Objectives Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing.

Resumen Objetivos La hipoplasia suprarrenal congénita ligada al cromosoma X es una enfermedad rara con base genética conocida, que se presenta con insuficiencia suprarrenal e hipogonadismo hipogonadotrófico y expresión clínica variable. Caso clínico Paciente varón, de 26 días, que ingresó con síntomas compatibles con insuficiencia suprarrenal, hiponatremia e hiperpotasemia, requiriendo sueroterapia con suplementos de NaCl y fludrocortisona, consiguiéndose estabilidad clínica. Se descartó la hiperplasia suprarrenal congénita tras la medición de 17-OH-progesterona. El resto de hormonas estaban dentro de los intervalos de referencia, salvo la hormona adrenocorticotrópica (ACTH), sensiblemente por encima, y la aldosterona, por debajo. En los siguientes análisis se estudiaron los ácidos grasos de cadena muy larga para descartar adrenoleucodistrofia, el gen CYP11B2 (aldosterona sintasa), y se realizó una RMN para descartar otras alteraciones morfológicas. Todas estas pruebas resultaron normales. Finalmente, tras detectar déficit de cortisol en una analítica, se realizó un estudio genético más amplio donde se describió una mutación en el gen NR0B1, estableciéndose el diagnóstico de hipoplasia suprarrenal congénita. Conclusiones La hipoplasia suprarrenal congénita es una enfermedad de diagnóstico complejo debido a la variabilidad en la expresión clínica y el grado de alteración de las pruebas de laboratorio, requiriéndose un seguimiento exhaustivo y la realización de pruebas genéticas para llegar al diagnóstico.

Post-transplant lymphoproliferative disorders (PTLD) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr Virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLD) has not been elucidated and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCL), mostly classified as activated B-cell, and seven Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing and copy-number (CN) arrays. Overall, PTLD-BL carried mutations in MYC,ID3, DDX3X, ARID1A or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL and less CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with worse outcome. All seven PTLD-BL were alive after treatment with pediatric B-cell Non-Hodgkin Lymphoma protocols, whereas 54% of DLBCL patients were cured with immunosuppression reduction, rituximab and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low intensity treatment and the shared pathogenesis between PTLD-BL and EBV+ IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.

The genetic landscape of post-transplant lymphoproliferative disorders (PTLD) in pediatric population has not been fully elucidated. This absence of information raises the question whether therapeutic strategies should be the same as for their counterparts in immunocompetent (IC) patients. The aim of this study was to characterize genetically and immunophenotypically pediatric monomorphic PTLD. Thirty-nine monomorphic PTLD ≤19 years-old (mean 10y, gender 25 male/14 female) were recruited and analyzed for germinal center markers, IRF4 and EBER expression. Presence of MYC, PAX5, IRF4, BCL2, BCL6 and 11q alterations was investigated by FISH. Additional molecular studies included clonality, copy number (CN) arrays, cell of origin-COO (Nanostring) and mutational analyses (Custom 167 lymphoma related genes panel, SureSelectXT, Agilent). Twenty-nine patients received solid organ transplantation and eight were hematopoietic stem cell transplant recipients. The mean time from transplant to PTLD diagnosis was 34 months (range 2-170) and the estimated 5-year overall survival (5y-OS) rate was 67%. Patients that received a solid organ had a better prognosis than hematopoietic stem cell transplant recipients (5y-OS 83% vs. 38%, p=0.03). Thirty-three cases were classified as diffuse large B-cell lymphoma (DLBCL) and six as Burkitt lymphoma (BL). Thirty-two cases had extranodal localization, 21 of which in the gastrointestinal tract. Among the DLBCL, 24/28 cases had an ABC/non-GC COO phenotype and the six BL were GCB. EBER was positive in 33/37 cases. Five out of six BL and one DLBCL had MYC rearrangements, while no 11q alterations or other rearrangements were observed. Ten out of the 23 pediatric monomorphic PTLD studied displayed CN alterations (mean 1.6 alt/case; range 0-12). Comparative analyses showed that pediatric PTLD had lower genetic complexity than BL (Scholtysik, 2010) and DLBCL (Ramis-Zaldivar, 2020) in IC patients and adult-PTLD (Ferreiro, 2016; Rinaldi, 2010) and lacked characteristic CN alterations of those groups. Regarding the mutational profile, all 6 PTLD-BL carried MYC mutations in addition to ID3 (4 cases), ARID1A (2 cases) or CCND3 (1 case) and a higher mutational burden than PTLD-DLBCL (12.3 vs 6.2, p=0.01). PTLD-DLBCL showed a very heterogeneous profile characterized by a lower number of mutations than their counterparts in IC patients (2.4 vs 6.5, p=0.01). Pathway enrichment analysis revealed that epigenetic modifiers and NOTCH pathway (4 cases each) were the most recurrently affected. Two out of 20 cases were classified as N1 according to LymphGen (Wright, 2020) algorithm while the rest remained undetermined. The mutational profile of pediatric PTLD-BL is similar to that observed in IC patients whereas PTLD-DLBCL are less complex than their counterpart in IC children and present a very heterogeneous mutational landscape with enrichment in NOTCH pathway mutations. Citation Format: Julia Salmeron, Natalia Castrejón-de-Anta, Pilar Guerra-Garcia, Joan Enric Ramis-Zaldivar, Mónica López-Guerra, Dolors Colomer, Francisco Diaz-Crespo, Marta Garrido, Javier Menarguez, Maria del Mar Andrés, Eugenia Garcia-Fernandez, Margarita Llavador, Noelia Garcia, Blanca Gonzalez-Farré, Idoia Martin-Guerrero, Carmen Garrido, Itziar Astigarraga, Alba Fernández, Jaime Verdú-Amorós, Soledad González-Muñíz, Berta Gonzalez, Verónica Celis, Elias Campo, Olga Balagué, Itziar Salaverria. Unravelling the heterogenous molecular landscape of pediatric post-transplant lymphoproliferative disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2502.