Original ArticleAn Unusual Combination of Mirror-Image Dextrocardia with Familial Medulloblastoma: Is There a Histogenetic Relationship?
Introduction
Medulloblastoma is a highly malignant, invasive embryonal neoplasm of the cerebellum. The prevalence of pediatric medulloblastoma ranges between 2.4 and 3.5 cases per million, with an incidence of 1.1–1.5 per million per year.1 It can metastasize throughout the central nervous system, and even to distant organs.2 Current therapy for these patients consists of maximal safe resection, followed by radiation of the entire brain and spinal cord and high-dose chemotherapy based on clinical features such as age at presentation, extent of resection, and the presence of metastases, as well as the histologic type.3 The overall 5-year survival ranges from 42% to 72%.4 Long-term survivors often have intellectual and neurologic disabilities secondary to both tumor invasion and therapy.5
On histopathology, medulloblastoma is a heterogeneous entity consisting of small, round blue cells. According to the 2016 World Health Organization classification, medulloblastoma comprises 5 histologic subtypes classic, desmoplastic/nodular, large-cell, anaplastic, and medulloblastoma with extensive nodularity.6 Medulloblastoma is also categorized into 4 molecular subgroups with different clinical characteristics: wingless-related integration (WNT) site, Sonic Hedgehog (SHH), group 3, and group 4. WNT tumors, showing activated wingless pathway signaling, carry a favorable prognosis under current treatment regimens. SHH tumors show hedgehog pathway activation and have an intermediate prognosis. Group 3 and 4 tumors are molecularly less well characterized and also present the greatest clinical challenges.7, 8
Most cases of medulloblastoma are sporadic. Nevertheless, familial medulloblastoma can occur in several well-characterized tumor syndromes, such as nevoid basal cell carcinoma syndrome, Turcot syndrome type 2, Li-Fraumeni syndrome, and rhabdoid tumor predisposition syndrome.9 However, the incidence of familial medulloblastoma in the absence of these syndromes is low. Here. we report 3 cases of cerebellar medulloblastoma in a Chinese family: 2 cousins were diagnosed based on postoperative pathology and their maternal uncle was diagnosed clinically. None of them had clinical features of a familial tumor syndrome. One of the 2 cousins had mirror-image dextrocardia with situs inversus. We confirmed the histologic and molecular subtypes of the cases available. We then reviewed the previously published cases of familial medulloblastoma. To the best of our knowledge, this is the first report of familial medulloblastoma with histologic and molecular classification, seen in combination with mirror-image dextrocardia and situs inversus in 1 case.
Section snippets
Methods
The 2 cases of medulloblastoma were identified in 2 male cousins. They were diagnosed and treated within weeks of each other. The proband's grandparents provided information on the medical history of the family, including that of the third case of suspected medulloblastoma. Informed consent was obtained from the proband's mother and is representative of the wishes of the entire family in this study.
Results
Three affected individuals in 2 generations were included in this family. They had no evidence of nevoid basal cell carcinoma syndrome, Turcot syndrome type 2, Li-Fraumeni syndrome, or rhabdoid tumor predisposition syndrome. A pedigree of this family is shown in Figure 4. The tumors of these 2 cousins were determined pathologically to be medulloblastoma and the other cerebellar tumor of their uncle was clinically considered to be medulloblastoma. The unaffected individuals of this family had no
Discussion
Since Leavitt11 first reported familial medulloblastoma in 2 identical twin brothers, a few more cases with medulloblastoma in 1 family have been reported. However, familial aggregations of medulloblastoma are extremely rare in patients without hereditary syndromes. Only 14 families with familial medulloblastoma have been reported in the literature.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 Detailed data of these cases are shown in Table 1. Dextrocardia with situs inversus viscerum is
Conclusions
We report 3 cases of cerebellar tumor in a family in the absence of known hereditary syndromes. Two were classified into the same histologic and molecular subtype of medulloblastoma, indicating that they may share the same cause and genetic background. One of these cases also had mirror-image dextrocardia with situs inversus viscerum, suggesting that dysfunction of certain signaling pathways such as Otx2 might play a role in the etiopathology of these 2 conditions.
Acknowledgments
We thank Professor Michael Taylor at The Hospital for Sick Children, University of Toronto, Toronto, Canada to provide nanoString nCounter Technology service to assign molecular subgroups in our samples.
The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit public platform (www.researchdata.org.cn), with the approval RDD number as RDDA2017000359.
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Conflict of interest statement: This work was supported by the National Natural Science Foundation of China (grant number: 81672484).