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Neurofibromatosis type 1, juvenile xanthogranuloma, and leukemia: Wasting a good worry?

DII small banner By Warren R. Heymann, MD
May 22, 2017

neurofibromatosis Type 1
A clinically pigmented neurofibroma associated with underlying café au lait macule.
Credit: JAAD
Worry comes with the territory of Neurofibromatosis Type I (NF-1). It often starts with the anxiety of determining if a child has enough criteria to confirm the diagnosis. According to the National Institutes of Health (NIH) consensus conference, a diagnosis of NF1 in children is established by the presence of at least 2 of 7 clinical criteria: 6 or more café au lait macules larger than 0.5 cm, 2 neurofibromas or 1 plexiform neurofibroma, axillary or inguinal freckling, optic glioma, at least 2 iris Lisch nodules, a characteristic bone lesion (pseudarthrosis or sphenoid dysplasia), or a first-degree relative with NF1. In children under the age of 2, only half display only 1 NIH criterion. In this group, the presence of either a juvenile xanthogranuloma or a nevus anemicus may be helpful in securing the diagnosis (1).

Mutations of NF1 cause inactivation of this tumor suppressor gene, predisposing patients to a variety of tumors arising from the embryonic neural crest, such as optic gliomas, meningiomas, hypothalamic tumors, neurofibrosarcomas, rhabdomyosarcomas, duodenal carcinoids, somatostatinomas, parathyroid adenomas, pheochromocytomas, pilocytic astrocytomas, and malignant peripheral nerve sheath tumors. Additionally, infants and children with NF1 have been considered at a high risk of developing malignant myeloid disorders such as juvenile myelomonocytic leukemia (JMML), as characterized by the case of a boy diagnosed with NF1 with coexisting JXG who developed JMML at the age of 22 months. He also had a glioma of the optical nerve and the optic chiasma. (2)

Paulus et al note that the coincidence of NF1, JXG, and JMML is relatively rare, with approximately 20 reports in the literature. Is this a true association? It is certainly debatable. Just as there are numerous reports in the literature similar to that presented by Paulus et al, there are multiple studies refuting the association. Cambiaghi et al detailed the clinical features and natural history of juvenile xanthogranuloma (JXG) in 14 children affected by NF-1. The onset of JXG was in the first 2 years of life in 13 of the patients. Mean follow-up in 11 of these patients was 4.3 years (range 1-10 years). None of the children developed hematologic malignancies during this period (3). Liy-Wong et al performed a retrospective case-control study comparing children with NF-1 and malignancy with sex- and age-matched control group of children with NF-1 without malignancy. They identified 739 patients with NF-1 over a 20-year period, 14 of whom also had a diagnosis of malignancy. These cases include 9 (64%) boys and 5 (36%) girls. JXGs were found in 4/14 (28.5%) cases and 6/29 (21%) controls. The authors concluded that JXGs do not appear to confer an increased risk for malignancy in children with NF-1. (4)

How should the clinician manage the young patient with NF-1 and JXG? If you are a minimalist, you can heed the advice provided by the commentary by Burgdorf and Zelger, who state: “there is no evidence that routine screening for JMML is of any benefit in patients with NF-1.” (5) The obsessive-compulsive physician may prefer to follow Paulus et al who “highly recommend monitoring the blood count regularly and providing strict clinical follow-up in children with coexisting NF1 and JXG.” (2).

In my opinion, patients with NF-1 need monitoring for several malignancies over the course of their lifetime. If you are seeing a patient with NF-1 and a JXG, acknowledge that there have been rare reports of JMML, explaining that this association may be tenuous. This information, presented to parents in a realistic way, is far better that having them discover it on the web. Get a CBC. Chances are it will be perfectly normal. The parents will be relieved. My wonderful mother-in-law Jean loves to quote the Peanuts cartoon accompanying this commentary. All they would have done is wasted a good worry.

1. Ferrari F, et al. Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type I. JAMA Dermatol 2014; 150: 42-6.
2. Paulus S, et al. Association between juvenile myelomonocytic leukemia, juvenile xanthogranulomas and neurofibromatosis type 1: Case report and review of the literature. Pediatr Dermatol 2017; 34: 114-8.
3. Cambiaghi S, et al. Juvenile xanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic malignancies. Pediatr Dermatol 2004; 21: 97-101.
4. Liy-Wong C, et al. The relationship between neurofibromatosis type 1, juvenile xanthogranuloma, and malignancy. J Am Acad Dermatol 2017; 76: 1084-7.
5. Burgdorf WHC, Zelger B. JXG, NF1, and JMML: Alphabet soup or a clinical issue? Pediatr Dermatol 2004; 21: 174-6.

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