Background/Objectives: Adrenocortical tumors (ACTs), including adrenocortical adenoma (ACA) and carcinoma (ACC), represent 0.3–0.4% of pediatric tumors. Beckwith–Wiedemann spectrum (BWSp) confer an increased risk of ACTs, but prognosis, management, and associated molecular characteristics are unclear. Methods: This paper combines a literature review of 54 published cases of BWSp-ACT with a report of one newly identified patient, totaling 55 cases with a confirmed BWSp clinical and/or molecular diagnosis. Results: Nineteen patients with ACA, 33 with ACC, and 3 with ACT of uncertain malignant potential (umACT) were included. Twenty patients had uniparental disomy of chromosome 11p15.5 (patUPD11), 11imprinting Center 2 Loss-of-methylation (IC2-LoM), and had 2 11p15 locus duplication. Eleven patients were diagnosed during cancer screening procedures, including two metastatic at diagnosis ACC. Conclusions: Almost half of ACC patients reached the minimum score for clinical BWSp diagnosis only after ACC onset, suggesting that the BWSp score has limited value for the early diagnosis in such a setting. Two patients with metastatic ACC had a histopathological Wieneke score ≤2, not correlating with clinical malignancy and confirming limitations of the current histopathological classification, as previously documented. Ultrasound screening failed identifying the ACC before metastasis in two cases, indicating an urgent need to develop new strategies for screening of ACTs in BWSp. Furthermore, some cases of metastatic ACC exhibited unexpectedly indolent behavior despite being malignant.

Background: Fas/FasL-mediated apoptosis is central to immune homeostasis and is implicated in autoimmune lymphoproliferative syndrome (ALPS) and immune thrombocytopenia (ITP). We aimed to compare whole-blood transcriptional levels of CASP8 and CASP3 across ALPS, chronic ITP, and healthy controls. Methods: CASP8 and CASP3 mRNA expression was quantified by real-time PCR in whole blood from clinically diagnosed ALPS patients, chronic ITP patients, and healthy controls. Results: CASP8 mRNA expression was significantly increased in ALPS and ITP versus controls (p = 0.0009 and p < 0.0001, respectively) and was lower in ALPS than in ITP (p = 0.0265). CASP3 mRNA was also increased in both patient groups versus controls (ALPS: p = 0.0045; ITP: p < 0.0001), with no significant difference between ALPS and ITP (p = 0.1692). Conclusions: ALPS and chronic ITP show distinct CASP8 transcriptional patterns and a shared upregulation of CASP3 at the whole-blood mRNA level. These findings are descriptive and do not directly assess caspase activation or apoptotic pathway activity; further protein- and cell subset-based studies are needed to clarify functional implications.

Background: Autoimmune lymphoproliferative syndrome (ALPS) is an immune dysregulation disorder caused by defective lymphocyte apoptosis, most commonly involving the FAS–FAS ligand pathway. Because ALPS frequently presents with autoimmune cytopenias, particularly immune thrombocytopenia (ITP), its diagnosis may be challenging. This study evaluated whether FAS and FAS ligand gene expression could distinguish ALPS from ITP. Methods: FAS and FAS ligand messenger RNA expression was measured by quantitative real-time polymerase chain reaction in whole-blood samples from patients with pediatric-onset ALPS ( n = 24), patients with chronic ITP ( n = 27), and healthy controls ( n = 22). Expression levels were compared among groups, and their diagnostic performance was assessed using receiver operating characteristic curve analysis. Results: FAS expression was significantly higher in patients with ALPS than in healthy controls ( p < 0.01), but no significant difference was observed between ALPS and ITP. FAS expression showed moderate discrimination between ALPS and healthy controls but poor discrimination between ALPS and ITP. FAS ligand expression did not differ significantly among groups and showed no meaningful diagnostic performance. Neither FAS nor FAS ligand expression correlated with double-negative T-cell percentages or differed according to treatment status in patients with ALPS. Conclusions: FAS and FAS ligand transcriptional levels do not provide disease-specific discrimination between ALPS and ITP. These findings support the continued use of clinical, immunophenotypic, functional, and genetic investigations for the diagnosis of ALPS.

Background: Autosomal recessive intellectual developmental disorder-13 (MRT13; OMIM #613192) is a rare neurodevelopmental disorder caused by pathogenic variants in TRAPPC9. Most reported variants are single-nucleotide variants (SNVs), small insertions/deletions, or copy number variants (CNVs), whereas complex structural variants (SVs) remain poorly characterized. Objectives: This study sought to review the clinical and molecular spectrum of TRAPPC9-related disorder, harmonize reported variants, explore genotype–phenotype correlations, and expand the mutational spectrum by reporting a novel patient with a cryptic SV. Methods: We report a novel patient whose diagnostic workup included array-CGH, whole-exome sequencing, karyotyping, and optical genome mapping. Additionally, a systematic literature search was primarily conducted in PubMed/MEDLINE from 2009 to January 2026, with Embase, Web of Science, Google Scholar, Orphanet, OMIM, and ClinVar used as supplementary sources. Patients carrying pathogenic/likely pathogenic TRAPPC9 variants were included. Clinical and molecular data were extracted and descriptively summarized. Genotype–phenotype correlations were explored. Reported variants were re-annotated using MANE Select reference transcripts. Results: The reported patient showed biallelic TRAPPC9 disruption due to two independently inherited structural variants: a maternal ~35 kb intragenic deletion involving exons 10–12, identified by 400K array-CGH, and a paternal balanced translocation t(4;8) disrupting TRAPPC9 within intron 8, characterized by trio-OGM and paired-end whole-genome sequencing (PE-WGS). Thirty-one studies reporting 75 previously published patients were included in the literature review; together with the novel patient described here, the final cohort comprised 76 patients. Intellectual disability was present in 100% of cases, followed by brain MRI abnormalities (95.9%), microcephaly (82.3%), motor delay (71.4%), dysmorphic features (69.8%), obesity (52.8%), behavioral abnormalities/autism spectrum disorder (49.2%/43.8%), and epilepsy (15.9%). Most patients (84.2%) harbored homozygous variants. Thirty-two distinct sequence variants were identified, predominantly loss-of-function. CNVs were identified in 13.2% of patients. No genotype–phenotype correlations were identified. Conclusions: The systematic review provides an updated and harmonized overview of the clinical and molecular spectrum of TRAPPC9-related disorder, supporting the presence of a recognizable phenotype and confirming the predominance of loss-of-function variants. Our case further highlights the contribution of cryptic structural variants to the mutational spectrum of TRAPPC9 and the diagnostic value of advanced genomic approaches.

Background: SATB2-associated syndrome (SAS), also known as Glass syndrome, is a neurodevelopmental disorder (NDD) characterized by intellectual disability, developmental delay, absent or limited speech, and distinctive craniofacial and dental anomalies. It is caused by autosomal dominant pathogenic variants in the SATB2 gene, which plays a crucial role in brain, dental, and jaw development. Due to its variable phenotype, clinical diagnosis can be challenging, necessitating genetic confirmation. Methods: We present six new cases of SAS with SATB2 germline variants identified through next generation sequencing (NGS) technologies, expanding the known genetic and clinical spectrum of the syndrome. Detailed clinical phenotyping was performed for all patients. Results: Our cohort exhibits a broad range of clinical manifestations consistent with SAS, encompassing severe intellectual disability, profound speech delay, various palatal and dental abnormalities. We report the oldest adult patient (56 years old) carrying an in-frame duplication, and a pediatric patient with a missense variant who presented a significant reduction in visual acuity, likely of neurological or cortical origin, in the absence of ophthalmological abnormalities. SATB2 variants include three missenses, two in-frame deletion/duplication and one frameshift variant, several of which are novel and classified as likely pathogenic or pathogenic according to ACMG guidelines. Conclusions: This report provides new clinical and genetic insights into the landscape of SAS. Our findings confirm the phenotypic heterogeneity of SAS and highlight the critical role of comprehensive genetic testing for accurate diagnosis in NDD patients.