Abstract
Multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare autosomal dominant disorder characterized by predisposition to a multitude of endocrine neoplasms. Cushing syndrome (CS) within MEN1 presents complex diagnostic and therapeutic challenges. We report a case of a 36-year-old male with adrenocorticotropic hormone (ACTH)-dependent Cushing disease and MEN1 syndrome with thymic and pancreatic neuroendocrine tumors. The patient presented with weight gain, weakness and proximal myopathy. Biochemical testing confirmed ACTH-dependent hypercortisolism. Imaging revealed a pituitary microadenoma, a large anterior mediastinal mass, and pancreatic lesions. Genetic analysis confirmed a pathogenic heterozygous MEN1 frameshift variant. After thymectomy, he declined further surgery. Treatment with thymectomy and octreotide long-acting release (LAR) was ineffective. Initiation of osilodrostat (titrated to 5 mg twice daily) resulted in a 76% reduction in urinary cortisol levels and a 47 kg weight loss, with significant functional improvement. Pancreatic and pituitary lesions remained stable. This is the first reported case of successful symptom management of MEN1-associated Cushing disease with osilodrostat, establishing it as an effective therapeutic option for medically complex MEN1 cases where surgery is not feasible or is declined.
Keywords: MEN1 syndrome, Cushing syndrome, osilodrostat, case study
Introduction
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder characterized by hyperparathyroidism and tumors of the duodenopancreatic neuroendocrine system and the anterior pituitary [1]. Adrenal involvement occurs in 20-73% of cases, but hormonal hypersecretion is uncommon [1]. Cushing syndrome (CS) in MEN1 can be adrenocorticotropic hormone (ACTH)-dependent, originating from either a pituitary adenoma (Cushing disease) or, more rarely, an ectopic ACTH-secreting tumor (thymic carcinoid), or ACTH-independent from an adrenal adenoma [2].
This complexity makes diagnosis and management challenging. We report a case of a patient with MEN1 syndrome presenting with ACTH-dependent Cushing disease, who declined definitive surgery and was subsequently managed successfully with the cortisol synthesis inhibitor, osilodrostat.
Case presentation
A 36-year-old Bahraini male with a 2-year history of type 2 diabetes and hypertension presented with a 25 kg weight gain over 1 year, generalized weakness, shortness of breath, and proximal myopathy. At presentation, his blood pressure was 175/92 mmHg, serum potassium was 3.1 mmol/L, and HbA1c was 8.5%. Physical examination revealed central obesity, abdominal striae, a dorsocervical fat pad, multiple skin bruises, and proximal muscle weakness. His symptoms severely impacted his activities of daily living and ability to work.
Diagnostic assessment
Initial biochemical testing confirmed ACTH-dependent Cushing disease: 2 elevated 24-hour urinary free cortisol (UFC) levels 1560 µg/24 hours (SI: 4305 nmol/24 hours); normal < 140 µg/24 hours (<386 nmol/24 hours), a nonsuppressed cortisol after a 1 mg overnight dexamethasone suppression test (6.4 µg/dL [SI: 178 nmol/L]; normal <1.8 µg/dL [SI: <50 nmol/L]), and an elevated ACTH level (208.9 pg/mL [SI: 46 pmol/L]; normal <45.4 pg/mL [SI: <10 pmol/L]). A low-dose DST was not performed, the strong clinical and biochemical evidence warranted direct localization with inferior petrosal sinus sampling (IPSS).
Pituitary magnetic resonance imaging (MRI) identified a 3 mm microadenoma (see Fig. 1). A computed tomography (CT) scan of the chest revealed a large 3.5 cm anterior mediastinal mass within the thymus. A Gallium-68 DOTATATE (Ga⁶⁸ DOTA-0-Tyr3-octreotate DOTATATE) positron emission tomography (PET)/CT scan revealed multiple somatostatin receptor-positive lesions: a 1 cm lesion in the pancreatic tail (maximum standardized uptake value [SUVmax] 27.9), a 1 cm lesion in the pancreatic body (SUVmax 50.2), and a 0.5 cm lesion in the pancreatic head (SUVmax 14.1). No significant uptake was noted in the anterior mediastinum post-thymectomy. The pancreatic lesions were not biopsied and were managed conservatively with surveillance.
Figure 1.
(A and B) Dynamic contrast-enhanced T1-weighted MRI of the pituitary gland demonstrating a small pituitary microadenoma. (A) Sagittal view. (B) Coronal view.
The patient underwent a partial thymectomy. Histopathological analysis confirmed an atypical carcinoid tumor, characterized by a mitotic activity of 4 mitotic figures per 10 high-power fields (MF/10HPF), a Ki67 proliferation index of 5%, and a pathological stage of pT1aN1. Given the multi-organ involvement, MEN1 syndrome was suspected. Genetic analysis performed at Centogene GmbH (Rostock, Germany) confirmed a pathogenic heterozygous MEN1 frameshift pathogenic variant (c.202_206dup; p.Asp70Profs*51).
Baseline hormonal profiling revealed secondary hypogonadism (low luteinizing hormone, follicle-stimulating hormone, and testosterone) and vitamin D deficiency with secondary hyperparathyroidism (elevated parathyroid hormone with normal calcium). Thyroid function tests, insulin-like growth factor 1 and growth hormone were within normal limits (Table 1).
Table 1.
Baseline hormonal and metabolic profile
| Parameter | Value | Reference range | Date |
|---|---|---|---|
| ACTH | 208.9 pg/mL (SI: 46 pmol/L) | < 45.4 pg/mL (SI: < 10 pmol/L) | Apr 2022 |
| Basal cortisol 0800h | 893 nmol/L (SI: 32.37 µg/dL) | 140-690 nmol/L (SI: 10-20 µg/dL) | Apr 2022 |
| 24-hour urinary free cortisol | 1560 µg/24 hours (SI: 4305 nmol/24 hours) | < 140 µg/24 hours (SI: <386 nmol/24 hours) | Apr 2022 |
| HbA1c | 8.5% (SI: 69 mmol/mol) | < 5.7% (SI: <39 mmol/mol) | Apr 2022 |
| Potassium | 3.1 mmol/L | 3.5-5.2 mmol/L | Apr 2022 |
| 1 mg ODST | 6.4 µg/dL (SI: 178 nmol/L) | < 1.8 µg/dL (SI: < 50 nmol/L) | Apr 2022 |
| Calcium | 9.1 mg/dL (SI: 2.27 mmol/L) | 8.6-10.4 mg/dL (SI: 2.15-2.60 mmol/L) | Apr 2022 |
| PTH | 143.5 pg/mL (SI: 15.1 pmol/L) | 18.6-88.6 pg/mL (SI: 1.96-9.33 pmol/L) | Apr 2022 |
| Vitamin D | 16.4 ng/mL (SI: 41 nmol/L) | >30 ng/mL (SI: >75 nmol/L) | Apr 2022 |
| LH | 1.2 IU/L | 1.5-9.3 IU/L | Apr 2022 |
| FSH | 2.1 IU/L | 1.6-11.0 IU/L | Apr 2022 |
| Testosterone | 61.2 ng/dL (SI: 2.12 nmol/L) | 262.5-1154.0 ng/dL (SI: 9.1-40 nmol/L) | Apr 2022 |
| Prolactin | 14 ng/mL (SI: 297 mIU/L) | 0.7-16.8 ng/mL (SI: 15-356 mIU/L) | Apr 2022 |
| TSH | 1.8 mIU/L | 0.4-4.0 mIU/L | Apr 2022 |
| Free T4 | 1.2 ng/dL (SI: 15.4 pmol/L) | 0.8-1.8 ng/dL (10.3-23.2 pmol/L) | Apr 2022 |
| IGF-1 | 145 ng/mL (SI: 145 µg/L) | 101-267 ng/mL (101-267 µg/L) | Apr 2022 |
| GH | 2.1 µg/L (SI: 2.1 ng/mL) | 0.4-10 µg/L (SI: 0.4-10 ng/mL) | Apr 2022 |
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; HbA1c, glycated hemoglobin; IGF1, insulin-like growth factor 1; LH, luteinizing hormone; ODST, overnight dexamethasone suppression test; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.
Treatment
Post-thymectomy, the patient was started on octreotide long-acting release (LAR) at 20 mg (monthly) for its potential antiproliferative effect on the pancreatic neuroendocrine tumors and to control ACTH secretion from a suspected ectopic source [3]. However, hypercortisolism persisted, with UFC levels elevated at 1560 µg/24H (SI: 4306 nmol/24H) (normal <140 µg/24H [SI: <386 nmol/24H]). A follow-up Ga68 -DOTATATE scan 6 months later showed mild progression of the pancreatic lesions, with the body lesion now measuring 1.4 cm (SUVmax 76.2). The octreotide LAR dose was subsequently increased to 30 mg monthly. The patient declined any further surgical interventions. We opted for osilodrostat over other adrenal steroidogenesis inhibitors like metyrapone due to its potent 11β-hydroxylase inhibition, newer approval, and twice-daily dosing schedule, which may improve adherence, and because metyrapone was not commercially available in our country at the time. Osilodrostat was initiated at 2 mg twice daily and titrated to 5 mg twice daily.
Outcome and follow-up
The response was dramatic. UFC levels were reduced by 76%, and the patient lost approximately 47 kg over 6 months (Fig. 2). This was accompanied by significant functional improvement, including the ability to walk 3 km daily and return to full-time work (Table 2). Pretreatment hypokalemia (3.1 mmol/L) and hypertension (175/92 mmHg) resolved without specific intervention, normalizing to 4.1 mmol/L and 135/75 mmHg, respectively (Table 2). The patient is monitored for potential adrenal insufficiency and is educated on sick-day rules.
Figure 2.
Changes in 24H urinary cortisol and body weight with osilodrostat treatment (including clinical response parameters). Conversion: nmol/24H ÷ 2.76 = µg/24H.
Table 2.
Osilodrostat response
| Timepoint | Dose | K (mmol/L) | BP (mmHg) | Functional improvement |
|---|---|---|---|---|
| Baseline | None | 3.1 mmol/L | 175/92 | Unable to climb stairs/pray |
| Week 4 | 2 mg BID | 3.3 mmol/L | 150/85 | Minimal mobility improvement |
| Week 12 | 5 mg BID | 3.6 mmol/L | 141/80 | Walking 1 Km, partial work return |
| Week 16+ | 5 mg BID | 4.1 mmol/L | 135/75 | Walking 3 Km, full work capacity |
Abbreviations: BID, bis in die (twice daily); BP, blood pressure
Osteoporosis was diagnosed by dual-energy X-ray absorptiometry (DXA) in April 2022, which revealed a T-score of −3.6 at the lumbar spine (L1-L4). The patient's current regimen therefore includes osilodrostat (5 mg twice daily [bid]), octreotide LAR (30 mg monthly), testosterone (250 mg intramuscular monthly), and denosumab (60 mg every 6 months) for bone protection. Follow-up imaging shows stable disease.
After a 6-week washout of osilodrostat, an IPSS procedure was performed, which confirmed a central pituitary source of ACTH (Table 3). Additionally, a corticotropin-releasing hormone (CRH) stimulation test was performed as part of the comprehensive diagnostic workup, the results of which were consistent with a pituitary etiology (Table 4).
Table 3.
Inferior petrosal sinus sampling with desmopressin (DDAVP)
| Peripheral | Right petrosal | Left petrosal | |
|---|---|---|---|
| Baseline | ACTH 465 pg/mL (SI: 102.3 pmol/L) Prolactin 39.5 ng/mL (SI: 39.5 µg/L) |
ACTH 6637 pg/mL (SI: 1461.4 pmol/L) Prolactin 104.8 ng/mL (SI: 104.8 µg/L) |
ACTH 813.7 pg/mL (SI: 179.2 pmol/L) Prolactin 96.76 ng/mL (SI: 96.8 µg/L) |
| Given DDAVP over 1 minute | |||
| Post injection ACTH | 442 pg/mL (SI: 97.3 pmol/L) | 752.8 pg/mL (SI: 165.8 pmol/L) | 1271 pg/mL (SI: 279.9 pmol/L) |
| 2 minutes ACTH | 437.3 pg/mL (SI: 96.3 pmol/L) | 875.5 pg/mL (SI: 192.8 pmol/L) | 1933 pg/mL (SI: 425.6 pmol/L) |
| 5 minutes ACTH | 452.4 pg/mL (SI: 99.6 pmol/L) | 709.1 pg/mL (SI: 156.1 pmol/L) | 1515 pg/mL (SI: 333.6 pmol/L) |
| 10 minutes ACTH | 406.2 pg/mL (SI: 89.4 pmol/L) | 570.5 pg/mL (SI: 125.6 pmol/L) | 1399 pg/mL (SI: 308.0 pmol/L) |
| Superior vena cava | 478.1 pg/mL (SI: 105.3 pmol/L) | ||
| Inferior vena cava | 383.4 pg/mL (SI: 84.4 pmol/L) | ||
Abbreviations: ACTH, adrenocorticotropic hormone; DDAVP, desmopressin.
Table 4.
Corticotrophin-releasing hormone stimulation test
| Time | −15 minutes | 0 minutes | 15 minutes | 30 minutes | 45 minutes | 60 minutes | 90 minutes | 120 minutes |
|---|---|---|---|---|---|---|---|---|
| Cortisol | 15.63 µg/dL (SI: 431 nmol/L) | 16.52 µg/dL (SI: 456 nmol/L) | 23.67 µg/dL (SI: 654 nmol/L) | 27.48 µg/dL (SI: 759 nmol/L) | 28.89 µg/dL (SI: 798 nmol/L) | 25.93 µg/dL (SI: 716 nmol/L) | 22.47 µg/dL (SI: 620 nmol/L) | 19.26 µg/dL (SI: 532 nmol/L) |
| ACTH | 108 pg/mL (SI: 23.7 pmol/L) | 135 pg/mL (SI: 29.8 pmol/L) | 437 pg/mL (SI: 96.2 pmol/L) | 212 pg/mL (SI: 46.8 pmol/L) | 253 pg/mL (SI: 55.6 pmol/L) | 236 pg/mL (SI: 52.1 pmol/L) | 157 pg/mL (SI: 34.6 pmol/L) |
Abbreviation: ACTH, adrenocorticotropic hormone.
Although pituitary surgery was offered, the patient declined and opted to resume medical therapy with osilodrostat.
Discussion
This case illustrates the intricate diagnostic and therapeutic challenges posed by MEN1 syndrome when it presents with ACTH-dependent Cushing disease. Our patient exhibited a classic clinical picture of CS, but the subsequent discovery of multi-organ involvement, a pituitary microadenoma, a thymic carcinoid, and pancreatic neuroendocrine tumors, signaled a more complex etiology. The diagnosis of MEN1 was unequivocally confirmed by genetic analysis performed at Centogene GmbH, which identified a pathogenic heterozygous MEN1 frameshift variant.
While MEN1 is most commonly associated with parathyroid tumors [4], its presentation with CS represents a major diagnostic challenge due to the potential for ACTH secretion from pituitary, ectopic (typically thymic), or adrenal sources [2, 5, 6].
Pituitary tumors are present in about 40% of MEN1 patients, and up to 5-10% of such tumors secrete ACTH. Ectopic tumoral ACTH secretion has also been observed in MEN1, almost exclusively originating from thymic neuroendocrine tumors [2]. Thymic neuroendocrine tumors in MEN1 are extremely rare, often exhibit an aggressive course, are typically nonfunctional and carry a poor prognosis [7, 8].
This complexity is underscored by analyses of large MEN1 cohorts, where the precise etiology of CS can sometimes remain elusive [5]. As summarized in Table 5, which categorizes the etiologies of CS in reported MEN1 cases, several cases of functional ACTH-secreting thymic tumors in MEN1 have been reported [6, 8-13], highlighting this clinical scenario. This case exemplifies this diagnostic dilemma, where the co-existence of a pituitary microadenoma, thymic carcinoid and pancreatic neuroendocrine tumors necessitated extensive investigation [2]. In this context of diagnostic uncertainty, where an ectopic ACTH source from the thymic or pancreatic tumors was a strong possibility, a trial of octreotide LAR was initiated for its potential antiproliferative effect and to reduce ACTH secretion from a suspected ectopic source [3]. It was initially thought that the source of hypercortisolism was the thymus, as many MEN1 cases with CS present with ectopic ACTH secretion [6, 8-13]. However, in this case, the failure of thymectomy to correct the hypercortisolism was a pivotal clue that the primary source lay elsewhere.
Table 5.
Etiology of Cushing syndrome in reported MEN1 cases
| Source of CS | Number of cases (representative references) | Notes |
|---|---|---|
| Pituitary (Cushing disease) | 70-80% [5, 14, 15] | Most common cause in larger cohorts |
| Adrenal | 20-30% [5, 16] | Can be adenoma or carcinoma |
| Thymic | Rare <5% [7, 8, 10-13] | Often aggressive, carries poor prognosis |
| Unknown | Reported [5] | Etiology not definitively established |
Abbreviations: CS, Cushing syndrome; MEN1, multiple endocrine neoplasia type 1.
The patient failed to respond biochemically to octreotide. The subsequent IPSS and CRH stimulation test (Tables 3 and 4) were therefore critical, as they definitively confirmed a pituitary source, classifying this as Cushing disease and explaining the lack of response to octreotide.
This case is noteworthy for 2 primary reasons. First, the patient's refusal of further surgery after thymectomy created a therapeutic impasse, compounded by the failure of medical therapy with octreotide LAR. Second, and most significantly, to the best of our knowledge, this represents the first reported case of successful long-term biochemical and clinical control of MEN1-associated Cushing disease using osilodrostat. While osilodrostat is established for Cushing disease, its successful application in the complex diagnostic and therapeutic landscape of MEN1 represents a novel clinical insight.
The response to osilodrostat was dramatic and sustained. Not only did it effectively achieve a 76% reduction in UFC levels (Fig. 2), but it also led to profound clinical improvement, including a 47 kg weight loss, resolution of hypokalemia and hypertension (Table 2), and a complete restoration of functional capacity and quality of life. This suggests that osilodrostat is a potent and viable therapeutic option for patients in whom surgical intervention is not feasible or is declined.
The efficacy of osilodrostat in this case can be attributed to its distinct mechanism of action. Osilodrostat is a potent oral inhibitor of 11β-hydroxylase, the enzyme responsible for the final step of cortisol synthesis in the adrenal gland [17]. By directly blocking adrenal cortisol production, it effectively controls hypercortisolism regardless of the ACTH source. This explains the rapid biochemical and clinical response observed in our patient.
While the response has been sustained and well-tolerated over 6 months, long-term vigilance is warranted. Potential challenges include escape from biochemical control due to compensatory rises in ACTH or the development of adverse effects such as hypoadrenalism, hypokalemia, or hypertension [18]. Furthermore, monitoring for potential growth of the pituitary microadenoma with periodic MRI is warranted. Ongoing monitoring of urinary free cortisol, electrolytes and blood pressure is also essential. This case adds to the growing evidence for osilodrostat's efficacy and supports its role as a viable long-term medical option for patients with Cushing disease who are not surgical candidates.
The case also underscores other management considerations in MEN1. Osteoporosis diagnosed by DXA scan justified the initiation of denosumab, highlighting the need for comprehensive bone health management. Furthermore, the persistent hypogonadism necessitated testosterone replacement, addressing another facet of this multi-system disorder.
In conclusion, navigating a concealed MEN1 syndrome manifesting as CS requires extensive imaging and genetic analysis. This case illustrates that in the presence of such complexity, a precise etiological diagnosis is paramount. Interventional procedures like IPSS remain the gold standard for differentiating between pituitary and ectopic ACTH sources. The initial lack of response to thymectomy and octreotide, followed by the definitive confirmation of a pituitary source, highlights this necessity. This case emphasizes that when surgery is not an option, osilodrostat can serve as an effective therapeutic pillar, offering complete clinical and biochemical control. This novel finding expands the treatment arsenal for this challenging patient population.
Learning points
First reported use of osilodrostat in MEN1-associated Cushing disease—achieved an approximate 76% reduction in urinary cortisol, 47 kg weight loss, and complete functional recovery when surgery was declined
IPSS confirmed pituitary source despite concurrent thymic carcinoid—highlighting that multiple potential ACTH sources can coexist in MEN1, requiring systematic localization even after partial tumor resection
Multi-modal therapy is required for comprehensive MEN1 management: osilodrostat for hypercortisolism, octreotide LAR for neuroendocrine tumors, testosterone replacement for hypogonadism, and denosumab for osteoporosis
Acknowledgments
The author gratefully acknowledges the Department of Endocrinology at King Hussain Medical City, Royal Medical Services, Amman, Jordan, for their expert management of this case and their performance of critical diagnostic procedures. The author also acknowledges Recordati Rare Diseases for funding editorial assistance in the form of language editing and formatting, provided by Guy Ramsay. The funder had no role in the study design, data collection, analysis, or writing of the scientific content.
Contributors
As sole author, H.F.J. was responsible exclusively for the study investigation, data collection and reporting, conception and drafting of the manuscript, and all revisions.
Funding
No public or commercial funding.
Disclosures
None declared.
Informed patient consent for publication
Signed informed consent obtained directly from the patient.
Data availability
Original data generated and analyzed during this study are included in this published article.
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Associated Data
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Data Availability Statement
Original data generated and analyzed during this study are included in this published article.