Avascular Necrosis in Patients With Cushing Syndrome

Posted on March 12, 2025 by MaryO

Abstract

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, leading to a range of clinical manifestations including avascular necrosis (AVN), a rare complication of CS. Although AVN is often associated with exogenous glucocorticoid treatment, it can occur in endogenous CS but may be unrecognized because of its rarity and possibly from a subclinical presentation. We describe a case of a 71-year-old male with florid Cushing disease who initially presented with bilateral hip AVN and later developed bilateral shoulder AVN despite achieving biochemical remission following transsphenoidal surgery and adjuvant stereotactic photon radiosurgery. AVN in endogenous CS is underreported, and guidance on routine screening is lacking. Our case underscores the importance of considering AVN in patients with CS, especially in those with persistent or recurrent joint symptoms and markedly elevated cortisol levels. Early detection of AVN is crucial as it can lead to irreversible joint damage and disability if untreated. Screening strategies should be explored to identify high-risk patients who are diagnosed with CS for timely intervention, thereby preventing long-term morbidity associated with AVN.

Introduction

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, either from exogenous glucocorticoids or endogenous sources. In endogenous CS, hypercortisolism may be due to an ACTH-dependent process, most often from a corticotroph adenoma in Cushing disease (CD) or from ectopic ACTH secretion from neuroendocrine tumors or other solid tumors such as small cell lung carcinoma. On the other hand, ACTH-independent CS is mainly driven from adrenal pathology including adrenal adenomas, adrenocortical carcinomas, adrenal hyperplasia, and primary pigmented micronodular disease [1]. The presenting symptoms and signs of CS include hypertension, diabetes mellitus, weight gain, facial plethora, dorsocervical fat pads, muscle weakness, and osteoporosis, most of which may be detected on physical examination or diagnosed biochemically. A less common symptom is avascular necrosis (AVN) of bone tissue [1, 2], which can present with pain or point tenderness of the hip or other joints as well as present subclinically [3].

AVN of the hip results from compromised blood supply to the bone tissue and usually impacts the hips and shoulders. This leads to necrosis of hematopoietic cells, adipocytes, and osteocytes. Subsequently, bone repair processes are activated, with differentiation of mesenchymal cells into osteoblasts to build new bone and hematopoietic stem cells into osteoclasts to remove necrotic tissue. However, because of impaired bone resorption and formation, subchondral fractures eventually occur [4]. Exogenous glucocorticoid treatment is 1 of the most common causes of AVN and may account for up to 38% of atraumatic AVN and is dose dependent [5]. Glucocorticoid treatment is theorized to cause AVN through increased systemic lipids, leading to compromised perfusion to the femoral head resulting from fat emboli or external lipocyte compression, as well as alterations in the inflammatory cytokines resulting in osteoclast activation and osteoblast apoptosis [4, 6]. Compared to exogenous glucocorticoid treatment, AVN caused by endogenous hypercortisolism is not frequently reported nor is it screened for on diagnosis of CS.

We describe a patient who presented with bilateral hip AVN in the context of florid CD. We aim to highlight this presenting feature to heighten awareness for screening for this progressive condition, which can potentially lead to joint damage, loss of mobility, and long-term disability.

Case Presentation

A 71-year-old male with medical history of active tobacco use and obstructive sleep apnea was diagnosed with new-onset hypertension during an annual health visit. He was started on antihypertensive medications (losartan, hydrochlorothiazide, and spironolactone) by his primary care doctor, but the hypertension remained uncontrolled. Over the course of 2 months, the patient developed progressive lower extremity edema and was started on furosemide, which led to hypokalemia and was subsequently discontinued. He clinically deteriorated, with progressive anasarca and dyspnea, and then developed acute left eye ptosis and diplopia and was admitted to the hospital. The patient also endorsed irritability, mood swings, easy bruising, low libido, increased appetite, 30-lb weight gain, and bilateral hip pain.

Diagnostic Assessment

Physical examination was significant for oral candidiasis, dorsocervical fat pad, facial plethora, proximal muscle weakness, and bilateral hip tenderness. Testing confirmed ACTH-dependent CS with elevated 24-hour urine free cortisol of 1116 μg/24 hours (30788.21 nmol/24 hours) and 1171.9 μg/24 hours (32330.38 nmol/24 hours) (normal reference range, 3.5-45 μg/24 hours; 96.56-1241.46 nmol/24 hours) and ACTH of 173 pg/mL (38.06 pmol/L) and 112 pg/mL (24.64 pmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L) on 2 separate occasions. He had hypogonadotropic hypogonadism with total testosterone levels of 41 ng/dL (1.42 nmol/L) (normal reference range, 250-1100 ng/dL; 8.68-38.17 nmol/mL) and suppressed LH and FSH at <0.2 mIU/mL (<0.2 IU/L) (normal reference range, 0.6-12.1; 0.6-12/1.1 IU/L) and 0.2 mIU/mL (<0.2 IU/L) (normal reference range, 1.0-12.0 2 mIU/mL; 1.0-12.0 2 IU/L) respectively, whereas the remaining pituitary hormones were normal, although IGF-1 was low normal at 66 ng/mL (8.65 nmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L). He also had new-onset diabetes mellitus with glycated hemoglobin of 8% (<5.7%) (Table 1). Imaging of the lungs showed a 15-mm solid noncalcified nodule in the posterior right upper lobe concerning for neoplasm. Pituitary magnetic resonance imaging (MRI) revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (Fig. 1). Additionally, pelvis computed tomography (CT) scan demonstrated bilateral avascular necrosis of the capital femoral epiphysis without evidence of fracture or subchondral collapse (Fig. 2A and 2B).

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Figure 1.

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Figure 2.

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Table 1.

Laboratory evaluation of the patient at presentation

Lab Value Reference Range
Conventional units (Système International units)
ACTH 173 pg/mL (38.06 pmol/L) 7.2-63 pg/mL (1.58-13.86 pmol/L)
24-h urine free cortisol 1116 μg/24 h (30,788.21 nmol/24 h) 4.0-55.0 μg/24 h (110.35-1517.34 nmol/24 h)
Total testosterone 41 ng/mL (1.42 nmol/L) 250-1100 ng/mL (8.68-38.17 nmol/L)
Free testosterone 12.3 pg/mL (0.07 nmol/L) 30.0-135.0 pg/mL (0.17-0.79 nmol/L)
LH <0.2 mIU/mL (<0.2 IU/L) 0.6-12.1 mIU/mL (0.6-12.1 IU/L)
FSH 0.2 mIU/mL (0.2 IU/L) 1-12 mIU/mL (1-12 IU/L)
Prolactin 9.6 ng/mL (9.6 μg/L) 3.5-19.4 ng/mL (3.5-19.4 μg/L)
TSH 0.746 mIU/L 0.450-5.330 mIU/L
Free T4 0.66 ng/dL (8.49 pmol/L) 0.61-1.60 ng/dL (7.85-20.59 pmol/L
IGF-1
Z score		 66 ng/mL (8.65 nmol/L)
−0.9		 34-245 ng/mL (4.45-32.09 nmol/L)
−2.0 to +2.0
HbA1c 8.2% <5.7%

Abbreviations: Hb A1c, hemoglobin A1C.

Treatment

Prophylactic treatment was started with subcutaneous heparin for anticoagulation and trimethoprim-sulfamethoxazole for opportunistic infections. Orthopedic evaluation did not recommend acute intervention for the hip AVN. Given the pituitary macroadenoma on imaging and left cranial nerve VI palsy, it was determined that the patient likely had CD, so he underwent transsphenoidal surgery. Surgical pathology confirmed the adenoma was ACTH positive, sparsely granulated, with Ki-67 index of 4%, and without increased mitotic activity (Fig. 3).

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Figure 3.

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Outcome and Follow-up

Due to ongoing hypercortisolism (Table 2) and residual tumor in the left cavernous sinus, the patient underwent adjuvant treatment with stereotactic photon radiosurgery at a dose of 13 Gy targeted to the left cavernous sinus and was started on osilodrostat, an oral, reversible inhibitor of 11β-hydroxylase that drives the final step of cortisol synthesis and aldosterone synthase, which converts 11-deoxycorticosterone to aldosterone [7]. The starting dose of osilodrostat was 2 mg twice per day. As the patient developed nausea, lack of appetite, and malaise with decreasing cortisol levels, osilodrostat was reduced to 1 mg daily, and he was started on hydrocortisone replacement therapy on week 11 postoperatively (Table 3). Ultimately, both osilodrostat and hydrocortisone were discontinued following normalization of cortisol levels. Regarding the rest of the hormonal deficiencies, his total testosterone and IGF-1 levels improved to levels of 483 ng/dL (16.76 nmol/L) and 99 (12.97 nmol/L), respectively, and he did not require hormone replacement therapy. Clinically, the patient improved with resolution of his hypertension and diabetes and achieved a 38-lb weight loss. Additionally, his diplopia improved and his hip pain resolved without any restriction in mobility. However, 1 year postoperatively, the patient developed bilateral shoulder pain. MRI of the shoulders demonstrated subchondral changes in the right humeral head (Fig. 2C) and a linear area of subchondral change involving the left humeral head (Fig. 2D) consistent with AVN, as well as a bilateral high-grade supraspinatus tear and acromioclavicular joint osteoarthritis. He was treated with an intraarticular methylprednisolone 40-mg injection to both shoulders, with subsequent improvement of the pain and joint mobility. He also underwent a coronary artery bypass graft surgery for 3-vessel disease. The patient has otherwise maintained normal urine and salivary cortisol levels off osilodrostat or hydrocortisone, and 1 year after surgery, the ACTH (cosyntropin) stimulation test was normal. The pulmonary nodule has remained stable on serial imaging.

Table 2.

Postoperative cortisol and ACTH levels

Postoperative day
Lab Reference Range Conventional units (Système International units) 1 2 2 3 4 5
Morning cortisol 3.7-19.4 μg/dL (102.08- 535.21 nmol/L) 26 μg/dL (717.29 nmol/L) 21.5 μg/dL (593.14 nmol/L) 6 μg/dL (165.53 nmol/L) 8.1 μg/dL (223.46 nmol/L) 16.4 μg/dL (452.44 nmol/L) 21.5 μg/dL (593.14 nmol/L)
ACTH 7.2-63.3 pg/mL (1.58- 13.93 pmol/L) 72 pg/mL (15.84 pmol/L) 62 pg/mL (13.64 pmol/L)

Table 3.

Titration of osilodrostat treatment based on cortisol levels

Postoperative week
Lab Reference range Conventional units (Système International units) 8 9 11 13 15 18 22 24
ACTH 7.2-63.3 pg/mL (1.58-13.93 pmol/L) 95.6 pg/mL (21.03 pmol/L) 131 pg/mL (28.82 pmol/L) 58.8 pg/mL (12.94 pmol/L) 79.3 pg/mL (17.45 pmol/L) 79.9 pg/mL (17.58 pmol/L) 73.4 pg/mL (16.15 pmol/L) 62 pg/mL (13.64 pmol/L) 71.5 pg/mL (15.73 pmol/L)
Morning cortisol 3.7-19.4 μg/dL (102.08-535.21 nmol/L) 23.9 μg/dL (659.35 nmol/L) 18.8 μg/dL (518.65 nmol/L) 6.6 μg/dL (182.08 nmol/L) 4.5 μg/dL (124.15 nmol/L) 3.3 μg/dL (91.04 nmol/L) 2.4 μg/dL (66.21) nmol/L 8.2 μg/dL (226.22. nmol/L) 4.1 μg/dL (113.11 nmol/L)
LNSC <0.010-0.090 μg/dL (0.28-2.48 nmol/L) 0.615 μg/dL (16.97 nmol/L) 0.058 μg/dL (1.60 nmol/L) 0.041 μg/dL (1.13 nmol/L) 0.041 μg/dL (1.13 nmol/L)
UFC, 24-h 5-64 μg/24 h (137.94-1765.63 nmol/24 h) 246 μg/24 h (6786.65 nmol/24 h) 226 μg/24 h (6234.89 nmol/24 h) 2 μg/24 h (55.18. nmol/24 h)
Osilodrostat dose 2 mg BID 2 mg BID 2 mg AM
3 mg PM		 2 mg BID 2 mg AM
1 mg PM		 1 mg BID 1 mg daily Oslidrostat discontinued

Abbreviations: BID, twice per day; LNSC, late night salivary cortisol; UFC, urine free cortisol.

Discussion

Our patient exhibited pronounced hypercortisolism secondary to CD, with bilateral hip AVN as 1 of the presenting symptoms. Despite achieving biochemical remission of the disease and resolution of other associated symptoms, the patient was later diagnosed with bilateral shoulder AVN.

AVN caused by endogenous hypercortisolism is seldom documented, and routine screening for it is not typically conducted during the diagnosis of CS. However, AVN has been reported to be a presenting symptom in several case reports or may manifest years after the initial diagnosis [8]. Reported causes of AVN in endogenous CS include pituitary adenomas, adrenal adenomas or carcinomas, adrenal hyperplasia, or neuroendocrine tumors [8‐23] (Table 4), with some cases of AVN associated with severe hypercortisolism [10, 15]. Other risk factors associated with AVN include hip trauma, femoral fractures, hip dislocation, systemic lupus erythematosus in the setting of concomitant corticosteroid treatments, or vasculitis, sickle cell disease, hypercoagulability, Gaucher disease, hyperlipidemia or hypertriglyceridemia, hyperuricemia, hematological malignancies, antiretroviral medications, alcohol use, and exogenous steroid treatment [4]. Our patient had no history of hip trauma or other aforementioned comorbidities. Furthermore, during presentation, his lipid levels were normal, with low-density lipoprotein cholesterol of 89 mg/dL (<130 mg/dL) and triglycerides of 97 mg/dL (<150 mg/dL). Therefore, it is likely that his bilateral hip and shoulder AVN was caused by severe endogenous hypercortisolism.

Table 4.

Published cases of avascular necrosis in patients with endogenous hypercortisolism

First author, year Age (y)/sex Time of diagnosis in relation to CS diagnosis AVN related symptoms Imaging modality Imaging description Diagnosis Treatment
Salazar D, 2021 [15] 38 F 3 y prior to diagnosis Right hip pain MRI
  • Right hip joint effusion and synovitis
  • Flattening of the femoral head-Subcortical edema
 Adrenal adenoma Right hip arthroplasty
Madell SH, 1964 [16] 41 F 1 month before diagnosis Right shoulder pain X-ray
  • Increased density of the right humeral head with spotty areas of radiolucency
  • Early flattening and beginning of fragmentation
 Adrenal adenoma Osteotomy
Anand A, 2022 [21] 47 M Bilateral hip pain MRI
  • Necrosis of bilateral femur heads
 adrenocortical carcinoma
Belmahi N, 2018 [9] 28 F Progressive limping and right hip pain MRI
  • Right femoral head AVN
 Pituitary adenoma Right total hip replacement
Wicks I, 1987 [10] 39 M 18 months before diagnosis Progressive hip pain and stiffens X-ray
Bone scan
  • Lucent and sclerotic regions within flattened femoral heads
  • Some loss of articular cartilage
 Pituitary adenoma Conservative management
Koch C, 1999 [11] 30 F Sudden onset of severe left hip pain MRI
  • Abnormal high intensity signal changes in the bone marrow of the left femoral head
  • Joint effusion
  • Stage 2 AVN
 Pituitary adenoma Immediate core decompression surgery with decongestion of the left femoral head
Premkumar M, 2013 [12] 26 F 2 y after pituitary surgery for Cushing, while on replacement steroid therapy Progressive bilateral hip pain resulting in difficulty in walking MRI
  • Bilateral multiple bony infarcts in the proximal femur and distal femur
  • Femoral head collapse fractures -Stage 2 avascular necrosis
 Pituitary adenoma
Bauddh N, 2022 [13] 24 M 2 y prior to diagnosis Progressive left hip pain and difficulty in walking X-ray
MRI
  • Left femoral head AVN
 Pituitary adenoma Planned for surgery of hip AVN
Joseph A, 2022 [14] 21 F 1 y prior to diagnosis Bilateral hip joint pain X-ray
MRI
  • Ill-defined mixed sclerotic and lytic pattern of the femoral heads
  • Cortical disruption of the round contour
  • Low signal intensity in the subchondral region of the femoral necks on T1-weighted images
 Pituitary adenoma Planned for total hip replacement.
Bisphosphonates.
Pazderska A, 2016 [19] 36 F Right leg pain MRI
  • Bilateral AVN of the femoral heads
  • Left femoral head with early bone fragmentation
 Bilateral primary pigmented micronodular adrenal disease Spontaneous healing of AVN after adrenalectomy.
Papadakis G, 2017 [22] 55 F MRI
PET/CT 68Ga-DOTATATE
  • Bilateral AVN
  • Bone marrow edema extending to the intertrochanteric area
  • Mild subchondral femoral head collapse of the left hip
  • Increased activity in bilateral femoral heads and in the bone marrow consistent with edema
  • Mild left femoral head collapse
 Ectopic ACTH- secreting tumor
Phillips K, 1986 [8] 24 F 4.5 y after diagnosis Right femoral AVN X-ray
  • Flattening and sclerosis of femoral head
 Cushing disease
25 F 4 y after diagnosis Right femoral AVN
  • Subchondral lucency
43 F 8 mo after diagnosis Right humeral AVN
  • Sclerosis and flattening of articular surface of humeral head
61 F 11 y after diagnosis Left femoral AVN and bilateral humeral heads
  • Cortical indistinctness and subchondral lucency
  • Left humeral head flattening and sclerosis
Cerletty J, 1973 [20] 54 M 3 mo before diagnosis Right femoral head fracture X-ray
  • Bilateral subchondral sclerosis of the femoral heads
  • Some narrowing of the joint space on the left
  • Infraction of the margin of the right femoral head
  • Femoral neck fracture.
 Bilateral adrenal cortical hyperplasia Total hip joint arthroplasty
Ha J-S, 2019 [18] 36 F 2 y before diagnosis 2 mo left hip restricted range of motion X-ray
MRI
  • Right femoral head with areas of hyperlucency and surrounding sclerosis
  • Subtle changes in the shape of the articular surface
  • Bilateral femoral head osteonecrosis -Increased amount of joint fluid and bone marrow edema in the left hip
  • Right femoral head necrosis
 Adrenal cortical adenoma Total hip replacement
Takada, J, 2004 [17] 55 F Intense right hip pain and a limp MRI
  • Low-intensity band on T1-weighted images
  • Stage 2 AVN.
 Adrenal adenoma Total hip arthroplasty
Modlinger RS, 1972 [23] 69 F Increased pain of right shoulder X-ray
  • Bilateral shoulders with aseptic necrosis of the humeral heads
 Ectopic ACTH secretion NET form pancreatic tumor

Abbreviations: AVN, avascular necrosis; F, female; M, male; MRI, magnetic resonance imaging; NET, neuroendocrine tumor.

AVN can result in irreversible femoral head collapse, leading to severe limitation in movement, reduced joint functionality, and decreased quality of life [24]. Initially, patients may be asymptomatic or endorse nonspecific pain when presenting with AVN and may not be diagnosed until an advanced stage when they develop more severe pain and disability [25]. In a meta-analysis assessing the prevalence of AVN in patients with systemic lupus erythematosus, including those who received corticosteroid treatment, asymptomatic AVN was detected in 29% of patients and symptomatic disease was noted in 9% [26]. AVN can diagnosed with MRI or CT imaging. Although noncontrast MRI has higher sensitivity and specificity in detecting early stages of the disease, CT is comparable to MRI in more advanced stages. Ancillary imaging modalities include plain radiography, positron emission tomography, and bone scan [27].

Staging of AVN relies on radiologic features and size of lesions. In earlier stages, imaging can be normal (stage 0) or with subtle abnormalities on MRI or bone scan and normal radiography (stage 1). As the disease progresses, structural changes, including cystic and sclerotic changes (stage 2), subchondral collapse (stage 3), flattening of the femoral head (stage 4), joint narrowing and acetabular changes (stage 5), and, finally, advanced degenerative changes (stage 6) can be detected on most imaging modalities.

Management of early stages of AVN includes observation or conservative weight-bearing management, medical therapy with bisphosphonates, anticoagulation therapy, statins, and vasodilators. Invasive procedures such as mesenchymal stem cells implantation, osteotomy, surgical joint decompression, and total hip replacement are reserved for more advanced stages [28]. Indeed, AVN accounts for approximately 10% of total hip replacements in the United States [29]. Staging has prognostic implications for treatment options and disease outcomes. Early-stage disease, when diagnosed and treated, can often regress, and be cured. Conservative measures, medical treatment, biophysical stimulation, extracorporeal shockwave therapy, or core decompression, can prevent femoral head collapse and further hip arthroplasty. On the other hand, late-stage disease, characterized by joint collapse, is irreversible and often requires joint replacement [30].

Although actual prevalence rates of AVN in endogenous CS is unknown, one should consider screening for AVN in this high-risk population, particularly in patients showing markedly elevated cortisol levels, as in our case. Such an approach would facilitate the early identification of individuals who would benefit from earlier medical or surgical interventions, thereby preventing permanent joint destruction and chronic disability.

Learning Points

  • AVN can be a complication of endogenous hypercortisolism.
  • AVN may present asymptomatically or with nonspecific symptoms such as joint pain.
  • AVN can affect multiple joints, including hips and shoulders, and its early diagnosis relies on MRI or CT imaging.
  • Early detection and intervention for AVN are crucial to prevent irreversible joint damage and disability.
  • Screening for AVN in patients with CS should be considered to enable timely intervention and prevent long-term complications, particularly in patients with hip or shoulder pain and severe hypercortisolism.

Contributors

All authors made individual contributions to authorship. N.T. and O.C. were involved in the diagnosis and management of the patient and manuscript submission. S.B. was involved in the histopathology section and preparation of histology images. T.L. was involved in the interpretation and preparation of the radiology images. A.N.M. was responsible for the patient’s surgery and treatment plan. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

Dr. Odelia Cooper is an Editorial Board member for JCEM Case Reports and played no role in the journal’s evaluation of the manuscript. There are no other disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

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

Abbreviations

  • AVN

    avascular necrosis

  • CD

    Cushing disease

  • CS

    Cushing syndrome

  • CT

    computed tomography

  • MRI

    magnetic resonance imaging

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

Filed under: Cushing's, pituitary, Rare Diseases, symptoms, Treatments | Tagged: , , , | Leave a comment »

From Weight Gain To Diabetes

Posted on March 10, 2025 by MaryO
Cushing’s syndrome happens when the body has too much cortisol, the stress hormone. It can cause weight gain, high blood pressure, and diabetes. So how to keep your health in check and what are the treatment options available? In an exclusive interview with Times Now, an Endocrinologist explains its symptoms, causes, and treatments.
We often blame stress for everything—from sleepless nights to stubborn weight gain. But did you know your body’s stress hormone, cortisol, could be at the root of more serious health issues like high blood pressure and diabetes? Yes, you read that right! But how? We got in touch with Dr Pranav A Ghody, Endocrinologist at Wockhardt Hospital, Mumbai Central, who explains how excessive cortisol levels can lead to a condition known as Cushing’s Syndrome.
What Exactly is Cortisol, and Why is it Important?
Hormones are the body’s chemical messengers, travelling through the bloodstream to regulate essential functions. Among them, cortisol, produced by the adrenal glands (tiny glands sitting above the kidneys), plays a crucial role in controlling blood pressure, blood sugar, energy metabolism, and inflammation. The pituitary gland, located at the base of the brain, regulates cortisol through another hormone called Adrenocorticotropic Hormone (ACTH).
Often referred to as the “stress hormone,” cortisol spikes when we’re under stress. However, when levels remain high for too long, it can lead to Cushing’s Syndrome, a disorder first identified in 1912 by Dr Harvey Cushing.

What Causes Cushing’s Syndrome?

Dr Ghody explains that Cushing’s Syndrome occurs when the body is exposed to excessive cortisol, which can happen in two ways:

1. Exogenous (External) Cushing’s Syndrome
This is the most common form and results from prolonged use of steroid medications (such as prednisone) to treat conditions like asthma, rheumatoid arthritis, and lupus, or to prevent transplant rejection. Since steroids mimic cortisol, long-term use can disrupt the body’s hormone balance.
2. Endogenous (Internal) Cushing’s Syndrome
This occurs when the body produces too much cortisol due to a tumour in the pituitary gland, adrenal glands, or other organs (lungs, pancreas, thymus). While rare—affecting about 10 to 15 people per million annually—it’s more common in women between 20 and 50 years old. When caused by a pituitary tumour, it’s specifically called Cushing’s Disease.

Symptoms: How To Recognize Signs Of Cushing’s Syndrome

Excess cortisol affects multiple organs, leading to a variety of symptoms. This includes:

– Weight gain around the belly (central obesity)
– Rounded, puffy face (moon face)
– Excess facial and body hair (hirsutism)
– Fat accumulation on the upper back (buffalo hump)
– Thin arms and legs
– Dark red-purple stretch marks on the chest and abdomen
– Extreme fatigue and muscle weakness
– Depression or anxiety
– Easily bruising with minimal trauma
– Irregular menstrual cycles in women
– Reduced fertility or low sex drive
– Difficulty sleeping
High blood pressure and newly diagnosed or worsening diabetes are also common red flags.

Why is Cushing’s Syndrome Often Misdiagnosed?

Dr Ghody explains that while severe cases of Cushing’s Syndrome are easier to identify, milder forms can often be missed or mistaken for conditions like obesity, diabetes, or polycystic ovary syndrome (PCOS).

Diagnosing Cushing’s Syndrome involves:
1. Measuring cortisol levels in the blood, urine, or saliva.
2. Identifying the source through ACTH hormone testing, MRI/CT scans, and advanced techniques like Inferior Petrosal Sinus Sampling (IPSS) or nuclear medicine scans
Treatment Options: How is Cushing’s Syndrome Managed?
Once diagnosed, the treatment depends on the cause:
– If due to steroid medication, the dosage is gradually reduced under medical supervision.
– If caused by a tumour, surgery is the primary treatment. Some patients, especially those with pituitary tumours, may require repeat surgery, gamma knife radiosurgery, or medications to control cortisol levels.

Can You Prevent Cushing’s Syndrome?

While complete prevention isn’t always possible, Dr Ghody shares some key strategies to reduce risk:

– Use steroids cautiously – If prescribed, take the lowest effective dose for the shortest time. Never stop abruptly without consulting a doctor.
– Genetic screening for people at risk – If you have a family history of pituitary or adrenal tumours, regular monitoring can help with early detection.
– Maintain a healthy lifestyle – A diet rich in fresh vegetables, and fruits, low sodium intake, adequate calcium, and vitamin D can help manage the metabolic effects of excess cortisol.
– Avoid alcohol and tobacco – These can further disrupt hormone balance and overall health.
“Cushing’s Syndrome can be life-threatening if left untreated, but early diagnosis and proper management can significantly improve quality of life. So if you experience unexplained weight gain, blood pressure spikes, or other symptoms, consult an endocrinologist to manage hormonal imbalances,” he said.

Filed under: Cushing's, Diagnostic Testing, symptoms, Treatments | Tagged: , , , , , | Leave a comment »

Sterotherapeutics begins Phase II trial for ST-002 targeting Cushing’s Syndrome

Posted on March 2, 2025 by MaryO

US-based clinical-stage company Sterotherapeutics has announced the commencement of a Phase II clinical trial for its drug candidate, ST-002, for treating Cushing’s Syndrome, a rare endocrine disorder.

The trial will assess the drug’s efficacy, tolerability, and safety in individuals with this condition. It is set to be conducted in several European clinical sites.

Sterotherapeutics CEO Manohar Katakam said: “After extensive preparations and based on a large body of scientific data, we are excited to convene this important Investigator Meeting as we progress to the next stage of our clinical development programme.

“This trial represents a significant step forward in our mission to develop transformative therapies for unmet medical needs. Collaboration with our expert investigators is essential to ensuring the highest standards of scientific rigour and patient safety.”

An orphan drug designation was granted by the US Food and Drug Administration (FDA) to the drug underscoring the requirement for new treatments alternatives for this rare condition.

Through this designation, Sterotherapeutics is eligible for various development incentives. These include assistance in the drug development process, certain FDA fee exemptions, post-approval marketing exclusivity of seven years, and tax credits for clinical expenses.

Characterised by longer exposure to high cortisol levels, Cushing’s Syndrome is stated to result in serious health complications like diabetes, osteoporosis, and hypertension.

Sterotherapeutics concentrates on the orphan diseases therapy development. The company stated that its leading programmes, ST-002 for Cushing’s Syndrome and ST-003 for primary sclerosing cholangitis, have shown promise in prior animal and human studies. ST-003 has also been granted an orphan drug designation by the US regulator.

From https://www.clinicaltrialsarena.com/news/sterotherapeutics-trial-st-002/?cf-view&cf-closed

Filed under: Cushing's, Treatments | Tagged: , , , , , , | Leave a comment »

Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

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

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

Filed under: Clinical trials, Cushing's, pituitary, Rare Diseases, Treatments | Tagged: , , , | Leave a comment »

Ectopic Adrenocorticotrophic Hormone Syndrome in a 10-Year-Old Girl With a Thymic Neuroendocrine Tumor

Posted on November 29, 2024 by MaryO

Abstract

Background

Thymic neuroendocrine tumor as a cause of Cushing syndrome is extremely rare in children.

Case presentation

We report a case of a 10-year-old girl who presented with typical symptoms and signs of hypercortisolemia, including bone fractures, growth retardation, and kidney stones. The patient was managed with oral ketoconazole, during which she experienced adrenal insufficiency, possibly due to either cyclic adrenocorticotropic hormone (ACTH) secretion or concurrent COVID-19 infection. The patient underwent a diagnostic work-up which indicated the possibility of an ACTH-secreting pituitary neuroendocrine tumor. However, after a transsphenoidal surgery, the diagnosis was not confirmed on histopathological examination. Subsequent bilateral inferior petrosal sinus sampling showed strong indications of the presence of ectopic ACTH syndrome. Detailed rereading of functional imaging studies, including 18F-FDG PET/MRI and 68Ga DOTATOC PET/CT, ultimately identified a small lesion in the thymus. The patient underwent videothoracoscopic thymectomy that confirmed a neuroendocrine tumor with ACTH positivity on histopathological examination.

Conclusion

This case presents some unique challenges related to the diagnosis, management, and treatment of thymic neuroendocrine tumor in a child. We can conclude that ketoconazole treatment was effective in managing hypercortisolemia in our patient. Further, a combination of functional imaging studies can be a useful tool in locating the source of ectopic ACTH secretion. Lastly, in cases of discrepancy in the results of stimulation tests, bilateral inferior petrosal sinus sampling is highly recommended to differentiate between Cushing disease and ectopic ACTH syndrome.

Peer Review reports

Background

In children above seven years of age, the majority of pediatric Cushing syndrome (CS) cases are caused by a pituitary neuroendocrine tumors (PitNET). However, a differential diagnosis of hypercortisolemia in children is often challenging concerning the interpretation of stimulation tests and the fact that up to 50% of PitNET may not be detected on magnetic resonance imaging (MRI) [1]. An ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is extremely rare in children. Its diagnosis is often missed or confused with Cushing disease (CD) [2]. Most ACTH-secreting tumors originate from bronchial or thymic neuroendocrine tumors (NETs), or less commonly, from NETs in other locations. To diagnose EAS, specific functional imaging studies are often indicated to elucidate the source of ACTH production.

Pharmacotherapy may be used before surgery to control hypercortisolemia and its symptoms/signs, or in patients in whom the source of hypercortisolism has not been found (e.g., EAS), or surgery failed. Ketoconazole or metyrapone, as adrenal steroidogenesis blockers, were found to be very efficient, although they exhibit side effects [3].

Furthermore, cyclic secretion of ACTH followed by fluctuating plasma cortisol levels is extremely rare in children, including those with EAS [4, 5]. Therefore, in cyclic EAS, the use of steroid inhibitors or acute illness or trauma can be associated with adrenal insufficiency, which can be life-threatening. Here we describe the clinical features, laboratory and radiological investigations, results, management, and clinical outcome of a 10-year-old girl with a thymic NET presenting with ACTH secretion.

Case presentation

A 10-year-old girl was acutely admitted to our university hospital for evaluation of facial edema and macroscopic hematuria in May 2021. A day before admission, she presented to the emergency room for dysuria, pollakiuria, nausea, and pain in her right lower back. Over the past year she had experienced excessive weight gain with increased appetite and growth retardation (Fig. 1). Her height over three years had shifted from the 34th to the 13th centile (Fig. 1). Her parents noticed facial changes, pubic hair development, increased irritability, and moodiness.

Fig. 1

figure 1

Body weight, body height, and body mass index development of the case patient. The black arrow indicates the first presentation, the blue arrow indicates the start of ketoconazole treatment and the yellow arrow indicates the time of thymectomy. Mid-parental height is indicated by the green line

At admission, she was found to have a moon face with a plethora, few acne spots on forehead, as well as facial puffiness. In contrast to slim extremities, an abnormal fat accumulation was observed in the abdomen. Purple striae were present on abdomen and thighs. She did not present with any bruising, proximal myopathy, or edema. On physical examination, she was prepubertal, height was 135 cm (13th centile), and weight was 37 kg (69th centile) with a BMI of 20.4 kg/m2 (90th centile). She developed persistent hypertension. Her past medical history was uneventful except for two fractures of her upper left extremity after minimal trips one and three years ago, both treated with a caste. Apart from hypothyroidism on the maternal side, there was no history of endocrine abnormalities or tumors in the family.

In the emergency room, the patient was started on sulfonamide, pain medication, and intravenous (IV) fluids. Her hypertensive crises were treated orally with angiotensin-converting enzyme inhibitor or with a combination of adrenergic antagonists and serotonin agonists administered IV. Hypokalemia had initially been treated with IV infusion and then with oral potassium supplements. A low serum phosphate concentration required IV management. The initial investigation carried out in the emergency room found hematuria with trace proteinuria. Kidney ultrasound showed a 5 mm stone in her right ureter with a 20 mm hydronephrosis. She did not pass any kidney stones, however, fine white sand urine analysis reported 100% brushite stone.

Hypercortisolemia was confirmed by repeatedly increased 24-hour urinary free cortisol (UFC), (5011.9 nmol/day, normal range 79.0-590.0 nmol/day). Her midnight cortisol levels were elevated (961 nmol/l, normal range 68.2–537 nmol/l). There was no suppression of serum cortisol after 1 mg overnight dexamethasone suppression test (DST) or after low-dose DST (LDDST). An increased morning plasma ACTH (30.9 pmol/l, normal range 1.6–13.9 pmol/) suggested ACTH-dependent hypercortisolemia. There was no evidence of a PitNET on a 1T contrast-enhanced MRI. The high-dose DST (HDDST) did not induce cortisol suppression (cortisol 1112 nmol/l at 23:00, cortisol 1338 nmol/l at 8:00). Apart from the kidney stone, a contrast-enhanced computed tomography (CT) of her neck, chest, and abdomen/pelvis did not detect any lesion. Various tumor markers were negative and the concentration of chromogranin A was also normal.

A corticotropin-releasing hormone (CRH) stimulation test induced an increase in serum cortisol by 32% at 30 min and ACTH concentration by 67% at 15 min (Table 1). A 3T contrast-enhanced MRI scan of the brain identified a 3 × 2 mm lesion in the lateral right side of the pituitary gland (Fig. 2). An investigation of other pituitary hormones was unremarkable. Apart from low serum potassium (minimal level of 2.8 mmol/l; normal range 3.3–4.7 mmol/l) and phosphate (0.94 mmol/l; normal range 1.28–1.82 mmol/l) concentrations, electrolytes were normal. The bone mineral density assessed by whole dual-energy X-ray absorptiometry was normal.

Fig. 2

figure 2

Coronal and sagittal 3T contrast-enhanced brain MRI scans. A suspected 3 × 2 mm lesion in the lateral right side of the pituitary gland (yellow arrows)

The patient was presented at the multidisciplinary tumor board and it was decided that she undergoes transsphenoidal surgery for the pituitary lesion. No PitNET was detected on histopathological examination and no favorable biochemical changes were noted after surgery. After the patient recovered from surgery, subsequent bilateral inferior petrosal sinus sampling (BIPSS) confirmed EAS as the maximum ratio of central to peripheral ACTH concentrations was only 1.7. During the investigation for tumor localization, she was started on ketoconazole treatment (300 mg/day) to alleviate symptoms and signs of hypercortisolism. Treatment with ketoconazole had a beneficial effect on patient health (Fig. 1). There was a weight loss of 2 kg in a month, a disappearance of facial plethora, and a decrease in vigorous appetite. Her liver function tests remained within the normal range.

Table 1 Result of corticotropin-releasing hormone stimulation test

The 24-hour UFC excretion normalized three weeks after ketoconazole initiation. However, six weeks after continuing ketoconazole therapy (400 mg/day), the patient complained of nausea, vomiting, and diarrhea. She was found to have adrenal insufficiency with a low morning serum cortisol of 10.70 nmol/l (normal range 68.2–537 nmol/l) and salivary cortisol concentrations < 1.5 nmol/l (normal range 1.7–29 nmol/l). She was also found to be positive for COVID-19 infection. Ketoconazole treatment was stopped and our patient was educated to take stress steroids in case of persisting or worsening symptoms. Her clinical status gradually improved and steroids were not required.

Meanwhile, whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI was performed with no obvious hypermetabolic lesion suspicious of a tumor. No obvious accumulation was detected on 68Ga-DOTATOC PET/CT images (Fig. 3). However, a subsequent careful and detailed re-review of the images detected a discrete lesion on 18F-FDG PET/MRI and 68Ga-DOTATOC PET/CT scans in the left anterior mediastinum, in the thymus (Fig. 4).

Fig. 3

figure 3

18F-FDG PET/MRI (A) and 68Ga-DOTATOC (B) PET/CT scans. Whole body MIP reconstructions. Subtle correspondent focal hyperactivity in the left mediastinum (black arrow). The 18F-FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Fig. 4

figure 4

Axial slices of PET/MRI (A–C) and 68Ga-DOTATOC (D–F) PET/CT scans. Subtle correspondent focal hyperactivity in the left mediastinum (white arrow). No obvious finding on MRI (C) and CT (F) scans. The FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Three weeks after the episode of adrenal insufficiency and being off ketoconazole treatment, our patient´s pre-surgery laboratory tests showed slightly low morning cortisol 132 nmol/l with surprisingly normal ACTH 2.96 pmol/l (normal range 1.6–13.9 pmol/). Given the upcoming surgery, she was initiated on a maintenance dose of hydrocortisone (15 mg daily = 12.5 mg/m2/day). Further improvement of cushingoid characteristics (improvement of facial plethora and moon face, weight loss) was noticed. Our patient underwent videothoracoscopic surgery, and a hyperplastic thymus of 80 × 70 × 15 mm with a 4 mm nodule was successfully removed. Tumor immunohistochemistry was positive for ACTH, chromogranin A, CD56, and synaptophysin. Histopathological findings were consistent with a well-differentiated NET grade 1. A subsequent genetic screening did not detect any pathogenic variant in the MEN1 gene.

After surgery, hydrocortisone was switched to a stress dose and gradually decreased to a maintenance dose. Antihypertensive medication was stopped and further weight loss was observed after thymectomy. Within a few weeks after the thoracic surgery, the patient entered puberty, her mood improved significantly, and potassium supplements were stopped. Finally, hydrocortisone treatment was stopped ten months after thymectomy.

Discussion and conclusions

The case presented here demonstrates a particularly challenging work-up of the pediatric patient with the diagnosis of CS caused by EAS due to thymic NET. Differentiating CD and EAS can sometimes be difficult, including the use of various laboratory and stimulation tests and their interpretation, as well as proper, often challenging, reading of functional imaging modalities, especially if a discrete lesion is present at an unusual location [1]. When using established criteria for Cushing disease (for the CRH test an increase of cortisol and/or ACTH by ≥ 20% or ≥ 35%, respectively, and a ≥ 50% suppression of cortisol for the HDDST) our patient presented discordant results. The CRH stimulation test induced an increase in cortisol by 32% and ACTH by 67% and the 3T MRI pointed to the right-side pituitary lesion, both to yield false positive results. The HDDST, on the other hand, did not induce cortisol suppression and was against characteristic findings for CD. We did not proceed with desmopressin testing, which also induces an excess ACTH and cortisol response in CD patients and has rarely been used in pediatric patients, except in those with extremely difficult venous access [6]. Recently published articles investigated the reliability of CRH stimulation tests and HDDST and both concluded that the CRH test has greater specificity than HDDST [7, 8]. Elenius et al. suggested optimal response criteria as a ≥ 40% increase of ACTH and/or cortisol (cortisol as the most specific measure of CD) during the CRH test and a ≥ 69% suppression of serum cortisol during HDDST [7]. Using these criteria, the CD would be excluded in our patient. To demonstrate that the proposed thresholds for the test interpretation widely differ, Detomas et al. proposed a ≥ 12% cortisol increase and ≥ 31% ACTH increase during the CRH test to confirm CD [8].

The fact that up to 50% of PitNET may not be detected on MRI [1] and that more than 20% of patients with EAS are reported to have pituitary incidentalomas [9] makes MRI somewhat unreliable in differentiating CD and EAS. However, finally, well-established and generally reliable BIPSS in our patient supported the diagnosis of EAS. Thus, BIPSS is considered a gold standard to differentiate between CD and EAS; however, it can still provide false negative results in cyclic CS if performed in the trough phase [10] or in vascular anomalies or false positive results as in a recent case of orbital EAS [11].

In children, the presence of thymus tissue may be misinterpreted as normal. Among other reports of thymic NET [12], Hanson et al. reported a case of a prepubertal boy in whom a small thymic NET was initially treated as normal thymus tissue on CT [13]. In our case, initially, the lesion was not detected on the 18F-FDG and 68Ga-DOTATOC PET scans. A small thymic NET was visible only after a detailed and careful re-reading of both PET scans. Although somatostatin receptor (SSR) PET imaging may be helpful in identifying ectopic CRH- or ACTH-producing tumors, there are still some limitations [13]. For example, in the study by Wannachalee et al., 68Ga-DOTATATE identified suspected primary lesions causing ECS in 65% of patients with previously occult tumors and was therefore concluded as a sensitive method for primary as well as metastatic tumors [14]. In our patient, the final correct diagnosis was based on the results of both PET scans. This is in full support of the article published by Liu et al. who concluded that 18F-FDG and SSR PET scans are complementary in determining the proper localization of ectopic ACTH production [15]. Additionally, it is worth noting that not all NETs stain positively for ACTH which may present a burden in its identification.

To control hypercortisolemia, both ketoconazole and metyrapone were considered in our patient. Due to the side effects of metyrapone on blood pressure, ketoconazole was started as a preferred option in our pediatric patient. A retrospective multicenter study concluded that ketoconazole treatment is effective with acceptable side effects, with no fatal hepatitis and adrenal insufficiency in 5.4% of patients [3]. During ketoconazole treatment, our patient developed adrenal insufficiency; however, it is impossible to conclude whether this was solely due to ketoconazole treatment or whether an ongoing COVID-19 infection contributed to the adrenal insufficiency or whether this was caused by a phase of lower or no ACTH secretion from the tumor often seen in patients with cyclic ACTH secretion. The patient’s cyclic ACTH secretion is highly probable since her morning cortisol was slightly lower and ACTH was normal, even after being off ketoconazole treatment for 3 weeks.

When retrospectively and carefully reviewing all approaches to the diagnostic and management care of our pediatric patient, it would be essential to proceed to BIPSS before any pituitary surgery, especially when obtaining discrepant results from stimulation tests, as well as detecting a discrete pituitary lesion (≤ 6 mm) as recommended by the current guidelines [16]. This was our first experience using ketoconazole in a young child, and although this treatment was associated with very good outcomes in treating hypercortisolemia, close monitoring, and family education on signs and symptoms of adrenal insufficiency are essential to recognizing adrenal insufficiency promptly in any patient with EAS, especially those presenting also with some other comorbidities or stress, here COVID-19 infection.

In conclusion, the pediatric patient here presenting with EAS caused by thymic NET needs very careful assessment including whether cyclic CS is present, the outline of a good management plan to use all tests appropriately and in the correct sequence, monitoring carefully for any signs or symptoms of adrenal insufficiency, and apply appropriate imaging studies, with experienced radiologists providing accurate readings. Furthermore, ketoconazole treatment was found to be effective in reducing the symptoms and signs of CS in this pediatric patient. Finally, due to the rarity of this disease and the challenging work-up, we suggest that a multidisciplinary team of experienced physicians in CS management is highly recommended.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACTH:
Adrenocorticotrophic hormone
BIPSS:
Bilateral inferior petrosal sinus sampling
CD:
Cushing disease
CRH:
Corticotropin-releasing hormone
CS:
Cushing syndrome
CT:
Computed tomography
DST:
Dexamethasone suppression test
EAS:
Ectopic adrenocorticotropic hormone syndrome
18F-FDG PET:
Fluorine-18 fluorodeoxyglucose positron emission tomography
HDDST:
High-dose dexamethasone suppression test
IV:
Intravenous
LDDST:
Low-dose dexamethasone suppression test
NET:
Neuroendocrine tumor
PitNET:
Pituitary neuroendocrine tumor
UFC:
Urinary free cortisol

References

  1. Streuli R. A rare case of an ACTH/CRH co-secreting midgut neuroendocrine tumor mimicking Cushing’s disease. Endocrinol Diabetes Metab Case Rep. 2017;2017:17–58. ,Krull I, Brändle M, et al.

    PubMed PubMed Central Google Scholar

  2. Karageorgiadis AS, Papadakis GZ, Biro J, et al. Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. J Clin Endocrinol Metab. 2015;100(1):141–8.

    Article CAS PubMed Google Scholar

  3. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab. 2014;99(5):1623–30.

    Article CAS PubMed Google Scholar

  4. Mi Q, Yin M-Z, Gao Y-J et al. Thymic atypical carcinoid with cyclical Cushing’s syndrome in a 7-year-old boy: a case report and review of the literature. Intern Med. 2014;4(5).

  5. Moszczyńska E, Pasternak-Pietrzak K, Prokop-Piotrkowska M, et al. Ectopic ACTH production by thymic and appendiceal neuroendocrine tumors – two case reports. J Pediatr Endocrinol Metab. 2020;34(1):141–6.

    Article PubMed Google Scholar

  6. Crock PA, Ludecke DK, Knappe UJ, et al. A personal series of 100 children operated for Cushing’s disease (CD): optimizing minimally invasive diagnosis and transnasal surgery to achieve nearly 100% remission including reoperations. J Pediatr Endocrinol Metab. 2018;31(9):1023–31.

    Article CAS PubMed Google Scholar

  7. Elenius H, McGlotten R, Nieman LK. Ovine CRH stimulation and 8 mg dexamethasone suppression tests in 323 patients with ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2023;109(1):e189–189.

    Article Google Scholar

  8. Detomas M, Ritzel K, Nasi-Kordhishti I, et al. Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing’s syndrome. Front Endocrinol (Lausanne). 2022;13:955945.

    Article PubMed Google Scholar

  9. Yogi-Morren D, Habra MA, Faiman C, et al. Pituitary MRI findings in patients with pituitary and ectopic ACTH-dependent Cushing syndrome: does a 6-mm pituitary tumor size cut-off value exclude ectopic ACTH syndrome? Endocr Pract. 2015;21(10):1098–103.

    Article PubMed Google Scholar

  10. Albani A, Berr CM, Beuschlein F, et al. A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome. BMC Endocr Disord. 2019;19(1):105.

    Article PubMed PubMed Central Google Scholar

  11. Tan H, Chen D, Yu Y, et al. Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS: a case report. BMC Endocr Disord. 2020;20(1):116.

    Article CAS PubMed PubMed Central Google Scholar

  12. Ahmed MF, Ahmed S, Abdussalam A, et al. A rare case of ectopic adrenocorticotropic hormone syndrome (EAS) in an adolescent girl with a thymic neuroendocrine tumour. Cureus. 2024;16(8):e66615.

    PubMed PubMed Central Google Scholar

  13. Hanson JA, Sohaib SA, Newell-Price J, et al. Computed tomography appearance of the thymus and anterior mediastinum in active Cushing’s syndrome. J Clin Endocrinol Metab. 1999;84:602–5.

    CAS PubMed Google Scholar

  14. Wannachalee T, Turcu AF, Bancos I, et al. The clinical impact of [68 Ga]-DOTATATE PET/CT for the diagnosis and management of ectopic adrenocorticotropic hormone – secreting Tumours. Clin Endocrinol (Oxf). 2019;91(2):288–94.

    Article PubMed Google Scholar

  15. Liu Q, Zang J, Yang Y, et al. Head-to-head comparison of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in localizing tumors with ectopic adrenocorticotropic hormone secretion: a prospective study. Eur J Nucl Med Mol Imaging. 2021;48(13):4386–95.

    Article CAS PubMed Google Scholar

  16. Flesiriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847–75.

    Article Google Scholar

Download references

Acknowledgements

The authors thank all the colleagues from the Thomayer University Hospital and Military University Hospital who were involved in the inpatient care of this patient.

Funding

This work was supported by the Charles University research program Cooperatio Pediatrics, Charles University, Third Faculty of Medicine, Prague.

Author information

Authors and Affiliations

  1. Department of Children and Adolescents, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 50, Prague, 100 34, Czech Republic

    Irena Aldhoon-Hainerová

  2. Department of Pediatrics, Thomayer University Hospital, Prague, Czech Republic

    Irena Aldhoon-Hainerová

  3. Department of Medicine, Military University Hospital, Prague, Czech Republic

    Mikuláš Kosák

  4. Third Department of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

    Michal Kršek

  5. Institute of Nuclear Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

    David Zogala

  6. Developmental Endocrinology, Metabolism, Genetics and Endocrine Oncology Affinity Group, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA

    Karel Pacak

Contributions

All authors made individual contributions to the authorship. IAH, MK, MK, and DZ were involved in the diagnosis and management of this patient. DZ was responsible for the patient´s imaging studies. IAH wrote the first draft of the manuscript. KP revised the manuscript critically. All authors reviewed and approved the final draft.

Corresponding author

Correspondence to Irena Aldhoon-Hainerová.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Signed informed consent was obtained from the patient and the patient´s parents for the publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-024-01756-5

Filed under: Cushing's, Rare Diseases, symptoms, Treatments | Tagged: , , , , , | Leave a comment »

« Previous Page — Next Page »