I was drawn to this blog post because the author mentioned that she had both Cushing’s and cancer, a kind of unusual combination.
1974 to Today: Seal it up
By Experience
I still haven’t heard what the consensus is on my aftercare: Cushing’s and Cancer. I don’t know what I will be expecting to feel like after surgery. My endocrinologist said that I should get sick after the surgery and need some kind of … 1974 to Today – http://1974totoday.blogspot.com/
I don’t usually comment on blog posts but I did on this one because we seem to share so much, disease-wise.
I said
Hi, I was drawn to your blog post because I have a blog with the same name, Cushings & Cancer.
I had my Cushing’s long ago and my cancer (kidney aka renal cell carcinoma) was 3 years ago but I sure know where you’re coming for.
My surgeon contacted my endo for the amounts of steroids during surgery (they came through the IV) then post-op, they kept cutting my dose in half until I was back down to normal.
Generally, you stress-dose after surgery if you feel like you have a flu coming on. Has your endo given you Cortef or another steroid to take for emergencies like this? Sometimes, they will give you an injectible to be faster acting.
Best of luck with the cancer surgery AND your Cushing’s.
MaryO
I sure hope that this isn’t a trend, Cushies getting cancer although I know of a couple others on the boards getting cancer.
I suppose Cushing’s doesn’t make us any more immune to other diseases but it seems like it should.
Haven’t we already “done our time”?
OTOH, I have a friend with a serious cancer (aren’t they all?) who recently learned that she has a second, unrelated, cancer. Makes you wonder sometimes.
What other diseases have you had in addition to your Cushing’s?
I found this article especially interesting. This question was asked of a group of endos at an NIH conference a few years ago – if you saw someone on the street who looked like they had symptoms of fill-in-the disease, would you suggest that they see a doctor. The general answer was no. No surprise there.
Patients, if you see someone who looks like s/he has Cushing’s, give them a discrete card.
Spread The Word! Cushing’s Pocket Reference
Robin Writes:
This has been a concern of mine for some time. Your post spurred me on to do something I’ve been meaning to do. I’ve designed something you can print that will fit on the business cards you can buy just about anywhere (Wal-mart included). You can also print on stiff paper and cut with a paper cutter or scissors. I’ve done a front and a back.
Passengers on a London bus. Photograph: David Levene
A Spanish woman of 55, Montse Ventura, recently met the woman she refers to as her “guardian angel” on a bus in Barcelona. The stranger – an endocrinologist – urged Ventura to have tests for acromegaly, a rare disorder involving an excesss of growth hormone, caused by a pituitary gland tumour. How had the doctor made this unsolicited diagnosis on public transport? Apparently the unusual, spade-like shape of Ventura’s hands was a dead giveaway.
But how many off-duty doctors would feel compelled to alert strangers to symptoms they spot? “If I was sitting next to someone on a bus with a melanoma, I’d say something or I wouldn’t sleep at night,” says GP Mary McCullins. “We all have a different threshold for interfering and you don’t want to terrify people, but this is the one thing I’d urge a total stranger to see a doctor about.” So what other symptoms might prompt a doctor to approach someone on the street?
Moon face
Cushing’s syndrome is another rare hormone disorder which can be caused by a non-cancerous tumour in the pituitary gland. “A puffy, rounded ‘moon face’ is one of the classic signs of Cushing’s,” says Dr Steve Field, chair of the Royal College of GPs. “In a social situation, I wouldn’t just say, ‘You’re dangerously ill’ but I’d try to elicit information and encourage them to see a doctor.”
Different-sized pupils
When one pupil is smaller than the other, perhaps with a drooping eyelid, it could be Horner’s syndrome, a condition caused when a lung tumour begins eating into the nerves in the neck. This can be the first obvious sign of the cancer. “I’d encourage someone to get this checked out,” says Dr Simon Smith, consultant in emergency medicine at the Oxford Radcliffe Hospitals Trust. “People often have an inkling that something’s wrong, and you might spur them to get help sooner.”
Clubbing fingers
Some people are born with club-shaped fingers, but if, over time, they become “drumstick-like”, this could signify serious problems such as lung tumours, chronic lung infections or congenital heart disease. “Because it happens gradually, some people disregard clubbing,” says Smith. “But I’d say something because it can be an important symptom in many serious illnesses.”
Lumpy eyelids
Whitish yellowy lumps around the eyelids can be a sign of high cholesterol, a major factor in heart disease. Sometimes you also get a yellow circle around the iris. “I would suggest they got a cholesterol test with these symptoms,” says Smith. “They can do something about it that could save their life.”
Suntan in unlikely places
A person with Addison’s disease, a rare but chronic condition brought about by the failure of the adrenal glands, may develop what looks like a deep tan, even in non sun-exposed areas such as the palms. Other symptoms (tiredness, dizziness) can be non-specific so the condition is often advanced by the time it is diagnosed. Addison’s is treatable with lifelong steroid replacement therapy. “If someone was saying they hadn’t been in the sun but had developed a tan, alarm bells would ring and I’d probably ask how they were feeling,” says McCullins.
Trench mouth
Putrid smelling breath – even if the teeth look perfect – can be a sign of acute necrotising periodontitis. “I’d be able to tell when someone walks through the door,” says dentist Laurie Powell. “But people become accustomed to it and don’t notice.” Untreated, the condition damages the bones and connective tissue in the jaw. It can also be a sign of other diseases such as diabetes or Aids.
Neuroendocrine tumours of the thymus are extremely rare, with an estimated incidence of about 1 in 5 million people. Although data is limited, complete surgical resection remains the most significant prognostic factor for improved survival and disease-free outcomes, with adjuvant radiotherapy playing a role in cases where resection margins are close. This case report details the management of a cortisol secreting pT1bN0 atypical carcinoid of the thymus in a 43-year-old male.
Case report
43-year-old male presented with Cushing’s syndrome and was diagnosed with a cortical secreting atypical carcinoid of the thymus. He underwent a robotic thymectomy. Recurrent disease on a DOTATATE-PET CT scan resulted in a second surgery involving complete resection of the mediastinal tumour which had invaded the pericardium, as well as wedge resection of the lung and lymph node sampling. This was followed by adjuvant radiotherapy due to close proximity of the lesion to the margin (< 3 mm).
Discussion
Although paraneoplastic syndromes such as Cushing’s syndrome are rare manifestations of thymic neuroendocrine tumours and can result in challenging diagnoses, it is vital to have a high index of suspicion towards ectopic ACTH secretion in order to facilitate timely initiation of multimodal disease management for these patients including surgery and radiotherapy.
Conclusion
Surgical management has been shown to offer the greatest prognosis in terms of overall survival and disease-free survival. Adjuvant radiotherapy plays a role where resection margins are close.
Neuroendocrine tumours of the thymus (NETT) are extremely rare, with an estimated incidence of about 1 in 5 million people [1], accounting for about 2–5% of thymic tumours and 0.4–3.4% of all carcinoid tumours [2]. Around 50% of neuroendocrine tumours of the thymus are hormonally active, with patients presenting with paraneoplastic symptoms such as Cushing’s syndrome due to ectopic production of ACTH. A review of 157 cases showed that males have a 3:1 increased risk of developing NETTs compared to women [3], with patients typically being heavy smokers and diagnosed between 40 and 60 years old. Atypical carcinoid tumours are differentiated from typical carcinoid tumours by their increased mitotic rate (2–10 per 2mm2/10 HPF) or areas of focal necrosis and account for about 40–50% of all thymic neuroendocrine tumours [1]. We present a case of a male patient who underwent complete excision and adjuvant radiotherapy for a neuroendocrine carcinoma with elevated mitotic count.
Case report
A previously fit and well 43-year-old male initially presented with features of Cushing’s syndrome, namely weight gain, hypertension and skin changes. He had a past medical history of polycystic kidney disease and asthma. The Cushing’s syndrome was found to be related to a 56 mm cortisol secreting pT1bN0 neuroendocrine carcinoma of the thymus. He underwent a right sided robotic thymectomy in July 2021.
A DOTATATE PET CT scan showed recurrence of his thymic carcinoid at the level of the groove between the right main pulmonary artery and right atrium, growing very close to the phrenic nerve. It was advised for him to undergo complete excision of the lesion requiring a joint approach from cardiac and thoracic surgeons. The patient subsequently underwent a median sternotomy, removal of recurrent mediastinal tumour invading the pericardium and wedge resection of the lung, lymph node sampling.
The patient was positioned supine. Femoral vessels were prepared in case there was bleeding which necessitated emergency bypass. Median sternotomy was performed with an oscillating saw due to previous right robotic thymectomy. The pericardium was opened. The tumour was identified at the level of the pulmonary vein and the cavo-atrial junction. En bloc resection of the tumour and the pericardium was performed, dissecting it away from the superior vena cava and the right atrium and wedge resection of the right lower lobe. The right phrenic was identified and spared. Due to previous surgery the phrenic nerve was surrounded by adhesions. A diaphragmatic plication was performed with 4 Ethibond no.5 sutures considering the risk of nerve palsy during dissection. The pericardium was reconstructed with a Prolene mesh fixed with Prolene 3/0.
Histology of the mediastinal tissue and right lung tissue sent showed a mitotic rate of more than 10 which according to the WHO classification of thoracic tumours, would make this a large cell neuroendocrine carcinoma. However, the morphological features were not of large cell type and therefore the tumour was best described as a NETT with elevated mitotic count. Histology confirmed the diagnosis as being a Neuroendocrine Carcinoma. The tumour had been excised completely with a 1.3 mm margin around the lesion. The patient required adjuvant radiotherapy due to the close proximity of the lesion to the margin (< 3 mm). A dose of 60 Gy over 30 daily fractions was selected in this postoperative adjuvant setting.
Discussion
This patient presented initially with Cushing’s syndrome associated with a cortisol secreting atypical carcinoid of the thymus. The excess glucocorticoid secretion presenting in the symptoms of Cushing’s syndrome can result from an ACTH secreting tumour of the pituitary which would be defined as Cushing’s disease, or less frequently from non-pituitary tumours secreting ACTH which would be defined as ectopic ACTH secretion [4]. Once the diagnosis of Cushing’s syndrome is made, it is essential to differentiate whether this is Cushing’s disease or an ectopic ACTH secretion. Current guidelines advise that inferior petrosal sinus sampling is the gold standard in distinguishing Cushing’s disease from ectopic ACTH secretion where a pituitary MRI is negative [5]. However, due to high cost, invasive nature and the risk of thromboembolic complications, investigations such as the CRH test and high dose dexamethasone suppression test are often preferred. A retrospective analysis looked at 719 patients with neuroendocrine tumours treated in EKPA-Laiko Hospital in Athens, Greece. They found that the prevalence of endocrine neoplastic syndromes in patients with neuroendocrine tumours was only 1.9% [6]. Kamp et al. studied the prevalence of specifically ectopic ACTH syndrome in 918 patients who had been diagnosed with either thoracic or gastroenteropancreatic neuroendocrine tumours. They found that 29 patients, or 3.2% had ectopic ACTH syndrome, with most of these cases being thoracic tumours and 4 of these patients having thymic tumours [7]. This study highlights that although the incidence of ectopic ACTH secretion in thoracic neuroendocrine tumours is relatively rare, resulting in challenging diagnosis, it is important to maintain a high index of suspicion in order to facilitate timely initiation of multimodal management such as surgery and radiotherapy.
A retrospective study at Fukuoka University Hospital looking at 9 cases of NETTs and 16 cases of thymic carcinomas, showed complete resection to be a statistically significant prognostic factor, with the 5-year survival rate and 5-year disease free survival rate being 87.5% and 75% in the thymic neuroendocrine tumour group, and 58.9% and 57.1% in the thymic carcinoma group respectively [8]. Chen et al. looked at a total of 104 patients diagnosed with NETTs, of which 97 underwent surgical resection, with 79 undergoing radical resection. The 1-year, 3-year and 5-year overall survival rates were found to be 91.8%, 70.2% and 54.6% respectively, with radical resection being found to be a significant factor in the overall survival of patients with NETTs [9]. Due to the rarity of NETTs, few cases are reported, and these studies are limited by their being retrospective in nature and spanning over several decades, possibly affecting the consistency and standardisation of patient treatment. However, it is important to note that complete radical resection of the tumour was consistently shown to be a strong prognostic factor in the overall survival and disease-free survival of patients and this should be attempted wherever possible.
The gentleman in our case required post operative radiotherapy due to the close proximity of the lesion to the margins. A large retrospective study looked at 205 patients treated for neuroendocrine thymic tumours, with 81 patients receiving radiotherapy and 70 out of the 81 receiving it as adjuvant therapy. In this particular study, radiotherapy was not shown to have any significant impact on survival outcomes [10]. An analysis of 12 cases of NETTs noted that 5 of the 6 patients who had presented with local recurrence during follow up had not received any post operative radiotherapy [11, 12], suggesting that adjuvant radiotherapy had resulted in better outcomes in terms of disease-free survival. A large retrospective analysis looking at 1489 patients diagnosed with NETTs or thymic carcinomas, found that the two factors which influenced positive survival outcomes were surgical resection and adjuvant radiotherapy. On sub-analysis, it was found that adjuvant radiotherapy had a good prognosis of survival in patients with margin positive tumours and was an independent predictor of survival for both thymic carcinomas and NETTs [12]. Wen et al. analysed 3947 patients in a retrospective study, including 293 neuroendocrine thymic tumours, 2788 thymomas and 866 thymic carcinomas. It was shown that post operative radiotherapy had a significant positive impact on overall survival and cancer specific survival in Masaoka-Koga stage III-IV thymic neuroendocrine tumour patients, as well as had a favourable impact on the overall survival of stage IIB patients [13]. Although these studies provide evidence of the benefits of adjuvant radiotherapy for favourable outcomes and prolonged survival, the last two studies are limited in that due to the rarity of neuroendocrine thymic tumours, they made up only 11 out of 329 (3.3%) of the thymic tumours analysed by Bakhos et al. and 7.4% of cases analysed by Wen et al.l, and the outcomes should therefore be interpreted with caution. The importance of multidisciplinary care involving maximal radical surgical excision as well as the involvement of oncologists and radiotherapists in the management of thoracic carcinoid tumours such as this, is emphasised in Busetto et al. [14].
Conclusion
Neuroendocrine tumours of the thymus (NETT) are exceedingly rare and often present diagnostic and therapeutic challenges due to their aggressive nature and associated paraneoplastic syndromes like Cushing’s syndrome. Complete surgical resection remains the most significant prognostic factor for improved survival and disease-free outcomes, with adjuvant radiotherapy playing a role in cases where resection margins are close. Although the data is limited by the rarity of the disease, existing studies suggest that a multidisciplinary, patient-specific approach, including surgery and radiotherapy, offers the best chance of long-term survival.
Fig. 1
Axial CT showing the carcinoid tumour (demonstrated by arrow) in close proximity to innominate vein
No datasets were generated or analysed during the current study.
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Lau J, Ioan Cvasciuc T, Simpson D, C de Jong M, Parameswaran R. Continuing challenges of primary neuroendocrine tumours of the thymus: A concise review. Eur J Surg Oncol [Internet]. 2022.
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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.
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”)
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. 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.
F. Beuschlein, T. Else, I. Bancos, S. Hahner, O. Hamidi, L. Van Hulsteijn, E.S. Husebye, N. Karavitaki, A. Prete, A. Vaidya, C. Yedinak, O.M. Dekkers
European society of endocrinology and endocrine society joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal insufficiency
Cyclic Cushing syndrome (CCS) is characterized by unpredictable, intermittent phases of excess cortisol, alternating with periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels. The mechanism is unclear. Due to its rarity and diverse clinical presentation, unpredictable phases, and various etiologies, CCS poses significant diagnostic and management challenges for endocrinologists. The authors describe 3 cases in which each patient’s initial presentation was a life-threatening hypercortisolemic phase that lasted from 4 days to 3 months, followed by spontaneous resolution to prolonged eucortisolemic phases lasting from 10 to 26 months. Further testing indicated an ectopic ACTH-secreting source; however, the locations of the offending tumors were indeterminate. The authors propose the term square wave CCS variant to characterize the unique, prolonged intercyclic phases of hypercortisolemia and eucortisolemia with this subtype that are distinct from conventional CCS characterized by shorter phases of transient hypercortisolemia shifting to periods of eucortisolemia or hypocortisolemia. This uncharacteristic pattern of cyclicity poses diagnostic and therapeutic challenges, thus underscoring the importance of careful diagnostic workup and treatment of these patients.
Cyclic Cushing syndrome (CCS) is a rare variant of Cushing syndrome (CS) characterized by intermittent episodes of cortisol peaks alternating with variable periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels (troughs) [1]. These cycles can occur at regular or irregular intervals [2], with unpredictable intercyclic phases typically lasting from days to months [3, 4]. The prevalence of CCS in patients with CS is low, ranging from 8% to 19% [3‐6]. Several alternative terms (eg, intermittent, variable, periodic, and episodic hypercortisolism) have been proposed to characterize the variable cyclicity of ACTH and cortisol secretion in patients with CCS [7].
We describe 3 cases of suspected ectopic ACTH-dependent CS with an indeterminate ACTH source that presented with life-threatening hypercortisolemia lasting from 4 days to 3 months, followed by spontaneous eucortisolemic phases lasting from 10 to 26 months. The term square wave is proposed to describe this unique cyclic pattern to highlight the unpredictability of severe hypercortisolemia followed by spontaneous prolonged eucortisolemic phases, which is distinct from previously described transient regular or irregular cycles with shorter intercyclic phases of CCS that require medical intervention.
Case Presentation
Case 1
A 75-year-old man with atrial fibrillation, bilateral leg edema, 6-month weight loss of 7 pounds (3.2 kg), and generalized muscle weakness was referred for cardiac ablation therapy. However, just before he underwent the procedure, he was found to be profoundly hypokalemic with potassium of 2.9 mEq/L (SI: 2.9 mmol/L) (reference range, 3.6-5.3 mEq/L [SI: 3.6-5.3 mmol/L]) and hyperglycemic, with blood glucose of 498 mg/dL (SI: 27.8 mmol/L) (reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]) and glycated hemoglobin (HbA1c) of 7.4%. He was emergently treated with potassium supplementation and insulin therapy.
Case 2
A 61-year-old woman presented to the emergency department with palpitations, uncontrolled hypertension, weight loss of 20 pounds (9.1 kg) over 2 weeks, new signs of hyperandrogenism (eg, hirsutism, acne, muscle atrophy), lower back pains, easy bruising, and proximal muscle weakness.
Case 3
A 57-year-old woman presented to the emergency department in August 2021 with a 2-month history of facial swelling and generalized muscle weakness. She had reported a similar episode in April 2019 with hypokalemia (potassium, 2.5 mEq/L [SI: 2.5 mmol/L]) that was treated with potassium repletion therapy.
Diagnostic Assessment
Case 1
Further laboratory tests revealed elevated morning (Am) cortisol of 76.8 µg/dL (SI: 2119 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]), Am ACTH of 368 pg/mL (SI: 81 pmol/L) (reference range, 6-50 pg/mL [SI: 1.3-11.0 pmol/L]), and 24-hour urine free cortisol (UFC) of 4223 µg/24 hours (SI: 11 656 nmol/24 hours) (reference range, 1.5-18.1 µg/24 hours [SI: 4-50 nmol/24 hours]) (Table 1). Magnetic resonance imaging (MRI) of the pituitary (Fig. 1) and 68Ga-DOTATATE positron emission tomography (PET) (Table 2) of the chest, pelvis, and abdomen failed to identify the source of ACTH secretion. Inferior petrosal sinus sampling (IPSS) showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source (Table 3).
Table 1.
Summary of biochemical testing data for the 3 patients with a square wave pattern of cyclic Cushing syndrome
Case 1. (A) Sagittal and (B) coronal magnetic resonance images demonstrating normal appearance of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.
Laboratory tests revealed elevated Am cortisol of 38.4 µg/dL (SI: 1060 nmol/L) and Am ACTH of 118 pg/mL (SI: 26 pmol/L), hypokalemia (potassium, 2.9 mEq/L [SI: 2.9 mmol/L]) and new-onset type 2 diabetes mellitus with a random blood glucose of 489 mg/dL (SI: 27.2 mmol/L) and HbA1c of 9.2% (reference range, < 5.7%) (Table 1). Lumbar spine radiography and spine MRI demonstrated compression fractures of L1 to L4 vertebrae, and pituitary MRI showed a 2-mm hypo-enhancing foci within the midline and to the right of the pituitary gland (Fig. 2).
Case 2. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland show 2-mm hypo-enhancing foci (arrows) within the midline and to the right side of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.
Case 3
During the present hospital admission, the patient was hypokalemic (potassium, 2.7 mEq/L [SI: 2.7 mmol/L]) and hypercortisolemic with Am cortisol and Am ACTH levels of 56.8 µg/dL (SI: 1568 nmol/L) and 159 pg/mL (SI: 35 pmol/L), respectively. After 4 days of hospitalization, the patient spontaneously became eucortisolemic with an Am cortisol of 16.8 µg/dL (SI: 464 nmol/L), 24-hour UFC of 670.5 µg/24 hours (SI: 1851 nmol), and late-night salivary cortisol of 0.03 µg/dL (SI: 0.828 nmol/L) with symptom improvement (Table 1). Pituitary MRI revealed a flattened, normal-appearing pituitary gland (Fig. 3).
Case 3. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland showing a flattened pituitary gland. No discrete, sizable, differentially enhancing mass is detected within the sella. From Barrow Neurological Institute, Phoenix, Arizona.
Treatment
Case 1
Because of the patient’s worsening clinical condition and severe hypercortisolemia with no identifiable ACTH source, ketoconazole was considered to induce eucortisolemia. While electrocardiography and liver function tests were being measured before starting ketoconazole, the patient’s Am cortisol levels spontaneously normalized to 14.2 µg/dL (SI: 392 nmol/L) with symptomatic improvement.
Case 2
The patient began insulin, spironolactone, and levothyroxine therapy. After 2 days in the hospital, her Am cortisol decreased to 17.9 µg/dL (SI: 494 nmol/L) and remained within the range of 9.4 to 17.9 µg/dL (SI: 259-494 nmol/L). An IPSS performed 3 weeks later showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source. By month 3, her Am cortisol levels consistently remained below 15 µg/dL (SI: 414 nmol/L). Blood pressure was controlled with one antihypertensive agent, and insulin was discontinued due to frequent hypoglycemic episodes.
Case 3
The patient was readmitted 18 months later with worsening muscle weakness, uncontrolled hypertension, hypokalemia (potassium, 2.4 mEq/L [SI: 2.4 mmol/L]), and hypercortisolemia with elevated Am cortisol and Am ACTH levels. 68Ga-DOTATATE PET did not reveal an ectopic ACTH source (Table 2), and IPSS did not reveal any significant ACTH gradient (Table 3). However, computed tomography (CT) of the chest, abdomen, and pelvis revealed a 0.7-cm lung nodule. During this hospitalization, the patient received supportive treatment, including antihypertensive therapy and electrolyte replacement. No pharmacologic intervention was required to control her cortisol levels.
Outcome and Follow-Up
Case 1
Late-night salivary cortisol levels measured were within the normal range (0.08 µg/dL, 0.06 µg/dL, and 0.08 µg/dL [SI: 2.2 nmol/L, 1.7 nmol/L, and 2.2 nmol/L]; reference range, < 0.09 µg/dL [SI: < 2.5 nmol/L]). Because of these biochemical and symptomatic improvements, ketoconazole therapy was deferred. At the most recent outpatient clinic follow-up 26 months after his cortisol levels normalized, the patient remained in remission without recurrence of hypercortisolemic symptoms.
Case 2
The patient remained in biochemical and clinical remission for 15 months until she began experiencing abdominal distention, bilateral leg edema, and facial swelling again. Blood pressure increased at this time, requiring 3 antihypertensive medications. Her Am cortisol levels rose to 29.1 µg/dL (SI: 803 nmol/L), but repeat IPSS showed no ACTH gradient, and 68Ga-DOTATATE PET/CT of the chest, abdomen, and pelvis was unremarkable (Tables 2 and 3). Block-and-replace therapy of osilodrostat and hydrocortisone was initiated to preemptively prevent hypercortisolemic episodes; after 3 months of therapy, she underwent successful bilateral adrenalectomy (BLA).
Case 3
On day 5 of hospitalization, her Am cortisol level decreased to 14.4 µg/dL (SI: 397 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]). Her symptoms improved, and she remained well for 11 months before recurrence of muscle weakness, hypokalemia, and hypercortisolemia with an Am cortisol of 58.7 µg/dL (SI: 1620 nmol/L) and Am ACTH of 194 pg/mL (SI: 43 pmol/L). The patient became eucortisolemic without any medical intervention and declined further treatment. She continues with regular outpatient follow-up.
Discussion
Diagnosing CCS poses considerable challenges because of its heterogeneous clinical manifestations, erratic intercyclic duration, frequency of phases, and various etiologies. Patients may experience transient or continuous symptoms with variable degrees of severity [1]. Our patients presented with severe hypercortisolemia lasting from days to months, followed by an extended period of spontaneous eucortisolemia, lasting from months to years. This unique presentation of cortisol kinetics differs from the classic presentation of CCS, which typically features shorter intercyclic phases [2].
We coined the term square wave variant of CCS to characterize this unique feature of prolonged cyclicity of hypercortisolemia shifting spontaneously to eucortisolemia without medical intervention. The term square wave was chosen because the cortisol secretion pattern in these cases resembles a square waveform, with abrupt transitions between prolonged periods of high and low cortisol levels rather than the gradual fluctuations or short irregular peaks seen in typical CCS. This visual and kinetic analogy helps distinguish the pattern observed in our patients from the more classically described forms of CCS.
The absence of a standardized definition of CCS complicates the classification of cases such as ours, which diverge from conventional descriptions in the medical literature [3, 4, 8]. Most cases of CCS are associated with pituitary tumors (67%), whereas ectopic ACTH-secreting tumors (17%) and adrenal tumors (11%) are less common [7, 9]. Our patients had evidence of ectopic CS, of which the ACTH-secreting source was unidentifiable despite extensive imaging. The variability of symptom duration, severity, and timing in our patients implies distinct mechanisms for suppressing or desensitizing adrenal cortisol synthesis during the extended symptom-free periods. Other mechanisms include enhanced effects of specific neurotransmitters, hypothalamic dysregulation, spontaneous tumor hemorrhage, cyclic growth and apoptosis of ACTH-secreting tumor cells, and positive and negative feedback mechanisms [7]. Another explanation for the prolonged eucortisolemic phase may be due to altered POMC gene expression and defective ACTH secretion from the ectopic tumor [10‐13]. Over time, the tumor may dedifferentiate or develop a transcriptional or posttranscriptional defect, leading to the secretion of ACTH with a decreased ability to stimulate adrenal cortisol secretion [14, 15]. Conversely, CCS might also be an exaggerated physiological cyclical variation of ACTH and cortisol secretion [14, 15]. However, the prolonged eucortisolemic phase observed in our patients argues against this exaggeration theory.
Recent studies have suggested that the anomalous cyclicity of cortisol and ACTH may be influenced by dysregulation of the peripheral clock system in endocrine tumors [16]. Certain tumors may exhibit aberrant expression of circadian regulators such as CLOCK, PER1, PER2, PER3, and TIMELESS, which can disrupt the physiological rhythmicity of cortisol and ACTH secretion [16, 17]. For instance, cortisol-secreting adrenal adenomas demonstrate downregulation of PER1, CRY1, and Rev-ERB, whereas adrenocortical carcinomas upregulate CRY1 and PER1 and downregulate BMAL1 and RORα. In patients with CS, clock gene expression in peripheral blood mononuclear cells has been shown to be significantly flattened, contributing to the loss of circadian variation in cortisol levels [16].
Surgery is the preferred treatment option for CCS patients, provided the tumor is localizable [18]. Medical therapy is used when the tumor is undetectable, unresectable, or recurs. Medical therapy can overtreat and induce iatrogenic adrenal insufficiency during the eucortisolemic phases. This risk can be mitigated by the block-and-replace strategy of high-dose steroidogenesis inhibitors to suppress adrenal cortisol production and supplemented with exogenous glucocorticoids [10]. In patients for whom the ectopic tumor is unidentifiable, the initial tumor resection is ineffective, or if medical management does not adequately control hypercortisolemia, BLA may be considered [19].
Although treatment of CCS resembles that of CS, the heterogeneity in the severity and duration of symptoms prohibits the implementation of some conventional treatment strategies. Consequently, long-term medical therapy may not align with the patient’s preferences, especially those whose course of illness is characterized by prolonged eucortisolemia and milder symptoms. Such patients should be educated to monitor symptoms closely during the eucortisolemic phase to recognize the signs and symptoms of hypercortisolism using objective parameters such as self-assessment of weight, blood pressure, and capillary blood glucose. Periodic biochemical monitoring may also be helpful, including standby kits for self-testing of late-night salivary cortisol and 24-hour UFC. If the source of ectopic ACTH secretion continues to elude detection, BLA during the eucortisolemic phase may be considered to prevent future life-threatening hypercortisolemic episodes.
Learning Points
Unlike typical CCS, there may be a subset of patients with a distinct square wave variant of CCS marked by severe hypercortisolemia followed by prolonged periods of eucortisolemia.
Ectopic ACTH-secreting sources in CCS may be linked to unusually long symptom-free intervals of eucortisolemia and hypocortisolemia between episodes of hypercortisolemia.
If possible, CCS management should be individualized to address its cause, with vigilant monitoring during the eucortisolemic phase to detect potential recurrence early.
If the source of the ectopic ACTH-secreting tumor is not identifiable, BLA may be considered during the eucortisolemic phase to prevent future life-threatening hypercortisolemic episodes.
Acknowledgments
We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.
Abbreviations
ACTH
adrenocorticotropic hormone
BLA
bilateral adrenalectomy
CCS
cyclic Cushing syndrome
CS
Cushing syndrome
CT
computed tomography
HbA1c
glycated hemoglobin
IPSS
inferior petrosal sinus sampling
MRI
magnetic resonance imaging
PET
positron emission tomography
UFC
urine free cortisol
Contributor Information
Mercedes Martinez-Gil, Department of Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85012, USA.
Tshibambe N Tshimbombu, Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA.
Yvette Li Yi Ang, Division of Endocrinology, Department of Medicine, National University Hospital, Singapore 119228, Singapore.
Monica C Rodriguez, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.
Kevin C J Yuen, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.
Contributors
All authors contributed substantially to the manuscript. K.C.J.Y. supervised the project, provided content review, and edited the text. M.M.-G. and T.N.T. contributed equally to the preparation, writing, and submission of the manuscript. M.C.R. was responsible for the clinical management of one of the cases. Y.L.Y.A. contributed to the diagnosis, management, and writing of one of the cases. All authors reviewed and approved the final version of the manuscript.
Funding
All authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this manuscript.
Disclosures
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this manuscript.
Informed Patient Consent for Publication
Signed informed consents were obtained directly from the patients.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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