pediatric | CushieBlog

Genetic mutation lowers obesity in Cushing’s syndrome

Posted on January 5, 2026 by MaryO

London E. J Clin Endocrinol Metab. 2013; doi:10.1210/jc.2013-1956.

Among adult patients with Cushing’s syndrome, those with mutations in PRKAR1A, the gene that controls cAMP-dependent protein kinase, are less obese than their counterparts without these mutations, according to a recent study.

The retrospective study evaluated adrenalectomy samples from 51 patients with Cushing’s syndrome, 13 with PRKAR1A mutations and 32 without. Of the 51 patients, 40 were female and 11 were male, and patients ranged in age from 4 to 74 years.

A non-Cushing’s syndrome comparison group consisting of 6 adrenalectomy patients with aldosterone producing adenomas (APAs) was included. Additional comparison groups comprising clinical data from 89 patients with Cushing’s disease and 26 with hyperaldosteronism were also studied.

Researchers recorded the weight, height and BMI of all patients, and measured abdominal subcutaneous adipose tissue (ScAT) and periadrenal adipose tissue (PAT) using computed tomography. PAT was collected and frozen for evaluation; the extracts were assessed for levels of cAMP and protein kinase (PKA) activity, as well as for protein and mRNA expression of subunits of PKA. Diurnal cortisol levels and urine-free cortisol were also measured preoperatively.

The study found that in adults with Cushing’s syndrome, the mean BMI of those with PRKAR1A mutations was lower than that of patients with noPRKAR1A mutations (P<.05), and was not inconsistent with the hyperaldosteronism comparison group.

In pediatric patients with adrenal Cushing’s syndrome, the presence of PRKAR1A mutation did not have an impact on mean BMI z-scores. However, in comparison with pediatric patients with pituitary Cushing’s disease, the BMI z-scores were significantly lower in pediatric Cushing’s disease patients with PRKAR1Amutations (P<.05). Patients with Cushing’s syndrome without PRKAR1A mutations had significantly more PAT and ScAT than non-Cushing’s syndrome patients. Additionally, the ratio of basal-to-total (cAMP-triggered) PKA activity was significantly lower in patients with PRKAR1A mutations, suggesting greater proportions of active PKA (P<.005).

“These findings have obvious implications in the establishment of the diagnosis of CS in patients with PRKAR1A mutations: These patients may be leaner than other patients with [Cushing’s syndrome],” the study authors wrote. “Perhaps more importantly, our findings point to the importance of cAMP and or PKA signaling in the regulation of adiposity.”

Disclosures: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B693f94cd-359d-4c52-8e0d-bfd0e4a51d03%7D/genetic-mutation-lowers-obesity-in-cushings-syndrome

Filed under: adrenal, Cushing's, pituitary, Rare Diseases | Tagged: abdominal subcutaneous adipose tissue, adenoma, adrenalectomy, adult, aldosterone, BMI, cAMP-dependent protein kinase, cortisol, Cushing's Syndrome, diurnal, gene, genetic, hyperaldosteronism, obesity, pediatric, periadrenal adipose tissue, pituitary, PRKAR1A, ScAT, study, UFC, urine free cortisol | Leave a comment »

The Neurosurgical Outcome of Pediatric Cushing’s Disease in a Single Center From China: A 20-Year Experience

Posted on September 29, 2025 by MaryO

Objective: Pediatric Cushing’s disease (CD) is exceptionally rare and poses significant diagnostic and therapeutic challenges. This study aimed to review the diagnostic features and to evaluate the long-term surgical outcomes of transsphenoidal surgery (TSS) in Pediatric CD patients at a single tertiary center in China over two decades.

Methods: A retrospective analysis included 22 pediatric CD patients (10 male, 12 female; mean age 15.8 ± 2.5 years) who underwent TSS between 2002 and 2022. Diagnosis was established through a multidisciplinary protocol involving standardized biochemical testing (LDDST, HDDST), bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin stimulation (n=19), and high-resolution pituitary MRI. Microscopic TSS (MTSS) was performed before 2016 (n=11) and endoscopic TSS (ETSS) thereafter (n=11). Surgical strategy was guided by MRI and BIPSS findings. Immediate remission was defined as a postoperative serum cortisol nadir <5 μg/dL or normal 24-h urinary free cortisol (UFC). Recurrence was defined as the reappearance of hypercortisolism after remission. Mean follow-up was 29.4 months (range 2-129).

Results: MRI identified the adenoma in 18/22 patients (81.8%; 16 microadenomas, 2 macroadenomas). BIPSS indicated lateralization in 14/19 patients (73.7%), with concordance between BIPSS and MRI lateralization in 57.9% (11/19) of cases. Immediate postoperative remission was achieved in 20 patients (90.9%). The two non-remitters (one macroadenoma, one MRI- and pathology-negative) received additional therapies. Among the 20 patients with initial remission, 2 (10.0%) developed recurrence (one microadenoma, one MRI-negative) during follow-up. The sustained long-term remission rate was 81.8% (18/22).

Conclusion: Transsphenoidal surgery represents a highly effective first-line treatment for pediatric CD, achieving high rates of immediate (90.9%) and long-term remission (81.8%) in a specialized center. A meticulous diagnostic approach incorporating BIPSS is crucial, particularly for MRI-negative cases. While recurrence occurred in a minority of patients, primarily those with microadenomas, durable disease control is attainable for the majority with appropriate surgical management. The transition to endoscopic techniques was feasible and effective.

Introduction

Cushing’s disease (CD), caused by excessive ACTH secretion from a pituitary corticotroph adenoma, is a rare disorder with an estimated prevalence of approximately 10 cases per 100,000. Its incidence is even lower in children, representing about 5% of adult cases (1). CD accounts for 75-80% of Cushing’s syndrome in pediatric patients (2, 3). Clinical manifestations include weight gain, facial rounding (“moon facies”), hypertension, fatigue, and pubertal arrest. If untreated, pediatric CD can severely impair quality of life and lead to significant morbidity and mortality.

Diagnosis of pediatric CD is frequently delayed due to atypical symptoms and remains significantly challenging for pediatricians and pediatric endocrinologists (4). It relies on standardized biochemical evaluation and neuroimaging. Transsphenoidal pituitary surgery (TSS), encompassing both microscopic and endoscopic approaches, remains the preferred treatment for pediatric CD. However, as the majority of pituitary adenomas in pediatric CD are microadenomas or radiologically occult, TSS poses significant technical challenges for neurosurgeons (5).

Here, we present a review of the diagnostic features and surgical outcomes of 22 pediatric CD patients treated at a single center in China over a 20-year period.

Patients and methods

Between 2002 and 2022, 519 patients underwent TSS for CD performed by a single neurosurgical team in the Department of Neurosurgery, Ruijin Hospital. Twenty-six patients aged 18 years or younger were initially identified as pediatric; four were excluded due to incomplete data or insufficient follow-up. Clinical features of the remaining 22 pediatric patients (10 male, 12 female) were retrospectively reviewed. Mean age at surgery was 15.8 ± 2.5 years (range 9-18), and mean symptom duration prior to diagnosis was 32.0 ± 30.8 months (range 3-108). Mean BMI was 26.4 ± 6.4 (range 18.0-39.7) (Table 1). Presenting symptoms included weight gain (18/22), acne (13/22), hirsutism (12/22), moon facies (18/22), striae (19/22), central obesity (10/22), pubertal delay or arrest (4/22), irregular menses (3/12 females), headaches (3/22), visual deficits (2/22), hypertension (7/22), and type 2 diabetes mellitus (2/22) (Table 2).

Table 1

Table 1. The demographic information of 22 patients at diagnosis of CD.

Table 2

Table 2. Clinical signs and symptoms of 22 patients at diagnosis of CD.

Diagnosis of CD was confirmed by a multidisciplinary team comprising radiologists, endocrinologists, interventional radiologists, pediatricians, and neurosurgeons. Clinical manifestations, plasma cortisol circadian rhythm, low-dose dexamethasone suppression test (LDDST, 2 mg dexamethasone), and high-dose dexamethasone suppression test (HDDST, 8 mg dexamethasone) were assessed by pediatricians or endocrinologists. Following the 2mg LDDST, the 48-hour serum cortisol level exceeded 1.8 μg/dL, indicating inadequate suppression. In contrast, after the 8mg HDDST, the 48-hour cortisol level was suppressed to <50% of baseline, demonstrating significant suppression. Bilateral inferior petrosal sinus sampling (BIPSS) with or without desmopressin (DDAVP) stimulation was performed by experienced interventional radiologists. Samples were immediately placed on ice after collection. All biochemical analyses were conducted in a College of American Pathologists-accredited laboratory (No. 7217913).

Preoperative pituitary magnetic resonance imaging (MRI) was performed at 1.5 T or 3.0 T in all patients. T1-weighted and T2-weighted spin-echo images were obtained in coronal and sagittal planes (2-mm slice thickness) before and after gadolinium injection. A dynamic coronal sequence was also acquired within 2 minutes post-injection (Table 3).

Table 3

Table 3. Preoperative endocrinological evaluation and neuroimaging results of 22 patients at diagnosis of CD.

The same surgical team performed TSS on all patients using a mononostril approach. Microscopic TSS (MTSS) was utilized in 11 patients treated before 2016, while endoscopic TSS (ETSS) was employed in the subsequent 11 patients. For patients with concordant MRI-identified adenomas and BIPSS lateralization, exploration focused on the imaging-identified region, and a rim of pituitary tissue surrounding the tumor cavity was resected. If the tumor involved the cavernous sinus (CS), the inner CS wall was also inspected/explored. If BIPSS lateralization conflicted with MRI findings, the pituitary side indicated by BIPSS was explored first. For MRI-negative tumors, exploration commenced on the side with higher ACTH levels on BIPSS (when available) and proceeded to complete gland inspection. If no adenoma was identified intraoperatively, approximately half of the gland was resected, guided by BIPSS results.

Immediate remission was defined as a postoperative serum cortisol nadir <5 μg/dL or normal 24-hour UFC. Recurrent hypercortisolism was defined as the reappearance of biochemical hypercortisolism after a period of hypocortisolism or clinical adrenal insufficiency. The concordance of BIPSS lateralization with MRI localization refers to whether the tumor side indicated by BIPSS corresponds to the tumor side identified on MRI.

Patients were followed in the outpatient clinic at regular intervals. If endocrine evaluations were performed at local hospitals, results were communicated to the authors via WeChat. Mean follow-up duration was 29.4 months (range 2–129 months).

Results

Preoperative plasma cortisol levels measured at three time points were: mean 28.10 μg/dL at 8:00 AM (range 14.70-125.62 μg/dL), 22.39 μg/dL at 4:00 PM (range 6.4-79.44 μg/dL), and 20.62 μg/dL at midnight (range 11.9-72.25 μg/dL). Mean preoperative plasma ACTH level at 8:00 AM was 95.21 pg/mL (range 12.51-272.6 pg/mL), and mean 24-hour UFC was 979.18 μg/24h (range 119.20-7669.48 μg/24h). HDDST was positive in 19/22 patients. BIPSS with DDAVP was performed in 19 patients, demonstrating lateralization in 14 patients (4/14 left, 10/14 right).

MRI localized an adenoma in 18/22 patients (81.8%), comprising 16 microadenomas and 2 macroadenomas. Tumor location on MRI was: right sellar (n=5), left sellar (n=8), and central sellar (n=5). Concordance between BIPSS lateralization and MRI localization was 57.89% (11/19).

Immediate postoperative remission was achieved in 20 patients (90.9%). The two patients without immediate remission (Case 2: macroadenoma; Case 6: MRI- and pathology-negative) received additional treatments (Case2: gamma knife radiosurgery; Case 6: ketoconazole). Among the 20 patients with initial remission, 2 (10.0%) experienced recurrence (Case 3: microadenoma; Case 10: MRI-negative). Case3 received pasireotide after recurrence; Case 10 underwent repeat TSS, which did not achieve remission. Subsequent gamma knife treatment also ultimately failed. Ketoconazole therapy was then initiated. The sustained long-term remission rate for the cohort was 81.8% (18/22).

In these cases, intraoperative bleeding was controlled in all cases, and no patient required transfusion. Case 10 experienced a CSF leak following repeat transsphenoidal surgery (TSS). All patients who achieved postoperative remission were administered cortisone replacement therapy. The requirement for levothyroxine replacement differed between groups: one child in the ETSS group (1/11) versus five patients in the MTSS group (5/11). For diabetes insipidus, oral desmopressin was administered to three patients in the ETSS group and two in the MTSS group (Table 4).

Table 4

Table 4. The neurosurgical outcome and follow-up results of 22 patients of CD.

Discussion

This 20-year single-center experience represents one of the largest reported cohorts of surgically managed pediatric Cushing’s disease patients. Our findings demonstrate that transsphenoidal surgery (TSS), whether microscopic (MTSS) or endoscopic (ETSS), is a highly effective first-line treatment for pediatric CD, achieving an immediate remission rate of 90.9% and a sustained long-term remission rate of 81.8%.

The diagnostic complexity of pediatric CD is highlighted by the significant diagnostic delay observed (mean 32.0 months) and the occurrence of MRI-negative cases (4/22, 18.2%). This aligns with established literature emphasizing the challenges of pediatric CD diagnosis stemming from its rarity, atypical presentation, and the high proportion of microadenomas or radiologically occult tumors (3, 4, 6–8). Our adherence to a rigorous multidisciplinary diagnostic protocol, incorporating standardized biochemical testing (LDDST, HDDST), BIPSS with DDAVP stimulation (performed in 19/22), and high-resolution dynamic pituitary MRI, reflects current best practices for confirming ACTH-dependent Cushing’s syndrome and tumor localization. The moderate concordance rate (57.89%) between BIPSS lateralization and MRI localization underscores their complementary roles, particularly in cases with equivocal imaging. BIPSS remains critical for guiding surgical exploration in MRI-negative or discordant cases, as evidenced by its use in our decision-making algorithm (9, 10).

Our immediate remission rate (90.9%) compares favorably with contemporary pediatric CD surgical series, which typically report rates between 70% and 98% (1–3, 8, 11–13). The two immediate surgical failures occurred in patients with a macroadenoma (Case 2) or an MRI- and pathology-negative diagnosis (Case 6), profiles consistently associated with lower remission rates. The long-term remission rate of 81.8% (18/22) is robust, although the recurrence rate of 10% (2/20 initially remitted patients) merits attention. Both recurrences arose in patients with microadenomas, one of whom was MRI-negative (Case 10). This recurrence rate falls within the reported range (5-30%) for pediatric CD and reinforces the need for lifelong endocrine surveillance (1, 14, 15). The relatively short mean follow-up (29.4 months) suggests that the true recurrence rate might be higher with extended observation, representing a limitation of this study.

Our experience reflects the evolution of surgical technique, with a transition from MTSS to ETSS after 2016. While the cohort size and follow-up duration preclude definitive conclusions regarding the comparative efficacy of MTSS versus ETSS in this specific pediatric population, both techniques yielded high success rates. In our group, no significant differences exist in remission or recurrence rates. However, regarding complications, ETSS demonstrates a lower incidence of hypopituitarism compared to MTSS, while the incidence of diabetes insipidus is similar. It should be noted, however, that this comparison remains limited by the small number of reported cases. The endoscopic approach offers theoretical advantages, such as wider panoramic visualization potentially aiding in the identification of small or laterally extending microadenomas, which are common in children. Larger, prospective studies with longer follow-up are warranted to directly compare outcomes between these surgical modalities in pediatric CD.

The spectrum of clinical manifestations observed (e.g., weight gain, moon facies, striae, hypertension, pubertal arrest/delay) demonstrates the profound multisystem impact of hypercortisolism in children. The notable prevalence of metabolic complications like hypertension (7/22) and type 2 diabetes mellitus (2/22), even in this young cohort, highlights the urgency of timely diagnosis and effective intervention to mitigate long-term morbidity (5, 16–18).

Limitations

This study shares the limitations inherent to retrospective, single-center designs. The modest sample size, though substantial for this rare condition, limits statistical power for subgroup analyses, such as rigorous comparison of MTSS vs. ETSS outcomes or identification of specific predictors of failure/recurrence. The mean follow-up period is relatively short for a disease with potential for late recurrence, long-term remission rates may be lower than reported, and the study could not capture long-term complications of TSS, particularly those affecting growth and development in pediatric patients. Detailed data on specific postoperative complications (e.g., diabetes insipidus, hypopituitarism) and pituitary function during follow-up would provide a more comprehensive assessment of treatment sequelae but were not the primary focus of this outcome report.

Conclusion

Despite the inherent diagnostic and therapeutic challenges of pediatric Cushing’s disease, transsphenoidal surgery performed in a specialized center achieves high rates of immediate and sustained remission. Our results support the efficacy of TSS as the primary treatment modality. A meticulous multidisciplinary diagnostic approach, including BIPSS when indicated, is crucial for success, particularly in MRI-negative cases. While recurrence remains a concern necessitating vigilant long-term follow-up, the majority of children with CD can attain durable disease control with appropriate surgical management. The transition to endoscopic techniques proved safe and effective, warranting further investigation in larger pediatric cohorts with extended follow-up.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by The ethics committee of Ruijin hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author contributions

BW: Methodology, Writing – original draft. HZ: Conceptualization, Data curation, Formal Analysis, Writing – original draft. TS: Methodology, Project administration, Writing – review & editing. JR: Data curation, Formal Analysis, Writing – original draft. QS: Resources, Supervision, Writing – review & editing. YS: Supervision, Writing – review & editing. LB: Supervision, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

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Keywords: Cushing’s disease, pediatric, transsphenoidal surgery, surgical outcome, surgical strategy

Citation: Wang B, Zhang H, Su T, Ren J, Sun Q, Sun Y and Bian L (2025) The neurosurgical outcome of pediatric Cushing’s disease in a single center from China: a 20-year experience. Front. Endocrinol. 16:1663624. doi: 10.3389/fendo.2025.1663624

Received: 10 July 2025; Accepted: 22 August 2025;
Published: 03 September 2025.

Edited by:

Sadishkumar Kamalanathan, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), India

Reviewed by:

Aleksandra Zdrojowy-Wełna, Wroclaw Medical University, Poland
Medha Bhardwaj, Mahatma Gandhi University of Medical Sciences Technology, India

Copyright © 2025 Wang, Zhang, Su, Ren, Sun, Sun and Bian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yuhao Sun, syh11897@rjh.com.cn; Liuguan Bian, Blg11118@rjh.com.cn

^†These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Filed under: Cushing's, pituitary, Treatments | Tagged: Bilateral inferior petrosal sinus sampling, BIPSS, pediatric, pituitary, remission, transphenoidal hyposection | Leave a comment »

Unilateral Adrenalectomy for Pediatric Cyclical Cushing Syndrome With Novel PRKAR1A Variant Associated Carney Complex

Posted on September 2, 2025 by MaryO

Abstract

Primary pigmented nodular adrenocortical disease is a rare cause of Cushing syndrome accounting for less than 1% of cases. We present a 9-year-old boy who presented at age 4 with cyclical Cushing syndrome and was eventually diagnosed with a novel, previously unreported, unpublished variant in PRKAR1A associated with Carney complex. He was treated with unilateral left adrenalectomy. At 1-year follow-up, he continues to be in remission of his symptoms of Cushing syndrome.

Carney complex, PPNAD, unilateral adrenalectomy, cyclical Cushing syndrome

Issue Section:

Case Report

Introduction

Cushing syndrome is characterized by prolonged exposure to excess glucocorticoids and is broadly classified as either ACTH-dependent or ACTH-independent [1, 2]. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome, characterized by bilateral adrenal hyperplasia with autonomous, hyperfunctioning nodules [1, 2]. Approximately 90% of PPNAD cases occur in the context of Carney complex, with isolated cases being exceedingly uncommon [1, 2].

PPNAD was first described in 1984 by Carney et al, who coined the term in a case series of 4 patients and a review of 24 previously reported cases [1]. In that series, patients presented with ACTH-independent Cushing syndrome and no radiographic evidence of adrenal tumors. All underwent bilateral adrenalectomy, with histopathology revealing bilateral pigmented nodules in otherwise small or normal-sized adrenal glands [1]. Histologically, the classic features of PPNAD include multiple small black or brown cortical nodules surrounded by an atrophic adrenal cortex—reflecting chronic ACTH suppression [1].

Clinically, PPNAD most often presents with cyclical Cushing syndrome, characterized by alternating periods of hypercortisolism and normocortisolemia [2]. This intermittent pattern poses a substantial diagnostic challenge, as biochemical confirmation requires detection of cortisol excess during active phases of the cycle.

Carney complex is a multiple neoplasia syndrome involving endocrine, cardiac, cutaneous, and neural tumors. First described by Carney et al in 1985, it is typically inherited in an autosomal dominant fashion. Approximately 70% of cases occur in familial settings, while the remaining 30% arise from de novo pathogenic variants [3, 4]. Over half of affected individuals harbor pathogenic variants in the PRKAR1A tumor suppressor gene on chromosome 17q24.2, while approximately 20% of cases are linked to alternate loci such as 2p16 [2, 4].

Diagnostic criteria for Carney complex include either 2 clinical manifestations or 1 clinical manifestation in combination with a pathogenic PRKAR1A variant or an affected first-degree relative [2]. The most common endocrine manifestation is PPNAD, reported in approximately 25% of patients with Carney complex, though this likely underestimates the true prevalence, as autopsy studies reveal histologic evidence of PPNAD in nearly all affected individuals [2].

The Endocrine Society clinical practice guidelines recommend bilateral adrenalectomy as the definitive treatment for PPNAD, effectively curing hypercortisolism but necessitating lifelong glucocorticoid and mineralocorticoid replacement therapy due to resultant adrenal insufficiency [5]. Unilateral adrenalectomy has emerged as an alternative approach, particularly in pediatric patients, with the potential to preserve endogenous adrenal function.

Herein, we present the case of a 9-year-old boy with Carney complex and cyclical Cushing syndrome due to PPNAD, successfully managed with unilateral adrenalectomy.

Case Presentation

A 4-year-old boy presented with a week-long history of facial swelling, hyperphagia, weight gain, and scrotal swelling. At presentation, his weight was 22 kg (99th percentile) and body mass index (BMI) was 18 kg/m² (96th percentile). Initial workup revealed normal 24-hour urinary free cortisol <0.0913 µg/day (SI: 274 nmol/day) with low urinary creatinine 215 mg/day (SI: 1.9 mmol/day) (normal reference range 973-2195 mg/day; SI: 8.6-19.4 mmol/day) suggesting an incomplete sample. A repeat collection produced similar results. A 1 mg dexamethasone suppression test demonstrated nonsuppressed cortisol (27.9 µg/dL; SI: 772 nmol/L), suggestive of Cushing syndrome.

Over 5 years, the patient experienced 2 to 3 episodes per year of rapid weight gain (20-50 lbs), facial flushing, abdominal distention, and mood changes. Despite persistent obesity (>97th percentile), linear growth remained normal.

Diagnostic Assessment

At age 7, midnight salivary cortisol was markedly elevated at 3.7 µg/dL (SI: 103 nmol/L) (normal reference range < 0.4 µg/dL; SI: < 11.3 nmol/L), raising suspicion for cyclical Cushing syndrome. Magnetic resonance imaging of the abdomen was negative for adrenal lesions. At age 8, during an active episode, 2 elevated salivary cortisol samples, 2.0 µg/dL (SI: 55.1 nmol/L) and 2.2 µg/dL (SI: 61.9 nmol/L) (normal reference range < 0.4 µg/dL; SI: < 11.3 nmol/L), were obtained. A high-dose dexamethasone suppression test yielded a low baseline cortisol 3.2 µg/dL (SI: 89 nmol/L) and nonsuppressed cortisol post-dexamethasone 3.0 µg/dL (SI: 83 nmol/L). Baseline ACTH was 7.7 pg/mL (SI: 1.7 pmol/L), suppressed to <3.2 pg/mL (SI: < 0.7 pmol/L) post-dexamethasone—consistent with ACTH-independent cortisol excess.

At age 9, the patient underwent the gold standard diagnostic testing for cyclical Cushing, the Liddle test. The test involves 6 days of urine collection: days 1 to 2 establish baseline urinary cortisol levels, days 3 to 4 assess response to low-dose dexamethasone, and days 5 to 6 evaluate response to high-dose dexamethasone. The patient’s cortisol increased paradoxically from 118.5 µg/day (SI: 327 nmol/day) to 402.0 µg/day (SI: 1109 nmol/day) over 6 days, consistent with PPNAD physiology. Genetic testing was performed with the following report: “A heterozygous variant, NM_002734.4(PRKAR1A):c.550-2_553delinsG, p.(Val184_Tyr185delinsAsp), was detected in exon 7 of this gene. This variant does not appear to have been reported in population (gnomAD, ESP, dbSNP) and clinical databases (ClinVar), or in the literature. The impact of this variant on RNA splicing as assessed by multiple algorithms (Alamut Suite) is: abolishment of canonical acceptor splice site. Based on the current evidence, this variant was classified as likely pathogenic, American College for Medical Genetics category 2”. Family testing revealed this to be a de novo pathogenic variant.

Further workup included echocardiogram and thyroid ultrasound, both of which were normal. During workup for scrotal swelling at initial presentation, the patient was found to have bilateral testicular masses with negative testicular cancer tumor markers: α-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase. The family declined invasive biopsy of these lesions. He was followed by pediatric urology with yearly serial ultrasound, and these were felt to be benign testicular tumors, presumed noncalcifying Sertoli cell tumors, associated with Carney complex (Fig. 1).

Figure 1.

Ultrasound of bilateral testicular lesions. A) Left testicle. B) Right testicle.

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Based on the presence of 2 major diagnostic criteria in combination with the molecular diagnosis of a likely pathogenic variant of PRKAR1A, the diagnosis of Carney complex was established.

Treatment

The patient was referred for surgical evaluation for consideration of adrenalectomy. A comprehensive discussion was conducted regarding the potential benefits and risks of unilateral vs bilateral adrenalectomy. The family was counseled that unilateral adrenalectomy might not fully resolve the hypercortisolemia and that a subsequent contralateral adrenalectomy could be necessary. In contrast, bilateral adrenalectomy would definitively address cortisol excess but result in permanent adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement. After multidisciplinary consultation with endocrinology and surgery, the decision was made to proceed with unilateral adrenalectomy.

Preoperative IV contrast-enhanced computed tomography (CT), reviewed by a physician experienced in PPNAD, demonstrated greater nodularity in the left adrenal gland compared to the right. Therefore, a laparoscopic left adrenalectomy was performed electively without intraoperative complications. The patient was discharged on postoperative day 1. At the time of surgery (age 9), his weight was 70 kg (100th percentile), and BMI was 31.6 kg/m² (99th percentile). The resected left adrenal gland was submitted for histopathologic evaluation. Gross examination revealed no overt nodularity (Fig. 2); however, microscopic analysis identified multiple pigmented cortical nodules consistent with PPNAD (Fig. 3).

Figure 2.

Left adrenal gland gross morphology. No macroscopic nodularity appreciable.

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Figure 3.

Hematoxylin and Eosin staining on microscopy of left adrenal gland demonstrating hyperpigmented nodule.

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Outcome and Follow-up

The patient was followed closely in the postoperative period and was last evaluated 11 months after adrenalectomy. He remained clinically well, with complete resolution of Cushingoid features and no evidence of recurrence. Since surgery, he had experienced significant weight loss of 11.4 kg, with a current weight of 58.6 kg and a BMI of 25 kg/m² (97th percentile).

In summary, this case describes a 9-year-old boy with ACTH-independent, cyclical Cushing syndrome secondary to PPNAD, associated with a de novo likely pathogenic variant in the PRKAR1A gene, consistent with Carney complex. Histopathologic analysis of the resected adrenal gland confirmed the diagnosis of PPNAD. At nearly 1 year post-unilateral adrenalectomy, the patient remains asymptomatic with no biochemical or clinical signs of disease recurrence.

Discussion

Diagnosis of cyclical Cushing is challenging due to the cyclical nature of the disease and the challenges with current available testing modalities. Late-night salivary cortisol testing was a more reliable screening tool in this case as the 24-hour urinary cortisol were affected by inaccurate collection. The cyclical nature of the disease, coupled with the necessity for appropriately timed testing, contributed to a prolonged interval before definitive diagnosis and treatment. Additionally, initial imaging was interpreted as normal, and it was only upon review by a clinician with expertise in PPNAD that subtle adrenal nodularity was identified on CT. Ultimately, the Liddle test and genetic testing were the highest yield for confirmation of disease. This test measures the suppressibility of endogenous cortisol following exogenous dexamethasone administration. In patients with PPNAD, a paradoxical increase in cortisol excretion may occur, attributed to glucocorticoid receptor–mediated activation of protein kinase A catalytic subunits [6]. The likely pathogenic variant found in this case is a novel, previously unreported, variant in the PRKAR1A gene. This rare variant impact both the canonical acceptor splice site in intron 6 as well as results in an in-frame protein change in exon 7 (Val184_Tyr185delinsAsp).

The treatment of PPNAD in the context of Carney complex is typically with bilateral adrenalectomy, as per Endocrine Society guidelines [5]. The drawback of bilateral adrenalectomy is the resultant adrenal insufficiency resulting in lifelong adrenal replacement. Unilateral adrenalectomy is an attractive option for the treatment of PPNAD given the ability to avoid adrenal insufficiency brought upon by bilateral adrenalectomy. Case reports and case series in adult patients have demonstrated variable success in unilateral treatment. In a case series of 17 patients with classic cyclical Cushing, 3 patients had recurrence of Cushing syndrome after unilateral adrenalectomy and were cured with contralateral adrenalectomy [7]. One patient had subtotal (<90%) left adrenalectomy and did not have recurrence with 66 years of follow-up [7].

A case series by Xu et al 2013 described 12 out of 13 patients with PPNAD successfully cured with unilateral adrenalectomy at median 47 months follow-up [8]. The side of adrenalectomy was selected based on CT/magnetic resonance imaging in 3 patients and adrenal iodine131-norcholesterol scintigraphy in the remaining. At our center, the iodine131-norcholesterol scintigraphy was not available so CT was the chosen imaging modality.

Ultimately, the efficacy and morbidity of unilateral adrenalectomy remains unclear. Furthermore, due to the rarity of PPNAD, the criteria for selection of patients who are candidates for unliteral adrenalectomy is challenging to establish. This case reports adds to the existing literature the clinical characteristics of one patient treated successfully by unilateral adrenalectomy.

Learning Points

Diagnosis of cyclical Cushing can be very challenging. Late-night salivary cortisol is more reliable than 24-hour urinary cortisol.
The paradoxical rise in cortisol in the Liddle test is confirmatory for cyclical Cushing, hence the testing should be considered early in affected patients.
Genetic testing assessing for Carney complex, PRAKA1A pathogenic variant, should be considered early in a patient with concern for cyclical Cushing and another system involved like testicular lesions.
Although bilateral adrenalectomy is the recommendation for PPNAD; in selected patients, unilateral adrenalectomy might provide several years of remission.

Acknowledgements

Thank you to Dr. Hong Wang, MD, PhD, DABMGG, FACMG, FCCMG, for her support on this project and in all things. Thank you to Dr. Andre Lacroix MD, FCAHS, for reviewing the preoperative CT adrenals with the team.

Contributors

All authors made individual contributions to authorship. F.B. was involved in the diagnosis and management of the patient. N.S. was responsible for the patient’s surgery. C.J.Z. was involved in the patient’s surgery and postoperative care. R.S., M.S., and P.W. were all medical professionals involved in his management and care. All authors contributed, reviewed, and approved the final draft.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient’s relatives or guardians

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Author notes

Natashia Seemann and Funmbi Babalola co-senior author.

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https://academic.oup.com/jcemcr/article/3/8/luaf155/8196447?login=false

Filed under: adrenal, Cushing's, Rare Diseases | Tagged: adrenalectomy, Carney Complex, cyclic, pediatric, PPNAD, Primary pigmented nodular adrenocortical disease, PRKAR1A, remission, unilateral adrenalectomy | Leave a comment »

A Case Series of Bilateral Inferior Petrosal Sinus Sampling Using Desmopressin for Evaluation of ACTH-Dependent Cushing’s Syndrome in Pediatric Patients

Posted on June 11, 2025 by MaryO

Abstract

Background

Pediatric Cushing Syndrome (CS) is rare and difficult to diagnose, especially when distinguishing ACTH-dependent subtypes. Bilateral inferior petrosal sinus sampling (BIPSS) is an essential but technically challenging procedure for this purpose. Because corticotropin-releasing hormone (CRH), the standard stimulant, has limitations, desmopressin is being explored as an alternative. This study assesses desmopressin-stimulated BIPSS for its diagnostic accuracy and tumor localization in pediatric CS within an Iranian cohort, addressing a gap in pediatric-specific diagnostic strategies and offering insights into the applicability of desmopressin in this context.

Methods

Four pediatric patients with inconclusive pituitary imaging and suspected Cushing’s disease (CD) underwent BIPSS with desmopressin at Taleghani Hospital, Tehran, Iran, between August 2015 and March 2019. Sensitivity of BIPSS for CD diagnosis was assessed, and tumor localization accuracy was evaluated during surgery.

Results

Bilateral IPSS demonstrated a sensitivity of 100% for diagnosing CD in pediatric patients. However, accuracy for tumor lateralization was moderate, with only 50% concordance between BIPSS lateralization and surgical findings. Specifically, two out of four patients had correct lateralization confirmed during surgery, while one patient with left lateralization was consistent with hypophysectomy findings. These discrepancies highlight challenges such as anatomical and drainage variations that can lead to mislocalization.

Conclusion

Desmopressin enhances the sensitivity of BIPSS for diagnosing pediatric CD, presenting as a viable alternative to CRH stimulation. Despite high sensitivity, caution is advised when interpreting BIPSS results for tumor localization. Further research is needed to optimize diagnostic strategies for pediatric CS management.

From https://link.springer.com/article/10.1007/s40200-025-01634-4

Filed under: Cushing's, Diagnostic Testing, pituitary | Tagged: ACTH-Dependent, BIPSS, CRH stimulation, Inferior petrosal sinus sampling, IPSS, pediatric, pituitary | Leave a comment »

Cushing Syndrome in Paediatric Population

Posted on November 4, 2024 by MaryO

Introduction

Cushing’s syndrome (CS) may be defined as a clinical condition characterised by signs and symptoms resulting from excessive and prolonged exposure to glucocorticoids. CS can be differentiated into an exogenous form due to high-dose and prolonged glucocorticoid treatments and an endogenous form caused by excessive cortisol secretion.

In paediatric population, the exogenous CS represents the most frequent type of CS due to the widespread therapeutic use of glucocorticoids (given by systemic or local routes) for pulmonary, renal, haematological, or rheumatological diseases, more rarely due to an unappropriated administration of glucocorticoids by parents (medical child abuse or “Munchausen syndrome by proxy”). Endogenous CS is very rare, with an overall incidence of 1.2-5 per million per year [1‐4], of which 10% of cases occurs in paediatric age [5, 6].

According to the origin of the hypercortisolism, endogenous CS can be also differentiated into an ACTH-dependent form resulting from ACTH-secreting pituitary neuroendocrine tumours (Cushing’s disease, CD) or ACTH-and or corticotropin releasing hormone (CRH) secreting neuroendocrine tumours outside the hypothalamic-pituitary area (ectopic Cushing syndrome, ECS), and an ACTH-independent form of adrenal origin (adrenal Cushing’s syndrome, ACS) (adenoma, carcinoma or bilateral adrenal hyperplasia). Finally, there are some clinical conditions, such as psychiatric disorders, severe obesity, poorly controlled diabetes mellitus, anorexia or intense physical exercise, that are associated with non-physiological hypercortisolism (non-neoplastic hypercortisolism, NNH, formerly known as Pseudo-Cushing’s syndrome) caused by chronic stimuli on hypothalamic-pituitary-adrenal axis.

NNH, particularly when characterized by moderate hypercortisolism, have often several clinical characteristics similar to CS and the first-line tests for screening endogenous hypercortisolism may provide misleading results, making the differential diagnosis very challenging. Besides the clinical history, the duration of symptoms and the first-line tests, second-line dynamic tests can be performed to better discriminate NNH from CS [7‐9]. A recent systematic review and metanalysis provide an overview about the usefulness of the second-line tests to differentiate NNH from CS [10].

Similar to adult population, CD represents the most common form of CS in paediatric age (about 75–80%), while about 15–20% of cases are ascribed to ACS and less than 2% to ectopic origin, although there is a different distribution by age [11, 12]. In fact, CD occurs often in adolescent and pre-adolescent age, while endogenous CS in children younger than 8 years is mainly caused by adrenal tumours [13, 14]. CD in younger children with a relevant family history may be caused by rare genetic causes, since the pituitary adenomas should be the first presentation of MEN1, AIP gene mutations or more rare genetic mutations (as CDKNIB or DICER1 gene) [15].

According to some large epidemiological series studies, adrenocortical tumours present a peak incidence during the first decade, with a median age at diagnosis of 3–4 years [16] and are relatively more frequent in paediatric age than in adulthood. Paediatric adrenocortical tumours are almost always functional, presenting with virilization due to excess androgen secretion alone or in combination with hypercortisolism in about 80% of cases [16]. Adrenal tumours can be isolated or in the context of predisposing genetic syndromes as Li-Fraumeni or Beckwith-Wiedemann syndrome. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare congenital disorder, occurring in late adolescence, mostly (about 95% of cases) associated with the multiple endocrine neoplasia (MEN) syndrome known as Carney complex [13]. Macronodular adrenal hyperplasia is rarely reported in the paediatric population, while another form of bilateral adrenocortical hyperplasia includes the adrenal lesions in McCune-Albright syndrome, which represents the first cause of CS in infants [5, 13, 17, 18]. ECS is extremely rare in childhood, and is associated to neuroendocrine tumours, mostly bronchial, thymic, renal and duodenal or pancreatic carcinoids [5, 13, 19, 20].

Methods

An extensive MEDLINE search was performed in 2023 for the research question by two authors (LC, GP) independently, and discrepancies were resolved by discussion. A literature search was performed from 1970 to 2023. The following search words were included: “Cushing’s Syndrome, Cushing’s disease, children, childhood, diagnosis, endogenous hypercortisolism”. Search terms were linked to the Medical Subject Headings (MeSH) when possible. Keywords and free words were used simultaneously. Additional articles were identified with manual searches and included thorough review of other meta-analyses, review articles, and relevant references.

Clinical presentation of CS in children

The diagnosis of CS is often difficult due to the insidious onset of hypercortisolism, in absence of relevant early signs of the disease, as well as the rarity of the disease in childhood. For these reasons, the time to diagnosis has been reported as a mean of 33 months (95% CI 29–38) and not dissimilar to adult population [21].

In childhood, the most common and earliest sign of CS is weight gain, which becomes pathognomonic when combined with concomitant growth failure. Generally, the discrepancy between height SDS and BMI SDS is suggestive of CS, although short stature (defined as height inferior to -2 SDS) is not always reported [22, 23]. On the other hand, decreased height velocity or growth arrest always occurs in childhood CS, due to the inhibitory action of glucocorticoids on growth plate cartilage, except for subjects presenting a concomitant hyperandrogenism in which growth may be normal or even increased. Some authors have suggested to consider children with height inferior to 0 SDS and BMI over + 1.5 SDS for CS diagnosis, allowing to differentiate from subjects with simple obesity, which often present tall stature [6, 24]. Ultimately, growth arrest could be considered the main red flag sign for paediatricians in suspected CS.

Other common signs reported in childhood and adolescence include swelling of the face (as plethora or moon face), headaches, striae rubrae, acanthosis nigricans, dorsal cervical or supraclavicular fat pads and osteopenia. The main clinical findings in paediatric CS are showed in Table 1.

Table 1

Clinical characteristics of paediatric cushing syndrome (CS)

	Magiakou 1994 [23]			Devoe 1997 [25]	Storr 2011 [26]	Shah 2011 [22]	Lonser 2013 [27]	Guemes 2016 [28]
Number of patients (F/M)	59 (37/22)			42 (25/17)	41 (15/26)	48 (19/29)	200 (106/94)	30 (14/16)
Period of observation	1982–1992			1974–1993	1983–2010	1988–2008	1982–2010	1983–2013
Subtype of CS	Pituitary (50)	Adrenal (6)	Ectopic (3)	Pituitary	Pituitary	Pituitary	Pituitary	Pituitary (16), Adrenal (11), Ectopic (2), Unknown (1)
Mean age at onset (y) or duration of symptoms (m)	11±4 y	9±6 y	10±3 y	NA	NA	23.6 ± 14.2 m	10.6 ± 3.6 y	12 m (6–18)
Mean age at diagnosis (range)	14±4	10±5	11±4	13.1 y (6.5–18)^a	12.3 ± 3.5 y (5.7–17.8)	14.85 ± 2.5 y (9–19)	13.7 ± 3.7 y	8.9 (0.2–15.5)^a
SDS Height at diagnosis (range)	-1.3±1.5	-1.0±1.3	-0.1±0.9	-1.8 (-3.5 to + 0.3)	-1.8 ± 1.3 (-1.2 to -4.2)	NA^b	NA	-0.3 (-3.2 to + 3.0)^c
Signs and symptoms (%)
Weight gain	90			92	98	98	93	76.6
Growth retardation	83			84	100	83	63	36.6
Facial changes				46	100	98	63
Fatigue	44			67	61		48	40
Pubertal lack or delay				60				10
Hirsutism	78			46	59		56	56.6
Acne	47			46	44		47	50
Amenorrhea (primary or secondary	78						49
Virilization	38				76			26.6
Gynecomastia							16
Osteopenia				74
Dorsal cervical fat pad				28			69
Striae rubrae	61			36	49	58	55	26.6
Acanthosis nigricans	12					75	32
Headache				26	51		38
Hypertension	47			63	49	71	36	50
Psychiatric disorders	19			44	59	46	31	43.3
Sleep disturbances								20
Muscle weakness						48
Easy bruising				28		17	25	20
Glucose intolerance or diabetes						25	7

Abbreviation. F: female; M: male; SDS: Standard deviation score; y: years; m: months; NA: not available. ^a median age; ^b 56% of subjects presented short stature; ^c median SDS height

The excess of adrenal androgens is responsible for the appearance of acne, hirsutism and early secondary sexual development (i.e., precocious pubic hair growth) in prepubertal children, while the consequent inhibition of gonadotropins secretion may lead of a lack or delay of pubertal development. However, in adolescence, adrenal hyperandrogenism and hypogonadism may result in menstrual changes (as oligo- or amenorrhea), virilization or gynecomastia. Adrenocortical tumours are often characterised by severe concomitant hyperandrogenism, presenting with hirsutism, acne or virilization.

Additional clinical features reported in paediatric population include depression, behaviour disorders (as anxiety, mood swings, emotional lability) and asthenia, while other typical signs of CS in adulthood as myopathy-related fatigue, easy bruising or hypertension are less common during childhood and adolescence [6, 22, 23, 25‐29].

Considering the extreme rarity of CS and the increasing incidence of obesity in childhood, an extensive screening of the entire paediatric population with obesity is not recommended. It is however important to raise awareness amongst paediatricians to recognize few key features of CS, like facial changes, weight gain with simultaneous growth failure, prepubertal virilisation as menstrual changes or hypogonadism signs in adolescence.

Since the clinical features of NNH are often indistinguishable from neoplastic CS, a good history and examination (as individual growth charts), in addition to specific diagnostic tests, are needed to better rule out any physical or psychological causes of NNH [9].

In identify the different origin of CS based on symptoms, it should be considered that ECS is more commonly associated with catabolic signs (muscle weakness, osteoporotic fractures), little or no weight gain, hypertension and hypokalaemia due to the mineralocorticoid effect of cortisol excess. In fact, very high cortisol levels can cause the saturation of the type-2 11β-Hydroxysteroid Dehydrogenase (11βHSD-2) enzyme, expressed in renal cortex and responsive to convert cortisol into inactive cortisone, leading to spillover of cortisol to the mineralocorticoid receptor. Because of this biochemical mechanism, severe hypercortisolism may be considered as a functional mineralocorticoid excess state causing hypokalaemia, increased renal tubular sodium reabsorption, consequent intravascular volume expansion and hypertension [30‐32]. However, since the clinical spectrum of presentation of ECS may overlap with CD, the differential diagnosis is challenging and requires the combination of dynamic biochemical testing and multimodal imaging, each with its own pitfalls [17, 20, 33].

Diagnostic workup for CS

Once a possible intake of exogenous corticosteroids has been ruled out through a careful medical history, the first step in the diagnostic workup is the identification of endogenous hypercortisolism.

Screening for endogenous hypercortisolism

Endogenous hypercortisolism in the paediatric population is essentially demonstrated with the following tests: 24-h urinary free cortisol (UFC), late-night salivary or serum cortisol and dexamethasone-suppression testing. Because none of these tests has 100% of diagnostic accuracy, as for adulthood, at least two tests are usually needed to confirm endogenous CS [7]. Table 2 shows the statistical features of the three diagnostic tests reported in the paediatric population.

Table 2

Diagnostic tests performed for endogenous hypercortisolism screening in the paediatric population

Author	Population Age (mean)	Subject characteristics (N)	Test	Cut-off	Sensibility	Specificity
Bickler 1994 [54]	15.7 y (pituitary) 8.1 y (adrenal)	Pituitary (10) Adrenal (2)	UFC	> 60 mg/m²	100% (8/8)
Bickler 1994 [54]	15.7 y (pituitary) 8.1 y (adrenal)	Pituitary (10) Adrenal (2)	LDDST	< 50% of basal serum cortisol	91% (10/11)
Devoe 1997 [25]	13.1 y (6.5–18)^a	Pituitary (42)	UFC	> 70 µg/m²	86% (25/29)
Martinelli 1999 [49]	10.2 ± 5 y	Pituitary (5), Adrenal (6), Obese controls (21)	Late-night salivary cortisol	> 7.5 nmol/l	100% (11/11)	95.2% (20/21)
Gafni 2000 [39]	5–17 y	CS patients (14), Healthy controls (53)	UFC	> 72 µg/m²	93% (13/14)	100% (53/53)
Gafni 2000 [39]	5–17 y	CS patients (14), Healthy controls (53)	Late-night salivary cortisol	> 7.5 nmol/l	93% (13/14)	100% (53/53)
Davies 2005 [47]	12.2 y	Pituitary (14)	Late-night serum cortisol	> 50 nmol/l [1.8 µg/dl]	100% (14/14)
Batista 2007 [38]	3–18 y	Pituitary (80), Adrenal (25), Controls (20)	UFC	> 70 µg/m²	88% (92/105) [PPV 98%]	90% (18/20) [NPV 58%]
Batista 2007 [38]	3–18 y	Pituitary (80), Adrenal (25), Controls (20)	Late-night serum cortisol	> 4.4 µg/dl	99% (104/105) [PPV 100%]	100% (20/20) [NPV 95%]
Shah 2011 [22]	14.85 ± 2.5 y	Pituitary (48)	Late-night serum cortisol	> 3.2 µg/dl	100% (38/38)
			LDDST (30 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h	≥ 1.8 µg/dl	100% (48/48)
				≥ 5 µg/dl	94% (45/48)
Storr 2011 [26]	12.3 ± 3.5 y	Pituitary (41)	LDDST (30 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h)	< 50 nmol/l [1.8 µg/dl]	92% (35/38)
Lonser 2013 [27]	13.7 ± 3.7 y	Pituitary (200)	UFC	Age-appropriate reference	99% (177/179)
			UFC	> 70 µg/m²	88% (155/177)
			Late-night serum cortisol	> 7.5 µg/dl	97% (188/193)
Shapiro 2016 [40]	11.7 y (pituitary), 12.9 y (adrenal), 11.5 y (controls)	Pituitary (39), Adrenal (8), Control (19)	UFC (different assays)	Corrected for BSA	89% (34/38)	100%
Wędrychowicz 2019 [55]	11.7 y	Pituitary (4)	UFC	> 55 µg/24 h	100% (4/4)
			Late-night serum cortisol	> 4.4 µg/dl	100% (4/4)
			Overnight DST (1 mg at 11.00 p.m.)	< 1.8 µg/dl	75% (3/4)
Guemes 2016 [28]	8.9 y (0.2–15.5)^a	Pituitary (16), Adrenal (11), Ectopic (2), Unknown (1)	UFC	> 275 nmol [100 µg]/24 h	94% (17/18)
			Late-night serum cortisol	> 138 nmol/l [5 µg/dl]	100% (27/27)
			LDDST (20 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h)	< 50 nmol/l [1.8 µg/dl]	100% (20/20)

Abbreviation. N: number; y: years; UFC: Urinary free cortisol; DST: dexamethasone suppression test; LDDST: low-dose DST; PPV: Positive Predictive Value; NPV: Negative Predictive Value; BSA: body surface area. ^a median age

Recently, some authors have reported the value of hair cortisol measurements as a good marker of hypercortisolism also in paediatric population [34], although further studies are needed to validate this test in the diagnostic workup for CS.

24-h Urinary free cortisol (UFC)

24-h UFC is a long-time used screening test for CS, widely performed in childhood for its non-invasive characteristics and the possibility to collect the 24-h samples at home, although this collection may be difficult for younger subjects. Differently from adults, in paediatric population UFC should be corrected for body surface area, conventionally used to make the normal range homogeneous despite the different cortisol secretion during childhood and puberty [35‐37]. The cut-off of 70 µg/m²/day is associated with an acceptable sensitivity and specificity (over 88% and 90% respectively) [27, 38, 39], even if the normal ranges varied among different paediatric studies, due to assay-specific reference range [25, 28, 40]. In order to reduce intra-patient variability and to provide a better diagnostic accuracy, it is now recognised that at least two UFC measurements should be performed in subjects suspected of CS [27, 38, 40, 41].

Mild forms of hypercortisolism may have a false-negative UFC assay, because free cortisol appears in the urine only when serum cortisol exceeds the plasma protein binding capacity. On the other hand, false-positive elevation of UFC measurements should be caused by NNH, as physical or emotional stress, severe obesity or depression. In fact, obese children and adolescents may present slightly elevated UFC, particularly when the obesity is associated with metabolic syndrome [42, 43].

Considering the extremely low prevalence of CS in the paediatric population, the positive predictive value of UFC measurements is considerably low. For this reason, UFC alone is not recognised as an ideal screening tool, while its use combined with another screening tests is desirable to better detect subjects with endogenous hypercortisolism.

In the last decades, liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays had demonstrated superior sensitivity and specificity compared to traditional immunoassays [44‐46], reducing a considerable analytical bias thanks to its ability to differentiate various glucocorticoid metabolites.

Late night cortisol

Abnormal circadian rhythm of cortisol secretion is a hallmark of CS. The lack of the physiological evening nadir in cortisol secretion is detectable with late-night serum or salivary cortisol tests. As for UFC, at least two late-night cortisol measurements are desirable to improve the diagnostic accuracy, particularly in patients with mild CS.

For serum cortisol measurement, an indwelling intravenous cannula should be placed before sleeping and the blood sample should be taken without waking the child. The assessment of midnight serum cortisol gives the highest sensitivity and specificity for the diagnosis of CS in childhood (99 and 100% respectively using the cut-off of 4.4 µg/dl) [38], despite different normal ranges (between 1.8 and 5 µg/dl) have been considered for paediatric subjects [22, 28, 47].

However, the late-night serum sample requires hospitalization and its use as a screening test for CS is limited.

On the other hand, late-night salivary cortisol measurement represents an easily executable, stress-free test also in outpatient setting. Conventionally, the salivary samples are collected at 11–12 pm, even if some authors suggest to performed it at usual bedtime in order to achieve unstressed levels, resulting from the request to the patient to stay awake beyond the usual bedtime [48]. This precaution, suggested for adult subjects, should be considered also for paediatric population to reduce a potential false-positive rate of the test.

Although the available data in paediatric population are limited, the sensitivity and specificity of late-night salivary cortisol assessment appear to be close to late-night serum cortisol (93–100% and 95–100% respectively) [39, 49].

For all these reasons, late-night salivary cortisol seems to be the best screening test for endogenous hypercortisolism in childhood.

Although the traditional immunoassay methods already have a very high sensitivity, LC-MS/MS assays had demonstrated an improvement of diagnostic specificity and appear to be the most accurate analytical tools also for modern salivary or serum steroid measurements [50‐52]. In fact, the use of LC-MS/MS assay allows the dosage of different cortisol metabolites (as cortisone) in order to better identify the endogenous cortisol production and consequently to reduce false-positive results [8, 51].

Low-dose dexamethasone suppression tests (DST)

In healthy individuals, a supraphysiological exogenous dexamethasone dose inhibits ACTH and consequently cortisol secretion. Therefore, a decrease of serum cortisol concentration below the value of 1.8 µg/dl after 1 or 2 mg dexamethasone dose is considered to be a normal response. The low-dose DST should be performed through two different forms: the 1 mg “overnight” (or Nugent) and the two-day 2 mg (or low-dose Liddle) test.

The “overnight” DST is performed with the administration of 1 mg (or 25 µg/kg in children with body weight < 40 kg) of dexamethasone at 11 PM to 12 AM (midnight), measuring serum cortisol at 8 AM the next morning. In order to ensure a proper DST in adult population, Ceccato et al. propose to measure also dexamethasone after 1 mg-DST with LC-MS/MS assay [53]. At present, no similar data are available among paediatric population, although dexamethasone measurement should be suggested also in children and adolescents to reduce false-positive results due to inadequate bioavailability or incorrect administration of dexamethasone.

The “low-dose Liddle” DST (LDDST) consists of the administration of 2 mg/day of dexamethasone (or 20–30 µg/kg/day in children < 30 kg), divided in 0.5 mg doses every six hours for 48 h, and measurement of serum cortisol within six hours after the last dose.

For both DST, the lack of the physiological serum cortisol suppression (< 1.8 µg/dL) is suspicious for CS. LDDST has demonstrated a good sensitivity (over 90%) for CS in paediatric patients [26, 28], whereas less data regarding the overnight DST sensitivity and specificity are available in childhood [54, 55].

For its ease analysis in an out-patient setting, LDDST is therefore a useful screening test for paediatric patients suspected of CS.

Recently, some authors have investigated the utility of salivary cortisone measurement after DST, that is characterized by a more linear relationship with serum cortisol than salivary cortisol [56]. Moreover, a prospective use of salivary cortisol/cortisone after DST in childhood should be encouraged for its non-invasive and stress-free peculiarity, avoiding venipuncture.

Etiological diagnosis of endogenous CS

Basal electrolytes and ACTH

Levels of serum electrolytes are usually normal, but potassium may be decreased, especially in children with ECS [57]. In children with CD, morning plasma ACTH is commonly detectable (> 5 pg/ml) while those with ACS showed suppressed ACTH [29]. Batista et al. showed that a cut-off of morning ACTH of 29 pg/ml had a sensitivity of 70% and specificity of 100% to differentiate ACTH-dependent from ACTH-independent CS [38]. ACTH concentrations are usually very high in patients with ECS but may be normal in patients with pituitary adenomas [17, 29, 57]. CD should be suspected in patients with biologically moderate signs, without hypokalaemia or marked plasma ACTH elevation and with progressive onset [17, 20, 33].

CRH stimulation test

The CRH test has been suggested as the best non-invasive tool for diagnosing CD. Sensitivity and specificity are reported to be around 80 and 92% (according to study in adults) [17, 58‐60]. This test consists in the intravenous injection of 1 µg/kg CRH (maximum dose 100 µg) [29]. The criterion for diagnosis of CD is a mean increase of 20% above baseline for cortisol value at 15 and 30 min and an increase in the mean ACTH concentration of at least 35% over basal value at 15 and 30 min after CRH administration [17, 29]. Some authors reported the use of ovine CRH (the only available form in the United States, until the mid-2020) in paediatric population [38, 61] as alternative to human CRH. Although it has been described as the ovine CRH can induce a stronger, more prolonged increase in ACTH and, particularly, cortisol compared with human CRH in adult subjects [62], no data are available comparing ovine and human CRH in paediatric population.

Despite children with CD seem to have a more evident cortisol response than adults, making this test more useful in the paediatric age than in adults [17, 26, 29, 63], the recent synthetic human CRH shortage [64] will make CRH test less feasible in favour of other dynamic tests as Desmopressin test [65].

Desmopressin test

Desmopressin is a preferential vasopressin receptor V2 and V3 agonist. Because of the overexpression of the V3 in human ACTH-secreting adenomas, the administration of desmopressin causes a significant rise in ACTH and cortisol levels in most patients with CD [17, 58]. This makes desmopressin administration a suitable test enabling the distinction between neoplastic from NNH [9, 10, 26]. Like CRH test, Desmopressin test results effective, well-tolerated, less expensive, and relatively non-invasive. While the sensitivity is comparable to CRH test, the specificity seems to be lower [17, 58, 60, 66]. Like the other tests, it is probabilistic: the more significant the elevation of ACTH and cortisol, the more probable the diagnosis of corticotropic adenoma [17, 58]. Different cut-off criteria were used to define a positive response. Malerbi et al. showed that the administration of Desmopressin 5–10 µg intravenous determines a cortisol increase above baseline ranging from 61 to 379% in patients with pituitary disease [67]. Sakai et al. using a high percent ACTH rise threshold of 120% reported a positive ACTH response in all 10 patients with CD, whereas all 3 patients with ECS were unresponsive to desmopressin [68]. Tsagarakis et al. showed that desmopressin test (10 µg intravenous) can produce a significant overlap of responses between CD and patients with ECS and therefore it is of limited value in the differential diagnosis of ACTH-dependent CS. This is probably due to the expression of the V2 receptors in tumours with ECS [69]. Desmopressin (10 µg intravenous) in combination with CRH may provide an improvement over the standard CRH test in the differential diagnosis of ACTH-dependent CS [70]. However, the benefit of a desmopressin-CRH combined test results limited [66]. It should be considered that all the above studies included adults [67‐69].

Desmopressin test proved to be effective in increasing the sensibility of Bilateral Petrosal Sinus Sampling (BIPSS) [71]. In a retrospective study including 16 children with CD, Chen et al. showed an increase of the sensitivity of BIPSS from 64.7% at baseline to 83.3% after desmopressin stimulation [72]. Many CD patients respond aberrantly to the desmopressin test. Loss of the desmopressin response, performed in the early post-operative period, is a good predictor for a favourable long-term outcome. Moreover, during follow-up, the return of desmopressin response is predictive of recurrence [66, 71].

Standard high dose dexamethasone suppression test (HDDST)

HDDST or high-dose Liddle test is the oldest described and it is used to differentiate CD from ECS. This test consists in the administration of dexamethasone at a dosage of 80–120µgr/kg/day divided into four doses every 6 h (maximum 2 mg/dose) for 48 h or a single cumulative dose of 80–120µgr/kg (maximum 8 mg) at 11 pm. Plasma cortisol is measured at 8–9 am the morning after the last administration of dexamethasone; the suppression of serum cortisol up to 50% of baseline is suspicious for CD as for adult population [17, 26, 28, 29, 38].

Liu et al. showed that HDDST in combination with pituitary dynamic enhanced MRI (dMRI) had a positive predictive value (98.6%), higher than that of Bilateral Petrosal Sinus Sampling (BIPSS) for the diagnosis of CD [73].

Despite HDDST had reported a good sensibility to identify CD in childhood, this test seems to have a low specificity to exclude ECS because of the high degrees of cortisol suppression after HDDST in children with ECS [19, 28, 29]. In addition, the administration of high-dose dexamethasone in CS patients with high cortisol level can cause severe side effects, including exacerbation of their hypertension and fluctuation of blood glucose. Because of the low accuracy and the risk of severe side effects, this test is less frequently used [29].

Fig. 1

Diagnostic algorithm for screening and differential diagnosis of cushing syndrome in paediatric population

Imaging

Pituitary magnetic resonance imaging (MRI)

Since ACTH-secreting pituitary adenomas are very small (usually < 6 mm in diameter), it is difficult to localize these tumours. Diagnostic workup of CD includes pituitary MRI, but in many patients no tumour is identified. Conventional MRI, even with contrast enhancement, mostly failed to identify ACTH-secreting microadenomas in children with CD. Up to one-third of paediatric and adolescent patients with CD don’t have pituitary tumour detectable at brain MRI. The acquisition protocol should comprise coronal and sagittal spin-echo (SE) slices with gadolinium-enhanced T1 and T2 and millimetric 3D T1 slices [17, 29, 57, 74]. In a retrospective study including 30 children with CD (mean age 12 ± 3 years), Batista et al. showed that pre- and post-contrast spoiled gradient-recalled acquisition in the steady state (SPGR) was superior to conventional pre- and post-contrast T1-weighted SE acquisition MRI in the identification of the microadenomas. In particular, the post-contrast SPGR-MRI identified the location of the tumour in 18 of 28 patients, whereas post-contrast SE-MRI identified the location and accurately estimated the size of the tumour in only 5 of 28 patients (p < 0.001) [74].

Bilateral petrosal sinus sampling (BIPSS)

BIPSS is another powerful diagnostic tool with high sensitivity and specificity, but its invasiveness and high cost limit its wide application, and the indication for BIPSS is still controversial [7, 17, 29, 75, 76]. It consists of the placement of femoral catheters that reach the inferior petrosal sinuses. Successively, blood samples are collected for measurement of ACTH from petrosal sinuses and from peripheral pathway before and after the administration of CRH. Inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and interpetrosal sinus gradient of one of the two sides to the contralateral side are calculated [75, 76]. In order to avoid incorrect results, it is recommended to verify hypercortisolism with serum cortisol sample immediately before performing BIPSS. Detomas et al. recently described the largest study on BIPSS.

According to the authors, the cut-offs for the ACTH IPS: P ≥ 1.9 at baseline (sensitivity 82.1%, specificity 85.7%) and ≥ 2.1 at 5 min post-CRH (sensitivity 91.3%, specificity 92.9%) allow for the best discrimination between CD and ECS [77]. In a multicentre study including 16 children aged between 4 and 16.5 years, Turan et al. showed that BIPSS is a superior diagnostic work-up than MRI to confirm the diagnosis of CD. Moreover, it showed a significantly higher sensitivity (92.8%) than MRI (53.3%) in detecting adenoma localization at pituitary level, which is crucial for surgical intervention [75]. The use of desmopressin has been reported in alternative to CRH [76]. In a review including case series of children with CS [76], the overall accuracy of BIPSS was 84.1% and became 92.3% after stimulation with desmopressin. The overall lateralizing accuracy of BIPSS was 50%. While BIPSS has a high diagnostic accuracy for the localization to the pituitary gland, it is not reliable for tumour lateralization to the right or left side of the gland. BIPSS is considered the gold standard to reliably exclude ECS and should performed in a specialized centre due to potential patient risk. However, BIPSS is not routinely available in many centres, it may have decreased specificity in children, especially when the pituitary tumour is not lateralized showing misleading results [77, 78]. For these reasons and for the risks related to the invasiveness of the procedure, BIPSS should be reserved only for exceptional cases in children [17, 75, 76].

Radiological anatomic imaging

Subjects with ACS should perform an adrenal Computer Tomography (TC) or MRI to determine the adrenal cause. Despite abdominal TC with contrast-enhanced studies is the cornerstone of imaging of adrenal tumours in adults, MRI scan should be initially preferred in childhood to avoid radiation exposure [79]. Adrenocortical carcinomas are usually unilateral, larger than adenomas, with irregular margins, inhomogeneous contents (with areas of necrosis, haemorrhage and calcification) and avidly enhancement after contrast administration due to their high vascularity [80]. PPNAD is more difficult di identify with radiological studies, because it usually presents normal- or small-sized adrenal glands.

In subjects with suspected ECS, a thin-multislice neck-chest-abdomen-pelvic CT, alone or eventually followed by MRI, should be performed to identify neuroendocrine tumours that generally are very small and difficult to identify [11].

Functional imaging

Second-line functional imaging studies (as Positron Emission Tomography, PET, or scintigraphy) may be useful to provide an accurate etiological diagnosis of CS, particularly when the traditional radiological exams are inconclusive to differentiate CD from ECS. Because of the rarity of ECS, a univocal algorithm regarding the use of new molecular imaging techniques is not well established.

Whereas the ectopic ACTH-secreting tumours express the cell-surface receptors for somatostatin, ¹¹¹In-pentetreotide (OCT) scintigraphy is often chosen as confirmatory exam [81].

The ⁶⁸Gallium-DOTATATE PET/CT scan, using a modified octreotide molecule that also binds to somatostatin receptors, has shown a greater sensitivity for small tumours and may be useful for the tumoral identification in case of negative OCT scan [7]. Finally, ¹⁸FDG-PET/CT seems to be highly sensitive for the detection of aggressive pancreatic lesions [81].

In ACS cases, when adrenocortical carcinoma is suspected and traditional imaging studies (MRI or TC) are not diriment, ¹¹C-metomidate-PET/CT scan allows a non-invasive characterization and staging of the adrenal lesion [82, 83].

Algorithm approach

Clinical history and the age at presentation of symptoms should guide throughout the different diagnosis of endogenous CS. A careful personal history, supported by patient growth charts, physical examination and screening tests should be able to rule out any physical or neuropsychiatric causes of NNH, even if second-line dynamic tests are sometimes needed to distinguish NNH from neoplastic CS.

Although CD is the main cause of CS in children older than 8 years, the clinical presentation of ECS may overlap with CD and the differential diagnosis of CS may be challenging, requiring the combination of dynamic biochemical tests and multimodal imaging.

Since none of the dynamic tests show a perfect sensitivity and specificity, using more than one dynamic test might improve accuracy. A non-invasive approach using a combination of three or four tests, specifically CRH and desmopressin stimulation tests plus MRI, followed by total-body CT, if biochemical and anatomical findings are discordant, correctly diagnose CD in approximately half of patients, potentially eliminating the need for BIPSS [17, 84]. If a pituitary tumour is detected on MRI and dynamic testing results are consistent with CD, BIPSS is not necessary for diagnosis. Since ECS in children is extremely rare, the algorithm approach in children may differ from the adult approach. Findings of ACTH-dependent CS, doubtful CRH test and normal pituitary MRI should be followed by extended imaging (whole-body CT/MRI or functional imaging). Considering the extremely rarity of ECS, the great majority of ACTH-dependent hypercortisolism, even with normal pituitary MRI, corresponds to CD due to a pituitary lesion not yet visible [17]. For this reason, BIPSS should be used only exceptionally in children. A diagnostic algorithm is proposed in Fig. 1.

Conclusions

We provide detailed revision on the diagnostic evaluation of children and adolescents presenting with signs and symptoms suspicious for CS and guidance on the workup from the confirmation of endogenous hypercortisolism to the etiological diagnosis of such a rare challenging condition.

Declarations

Ethical approval

This article does not include research on human participants and/or animals.

Informed consent is not required.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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From https://www.springermedizin.de/cushing-syndrome-in-paediatric-population-who-and-how-to-screen/50061094

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Unilateral Adrenalectomy for Pediatric Cyclical Cushing Syndrome With Novel PRKAR1A Variant Associated Carney Complex

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A Case Series of Bilateral Inferior Petrosal Sinus Sampling Using Desmopressin for Evaluation of ACTH-Dependent Cushing’s Syndrome in Pediatric Patients

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Cushing Syndrome in Paediatric Population

Introduction

Methods

Clinical presentation of CS in children

Diagnostic workup for CS

Screening for endogenous hypercortisolism

24-h Urinary free cortisol (UFC)

Late night cortisol

Low-dose dexamethasone suppression tests (DST)

Etiological diagnosis of endogenous CS

Basal electrolytes and ACTH

CRH stimulation test

Desmopressin test

Standard high dose dexamethasone suppression test (HDDST)

Imaging

Pituitary magnetic resonance imaging (MRI)

Bilateral petrosal sinus sampling (BIPSS)

Radiological anatomic imaging

Functional imaging

Algorithm approach

Conclusions

Declarations

Ethical approval

Informed consent

Conflict of interest

Publisher’s note

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