Secondary Adrenal Insufficiency and Iatrogenic Cushing’s Syndrome in a 13-Year-Old Male With Vogt-Koyanagi-Harada Disease

Posted on November 9, 2025 by MaryO

ABSTRACT

Vogt-Koyanagi-Harada disease (VKH) is a rare autoimmune disorder, especially in children, requiring long-term corticosteroids. We report a 13-year-old male with VKH who developed iatrogenic Cushing’s syndrome and secondary adrenal insufficiency after prolonged prednisone treatment. Despite adding mycophenolate mofetil, tapering failed due to relapses. He showed weight gain, growth delay, striae, and suppressed cortisol and adrenocorticotropic hormone, confirming hypothalamic-pituitary-adrenal axis suppression. Hydrocortisone was given for stress coverage. A relapse followed steroid discontinuation. This case highlights the risk of endocrine complications in pediatric VKH and emphasizes the importance of early hormonal evaluation and individualized tapering during chronic steroid therapy.

KEYWORDS

Vogt-Koyanagi-syndrome
Cushing syndrome
Adrenal insufficiency
Pediatrics

INTRODUCTION

Vogt-Koyanagi-Harada disease (VKH) is a rare autoimmune disorder that can significantly affect the eyes, skin, and central nervous system (Stern & Nataneli, 2025). Among the various forms of autoimmune uveitis, VKH is particularly notable for its broad clinical spectrum, encompassing ocular, neurologic, and cutaneous manifestations (Herbort & Mochizuki, 2007). In pediatric patients, age-specific considerations become paramount, as prolonged corticosteroid therapy is frequently required to control inflammation but can result in serious endocrine complications. One such complication is iatrogenic Cushing’s syndrome (ICS), which may predispose to secondary adrenal insufficiency (SAI), especially when steroid withdrawal is abrupt or inadequately tapered (Improda et al., 2024; Prete & Bancos, 2021). Despite increasing recognition of pediatric VKH, endocrine consequences of its treatment remain underreported.
We present the case of a 13-year-old male with VKH who displayed overt signs of hypercortisolism and biochemical evidence of adrenal suppression after discontinuing corticosteroids, underscoring the importance of vigilant monitoring and a carefully structured tapering protocol in pediatric patients requiring long-term steroid therapy. Given that many pediatric patients with VKH and steroid-related complications are managed not only by pediatric endocrinologists but also by pediatric providers, including nurse practitioners, this case highlights aspects relevant to a broad clinical audience.

CASE PRESENTATION

A 13-year-old male with a known history of VKH was referred to our clinic for growth and pubertal assessment following significant weight gain and clinical features suggestive of ICS. His perinatal period was uneventful; he was born at term via cesarean section for maternal indications (bicornuate uterus), with a birth weight of 2980 g and a length of 49 cm. Family history was notable for celiac disease in the mother, mixed hypercholesterolemia in the father, vitiligo in the maternal grandfather, and autoimmune diseases (Sjögren’s syndrome and multiple sclerosis) in second-degree maternal relatives.
The patient first presented, at age 11 years and 11 months, with redness, pain, and photophobia of the right eye [Figure 1]. Initial ophthalmological examination revealed panuveitis, with signs of posterior synechiae and optic disc edema. Fluorescein and indocyanine green angiography confirmed bilateral granulomatous involvement. Systemic workup excluded other infectious and autoimmune causes of uveitis. Neurological imaging revealed a non-specific thalamic lesion, classified as a radiological isolated syndrome, with no clinical neurological deficits.
FIGURE 1

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FIGURE 1. Timeline of notable events. Timeline summarizing key events including clinical course, treatments, and relapses.

Abbreviations: ACTH, adrenocorticotropic hormone; VKH, Vogt-Koyanagi-Harada disease.
Oral prednisone (25 mg/day) was initiated, along with topical ocular corticosteroids, leading to clinical improvement. The first tapering and discontinuation of prednisone occurred after seven months of therapy. Three months later, a clinical relapse occurred, requiring re-initiation of prednisone and subsequent addition of mycophenolate mofetil as a steroid-sparing agent. Prednisone was then tapered and discontinued again after another seven months of treatment. Over the course of therapy, the patient gained approximately 15 kg and developed progressive cushingoid features [Table 1].

TABLE 1. Clinical and biochemical features of ICS and SAI in the patient

Empty Cell Clinical Findings Interpretation
Growth and development Height: 143.5 cm (3rd percentile); mid-parental height: 171 ± 8 cm Growth deceleration likely related to chronic glucocorticoid exposure and ICS
Weight and body composition Weight: 53.3 kg (75th–90th percentile); BMI: 25.8 kg/m²; central obesity Suggestive of glucocorticoid-induced lipogenesis and altered fat distribution
Skin and soft tissue Striae rubrae on flanks; mild dorsal fat pad (“buffalo hump”) Classic phenotypic features of ICS
Pubertal status Tanner stage I; testicular volume 5–6 mL; pubic hair stage I Early puberty with preserved testicular volume; no signs of delayed or precocious puberty
HPA axis function Cortisol: 0.5 → 9.9 → 3.1 µg/dL; ACTH: 7–23 pg/mL Suppressed HPA axis consistent with SAI
Glucose metabolism HbA1c: 5.9%; fasting glucose: 72 mg/dL; insulin: 16.9 mcU/mL Normal glucose metabolism; mild hyperinsulinemia possibly due to steroid exposure
Thyroid function TSH: 2.32 µU/mL; free T4: 1.59 ng/dL Euthyroid; no evidence of central or primary thyroid dysfunction
Neurologic imaging Right thalamic signal abnormality; stable; no neurological deficits No CNS involvement of VKH; imaging excluded alternative diagnoses
Family history Autoimmune conditions in maternal relatives; vitiligo in grandfather Suggests genetic predisposition to autoimmune diseases; relevant to VKH etiology
Therapeutic course Initial improvement with prednisone; relapses on tapering; mycophenolate added; steroids reintroduced Demonstrates difficulty in achieving steroid-free remission and the need for steroid-sparing agents
Abbreviations: ACTH, adrenocorticotropic hormone; BMI, body mass index; CNS, central nervous system; HPA, hypothalamic-pituitary-adrenal; ICS, iatrogenic Cushing’s syndrome; SAI, secondary adrenal insufficiency; TSH, thyroid-stimulating hormone; VKH, Vogt-Koyanagi-Harada disease.
Summary of patient’s clinical signs and biochemical parameters during corticosteroid therapy, including features of ICS and evidence of SAI.
Laboratory testing during steroid tapering attempts revealed HbA1c of 5.9% (41 mmol/mol), fasting glucose of 72 mg/dL, and insulin of 16.9 mcU/mL; morning serum cortisol was markedly reduced (0.5 mcg/dL; ref. 2.4–22.9), raising concerns for SAI. Gonadotropins (follicle-stimulating hormone 4.3 mcU/mL, luteinizing hormone 1.1 mcU/mL) and testosterone (0.03 ng/mL) were consistent with early puberty. Thyroid function (thyroid-stimulating hormone 2.32 mcU/mL, free thyroxine 1.59 ng/dL) and celiac serology were normal. Brain magnetic resonance imaging confirmed a stable right thalamic signal abnormality and minor asymmetry of cerebral arteries, in line with prior findings; cardiac and abdominal ultrasounds were unremarkable.
When first evaluated in our endocrinology clinic (at age 13 years and 6 months), the patient’s height was 143.5 cm (3rd percentile; mid-parental height target: 171 ± 8 cm), and his weight was 53.3 kg (75th–90th percentile), corresponding to a body mass index of 25.8 kg/m². He exhibited central obesity, striae rubrae on the flanks, and a mild dorsal hump. Genital examination showed bilateral testicular volumes of 5–6 mL and pubic hair at Tanner stage I, compatible with early puberty. The remainder of the physical exam was unremarkable.
In light of clinical and biochemical evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, further hormonal testing was performed. Serum cortisol had partially recovered (9.9 mcg/dL; ref. 2.7–18.4) with adrenocorticotropic hormone (ACTH) at 23.1 pg/mL (ref. 7.3–63.3). Hydrocortisone was prescribed for use during stressful events. However, two months after prednisone discontinuation, at age 13 years and 8 months, a clinical relapse of VKH occurred, requiring escalation of mycophenolate mofetil and re-initiation of prednisone therapy.
The patient currently remains under combined rheumatologic, ophthalmologic, and endocrinologic management. Steroids have been successfully tapered and discontinued, but signs of chronic adrenal suppression and cushingoid features persist. Mycophenolate mofetil is ongoing as maintenance immunosuppression, and adrenal function is being closely monitored.

DISCUSSION

VKH is a rare granulomatous autoimmune condition targeting melanocyte-containing tissues, including the uveal tract, meninges, inner ear, and skin. While more frequently diagnosed in adults, pediatric-onset VKH is increasingly recognized and often presents with bilateral panuveitis, optic disc edema, serous retinal detachments, and systemic manifestations such as meningismus, tinnitus, hearing loss, vitiligo, and poliosis (Abu El-Asrar et al., 2021; Reiff, 2020). Early and aggressive immunosuppression is essential to prevent chronic recurrent uveitis and progressive vision loss (Abu El-Asrar et al., 2008).
Systemic corticosteroid therapy—using high-dose oral prednisone or intravenous pulse methylprednisolone—is the first-line treatment for pediatric VKH, and is effective in rapidly controlling intraocular inflammation and achieving favorable visual outcomes when initiated early (Leal et al., 2024; Reiff, 2020). Gradual tapering of corticosteroids over at least six months is critical to minimize recurrence and prevent chronic disease evolution (Ei Ei Lin Oo et al., 2020; Wang et al., 2023). Rapid tapering is associated with higher rates of relapse and chronicity. Nonetheless, corticosteroid monotherapy is often insufficient to prevent long-term recurrence and chronic complications in pediatric VKH (Abu El-Asrar et al., 2021; Park et al., 2022; Sakata et al., 2015). Early addition of immunosuppressive agents—such as mycophenolate mofetil or methotrexate—within three months of disease onset improves long-term control, reduces the risk of chronic recurrent uveitis, and enhances visual outcomes (Ei Ei Lin Oo et al., 2020; Park et al., 2022). Long-term remission rates are higher when immunosuppressive therapy is maintained for several years with sustained inflammation control (Wang et al., 2023).
Children are especially vulnerable to the adverse effects of prolonged corticosteroid exposure, including growth failure, pubertal delay, obesity, insulin resistance, ICS, and suppression of the HPA axis with subsequent SAI (Bornstein et al., 2016; Messazos & Zacharin, 2016; Santos-Oliveira et al., 2025). ICS results from chronic exposure to supraphysiologic doses of glucocorticoids and may present with weight gain, central obesity, facial rounding, and violaceous striae—many of which were observed in our patient. In children, these manifestations may overlap with common features of puberty or lifestyle-related obesity, making early diagnosis more challenging (Savage & Storr, 2012). SAI is a potentially life-threatening complication that occurs when exogenous glucocorticoids suppress the endogenous production of corticotropin-releasing hormone and ACTH. The risk is highest with longer treatment durations (typically > 12 weeks) and higher cumulative doses, particularly with long-acting steroids such as betamethasone or dexamethasone (Beuschlein et al., 2024).
Our patient presented with markedly reduced morning cortisol levels and low-normal ACTH, consistent with central adrenal suppression. Partial biochemical recovery occurred months after discontinuation, yet persistently suboptimal cortisol levels indicated incomplete restoration of HPA function. These findings align with a meta-analysis by Broersen et al., which showed that although adrenal recovery improves over time, a significant proportion of patients remain functionally insufficient even six months after stopping corticosteroids (Broersen et al., 2015).
To our knowledge, this is among the first reported pediatric cases of VKH complicated by both ICS and SAI. Although the literature contains extensive documentation of glucocorticoid side effects in autoimmune and inflammatory conditions (Arroyo et al., 2023), there remains a notable gap in addressing endocrine sequelae within VKH, particularly in children. Most published pediatric VKH case reports focus on ophthalmologic or immunologic outcomes, with limited attention to longitudinal hormonal monitoring and risk mitigation. VKH is rare in childhood, representing an uncommon cause of uveitis, with pediatric-onset forms accounting for fewer than 10% of all VKH cases (Martin et al., 2010; Yang et al., 2023). Several works have documented its course and treatment (Abu El-Asrar et al., 2008; Albaroudi et al., 2020; Sadhu et al., 2024); none of the reports explicitly addressed endocrine complications, highlighting a major gap in longitudinal follow-up and inter-specialty collaboration in such cases.
The recent 2024 Joint Clinical Guideline from the European Society of Endocrinology and the Endocrine Society offers important insight into the diagnosis and management of glucocorticoid-induced adrenal insufficiency (Beuschlein et al., 2024). Although not providing pediatric-specific recommendations, it emphasizes that children are included among at-risk populations, and that the same diagnostic and tapering principles apply across age groups. It highlights that the risk of SAI depends not only on dose and duration, but also on the glucocorticoid formulation, route of administration, and individual susceptibility. The guideline recommends transitioning from long-acting to short-acting glucocorticoids (e.g., prednisone or hydrocortisone) to facilitate tapering and adrenal recovery. Tapering should begin only after adequate disease control and must proceed gradually—especially once physiologic dose equivalents are reached (4–6 mg/day of prednisone). Morning serum cortisol serves as the initial screening tool for HPA recovery, with levels > 10 µg/dL (> 300 nmol/L) indicating recovery and < 5 µg/dL (< 150 nmol/L) indicating suppression. Importantly, symptoms of glucocorticoid withdrawal (e.g., fatigue, myalgias, mood changes) may mimic adrenal insufficiency and require temporary increases in glucocorticoid dose and a slower taper.
In our case, hydrocortisone was prescribed for use during stress, such as illness or surgery, in accordance with these recommendations. Given his partial biochemical recovery, the patient was also advised to carry steroid warning documentation and to continue close endocrine follow-up. This approach reflects best practice in managing patients transitioning off chronic corticosteroid therapy, particularly in pediatric populations where risks are amplified (Beuschlein et al., 2024).
We strongly advocate for multidisciplinary collaboration in managing complex VKH cases [Figure 2]. Ophthalmologists and rheumatologists should remain alert to endocrine warning signs such as growth deceleration, cushingoid appearance, and fatigue (Santos-Oliveira et al., 2025), while endocrinologists should consider autoimmune or inflammatory etiologies in children with ICS or SAI. Importantly, the early use of steroid-sparing immunosuppressants—as was done with mycophenolate mofetil in our case—can reduce glucocorticoid burden and mitigate downstream complications. Agents such as azathioprine, methotrexate, or mycophenolate have demonstrated efficacy in reducing steroid dependence in pediatric uveitis (Simonini et al., 2013; Sood & Angeles-Han, 2017).
FIGURE 2

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FIGURE 2. Multidisciplinary management plan for pediatric VKH with chronic corticosteroid therapy. Schematic representation of the recommended multidisciplinary team for pediatric patients with VKH requiring prolonged corticosteroid therapy. The model emphasizes collaboration among health professionals for early recognition and management of VKH manifestations.

(abbreviations: CNS, central nervous system; HPA, hypothalamic-pituitary-adrenal; VKH, Vogt-Koyanagi-Harada disease).

CONCLUSION

This case highlights the dual endocrine risks associated with prolonged corticosteroid therapy in pediatric patients with VKH: ICS and SAI. It underscores the importance of routinely monitoring growth, pubertal development, and HPA axis function both during and after steroid treatment.
Given the widespread use of systemic corticosteroids in pediatric inflammatory disorders, proactive endocrine screening, multidisciplinary collaboration, and adherence to guideline-based tapering protocols are essential to ensure effective disease management while minimizing preventable hormonal complications. Further research and the development of pediatric-specific guidelines are warranted to optimize endocrine care in children receiving long-term glucocorticoid therapy.

REPORTING CHECKLIST DISCLOSURE

We are submitting this case report using the CARE checklist.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

FUNDING

The authors did not receive support from any organization for the submitted work.

PATIENT CONSENT

Written informed consent and permission to share this case were obtained from the legal guardians/parents.

ETHICAL STATEMENTS

Please find attached the AIFA regulation regarding observational studies, provided in Italian. For your convenience, we have translated the relevant section (highlighted in light blue, pages 7-8) into English:
“The registration of studies covered by this provision in the Register of Observational Studies (RSO) is mandatory for review by the Ethics Committee, except for the exemptions listed below. This guideline does not apply to the following categories: […] Case reports and case series (typically involving 3-5 patients at most) that do not have a methodological approach qualifying them as clinical studies.”
Our study falls precisely into the category of a case report, rather than a clinical study.

CRediT authorship contribution statement

Roberto Paparella: Writing – original draft, Conceptualization. Irene Bernabei: Writing – original draft. Arianna Bei: Writing – original draft. Cinzia Fiorentini: Resources. Norma Iafrate: Resources. Roberta Lucibello: Resources. Francesca Pastore: Resources. Ida Pucarelli: Writing – review & editing, Supervision, Conceptualization. Luigi Tarani: Writing – review & editing, Supervision.

CONFLICTS OF INTEREST

None to report.

REFERENCES

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Cushing’s Syndrome in a Young Woman Due to Prolonged Betamethasone Nasal Drop Use

Posted on August 11, 2025 by MaryO

Abstract

Background

Cushing’s syndrome is an uncommon but serious condition caused by long-term exposure to elevated cortisol levels, which is usually iatrogenic in origin. Although systemic corticosteroids are the most frequent agents, the association of intranasal corticosteroids with this condition is remarkably rare.

Case presentation

This report is about a 21-year-old Iranian woman using betamethasone nasal drops for nasal obstruction. The patient presented with weight gain, Amenorrhea, mood disturbances, red purplish striae, and mild hirsutism. Hormonal assessments revealed suppression of the hypothalamic–pituitary–adrenal axis.

Conclusion

This case demonstrates the underappreciated systemic effects of intranasal betamethasone to induce Cushing’s syndrome. It serves as a pivotal reminder of the need for vigilance in prescribing practices and reinforces the importance of early diagnosis to ensure favorable patient outcomes.

Peer Review reports

Background

Iatrogenic Cushing’s syndrome (CS) is an endocrine disease caused by long-term or high-dose glucocorticoid use [1]. Although iatrogenic cases are commonly associated with oral or injectable glucocorticoids [2], few reports described CS after the use of intranasal steroid sprays (INS) such as betamethasone in adults [3,4,5,6,7]. Currently, INS is widely used for managing conditions such as allergic rhinitis, nasal polyposis, and other upper airway disorders owing to their localized effects and limited systemic absorption [8, 9]. However, prolonged use, high doses, or using potent formulations can lead to significant systemic absorption, resulting in Hypothalamic–pituitary–adrenal (HPA) axis suppression, and frank CS [10]. Betamethasone nasal spray, a cornerstone in the treatment of nasal congestion, has the potential for systemic absorption by the nasal mucosa, particularly with prolonged or excessive use [11].

This report presents the case of a young woman who developed CS following the overuse of betamethasone nasal drops. It also highlights the importance of detailed patient histories when diagnosing CS and highlights the critical need to educate patients on the proper use and potential risks of steroid therapies to prevent complications. This case report adheres to the case report (CARE) guidelines [12].

Case presentation

This is the case of a 21-year-old Iranian female who presented with a history of rapid weight gain (30 kg in 8 months), irregular menstrual cycles, and significant mood changes. Her body mass index (BMI) was calculated at 40.07 kg/m2, classifying her as obese, and her blood pressure was recorded at 115/75 mmHg. In addition, she exhibited red–purple striae on her abdomen and limbs and mild hirsutism (modified Ferriman–Gallwey Score (FGS) score = 10), prompting admission for further evaluation after multiple outpatient visits yielded no definitive diagnosis.

Figure 1 is a clinical photograph (with patient consent) or an illustration of the red–purple striae.

Fig. 1

figure 1

Clinical photograph showcasing the red–purplish striae on the patient’s abdomen, arms, and lower limbs

Upon admission, the patient’s history revealed prolonged use of betamethasone 0.1% 1 mg/mL nasal drops, administered at a daily dosage of 5 cc, in combination with oxymetazoline (a sympathomimetic nasal preparation) at a daily dosage of 1 cc, over approximately 12 months, to address nasal obstruction. Her symptoms began 6 months after starting the nasal drops. Further medication history revealed no other corticosteroid use. Notably, the patient had a past diagnosis of polycystic ovary (PCO) syndrome made on the basis of Rotterdam 2003 criteria (oligomenorrhea since menarche and clinically androgen excess) but did not undergo treatment or maintain laboratory records.

A detailed hormonal evaluation was undertaken. Morning plasma cortisol less than 0.05 µg/dL and adrenocorticotropic hormone (ACTH) less than 5 (10–56 pg/mL) measurements were abnormally low. Her 24-hour urine-free cortisol concentrations of 1.04 µg/24 h were significantly reduced, indicating suppression of the HPA axis secondary to prolonged exogenous corticosteroid exposure. All tests were repeated several times by endocrinologists during the time course of disease manifestations.

Table 1 summarizes the hormonal test results to clearly display the abnormalities.

Table 1 Hormonal and biochemical test results with reference values

Imaging studies before admission included a computed tomography (CT) scan of the adrenal glands, which showed that both adrenal glands were of normal size. However, a dynamic pituitary magnetic resonance imaging (MRI) revealed an 11 mm pituitary gland, despite there being no rationale for imaging studies in this scenario.

The patient was counseled extensively about the condition, and betamethasone nasal drops were discontinued immediately. Ear, nose, and throat (ENT) consultation revealed normal findings and the psychiatric team diagnosed her with major depressive disorder (MDD). She was discharged on 15 mg prednisolone with a structured tapering plan to allow for gradual recovery of adrenal function and to prevent acute adrenal insufficiency. Follow-up appointments were scheduled to monitor her clinical progress and re-evaluate her HPA axis recovery.

Discussion

This case highlights the rare but significant occurrence of iatrogenic CS secondary to prolonged use of intranasal betamethasone. Although oral corticosteroids are well-known to cause HPA axis suppression, INS is generally considered safer owing to their localized effects and lowering systemic absorption side effects. However, the associated potential of systemic absorption in INS remains a concern [13]. As demonstrated in this case, prolonged use of potent formulations such as betamethasone can lead to significant systemic effects, particularly when administered inappropriately or at high doses.

Betamethasone nasal drops, although effective for treating nasal congestion and inflammation [14, 15], carry a potential risk of systemic absorption through the nasal mucosa. Factors, such as prolonged use [6, 16, 17], and high potency [18], can significantly increase systemic bioavailability. R. J. Perry et al. [19] in study of seven children highlights that even patients receiving doses within conventional safety ranges may exhibit varying sensitivity to glucocorticoids, leading to symptomatic adrenal suppression or glucocorticoid excess. Unlike newer corticosteroid compounds, such as fluticasone or mometasone, which undergo extensive first-pass metabolism in the liver, betamethasone exhibits minimal hepatic metabolism, contributing to its prolonged systemic activity [20, 21]. This pharmacokinetic profile underscores the need for careful regulation and monitoring of its use, even in ostensibly localized therapies.

The clinical manifestations in this patient, including central obesity, striae, hirsutism, and mood changes, were classic features of CS and guided the diagnostic process [22]. Scutelnicu et al. [23] reported a case of a patient in the second trimester of pregnancy who, owing to chronic sinusitis, underwent intranasal betamethasone spray therapy. The patient manifested extensive striae on the lower limbs, as well as edema in the legs, arms, and face, accompanied by a weight gain of 22 kg over 3 months. After switching the patient’s treatment to an alpha-1 adrenergic agonist spray, the condition was managed uneventfully without any symptoms of adrenal insufficiency.

Requesting imaging assessments, including a CT scan and MRI, as a first step further complicated the diagnostic process. This highlights a common diagnostic pitfall: the use of imaging as an initial approach can lead to the discovery of incidentalomas, which may misdirect clinical attention. Such findings risk overshadowing the primary etiology of the condition, potentially resulting in misdiagnosis or delayed treatment. This emphasizes the importance of prioritizing functional assessments over imaging in the early diagnostic workup to avoid unwarranted diagnostic confusion and ensure accurate identification of the underlying pathology.

Management involved the immediate cessation of betamethasone nasal drops and initiation of a structured tapering regimen with prednisolone to support adrenal recovery. The importance of stress-dose precautions during intercurrent illnesses was emphasized, alongside comprehensive patient education to prevent future misuse of corticosteroids. The gradual improvement in adrenal function during follow-up highlights the reversibility of glucocorticoid-induced adrenal suppression with appropriate intervention.

Conclusion

This case underscores several critical lessons. First, it emphasizes the importance of heightened awareness among healthcare providers regarding the potential systemic effects of topical corticosteroids, particularly potent formulations such as betamethasone. Second, it highlights the need for thorough history-taking and detailed patient education to prevent corticosteroid misuse. This report contributes to the limited body of literature on iatrogenic CS from intranasal corticosteroids, particularly in adults. Documenting the clinical presentation, diagnostic challenges, and successful management of this case, provides valuable insights into preventing, recognizing, and treating similar cases. It serves as a reminder of the delicate balance between therapeutic benefit and potential harm in corticosteroid therapy and advocates for ongoing research to establish safer prescribing practices.

Data availability

The data analyzed and generated in this study can be accessed through the corresponding author upon reasonable request.

Abbreviations

CS:
Cushing’s syndrome
INS:
Intranasal corticosteroids
HPA axis:
Hypothalamic–pituitary–adrenal axis
BMI:
Body mass index
FGS:
Ferriman–Gallwey Score
PCO:
Polycystic ovary
ACTH:
Adrenocorticotropic hormone
CT:
Computed tomography
MRI:
Magnetic resonance imaging
ENT:
Ear, nose, and throat
MDD:
Major depressive disorder

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Acknowledgements

Not applicable.

Funding

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Author information

Authors and Affiliations

  1. Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran

    Mohammadsadra Shamohammadi

  2. M.D., Endocrinologist Assistant Professor of Internal Medicine Assistant Professor of Internal Medicine, Iran University of Medical Sciences at Rasool Akram General Hospital, Tehran, Iran

    Delaram Eskandari

  3. Professor of Endocrinology Department of Endocrinology, Rasool Akram Medical Complex, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Amir Ziaee

  4. Assistant Professor of Endocrinology & Metabolism Department of Internal Medicine, School of Medicine Hazrat-e Rasool General Hospital Iran University of Medical Sciences Medical Doctor at Iran University of Medical Sciences, Tehran, Iran

    Seyed Hossein Samadanifard

  5. Assistant Professor of Endocrinology & Metabolism Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Haleh Chehrehgosha

  6. M.D., Endocrinologist Assistant Professor of Internal Medicine Assistant Professor of Internal Medicine, Iran University of Medical Sciences at Rasool Akram General Hospital, Tehran, Iran

    Amir Hossein Ghanooni

Contributions

MS and DE wrote the original draft; AZ and SHS collected the data. DE and HC were the patient’s doctors; MS and AHG reviewed, edited, and supervised the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Delaram Eskandari.

Ethics declarations

Ethics approval and consent to participate

This study was conducted in accordance with ethical guidelines and was approved by the Research Ethics Committee of Iran University of Medical Sciences under approval number IR.IUMS.REC.1404.208.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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A Patient With a Bronchial Carcinoid Presents With Cushingoid Symptoms Due To An Atypical and Potentially Dangerous Supplement

Posted on October 11, 2023 by MaryO

Highlights

•

The most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer; however it is a relatively uncommon complication of pulmonary neoplasms.

•

The most common cause of Cushing syndrome is iatrogenic corticosteroid use and it should be considered in all patients regardless of clinical background.

•

Low urine cortisol levels may be associated with exogenous glucocorticoid exposure.

•

Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography.

•

Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products.

Abstract

Background

Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background.

Case report

A 59 year old woman with an 11 year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Laboratory results were not consistent with an ACTH dependent Cushing Syndrome and exogenous steroids were suspected. The patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain.

Discussion

Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing.

Conclusion

Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing.

1. Introduction

Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and can rarely exhibit Cushing syndrome due to ectopic production of adrenocorticotropic hormone (ACTH). However the most common cause of Cushing syndrome is iatrogenic corticosteroid use and should be considered in all patients regardless of clinical background (see Fig. 1, Fig. 2, Fig. 3, Fig. 4).

Fig. 1

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Fig. 1. DOTATATE PET/CT demonstrates a right upper lobe pulmonary nodule with intense uptake.

Fig. 2

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Fig. 2. DOTATATE PET/CT demonstrates intense uptake within a right upper lobe pulmonary nodule, consistent with biopsy-proven carcinoid tumor. There are no distant sites of abnormal uptake to suggest metastatic disease.

Fig. 3

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Fig. 3. Artri Ajo King Supplement (Source: FDA). The label claims that the product contains glucosamine, chondroitin, collagen, vitamin C, curcumin, nettle, omega 3, and methylsulfonylmethane.

Fig. 4

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Fig. 4. Artri King Supplement (Source: FDA).

2. Case report

A 59–year old woman with an 11 year history of a 1.5 cm well-differentiated bronchial carcinoid, presented with 20 lb. weight gain, facial swelling, flushing, lower extremity edema and shortness of breath over 3 months. On exam, the patient was normotensive, centrally obese with mild hirsutism, facial fullness and ruddiness with evidence of a dorsocervical fat pad. Initially there was concern for hormonal activation of her known bronchial carcinoid. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n < 15 mg/dL), elevated chromogranin A (201 ng/mL, n < 103 ng/mL), normal histamine (<1.5 ng/mL, n < 1.7 ng mL), low-normal 7 AM serum cortisol (5.1 μg/dL, n 3.6–19.3 μg/dL), normal 7 AM ACTH (17 pg/mL, n < 46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0–50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4–16.8 mcg/dL). Testosterone, IGF-1, glucose and electrolytes were appropriate. An echocardiogram showed an ejection fraction of 60% with no evidence of carcinoid heart disease. A Dotatate PET-CT was obtained to evaluate for progression of the neuro-endocrine tumor and revealed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Given low cortisol levels, ectopic Cushing syndrome was excluded and exogenous steroids were suspected, however the patient denied use of oral,inhaled, or injected steroids. A cosyntropin stimulation study yielded a pre-stimulation cortisol 6.2 μg/dL with an adequate post-stimulation cortisol 23.5 μg/dL. At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King Glucosamine supplements not listed on the product label but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and even death associated with such products. The patient’s symptoms gradually improved after discontinuation of the supplement.

3. Discussion

3.1. Ectopic ACTH syndrome

This patient’s Cushingoid features were initially suspected to be secondary to the known bronchial neuroendocrine tumor. Ectopic ACTH production accounts for about 5–10% of all Cushing Syndrome cases [1]. The most common location of ectopic ACTH is the lungs with pulmonary carcinoid tumors being the most common cause, followed by squamous cell lung cancer [2]. Despite this patient’s history of bronchial carcinoid tumor and positive chromogranin histopathological marker, her laboratory results were not consistent with an ACTH dependent Cushing Syndrome. In fact, Cushing syndrome is a relatively uncommon neuroendocrine neoplasm complication. The prevalence of ectopic ACTH production in patients with lung tumors is rare, at less than 5% in squamous cell lung cancer and about 3% in patients with lung or pancreatic (non-MEN1) neuroendocrine tumors1.

Patients with ACTH dependent Cushing syndrome not suspected to originate from the pituitary, undergo further testing to evaluate for an ectopic ACTH secreting tumor. These tests include conventional imaging of the chest, abdomen and pelvis, as well as functional imaging such as octreotide scans, fluoride 18-fluorodeoxyglucose-positron emission tomography [18F-FDG PET], and gallium-68 DOTATATE positron emission tomography-computed tomography [Dotatate PET-CT] scan [3]. In our literature review, we found that there was insufficient evidence to determine the sensitivity and specificity of nuclear medicine imaging techniques [4,5]. In this case, the patient had no laboratory evidence for ACTH dependent Cushing Syndrome, but given the known bronchial carcinoid tumor, a repeat Dotatate PET-CT scan was obtained which demonstrated no indication of growth or spread of the known bronchial tumor.

3.2. Supplement induced Cushing Syndrome

One of the most remarkable findings in this case was the patient’s low urine cortisol level in the setting of her overt Cushingoid features. In our survey of the literature, we found that low urine cortisol levels were associated with exogenous glucocorticoid use [6,7]. The low urine cortisol levels may be reflective of intermittent glucocorticoid exposure. Indeed, this patient’s Cushingoid features were determined to be secondary to prolonged use of Artri King supplement.

Occult glucocorticoid use is difficult to diagnose even after performing a thorough medication reconciliation as patients may unknowingly consume unregulated doses of glucocorticoids in seemingly harmless supplements and medications. The incidence of supplement induced Cushing Syndrome is currently unknown as supplements are not regularly tested to detect hidden glucocorticoid doses. Additionally, the likelihood of developing supplement induced Cushing syndrome is dependent on dosage and duration of use.

In our literature review we found nine published articles describing supplement induced Cushing Syndrome [[7], [8], [9], [10], [11], [12], [13], [14], [15]], one case report of tainted counterfeit medication causing Cushing Syndrome [16], and two cases of substances with probable glucocorticoid-like activity [17,18]. Of the nine published articles of supplement induced Cushing Syndrome, six were associated with supplements marketed as arthritic joint pain relief products including ArtriKing, Maajun, and AtriVid [[7], [8], [9], [10], [11], [12]]. These products later received government issued warnings in Mexico, Malaysia, and Colombia respectively [[19], [20], [21]].

To our knowledge there have been four published reports of ArtiKing supplement induced Cushing Syndrome [[7], [8], [9], [10]]. The first documented cases were reported in 2021 in Vera Cruz, Mexico; since then the Mexican medical community reported seeing a disproportionate increase in cases of iatrogenic Cushing Syndrome due to these supplements [7]. There have also been three American published articles describing a total of 4 cases of ArtriKing supplement induced Cushing syndrome [[8], [9], [10]]. In January 2022 the FDA issued a warning about Atri Ajo King containing diclofenac, which was not listed in the product label [22]. In April 2022 the FDA expanded its warning, advising consumers to avoid all Artri and Ortiga products after the FDA found these products contained dexamethasone and diclofenac [23]. In October 2022 the FDA issued warning letters to Amazon, Walmart, and Latin Foods market for distributing Artri and Ortiga products [24].

Many supplements are not regulated by the government and may contain hidden ingredients such as glucocorticoids. In these cases further evaluation of suspected products [25], medications [16], and patient serum [26] and urine [6] utilizing techniques such as liquid chromatography may be used to confirm occult glucocorticoid exposure.

This case highlights the importance of educating patients to exercise caution when purchasing health products both online and abroad. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products.

4. Conclusion

Although the most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer, it is a relatively uncommon complication of pulmonary neoplasms.

Exogenous Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. This case report emphasizes the importance of teaching patients to be vigilant and appropriately research their health supplements.

Patient consent

Formal informed consent was obtained from the patient for publication of this case report.

Declaration of competing interest

The authors (Tomas Morales and Shanika Samarasinghe) of this case report declare that they have no financial conflicts of interest. Shanika Samrasinghe is an editorial member of the Journal of Clinical and Translational Endocrinology: Case Reports, and declares that she was not involved in the peer review and editorial decision making process for the publishing of this article.

References

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Topical Corticosteroid-Induced Iatrogenic Cushing Syndrome in an Infant

Posted on December 16, 2021 by MaryO
https://doi.org/10.1016/j.amsu.2021.102978Get rights and content
Under a Creative Commons license

Highlights

•

Cushing syndrome is an abnormality resulting from high level of blood glucocorticoids.

•

Iatrogenic Cushing syndrome due to the overuse of topical corticosteroids is rarely reported.

•

This report presents a case of topical corticosteroid induced iatrogenic Cushing syndrome in an infant.

Abstract

Introduction

Cushing syndrome (CS) is an endocrinological abnormality that results from a high level of glucocorticoids in the blood. Iatrogenic CS due to the overuse of topical corticosteroids is rarely reported. The current study aims to present a rare case of topical corticosteroid induced iatrogenic CS in an infant.

Case presentation

A 4-month-old female infant presented with an insidious onset of face puffiness that progressed over a 2-month period. The mother reported to have used a cream containing Betamethasone corticosteroid 5–8 times a day for a duration of 3 months to treat diaper dermatitis. Laboratory findings revealed low levels of adrenocorticotrophic hormone (ACTH) and serum. Abdominal ultrasound showed normal adrenal glands. The topical corticosteroid was halted and physiologic topical hydrocortisone doses were administered.

Clinical discussion

Infants are more likely to acquire topical corticosteroid induced iatrogenic CS due to their thin and absorptive skin, higher body surface area, and the high prevalence of conditions that necessitates the use of these medications. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis that are most commonly treated with Clobetasol and Bethamethasone.

Conclusion

Infants are susceptible to develop CS due to topical corticosteroid overuse. Hence, physicians need to consider this in infantile CS cases, and take appropriate measures to avoid their occurrence.

Keywords

Cushing syndrome
Infant
Iatrogenic
Topical corticosteroid

1. Introduction

Cushing syndrome (CS) is a reversible endocrinological abnormality that results from high level of cortisol or other glucocorticoids in the blood [1]. It can be caused by either endogenous factors such as excess steroid production and secretion due to adrenal or pituitary tumors, or exogenously through prolonged use of corticosteroid medications resulting in iatrogenic CS [2]. Iatrogenic CS due to the overuse of oral or parenteral corticosteroids is common, however, while topical corticosteroids are one of the most widely prescribed medications by dermatologists, they are less frequently reported to cause iatrogenic CS [3,4]. Even though CS is very rare in the pediatric population with an annual incidence of only 5 cases per million, children of the pediatric age have a higher risk of developing iatrogenic CS, which is likely due to the high prevalence of conditions that necessitates the use of topical corticosteroids and the thinness of their skin that can more easily absorb the steroid [5,6].

The aim of the current study is to present a rare case of topical corticosteroid induced iatrogenic CS in an infant. SCARE guidelines are considered in writing this report [7].

2. Case presentation

2.1. Patient information

A 4-month-old female infant presented with an insidious onset of puffiness of the face; the swelling progressed over a period of 2 months without any other associated symptoms. The infant’s prenatal, developmental, and family history were insignificant, and she was born full term to consanguineous parents via caesarian delivery. After delivery she did not require neonatal intense care unit (NICU) and was discharged in good health. She has been given both bottle and breastfeeding every one to two hrs, and she has received all the required vaccinations at their proper times.

The mother reported to have used a topical corticosteroid cream (Optizol-B cream; a combination of Clotrimazole and Betamethasone) for a period of 3 months with a dose of 5–8 times a day to treat diaper dermatitis of the infant.

2.2. Clinical findings

The infant’s physical examination revealed facial puffiness (Moon face) with no body edema, and cutaneous examination showed the diaper rash without any other cutaneous manifestations. The infant was vitally stable with no dysmorphic features and no skeletal deformities. Her growth parameters were within normal limits, and her systemic examination was unremarkable.

2.3. Diagnostic approach

Laboratory findings revealed low adrenocorticotropic hormone (ACTH) level in the blood measuring 5.9 p.m./l, a serum cortisol level of 24 nmol/l, and normal serum sodium and potassium levels of 144 mEq/l and 4.8 mmol/l, respectively. Abdominal ultrasonography (US) showed normal adrenal glands.

2.4. Therapeutic intervention

The topical corticosteroid cream that contained Bethamethasone was halted and oral hydrocortisone was given (10 mg/m2) tapered over one month. The patient was given a card addressing Cushing syndrome to inform the health care providers in case of emergency situation or unexpected surgical intervention.

2.5. Follow-up and outcome

The infant’s facial puffiness was significantly improved after 7-month follow-up of the patient.

3. Discussion

CS is an endocrinological disorder resulting from high glucocorticoid level in the blood, it is categorized into ACTH dependent (due to pituitary tumors or excess ACTH administration) or ACTH independent CS (due to adrenal neoplasms or excessive glucocorticoid intake) [8,9]. Under normal circumstances, ACTH is secreted by the pituitary gland which in turn stimulates the secretion of cortisol by the adrenal glands [10]. Prolonged exogenous corticosteroid administration can lead to a number of adverse effects based on potency and duration of the treatment, including the suppression of hypothalamic-pituitary-adrenal (HPA) axis and iatrogenic CS, severe infections, and failure to thrive [11]. While iatrogenic CS is frequent with prolonged administration of oral or parenteral corticosteroids, it is occurrence due to topical corticosteroids have rarely been reported [12].

Multiple factors can increase the probability of acquiring the condition, such as corticosteroid potency, amount and frequency of application, age, skin quality, presence of occlusion, and duration of application [4]. In general, infants are more likely to develop topical corticosteroid induced iatrogenic CS, this is due to their thin and absorptive skin, higher body surface area, underdeveloped skin barrier, and the high prevalence of conditions that necessitates the use of these medications [5,6]. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis [8]. This was also the case in this study. This is likely because the diaper area provides occlusion, the perineal skin has intrinsically absorptive properties, the steroid causes local skin atrophy, and percutaneous absorption is even more increased as the result of skin inflammation [13].

The most frequently used corticosteroid for the treatment of diaper dermatitis is reported to be Clobetasol followed by Bethamethasone, with a mean application duration of 2.75 (1–17) months to induce cortisol and ACTH levels suppression [4]. Typical clinical manifestations of CS include facial puffiness (Moon face), generalized body edema and obesity, hirsutism, buffalo hump, hypertension, skin fragility, and purple striae [3,5]. The causative corticosteroid in the current case was Bethamethasone that only resulted in facial puffiness (Moon face) without generalized body edema.

A specific and definitive diagnostic approach for iatrogenic CS is currently lacking [5]. However, prolonged exogenously administered glucocorticoids can suppress ACTH secretion which results in dismissing the need for proper endogenous production of cortisol [14]. Hence, almost all iatrogenic CS cases are associated with low ACTH and cortisol levels which can aid in the diagnosis of the condition [8]. Same findings were observed in this case. According to multiple studies, exogenous corticosteroid administration can often lead to HPA axis suppression alongside CS [15,16]. However, topical corticosteroid induced iatrogenic CS has been reported without HPA axis suppression [8].

The management of these cases start with the cessation of the causative corticosteroid medication and administration of physiologic topical hydrocortisone [5]. The same approach was followed in this study. In order to prevent the development of this condition in the first-place; clinicians should avoid prescribing high potency corticosteroids in the treatment of infantile dermatological disorders and instead choose low potency topical steroids, and also parents should be advised not to overuse these medications and only apply a thin layer to the affected area [6].

In conclusion, even though iatrogenic CS in infants is rare, overuse of topical corticosteroids can lead to their occurrence. Hence, physicians need to consider extensive steroid use as a causative agent of infantile CS. Appropriate measures need to be taken to avoid their occurrence by prescribing less potent steroids, limiting the use of high potent steroids, and informing parents about adverse effects of steroid overuse in infants.

Source of funding

None is found.

Author statement

Soran Mohammed Ahmed: physician managing the case, follow up the patient, and final approval of the manuscript.

Shaho F. Ahmed, Snur Othman, Berwn A. Abdulla, Shvan M.Hussein, Abdulwahid M.Salih, and Fahmi H. Kakamad: literature review, writing the manuscript, final approval of the manuscript.

Patient consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Guarantor

Fahmi Hussein Kakamad.

Declaration of competing interest

None to be declared.

References

© 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

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Topical Ocular Glucocorticoid Leads to Cushing’s Syndrome in 9-Year-Old

Posted on January 21, 2017 by MaryO

In a case report published online January 19 in Pediatrics, iatrogenic Cushing’s syndrome (CS) is described in a 9-year-old girl who received topical ocular glucocorticoid (GC) treatment for bilateral iridocyclitis.

Daisuke Fukuhara, MD, PhD, from the Kyorin University School of Medicine in Mitaka, Japan, and colleagues present the case of a 9-year-old girl suffering from idiopathic uveitis. She arrived at the ophthalmology department with a complaint of painful eyes, and was diagnosed with bilateral iridocyclitis and started on betamethasone sodium phosphate eye drop treatment.

The authors note that the patient was referred to the pediatric department with stunted growth, truncal obesity, purple skin striae, buffalo hump, and moon face six months after initiation of topical ocular GC treatment. She was diagnosed with iatrogenic CS as her serum cortisol and plasma adrenocorticotropic hormone levels were undetectable. The clinical symptoms of CS were improved after the doses of topical ocular GC were reduced. On genetic analysis, the patient was found to have a single heterozygous nucleotide substitution in the 3′ untranslated region of the NR3C1 gene.

“However, additional investigations are required to determine if our findings can be extrapolated to other patients,” the authors write. “In conclusion, clinicians should be aware that even extremely low doses of topical ocular steroid therapy can cause iatrogenic CS.”

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From http://www.empr.com/news/iatrogenic-cushings-syndrome-topical-ocular-glucocorticoid-iridocyclitis/article/632840/

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