Malignant rhabdoid tumors are lethal neoplasms of infancy, which can affect renal and extrarenal locations, including soft tissues and brain [19, 20]. Notably, these tumors also represent the sole manifestation of a heritable cancer predisposition syndrome caused by constitutional alterations of SMARCB1/INI1 tumor suppressor gene [5, 6]. Overall survival in rhabdoid tumor patients is dismal and survival is worst in the setting of infant patients and patients affected by rhabdoid tumor predisposition syndrome . In malignant rhabdoid tumors affecting the brain (called Atypical Teratoid Rhabdoid Tumors – ATRT), similar results are reported and germline mutations are associated with fatal outcome within two-years from diagnosis .
Outcome improvements in ATRT have been reported with the adoption of high-dose, multimodality chemotherapy regimens [13, 21–23]. Indeed, case reports of long-term survival in ATRT have been described [24–26] but, to our knowledge, no case reported so far carried constitutional SMARCB1/INI1 alterations as our infant index case.
We here describe a long-term surviving patient affected by syndromic ATRT and who is alive 7.5 years after the original diagnosis and 2 years after onset of a spinal metastatic lesion. All the analyses performed showed an identical genetic profile between the primary and metastatic ATRT lesions. Although we cannot formally exclude that the two lesions represent the occurrence of two independent primary ATRTs, our genetic analyses as well as the clinical history of the patient, characterized by the presence of metastatic spread since the occurrence of the primary tumor, make this hypothesis very unlikely and support a clonal origin of the two lesions.
ATRT tumor from proband case displayed a biallelic inactivation of SMARCB1/INI1 gene by heterozygous loss of one allele and Arg40X mutation in the exon 2 of the second allele. This mutation, by causing a premature stop codon, is of obvious pathogenic consequence and has already been reported in the spectrum of mutations occurring in malignant rhabdoid tumors . Although to our knowledge this is the first report of Arg40X occurrence in a syndromic ATRT patient, such mutation has been already reported in syndromic extracerebral MRT and has functional consequences overlapping those of other exon 2 mutations previously reported in syndromic ATRT patients, such as Arg53X . These data indicate that Arg40X mutation can occur in both sporadic and syndromic, and in both cerebral and extracerebral MRTs, thus suggesting that no specific genotype-phenotype correlation exists.
The patient under study was affected by mosaicism for Klinefelter syndrome, the most common human sex chromosome disorder, presenting 18% of peripheral blood lymphocytes with chromosome X aneuploidy and this report represents, to our knowledge, the first association of ATRT with Klinefelter. Despite individual case reports emphasized the association between Klinefelter and specific cancers’ risk, reviews of epidemiological data do not support a generalized increased risk of cancer in Klinefelter patients [27, 28], which remains significant only for breast cancer if compared to the general population of males but not of females . In addition, there is no evidence of recurrent X chromosome abnormalities or X-chromosome gene(s) mutation in ATRT tumor samples analyzed by whole-genome approaches [4, 29], so we suggest that the occurrence of ATRT in our patient is unrelated to Klinefelter syndrome. Furthermore, in cancer patients Klinefelter is associated with increased risk of cancer mortality  and, although the risk is variable in different cancer types, Klinefelter did not display a protective effect in any individual tumor type investigated. Therefore, we consider very unlikely the possibility that the constitutional karyotype of the patient may have positively affected the course of ATRT, being responsible for the observed long-term survival.
The patient presents cognitive and developmental delay, as a consequence of Klinefelter syndrome as well as ATRT treatment complications. In this complex scenario, the lack of multiple neuropsychological assessments during the different disease stages impedes to draw any conclusion on the morbidity and cognitive/developmental impact of specific therapies applied.
To conclude, the observed successful local control of disease and achievement of long-term survival in our molecularly-proven ATRT patient even in the setting of rhabdoid tumor predisposition syndrome justifies the efforts to advance the management of this severe condition.