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Context: SRY, an architectural transcription factor containing a SOX-related high-mobility group (HMG) box, initiates testis formation in the mammalian bipotential gonadal ridge. Inherited human SRY mutations can be associated with differences in sexual differentiation (DSD) with variable phenotypes in a family. Objective: To describe the clinical, histopathological and molecular features of a novel inherited SRY allele (pMet64Val; consensus box position 9) observed within an extensive pedigree: two 46, XY sisters with primary amenorrhea (16 and 14 years of age; probands P1 and P2), their normal father and brother, and an affected paternal XY grandaunt. Design, Setting, Participants and Outcome Measurements: Following DNA sequencing to identify the SRY mutation, hormonal studies of the probands and histopathological examination of their gonads were performed. Functional consequences of p.Met64Val (and other mutations at this site) were also investigated. Results: Breast development in P1 and P2was Tanner II and IV, respectively. Müllerian structures and gonads resembling ovaries were found in each sister. Histopathology revealed gonadal dysgenesis, gonadoblastoma and dysgerminoma. AMH/MIS, P450 SCC, and P450 aromatase were expressed in gonadoblastoma tissues. Variant p.Met64Val impaired Sox9 transcriptional activation associated with attenuated occupancy of the testis-specific enhancersEnh13 and TESCO. Conclusion: The partial biological activity of p.Met64Val SRY, maintained at the threshold of SRY function, rationalizes opposing paternal and proband phenotypes (the “the father-daughter paradox”).Sex steroids biosynthesis by gonadoblastoma may delay genetic diagnosis and recognition of gonadal tumors. Quantitative assessment of inherited SRY alleles highlights the tenuous transcriptional threshold of developmental decision-making in the bipotential gonadal ridge.

Background: High-Dose chemotherapy is necessary one of the most important tools for improving response rates and for decreasing relapse rate in childhood B-cell malignancies. However, deaths during induction or in Complete Remission (CR) in children with higher disease burden had adversely influenced pEFS in our setting, and for this reason an accomplished clinical support is mandatory for achieving these better results. Objective: Our aim was to diminish morbidity and mortality of patients with B-cell malignancies with the administration of a reduced intensity BFM-based induction phase, plus the addition of rituximab in a pilot study. We also retrospectively analyzed the outcome of this group of patients. Methods: This is a prospective study, single arm, non-randomized local trial for treatment of B-cell malignancies. Between December-2008 and March-2016, 81 pts consecutive ( Patients were stratified according stage and DHL level in Risk-1, Risk-2, Risk-3 and Risk-4. Risk-4 included patients with stage IV and stage III with DHL levels higher than 1,000 U/dl. The pathology, flow-cytometry and cytogenetic findings disclosed 60 cases of Burkitt Lymphoma, 11 diffuse large B cell Lymphomas, 9 mature-B acute lymphoblastic leukemia, and 1 Precursor-B ALL with with t(8;14). The treatment locally-none BFM-counterpart included 4 doses of Rituximab administered to Risk-4 cases during early phases of treatment and intensified chemotherapy with HDMTX (24 hr) 5 g/m2, plus reduced intensity induction with pre-phase followed by A1 block (MTX 1 g/m2 4 hr infusion), in order to decrease morbidity and early mortality rates. Results: Distribution of patient according to risk-groups was: Risk-1 (n=2) 2%, Risk-2 (n=9) 11%, Risk-3: (n=13) 16% and Risk-4 (n=46) 57% of cases. Median DHL= 3,642 (range: 396-33,673) UI/dl, CNS+ cases was observed in 6 cases. Complete remission (CR) was achieved in 95.1% of the cases and 4.9% of patients died in early phases of treatment. From patient who achieve CR, 6 adverse events were observed (all of them in Risk-4 group): 2 relapses and 4 death in CR (1 Steven´s-Johnson Syndrome, 2 tumor lysis syndrome plus CID and 1 patient died after extensive initial surgery) The pEFS for R1, R2, and R3 was 100%. With a median follow-up of 48 (range:6-61) months, the pEFS (SE) for all risks groups was 91 (4)% and for Risk-4 85 (6)%. Conclusions: Risk-4 group accounted for 66% of the total population of patients, defining a more aggressive disease prevalence in our setting. Locally-adapted strategy based on BFM experience was successfully implemented, reducing induction intensity and with the incorporation of 4 doses of Rituximab. The outcome of this group of patients was very good. Reduction of induction intensity and addition of Rituximab resulted in low mortality rate and excellent survival outcome. Disclosures No relevant conflicts of interest to declare.