Rare Challenges in Diagnosing Cushing’s Syndrome and Primary Aldosteronism: A Case Report of a Female With a Negative Workup

Posted on September 18, 2023 by MaryO

Abstract

Cushing’s syndrome with concurrent primary aldosteronism (PA) is a rare presentation, and establishing an early diagnosis is imperative to preventing morbidity and long-term sequelae. The diagnosis is established by sequential lab work, showing an elevated cortisol and aldosterone level.

Taking the above into consideration, it is evident that repeatedly negative results on all three tests can present an extremely challenging case. In this report, we discuss a female who presented with an adrenal incidentaloma and features suggestive of primary hyperaldosteronism as well as Cushing’s syndrome but no elevations in serum, urine, or salivary cortisol.

In this study, we present a 37-year-old female with resistant hypertension and tachycardia. She had several features suggestive of Cushing’s syndrome including resistant hypertension, proximal muscle weakness, weight gain, easy bruising, hair loss, and a history of tachycardia and chest pain. Examination revealed an obese female with thin silvery abdominal striae. The patient’s labs revealed normal serum cortisol, urine-free cortisol (UFC), late-night salivary cortisol, and a normal dexamethasone suppression test. An abdominal computed tomography (CT) scan revealed a right adrenal mass measuring 2.1 x 1.5 x 2.5 cm. Due to a high index of suspicion, adrenal venous sampling was performed, which revealed high levels of cortisol and aldosterone in the right vein, confirming the diagnosis. The patient subsequently underwent a right adrenalectomy. She developed hypotension post-op, leading to the diagnosis of glucocorticoid-remediable aldosteronism.

Introduction

Primary aldosteronism (PA) is the excess production of aldosterone by the adrenal glands, despite a low serum renin level. The presentation of hyperaldosteronism can be vague and include symptoms such as muscle weakness, fatigue, headaches, numbness, and cramps. More specific findings include resistant hypertension, low serum potassium, and metabolic alkalosis. The etiologies are variable and can include an adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia [1].

Cushing’s syndrome is also caused by excess hormone secretion by the adrenal glands. The etiologies include a primary adrenal adenoma, hyperplasia, carcinoma, or exogenous corticosteroid use. It can also be caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma or as a result of paraneoplastic ACTH secretion. The clinical presentation is highly variable and leads to difficulties in establishing a diagnosis.

The concurrent existence of primary hyperaldosteronism and Cushing’s syndrome creates additional hindrances in diagnosis, yet further obscured in a patient with a repeatedly negative workup for both conditions.

Case Presentation

A 37-year-old female presented to her primary care physician with complaints of proximal muscle weakness, tachycardia, and chest pain. Repeated blood pressure readings revealed that she was hypertensive, and she was started on amlodipine and benazepril, which elevated her blood pressure further. A computed tomography (CT) scan (Figure 1) of the abdomen was performed due to resistant hypertension, which revealed an adrenal incidentaloma (right adrenal gland measuring 2.1 x 1.5 x 2.5 cm). Precontract density was 5 Hounsfield units, and a 15-minute delayed washout showed 11 Hounsfield units for a 72% washout. She was thus referred to endocrinology.

Abdominal-CT-scan-showing-a-nodule-in-the-right-adrenal-gland-measuring-2.1-x-1.5-x-2.5-cm
Figure 1: Abdominal CT scan showing a nodule in the right adrenal gland measuring 2.1 x 1.5 x 2.5 cm

She presented to the endocrinology clinic on March 12, 2021. A thorough physical examination was performed, which revealed a well-appearing obese female (BMI of 38.86 kg/m2) with no acute distress. Her blood pressure was 144/108 mmHg, her pulse was 95, and she was afebrile. Thin silvery striations were present on the abdomen, and alopecia was present on the crown. A review of all other systems was unremarkable. A detailed family history revealed early-onset hypertension in her brother (age: 35 years) and her mother (age: 30 years). Personal history included elevated anxiety, weight gain, headaches (frontal band distribution), increased thirst, easy bruising as well as delayed clearance of bruises, and proximal muscle weakness presenting as difficulty in climbing stairs and inability to lift heavy objects. She reported no change in menstrual cycles. There was no history of exogenous corticosteroid use.

Serum biochemistries were sent (Table 1), which showed normal levels of thyroid stimulating hormone (TSH), creatinine, liver function tests, and serum electrolytes. However, mildly elevated aldosterone (23 ng/dl), mild hypokalemia (3.3 mEq/L), and suppressed ACTH and dehydroepiandrosterone (DHEA) sulfate were discovered. The aldosterone to renin ratio was also elevated at 59.9 on spironolactone and was 71.4 three months later when spironolactone was discontinued. These findings lead to a preliminary diagnosis of primary hyperaldosteronism.

Test Result
Calcium 9.1 mmol/L
Sodium 137 mmol/L
Potassium 4.1 mmol/L
Chloride 106 mmol/L
CO2 27
BUN 15 mmol/L
Glucose 95 mmol/L
Creatinine 1.1 μmol/L
AST 24 U/L
ALT 20 U/L
Albumin 4.4 g/L
Total protein 7.0 g/L
Total bilirubin 0.4 μmol/L
Alkaline phosphatase 40 U/L
Renin 0.44
Table 1: Patient serum biochemistries

BUN: Blood urea nitrogen; AST: Aspartate transaminase; ALT: Alanine transaminase.

A workup for elevated cortisol was also performed as the patient was phenotypically Cushingoid, and the following biochemistries were sent sequentially: serum cortisol, 24-hour urine-free cortisol (UFC), salivary cortisol, and a low-dose dexamethasone suppression test (Table 2). The bloodwork was hence nonconfirmatory.

Endocrine workup
Serum cortisol 4.5 mcg/dL
Urine-free cortisol 1.57 g/24 h
Salivary cortisol <0.03 μg/dL
Dexamethasone suppression test 1.5 mcg/dL
Aldosterone <4.0
Table 2: Patient follow-up bloodwork

Despite a repeatedly negative workup for Cushing’s syndrome, adrenal venous sampling was performed due to a high index of suspicion. The results revealed an inferior vena cava (IVC) cortisol of 20, left adrenal venous (LAV) cortisol of 81, and right adrenal vein (RAV) cortisol of 1280. The results of the IVC aldosterone were 24, LAV aldosterone was 660 and RAV aldosterone was 1500. The elevated levels of cortisol in the RAV were in complete contradiction to the aforementioned workup. A diagnosis of Cushing’s syndrome and concurrent PA was determined.

Adrenal veinous sampling was instrumental in establishing the diagnosis but was equivocal and did not lateralize aldosterone and cortisol excess. However, the amount of aldosterone and cortisol were both significantly higher on the right side. After a panel discussion with doctors from several disciplines, a laparoscopic adrenalectomy was planned. The procedure was successful, and the patient was initially showing clinical improvement. The specimen was sent for pathological evaluation and revealed an adrenal cortical adenoma.

After initial improvement, the patient developed hypotension, which was likely due to adrenal insufficiency. The patient was supplemented with 1-mg dexamethasone tablets, which stabilized her condition, and a diagnosis of glucocorticoid-remediable-aldosteronism was made.

Based on a strong family history of early onset-resistant hypertension, a genetic component was suspected. Several genes associated with PA with autosomal dominant inheritance have been identified [2], such as CYP11B2, CLCN2, KCNJ5, CACNA1D, and CACNA1H. The patient was offered genetic testing but was unable to follow through due to financial reasons.

Discussion

This patient presented as an extremely rare example of PA and Cushing’s syndrome, with negative serum cortisol, 24-hour UFC, late-night salivary cortisol, and a dexamethasone suppression test. Despite repeatedly negative lab results, the patient presented with a markedly elevated cortisol on adrenal venous sampling. In our literature search, we found an instance of a patient with several negative UFCs [3]; however, to the best of our knowledge, there have been no reported instances of a completely negative workup in a patient who is positive for Cushing’s syndrome. In fact, in the practice guidelines published by the Journal of Clinical Endocrinology & Metabolism [4], it is recommended that patients with a suspected diagnosis of Cushing’s syndrome or an adrenal incidentaloma and two concordant negative test results need not undergo further investigations.

One proposed mechanism for the misleading workup could be assay interference. Interference occurs when a substance or process falsely alters an assay result [5]. This can lead to incorrect diagnosis and subsequent treatment and poses a threat to the patient. Another suggested mechanism causing false negative test results could be the hook effect [6]. The hook effect is described as a phenomenon that leads to falsely low results due to the presence of excessive analyte.

In a study by Friedman et al. [7], it was noted that patients with “episodic Cushing’s syndrome” or those with mild symptoms had a negative workup. The study recommended serial monitoring for the disease. The interesting fact is that our patient had several features suggestive of active Cushing’s syndrome, and the hypotension seen postoperatively was a testament to the fact that there was in fact a cortisol excess, which led to adrenal insufficiency. In light of the above, a consistently negative workup is perplexing.

Zhang et al. suggested performing a low-dose dexamethasone suppression test in individuals presenting with PA, prior to adrenal vein sampling (AVS) and surgery due to the high prevalence of Cushing’s syndrome in patients with PA [8]. A positive test result can lead to a straightforward diagnosis; however, in this rare case where the patient had severe negative tests, it can present as a challenge in diagnosis and treatment.

Conclusions

The presence of PA and concurrent Cushing’s syndrome can present as a diagnostic challenge. It is recommended to follow up on the signs of Cushing’s syndrome with preliminary tests and to presume its absence if two concordant tests are negative. Our patient, however, was an exceptional case.

This case highlighted the importance of maintaining a high index of suspicion for patients presenting with several signs and symptoms of the disease and a negative workup. More attention should be paid to the patient’s history, and a thorough physical examination should be conducted. In those with an uncertain diagnosis, adrenal venous sampling can provide a clearer picture and lead to a more accurate understanding of the case.

References

  1. Reincke M, Bancos I, Mulatero P, Scholl UI, Stowasser M, Williams TA: Diagnosis and treatment of primary aldosteronism. Lancet Diabetes Endocrinol. 2021, 9:876-92. 10.1016/S2213-8587(21)00210-2
  2. Dutta RK, Söderkvist P, Gimm O: Genetics of primary hyperaldosteronism. Endocr Relat Cancer. 2016, 23:R437-54. 10.1530/ERC-16-0055
  3. Moloney KJ, Mercado JU, Ludlam WH, Broyles FE: Diagnosis of Cushing’s disease in a patient with consistently normal urinary free cortisol levels: a case report. Clin Case Rep. 2016, 4:1181-3. 10.1002/ccr3.647
  4. 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
  5. Dimeski G: Interference testing. Clin Biochem Rev. 2008, 29:S43-8.
  6. The hook effect. (2014). Accessed: June 19, 2023: https://www.aacc.org/science-and-research/clinical-chemistry-trainee-council/trainee-council-in-english/pearls-of-lab….
  7. Friedman TC, Ghods DE, Shahinian HK, et al.: High prevalence of normal tests assessing hypercortisolism in subjects with mild and episodic Cushing’s syndrome suggests that the paradigm for diagnosis and exclusion of Cushing’s syndrome requires multiple testing. Horm Metab Res. 2010, 42:874-81. 10.1055/s-0030-1263128
  8. Zhang Y, Tan J, Yang Q, et al.: Primary aldosteronism concurrent with subclinical Cushing’s syndrome: a case report and review of the literature. J Med Case Rep. 2020, 14:32. 10.1186/s13256-020-2353-8

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Unique Gene Expression Signature in Periadrenal Adipose Tissue Identifies a High Blood Pressure Group in Patients With Cushing Syndrome

Posted on September 13, 2023 by MaryO

Abstract

Background:

Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of periadrenal adipose tissue in response to cortisol excess impact systemic blood pressure levels in patients with CS.

Methods:

We investigated gene expression signatures in periadrenal adipose tissue from patients with adrenal CS collected during adrenal surgery.

Results:

During active CS we observed a downregulation of gene programs associated with inflammation in periadrenal adipose tissue. In addition, we observed a clustering of the patients based on tissue gene expression profiles into 2 groups according to blood pressure levels (CS low blood pressure and CS high blood pressure). The 2 clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system. Renin was the strongest regulated gene compared with control patients and its expression correlated with increased blood pressure observed in our patients with CS. In the CS high blood pressure group, systemic renin plasma levels were suppressed indicative of an abnormal blood pressure associated with periadrenal adipose tissue renin-angiotensin-aldosterone-system activation.

Conclusions:

Here, we show for the first time a relevant association of the local renin-angiotensin-aldosterone-system and systemic blood pressure levels in patients with CS. Patients from the CS high blood pressure group still had increased blood pressure levels after 6 months in remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.

Footnotes

*U. Stifel and F. Vogel contributed equally.

For Sources of Funding and Disclosures, see page xxx.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.123.21185.

Correspondence to: Martin Reincke, Department of Medicine IV, University Hospital, LMU Munich, GermanyEmail martin.reincke@med.uni-muenchen.de
Jan Tuckermann, Institute of Comparative Molecular Endocrinology (CME), Ulm University, GermanyEmail jan.tuckermann@uni-ulm.de

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From https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.21185

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Severe McCune–Albright Syndrome Presenting with Neonatal Cushing Syndrome: Navigating Through Clinical Obstacles

Posted on August 25, 2023 by MaryO

Background: Café-au-lait skin macules, Cushing syndrome (CS), hyperthyroidism, and liver and cardiac dysfunction are presenting features of neonatal McCune–Albright syndrome (MAS), CS being the rarest endocrine feature. Although spontaneous resolution of hypercortisolism has been reported, outcome is usually unfavorable. While a unified approach to diagnosis, treatment, and follow-up is lacking, herein successful treatment and long-term follow-up of a rare case is presented.

Clinical case: An 11-day-old girl born small for gestational age presented with deterioration of well-being and weight loss. Large hyperpigmented macules on the trunk, hypertension, hyponatremia, hyperglycemia, and elevated liver enzymes were noted. ACTH-independent CS due to MAS was diagnosed. Although metyrapone (300 mg/m2/day) was started on the 25th day, complete remission could not be achieved despite increasing the dose up to 1,850 mg/m2/day. At 9 months, right total and left three-quarters adrenalectomy was performed. Cortisol decreased substantially, ACTH remained suppressed, rapid tapering of hydrocortisone to physiological dose was not tolerated, and supraphysiological doses were required for 2 months. GNAS analysis from the adrenal tissue showed a pathogenic heterozygous mutation. During 34 months of follow-up, in addition to CS due to MAS, fibrous dysplasia, hypophosphatemic rickets, and peripheral precocious puberty were detected. She is still regularly screened for other endocrinopathies.

Conclusion: Neonatal CS due to MAS is extremely rare. Although there is no specific guideline for diagnosis, treatment, or follow-up, addressing side effects and identifying treatment outcomes will improve quality of life and survival.

Introduction

McCune–Albright syndrome (MAS) is a rare mosaic disorder of remarkable complexity with an estimated prevalence of 1/100,000 and 1/1,000,000 (1). Timing of postzygotic missense gain of function mutation of GNAS encoding stimulatory Gαs determines the extent of tissue involvement, imposing a unique clinical phenotype. Although a combination of two or more classical features, such as fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies (gonadotropin-independent gonadal function, nonautoimmune hyperthyroidism, growth hormone excess, and neonatal hypercortisolism), are diagnostic, renal, hepatobiliary, and cardiac involvement have also been reported (2–4).

Adrenocorticotropic hormone (ACTH)-independent adrenal Gαs activation results in the rarest endocrine feature of MAS, which almost invariably presents in the neonatal period: Cushing syndrome (CS). Due to greater burden of Gαs-mutation-bearing cells, the presence of CS is correlated with increased number of accompanying features of MAS and a poorer outcome. Although there is spontaneous resolution in 33% of cases with neonatal CS, mortality occurs with a high rate of 20% (4).

A dilemma for the clinician is that most publications to date have been case reports, and there is as yet no guideline for diagnosis, treatment, or follow-up. Here, a rare case of severe CS due to MAS, underlining the unique clinical phenotype specific to the neonatal period, is presented. Our goal is to offer a practical approach based on 3 years of clinical experience of this rare disorder that will help navigate challenges during follow-up.

Case presentation

A baby girl, born small for gestational age with a birthweight of 2,340 g (−2.1 SDS) and a head circumference of 32.6 cm (−1.61 SDS) was admitted to the neonatal intensive care unit in the first day of life for respiratory distress. She was the second child of a healthy non-consanguineous Caucasian couple, born 38 weeks of gestation via cesarean section following an uneventful pregnancy. Alanine aminotransferase [ALT, 2,376 U/L (normal, 0–40)] and aspartate aminotransferase [AST, 875 U/L (normal, 0–40)] were elevated; gamma-glutamyl transferase and bilirubin were normal. Antibiotics were administered intravenously after a diagnosis of possible neonatal sepsis. Respiratory distress resolved, and liver enzymes decreased (ALT, 687 U/L; AST, 108 U/L). As soon as the antimicrobial treatment was completed, she was discharged in the seventh day of life.

She was referred to our center, 4 days later, for failure to thrive (2,315 g), difficulty in feeding, and deterioration of general health. On physical examination, round facies, elongated philtrum and retro-micrognatia, hyperpigmented macules both at the front and back of the trunk and on labia majora, which do not cross midline, and hypertrichosis on the forehead and extremities were noted (Supplementary Figure S1). Newborn reflexes were hypoactive, blood pressure was 100/70 mmHg, and second-degree cardiac murmur was also detected. Systems were normal otherwise. Laboratory findings revealed hyponatremia, impaired renal and liver function tests, tubulopathy, and proteinuria, while blood count was normal (hemoglobin, 10.4 g/dl; leukocyte, 25.0 × 103/μl; platelet count, 449×103/μl) (Table 1). Hyponatremia resolved with fluid treatment, while liver enzymes, blood urea nitrogen, and creatinine remained elevated. Further endocrine evaluation revealed an elevated serum basal cortisol [225.68 g/dl (N, 6.7–22.6 µg/dL)] and 24-h urinary free cortisol [1,129 μg/day (N, 1.4–20 μg/day)]. Serum cortisol was not suppressed during overnight high-dose dexamethasone suppression test (Table 2) (5). Thyroid hormones were consistent with non-thyroidal illness.

Table 1
www.frontiersin.orgTable 1 Laboratory investigations on admission, prior to medical treatment (19 days), after medical treatment (6 months), and post-adrenalectomy.

Table 2
www.frontiersin.orgTable 2 Endocrine evaluation prior to medical treatment (19 days), after medical treatment (6 months), and post-adrenalectomy.

ACTH-independent CS and café-au-lait spots suggested MAS. Hypercortisolism-related complications emerged. On the 11th day, hyperglycemia (blood glucose, 250 mg/dl) was seen, and it persisted after cessation of intravenous fluids in the exclusively breastfed neonate; thus, 0.5 U subcutaneous neutral protamine Hagedorn insulin (NPH) (three times a day) was initiated on the 16th day of life when blood glucose was 340 mg/dl, and serum insulin was 18.10 μIU/ml. Hypertension (110/90 mmHg) and hypokalemia were triggered by mineralocorticoid action of excessive cortisol on 20th day. Spironolactone (2 mg/kg/day) was started, and nifedipine (0.5 mg/kg/day) was added in order to control blood pressure (Supplementary Figure S2). Since immunosuppressive effects of excess cortisol may increase the risk for opportunistic infections, Pneumocystis jirovecii prophylaxis was started and live vaccines were postponed.

Features of MAS and accompanying hyperfunctioning endocrinopathies were screened (Table 2). On ultrasonography, adrenal glands were hypertrophic; kidneys showed increased parenchymal echogenicity, loss of separation between the cortex and medulla, and enhanced medullary echogenicity; and size and echogenicity of the liver were normal. Magnetic resonance imaging of the abdomen confirmed that adrenal glands were hypertrophic (right and left adrenal gland were 24×22×18 mm and 18×19×20 mm in size, respectively) and lobulated. Echocardiogram revealed left ventricular hypertrophy. Bone survey verified generalized decrease in bone mass and revealed areas of irregular ossification and radiolucency in radius, ulna, and distal tibia, which were interpreted as osteoporosis due to hypercortisolism (Supplementary Figure S1).

Medical treatment

Metyrapone (300 mg/m2/day, per oral, in four doses) was started on the 25th day (Supplementary Figure S2) (6). Since liver function tests were impaired, metyrapone was preferred over ketoconazole. Soon after metyrapone was started, hyperglycemia and hypertension improved, enabling the discontinuation of insulin and nifedipine. Spironolactone was also gradually tapered and discontinued after 13 days of metyrapone treatment, and she was discharged.

The dose of metyrapone was adjusted frequently, according to clinical findings and serum cortisol levels during regular visits. However, even after gradually increasing metyrapone dose to 1,850 mg/m2/day over the course of 6 months, total biochemical suppression of serum cortisol could not be achieved (Supplementary Figure S3A), and the patient had progressive loss of bone mineral density, persistent left ventricular hypertrophy, and a lack of catch-up growth. In addition to that, café-au-lait macules became darker, dehydroepiandrosterone sulfate (DHEA-S) gradually increased (Table 2), and previously non-existent marked clitoromegaly was noted as a side effect of high-dose metyrapone. She was also prescribed ursodeoxycholic acid (15 mg/kg/day); however, liver enzymes remained high (Table 1).

Right total and left three-quarters adrenalectomy

Right total and left three-quarters adrenalectomy was carried out at 9 months of age in light of the patient’s continued clinical findings of hypercortisolism, the existence of unfavorable prognostic markers (high cortisol levels upon admission and heart and liver problems), and the adverse effects of high-dose metyrapone. The patient was administered 100 mg/m2/day glucocorticoids (GC) perioperatively; however, she developed symptoms of adrenal insufficiency. The required GC dose to attain euglycemia, restore general well-being, and resolve adrenal insufficiency was 300 mg/m2/day. Fludrocortisone (0.05 mg/day) was also started. Following surgery, supraphysiological doses of GC were required, as she suffered frequent symptoms of adrenal insufficiency (hypoglycemia, malaise, and loss of appetite). GC dose could be tapered very slowly, and a daily dose of 15 mg/m2/day could be attained in 2 months.

As liver function tests, serum cortisol levels and left ventricular hypertrophy all improved following adrenalectomy (Table 1). Bilateral nodular adrenal hyperplasia was observed in the pathological evaluation of surgical specimen, while the findings of liver wedge biopsy were non-specific (Supplementary Figure S4). Sequence analysis of GNAS from the surgical sample of adrenal gland revealed a heterozygous, previously described missense mutation in exon 8 (c.2530C>A, p.Arg844Ser), while the sequence analysis of the GNAS gene from peripheral blood sample was normal. Lymphocyte activation was normal 3 months post-adrenalectomy, and immunization schedule for live vaccines was established.

Other findings of MAS

She had breast development and vaginal bleeding that lasted 2 days when she was 7 months old, which repeated five more times after the adrenalectomy till 26 months of age. Breast development was Tanner stage 3, and bone age was markedly advanced (4 years and 2 months), despite severe hypercortisolism. On pelvic ultrasonography, uterus was enlarged to 34×22×24 mm; thus, letrozole (0.625 mg, per oral) was started at 26 months of age.

She also developed marked hypophosphatemia at the age of 6 months (Table 1). Radiological investigations since birth demonstrated severe osteopenia and lytic lesions, which were attributed to severe hypercortisolism; however, overt lesions of FD were not confirmed. When she was 9 months old, FGF-23 was elevated [122 pg/ml (normal <52)], which suggested hypophosphatemic rickets associated with FD. Oral phosphate (8 mg/kg) and calcitriol (18 ng/kg) were started. At the age of 23 months, bone survey revealed sclerosis of the base of the skull and maxilla and FD in the lower extremities. She has been on oral phosphate (58.7 mg/kg/day), while calcitriol was ceased.

She is now 34 months old with severe short stature [height, 81 cm (−3.5 SDS); weight, 9,580 g (−3.7SDS)] (Supplementary Figure S3B). She had been under regular clinic visits and has been on 15 mg/m2/day hydrocortisone and fludrocortisone 0.025 mg/day, letrozole (1×6.25 mg/day), phosphate (58 mg/kg), and ursodeoxycholic acid (100 mg/day) (Supplementary Figure S2). She has six words, cannot form two-word sentences, shows body parts, cannot stand up from supine position without support, and takes a few steps with support. Despite regular physiotherapy and ergotherapy, developmental delay is evident (Bayley Scales of Infant and Toddler Development III language scale, 13/79; motor scale, 2/46).

Discussion

ACTH-independent CS and café-au-lait macules suggested MAS in this case. Interestingly, this patient was admitted for hyponatremia and hyperglycemia requiring insulin treatment. Neonatal MAS and CS are rare conditions, and presentation of this case is quite unique (4).

The earlier the timing of somatic mutation, the greater the burden of Gsα-mutation-bearing cells leading to widespread tissue involvement in MAS. In the current case, adrenal, hepatic, cardiac, renal, and bone tissue involvement were evident in first weeks of life, while precocious puberty and hypophosphatemic rickets were observed later. A lifetime risk of additional tissue involvement is being acknowledged. CS is the rarest endocrine manifestation of MAS, which appears in <5%–7.1%. It presents exclusively within the first year of life (median age, 3.1 months) where features may develop as early as in utero (2–4, 7). The fact that our case was SGA and had moon facies and hirsutism with impaired linear growth, weight gain, hyperglycemia, hypertension, and nephrocalcinosis detected in the neonatal period, suggested severe, in utero onset CS. Upon suspicion, both comorbidities (hyperthyroidism, excess growth hormone, FD, and cardiac and hepatobiliary function) of MAS and complications of GC excess (hypertension, hyperglycemia, hyperlipidemia, nephrocalcinosis, decreased bone mineral density, and muscle atrophy) were assessed (1, 3).

Since the initial description of MAS, only 20 neonates with CS have been described with various initial basal serum cortisol ranging from 9.6 to 80.1 µg/dl, and data regarding long-term follow-up and outcome are still developing (1, 2, 8–11). Disease course is heterogenous, and spontaneous resolution of hypercortisolism has been reported (30%) since Gs-bearing cells are mostly located in the fetal adrenal zone, which normally undergoes apoptosis after birth. However, the outcome is mostly unfavorable in cases with extensive endocrine and extra-endocrine manifestations (1, 2, 8–15). Brown et al. reported poorer prognosis and a lower likelihood of spontaneous remission of adrenal disease in patients with cardiac (cardiomyopathy) and liver involvement (hepatocellular adenomas, inflammatory adenomas, choledochal cysts, neonatal cholestasis, and hepatoblastoma). It was hypothesized that these patients have a greater burden of Gsα mutation (3, 4).

Treatment of neonatal CS is a long and challenging path where both cortisol excess and its complications should be targeted. Marked hypercortisolism that precipitate neonatal diabetes requiring insulin treatment like our patient is rare and was previously reported only in six patients with CS (4). Until hypercortisolism is managed, hyperglycemia should be treated with insulin. Hypertension is due to mineralocorticoid effect of excess cortisol; thus, blood pressure lowering agents of choice should be aldosterone antagonists (spironolactone) or potassium-sparing diuretics.

The treatment strategy of hypercortisolism is determined by disease severity. In a mildly affected case, medical treatment with an expectation of spontaneous resolution (due to previously stated apoptosis of fetal adrenal zone) may be of choice (3, 4, 16–19). Metyrapone, ketoconazole, and mitotane are medical options for lowering cortisol (20–23). Since our patient had impaired liver function, metyrapone, a potent, rapid acting relatively selective inhibitor of 11-hydroxylase was preferred over ketoconazole for its low risk of hepatotoxicity. Reports reviewing adult data suggest an initial dose of 500–750 mg/day and achievement of biochemical control with 1,500 mg/day (23). However, the initial and maximum dose of metyrapone in neonates is unclear; some authors recommend 300 mg/m2/day in four equal doses (6). In our case, adequate biochemical and clinical suppression of cortisol with metyrapone was not achieved despite an increase in dose from 300 to 1,850 mg/m2/day.

There are important issues to be considered while using a steroidogenesis inhibitor like metyrapone. Monitoring biochemical response is essential, not only for dose titration and management of cortisol excess but also for adrenal insufficiency due to possible overtreatment. Clinical signs of adrenal insufficiency should always be questioned and assessed. The 24-h urinary free cortisol is the commonly used method; however, it may be impractical due to difficulties in the collection of urine in infants. Alternative methods may be the measurement of early morning serum cortisol and ACTH (23). Low ACTH level may indicate hypercortisolism or may be a sign of suppression due to long-term exposure to hypercortisolism. However, there are deadlocks to be considered in the evaluation of these measurements. A high cortisol level measured by immunoassays does not always indicate an actual elevation. It should be kept in mind that cortisol immunoassays exhibit significant cross-reactivity with cortisol precursors that may be elevated in patients treated with a steroidogenesis inhibitor (especially with metyrapone, which is known to increase 11-deoxycortisol). Such cross-reactivity can be a cause for overestimation of cortisol and may lead to risk of overtreatment (24, 25). It has been suggested that the patients on metyrapone should be biochemically monitored via specific methods, such as mass spectrometry (24–26).

Metyrapone is a relatively selective inhibitor of 11-hydroxylase and 18-hydroxylase. Recent in vitro studies indicate greater inhibitory action of metyrapone on aldosterone synthase, resulting in significant reversible reduction in both cortisol and aldosterone. The loss of negative feedback leads to an increase in ACTH, which causes an accumulation of cortisol and aldosterone precursors resulting in an increase in adrenal androgens (23). Although we could not serologically prove an increase in ACTH, hyperpigmentation and the increase in adrenal androgens confirm this mechanism. As far as we know, an increase in DHEA-S causing virilization was an unreported side effect of metyrapone. Clinical (clitoromegaly and hirsutism) and laboratory (DHEA-S) signs of hyperandrogenism should be monitored when higher doses of metyrapone are required.

In the severely affected case with CS, where medical treatment is inadequate and the chance of spontaneous resolution is subsiding, adrenalectomy is indicated when medically feasible. Brown et al. suggested that the presence of comorbid cardiac and liver disease like in our case should prompt consideration for early adrenalectomy (4). Although a previous correlation with initial serum cortisol level and prognosis was not established, it may be speculated that excessively high serum cortisol level is associated with increased number of Gsα-mutation-bearing adrenal cells. Thus, we suggest that in neonatal CS due to MAS, initial very high serum cortisol levels, like our case, may be a negative prognostic factor both for spontaneous resolution and clinical response to medical treatment. In infants with severe CS, bilateral adrenalectomy is generally performed. Alternatives like unilateral adrenalectomy and one-side total, other-side three-quarters adrenalectomy may be considered to avoid the requirement for lifelong GC and mineralocorticoid replacement. Unilateral adrenalectomy was reported to successfully improve clinical symptoms and endocrinological status in adult studies; nevertheless, recurrence during follow-up was 23.1%, while 17.5% required contralateral adrenalectomy (27–29). Since the causes of CS in adult series are variable and different from pediatric CS due to MAS, it should be borne in mind that reproducibility of adult data is poor. In CS due to MAS, Gsα-mutation-bearing adrenal gland cells are heterogeneously distributed, and partial adrenalectomy may carry the risk of inadequate management and recurrence. Only a few pediatric case reports addressed this issue. Unilateral adrenalectomy of the larger gland was performed in two neonates with CS due to MAS; remission was achieved for 2 years (30, 31). Itonaga et al. reported a 6-month-old neonate with MAS-associated CS treated with right-sided total adrenalectomy and left-sided half adrenalectomy with remission for 2 years (32). Although these cases were less severe [basal serum cortisol: 16.9, 18.5, and 23.4 µg/dl, respectively (N: 6.2–18.0 µg/dL)], we preferred to perform partial adrenalectomy (right total and left three-quarters adrenalectomy) and succeeded. Our patient has been in remission for more than 2 years.

In the largest case–control analysis of CS in patients with MAS, overall mortality was 20% (six cases) where four of them were deceased following bilateral adrenalectomy (66.7% of all deaths) (4). Anaphylaxis (or adrenal insufficiency), sudden cardiac arrest, sepsis, and sudden death were listed as causes of mortality in those four cases where GC dose and process of GC tapering were not clearly described. The fact that our patient required high-dose GC during peri- and postoperative period to restore well-being, tapering to maintenance dose was very slow, and she is still on maintenance dose GC, suggests that rapid tapering of GCs should be avoided and, although being speculative, may explain sudden death following adrenalectomy.

Gross motor developmental delay may be caused by prenatal exposure to excess GCs. Prenatal GC treatment for possible congenital adrenal hyperplasia or risk of premature birth have been shown to result in cognitive deficits after birth. Furthermore, children who develop CS later in life may experience a decline in cognitive and school performance where the younger the age of onset, the greater the deterioration in IQ scores (3, 4, 33, 34). Since transgenic mice with Gsα mutation was shown to have short- and long-term memory deficits and impaired associative and spatial learning, it may also be speculated that Gsα mutation may also be present in the central nervous system (35, 36).

The establishment of diagnosis of FD follows a characteristic and predictable time course. Although GNAS mutations are acquired early in embryogenesis, skeletal development appears to be relatively normal in utero, without frank clinical signs of FD at birth. Boyce et al. affirmed that FD lesions become apparent over the first several years of life and expand during childhood and adolescence, like our case. Previous case reports have also stated severe osteoporosis, rickets, polyostotic irregular lucencies, pathological fractures, and biopsy-proven FD during infancy (1, 2, 8–15). The exact pathophysiological mechanism is unclear, and Gsα activation in abnormally differentiated osteocytes is accused. FGF-23 overproduction is an inherent feature of FD, and most patients have elevated circulating levels of FGF-23, but frank hypophosphatemia is rare. The increase in FGF-23 is linked to substantial skeletal involvement. Although FGF-23 levels may wax and wane over time, an increase in FGF-23 usually occurs during periods of rapid growth like infancy and adolescence. Concurrent hyperfunctioning endocrinopathies like hyperthyroidism or CS may also adversely affect bone health.

Peripheral precocious puberty (PP) is the most frequent presenting feature in female patients with MAS (85%) (6). To date, a safe, effective, and long-term treatment for PP in girls with MAS has not been established. The benefits of current interventions on the ultimate outcome of interest, adult height, have not been well-established due to the rarity of the condition and heterogeneous nature of the disease. Despite the small sample size, studies have concluded that letrozole resulted in a statistically significant decrease in the bone age/chronological age ratio, growth velocity, hence increasing predicted adult height (37). Growth outcome in MAS is not only dependent on timing of pubertal onset but on several other disease components (skeletal involvement and endocrinopathies) as well. Hyperthyroidism and growth hormone excess may accelerate growth, while CS may decelerate it (37, 38).

Lack of consensus on both medical and surgical treatment strategies were major obstacles while navigating this case of severe neonatal MAS. The eminence of this report is that it presents current literature with clinical experience on this rare case of neonatal CS due to MAS. High index of suspicion for MAS in a neonate with extensive café-au-lait macules and symptoms of hypercortisolism is the key for early recognition and intervention. Initial excessive cortisol in neonatal CS may be a negative prognostic factor for spontaneous resolution and response to medical treatment, indicating early right total and left three-quarters adrenalectomy. Post-adrenalectomy survival may be related to close supervision during GC tapering.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

Ethics statement

Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author contributions

YU collected and analyzed data, drafted the initial manuscript, and reviewed and revised the manuscript. OG collected data. İU, HH, BG, SE, and TK collected data and reviewed and revised the manuscript. ZO and EG analyzed data, conceptualized the work, and revised and critically reviewed the manuscript for important intellectual and medical content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgments

We thank our patient’s family for providing consent for publication of this work.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1209189/full#supplementary-material

Supplementary Figure 1 | (A) The findings of physical and radiologic examination. Notice cushingoid facies, hyperpigmented macules that does not cross the midline at the front of the trunk. (B) Anteroposterior radiographs reveal irregularities in radius, ulna and femur. Although generalized osteopenia improves at 34 months, FD lesions become prominent over months.

Supplementary Figure 2 | Timeline of the course of symptoms in neonatal McCune Albright Syndrome noting adjustments made in treatment. Grey box denotes age in days for the first month of life then in months. NPH: Neutral Protamine Hagedorn insulin, CS: Cushing syndrome, PP: precocious puberty.

Supplementary Figure 3 | (A) Change in serum cortisol with increased metyrapone (methyrapone was initiated on day 25). (B) Growth chart, the arrow represents right total and left three quarters adrenalectomy.

Supplementary Figure 4 | Representative histological features of nodular adrenal hyperplasia. (A, B) show low-power while (C) Show high-power views.

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Keywords: McCune Albright syndrome, neonatal Cushing syndrome, metyrapone, adrenalectomy, follow-up

Citation: Unsal Y, Gozmen O, User İR, Hızarcıoglu H, Gulhan B, Ekinci S, Karagoz T, Ozon ZA and Gonc EN (2023) Case Report: Severe McCune–Albright syndrome presenting with neonatal Cushing syndrome: navigating through clinical obstacles. Front. Endocrinol. 14:1209189. doi: 10.3389/fendo.2023.1209189

Received: 20 April 2023; Accepted: 04 July 2023;
Published: 25 July 2023.

Edited by:

Martin Oswald Savage, Queen Mary University of London, United Kingdom

Reviewed by:

Li Chan, Queen Mary University of London, United Kingdom
Sasha R Howard, Queen Mary University of London, United Kingdom
Tomoyo Itonaga, Oita University, Japan

Copyright © 2023 Unsal, Gozmen, User, Hızarcıoglu, Gulhan, Ekinci, Karagoz, Ozon and Gonc. 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) and the copyright owner(s) 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: Yagmur Unsal, yagmurunsal@yahoo.com

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/articles/10.3389/fendo.2023.1209189/full

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Asymptomatic Pheochromocytoma Associated with MEN Syndrome and Subclinical Cushing’s Syndrome

Posted on August 23, 2023 by MaryO

Abstract

Introduction and importance

Pheochromocytoma and Cushing’s syndrome are rare endocrine conditions caused by tumors in the adrenal gland. These conditions are classified under Multiple Endocrine Neoplasia (MEN) syndrome, characterized by the development of multiple tumors in the endocrine system. However, diagnosing these conditions can be challenging as they often lack clear symptoms, requiring careful evaluation, monitoring, and treatment to prevent complications.

Case presentation

A 23-year-old male recently presented with right-sided abdominal fullness and lipoma-like masses on the torso. Over a span of six months, the abdominal mass nearly doubled in size, accompanied by elevated levels of catecholamines, cortisol, parathyroid hormone (PTH), and calcitonin. Surprisingly, the patient remained asymptomatic despite these abnormal lab values. CT imaging revealed a substantial increase in the size of the mass in the right adrenal gland, from 6 × 7 cm to approximately 11.2 × 10.2 × 9 cm.

Clinical discussion

Pheochromocytoma secretes catecholamines and often leads to hypertension and related symptoms. Interestingly, most individuals with pheochromocytoma do not exhibit obvious symptoms, necessitating blood and urine tests, along with imaging studies, for accurate diagnosis. The size of the tumor does not necessarily indicate the severity of symptoms. MEN-2, a genetic syndrome, is characterized by pheochromocytoma, medullary thyroid carcinoma, and hyperparathyroidism. Additionally, methods for diagnosing Cushing’s syndrome, caused by excess cortisol production, are discussed.

Conclusion

Early diagnosis and genetic counseling are crucial in preventing complications associated with these conditions. By identifying them, appropriate treatment can be ensured for positive outcomes of patients and their families.

Keywords

Pheochromocytoma
Multiple Endocrine Neoplasia (MEN) syndrome
Cushing’s syndrome
Rare Case Report

Abbreviations

CT

computed tomography

MRI

Magnetic resonance imaging

USG

Ultrasonography

131I-MIBG

iodine 131 labeled meta-iodobenzylganidine

RAAS

Renin-angiotensin-aldosterone system

    1. Introduction

    Pheochromocytoma are catecholamine secreting tumors of chromaffin cells of adrenal medulla. It can be found anywhere in the body, with the majority being intra-abdominal and those other than adrenal medulla are referred to as paragangliomas [1,2]. Pheochromocytoma typically secretes norepinephrine and epinephrine, with norepinephrine being the primary catecholamine. However, some tumors may only secrete one of the two, and rarely, some may secrete dopamine or dopa [3].

    Vast majority >90 % of adrenal neoplasms are benign non-functional adenomas [4].About 10 % of pheochromocytomas are malignant and 10 % of cases are found on both sides. Additionally, approximately 40 % of pheochromocytomas are caused by genetic factors and can be associated with inherited syndromes [5].

    Pheochromocytoma is found to be associated with MEN-2. MEN-2 is a hereditary genetic condition that is caused by a de novo mutation in the RET gene. It is inherited in an autosomal dominant fashion and is mainly characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid adenoma or hyperplasia [6].

    MEN syndrome can be MEN-1, MEN-2A and MEN-2B. MEN-1 is characterized by pituitary tumors (prolactin or growth hormone), pancreatic endocrine tumors and parathyroid adenomas. Additionally, other tumors such as foregut carcinoids, adrenocortical adenomas, meningioma, lipomas, angiofibromas and collagenomas may also occur in MEN-1. MEN-2A is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma/hyperplasia; it can also be associated with cutaneous lichen amyloidosis and Hirschsprung disease. On the other hand, MEN-2B is characterized by familial medullary thyroid cancer, pheochromocytoma, mucosal neuromas, gastrointestinal tract issues, musculoskeletal and spinal problems. [7].

    Cushing syndrome results from hypercortisolism and is characterized by hypertension, weight gain, easy bruising, and central obesity [4]. Cushing’s disease refers to ACTH-dependent cortisol excess caused by a pituitary adenoma, while ACTH-independent cortisol excess due to non-pituitary causes such as excess use of glucocorticoids, adrenal adenoma, hyperplasia, or carcinoma is referred to as Cushing syndrome [8].

    This case report has been written according to the SCARE checklist [9].

    2. Case presentation

    A 23-year-old male presented to our surgery department with the chief complaint of right sided abdominal fullness for six months. According to the patient a mass was incidentally reported six months back while he was under-evaluation for mild trauma due to road traffic accident. Six months back, the mass was approximately 6 × 7 cm, while at the time of presentation to our department the mass was approximately 11.2 × 10.2 × 9 cm (CT abdomen) which was globular in shape, had regular margin, and moved with respiration. He had no history of hypertension, headache, palpitation, sweating, pallor, recent weight loss, abdominal pain, psychological disturbance, dizziness, loss of consciousness, dark color urine, burning micturition, had normal bowel and bladder habit.

    Past history and family history were insignificant. He was not under any long-term medication and no known drug allergies. He occasionally smokes and consumes alcohol.

    On physical examination at the time of presentation, multiple soft, mobile, painless, subcutaneous nodules like lipoma were present over the torso. His height was 176.8 cm, weight 68 kg, BMI 21.8 kg/m2 (body mass index). He had blood pressure of 110/70 mm of Hg taken in left arm at sitting position, heart rate of 62 beats/min, respiratory rate of 24/min, temperature of 96.6 °F, SPO2 of 98 % at right hand. A mass was palpable on the right side of abdomen, otherwise abdomen was soft, non-tender, normal bowel sound was present. Chest, cardiac and neurologic examinations were all normal.

    Initial laboratory evaluation revealed 24 h. urine metanephrine of 5415 μg/24 h (normal: 25–312 μg/24 h.); 24 h. urine VMA of 32.2 mg/24 h. (normal: <13.60 mg/24 h.); serum cortisol of 535.16 nmol/l after overnight low dose dexamethasone(1 mg) suppression test (normal: <50 nmol/l);24 h. Urine free cortisol of 526.61 nmol/24 h. (normal: 30–145 nmol/24 h) PTH(intact) of 89.2 pg./ml (normal: 15–65 pg./ml); serum calcitonin of 15.2 pg./ml (normal: ≤8.4 pg./ml); serum CEA of 4.72 ng/ml (normal: 0.0–4.4 ng/ml); serum DHEA of 1.19 ng/ml (normal: 1.7–6.1 ng/ml). Baseline investigation: Hematology, urine routine/microscopic, electrolytes were within the normal range.

    Additional laboratory findings were as in the Table 1.

    Table 1.

    Lab evaluation Result Reference Unit
    Metanephrine, urine 24 h 5415 25–312 μg/24 h
    VMA, urine 24 h 32.2 <13.60 mg/24 h
    VMA, urine 12.88 – ng/l
    Cortisol, serum, overnight DST 535.16 <50 nmol/l
    Cortisol, urine 24 h 526.61 30–145 nmol/24 h
    ACTH, complete 28.3 7.2–63.3 pg/ml
    DHEA, serum 1.19 1.7–6.1 ng/ml
    CEA, serum 4.72 0.0–4.4 ng/ml
    Phosphorus, serum 3.0 2.5–4.5 mg/dl
    Albumin, serum 5.2 3.5–5.2 g/dl
    Calcitonin, serum 15.2 ≤8.4 pg/ml
    Calcium, serum 8.94 8.6–10.0 mg/dl
    PTH (intact) 89.2 15–65 pg/ml
    aldosterone 8.7 7.0–30 g/dl
    Plasma rennin activity 1.42 0.10–6.56 ng/ml/h
    Aldosterone-rennin ratio 6.13 ≤20
    Creatinine, urine 36 – mg/dl

    DST – dexamethasone suppression test; VMA – vanilmandelic acid; ACTH – adrenocorticotropic hormone; DHEA – dehydroepiandrosterone; CEA – carcino-embryonic-antigen; PTH – parathyroid hormone.

    2.1. USG abdomen

    USG abdomen (Fig. 1, Fig. 2) showed well defined mixed echoic area in Right adrenal region measuring 12.7 × 10.7 cm in size. There was presence of internal vascularity with multiple foci of cystic compound. The lesion displaced the right kidney inferiorly.

    Fig. 1

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    Fig. 1. USG abdomen.

    Fig. 2

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    Fig. 2. USG abdomen.

    2.2. Plane and contrast CT scan of abdomen

    Plane and contrast CT scan of Abdomen (Fig. 3) showed approximately 11.2 × 10.2 × 9 cm sized, relatively well defined heterogeneous soft tissue density lesion with well-defined enhancing wall in right adrenal region. Non-enhancing areas were noted within the mass suggestive of necrosis. Few calcific foci were noted within the mass with no obvious hemorrhagic component. The lesion showed heterogeneous enhancement post contrast image.

    Fig. 3

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    Fig. 3. CT abdomen.

    After all the workup patient was given diagnosis of right sided Pheochromocytoma associated with MEN syndrome, with ACTH-independent Cushing’s syndrome and right adrenalectomy was performed.

    2.3. Pathology report

    2.3.1. Gross descriptions

    The specimen was globular mass measuring 14.5 × 10 cm, with smooth outer surface. On sectioning, the mass was well circumscribed, soft and yellow-brown, predominantly solid with cyst formation. The size of cyst ranges from 0.3 to 3.5 cm in diameter. Areas of hemorrhages were noted.

    2.3.2. Microscopic description

    Section showed tumor cells arranged in well-defined nests (Zellballen), alveolar and diffuse pattern with intervening fibrovascular stroma. The cells were intermediate to large sized, polygonal with finely granular amphophilic cytoplasm. The nuclei showed mild to moderate pleomorphism and were round to ovoid, with prominent nuclei noted. No capsular invasion, vascular invasion and necrosis. Areas of hemorrhage were seen. Mitosis 0–1/10 high power field was noted (Figs. 4 and 5).

    Unlabelled Image

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    Fig.a Diffuse Zellbalen pattern with intervening fibrous stroma.

    Fig.b Mild to moderate pleomorphic nuclei with abundant hemorrhage.

    Fig.c Low power field with intact capsule.

    Figs. 4 and 5

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    Figs. 4 and 5. Fig. 4 Intra-operative resection of tumor; Fig. 5 tumor after resection.

    3. Discussion

    In Pheochromocytoma activation of the alpha-one adrenergic receptor by catecholamine in the vascular bed causes vasoconstriction and leads to a rise in blood pressure. Similarly, activation of the beta-one receptor in the heart enhances the chronotropic and inotropic effect of the myocardium, leading to an increase in heart rate and cardiac output. In addition, activation of the beta-one receptor in the juxtaglomerular cells of the kidney activates the RAAS system. These receptor activation result in cardiovascular and sympathetic changes, such as hypertension, palpitation, headache, sweating, trembling, and anxiety [10].

    In Pheochromocytoma, the patient may have a 10-fold increase in plasma catecholamines, but the hemodynamic response can still fall within the normal range due to desensitization of the cardiovascular system. When catecholamine levels are elevated for a prolonged period, the alpha-one receptors in blood vessels may be down-regulated, making norepinephrine unresponsive in raising peripheral vascular resistance, which can lead to normal blood pressure. Similarly, a marked decrease in beta-one receptors in the heart could explain the normal heart rate, which was observed in our asymptomatic patient with Pheochromocytoma [11].

    Sometimes in asymptomatic patients, the size of the tumor tends to be larger than in those with hyperfunctioning tumors [12]. However, medical interventions such as surgery, anesthesia induction, intravenous urography contrast, or manipulation of the tumor can trigger adrenergic and hypertensive crises, so biopsy is usually contraindicated in pheochromocytoma [13].

    The diagnosis of pheochromocytoma is typically based on measuring plasma and urinary levels of catecholamines and their derivatives such as metanephrine and vanillylmandelic acid. The most reliable test is the measurement of urinary metanephrine as its excretion levels are relatively higher [13,14]. The combination of 131I-MIBG scintigraphy along with diagnostic urinary and blood tests can further enhance the sensitivity of the test. Specifically, the urinary normetanephrine test is considered the most sensitive single test for detecting Pheochromocytoma [15,16].

    In addition to a 24-h urine test and blood test, if the lab results are positive for Pheochromocytoma or paragangliomas, further diagnostic tests may be recommended, such as a CT scan, MRI, m-iodobenzylganidine (MIBG) imaging, or positron emission tomography (PET) [16,17]. In our patient 24 h. urine metanephrine of 5415 μg/24 h (normal: 25–312 μg/24 h.); 24 h. urine VMA of 32.2 mg/24 h. (normal: <13.60 mg/24 h.) and imaging confirmation of right adrenal mass lead to the diagnosis of right sided pheochromocytoma.

    Our patient with pheochromocytoma was tested for parathyroid hormone and calcitonin due to the association of pheochromocytoma with MEN-2 [18]. MEN-2 can be diagnosed biochemically by measuring the baseline levels of calcitonin, parathyroid hormone and serum calcium along with blood tests for catecholamines and their metabolites to detect pheochromocytoma [19]. In our patient, multiple soft, mobile, painless, subcutaneous nodules like lipoma were present over the torso(MEN-1) and high levels of parathyroid hormone and calcitonin were detected(MEN-2). These findings can be correlated with MEN syndrome.

    USG of the neck revealed no abnormalities of thyroid and parathyroid gland in our patient so prophylactic thyroidectomy was not done, instead he was counseled for follow up if any symptoms or thyroid swelling appears.

    The diagnosis of Cushing’s syndrome typically involves measuring the levels of 24-h urine free cortisol and assessing the suppression of cortisol in response to a 1 mg overnight dexamethasone test. If cortisol levels remain elevated despite the test, the next step is to measure serum ACTH levels. If ACTH levels are suppressed, it suggests an ACTH-independent cause of Cushing’s syndrome, while elevated ACTH levels suggest an ACTH-dependent cause. Further evaluation may include a CT scan of the chest, abdomen, and pelvis to identify potential ectopic sources, as well as an MRI of the pituitary gland [8]. Our patient had a high level of 24 h. urine free cortisol of 526.61 nmol/24 h (reference range: 30–145 nmol/24 h) and serum cortisol of 535.16 nmol/L(reference range: <50 nmol/L) after overnight 1 mg dexamethasone suppression test, but normal level of ACTH of 28.3 pg./ml (reference range: 7.2–63.1 ng/ml), this suggests the diagnosis of ACTH independent Cushing’s syndrome.

    4. Conclusion

    Large Pheochromocytoma patients can be asymptomatic and can present in association with other endocrine disorders. So proper evaluation is necessary to find out associated conditions and manage accordingly to prevent the possible outcomes.

    Patient consent

    Written, informed consent was obtained from the patient for the publication of the report.

    Ethical approval

    It is exempted at my institution. We don’t need to take approval from ethical committee for case report.

    Funding

    N/A.

    Author contribution

    Conceptualization: Sanjit Kumar Shah.

    Clinical diagnosis and patient management: Mahipendra Tiwari.

    Microscopic slide preparation: Sneh Acharya.

    Writing original draft: Sanjit Kumar Shah and Avish Shah.

    All authors were involved in reviewing, editing, supervision and in preparing the final

    manuscript.

    Guarantor

    Guarantor: Sanjit Kumar Shah

    Email: sanjitshah023@gmail.com

    Conflict of interest statement

    N/A.

    References

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

    BMD may Underestimate Bone Deterioration for Women with Endogenous Cushing’s Syndrome

    Posted on August 16, 2023 by MaryO

    Nearly one-third of women with endogenous Cushing’s syndrome and normal bone mineral density have a low trabecular bone score, according to study data.

    “A large proportion of patients had degraded microarchitecture despite normal BMD,” Hiya Boro, DM, MD, MBBS, consultant in endocrinology, diabetes and metabolism at Aadhar Health Institute in India, and colleagues wrote. “The risk of fracture may be underestimated if BMD alone is measured. Hence, trabecular bone score should be added as a routine complementary tool in the assessment of bone health in patients with Cushing’s syndrome.”

    About one-third of women with endogenous Cushing's syndrome have normal BMD and low trabecular bone score. Data were derived from Boro H, et al. Clin Endocrinol. 2023;doi:10.1111/cen.14944.

    Researchers conducted a cross-sectional study at a single center in India from March 2018 to August 2019. The study included 40 women with overt endogenous Cushing’s syndrome and 40 healthy sex-matched controls. Seum and salivary cortisol and plasma adrenocorticotropic hormone (ACTH) were measured. Participants were considered ACTH independent if they had a level of less than 2.2 pmol/L. Areal BMD was measured at the lumbar spine, femoral neck, total hip and distal one-third of the nondominant distal radius. Low BMD for age was defined as a z score of less than –2. Trabecular bone score was measured at the lumbar spine. Fully degraded microarchitecture was defined as a trabecular bone score of 1.2 or lower and partial degradation was a trabecular bone score of 1.21 to 1.34.

    Of the 40 women with Cushing’s syndrome, 32 were ACTH-dependent and the other eight were ACTH independent. Of the independent group, seven had adrenal adenoma and one had adrenocortical carcinoma.

    Women with Cushing’s syndrome had lower BMD at the lumbar spine (0.812 g/cm2 vs. 0.97 g/cm2; P < .001), femoral neck (0.651 g/cm2 vs. 0.773 g/cm2; P < .001) and total hip (0.799 g/cm2 vs. 0.9 g/cm2; P < .001) than the control group.

    “No significant difference was noted in the distal radius BMD,” the researchers wrote. “This may be explained by the fact that cortisol excess predominantly affects trabecular rather than cortical bone.”

    Absolute trabecular bone score was lower in the Cushing’s syndrome group compared with controls (1.2 vs. 1.361; P < .001). Based on trabecular bone score, 42.5% of women with Cushing’s syndrome had fully degraded bone microarchitecture, 45% had partially degraded microarchitecture and 12.5% had normal microarchitecture.

    “In our study, 32.5% of patients had normal BMD with low trabecular bone score, thus highlighting the fact that patients may have normal BMD despite degraded microarchitecture,” the researchers wrote. “As such, assessment of BMD alone may underestimate the risk of fractures in patients with Cushing’s syndrome.”

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

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