Elisa Vaiani

Background/Objective: DICER1 ‐related tumor predisposition is a rare hereditary tumor predisposition disorder characterized by autosomal dominant inheritance, reduced penetrance, and variable expressivity. This study is aimed at describing the clinical and molecular spectrum of DICER1 ‐related tumor predisposition in an Argentine pediatric cohort. Design and Methods: Seventeen unrelated patients with DICER1 ‐related tumor predisposition and 54 relatives were evaluated at “Prof. Dr. J. P. Garrahan” Pediatric Hospital (Buenos Aires, Argentina) between 2014 and 2024. Germline and somatic DICER1 variants were analyzed using Sanger or next‐generation sequencing. Functional assays were performed for selected intronic variants. Three samples of poorly differentiated thyroid carcinoma were also included. Results: Sixteen distinct germline variants were identified in the 17 index cases, including 12 novel alterations (75%). One quarter of the variants were de novo. Thyroid involvement, particularly multinodular goiter and papillary thyroid carcinoma, was the most common presentation and frequently coexisted with ovarian Sertoli–Leydig cell tumors or embryonal rhabdomyosarcoma. Two novel intronic variants were confirmed to affect splicing by RT‐PCR. Somatic “hotspot” mutations in exons 24–25 (RNase IIIb domain) were detected in most tumors, consistent with the two‐hit model. The identification of asymptomatic carriers enabled early surveillance and preventive interventions. Conclusions: This study expands the molecular spectrum of germline DICER1 variants, reinforces the predominance of thyroid involvement, and highlights the value of molecular testing for diagnosis, genetic counseling, and early intervention. Ethical considerations regarding surveillance and management of asymptomatic carriers remain an important area in need of future guidance.

PNPLA6 is a conserved lysophospholipase essential for maintaining nervous system integrity. Biallelic mutations in PNPLA6 have been identified in individuals with a broad spectrum of disorders that can include ataxia, vision loss, and pituitary hormone deficiency. Here, we report the identification of novel compound heterozygous variants in PNPLA6 (p.T1115P and p.Pro1142_Ala1143ins14) in a 10‐year‐old girl with combined pituitary hormone deficiency, including growth hormone, thyroid‐stimulating hormone, and gonadotropins. She also has vision loss and neurodevelopmental delay. Functional validation demonstrates that both variants, a missense substitution affecting a highly conserved residue within the catalytic domain and an intronic variant generating a novel splice acceptor site, completely abolish NTE activity, establishing their pathogenicity. Little is known about the cause of hypopituitarism in individuals with PNPLA6 deficiency. Here, we report the cell‐type‐specific expression of PNPLA6 in mouse pituitary development and in adult animals. PNPLA6 is expressed broadly in SOX2+ stem cells within the pituitary primordium as early as e10.5, prior to lineage specification, suggesting a role in progenitor maintenance and early differentiation. In neonates and adults, expression predominates in the cells that produce growth hormone and pro‐opiomelanocortin. These findings suggest that PNPLA6 could influence pituitary development at early stages, as well as contribute to the altered function of hormone‐secreting cells.

Context: P450 oxidoreductase (POR) deficiency is a rare congenital adrenal hyperplasia with variable severity. The mechanisms of severe mutations and their full metabolic consequences, including drug metabolism, are not fully characterized. Objective: To define the clinical, biochemical, and molecular consequences of a novel homozygous POR missense mutation, p.Gly88Ser (G88S), identified in 4 unrelated Argentine families. Design: A translational study combining clinical case series analysis with comprehensive in vitro molecular and functional characterization of the novel protein variant. Setting: Tertiary pediatric endocrine centers in Argentina and Switzerland. Patients: We report 5 individuals (4 46,XY; 1 46,XX) from 4 unrelated families presenting with disorders of sex development and adrenal dysfunction. Main Outcome Measures: Clinical phenotypes, hormonal profiles, and POR gene sequencing. In vitro analysis of recombinant POR measured flavin content, reductase activity, and support of steroidogenic and drug-metabolizing P450s. Results: All patients were homozygous for the c.262G>A (p.G88S) mutation. This FMN binding domain variant caused protein instability with severe loss of FMN (<30%) and FAD (<15%) cofactors. Steroidogenic activities were virtually abolished (CYP21A2: 1.3%; CYP17A1 17,20-lyase: 5.5% of wild-type), explaining the clinical phenotype. Activities of major drug-metabolizing enzymes were also severely impaired (3%-9% of wild-type), establishing a “poor metabolizer” phenotype. Conclusion: The POR G88S mutation causes one of the most severe forms of PORD described, driven by dynamic protein instability and cofactor loss. It is a critical pharmacogenomic marker, and its recurrence in Argentina suggests a potential screening target.