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Nocturia has been increasingly recognized as a manifestation of various non-urological conditions including hypertension. In adults, blood pressure (BP) elevation has been identified as a robust correlate of nocturia, but such a relationship has not been studied in pediatric populations where nocturia is often attributed to hormonal, sleep, physiological or psychological disorders. Accordingly, this study aimed to determine the relationship between nocturia and BP elevation in adolescents. We prospectively studied 100 patients, aged 10-18 years, recruited from pediatric clinics at our institution. Nocturia (defined as ≥ 1 voids on voiding diary analysis) was present in 45% of the study sample (range: 1-4 voids/night). 37% of subjects self-reported awakening to urinate, and 34% of subjects had BP elevation according to age-dependent thresholds from current Pediatrics guidelines. On multivariate analyses, BP elevation was strongly associated with nocturia determined by both voiding diary (OR 26.2, 95% CI: 6.5, 106.0) and self-report. Conversely, nocturia was associated with increased odds of elevated BP by diary (26.3, 95% CI: 6.5, 106.4) and self-report (OR 8.1, 95% CI: 3.2, 20.5). In conclusion, nocturia appears to be common and is strongly associated with BP elevation in adolescents. These findings suggest that eliciting a history of nocturia holds promise as a simple method of identifying adolescents at risk for hypertension., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Herein, we report a case of a 12-year-old girl who presented with diabetic ketoacidosis and a leukemoid reaction. Although this association has been described in a few adult patients, pediatric cases have not been reported. A leukemoid reaction is commonly defined as an elevation in the white blood cell count greater than 50,000/μL in response to severe illness or stress other than hematologic malignancy; it is considered to be mediated by various hormones, cytokines, and factors that are released in response to inciting triggers, such as acidosis. As highlighted in our report, distinguishing a benign leukemoid reaction from a hematologic malignancy and even tumor lysis syndrome, particularly in a setting of diabetic ketoacidosis, is crucial to ensuring safe and efficacious therapeutic interventions.

Adrenocortical carcinoma (ACC) is a rare malignancy and even rarer in infancy. Most of these tumors in pediatric age group are hormonally active and predominantly present with virilization. Cortisol hypersecretion presenting as Cushing syndrome is extremely rare and seen in older age groups. We report a 4-month-old infant who presented with linear growth arrest and excessive weight gain in early infancy, consequently diagnosed with ACC. On long-term follow-up for 7 years, he remained metastasis free following surgical resection and was not treated with chemotherapy.

Introduction: Neonatal thyrotoxicosis is a life-threatening condition with potentially irreversible neurologic sequelae. Most cases are seen in neonates born to mothers with Graves' disease. Topical iodine-induced hypothyroidism has been reported in neonates, but iodine-induced neonatal hyperthyroidism has not been described; albeit a familiar entity in adults., Case Description: Herein we present a unique case of a neonate, born with a giant omphalocele, who was treated with topical povidone-iodine dressings to promote escharification, in preparation for delayed surgical closure. By third day of life (DOL), the baby presented with a suppressed thyroid stimulating hormone of 0.59 µIU/mL, elevated free thyroxine of 5.63 ng/dL, and frank cardiovascular manifestations of thyrotoxicosis. After replacement of the topical iodine dressings with iodine-free silver sulfadiazine, the thyroid status gradually improved with complete resolution of hyperthyroidism by 17th DOL., Conclusion: This case emphasizes that significant topical iodine exposure can result in both hypothyroidism and hyperthyroidism, and therefore, vigilance in monitoring thyroid function is imperative.

Background: Current clinical practice is to evaluate children presenting with premature adrenarche (PA) for non-classical congenital adrenal hyperplasia (NC-CAH). Our main objective was to assess the prevalence of NC-CAH among children presented with PA. Additional objectives were to ascertain whether subpopulations were prone to NC-CAH, and therefore justified to be tested, and if obesity is a factor that can exclude the need for CAH testing., Methods: A retrospective chart review of all children ≤11 years, who presented to our clinic with PA between January 2012 and May 2015 (n=103) was conducted. PA was defined based on commonly accepted clinical criteria., Results: We did not identify any subjects with NC-CAH but one was affected with previously undiagnosed classical simple virilizing CAH (SV-CAH). The subject was born prior to the implementation of CAH newborn screening in the state of birth. The affected subject was of Middle Eastern origin and also obese (BMI >95 percentile for age and sex)., Conclusions: Undiagnosed CAH is an uncommon cause of PA, and therefore routine screening for NC-CAH in every case of PA may not be justified, although, perhaps, should still be considered in high risk ethnicities. Obesity does not appear to exclude the possibility of being affected with mild or NC-CAH.

Inhaled corticosteroids (ICSs) are widely used as first-line treatment for various chronic respiratory illnesses. Advances in devices and formulations have reduced their local adverse effects. However, as delivery of ICSs to the lungs improves, the systemic absorption increases, and an adverse effect profile similar to, although milder than, oral corticosteroids has emerged. The most serious potential adverse effect is adrenal insufficiency, which can be life threatening. Adrenal insufficiency occurs most in patients taking the highest doses of ICSs but is reported with moderate or even low doses as well. Our recommendations include greater vigilance in testing adrenal function than current standard practice. In patients with diabetes mellitus (types 1 and 2), an increase in glucose levels is likely, and diabetes medication adjustment may be needed when initiating or increasing ICSs. The risk of linear growth attenuation and adverse effects on bone mineral density is generally low but should be considered in the face of additional risk factors. On behalf of the Pediatric Endocrine Society Drugs and Therapeutics Committee, we present a review of the endocrine adverse effects of ICSs in children and offer recommendations relating to testing and referral. Limited data in particular realms diminish the strength of certain recommendations, and clinical judgment continues to be paramount.

Purpose: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two., Methods: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays., Results: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling., Conclusion: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

Context: Although vitamin D toxicity is rare in children, increased use of vitamin D formulations, re-examination of optimal vitamin D levels, and use of higher doses lend potential for an increased incidence of vitamin D toxicity., Evidence Acquisition: A PubMed search was conducted through May 2013 for cases of vitamin D intoxication and vitamin D trials in pediatrics. Safety data were collected and reviewed., Evidence Synthesis: A small number of pediatric studies tested vitamin D doses at or above the currently recommended upper tolerable intake. In children and adolescents, vitamin D excess was rare and usually asymptomatic. Recent cases of intoxication relate to errors in manufacturing, formulation, or prescription; involve high total intake in the range of 240,000 to 4,500,000 IU; and present with severe hypercalcemia, hypercalciuria, or nephrocalcinosis. However, mild hypercalcemia and hypervitaminosis using currently recommended doses have been reported in infants with rickets., Conclusions: Although rare, cases of vitamin D intoxication that present with dramatic life-threatening symptoms still occur in children. Moreover, recent studies in infants raise a potential need for monitoring vitamin D levels when doses at or above the currently recommended upper range are used. Further studies are needed to clarify these findings. The Drugs and Therapeutics Committee of the Pediatric Endocrine Society suggests obtaining serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended.

Excessive thyroid hormone production, as seen in Graves' disease, stimulates osteoblast-mediated bone turnover in favor of bone resorption. Acute reversal of bone resorption can lead to hungry bone syndrome (HBS), a state of rapid calcium deposition into newly synthesized osteoid resulting in hypocalcemia. Hypocalcemia due to subsequent functional or relative hypoparathyroidism is a recognized complication of therapy for Graves' disease. HBS is most recognized as an outcome of rapid correction of vitamin D deficiency or of acute hypoparathyroidism in cases of parathyroid gland function disruption after surgical removal of the thyroid. We report the case of an adolescent boy with Graves' disease who presented with hypocalcemia after radioactive iodine (131I) therapy due to HBS. Our report highlights the risk of HBS and severe hypocalcemia following treatment for Graves' disease in pediatric patients and also underscores the importance of pretreatment assessment and intervention for coexistent vitamin D deficiency.

CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly; to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis.

Context: FGFR1 mutations have been identified in about 10% of patients with Kallmann syndrome. Recently cases of idiopathic hypogonadotropic hypogonadism (IHH) with a normal sense of smell (nIHH) have been reported., Aims: The objective of the study was to define the frequency of FGFR1 mutations in a large cohort of nIHH, delineate the spectrum of reproductive phenotypes, assess functionality of the FGFR1 mutant alleles in vitro, and investigate genotype-phenotype relationships., Design: FGFR1 sequencing of 134 well-characterized nIHH patients (112 men and 22 women) and 270 healthy controls was performed. The impact of the identified mutations on FGFR1 function was assessed using structural prediction and in vitro studies., Results: Nine nIHH subjects (five males and four females; 7%) harbor a heterozygous mutation in FGFR1 and exhibit a wide spectrum of pubertal development, ranging from absent puberty to reversal of IHH in both sexes. All mutations impair receptor function. The Y99C, Y228D, and I239T mutants impair the tertiary folding, resulting in incomplete glycosylation and reduced cell surface expression. The R250Q mutant reduces receptor affinity for FGF. The K618N, A671P, and Q680X mutants impair tyrosine kinase activity. However, the degree of functional impairment of the mutant receptors did not always correlate with the reproductive phenotype, and variable expressivity of the disease was noted within family members carrying the same FGFR1 mutation. These discrepancies were partially explained by additional mutations in known IHH loci., Conclusions: Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity.

Idiopathic Hypogonadotropic Hypogonadism (IHH), a syndrome of GnRH deficiency, is characterized by varying degrees of sexual development disruption. When associated with anosmia, it is termed Kallmann Syndrome (KS). Although it was identified as a hereditary disorder over half a century ago, only during the last two decades have specific putative IHH genes been revealed, including: KAL1, GnRHR, FGFR1, GPR54, PROK2, PROKR2, FGF8, CHD7, TAC3 and TAC3R. Human mutations have shed light on the molecular control of GnRH neuronal embryogenesis and have elucidated elements critical in sexual development. Furthermore, the newly proposed oligogenic model has challenged the dogma of IHH being a single gene disorder and has heightened appreciation for the functional overlap of distinct signaling systems. This review offers an historical perspective to gene discoveries in IHH, genotype-phenotype correlations, and finally, discussion of the evolving complexity of the new IHH genetic model, no longer simply characterized by Mendelian inheritance.

Type 2 diabetes mellitus is a chronic disease with potentially devastating long-term complications. Despite the tremendous body of research and experience in the adult population, relatively little is established regarding this condition and its optimal management in children and adolescents. The pediatric community awaits results of ongoing trials as well as further study of optimal intervention in children, as they continue to extrapolate management practices from their adult counterparts.