Day 13, Cushing’s Awareness Challenge

Posted on April 13, 2024 by MaryO

UVA 2004
Cushing’s Conventions have always been special times for me – we learn a lot, get to meet other Cushies, even get referrals to endos!

As early as 2001 (or before) my pituitary function was dropping.  My former endo tested annually but did nothing to help me with the symptoms.

In the fall of 2002 my endo refused to discuss my fatigue or anything at all with me until I lost 10 pounds. He said I wasn’t worth treating in my overweight condition and that I was setting myself up for a heart attack. He gave me 3 months to lose this weight. Those 3 months included Thanksgiving, Christmas and New Years.  Needless to say, I left his office in tears, again.

Fast forward 2 years to 2004.  I had tried for a while to get my records from this endo. He wouldn’t send them, even at doctors’ or my requests.

I wanted to go see Dr. Vance at UVa but I had no records so she wouldn’t see me until I could get them.

Finally, my husband went to the former endo’s office and threatened him with a court order. The office manager managed to come up with about 13 pages of records. For going to him from 1986 to 2001 including weeks and weeks at NIH and pituitary surgery, that didn’t seem like enough records to me.

In April of 2004, many of us from the message boards went to the UVa Pituitary Days Convention. That’s where the picture above comes in.  Other pictures from that convention are here.

By chance, we met a wonderful woman named Barbara Craven. She sat at our table for lunch on the last day and, after we learned that she was a dietitian who had had Cushing’s, one of us jokingly asked her if she’d do a guest chat for us. I didn’t follow through on this until she emailed me later. In the email, she asked how I was doing. Usually I say “fine” or “ok” but for some reason, I told her exactly how awful I was feeling.

Barbara emailed me back and said I should see a doctor at Johns Hopkins. I said I didn’t think I could get a recommendation to there, so SHE referred me. The doctor got right back to me, set up an appointment. Between his vacation and mine, that first appointment turned out to be Tuesday, Sept 14, 2004.

Just getting through the maze at Johns Hopkins was amazing. They have the whole system down to a science, moving from one place to another to sign in, then go here, then window 6, then… But it was very efficient.

My new doctor was wonderful. Understanding, knowledgeable. He never once said that I was “too fat” or “depressed” or that all this was my own fault. I feel so validated, finally.

He looked through my records, especially at my 2 previous Insulin Tolerance Tests (ITT). From those, he determined that my growth hormone has been low since at least August 2001 and I’ve been adrenal insufficient since at least Fall, 1999 – possibly as much as 17 years! I was amazed to hear all this, and astounded that my former endo not only didn’t tell me any of this, he did nothing. He had known both of these things – they were in the past records that I took with me. Perhaps that was why he had been so reluctant to share copies of those records. He had given me Cortef in the fall of 1999 to take just in case I had “stress” and that was it.

The new endo took a lot of blood (no urine!) for cortisol and thyroid stuff. I went back on Sept. 28, 2004 for arginine, cortrosyn and IGF testing.

He said that I would end up on daily cortisone – a “sprinkling” – and some form of GH, based on the testing the 28th.

For those who are interested, my new endo is Roberto Salvatori, M.D.
Assistant Professor of Medicine at Johns Hopkins

Medical School: Catholic University School of Medicine, Rome, Italy
Residency: Montefiore Medical Center
Fellowship: Cornell University, Johns Hopkins University
Board Certification: Endocrinology and Metabolism, Internal Medicine

Clinical Interests: Neuroendocrinology, pituitary disorders, adrenal disorders

Research Interests: Control of growth hormone secretion, genetic causes of growth hormone deficiency, consequences of growth hormone deficiency.

Although I have this wonderful doctor, a specialist in growth hormone deficiency at Johns Hopkins, in November, 2004, my insurance company saw fit to over-ride his opinions and his test results based on my past pharmaceutical history! Hello??? How could I have a history of taking GH when I’ve never taken it before?

Of course, I found out late on a Friday afternoon. By then it was too late to call my case worker at the drug company, so we had to appeal on Monday. My local insurance person also worked on an appeal, but the whole thing was  just another long ordeal of finding paperwork, calling people, FedExing stuff, too much work when I just wanted to start feeling better by Thanksgiving.

As it turned out the insurance company rejected the brand of hGH that was prescribed for me. They gave me the ok for a growth hormone was just FDA-approved for adults on 11/4/04. The day this medication was approved for adults was the day after my insurance said that’s what is preferred for me. In the past, this form of hGH was only approved for children with height issues. Was I going to be a ginuea pig again?

The new GH company assigned a rep for me, submitted info to pharmacy, and waited for insurance approval, again.

I finally started the Growth Hormone December 7, 2004.

Was the hassle and 3 year wait worth it?

Stay tuned for April 15, 2016 when all will be revealed.

Read

Read Dr. Barbara Craven’s Guest Chat, October 27, 2004

Thanks for reading 🙂

MaryO

Filed under: adrenal crisis, Cushing's, Meetings and Conferences, pituitary, symptoms, Treatments | Tagged: , , , , , , , , , , , , , , , , , , , | 3 Comments »

Hiding In Plain Sight: Florid Cushing’s Disease Presenting As A Severe Extremity Cellulitis

Posted on April 12, 2024 by MaryO

Abstract

Disclosure: C.M. Godar: None. E.B. Noble: None. N.O. Vietor: None. T.S. Knee: None.

Background: Cushing’s syndrome may rarely present as an emergency known as Florid Cushing’s Syndrome. Patients can exhibit severe hyperglycemia, hypertension, hypokalemia, infections, and hypercoagulability. Cushing’s syndrome is a rare disease, and the constellation of clinical features can be overlooked if clinicians are not aware of the manifestations of hypercortisolism. We present the case of a patient with Cushing’s syndrome that went unrecognized with life-threatening sequelae.

Case presentation: A 52-year-old woman with well-controlled type 2 diabetes and hypertension was admitted to the hospital for severe left lower extremity cellulitis. Prior to hospitalization she had noted rapid weight gain, fatigue, weakness, mental clouding, and moodiness. She was admitted for antibiotics and surgical debridement. The infection persisted despite broad spectrum antibiotics, multiple surgical debridements, and skin grafting. She became bacteremic, and extremity amputation was considered. She additionally developed hypertensive emergency, refractory hypokalemia, and hyperglycemia to 396 mg/dL. Exam was notable for facial plethora, supraclavicular fullness, dorsocervical fat pad, and violaceous abdominal striae. Cushing’s Syndrome was suspected, and labs revealed a significantly elevated random serum cortisol of 60.5mcg/dL (Ref 6.2-19.4), significantly elevated 24H urine cortisol of 2157mcg/24H (Ref 0-50), and ACTH elevated to 81.8pg/mL (Ref 7.2-63.3) that confirmed Cushing’s Disease. MRI sella and octreotide scans did not localize a lesion. Inpatient therapy included multiple antihypertensive agents, insulin drip, aggressive potassium repletion, and initiation of ketoconazole to reduce cortisol levels. Ketoconazole was maximally dosed and she underwent surgical exploration and removal of a small pituitary microadenoma. Following surgery, she developed transient adrenal insufficiency requiring hydrocortisone and she no longer required antihypertensives, insulin, or potassium therapy. Follow up 7 years later has revealed no recurrence of Cushing’s Disease.

Discussion: Cushing’s Syndrome may present with a variety of clinical features and rarely may present as a medical emergency. Delay in diagnosis can lead to Florid Cushing’s Syndrome which carries high risk for morbidity and mortality. This case illustrates the need for clinician awareness of the features of Cushing’s Syndrome: hypertension, hyperglycemia, rapid weight gain, cushingoid exam features, hypokalemia, hirsutism, virilization, infection, and/or hypercoagulable state. Severe hypercortisolism was responsible for this patient’s refractory infection, and if not controlled, she likely would have endured a lower extremity amputation. Rapid detection with elevated random serum and/or urine cortisol and treatment with a cortisol-lowering agent is critical and lifesaving.

Presentation: Thursday, June 15, 2023

This content is only available as a PDF.

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Talus Avascular Necrosis as a Rare Complication of Cushing’s Disease

Posted on April 8, 2024 by MaryO

Abstract

Avascular necrosis (AVN), also called osteonecrosis, stems from blood supply interruption to the bone and is often idiopathic. It has risk factors like trauma, alcohol, and corticosteroids. AVN in the talus (AVNT) is less common than in the femoral head. Most cases of talar osteonecrosis are associated with trauma, while a smaller proportion is linked to systemic conditions such as sickle cell disease or prolonged prednisone use. Glucocorticoids are a key nontraumatic cause. We report a middle-aged woman with Cushing’s syndrome symptoms, such as hypertension and moon face, since her youth. A few years ago, she experienced pain and swelling in her ankle, which was diagnosed as atraumatic AVNT and treated with hindfoot fusion. Years later, she was diagnosed with Cushing’s disease caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma in laboratory tests and imaging, which was resected in 2020. She experienced significant weight loss, and her Cushing’s syndrome symptoms were relieved after tumor resection. Mechanisms behind AVN in hypercortisolism involve fat cell hypertrophy, fat embolization, osteocyte apoptosis, and glucocorticoid-induced hypertension. Traditional X-rays may miss early AVN changes; MRI is preferred for early detection. Although there are some cases of femoral AVN caused by endogenous hypercortisolism in the literature, as far as we know, this is the first case of AVNT due to Cushing’s disease. AVNT treatment includes conservative approaches, hindfoot fusion, and core decompression. Cushing’s disease is a rare cause of AVNT, and a multidisciplinary approach aids in the rapid diagnosis of elusive symptoms.

Introduction

Avascular necrosis (AVN), also known as osteonecrosis, is a condition arising from the temporary interruption or permanent cessation of blood supply to a bone, leading to tissue necrosis or its demise. While AVN is frequently idiopathic, certain established risk factors are known including trauma, alcohol abuse, and the use of exogenous corticosteroids [1]. While not as prevalent as in the femoral head, AVN of the talus (AVNT) in the ankle presents a painful and disabling issue for patients and poses a challenging dilemma for orthopedic surgeons [2]. About 75% of cases of talar osteonecrosis stem from traumatic injuries, while approximately 25% of nontraumatic instances are typically associated with systemic conditions such as sickle cell disease or prolonged use of prednisone, which impede blood flow. [3]

The use of glucocorticoids is one of the most important non-traumatic causes of AVN. Nevertheless, there are some case reports where AVN in the femoral head is reported as a manifestation of endogenous hypercortisolism, particularly associated with Cushing’s syndrome [4-12].

In this article, we describe the case of a middle-aged woman who was diagnosed with idiopathic severe progressive AVNT for two years. She had retrogradely diagnosed masked symptoms of Cushing’s disease since her youth, but the diagnosis was confirmed after undergoing ankle arthrodesis.

Case Presentation

A 43-year-old woman visited our office in June 2018 with a complaint of severe pain and swelling in her left ankle, which had persisted for the past two years. She had hypertension since her youth and blurry vision since 2013 but had no other significant medical or family history. She was also diagnosed with major depressive disorder (MDD) in 2015 when she lost her husband. She had no history of smoking, alcohol consumption, or addiction. She had not experienced any significant trauma during this period and sought consultations from various specialties, including neurology, psychology, internal medicine, nephrology, rheumatology, and orthopedics. She had received a platelet-rich plasma (PRP) injection in the ankle, but it did not improve her symptoms. Despite undergoing various diagnostic workups, no precise diagnosis had been established.

Back in 2013, she remembers suddenly experiencing blurry vision in her right eye. This condition underwent a misdiagnosis, which almost led to a loss of vision. She had been struggling with her eye problems until her last visit, during which she received intravitreal bevacizumab injections. Additionally, she previously had iron deficiency anemia, which was treated with ferrous sulfate before 2018.

In our first visit, during the physical examination, the pain was localized in the ankle mortise with some posterolateral pain along the course of the peroneal tendons posterior to the fibula. Based on the physical examination and available ankle radiographs, we diagnosed AVNT. The patient subsequently underwent ankle arthroscopy through the standard anterior portals, the joint was cleaned, the synovium was shaved, and a small incision was conducted for peroneal assessment; this procedure revealed a subchondral collapse and extensive necrosis in the talus. Following the procedure, she experienced a partial improvement in her symptoms. However, six months later, she returned with a recurrence of symptoms (Figure 1). Upon further inquiry, she mentioned that her symptoms had recurred a month ago when she was dancing at a family party. Radiographs showed a stress fracture in her fibula and extensive AVNT. This diagnosis was confirmed through a CT scan, MRI, and bone scan (Figure 2).

Ankle-X-ray-six-months-after-arthroscopy
Figure 1: Ankle X-ray six months after arthroscopy

Pain had reduced for four months, then pain increased with activity and disabled her after a night of dancing. Subchondral fracture and fibular stress fracture are evident (A and B, respectively).

MRI,-CT-scan,-and-technetium-99m-(Tc-99m)-bone-scan
Figure 2: MRI, CT scan, and technetium-99m (Tc-99m) bone scan

Coronal MRI confirmed avascular necrosis of the talar dome with subchondral fracture (A and B, respectively). CT scan (C) and Tc-99 bone scan (D) images also revealed the pathologies.

In the second visit after arthroscopy, upon confirmation of a fibular stress fracture and significant subchondral collapse, and following a discussion of the next available options with the patient, the second procedure was performed as an ankle arthrodesis with an anterior approach. A 6 cm longitudinal incision was made anteriorly, and through the plane between the tibialis anterior and extensor hallucis longus, the ankle joint was accessed. Joint preparation was done with an osteotome, ensuring a bleeding surface on both sides. Then, manual compression with provisional pin fixation in the corrective position was performed. The fusion was planned at less than 5 degrees of valgus, 10 degrees of external rotation, and approximately 10 degrees of plantar flexion, suitable for the high-heeled shoes that she was using in her daily living activities. After confirming fluoroscopy in two planes, final 6.5 mm cannulated cancellous screws were used, and fixation was augmented with an anterior molded 4.5 mm narrow dynamic compression plate (DCP), according to our previously published anterior ankle fusion technique [13]. The foot was placed in a splint for 10 days, after which stitches were removed, and a cast was applied for four weeks. Then, walking with gradual, as-tolerated weight-bearing was initiated (Figure 3). Three months after surgery, she was pain-free, and by the sixth month, she could walk without any boot or brace, only using high-heeled shoes.

Post-operative-radiographies
Figure 3: Post-operative radiographies

Six months after the ankle surgery, a huge osteonecrosis and fibular stress fracture were managed with an acceptable, painless ankle fusion (not solid) despite the remaining necrosis (A and B, respectively). In 2024, four years after the tumor resection, complete healing of talus necrosis and solid fusion were achieved (C and D, respectively).

In 2020, two years after her ankle surgery, she was referred to an endocrinologist due to excessive weight gain and hirsutism. The biochemical assessment revealed the following: cortisol (8 AM) (chemiluminescence immunoassay (CLIA)) was 96 µg/dl (normal range: 4.82 – 19.5 µg/dl), and it was 22.1 µg/dl after overnight dexamethasone (normal range: < 1.8 µg/dl). Adrenocorticotropic hormone (ACTH) (CLIA) was 44.4 pg/ml (normal range: 7.2-63.3 pg/ml), and cortisol measured 5.7 µg/dl after the 48-hour low-dose dexamethasone suppression test (normal < 5 µg/dl). The results, along with symptoms (Table 1), are documented in the laboratory tests (Table 2). She was diagnosed with Cushing’s syndrome, which was subsequently confirmed as Cushing’s disease due to an ACTH-producing pituitary adenoma observed in the MRI and Brain CT (Figure 4).

Sign/symptom Severity
Weight Gain Severe
Hirsutism Severe
Hypertension Severe
Easy bruising Severe
Depression Severe
Moon face Moderate (masked with makeup)
Lethargy Moderate
Headache Moderate
Peripheral edema       _
Buffalo hump       _
Myopathy       _
Acne       _
Purple striae       _
Table 1: Cushing’s disease symptoms and signs

The hyphens in the table indicate that the patient does not have those symptoms or signs.

Laboratory test Result Reference range
Cortisol (8 AM) (CLIA) 96 µg/dl 4.82-19.5 µg/dl
Cortisol (8 AM) (after overnight dexamethasone) (CLIA) 22.1 µg/dl <1.8 µg/dl
ACTH (CLIA) 44.4 pg/ml 7.2-63.3 pg/ml
Cortisol after 48 hours of LDDST (CLIA) 5.7 µg/dl < 5 µg/dl
Table 2: Laboratory tests

CLIA: chemiluminescence immunoassay; ACTH: adrenocorticotropic hormone; LDDST: low-dose dexamethasone suppression test

Brain-MRI
Figure 4: Brain MRI

Finally, a pituitary adenoma was diagnosed using a Brain MRI as the cause of Cushing’s disease symptoms (A and B).

Finally, she underwent a tumor resection and had a dramatic response after treatment (30 kg weight loss). She revealed that she had Cushing’s syndrome symptoms since she was young. These symptoms included a puffy face, which she covered with makeup, high blood pressure, and hirsutism. In January 2024, four years after her brain surgery, during our last visit, her symptoms had significantly improved. She reported no problems with her ankle, and talus necrosis was completely healed, with a solid fusion achieved in radiographs (Figure 3).

Discussion

As far as we are aware, this case presentation represents the first instance of AVNT attributed to Cushing’s disease in the existing literature. Nevertheless, some individuals with endogenous Cushing’s syndrome have been reported to experience AVN of the femoral head [4-12].

Cushing’s syndrome is an uncommon endocrine condition marked by manifestations of hypercortisolism. The predominant cause is often an adenoma in the anterior pituitary gland that produces ACTH, referred to as Cushing’s disease [14]. The presentation of Cushing’s syndrome can vary significantly in both adults and children, influenced by the extent and duration of hypercortisolemia. However, the typical signs and symptoms of Cushing’s syndrome are widely known [15]. Although some individuals may perceive these alterations as normal and physiological, the disease can go unnoticed for an extended period, as in our case, in which it remained undiagnosed for more than 20 years.

However, it is known that steroid use is a significant contributing factor to the occurrence of bone osteonecrosis, accounting for up to 40% of non-traumatic instances of AVN [16]. The mechanisms leading to AVN due to either endogenous hypercortisolism or excess exogenous glucocorticoids are not completely understood. There are just some hypotheses that suggest that the hypertrophy of fat cells, embolization of fat, and osteocytes’ apoptosis result in impaired blood flow in the bone, ultimately causing ischemic tissue necrosis [17]. An alternative proposed theory suggests that elevated levels of glucocorticoids may cause insulin resistance and subsequently contribute to AVN [18].

Traditional X-rays often fail to detect the initial changes of AVN (as observed in our case). MRI stands as the preferred method for identifying AVN in its early phases, providing an opportunity for timely therapeutic interventions [19,20].

In an analysis of 321 cases of AVNT, the predominant treatment modalities included conservative therapies (n = 104), hindfoot fusion (n = 62), and core decompression (n = 85) [21]. These approaches reflect the primary methods employed in contemporary clinical practice for addressing AVNT.

After all, we confirmed the AVNT diagnosis using MRI and bone scan and managed it with hindfoot fusion. Subsequently, the underlying issue, endogenous hypercortisolism due to an ACTH-producing pituitary adenoma, was identified and treated through resection of the tumor (Figure 5).

Case-report-timeline
Figure 5: Case report timeline

* Avascular necrosis in the talus

Conclusions

Cushing’s syndrome is a rare endocrine disorder characterized by excessive cortisol levels, commonly caused by an ACTH-producing adenoma in the pituitary gland, known as Cushing’s disease. Cushing’s disease may be one of the rare causes of AVNT. To the best of our knowledge, this is the first instance of AVNT due to Cushing’s disease described in the literature. Since atraumatic AVNT is rare in itself, a multidisciplinary approach can lead us to a more rapid and proper diagnosis, as each symptom may be masked or considered rare within its subspecialty field.

References

  1. Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum. 1993, 23:47-69. 10.1016/s0049-0172(05)80026-5
  2. Zhang H, Fletcher AN, Scott DJ, Nunley J: Avascular osteonecrosis of the talus: current treatment strategies. Foot Ankle Int. 2022, 43:291-302. 10.1177/10711007211051013
  3. Parekh SG, Kadakia RJ: Avascular necrosis of the talus. J Am Acad Orthop Surg. 2021, 29:e267-78. 10.5435/JAAOS-D-20-00418
  4. Belmahi N, Boujraf S, Larwanou MM, El Ouahabi H: Avascular necrosis of the femoral head: an exceptional complication of Cushing’s disease. Ann Afr Med. 2018, 17:225-7. 10.4103/aam.aam_75_17
  5. Salazar D, Esteves C, Ferreira MJ, Pedro J, Pimenta T, Portugal R, Carvalho 😧 Avascular femoral necrosis as part of Cushing syndrome presentation: a case report. J Med Case Rep. 2021, 15:287. 10.1186/s13256-021-02882-7
  6. Alaya Z, Braham M, Bouajina E: Aseptic femur head necrosis revealing Cushing’s disease: a rare presentation. J Clin Surg Res. 2020, 1:10.31579/2768-2757/002
  7. Phillips KA, Nance EP Jr, Rodriguez RM, Kaye JJ: Avascular necrosis of bone: a manifestation of Cushing’s disease. South Med J. 1986, 79:825-9. 10.1097/00007611-198607000-00011
  8. Koch CA, Tsigos C, Patronas NJ, Papanicolaou DA: Cushing’s disease presenting with avascular necrosis of the hip: an orthopedic emergency. J Clin Endocrinol Metab. 1999, 84:3010-2. 10.1210/jcem.84.9.5992
  9. Modroño N, Torán CE, Pavón I, Benza ME, Guijarro G, Navea 😄 Cushinǵs syndrome and avascular hip necrosis: presentation of two patients [Article in Spanish]. Rev Clin Esp (Barc). 2014, 214:e93-6. 10.1016/j.rce.2014.05.003
  10. Camporro F, Bulacio E, Gutiérrez Magaldi I: Bilateral osteonecrosis of the hip secondary to endogenous Cushing’s syndrome due to a recently-diagnosed carcinoid tumour of the lung [Article in Spanish]. Med Clin (Barc). 2016, 147:228. 10.1016/j.medcli.2016.03.042
  11. Ha JS, Cho HM, Lee HJ, Kim SD: Bilateral avascular necrosis of the femoral head in a patient with asymptomatic adrenal incidentaloma. Hip Pelvis. 2019, 31:120-3. 10.5371/hp.2019.31.2.120
  12. Anand A, Jha CK, Singh PK, Sinha U, Ganesh A, Bhadani PP: Avascular necrosis of femur as a complication of Cushing’s syndrome due to adrenocortical carcinoma. Am Surg. 2023, 89:2701-4. 10.1177/00031348221129510
  13. Gharehdaghi M, Rahimi H, Mousavian A: Anterior ankle arthrodesis with molded plate: technique and outcomes. Arch Bone Jt Surg. 2014, 2:203-9.
  14. Lindholm J, Juul S, Jørgensen JO, et al.: Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001, 86:117-23. 10.1210/jcem.86.1.7093
  15. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  16. Konarski W, Poboży T, Konarska K, Śliwczyński A, Kotela I, Hordowicz M, Krakowiak J: Osteonecrosis related to steroid and alcohol use-an update on pathogenesis. Healthcare (Basel). 2023, 11:1846. 10.3390/healthcare11131846
  17. Chan KL, Mok CC: Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Orthop J. 2012, 6:449-57. 10.2174/1874325001206010449
  18. Hartmann K, Koenen M, Schauer S, Wittig-Blaich S, Ahmad M, Baschant U, Tuckermann JP: Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev. 2016, 96:409-47. 10.1152/physrev.00011.2015
  19. Kaste SC, Karimova EJ, Neel MD: Osteonecrosis in children after therapy for malignancy. AJR Am J Roentgenol. 2011, 196:1011-8. 10.2214/AJR.10.6073
  20. Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA: Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med. 2015, 8:221-7. 10.1007/s12178-015-9279-6
  21. Gross CE, Haughom B, Chahal J, Holmes GB Jr: Treatments for avascular necrosis of the talus: a systematic review. Foot Ankle Spec. 2014, 7:387-97. 10.1177/1938640014521831

From https://www.cureus.com/articles/221491-talus-avascular-necrosis-as-a-rare-complication-of-cushings-disease-a-case-report?score_article=true#!/

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Olfactory Neuroblastoma Causing Cushing’s Syndrome Due to the Ectopic Adrenocorticotropic Hormone (ACTH) Secretion

Posted on March 27, 2024 by MaryO

Abstract

Cushing’s syndrome is a constellation of features occurring due to high blood cortisol levels. We report a case of a 47-year-old male with a history of recurrent olfactory neuroblastoma (ONB). He presented with bilateral lower limb weakness and anosmia and was found to have Cushing’s syndrome due to high adrenocorticotropic hormone (ACTH) levels from an ectopic source, ONB in this case. Serum cortisol and ACTH levels declined after tumor removal.

Introduction

Olfactory neuroblastoma (ONB), or esthesioneuroblastoma, is a rare malignancy arising from neuroepithelium in the upper nasal cavity. It represents approximately 2% of all nasal passage tumors, with an incidence of approximately 0.4 per 2.5 million individuals [1]. ONB shares similar histological features with small round blue cell neoplasms of the nose. Ectopic hormone secretion is a very rare feature associated with these tumors. Five-year overall survival is reported to be between 60% and 80% [2,3]. The age distribution is either in the fifth to sixth decade of life [4,5], or in the second and sixth decades [6].

Features of Cushing’s syndrome (moon face, buffalo hump, central obesity hypertension, fragile skin, easy bruising, fatigue, muscle weakness) are due to high blood cortisol levels [7]. It can be either primary (cortisol-secreting adrenal tumor), secondary (adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, also called Cushing disease), or ectopic ACTH secretion (from a non-pituitary source). All three types share similar features [8].

Ectopic ACTH syndrome (EAS) is due to an extra pituitary tumor, producing ACTH. It accounts for 12-17% of Cushing’s syndrome cases [9]. Most cases of EAS-producing tumors are in the lungs, mediastinum, neuroendocrine tumors of the gastrointestinal tract, and pheochromocytomas [9]. Ectopic ACTH secretion from an ONB is very rare. As of 2015, only 18 cases were reported in the literature [10]. Here, we report such a case.

Case Presentation

Our patient is a 47-year-old Bangladeshi male, with a history of recurrent ONB that was resected twice in the past (transsphenoidal resection in 2016 and 2019) with adjuvant radiotherapy, no chemotherapy was given. He also had diabetes mellitus type 1 (poorly controlled) and hypertension. He presented with bilateral lower limb weakness, anosmia, decreased oral intake, loss of taste for one week, and bilateral submandibular swelling that increased in size gradually over the past two years. There was no history of fever, cough, abdominal pain, or exposure to sick contacts. The patient reported past episodes of similar symptoms, but details are unclear. The patient’s family history is positive for diabetes mellitus type 1 in both parents. Lab tests in the emergency department showed hypokalemia and hyperglycemia as detailed in Table 1. He was admitted for further workup of the above complaints.

Test Patient Results Reference Range Unit Status
Hemoglobin 14.7 13-17 g/dL Normal
White blood cell (WBC) 17.9 4-10 10*9/L High
Neutrophils 15.89 2-7 10*9/L High
Lymphocytes 1.07 1-3 10*9/L Normal
Sodium 141 136-145 mmol/L Normal
Potassium 2.49 3.5-5.1 mmol/L Low (Panic)
Chloride 95 98-107 mmol/L Low
Glucose 6.52 4.11-5.89 mmol/L Elevated
C-reactive protein (CRP) 0.64 Less than 5 mg/L Normal
Erythrocyte sedimentation rate (ESR) 2 0-30 mm/h Normal
Creatinine 73 62-106 µmol/L Normal
Uric acid 197 202.3-416.5 µmol/L Normal
Alanine aminotransferase (ALT) 33.2 0-41 U/L Normal
Aspartate aminotransferase (AST) 18.6 0-40 U/L Normal
International Normalised Ratio (INR) 1.21 0.8-1.2 sec High
Prothrombin time (PT) 15.7 12.3-14.7 sec High
Lactate dehydrogenase (LDH) 491 135-225 U/L High
Thyroid-stimulating hormone (TSH) 0.222 0.27-4.20 mIU/L Low
Adrenocorticotropic hormone (ACTH) 106 ≤50 ng/L Elevated
Cortisol (after dexamethasone suppression) 1750 Morning hours (6-10 am): 172-497 nmol, Afternoon hours (4-8 pm): 74.1-286 nmol nmol/L Elevated (failure of suppression)
24-hour urine cortisol (after dexamethasone suppression) 5959.1 <120 nmol/24 hrs nmol/24hr Elevated (failure of suppression)
Table 1: Results of blood test at the time of hospitalization. Hypokalemia and high values of adrenocorticotropic hormone and cortisol were confirmed.

On examination, the patient’s vital signs were as follows: blood pressure was 154/77 mmHg, heart rate of 60 beats per minute, respiratory rate was 18 breaths per minute, oxygen saturation of 98% on room air, and a temperature of 36.7°C. The patient had a typical Cushingoid appearance with a moon face, buffalo hump, purple striae on the abdomen, central obesity, and hyperpigmentation of the skin. Submandibular lymph nodes were enlarged bilaterally. The examination of the submandibular lymph nodes showed a firm, fixed mass extending from the angle of the mandible to the submental space on the left side. Neurological examination showed weakness in both legs bilaterally (strength 3/5) and anosmia (checked by orthonasal smell test). The rest of the neurological exam was normal.

Laboratory findings revealed (in Table 1) a marked hypokalemia of 2.49 mmol/L and hyperglycemia of 6.52 mmol/L. The serum cortisol level was elevated at 1587 nmol/L. Serum ACTH levels were raised at 106 ng/L (normal value ≤50 ng/L). Moreover, the high-dose dexamethasone suppression test failed to lower the serum ACTH levels and serum and urine cortisol. Serum cortisol level after the suppression test was 1750 nmol/L, while 24-hour urine cortisol after the test was 5959.1 nmol/24hr. Serum ACTH levels after the test also remained high at 100mg/L. This indicated failure of ACTH suppression by high-dose dexamethasone, which points towards ectopic ACTH production. Other blood tests (complete blood count, liver function tests) were insignificant.

A computed tomography scan with contrast (CT scan) of the chest, abdomen, and pelvis, with a special focus on the adrenals, was negative for any malignancy or masses. CT scan of the neck showed bilaterally enlarged submandibular lymph nodes and an enlarged right lobe of the thyroid with nodules. Fine needle aspiration (FNA) of the thyroid nodules revealed a benign nature. Magnetic resonance imaging (MRI) of the brain showed a contrast-enhancing soft tissue lesion (18x18x10mm) in the midline olfactory groove area with extension into the frontal dura and superior sagittal sinus, suggesting recurrence of the previous ONB. There was evidence of previous surgery also. The pituitary gland was normal (Figures 1–2).

A-brain-MRI-(T1-weighted;-without-contrast;-sagittal-plane)-shows-a-soft-tissue-lesion-located-in-the-midline-olfactory-groove-area.-Dural-surface-with-extension-into-anterior-frontal-dura.
Figure 1: A brain MRI (T1-weighted; without contrast; sagittal plane) shows a soft tissue lesion located in the midline olfactory groove area. Dural surface with extension into anterior frontal dura.

MRI: Magnetic resonance imaging

A-brain-MRI-(T2-weighted;-without-contrast;-axial-plane)-shows-a-soft-tissue-lesion-located-in-the-midline-olfactory-groove-area.
Figure 2: A brain MRI (T2-weighted; without contrast; axial plane) shows a soft tissue lesion located in the midline olfactory groove area.

MRI: Magnetic resonance imaging

Octreotide scintigraphy showed three focal abnormal uptakes in the submandibular cervical nodes. Additionally, there was a moderate abnormal uptake at the midline olfactory groove with bilateral extension (Figure 3).

Whole-body-octreotide-scan-(15-mCi-99mTc-Octreotide-IV)-demonstrates-three-focal-abnormal-uptakes:-the-largest-(5.2-x-2.4-cm)-in-the-left-submandibular-region,-and-two-smaller-ones-on-the-right,-suggestive-of-lymph-node-uptake.-Additional-abnormal-uptake-was-seen-along-the-midline-of-the-olfactory-groove-region-with-bilateral-extension.-No-other-significant-abnormal-uptake-was-identified.
Figure 3: Whole-body octreotide scan (15 mCi 99mTc-Octreotide IV) demonstrates three focal abnormal uptakes: the largest (5.2 x 2.4 cm) in the left submandibular region, and two smaller ones on the right, suggestive of lymph node uptake. Additional abnormal uptake was seen along the midline of the olfactory groove region with bilateral extension. No other significant abnormal uptake was identified.

On microscopic examination, an excisional biopsy after the transcranial resection surgery of the frontal skull base tumor showed nests and lobules of round to oval cells with clear cytoplasm, separated by vascular and hyalinized fibrous stroma (Figures 4A–4B). Tumor cells show mild to moderate nuclear pleomorphism, and fine chromatin (Figure 4C). A fibrillary neural matrix is also present. Some mitotic figures can be seen. Immunohistochemical stains revealed positive staining for synaptophysin (Figure 4D) and chromogranin (Figure 4E). Stains for CK (AE1/AE3), CD45, Desmin, and Myogenin are negative. Immunostaining for ACTH was focally positive (Figure 4F), while the specimen of the cervical lymph nodes showed the same staining, indicating metastases. The cytomorphologic and immunophenotypic features observed are consistent with a Hyams grade II ONB, with ectopic ACTH production.

Histopathological-and-immunohistochemical-findings-of-olfactory-neuroblastoma.
Figure 4: Histopathological and immunohistochemical findings of olfactory neuroblastoma.

A (100x magnification) and B (200x magnification) – hematoxylin and eosin (H-E) staining shows cellular nests of round blue cells separated by hyalinized stroma. C (400x magnification) – nuclei show mild to moderate pleomorphism with fine chromatin. D (100x magnification) – an immunohistochemical stain for synaptophysin shows diffuse, strong cytoplasmic positivity within tumor cells. E (200x magnification) – tumor cells are positive for chromogranin. F (400x magnification) – ACTH cytoplasmic expression in tumor cells.

ACTH: adrenocorticotropic hormone

For his resistant hypokalemia, he had to be given intravenous (IV) and oral potassium chloride (KCL) repeatedly. The patient underwent transcranial resection of the frontal skull base tumor. The patient received cefazolin for seven days, and hydrocortisone for four days. After transcranial resection, his cortisol level decreased to 700 nmol/L. Furthermore, ACTH dropped, and serum potassium also normalized. Subsequently, the patient was transferred to the intensive care unit (ICU) for meticulous monitoring and continued care. In the ICU, the patient developed one episode of a generalized tonic-clonic seizure, which aborted spontaneously, and the patient received phenytoin and levetiracetam to prevent other episodes. A right-sided internal jugular vein and left transverse sinus thrombosis were also developed and treated with enoxaparin sodium. Following surgery, his low potassium levels improved, resulting in an improvement in his limb weakness. His other symptoms also gradually improved after surgery. Three weeks following the primary tumor resection, he underwent bilateral neck dissection with right hemithyroidectomy, for removal of the metastases. The patient opted out of chemotherapy and planned for an international transfer to his home country for further management. Other treatments that he received during hospitalization were ceftriaxone, azithromycin, and Augmentin®. Insulin was used to manage his diabetes, perindopril to regulate his blood pressure, and spironolactone to increase potassium retention. Omeprazole was administered to prevent GI bleeding and heartburn/gastroesophageal reflux disease relief after discharge.

Discussion

ONB was first described in 1924, and it is a rare neuroectodermal tumor that accounts for 2% of tumors affecting the nasal cavity [11]. Even though ONB has a good survival rate, long-term follow-up is necessary due to the disease’s high recurrence rate [2]. ONB recurrence has been approximated to range between 30% and 60% after successful treatment of the primary tumor [12]. Recurrent disease is usually locoregional and tends to have a long interval to relapse with a mean of six years [12]. The first reported case of ectopic ACTH syndrome caused by ONB was in 1987 by M Reznik et al., who reported a 48-year-old woman with ONB who developed a Cushing-like syndrome 28 months before her death [13].

The occurrence of Cushing’s syndrome due to ectopic ACTH can occur either in the initial tumor or even years later during its course or after recurrence [3,6,9,14]. Similar to the case of Abe et al. [3], our patient also presented with muscle weakness due to hypokalemia, which is a feature of Cushing’s syndrome. Hypokalemia is present at diagnosis in 64% to 86% of cases of EAS and is resistant to treatment [9,14], as seen in our case. In our patient, the exact time of development of Cushing’s syndrome could not be ascertained due to the non-availability of previous records. However, according to the patient, he started developing abdominal obesity, pigmentation, and buffalo hump in 2021 about two years after his second surgery for ONB.

The distinction between pituitary ACTH and ectopic ACTH involves utilizing CT/MRI of the pituitary, corticotropin-releasing hormone (CRH) stimulation test with petrosal sinus blood sampling, high dose dexamethasone suppression test, and checking serum K+ (more commonly low in ectopic ACTH) [2,15,16]. In our case, a CRH stimulation test was not available but CT/MRI brain, dexamethasone test, low serum potassium, plus the postoperative fall in cortisol levels, all pointed towards an ectopic ACTH source.

Conclusions

In conclusion, this case highlights the rare association between ONB and ectopic ACTH syndrome, which developed after tumor recurrence. The patient’s unique presentation of bilateral lower limb weakness and hypokalemia can cause diagnostic challenges, emphasizing the need for comprehensive diagnostic measures. Surgical intervention proved crucial, with postoperative cortisol values becoming normal, highlighting the efficacy of this approach. The occurrence of ectopic ACTH production in ONB patients, although very rare, is emphasized, so that healthcare professionals who deal with these tumors are aware of this complication. This report contributes valuable insights shedding light on the unique ONB manifestation causing ectopic ACTH syndrome. The ongoing monitoring of the patient’s clinical features will further enrich the understanding of the course of this uncommon phenomenon in the medical literature.

References

  1. Thompson LD: Olfactory neuroblastoma. Head Neck Pathol. 2009, 3:252-9. 10.1007/s12105-009-0125-2
  2. Abdelmeguid AS: Olfactory neuroblastoma. Curr Oncol Rep. 2018, 20:7. 10.1007/s11912-018-0661-6
  3. Abe H, Suwanai H, Kambara N, et al.: A rare case of ectopic adrenocorticotropic hormone syndrome with recurrent olfactory neuroblastoma. Intern Med. 2021, 60:105-9. 10.2169/internalmedicine.2897-19
  4. Yin Z, Wang Y, Wu Y, et al.: Age distribution and age-related outcomes of olfactory neuroblastoma: a population-based analysis. Cancer Manag Res. 2018, 10:1359-64. 10.2147/CMAR.S151945
  5. Platek ME, Merzianu M, Mashtare TL, Popat SR, Rigual NR, Warren GW, Singh AK: Improved survival following surgery and radiation therapy for olfactory neuroblastoma: analysis of the SEER database. Radiat Oncol. 2011, 6:41. 10.1186/1748-717X-6-41
  6. Elkon D, Hightower SI, Lim ML, Cantrell RW, Constable WC: Esthesioneuroblastoma. Cancer. 1979, 44:3-1087. 10.1002/1097-0142(197909)44:3<1087::aid-cncr2820440343>3.0.co;2-a
  7. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  8. Chabre O: Cushing syndrome: physiopathology, etiology and principles of therapy [Article in French]. Presse Med. 2014, 43:376-92. 10.1016/j.lpm.2014.02.001
  9. Isidori AM, Lenzi A: Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol. 2007, 51:1217-25. 10.1590/s0004-27302007000800007
  10. Kunc M, Gabrych A, Czapiewski P, Sworczak K: Paraneoplastic syndromes in olfactory neuroblastoma. Contemp Oncol (Pozn). 2015, 19:6-16. 10.5114/wo.2015.46283
  11. Finlay JB, Abi Hachem R, Jang DW, Osazuwa-Peters N, Goldstein BJ: Deconstructing olfactory epithelium developmental pathways in olfactory neuroblastoma. Cancer Res Commun. 2023, 3:980-90. 10.1158/2767-9764.CRC-23-0013
  12. Ni G, Pinheiro-Neto CD, Iyoha E, et al.: Recurrent esthesioneuroblastoma: long-term outcomes of salvage therapy. Cancers (Basel). 2023, 15:1506. 10.3390/cancers15051506
  13. Reznik M, Melon J, Lambricht M, Kaschten B, Beckers A: Neuroendocrine tumor of the nasal cavity (esthesioneuroblastoma). Apropos of a case with paraneoplastic Cushing’s syndrome [Article in French]. Ann Pathol. 1987, 7:137-42.
  14. Kadoya M, Kurajoh M, Miyoshi A, et al.: Ectopic adrenocorticotropic hormone syndrome associated with olfactory neuroblastoma: acquirement of adrenocorticotropic hormone expression during disease course as shown by serial immunohistochemistry examinations. J Int Med Res. 2018, 46:4760-8. 10.1177/0300060517754026
  15. Clotman K, Twickler MTB, Dirinck E, et al.: An endocrine picture in disguise: a progressive olfactory neuroblastoma complicated with ectopic Cushing syndrome. AACE Clin Case Rep. 2017, 3:278-83. 10.4158/EP161729.CR
  16. Chung YS, Na M, Ku CR, Kim SH, Kim EH: Adrenocorticotropic hormone-secreting esthesioneuroblastoma with ectopic Cushing’s syndrome. Yonsei Med J. 2020, 61:257-61. 10.3349/ymj.2020.61.3.257

From https://www.cureus.com/articles/226080-olfactory-neuroblastoma-causing-cushings-syndrome-due-to-the-ectopic-adrenocorticotropic-hormone-acth-secretion-a-case-report?score_article=true#!/

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Violaceous Abdominal Striae Noted on Physical Examination: A Clue to the Diagnosis of Cushing’s Syndrome

Posted on March 21, 2024 by MaryO

This article costs $70 to buy :(  https://doi.org/10.1136/bcr-2024-259687

Doctors should suspect Cushing’s syndrome when they see patients with purple stretch marks and metabolic conditions such as diabetes, even if those symptoms aren’t the reasons for a medical visit, physicians in Japan wrote in a case study describing how they reached that diagnosis for a woman in her early 30s.

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