Seattle Children's Hospital

While there is considerable overlap in the treatment of patients with intersex traits and differences in sex development (I/DSD) with transgender and gender diverse (TGD) youth, the initial medical evaluation varies significantly. I/DSD youth often present due to differences in genitalia development in infancy or pubertal development in adolescence, and this leads to comprehensive biochemical, radiologic, and genetic evaluation. TGD youth, however, tend to have typical development noted at birth and during puberty, but present with a gender identity that does not align with their sex assigned at birth and do not require evaluation for underlying pathology. For both I/DSD and TGD youth, the mainstays of treatment are to better align one’s physical appearance to their gender identity. This review discusses the non-medical and medical interventions utilized in gender affirming care. A multidisciplinary team of mental health providers, pediatric medical providers, and surgeons is recommended for providing gender affirming care to both I/DSD youth and TGD youth and their families. Radiologists have an important role in initial evaluation of I/DSD youth and in ongoing monitoring of growth and bone mineral density during puberty induction in I/DSD and TGD youth. Graphical abstract

Electrical stimulation mapping (ESM) is used to locate the brain areas supporting language directly within the human cortex to minimize the risk of functional decline following epilepsy surgery. ESM is completed by utilizing subdural grid or depth electrodes (stereo‐electroencephalography [sEEG]) in combination with behavioral evaluation of language. Despite technological advances, there is no standardized method of assessing language during pediatric ESM. To identify current clinical practices for pediatric ESM of language, we surveyed neuropsychologists in the Pediatric Epilepsy Research Consortium. Results indicated that sEEG is used for functional mapping at >80% of participating epilepsy surgery centers ( n = 13/16) in the United States. However, >65% of sites did not report a standardized protocol to map language. Survey results indicated a clear need for practice recommendations regarding ESM of language. We then utilized PubMed/Medline and PsychInfo to identify 42 articles that reported on ESM of language, of which 18 met inclusion criteria, which included use of ESM/signal recording to localize language regions in children (<21 years) and a detailed account of the procedure and language measures used, and region‐specific language localization outcomes. Articles were grouped based on the language domain assessed, language measures used, and the brain regions involved. Our review revealed the need for evidence‐based clinical guidelines for pediatric language paradigms during ESM and a standardized language mapping protocol as well as standardized reporting of brain regions in research. Relevant limitations and future directions are discussed with a focus on considerations for pediatric language mapping.

Objectives Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. It is expensive, frequently used, and not without risk. There is limited evidence supporting a standard approach to initiation and weaning. Our objective was to optimize the use of iNO in the cardiac ICU (CICU), PICU, and neonatal ICU (NICU) by establishing a standard approach to iNO utilization. Design A quality improvement study using a prospective cohort design with historical controls. Setting Four hundred seven-bed free standing quaternary care academic children’s hospital. Patients All patients on iNO in the CICU, PICU, and NICU from January 1, 2017 to December 31, 2022. Interventions Unit-specific standard approaches to iNO initiation and weaning. Measurements and Main Results Sixteen thousand eighty-seven patients were admitted to the CICU, PICU, and NICU with 9343 in the pre-iNO pathway era (January 1, 2017 to June 30, 2020) and 6744 in the postpathway era (July 1, 2020 to December 31, 2022). We found a decrease in the percentage of CICU patients initiated on iNO from 17.8% to 11.8% after implementation of the iNO utilization pathway. We did not observe a change in iNO utilization between the pre- and post-iNO pathway eras in either the PICU or NICU. Based on these data, we estimate 564 total days of iNO (–24%) were saved over 24 months in association with the standard pathway in the CICU, with associated cost savings. Conclusions Implementation of a standard pathway for iNO use was associated with a statistically discernible reduction in total iNO usage in the CICU, but no change in iNO use in the NICU and PICU. These differential results likely occurred because of multiple contextual factors in each care setting.

Mental health conditions during adolescence have become a public health crisis that requires attention at all levels of health care. Understanding the criteria to make the diagnosis of depression and anxiety, specifically at the primary care level, and expediting care to decrease the risk for suicide is paramount. Over the past decade, suicide has become the second leading causes of mortality for adolescents and young adults, according to the Centers for Disease Control and Prevention (Bitsko, MMWR 71:1–42, 2022). Various barriers limit access to care, resulting in delayed treatment and elevated rates of poor outcomes related to mental health. Prevalence rates for adolescent mental health conditions have increased over recent years, the COVID-19 outbreak and subsequent lockdowns and school closures being a major contributing factor. These mitigating practices to limit the transmission of COVID-19 were additional barriers to access the health-care system. The incorporation of telehealth practices has long been considered and is currently deployed in primary care clinics with increased utilization during the COVID-19 pandemic.

As the COVID-19 pandemic catalyzed the rapid expansion of telemedicine services, medical educators were tasked with the challenge of incorporating students and trainees into clinical care with little guidance. Clinical faculty have strived to keep learners engaged, yet to date there have been few established formal training curricula for teachers or learners in providing care via telehealth. An emerging body of literature illustrates the unique advantages medical learners may experience engaging in telehealth encounters and offers mechanisms to effectively include them in virtual visits. The aim of this chapter is to describe approaches to clinical workflow with learners in telemedicine encounters, to review an assortment of telehealth teaching techniques, and to highlight the evidence regarding telehealth’s impact on clinical education and inclusion in medical education curricula.

Children and adolescents involved in the juvenile justice system have experienced childhood trauma and have complex healthcare, social, and legal needs. While the number of youth under the age of 18 who experienced arrest or detention have decreased, as of 2017, over 200,000 delinquency cases still involved detention (Harp and Muhlhausen. Juvenile justice statistics: national report series fact sheet [Internet]. Ojjdp.gov 2019. [cited 19 November 2022]. Available from: https://ojjdp.ojp.gov/sites/g/files/xyckuh176/files/media/document/253105.pdf). Each encounter places youth at a higher risk for repeated exposure to trauma and recidivism. Interprofessional collaboration across different service providers, both within and outside of juvenile detention, through emerging avenues of communication and healthcare delivery, such as telehealth, can help improve health assessments, expand provision of services, and facilitate discharge planning, in efforts to promote a healthy and successful reentry of detained youth to their home communities. This chapter provides an overview of provisions of health services for detained youth, opportunities to use telehealth to expand access to care for youth in detention, and recommendations on ways to incorporate telehealth to facilitate discharge planning and safe reentry for youth involved in the juvenile justice system.

The COVID-19 Public Health Emergency (PHE) declaration changed the way in which substance use treatment could be provided. This included allowances for medications for opioid use disorder. Telemedicine is a tool for allowing providers to offer substance use treatment to adolescents.

The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD.

Nucleic acid–sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

As rapid discharge protocols for pediatric spine fusion shorten stays, gastrointestinal (GI) complications are uncovered and cause delays in discharge. A pre-operative carbohydrate (CHO) drink has been shown to improve perioperative GI symptoms and functional return but has not been examined in pediatric spine patients. We aimed to determine if a preoperative CHO drink is safe in pediatric spine fusion patients, and if it improves their comfort scores and return of bowel function. We prospectively randomized ASA-1 and -2 pediatric spine fusion patients to either a pre-anesthesia carbohydrate drink 2 h prior to surgery or to a control group (standard 8 h NPO), blinded to surgical team. We documented time to return to flatus, bowel movement, GI symptoms, and comfort scores for 72 h post-operatively or until discharge. 62 patients were randomized. There was no significant differences between the groups’ pre-operative characteristics, surgical details, nor post-operative morphine dose equivalents, except for EBL (405 cc control, 340 cc CHO drink, p = 0.044). There were no perioperative complications related to ingestion of the CHO drink. CHO group had a positive trend for earlier return of flatus (21% vs. 3% return at 12 h), and comfort scores for anxiety and abdominal pain, but no statistically significant differences. There was no difference in length of stay or time to first bowel movement. There were no complications related to ingestion of a CHO drink 2 h prior to pediatric spinal fusion surgery. Further studies are needed to develop a study blinded to the participants with larger sample size. Level of evidence I.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up‐to‐date evidence‐based approach to the treatment of children with relapsed or refractory SAA.

Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling ( RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8 -associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2. However, laterality defects are present in nearly half of those with MEGF8 -associated CRPT2, but are rare in RAB23 -associated CRPT1. Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1. No patient to date has carried two MEGF8 gene alterations that are both predicted to lead to complete loss-of-function, suggesting that a variable degree of residual MEGF8 activity may be essential for viability and potentially contributing to variable phenotypic severity. These data refine the phenotypic spectrum of CRPT2 in comparison to CRPT1 and more than double the number of likely pathogenic MEGF8 variants in this rare disorder.

OBJECTIVES To identify and examine demographic variation in estimates of gender-diverse youth (GDY) populations from the PEDSnet learning health system network and the Youth Risk Behavior Survey (YRBS). METHODS The PEDSnet sample included 14- to 17-years-old patients who had ≥2 encounters at a member institution before March 2022, with at least 1 encounter in the previous 18 months. The YRBS sample included pooled data from 14- to 17-year-old in-school youth from the 2017, 2019, and 2021 survey years. Adjusted logistic regression models tested for associations between demographic characteristics and gender dysphoria (GD) diagnosis (PEDSnet) or self-reported transgender identity (YRBS). RESULTS The PEDSnet sample included 392 348 patients and the YRBS sample included 270 177 youth. A total of 3453 (0.9%) patients in PEDSnet had a GD diagnosis and 5262 (1.9%) youth in YRBS self-identified as transgender. In PEDSnet, adjusted logistic regression indicated significantly lower likelihood of GD diagnosis among patients whose electronic medical record-reported sex was male and among patients who identified as Asian, Black/African American, and Hispanic/Latino/a/x/e. In contrast, in the YRBS sample, only youth whose sex was male had a lower likelihood of transgender identity. CONCLUSIONS GDY are underrepresented in health system data, particularly those whose electronic medical record-reported sex is male, and Asian, Black/African American, and Hispanic/Latino/a/x/e youth. Collecting more accurate gender identity information in health systems and surveys may help better understand the health-related needs and experiences of GDY and support the development of targeted interventions to promote more equitable care provision.

Purpose Clinical sequencing of tumor DNA is necessary to render an integrated diagnosis and select therapy for children with primary central nervous system (CNS) tumors, but neurosurgical biopsy is not without risk. In this study, we describe cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) as sources for “liquid biopsy” in pediatric brain tumors. Methods CSF samples were collected by lumbar puncture, ventriculostomy, or surgery from pediatric patients with CNS tumors. Following extraction, CSF-derived cfDNA was sequenced using UW-OncoPlex™, a clinically validated next-generation sequencing platform. CSF-derived cfDNA results and paired plasma and tumor samples concordance was also evaluated. Results Seventeen CSF samples were obtained from 15 pediatric patients with primary CNS tumors. Tumor types included medulloblastoma (n = 7), atypical teratoid/rhabdoid tumor (n = 2), diffuse midline glioma with H3 K27 alteration (n = 4), pilocytic astrocytoma (n = 1), and pleomorphic xanthoastrocytoma (n = 1). CSF-derived cfDNA was detected in 9/17 (53%) of samples, and sufficient for sequencing in 8/10 (80%) of extracted samples. All somatic mutations and copy-number variants were also detected in matched tumor tissue, and tumor-derived cfDNA was absent in plasma samples and controls. Tumor-derived cfDNA alterations were detected in the absence of cytological evidence of malignant cells in as little as 200 µl of CSF. Several clinically relevant alterations, including a KIAA1549::BRAF fusion were detected. Conclusions Clinically relevant genomic alterations are detectable using CSF-derived cfDNA across a range of pediatric brain tumors. Next-generation sequencing platforms are capable of producing a high yield of DNA alterations with 100% concordance rate with tissue analysis.

Chronic thromboembolic pulmonary hypertension is a rare form of pulmonary hypertension in patients who have evidence of chronic thromboembolic occlusion of the pulmonary vasculature. Historically, surgical pulmonary thromboendarterectomy has been the treatment of choice. However, with up to 40% of patients deemed inoperable, balloon pulmonary angioplasty has emerged as an additional treatment strategy. Balloon pulmonary angioplasty is a complementary strategy alongside surgical pulmonary thromboendarterectomy and offers the opportunity for pulmonary revascularization in patients who have more distal disease, higher comorbidities, or residual obstruction following operative intervention. This review examines the history of balloon pulmonary angioplasty, highlights its effectiveness, discusses important complications and risk reduction strategies, and emphasizes the importance of centers forming a multidisciplinary team of providers to manage the complexity of patients with chronic thromboembolic pulmonary hypertension.