BWS is a heterogeneous overgrowth syndrome caused by diverse genetic and/or epigenetic disorders, usually affecting the regulation of genes imprinted on chromosome 11p15. BWS was initially reported by Beckwith in 1963 and Hans-Rudolf Wiedemann in 1964, and the syndrome was subsequently named after these two investigators. BWS is equally represented in males and females, with a reported incidence of approximately 1/10,000–13,700 [1]. Among patients with BWS, 85% have no relevant family history and only a few chromosomal abnormalities of 11p15 have been reported [8]. Most patients have good physical and developmental prognoses, but severe complications including prematurity, giant tongue, or cardiomyopathy can lead to fatal outcomes [9]. The most characteristic clinical features of BWS are exomphalos, macroglossia, and gigantism; however, only 56% of patients develop this triad [10], and other clinical features include ear anomalies, neonatal hypoglycemia, unilateral hypertrophy, organomegaly, cardiac anomalies, and musculoskeletal abnormalities. Hemihypertrophy is known to be associated with tumor development (nephroblastoma, adrenal neoplasm, and liver neoplasm), usually on the ipsilateral side [1].

BWS is diagnosed clinically by the presence of at least three major features, or two major and one minor finding [11], while molecular testing may play an important diagnostic role in children with clinical features of BWS who do not meet the diagnostic criteria. BWS is caused by diverse genetic and/or epigenetic disorders that usually affect the regulation of genes imprinted on chromosome 11p15.5. The most common cause is loss of methylation at independent IC2, which occurs in 50%–60% of all cases. Other causes include pUPD of chromosome 11 (pUPD11) in 20%, gain of methylation at imprinting center (IC1) in about 5% of cases, and mutations in the CDKN1C gene in about 5% [8, 12]. BWS is associated with an increased risk of embryonal tumors, such as Wilms tumor and hepatoblastoma, as well as other benign and malignant neoplasms. Hypermethylation of IC1 and pUPD11 result in upregulation of the biallelic expression of IGF2, which has been associated with tumorigenesis in various subtypes of breast tumors [13].

The PubMed database includes six case reports of benign phyllodes tumor and fibroadenoma in patients with BWS (Table 1) [2,3,4,5,6,7]. All patients were female and five patients had hemihypertrophy, of whom four had lesions located at the ipsilateral side of hemihypertrophy. Two patients experienced recurrence [2, 7]. Of these six cases, chromosomal disorders were only reported in two cases [4, 5]. Takama et al. reported pUPD of chromosome 11p15.5 detected by microsatellite marker analysis, with the possibility to increase IGF2 expression, and which has reportedly been associated with fibroadenoma [5]. Cappuccio et al. reported the results of DNA methylation by combined bisulfite restriction analyses [4]. Although methylation levels at IC1 and IC2 were normal, a single nucleotide polymorphism array revealed a de novo 7p22.1 loss in both blood and breast tumor tissue involving the mismatch repair gene PMS2; however, they concluded that the relationship between this molecular defect and the risk of breast tumorigenesis was unclear.

In the current case, immunohistochemical staining of IGF2 in surgical breast tissue revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. IGF2 expression is reportedly more upregulated in breast tumors including fibroadenoma than in non-neoplastic mammary grand tissue [14]. To the best of our knowledge, this is the first report to indicate a relationship between IGF2 overexpression and benign breast tumors in a patient with BWS. Francisco et al. showed that the clinical features of BWS depended on its molecular defects [1]; patients with pUPD11 often present with hemihypertrophy and tumor development, while patients with hypermethylation of IC1 often present with umbilical hernia and macrosomia. The present case demonstrated hemihypertrophy and umbilical hernia, suggesting possible pUPD11 or hypermethylation of IC1. Both of these molecular defects result in overexpression of IGF2, which may be associated with tumorigenesis in various subtypes of breast cancer and may cause juvenile fibrous and lobular breast tumors, as in the current case. Nevertheless, the association between BWS and the risk of breast lesions and the molecular defects responsible for the occurrence of these breast tumors is still unknown.