Postoperative Diabetes Insipidus and Hyponatremia in Children after Transsphenoidal Surgery for Adrenocorticotropin Hormone and Growth Hormone Secreting Adenomas.

OBJECTIVES: To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas. STUDY DESIGN: We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH). RESULTS: Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P < .001), or invasion 4 of 15 (P = .022) of the PP. Sixty patients developed hyponatremia, 19 because of SIADH, 39 to hypotonic fluids and 2 to cerebral salt wasting syndrome. Patients with SIADH were placed on fluid restriction; 1 received salt tablets. CONCLUSIONS: Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00001595 and NCT00060541.

Kidney Stones as an Underrecognized Clinical Sign in Pediatric Cushing Disease.

OBJECTIVE: To investigate the prevalence of kidney stones in a population of children with Cushing disease (CD) and to compare it with the prevalence of kidney stones in healthy children. STUDY DESIGN: Clinical and biochemical data from 139 pediatric patients with CD (68 females, 71 males) were analyzed retrospectively. Computed tomography scans were reviewed for kidney stones. RESULTS: Among 139 patients, 27 with CD (19.4%) had either radiographic evidence and/or a history of kidney stones. Those with kidney stones had higher urine free cortisol (P = .008) and transsphenoidal surgery at an older age (P = .007). The average urinary calcium/creatinine ratio was elevated in patients with CD (0.22 ± 0.11). The prevalence of kidney stones was higher in children with CD than in normal children (19.42% vs 1.0%; P < .001). CONCLUSION: Our results illustrate that kidney stones are an underestimated complication of pediatric CD, especially when compared with the prevalence of nephrolithiasis in the general pediatric population. Long-term consequences for kidney function are not known and need to be studied.

Skeletal maturation in children with Cushing syndrome is not consistently delayed: the role of corticotropin, obesity, and steroid hormones, and the effect of surgical cure.

OBJECTIVE: To assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements. STUDY DESIGN: This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA. RESULTS: Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001). CONCLUSION: Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

Effects of Cushing disease on bone mineral density in a pediatric population.

OBJECTIVE: To evaluate bone mineral density (BMD) in children with Cushing disease before and after transphenoidal surgery (TSS). STUDY DESIGN: Hologic dual-energy x-ray absorptiometry (DXA) scans of 35 children with Cushing disease were analyzed retrospectively. Sixteen of the 35 patients had follow-up DXA scans performed 13 to 18 months after TSS. BMD and bone mineral apparent density (BMAD) for lumbar spine (LS) L1 to L4 and femoral neck (FN) were calculated. RESULTS: Preoperatively, 38% and 23% of patients had osteopenia of the LS and FN, respectively. Both BMD and BMAD Z-scores of the LS were worse than those for the FN (-1.60 +/- 1.37 versus -1.04 +/- 1.19, P = .003), and (-1.90 +/- 1.49 versus -0.06 +/- 1.90, P < .001); postoperative improvement in BMD and BMAD were more pronounced in LS than in the FN (0.84 +/- 0.88 versus 0.15 +/- 0.62, P<.001; and 0.73 +/- 1.13 versus -0.26 +/- 1.21, P = .015). Pubertal stage, cortisol levels, and length of disease had no effect on BMD. CONCLUSIONS: In children with Cushing disease, vertebral BMD was more severely affected than femoral BMD and this effect was independent of degree or duration of hypercortisolism. BMD for the LS improved significantly after TSS; osteopenia in this group may be reversible.

Insulin resistance, hyperinsulinemia, and energy intake in overweight children.

OBJECTIVE: To examine the relationship between energy intake during a buffet meal and indexes of insulin dynamics in overweight children. STUDY DESIGN: Ninety-five nondiabetic, overweight (body mass index > or = 95th percentile) children (age 10.3 +/- 1.4 years) selected lunch from a 9835-kcal buffet eaten ad libitum after an overnight fast. The associations between energy intake and measures of insulin dynamics, in the postabsorptive state and during a 2-hour hyperglycemic clamp, were determined. Covariates in the statistical model included race, sex, skeletal age, fat-free mass, fat mass, socioeconomic status, and number of foods in the buffet rated as acceptable. RESULTS: Energy intake was positively associated with the fasting homeostasis model assessment for insulin resistance index (beta = 0.24, P = .042), fasting insulin/glucose ratio (beta = 0.24, P = .044), first-phase insulin (beta = 0.23, P = .032), and first-phase C-peptide (beta = 0.21, P = .046); energy intake was negatively associated with clamp-derived insulin sensitivity (beta = -0.29, P = .042). Each 10% decrease in clamp-derived insulin sensitivity predicted a 27-kcal greater energy intake. CONCLUSIONS: Insulin resistance and hyperinsulinemia are associated with greater energy intake after an overnight fast in overweight children. These associations suggest mechanisms whereby insulin resistance may contribute to excessive weight gain in children.

Health-related quality of life in overweight and nonoverweight black and white adolescents.

OBJECTIVES: To assess the impact of obesity on quality of life (QOL) in black and white adolescents. STUDY DESIGN: One hundred ten overweight (body mass index [BMI], 41.7 +/- 8.9 kg/m2) and 34 nonoverweight adolescents (BMI, 20.6 +/- 2.9 kg/m2) and their parents completed measures of QOL. RESULTS: Overweight was associated with poorer adolescent-reported QOL and parent reports of their children's QOL. Examining groups by weight status and race, overweight whites reported the greatest impairment on Social/Interpersonal, Self-Esteem, and Physical Appearance QOL (all P < .01), whereas parents of overweight blacks reported the poorest General Health Perceptions scores regarding their children. Interactions between BMI z-score and race were detected for Social/Interpersonal, Self-esteem, Daily Living, Self-Efficacy, Self-regard, and Physical Appearance QOL (all P < .05): Higher BMI in whites was associated with greater impairments in QOL than in blacks. Parents reported similar relations for their children. CONCLUSIONS: According to adolescent and parent reports, overweight is associated with poorer QOL in adolescence, regardless of race; however, compared with overweight white adolescents, blacks report less impairment in QOL. Future research is required to determine whether differences in QOL are predictive of treatment success.

Differences in insulin secretion and sensitivity of Caucasian and African American prepubertal children.

OBJECTIVE: To investigate whether differences in body composition of African American children (AA) and Caucasian children (C) explain differences in insulin sensitivity and secretion. STUDY DESIGN: Prepubertal nondiabetic children (31 AA and 54 C) were studied; 84% were overweight. Participants underwent a 2-hour hyperglycemic clamp, to estimate insulin sensitivity (SI(clamp)) and secretion, and dual energy x-ray absorptiometry, to assess body composition. RESULTS: AA had greater total body fat mass (P =.01), fasting, 1st phase, 2nd phase, and steady state insulin levels (P <.05). AA and C had similar glucose disposal rates, but AA had lower SI(clamp) (P <.05). Fasting, 1st phase, and steady state C-peptide were less in C (P <.05), whereas corresponding C-peptide/insulin ratios were higher (all P <.005). Insulin levels and SI(clamp) remained different in AA and C after adjustment for body fat or lean mass differences. Analyses restricted to only overweight AA and C showed similar trends. CONCLUSION: Prepubertal African American children have higher baseline and glucose-stimulated insulin and C-peptide levels, as well as reduced insulin sensitivity that is not entirely explained by differences in adiposity. The lower C-peptide/insulin molar ratio in AA suggests that they probably have lower hepatic insulin clearance than Caucasian children.