Boston Children's Hospital

Mania symptoms in youth predict poor long-term mental health outcomes, yet their developmental trajectories and associated risk factors remain unclear. Leveraging data from the Adolescent Brain Cognitive Development Study (N=10,474; 9-10 years at baseline; 48% female, 65% white), we used latent growth mixture models to identify trajectories of mania symptoms across two years in early adolescence. We used multinomial logistic regressions to examine associations between trajectories and risk factors across mental and physical health, cognition, and family/environmental domains. We identified three trajectories: Low (58%), Moderate (32%), and High/Variable Mania Symptoms (10%). All mental health symptoms (depression, attention deficit hyperactivity disorder, conduct and oppositional defiant disorders and anxiety), two physical health factors (sleep disturbances, irritable bowel syndrome symptoms), one cognitive factor (verbal learning impairment), and three family/environmental factors (trauma, parent- and youth-reported family conflict) significantly differentiated between all three trajectories, reflecting incremental increases in risk factor severity with increasing mania symptoms. Other physical, cognitive, family and environmental factors were also associated with more severe mania symptom trajectories. More severe mania symptom trajectories in early adolescence are associated with multiple mental, physical, cognitive, family and environmental risk factors, underscoring the need for comprehensive risk prediction approaches in youth.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Systematic clinical phenotyping using Human Phenotype Ontology (HPO) is central to rare disease diagnosis. However, current disease prioritization (ranking candidate diseases from HPO for a patient) methods face key challenges: they often fail to account for the hierarchical structure of HPO terms, ignore dependencies among correlated terms, and do not adjust for batch effects arising from systematic differences in phenotype documentation across cohorts, institutions, or clinicians. We aim to develop a scalable and statistically principled framework to address these limitations for rare disease prediction and patient stratification. We developed PhenoSS, a Gaussian copula-based framework that models disease-specific marginal prevalence of HPO terms while capturing their joint dependencies through a multivariate normal distribution. Phenotype frequencies were estimated using external curated resources, including OARD (Open Annotations for Rare Diseases) and HPO annotations. PhenoSS supports both pair-wise phenotype similarity calculation for patient clustering and posterior odds estimation for patient-specific disease prioritization. A batch-effect correction module mitigates systematic phenotyping differences across datasets. Across diverse simulation scenarios, PhenoSS demonstrated robust disease-prediction performance and consistently improved accuracy after batch-effect correction. In real electronic health record (EHR) data, PhenoSS identified clinically meaningful patient clusters and effectively distinguished patients with different rare diseases. In disease prioritization tasks, PhenoSS achieved competitive performance with existing methods, particularly for patients exhibiting sparse or noisy phenotype annotations. PhenoSS provides a statistically interpretable framework for modeling phenotypic heterogeneity in rare disease research and is adaptable to other structured clinical vocabularies such as SNOMED-CT and ICD codes.

Selective serotonin reuptake inhibitors (SSRIs) are generally regarded as safe and widely used in children and adolescents. Although rare, SSRIs can cause neuroendocrine side effects such as hyperprolactinemia and galactorrhea. Galactorrhea is inappropriate milk secretion outside of pregnancy or breastfeeding and may occur with normal prolactin levels. Although numerous cases have been reported in adults, only a few have been reported in adolescents. A PubMed and Embase search was conducted to identify English-language case reports and case series involving patients ≤18 years with SSRI-associated galactorrhea. Seven adolescent female cases were identified, including five case reports and two cases from pharmacovigilance data. SSRIs involved included citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, as well as sequential exposure to other serotonergic antidepressants. Time to onset ranged from days to several weeks after initiation or dose escalation, with longer latency reported in a pharmacovigilance case. Prolactin levels ranged from normal to markedly elevated. In all cases, galactorrhea improved or resolved after dose reduction, discontinuation of the offending agent, or treatment modification, with recurrence observed in some patients following exposure to another serotonergic antidepressant. Reports show that SSRI-induced galactorrhea and hyperprolactinemia, though uncommon, can occur in adolescents. Clinicians should be aware that SSRI-related galactorrhea may occur even when prolactin levels are normal or mildly elevated and should actively inquire about this adverse effect. Further research is needed to clarify prevalence, risk factors, and mechanisms involved.

The study goal was to evaluate the outcomes associated with albumin use in children with sepsis and shock compared with those without shock, using causal inference analysis in a multicenter cohort. This was a secondary analysis of electronic health record data collected from 13 U.S. PICUs between 2012 and 2018, consisting of children younger than 18 years who met Phoenix sepsis criteria within the first 24 hours of PICU admission. Covariate-balancing propensity score weighting was applied to adjust for indication bias in the albumin use. Patients receiving at least 0.5 g/kg albumin within 24 hours of PICU admission were assigned to the albumin group; others to the control. Only 24-hour survivors were included to address immortal time bias. Overall, 17,307 children with sepsis survived at least 24 hours. Of these, 1,344 patients (7.8%) who received albumin within the first 24 hours, and 9,678 (55.9%) met the criteria for septic shock. A significant interaction between albumin use and shock status was observed (interaction: -0.353, p = 0.007), with albumin administration in pediatric septic shock patients associated with lower in-hospital mortality: odds ratio equals to 0.698 (95% CI, 0.629-0.774), risk ratio equals to 0.746 (95% CI, 0.625-0.891), and hazard ratio equals to 0.688 (95% CI, 0.558-0.848). In contrast, there was no difference in outcomes between the albumin and control groups in the non-shock group. Early albumin administration was associated with improved outcomes in children with septic shock, but not in those without shock. These results highlight the importance of considering clinical heterogeneity, such as the presence of shock, in identifying treatment-responsive subgroups and enabling more targeted interventions in pediatric sepsis. Further prospective validation is warranted.

Climbing fibre (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum1-3. Paradoxically, CFs also excite molecular layer interneurons (MLIs)4,5, a cell type that inhibits PCs and can restrict plasticity and learning6,7. However, two types of MLI with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals and suppress plasticity of granule cell to PC synapses2,6-9, whereas MLI2s inhibit MLI1s and disinhibit PCs8. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial electron microscopy reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 through more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s through glutamate spillover4,5. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s and disinhibits PCs. By contrast, learning-related sensory stimulation produces more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted towards MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for long-term depression. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity.