Cushing's Syndrome in Pediatrics: An Update.

Cushing syndrome (CS) in childhood results mostly from the exogenous administration of glucocorticoids; endogenous CS is a rare disease. The latter is the main reason pediatric patients with CS escape diagnosis for too long. Other barriers to optimal care of a pediatric patient with CS include improper following of the proper sequence of testing for diagnosing CS, which stems from lack of understanding of pathophysiology of the hypothalamic-pituitary-adrenal axis; lack of access to proper (i.e., experienced, state-of-the-art) surgical treatment; and unavailability of well-tolerated and effective medications to control hypercortisolemia. This report reviews the state-of-the-art in diagnosing CS and provides an update on the most recent discoveries in its genetics and treatment.

An update on Cushing syndrome in pediatrics.

Cushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section. 

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Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP) on diagnosis of Cushing's syndrome.

Many studies have described the relationship between kidney stones and stroke, but the results are controversial, so we conducted this meta-analysis to estimate the relationship between kidney stones and the risk of developing stroke. Studies were marked with a comprehensive search of PubMed, EMBASE, Google, and ISI Web of Science databases through 25 March 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted, and a random-effects model or fix-effects model was used to compute the pooled combined risk estimate. Heterogeneity was reported as I2. We performed subgroup and sensitivity analysis to assess potential sources of heterogeneity. Eight studies of seven articles involving 3,526,808 participants were included in the meta-analysis. Overall, kidney stones were associated with a moderate risk of stroke incidence (HR, 1.24; 95% CI, 1.11–1.40; I2=79.6%; p=0.000). We conducted a sensitivity analysis by removing the studies that had a high risk of bias. Heterogeneity subsequently decreased significantly, while an increased risk of stroke in patient with kidney stones was again demonstrated (HR, 1.16; 95% CI, 1.11–1.23; I2=28.7%; p=0.000). Stratifying analysis showed that the results were more pronounced for ischemic stroke (HR, 1.14; 95% CI, 1.08–1.22; I2=15.6%; p=0.00) and the follow-up duration ≥10 years (HR, 1.18; 95% CI, 1.10–1.27; I2=31.6%; p=0.003). Our meta-analysis suggests that patients with kidney stones may have a modestly increased risk of developing stroke, especially in ischemic stroke. More large-scaled and clinical trials should be done to identify the relative impact of kidney stones on stroke outcomes in the future.

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Association between kidney stones and risk of developing stroke: a meta-analysis.

Pituitary corticotroph adenomas (causing Cushing disease, CD) are the most common cause of endogenous Cushing syndrome (CS) in children although their prevalence varies within age groups. The initial workup of a patient suspected to have CS involves the demonstration of hypercortisolemia and/or excess urinary free cortisol excretion, the loss of the normal circadian rhythm of cortisol production, and the lack of suppression of cortisol secretion after low-dose dexamethasone suppression test. The identification of the source of CS involves the measurement of the morning corticotropin (ACTH) levels, imaging studies (pituitary magnetic resonance imaging and adrenal gland computed tomography), and other tests, including high-dose dexamethasone suppression and corticotropin-releasing hormone (CRH) stimulation. The first-line management of CD is the transsphenoidal (TSS) resection of the pituitary adenoma. In cases where TSS fails, radiation and/or medical therapy and medical or surgical (bilateral) adrenalectomy may eventually lead to control of the hypercortisolemia.

Cushing Disease: Diagnosis and Treatment

Kidney Stones as an Underrecognized Clinical Sign in Pediatric Cushing Disease

We report here a pediatric patient whose Cushing's Disease was diagnosed late because of her cyclical presentation, presumably due to subclinical pituitary apoplexy. Starting at age 8, she presented with observable signs of Cushing's but was not clinically assessed for Cushing's Syndrome until the age of 15. Initial tests at age 15 were consistent with Cushing's Disease, however, the patient presented with spontaneous remission of hypercortisolemia just a few short months later. Her cushingoid features never subsided, and at age 17, her MRI showed a partially empty sella; this finding of an empty sella contributed evidence to our suspicion of asymptomatic apoplexy, especially since the patient never reported an episode of acute headache. Pituitary apoplexy in corticotroph adenomas is very uncommon, but even more rare in microadenomas, making this case very unusual. Lost to follow-up, she was not reevaluated for Cushing's Disease until age 25, and her laboratory tests were consistent with an adrenocorticotrophic-dependent pituitary tumor; Pituitary magnetic resonance imaging revealed a 9 mm X 6 mm X 8 mm mass projecting on the superior aspect of pituitary and abutting the wall of the right cavernous sinus. The patient had a transsphenoidal surgery to remove the microadenoma and is planned to undergo radiation therapy. To the best of our knowledge, this is the first report of subclinical apoplexy of a microadenoma in a pediatric patient with Cushing's Disease. It brings to light the importance of long term follow up for pediatric patients presenting with clinical symptoms of Cushing's Syndrome.

Sara H. Rahman

Papers

Kidney Stones as an Underrecognized Clinical Sign in Pediatric Cushing Disease

Delayed Diagnosis of Cushing's Disease in a Pediatric Patient due to Apparent Remission from Spontaneous Apoplexy.