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Juvenile papillomatosis of the breast associated with neurofibromatosis 1

To the Editor: Recently in this journal Pacilli et al. [1] described juvenile papillomatosis (JP) of the breast in a male with a proposed diagnosis of Noonan syndrome (NS) and café-au-lait spots. We describe here a male with neurofibromatosis 1 (NF1) who was diagnosed with JP at age 9 months. The patient, now aged 3 years, has >50 café-au-lait spots, short stature, macrocephaly, axillary and inguinal freckling, and a cutaneous plexiform neurofibroma, clearly fulfilling the NIH diagnostic criteria for NF1 [2]. He also has a left-sided congenital ptosis. Neurodevelopment is age-appropriate. There is no family history of either NF1 or breast cancer. At age 9 months, the patient presented with a lump in the right breast. The lump was excised and measured 23 23 12mm. The excised lesionwas nodular and the cut surface showed extensivemicrocysts. Histology showedmarked proliferation of the ductal epithelium with a prominent papillary pattern and focally a cribriform pattern (Fig. 1). There was no necrosis or conspicuous nuclear irregularity. The features are those of JP. JP is a benign lesion that typically occurs in young women, including some with a family history of breast cancer [3]. In males, JP is exceedingly rare, having been reported only on eight occasions [1,4–8]. Of these, three occurred prior to 2 years of age and the remainder occurred between ages 11 and 33 years. Although JP has not been reported in association with NF1, it is notable that multiple café-au-lait spots were observed in two of the three boys diagnosed with JP prior to age 2 years [1,7]. At this age, café-au-lait spots are frequently the only manifestation of NF1; however, the majority of young children with multiple café-au-lait spots will ultimately be diagnosed with NF1 [9,10]. In one of these reported cases a diagnosis of NS had been made, based upon the presence of unilateral cryptorchidism, gastroesophageal reflux, long QT interval, and hypertrophic cardiomyopathy [1]. On the basis of the clinical information presented, and the fact that a mutation in the PTPN11 gene [11] was not detected, we think it is more likely that this boy has ‘Neurofibromatosis-Noonan syndrome’ (NFNS), a diagnosis that was also proposed by the authors. NFNS describes individuals exhibiting features of both NF1 and NS; however, at a molecular level, NFNS appears to be a variant of NF1 rather than of NS [12]. The clinical overlap between NF1 and NS is not surprising because their protein products (neurofibromin and SHP-2, respectively) function in the samemolecular pathwaywith important roles in modulating cell proliferation and tumorigenesis [13,14]. We conclude that out of four cases of JP diagnosed in male infants, a diagnosis of NF1 is definite in one and probable in two others. JP of the breast appears to be a rare and previously unreported manifestation of NF1 and features of NF1 should be sought in males presenting with JP of the breast.