Severe Osteoporosis in a Young Man with Bilateral Cushing’s Syndrome

Posted on June 28, 2023 by MaryO

Abstract

Background

The diagnosis of Cushing’s syndrome is challenging; however, through the clinical picture and the search for secondary causes of osteoporosis, it was possible to reach the diagnosis of the case reported. There was an independent, symptomatic ACTH hypercortisolism manifested by typical phenotypic changes, severe secondary osteoporosis and arterial hypertension in a young patient.

Case presentation

A 20-year-old Brazilian man with low back pain for 8 months. Radiographs showed fragility fractures in the thoracolumbar spine, and bone densitometry showed osteoporosis, especially when evaluating the Z Score (− 5.6 in the lumbar spine). On physical examination, there were wide violaceous streaks on the upper limbs and abdomen, plethora and fat increase in the temporal facial region, hump, ecchymosis on limbs, hypotrophy of arms and thighs, central obesity and kyphoscoliosis. His blood pressure was 150 × 90 mmHg. Cortisol after 1 mg of dexamethasone (24.1 µg/dL) and after Liddle 1 (28 µg/dL) were not suppressed, despite normal cortisoluria. Tomography showed bilateral adrenal nodules with more severe characteristics. Unfortunately, through the catheterization of adrenal veins, it was not possible to differentiate the nodules due to the achievement of cortisol levels that exceeded the upper limit of the dilution method. Among the hypotheses for the differential diagnosis of bilateral adrenal hyperplasia are primary bilateral macronodular adrenal hyperplasia, McCune–Albright syndrome and isolated bilateral primary pigmented nodular hyperplasia or associated with Carney’s complex. In this case, primary pigmented nodular hyperplasia or carcinoma became important etiological hypotheses when comparing the epidemiology in a young man and the clinical-laboratory-imaging findings of the differential diagnoses. After 6 months of drug inhibition of steroidogenesis, blood pressure control and anti-osteoporotic therapy, the levels and deleterious metabolic effects of hypercortisolism, which could also impair adrenalectomy in the short and long term, were reduced. Left adrenalectomy was chosen, given the possibility of malignancy in a young patient and to avoid unnecessary definitive surgical adrenal insufficiency if the adrenalectomy was bilateral. Anatomopathology of the left gland revealed expansion of the zona fasciculate with multiple nonencapsulated nodules.

Conclusion

The early identification of Cushing’s syndrome, with measures based on the assessment of risks and benefits, remains the best way to prevent its progression and reduce the morbidity of the condition. Despite the unavailability of genetic analysis for a precise etiological definition, it is possible to take efficient measures to avoid future damage.

Peer Review reports

Background

Cushing’s syndrome may be exogenous or endogenous and, in this case, can be ACTH-dependent or independent. In the case reported, there was an independent, symptomatic ACTH hypercortisolism manifested by typical phenotypic changes, severe secondary osteoporosis and arterial hypertension in a young patient. Osteoporosis secondary to hypercortisolism occurs due to chronic reduction in bone formation, loss of osteocytes and increased reabsorption caused by intense binding of cortisol to glucocorticoid receptors present in bone cells [1]. In addition, excess cortisol impairs vitamin D metabolism and reduces endogenous parathyroid hormone secretion, intestinal calcium reabsorption, growth hormone release, and lean body mass [2]. Subclinical Cushing disease occurs in up to 11% of individuals diagnosed with early-onset osteoporosis and 0.5–1% of hypertension patients. [3] A cross-sectional study published in 2023 revealed a prevalence of 81.5% bone loss in 19 patients with Cushing’s syndrome [2]. The prevalence of osteopenia ranges from 60 to 80%, and the prevalence of osteoporosis ranges from 30 to 65% in patients with Cushing’s syndrome. Additionally, the incidence of fragility fractures ranges from 30 to 50% in these patients [4] and is considered the main cause of morbidity affecting the quality of life. The diagnosis is challenging, given the presence of confounding factors; however, through the clinical picture and the search for secondary causes of osteoporosis, it was possible to reach a syndromic diagnosis. Early identification of this syndrome, with measures based on the assessment of risks and benefits, remains the best way to prevent progression and reduce morbidity related to this disease [2].

Case presentation

A 20-year-old Brazilian male patient reported low back pain that had evolved for 8 months, with no related trauma. He sought emergency care and performed spinal radiographs on this occasion (03/2019). Due to the several alterations observed in the images, he was referred to the Orthopedics Service of the Hospital of Federal University of Juiz de Fora, which prescribed orthopedic braces, indicated physical therapy and was referred again to the Osteometabolic Diseases outpatient clinic of the Endocrinology and Rheumatology Services of the Hospital of Federal University of Juiz de Fora on 10/2019.

The radiographs showed a marked reduction in the density of bone structures, scoliotic deviation with convexity toward the left and reduction in the height of the lumbar vertebrae, with partial collapses of the vertebral bodies at the level of T12, L1, L2, L3 and L5, with recent collapses in T12 and L1, suggesting bone fragility fractures. The same can be seen in posterior magnetic resonance imaging (Fig. 1).

Fig. 1

figure 1

Radiography and Magnetic Resonance Imaging (MRI) of lumbosacral spine in profile

Bone scintigraphy on 08/2019 did not reveal hyper flow or anomalous hyperemia in the topography of the thoracolumbar spine, and in the later images of the exam, there was a greater relative uptake of the tracer in the lumbar spine (vertebrae T10–T12, L2–L4), of nonspecific aspect, questioning the presence of osteoarticular processes or ankylosing spondylitis.

It was also observed in the bone densitometry requested in October 2019, performed by dual-energy X-ray absorptiometry (DXA), low bone mineral density (BMD) in the lumbar spine, femoral neck and total femur, when comparing the results to evaluating the Z Score (Table 1).

Table 1 Dual-energy X-ray absorptiometry (DXA)

Thus, the diagnosis of osteoporosis was established, and treatment with vitamin D 7000 IU per week was started due to vitamin D3 insufficiency associated with the bisphosphonate alendronate 70 mg, also weekly. The patient had a past pathological history of fully treated syphilis (2018) and perianal condyloma with a surgical resection on 09/2017 and 02/2018. In the family history, it was reported that a maternal uncle died of systemic sclerosis. In the social context, the young person denied drinking alcohol and previous or current smoking.

On physical examination, there were no lentiginous skin areas or blue nevi; however, wide violet streaks were observed on the upper limbs and abdomen, with plethora and increased fat in the temporal facial region and hump (Fig. 2a, b), limb ecchymosis, hypotrophy of the arms and thighs, central obesity and kyphoscoliosis. Systemic blood pressure (sitting) was 150 × 90 mmHg, BMI was 26.09 kg/m2, and waist circumference was 99 cm, with no reported reduction in height, maintained at 1.55 m.

Fig. 2

figure 2

Changes in the physical examination. a Violet streaks on the upper limbs, b Violet streaks on abdomen

An investigation of secondary causes for osteoporosis was initiated, with the following laboratory test results (Table 2).

Table 2 Laboratory tests

Computed tomography of the abdomen with adrenal protocol performed on 08/13/2020 characterized isodense nodular formation in the body of the left adrenal and in the lateral portion of the right adrenal, measuring 1.5 cm and 0.6 cm, respectively. The lesions had attenuation of approximately 30 HU, showing enhancement by intravenous contrast, with an indeterminate washout pattern in the late phase after contrast (< 60%) (Fig. 3).

Fig. 3

figure 3

Computed tomography abdomen with adrenal protocol

After contact with the interventional radiology of the Hospital of Federal University of Juiz de Fora, catheterization of adrenal veins was performed on 10/2020; however, it was not possible to perform adequate lesion characterization due to obtaining serum cortisol levels that extrapolated the dilutional upper limit of the method (Table 3).

Table 3 Adrenal catheterization

The calculation of the selectivity index was 6.63 (Reference Value (RV) > 3), confirming the good positioning of the catheter within the vessels during the procedure. The calculated lateralization index was 1.1296 (VR < 3), denoting bilateral hormone production. However, as aldosterone was not collected from a peripheral vein, it was not possible to obtain the contralateral rate and define whether there was contralateral suppression of aldosterone production [5].

Due to pending diagnoses for a better therapeutic decision and Cushing’s syndrome in clear evolution and causing organic damage, it was decided, after catheterization, to make changes in the patient’s drug prescription. Ketoconazole 400 mg per day was started, the dose of vitamin D was increased to 14,000 IU per week, and ramipril 5 mg per day was prescribed due to secondary hypertension. In addition, given the severity of osteoporosis, it was decided to replace previously prescribed alendronate with zoledronic acid.

Magnetic resonance imaging of the upper abdomen was performed on 06/19/2021, which demonstrated lobulated nodular thickening in the left adrenal gland with areas of decreased signal intensity in the T1 out-phase sequence, denoting the presence of fat, and homogeneous enhancement using contrast, measuring approximately 1.7 × 1.5 × 1.3 cm, suggestive of an adenoma. There was also a small nodular thickening in the lateral arm of the right adrenal, measuring approximately 0.8 × 0.6 cm, which was difficult to characterize due to its small dimensions and nonspecific appearance.

PPNAD or carcinoma became an important etiological hypothesis for the case described when comparing the epidemiology in a young man and the clinical-laboratory-imaging findings of the differential diagnoses. According to a dialog with the patient and family, the group of experts opted for unilateral glandular surgical resection on the left side (11/11/2021), where more significant changes were visualized, as there was a possibility of malignancy in a young patient and to avoid a definitive adrenal insufficiency condition because of bilateral adrenalectomy. This would first allow the analysis of the material and follow-up of the evolution of the condition with the permanence of the contralateral gland.

In the macroscopic analysis of the adrenalectomy specimen, adrenal tissue weighing 20 g and measuring 9.3 × 5.5 × 2.0 cm was described, completely surrounded by adipose tissue. The gland has a multinodular surface and varies between 0.2 and 1.6 cm in thickness, showing a cortex of 0.1 cm in thickness and a medulla of 1.5 cm in thickness (Fig. 4).

Fig. 4

figure 4

Left adrenal

The microscopic analysis described the expansion of the zona fasciculate, with the formation of multiple nonencapsulated nodules composed of polygonal cells with ample and eosinophilic cytoplasm and frequent depletion of intracytoplasmic lipid content. No areas of necrosis or mitotic activity were observed. The histopathological picture is suggestive of cortical pigmented micronodular hyperplasia of the adrenal gland.

For the final etiological definition and an indication of contralateral adrenalectomy, which could be unnecessary and would avoid chronic corticosteroid therapy, or else, it would be necessary to protect the patient from future complications with the maintenance of the disease in the right adrenal gland, it would be essential to search for mutations in the PRKAR1A, PDE11A, PDE8B and PRKACA genes [15]; however, such genetic analysis is not yet widely available, and the impossibility of carrying it out at the local level did not allow a complete conclusion of the case.

Discussion

Through the clinical picture presented and the research of several secondary causes for osteoporosis, it was possible to arrive at the diagnosis of Cushing syndrome [6]. There was symptomatic independent ACTH hypercortisolism, manifested by typical phenotypic changes, severe secondary osteoporosis, and arterial hypertension in a young patient.

The diagnosis of Cushing’s syndrome is always challenging, given the presence of confounding factors such as the following:

  • Physiological states of hypercortisolism—pseudo Cushing (strenuous exercise, pregnancy, uncontrolled diabetes, sleep apnea, chronic pain, alcohol withdrawal, psychiatric disorders, stress, obesity, glucocorticoid resistance syndromes);
  • Cyclic or mild—subclinical Cushing’s pictures;
  • Frequent and, even unknown, short- and long-term use of corticosteroids under different presentations;
  • Increase in the general population incidence of diabetes and obesity;
  • Screening tests with singularities for collection and individualized for different patient profiles.

It is important to note that the basal morning cortisol measurement is not the ideal test to assess hypercortisolism and is better applied to the assessment of adrenal insufficiency. However, the hypercortisolism of the case was unequivocal, and this test was also shown to be altered several times. As no test is 100% accurate, the current guidelines suggest the use of at least two first-line functional tests that focus on different aspects of the pathophysiology of the hypothalamic‒pituitary‒adrenal axis to confirm the hypercortisolism state: 24-hours cortisol, nocturnal salivary cortisol, morning serum cortisol after suppression with 1 mg of dexamethasone or after Liddle 1. Given that night-time salivary cortisol would require hospitalization, the other suggested tests were chosen, which are easier to perform in this context [7, 8].

Subsequently, tests were performed to determine the cause of hypercortisolism, such as serum ACTH levels and adrenal CT. The suppressed ACTH denoted the independence of its action. CT showed bilateral adrenal nodules with more severe features: solid lesion, attenuation > 10 UI on noncontrast images, and contrast washout speed < 60% in 10 minutes. In this case, it is essential to make a broad clinical decision and dialog with the patient to weigh and understand the risks and benefits of surgical treatment [9].

Among the main diagnostic hypotheses for the differential diagnosis of bilateral adrenal hyperplasia are primary bilateral macronodular adrenal hyperplasia, McCune–Albright syndrome (MAS) and bilateral primary pigmented nodular hyperplasia (PPNAD) isolated or associated with Carney’s complex. Another possibility would be bilateral adrenocorticotropic hormone (ACTH)-dependent macronodular hyperplasia secondary to long-term adrenal stimulation in patients with Cushing’s disease (ACTH-secreting pituitary tumor) or ectopic ACTH production, but the present case did not present with ACTH elevation.

Primary macronodular adrenal hyperplasia (nodules > 1 cm) predominates in women aged 50–60 years and may also be detected in early childhood (before 5 years) in the context of McCune–Albright syndrome. Most cases are considered sporadic; however, there are now several reports of familial cases whose presentation suggests autosomal dominant transmission. Several pathogenic molecular causes were identified in the table, indicating that it is a heterogeneous disease [10]. The pathophysiology occurs through the expression of anomalous ectopic hormone receptors or amplified eutopic receptors in the adrenals. It usually manifests in an insidious and subclinical way, with cortisol secretion mediated through receptors for gastric inhibitory peptide (GIP), vasopressin (ADH), catecholamines, interleukin 1 (IL-1), leptin, luteinizing hormone (LH), serotonin or others. Nodular development is not always synchronous or multiple; thus, hypercortisolism only manifests when there is a considerable increase in the number of adrenocortical cells, with severe steroidogenesis observed by cortisoluria greater than 3 times the upper limit of normal. Patients with mild Cushing’s syndrome should undergo screening protocols to identify aberrant receptors, as this may alter the therapeutic strategy. If there is evidence of abnormal receptors, treatment with beta-blockers is suggested for patients with beta-adrenergic receptors or with gonadotropin-releasing hormone (GnRH) agonists (and sex steroid replacement) for patients with LH/hCG receptors. In patients in whom aberrant hormone receptors are not present or for whom no specific pharmacological blockade is available or effective, the definitive treatment is bilateral adrenalectomy, which is known to make the patient dependent on chronic corticosteroid therapy [11]. Studies have shown the effectiveness of unilateral surgery in the medium and long term, opting for the resection of the adrenal gland of greater volume and nodularity by CT, regardless of the values obtained by catheterization of adrenal veins, but with the possibility of persistence or recurrence in the contralateral gland. Another possibility would be total unilateral adrenalectomy associated with subtotal contralateral adrenalectomy [12].

In McCune–Albright syndrome (MAS), there are activating mutations in the G-protein GNAS1 gene, generating autonomic hyperfunction of several tissues, endocrine or not, and there may be, for example, a constant stimulus similar to ACTH on the adrenal gland. In this case, pituitary levels of ACTH are suppressed, and adrenal adenomas with Cushing’s syndrome appear. Hypercortisolism may occur as an isolated manifestation of the syndrome or be associated with the triad composed of polyostotic fibrous dysplasia, café au lait spots with irregular borders and gonadal hyperfunction with peripheral precocious puberty. The natural history of Cushing’s syndrome in McCune-Albright syndrome (MAS) is heterogeneous, with some children evolving with spontaneous resolution of hypercortisolism, while others have a more severe condition, eventually requiring bilateral adrenalectomy [13].

PPNAD predominates in females, in people younger than 30 years, multiple and small (< 6 mm) bilateral pigmented nodules (surrounded by atrophied cortex), which can reach 1.5 cm in adulthood, with family genetic inheritance (66%) or sporadic inheritance (33%), and as part of the Carney complex reported in 40% of cases. In 70% of cases, inactivating mutations are identified in the PKA regulatory 1-alpha subunit (PRKAR1A), a tumor suppressor gene [14]. Osteoporosis is often associated with this condition [15]. One test that can distinguish patients with PPNAD from other primary adrenocortical lesions is cortisoluria after sequential suppression with low- and high-dose dexamethasone. In contrast to most patients with primary adrenocortical disease, who demonstrate no change in urinary cortisol, 70% of PPNAD patients have a paradoxical increase in urinary cortisol excretion [16]. The treatment of choice for PPNAD is bilateral adrenalectomy due to the high recurrence rate for primary adrenal disease [17].

Carney complex is a multiple neoplastic syndrome with autosomal dominant transmission, characterized by freckle-like cutaneous hyperpigmentation (lentiginosis), endocrine tumors [(PPNAD), testicular and/or thyroid tumors and acromegaly] and nonendocrine tumors, including cutaneous, cardiac, mammary, and osteochondral myxomas, among others. In the above case, the transthoracic echocardiogram of the patient on 03/18/2021 showed cavities of normal dimensions, preserved systolic and diastolic functions, no valve changes and no lentiginous skin areas and blue nevi, making the diagnosis of the syndrome less likely. The definitive diagnosis of Carney requires two or more main manifestations. Several related clinical components may suggest the diagnosis but not define it. The diagnosis can also be made if a key criterion is present and a first-degree relative has Carney or an inactivating mutation of the gene encoding PRKAR1A [18].

The adenoma is usually small in size (< 3 cm), similar to the nodules in this case; however, it is usually unilateral, with an insidious and mild evolution, especially in adult women over 35 years of age, producing only 1 steroid class. Carcinomas are usually large (> 6 cm), and only 10% are bilateral. They should be suspected mainly when the tumor presents with hypercortisolism associated with hyperandrogenism. They have a bimodal age distribution, with peaks in childhood and adolescence, as well as at the end of life [3].

Conclusion

Early identification of Cushing’s syndrome, with measures based on the assessment of risks and benefits, remains the best way to prevent progression and reduce morbidity [2]. After 6 months of drug inhibition of steroidogenesis, blood pressure control and anti-osteoporotic therapy, the objective was to minimize the levels and deleterious metabolic effects of hypercortisolism, which could also harm the surgical procedure in the short and long term through infections, dehiscence, nonimmediate bed mobilization and cardiovascular events. Unilateral adrenalectomy was chosen, given the possibility of malignancy in a young patient and to avoid definitive surgical adrenal insufficiency if the adrenalectomy was bilateral. Despite the unavailability of genetic analysis for a precise etiological definition, it is possible to take efficient measures to avoid unnecessary consequences or damage.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its Additional file 1]. The datasets generated and/or analysed during the current study are available in the link https://ufjfedubr-my.sharepoint.com/:v:/g/personal/barbara_reis_ufjf_edu_br/EVpIR005sPZGlQvMJhIwSaUB0Hig4KOjhkG4D4cMggUwHA?e=Dk8tng.

Abbreviations

ACTH:
Adrenocorticotropic hormone
PPNAD:
Bilateral primary pigmented nodular hyperplasia
DXA:
Dual energy X-ray absorptiometry
GIP:
Gastric inhibitory peptide
GnRH:
Gonadotropin-releasing hormone
IL-1:
Interleukin 1
BMD:
Low bone mineral density
LH:
Luteinizing hormone
MAS:
McCune–Albright syndrome
PRKAR1A:
PKA regulatory 1-alpha subunit
ADH:
Vasopressin

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Acknowledgements

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Author information

Authors and Affiliations

  1. Serviço de Endocrinologia, Hospital Universitário da Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil

    Bárbara Oliveira Reis, Christianne Toledo Sousa Leal, Danielle Guedes Andrade Ezequiel, Ana Carmen dos Santos Ribeiro Simões Juliano, Flávia Lopes de Macedo Veloso, Leila Marcia da Silva, Lize Vargas Ferreira, Mariana Ferreira & Gabriel Zeferino De Oliveira Souza

Contributions

All the authors contributed to the conception and design of the work and have approved the submitted version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bárbara Oliveira Reis.

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

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1. Surgical removal of adrenal gland.

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Cushing’s Disease Associated With Partially Empty Sella Turcica Syndrome

Posted on June 28, 2023 by MaryO

Abstract

The association between empty sella turcica (EST) syndrome and Cushing’s disease has been rarely reported. It is plausible to hypothesize that EST syndrome in association with Cushing’s disease can be attributed to intracranial hypertension. In this case report, we present a 47-year-old male patient who presented with weight loss, fatigue, easy bruising, acanthosis nigricans, and skin creases hyperpigmentation. Investigations revealed hypokalemia and confirmed the diagnosis of Cushing’s disease. Magnetic resonance imaging (MRI) brain showed a partial EST syndrome and a new pituitary nodule as compared with previous brain imaging. Transsphenoidal surgery was pursued and was complicated by cerebrospinal fluid leakage. This case reflects the rare association of EST syndrome and Cushing’s disease, suggesting the increased risk of postoperative complications in this setting and the diagnostic challenge that EST syndrome imposes. We review the literature for a possible mechanism of this association.

Introduction

Cushing’s disease is commonly caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma, which can be very challenging to be seen on brain magnetic resonance imaging (MRI) [1]. Empty sella turcica (EST) syndrome is a radiological diagnosis of apparently empty turcica secondary to outpouching of the arachnoid mater into the turcica, which can be attributed to intracranial hypertension (ICHTN). This can make the visual diagnosis of pituitary adenoma even more challenging in clinical practice. ICHTN has been also associated with Cushing’s disease and might explain this infrequent association between EST and Cushing’s disease [1]. EST syndrome can be either partial or complete, primary or secondary and has been seen infrequently with Cushing’s disease. In this setting, not only that it is likely to obscure an underlying pituitary lesion, but also it does contribute to the risk of postoperative complications [2].

Case Presentation

A 47-year-old male presented to the emergency department (ED) with slowly progressive generalized limb muscle weakness affecting both distal and proximal muscles over a few weeks and gait instability for three days prior to presentation. He also reported unintentional 40 pounds weight loss over the previous four months. Past medical history was significant for type II diabetes mellitus, hypothyroidism, hypertension, and dyslipidemia. In the ED, vital signs included a blood pressure of 140/90 mmHg, a heart rate of 66 beats per minute, a respiratory rate of 16 cycles per minute, and SpO2 of 97% on room air. Body mass index has decreased to 22 kg/m2 from a baseline of 26 kg/m2 one month prior. On the physical exam, he exhibited cachexia, easy bruising, acanthosis nigricans, and hyperpigmentation of skin creases. All other systems were negative. Complete metabolic panel and complete blood count were obtained showing hyperglycemia of 311 mg/dl, see Table 1. Further lab evaluation showed elevated salivary cortisol at 2.96 microgram/dl (reference range 0.094-1.551 mcg/dl), elevated 24-hour urinary free cortisol at 156 mcg/24 hour (reference 10-100 mcg/24h), positive overnight dexamethasone suppression test with serum cortisol at 2.8 mcg/dl (reference more than 2 mcg/dl), negative anti-adrenal antibodies, normal aldosterone, and elevated dehydroepiandrostenedione at 401 mcg/dl (reference 32-240 mcg/dl), with lack of suppression of the ACTH level at 35.1 pg/ml (reference 10-60 pg/ml). This confirmed the diagnosis of Cushing’s disease.

Variable Finding Reference
Random glucose 311 Less than 200 mg/dl
Sodium 141 137-145 mmol/L
Potassium 2.5 3.5-5.1 mmol/L
Chloride 96 98-107 mmol/L
Bicarbonate 32 22-30 mmol/L
Blood urea nitrogen 32 9-20 mg/dl
Creatinine 0.52 0.66-1.25 mg/dl
Calcium 8.7 8.6-10.3 mg/dl
Total protein 5.5 6.5-8.5 g/dl
Albumin 3.3 3.5-5 g/dl
Total bilirubin 0.6 0.2-1.3 mg/dl
Alkaline phosphatase 115 38-126 U/L
Aspartate transaminase 17 17-59 U/L
Alanine transaminase 39 Less than 49 U/L
White blood cell count 10×10^3 cells/mcl 4-10×1063 cells/mcl
Hemoglobin 15.3 13.7-17.5 g/dl
Platelet 281 150-400×10^3 cells/mcl
Table 1: Lab Findings

Computed tomography (CT) scan of the head was unremarkable. CT scan of the chest was also unremarkable. CT scan of abdomen and pelvis showed no adrenal mass. Ultrasound of the kidneys was unremarkable. Pituitary MRI brain protocol for adenoma showed a partial EST, shortening within neurohypophysis and a new 10 x 8 x 4 mm nodule along the floor of pituitary sella as compared to MRI four years ago (Figure 1).

Magnetic-Resonance-Imaging-(MRI)-Brain
Figure 1: Magnetic Resonance Imaging (MRI) Brain

MRI brain showing partially empty sella turcica syndrome ( black arrow) with a small nodule at the floor of the turcica (white arrow).

The diagnosis of Cushing’s disease was confirmed, and the patient underwent trans-sphenoidal resection of pituitary adenoma. Histological examination showed positive CAM 5.2, positive chromogranin, and ACTH immunostains. The patient presented to the ED five days after discharge home. He stated that he noticed drainage from the nose that transitioned from bloody to clear fluid and has been increasing in quantity for two days with associated intermittent headaches since the surgery. He was afebrile with stable vital signs. No signs of infection were noted on basic labs. These were significant only for mild asymptomatic hyponatremia of 131 mmol/L and hypokalemia of 3.3 mmol/L. The patient was diagnosed with cerebrospinal fluid (CSF) leakage and had a lumbar drain trial. The trial was unsuccessful after several days, and the patient underwent a transnasal endoscopic repair of CSF rhinorrhea using nasoseptal flaps. At an outpatient follow-up one month and three months after the surgery, prior lab abnormalities including hypokalemia, hyponatremia, and hyperglycemia resolved. No further evidence of CSF leakage was appreciated, and he remained asymptomatic.

Discussion

EST syndrome is characterized by herniation of the subarachnoid space into the intrasellar space with compression of the pituitary gland into the posteroinferior wall [3]. This is likely to obscure the presence of underlying pituitary mass. The incidence of EST syndrome in the general population is estimated at 20%. The association between EST syndrome and Cushing’s disease has been reported infrequently. A retrospective study of 68 patients with Cushing’s disease found that 16% of these have EST syndrome [3].

Cushing’s disease usually results from pituitary adenomas secreting ACTH, and even the smallest microadenomas can produce a systemic disease. These microadenomas can be very difficult to recognize on brain MRI [4]. This is complicated in EST syndrome and even further with the possibility of ectopic ACTH production. A retrospective study of 197 patients diagnosed with Cushing’s disease concluded that EST syndrome is associated with higher prevalence of MRI-negative Cushing’s disease. This was attributed to ICHTN and pituitary gland compression [1]. Although surgery is curative in 70-90% of cases, EST syndrome was found to have higher risk of postoperative complications among those with Cushing’s disease including diabetes insipidus, hypopituitarism, and CSF leakage [3]. This is usually because in the case of MRI-negative Cushing’s disease with total EST syndrome, empiric surgical exploration is sought after inferior petrosal sampling confirms the pituitary origin of excess ACTH, and postoperative remission indicates adequate tumor resection [2]. This entails a higher chance of uncertainty and injury to healthy pituitary tissue.

EST syndrome can be either primarily due to defects in the sellar diaphragm or anatomical variant or secondary to ICHTN. EST syndrome has been reported in association with many conditions associated with elevated intracranial pressure including tumors, thrombosis, meningitis, hydrocephalus, and Arnold-Chiari malformation [5]. Reversal of EST syndrome has been reported in those with idiopathic ICHTN with therapy by acetazolamide, ventriculoperitoneal shunt, and lumbar puncture [6,7]. A study has shown correlation between CSF circulation impairment or blockage and EST syndrome [8]. The incidence of EST syndrome in association with symptomatic intracranial hypertension is variable and ranges from 2.5% for total EST syndrome to 94% for partial EST syndrome [9]. Impaired CSF circulation and dynamics have been reported in 77% of patients with EST syndrome [10]. In addition to intracranial hypertension, EST syndrome has also been described in association with obesity, meningioma, pediatric nevoid basal cell carcinoma, therapy for growth hormone deficiency and even in healthy individuals [9]. Lack of symptoms of intracranial hypertension in this patient does not rule it out as intracranial hypertension in EST syndrome represents a spectrum that ranges from asymptomatic, milder intracranial hypertension to symptomatic intracranial hypertension with headache, visual disturbance, and papilledema [10]. This explains the fact that only 8-14% of EST syndrome progress to symptomatic ICHTN, while symptomatic ICHTN has been associated with EST syndrome in 94% of cases.

ICHTN has been seen in association with disturbance of the hypothalamic-pituitary-adrenal axis. This has been reported after surgical and medical treatment of Cushing’s disease, withdrawal of long-term steroid therapy, initial presentation of Addison’s disease, or relative glucocorticoids deficiency [11]. Cortisol excess increases CSF production and reduces its absorption, hence increasing intracranial pressure [12]. Another possible mechanism is the expression of both mineralocorticoid responsive epithelial sodium channel receptors on the basolateral membrane of the CSF producing epithelial cells of the choroid plexus as well as the expression of 11-beta hydroxysteroid dehydrogenase type 1 enzyme, which is a bidirectional enzyme that mainly functions to convert the inactive cortisone to active cortisol. These mechanisms play a role in maintaining the balance between CSF production and absorption [13,14].

In this case, the patient presented some clinical findings that are rarely associated with Cushing’s disease, combined with a radiological feature that masked the true diagnosis. Our patient presented with significant weight loss, rather than central obesity, which is normally associated with Cushing’s disease. Although possible, the increase in ACTH due to Cushing’s disease is not sufficient to cause hyperpigmentation, which is a classical finding of Addison’s disease, where the entire adrenal cortex is usually affected due to an autoimmune destruction; however, the zona glomerulosa of the adrenal cortex produces aldosterone and its deficiency would lead to hyperkalemia [15]. Our patient presented with both hyperpigmentation and hypokalemia.

Conclusions

EST syndrome is an uncommon radiological finding of apparently EST that has been reported in association with ICHTN. The latter has also been seen in association with Cushing’s disease/syndrome. This is likely to result from glucocorticoid excess-induced change in CSF flow dynamics. EST has been infrequently described in association with Cushing’s disease. This association has a clinical implication as it is likely to obscure the visualization of pituitary lesions responsible for Cushing’s disease, contribute to diagnostic uncertainty, and increase the risk of healthy pituitary tissue injury and the risk of postoperative complications including CSF leakage.

References

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  2. Sun Y, Sun Q, Fan C, et al.: Diagnosis and therapy for Cushing’s disease with negative dynamic MRI finding: a single-centre experience. Clin Endocrinol (Oxf). 2012, 76:868-76. 10.1111/j.1365-2265.2011.04279.x
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From https://www.cureus.com/articles/161111-cushings-disease-associated-with-partially-empty-sella-turcica-syndrome-a-case-report#!/

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