highlighted by some experts in the disease.27

Figure 3.

Hypopigmented lesions in a female patient with NF1.

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ONGs account for 85% of low-grade gliomas (pilocytic astrocytomas) in patients with NF1, and affect between 15% and 30% of children aged between 3 and 5 years.36,37 They are a diagnostic criterion for the disease. Most cases are asymptomatic, but they can cause loss of vision in up to 12% of patients37 or provoke early onset of puberty.35 In view of the high incidence of ONGs, close ophthalmological follow-up is advisable in children with NF1, whether this is clinical or radiological, as clinical detection by physical examination can be difficult and some neuropediatricians prefer conducting complementary tests (Fig. 6).37 The remaining 15% of low-grade gliomas also occur more frequently in the first 10 years of life, and can appear in any part of the brain. They are manifest clinically as headaches, unstable gait, or lethargy.35 By contrast, high-grade gliomas (glioblastoma multiforme) are more often seen in young adults. The risk of such tumors is 5-fold greater in patients with NF1 than in the general population and prognosis is poor.35,38 Treatment for ONG in patients with NF1 is usually conservative, unless a decrease in visual acuity or progression in the size of the tumor in imaging tests is observed. If necessary, first-line treatment is chemotherapy with vincristine and carboplatin. Radiotherapy is not recommended given the high risk of secondary tumors. Surgery is reserved for large orbital tumors in which the patient has no useful vision, when the cornea is exposed, or if there is proptosis.39

Figure 6.

Optic nerve glioma. T1-weighted coronal magnetic resonance imaging. Circumferential thickening of the left optic chiasm is observed (arrow), consistent with optic nerve glioma.

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MPNST (or neurofibrosarcoma) is a type of sarcoma that is thought to be derived from Schwann cells. It accounts for 3% to 10% of all sarcomas and is almost always associated with NF1. The approximate prevalence in patients with NF1 is 0.1% and the cumulative life-long risk is 8% to 13%.35 In NF1, these tumors present in less than 5% of adult patients40,41 and in less than 2% of children.36 The sites at greatest risk are areas with preexisting plexiform neurofibroma, when there is complete deletion of the gene or a history of prior radiotherapy. Factors predictive of the presence of internal (or deep) plexiform neurofibromas have been discussed in another section, but although the majority of MPNST result from malignant transformation of plexiform neurofibromas, they can also appear on subcutaneous neurofibromas and even where there are no prior lesions.36,40,42 The molecular mechanisms of malignant transformation of neurofibromas are not well known, but mutation of the NF1 gene on both alleles in tumors, along with other epigenetic mechanisms, may lead to mutation of other important genes such as p53 and InK4A.41 Warning symptoms include sudden increase in size, change in texture (increased consistency), intense or unremitting pain, and neurological symptoms other than those usually present.40 In these cases, a radiological assessment and biopsy (with surgical resection if appropriate) should be performed immediately as a delay in diagnosis (in direct relation to the tumor size) is directly correlated to prognosis.43 It should be remembered that magnetic resonance imaging offers data on the extent and site, but not on the biological behavior of the tumor. For such information, positron emission tomography with 18-fluorodesoxyglucose is necessary. This imaging technique will also provide information on potential metastases. Fine needle aspiration biopsy is not necessary as the histological sample should provide enough tissue sample for analysis. Radical surgery is the only curative therapeutic procedure, but it is often impossible or too disfiguring. Use of coadjuvant chemotherapy is controversial and not standard practice, except the use of anthralin in patients with metastatic tumors.44,45 Currently, MPNST has poor prognosis for survival.35

It is not clear whether there is a true association between NF1 and melanoma or whether the published cases, which are usually sporadic, are merely anecdotic. In the largest series, which included 11 patients with NF1 and cutaneous melanoma, melanoma was found to occur more frequently in women (in a proportion of 1:10), and young people (median age, 33 years). The mean Breslow depth was 3.2mm, that is, considerably greater than in other series of patients with melanoma without NF1,46 perhaps because other pigmented lesions make detection more difficult. Despite the uncertainty of the association, the relationship between melanoma and the RAS pathways is irrefutable, as not only do 50% of melanomas have BRAF mutations (particularly V600E) and 15% to 20% of these have NRAS mutations (particularly in codon 61) but also many melanomas have NF1 mutations, whether associated or not with the aforementioned mutations.47 The NF1 gene is therefore the third most affected gene in melanoma. NF1 mutations are particularly common in desmoplastic melanomas, where they are detected in 93% of cases, compared with 20% in nondesmoplastic melanomas.48 However, the predictive value for response to treatment with MEK inhibitors of the presence of these mutations is subject to debate.49,50 In addition to melanoma, mutations in the neurofibromin gene have been detected sporadically in other cancers, such as brain tumors, breast cancer, ovarian cancer, and leukemias, and this is a promising line of research.51

Finally, it is important to note that the rate of mortality due to cancer in individuals with NF1 is somewhat higher in individuals under 50 years of age, with this increased rate driven mainly by breast cancer and JMML, but the rates of cancer compared with the general population even out above this age.52 Likewise, although the mean life expectancy is somewhat lower in patients with NF1 than in healthy individuals, the majority of NF1 patients live past 70 years of age.