A Rare Case of Embryonal Carcinoma in a Patient with Turner Syndrome without Y Chromosomal Material but Mutations in <b><i>KIT</i></b>, <b><i>AKT1</i></b>, and <b><i>ZNF358</i></b> Demonstrated Using Exome Sequencing

Abstract

Gonadoblastoma and malignant transformations thereof can occur in females with Turner syndrome (TS) and Y chromosomal material. However, in females with TS and no Y chromosomal material, this is rarely seen. We report a female with an apparent 45,X karyotype (in blood and tumor) who was diagnosed with a metastatic embryonal carcinoma. Exome sequencing of blood and the tumor was done, and no Y chromosomal material was detected, while predicted deleterious mutations in KIT (likely driver), AKT1, and ZNF358 were identified in the tumor. The patient was treated with chemotherapy (first-line: cisplatin, etoposide, and bleomycin; second-line: paclitaxel and gemcitabine), and after that surgical debulking was performed. She is currently well and without signs of relapse. We conclude that embryonal carcinoma can apparently occur in 45,X TS without signs of Y chromosomal material.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years

“…As discussed previously, Turner syndrome mosaicism with Y chromosome material is associated with a higher risk of gonadoblastoma (or related germ cell tumor), but these tumors can occur in women with Turner syndrome without apparent Y chromosome material (Cools, Looijenga, Wolffenbuttel, & T'Sjoen, ; Gravholt et al, ; Gravholt, Andersen, et al, , section 1.3).…”

Turner Syndrome with Y Chromosome: Spontaneous Thelarche, Menarche, and Risk of Malignancy

“…13 In 2016, the International Turner Syndrome Consensus Group published clinical practice guidelines for TS, recommending that girls with TS + Y undergo gonadectomy at the time of diagnosis, but acknowledged this is on the basis of a low level of evidence and further research is needed. 14 The recommendation for gonadectomy at the time of diagnosis aims to prevent malignancy and is on the basis of an assumption that the gonads have little potential for hormone production or fertility. 2,3 For an individual or family, accurate information about potential future hormone function and fertility is one important factor that might inform if and when to perform gonadectomy.…”

Dysgerminoma with a Somatic Exon 17 KIT Mutation and SHH Pathway Activation in a Girl with Turner Syndrome

“…Previously, Gravholt et al reported a single case of a metastatic embryonal carcinoma in a 40-year-old female with a 45,X chromosomal constitution without signs of the Y chromosome. Remarkably, whole exome sequencing revealed that the tumor harbored a gain-of-function pathogenic variant in exon 13 of the KIT gene (namely c.1965T>A; p.N655K; NM 000222.2) and additional putative somatic pathogenic variants in the AKT1 and ZNF358 genes, as well as a few genomic copy-number variations of uncertain importance [ 26 ]. The patient was successfully treated according to the poor prognosis germ cell tumor group protocol consisting of multimodal chemotherapy and eventual surgical debulking.…”

“…The patient was successfully treated according to the poor prognosis germ cell tumor group protocol consisting of multimodal chemotherapy and eventual surgical debulking. For disease relapse, it seems that the use of imatinib or other tyrosine kinase inhibitors could provide a therapeutic option in tumors with KIT alternations [ 26 , 27 , 28 ].…”