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Excerpt
A recent letter in this journal by Sasaki et al. (1) reports a case of right adrenal ganglioneuroma in a 6-year-old girl with Turner syndrome (TS), a genetic anomaly characterized by X monosomy. These authors suggest that the positive association between TS and neuroblastoma or other neurogenic tumors could be related to this constitutional chromosome anomaly. They consider that genetic investigation is needed to determine how X chromosome deletion relates to the development of these tumors.
In complete agreement with Sasaki's observation, we would like to add that a constitutional supernumerary X chromosome may also protect against the same tumor. An extensive review of the literature on constitutional chromosomal anomalies associated with a neuroblastic tumor (2) revealed that TS accounted for 12 of the 45 published cases (26%). On the contrary, we could not find a single published case of Klinefelter syndrome (KS), i.e., XXY or triple-X syndrome (TXS), that exhibited a neuroblastic tumor. Furthermore, a computerized search on MEDLINE and Biosis using the key words “Klinefelter syndrome,” “XXY karyotype,” or “triple-X syndrome” and “XXX karyotype” combined with the key words “neuroblastoma,” “ganglioneuroblastoma,” and “ganglioneuroma” was negative. It is clear that patients with KS are more prone to cancers such as leukemias, germ cell tumors, prostate tumors, and breast tumors (3,4); other tumors such as leukemias and gonadal tumors have also been described with TSX (4). This suggests that the lack of peripheral neurogenic tumors may be specifically associated with a supernumerary X chromosome.
Assuming a neutral effect of a constitutional karyotype with a monosomy or a supernumerary X chromosome, one would expect the same frequency of neoplasms in TS, KS, and TSX syndromes. There are 12 published cases of patients with TS (1 of 4,091 live-born girls) (5) with neuroblastic tumors. Therefore, we would expect many more patients with KS (1 of 969 live-born boys) (5) or TXS (1 of 909 live-born girls) (5). However, to our knowledge, such an association has not been reported. This negative finding may be explained by an underreporting of tumors occurring during infancy because the definite genetic diagnoses of KS and TSX are usually made in adolescence and early adulthood. However, this is not likely because many tumors of various types (leukemias, germ cell tumors, carcinomas, and others) are reported in KS. In addition, a rare tumor of early childhood such as retinoblastoma has been reported both in KS and TXS (6). Therefore, we believe that the lack of case reports of neuroblastoma and related tumors in those syndromes is not a chance event, but is related to the genetic background.
According to Plantaz's data (7), a whole X chromosome loss was found by comparative genomic hybridization in 18 of 116 (16%) stage 1, 2, 3, or 4S neuroblastic tumors. These stages are known to be prone to undergo neuronal differentiation and to be associated with a favorable clinical prognosis. By contrast, no complete or even partial X chromosome loss was observed among 83 stage 4 tumors (P = 0.0002). A loss of function of genes located on X chromosome could provide to abnormal proliferative neuroblasts either an advantage over acquisition of malignant phenotype or an ability to undergo differentiation, or, even alternatively, apoptosis. As a matter of fact, and importantly, half (6 of 12) of the tumors in patients with TS were ganglioneuromas, a rare neuroblastic tumor of good prognosis, and were made of fully differentiated ganglionic sympathetic cells. By contrast, this form was exceptional (1 of 33) among the other groups of constitutional karyotype anomalies containing trisomies, balanced translocations, and unbalanced structural abnormalities of autosomes (P = 0.0004).
