Cushing syndrome (CS) is a multisystem disorder resulting from the prolonged exposure to excess glucocorticoids. In children, CS most commonly results from the exogenous administration of steroids and the typical presentation is height deceleration concomitant with weight gain. Endogenous and ectopic causes are rare. CS in children may be associated with distinct germline and somatic mutations. Clinical practice guidelines are available assist clinicians. Patients should be referred to multidisciplinary centers of excellence with experience in endocrinology and surgery. Early detection and treatment is essential to reduce associated acute and long-term morbidity and potential death.

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Cushing syndrome (CS) in children is rare. Delayed diagnosis and treatment of CS may be associated with increased morbidity and, unfortunately, mortality. We performed a retrospective review of all patients with CS under the age of 18 years referred to the National Institutes of Health (NIH) from 1998 to 2013 in order to describe deceased patients among cases of pediatric CS referred to the National Institutes of Health (NIH). The deaths of four children (three females and one male), aged 7.5-15.5 years (mean age 11.2 years) with length of disease 2-4 years, were recorded among 160 (2.5 %) children seen at or referred to the NIH over the last 15 years. All died at different institutions, prior to coming to the NIH (two) or after leaving NIH (two). Presenting symptoms included increasing weight and decreasing height gain, facial plethora, dorsocervical fat pad (webbed neck), striae, headache, vision disturbances, and depression and other mood or behavior changes; there were no differences between how these patients presented and the others in our cohort. The causes of CS in the deceased patients were also not different, in fact, they spanned the entire spectrum of CS: pituitary disease (one), ectopic corticotropin production (one), and primary adrenal hyperplasia (one). In one patient, the cause of CS could not be verified. Three died of sepsis and one due to residual disease and complications of the primary tumor.

Conclusions

Despite the advances in early diagnosis and treatment of pediatric CS, a 2.5 % mortality rate was identified in a large cohort of patients with this condition referred to an experienced, tertiary care referral center (although these deaths occurred elsewhere). Pediatricians need to recognize the possibility of death, primarily due to sepsis, in a patient with pediatric CS and treat accordingly.

Objective

To analyse gender differences in the clinical presentation and recovery of paediatric patients with Cushing's disease (CD) after transsphenoidal surgery (TSS). Indeed, gender differences between paediatric patients with CD during presentation, after TSS and postoperative recovery have not been adequately studied.

Design

Data were obtained and retrospectively analysed from clinical reports and biochemical tests at the time of presentation, 5-9 days after TSS and at the 6 and 12 months postoperative follow-up visits to determine hypothalamic-pituitary-adrenal axis (HPAA) recovery.

Patients

Data from 102 paediatric patients (48 females, 54 males, mean age 12.9 ± 3.0) with CD who underwent TSS at the National Institute of Health (NIH) Clinical Center between 1997 and 2011.

Results

There was equal distribution of paediatric CD between males and females (53% vs 47%; n = 102, P = 0.484). Males were more likely than females to present with higher mean BMI Z-scores (2.2 ± 0.7 vs 1.9 ± 0.6, P = 0.0079), lower mean height Z-scores (-1.2 ± 1.3 vs -0.7 ± 1.1, P = 0.0467) and higher median plasma ACTH (12.2 vs 8.5 pmol/l; P = 0.0495). Females did not present more frequently with any single sign or symptom. No significant differences were found between males and females for CD cure rates 5-9 days after TSS (87.0% males vs 87.5% females, P = 1.0), long-term cure rates (86.5% vs 93.7%; n = 69; P = 0.4374) and HPAA recovery time (11.2 ± 2.5 vs 11.7 ± 2.5 months; n = 47; P = 0.1992).

Conclusions

Paediatric CD is found to have equal distribution between males and females, but male patients present with elevated BMI and potentially shorter height and higher plasma ACTH. There is no significant difference in the cure rate or HPAA recovery time after TSS between males and females.

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.

Objective

Cushing disease (CD) is a rare entity caused by ACTH-secreting pituitary tumours, leading to prolonged hypercortisolism. Most cases are sporadic but can rarely occur in the context of familial predisposition, due to germline mutations in genes such as MEN1, leading to multiple endocrine neoplasia type 1, MEN1. We have reported previously that CD can be the first and only presenting manifestation of MEN1. In this report, we describe a cohort of paediatric patients who presented with CD as the first manifestation of MEN1.

Materials and methods

A retrospective analysis of paediatric patients admitted to the National Institutes of Health (NIH) Clinical Center for evaluation of hypercortisolism, between 1997 and 2017. MEN1 was diagnosed on a clinical, familial and/or genetic basis.

Results

Of a total of 238 children with CD, six patients were subsequently diagnosed with MEN1, three males and three females with a mean age at diagnosis of CD at 13.4 ± 2.9 years. Five of the six patients had familial MEN1 and one patient was a sporadic case. Additional manifestations of MEN1 included primary hyperparathyroidism in three patients and hyperprolactinemia in two patients.

Discussion

This report describes a paediatric patient population with MEN1 in whom CD was the initial manifestation, confirming a previous observation that paediatric patients with MEN1 may present first with an ACTH-producing adenoma. Therefore, germline MEN1 mutations should be sought in paediatric CD and tested for when there is a suggestive family history and/or other manifestations.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.