Updates in hyponatremia and hypernatremia.

PURPOSE OF REVIEW: Hyponatremia and hypernatremia are commonly encountered electrolyte abnormalities that require timely and careful intervention, as they can be associated with significant morbidity and mortality. RECENT FINDINGS: This review article addresses the etiology, presentation, diagnosis, and management of both hyponatremia and hypernatremia, emphasizing the latest advancements and emerging trends in pediatric care. SUMMARY: A methodical approach is needed to accurately assess and treat hyponatremia and hypernatremia. Both conditions continue to rely on serum and urine testing, however newer tests such as copeptin and stimulated testing may hold promise to further refine testing in the future.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Profound Hypoglycemia and High Anion Gap Metabolic Acidosis in a Pediatric Leukemic Patient Receiving 6-Mercaptopurine.

A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL), presented with vomiting due to severe hypoglycemia with metabolic acidosis. While his laboratory values were concerning for a critically ill child, the patient was relatively well appearing. Hypoglycemia is a rare but serious side effect of 6MP with an unexpectedly variable presentation; therefore, a high index of suspicion is needed for its prompt detection and treatment. This patient also had severe metabolic acidosis, likely secondary to hypoglycemia, creating a serious clinical picture despite a well-appearing child. This example of incongruity between laboratory tests and clinical appearance adds nuance to the existing literature. Moreover, although 6MP-associated hypoglycemia is rare, it may be more prevalent than the literature suggests, as symptoms of hypoglycemia-nausea, vomiting, and somnolence-mirror common chemotherapy side effects. 6MP-induced hypoglycemia can be ameliorated with the addition of allopurinol to shunt metabolism in favor of the production of therapeutic metabolites over hepatotoxic metabolites. Additionally, a morning administration of 6MP and frequent snacks may also help to prevent hypoglycemia. Overall, this case adds to the literature of unusual reactions to 6MP including hypoglycemia in an older child without traditional risk factors.

Vitamin D levels, insulin resistance, and cardiovascular risks in very young obese children.

OBJECTIVE: To examine the relationships of 25-hydroxyvitamin D (25-OHD) levels with the measures of insulin resistance and cardiovascular risk, and identify the clinical factors associated with low 25-OHD in young obese children. DESIGN AND METHODS: Data from 83 children ages 2-6 years seen for obesity care (clinic latitude 42°N) were analyzed. Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] and cardiovascular risks were examined in relationship to 25-OHD levels using correlation statistics. χ2 and logistic regression models were applied to identify the factors associated with vitamin D deficiency (25-OHD levels <20 ng/mL) and insufficiency (<30 ng/mL). RESULTS: Children's mean age was mean 4.9 years and they were predominantly Hispanic. Mean body mass index (BMI) Z-score was 3.2 and mean HOMA-IR was 2.8. Mean 25-OHD was 30.9 ng/mL (6% <20 ng/mL and 46% 20-29 ng/mL). There were no significant correlations between 25-OHD and BMI (Spearman's ρ=-0.096, p=0.389), BMI Z-score (Spearman's ρ=0.104, p=0.350), HOMA-IR (Spearman's ρ=-0.144, p=0.269), total cholesterol (Spearman's ρ=-0.028, p=0.833), or triglycerides (Spearman's ρ=-0.026, p=0.846). Vitamin D deficiency was significantly associated with older age, lower milk intake, and testing in winter months. 25-OHD level <30 ng/mL was associated with older age, African-American and Hispanic race/ethnicity, and testing in winter months. All factors retained significance in a multivariate logistic regression model, with African-American (odds ratio=14.4) and Hispanic (odds ratio=7.2) race/ethnicity being the strongest predictors of 25-OHD levels <30 ng/mL. CONCLUSIONS: In these children, 25-OHD was not associated with insulin resistance or cardiovascular risks. Considering age, race/ethnicity, diet, and season may help identify young obese children needing vitamin D management.

Exogenous Insulin Antibody Syndrome in a Pediatric Patient: Successful Treatment with Mycophenolate Mofetil.

INTRODUCTION: Exogenous insulin antibody syndrome (EIAS) rarely occurs in type 1 diabetes and should be considered in those with blood glucose levels outside the target range requiring greater than 2 units/kg/day of insulin without obesity. We describe the novel treatment of this condition using mycophenolate mofetil monotherapy in a pediatric patient in the outpatient setting. CASE PRESENTATION: A 17-year-old Caucasian male with type 1 diabetes experienced an abrupt increase in insulin requirements from 1.7 to 3.3 units/kg/day. Total insulin level was 7 µIU/mL with free insulin of 4.8 µIU/mL (68% of the total insulin), suggesting the presence of insulin antibodies. Switching from insulin aspart to glulisine was unsuccessful as insulin requirements increased to 4.4 units/kg/day. Treatment with oral mycophenolate mofetil decreased insulin requirements to 1.4 units/kg/day after 7 months. Total and free insulin levels improved to 5.2 and 4.6 µIU/mL, respectively (free insulin was 88% of total insulin). No adverse effects were encountered. CONCLUSION: Mycophenolate mofetil monotherapy is successful in safely treating EIAS in a pediatric patient.

Oral Glucose Tolerance Testing Using Candy: A Sweet Solution to Improve Screening in Children with Cystic Fibrosis?

INTRODUCTION: Oral glucose tolerance testing is recommended for all children with CF older than 9 years, yet compliance remains poor across centers. METHODS: We performed a small pilot study assessing the glycemic curves and participant satisfaction in seven children and adolescents. RESULTS: We chose a dextrose-based candy (Nerds®) free of any fat, fiber, gelatin, or corn syrup and performed the candy OGTT 1-4 days following the standard oral dextrose solution OGTT. Glucose values at 120 min were similar between the candy and oral dextrose solution (p = 0.8986). CONCLUSIONS: Our small pilot suggests that a carefully selected candy alternative may result in similar glycemic OGTT when compared to the standard oral dextrose solution. However, some participants preferred the oral dextrose solution to candy due to having to consume a large volume in a short period of time. This may have significant implications as centers consider candy alternatives to increase OGTT adherence rates.

Patient Satisfaction Scores Impact Pediatrician Practice Patterns, Job Satisfaction, and Burnout.

Patient satisfaction (PS) surveying has become a commonly used measure of physician performance, but little is known about the impact on pediatricians. To investigate our hypothesis that PS surveys negatively impact pediatricians, we conducted a survey at an academic children's medical center. Of 155 eligible physicians, 115 responded (response rate 74%). Two-thirds (68%) did not find the PS score report useful and 88% did not feel that PS scores accurately reflect the physician's clinical ability. A third reported ordering tests, medications, or consultations due to pressure for higher PS scores. In addition, one-third agreed that PS surveys contribute to burnout and make it difficult to practice meaningful medicine. Overall, PS score reporting has a negative impact on pediatricians, especially those who are female, BIPOC (Black, Indigenous, and People of color), subspecialists, younger, and attended non-US medical schools. Further investigation into improved methods for providing feedback to pediatric physicians is warranted.

Copeptin levels in hospitalized infants and children with suspected vasopressin-dependent disorders: a case series.

OBJECTIVES: There have been recent advances assessing copeptin levels in adults with suspected disorders of vasopressin release. Very limited data exits on copeptin levels in children and infants, especially in a critically-ill hospitalized population where hyper- and hypo-natremia are very common. Our objective is to describe the institutional experience assessing copeptin levels in hospitalized infants and children with hyper- or hypo-natremia. METHODS: We performed a single-center retrospective case series of all infants, children, and adolescents who had an ultrasensitive plasma copeptin level obtained between 2019-2021. RESULTS: A total of 29 critically ill patients (6 infants) were identified with 38 % of patients having copeptin levels after neurosurgical procedures for tumors or trauma. Approximately 13/17 children with hypernatremia had central diabetes insipidus (central diabetes insipidus) to diagnose CDI, A copeptin level ≤ 4.9 pmol/L resulted in an 88 % sensitivity (95 % CI 47-99 %), and 66 % specificity (95 % CI 30-93 %). Amongst those with hyponatremia levels were more variable, 8/12 children had syndrome of inappropriate antidiuresis (SIAD) with copeptin levels ranging 4.7-72.6 pmol/L. CONCLUSIONS: While difficult to conclude due to multiple limitations, this case series highlights that typical copeptin cutoffs used to diagnose DI in adults in an ambulatory setting may also translate to a critically-ill pediatric population. Large prospective studies are needed to confirm this observation. In addition, postoperative copeptin levels could potentially be utilized as an additional marker to predict permanent from transient DI, but much larger studies are needed. Further work is needed to establish normative copeptin levels in infants and patients with SIAD.

Glucagon fill rates and cost among children and adolescents with type 1 diabetes in the United States, 2011-2021.

AIMS: To characterize glucagon fill rates and costs among youth with type 1 diabetes mellitus (T1DM). METHODS: Claims-based analysis of commercially-insured youth with T1DM included in OptumLabs® Data Warehouse between 2011 and 2021. Glucagon fill rates and costs were calculated overall and by formulation (injectable, intranasal, autoinjector, and pre-filled syringe). Sociodemographic and clinical factors associated with glucagon fills were examined using Cox regression. RESULTS: We identified 13,267 children with T1DM (76.4% non-Hispanic White). Over mean follow-up of 2.81 years (SD 2.62), 70.0% filled glucagon, with stable fill rates from 2011 to 2021. Intranasal glucagon had rapid uptake following initial approval, and it accounted for almost half (46.6%) of all glucagon fills by 2021. Family income was positively associated with glucagon fills in a stepwise fashion (HR 1.39 [95% CI 1.27-1.52] for annual household income ≥$200,000 vs. <$40,000), while Black race was negatively associated with fills (HR 0.83 [95% CI 0.76-0.91]) compared to White race). Annual mean out-of-pocket costs ranged from $21-$68 (IQR $29-$44). CONCLUSION: Roughly 30% of commercially-insured youth with T1DM may lack access to unexpired glucagon, with significant disparities among Black and low-income patients. Health systems, clinicians, schools, and caregivers should work together to ensure children have reliable access to this critical medication.

Variable Clinical Presentation of Children with Hereditary Hypophosphatemic Rickets with Hypercalciuria: A Case Series and Review of the Literature.

INTRODUCTION: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare condition of renal phosphate wasting due to SLC34A3 mutations [Am J Hum Genet. 2006;78(2):193-201]. Patients exhibit low serum phosphorus, high 1,25-dihydroxyvitamin D, and inappropriately high urine phosphate and calcium. However, symptoms vary, and little is known about specific phenotype-genotype correlations. METHODS: We report 3 HHRH cases in unrelated 12-year-old, 9-year-old, and 14-year-old patients and perform a systematic literature review. RESULTS: All 3 patients exhibited labs typical of HHRH. Yet, their presentations differed, and 2 novel SLC34A3 variants were identified. As found in the literature review, bone symptoms are most common (50%), followed by renal symptoms (17%), combined bone and renal symptoms (18%), and asymptomatic (9%). CONCLUSION: These 3 cases highlight the variability of presenting signs and symptoms among individuals with HHRH. An accurate diagnosis is critical as treatment differs from other disorders of phosphate wasting, urinary stones, and mineralization defects.

Vasopressin-Dependent Disorders: What Is New in Children?

Arginine vasopressin (AVP)-mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP's chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.

Ovarian Steroid Cell Tumor Masquerading as Steroid-Unresponsive Congenital Adrenal Hyperplasia.

OBJECTIVE: Ovarian neoplasms in children are rare. The objective of this report is to emphasize the importance of considering those neoplasms in the differential diagnosis of hyperandrogenism even with negative diagnostic imaging. METHODS: We report the case of a 12-year-old girl who presented with virilization and elevated 17 hydroxyprogesterone (17-OHP) and who was subsequently diagnosed with an ovarian neoplasm. RESULTS: The patient was initially seen for hirsutism and deepening of the voice. Elevated 17-OHP, androstenedione, and testosterone prompted the initial diagnosis of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, but those levels failed to suppress on corticosteroid therapy. Ultrasound, computed tomography scan, and magnetic resonance imaging of the abdomen and pelvis were normal. Genetic testing for congenital adrenal hyperplasia was negative. Bilateral selective adrenal and ovarian venous sampling confirmed the ovarian origin of her hyperandrogenism. A unilateral salpingo-oophorectomy revealed a steroid cell tumor. Postoperatively there was normalization of testosterone and 17-OHP. CONCLUSION: This report highlights the utility of selective adrenal and ovarian sampling when suspecting a primary androgen-secreting neoplasm, even in the setting of elevated 17-OHP levels and negative imaging studies, as early diagnosis can prevent manifestation of irreversible symptoms of virilization.

Brain functions and cognition on transient insulin deprivation in type 1 diabetes.

BACKGROUNDType 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function.METHODSWe therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions.RESULTSInsulin deprivation in T1D increased blood glucose, and ß-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition.CONCLUSIONTransient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation.TRIAL REGISTRATIONClinicalTrials.gov NCT03392441.FUNDINGClinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.

Thyroid storm after choking.

BACKGROUND: A thyroid storm (TS) is a rare, but life-threatening condition in hyperthyroid patients. Mortality in adult TS patients may be as high as 10%. Typically, a trigger precipitates the storm in hyperthyroid patients. CASE PRESENTATION: We report the case of an adolescent girl with untreated hyperthyroidism who developed fulminant TS after a significant choking episode. Initially, she was found to have neck swelling and tachycardia leading providers to suspect infection. She deteriorated after a CAT Scan (CT) was performed with iodine contrast, potentially worsening storm symptoms. Here, we describe the case, the treatment strategy and propose a treatment modification for pediatric patients. CONCLUSIONS: While many children are found to have minor abnormalities in thyroid studies, this case highlights the critical importance of prompt medical attention for any child with significantly elevated free thyroxine (FT4) levels as morbidity can occur when left untreated.

Productive Pumping: A Pilot Study to Help Postpartum Residents Increase Clinical Time.

BACKGROUND: Many female residents choose to start families during training, and they want to breastfeed their infants. Continuing lactation while balancing service and education demands can be challenging. OBJECTIVE: We hypothesized that the presence of a dedicated and fully equipped lactation room with a hospital-grade pump (HGP) would increase ease and efficiency of lactation during residency. METHODS: A quiet HGP was purchased for resident use, and it was stored in a designated room with a computer, telephone, and dictation system. Lactating residents provided information about pumping time and production using their own portable double electric pump (PP) versus the HGP based on the first pump of the morning (for consistency), averaged over the first month back from maternity leave. RESULTS: Among 6 residents, lactation time with PP averaged 24 minutes (range, 15-40 minutes) versus 15.5 minutes with HGP (range, 10-32 minutes). Use of the HGP reduced total pumping time by 8.5 minutes (95% confidence interval 3.8-12.2, P = .045). Production volume increased from 6 ounces (range, 3.5-8.5 ounces) with PP to 8.8 ounces (range, 8-11 ounces) with HGP, for a mean increase of 2.8 ounces (95% confidence interval 1.2-4.3, P = .06) despite decreased lactation time. CONCLUSIONS: In our pilot, an HGP significantly decreased lactation time, while increasing expressed milk volume. Residents completed clinical and educational tasks while pumping. Providing an HGP and equipped lactation space helped residents continue breastfeeding and decreased the burden of lactation on patient care and educational tasks.

Prevalence of Metabolic Bone Disease in Tube-Fed Children Receiving Elemental Formula.

BACKGROUND: Previous studies suggest normal mineral status in children receiving elemental formula. However, a recent multicenter survey described 51 children who developed hypophosphatemia and bone disease while receiving elemental formula. Our aim is to determine the prevalence of metabolic bone disease in children receiving extensively hydrolyzed or amino acid-based formula. METHODS: We established a retrospective cohort using an institutional database of tube-fed children. We defined a "confirmed case" as a child with biochemical and radiographic evidence of bone disease (rickets and/or low-trauma fractures). We defined a "suspected case" as a child who had biochemical evidence and/or radiographic evidence of bone disease but with incomplete data during the review period. RESULTS: A total of 102 tube-fed children receiving elemental or semi-elemental formula were identified. The four elemental and semi-elemental formulas evaluated were Neocate®, EleCare®, Pregestimil®, and Alimentum®. Not all children had complete monitoring data performed during the review period. Of the children receiving Neocate who had monitoring data (46%), 23% developed hypophosphatemia and radiographic abnormalities (fractures or rickets), which resolved with phosphorus supplementation and/or change in the formula brand. CONCLUSIONS: We estimate that at least 11% and up to 23% of all tube-fed children receiving Neocate develop metabolic bone disease. Based upon the estimated prevalence, we recommend cautious use of this formula with monitoring for evolving bone disease in this population.