Simple Clinical Presentation of a Complicated Disease: The Story of Two Women with MEN 1

Case 1: A 47-Year-Old Female

Clinical Presentation A 47-year-old unmarried female with a history of chronic kidney disease (CKD) and hypothyroidism presented with a five-day history of watery diarrhea, nausea, and vomiting. The diarrhea was waxing and waning in nature, and there was no associated fever, pain abdomen, or weight loss. She had a prior history of hospital admissions for similar complaints and was managed with IV fluids, antibiotics, and probiotics, which showed minimal improvement.

On examination, she was noted to have mild pallor and clinical signs of dehydration. No lymphadenopathy or hepatosplenomegaly was observed. The physical examination of the abdomen was unremarkable.

Investigations and Findings The investigations revealed significant abnormalities, as summarized in Table 1. Key findings included elevated serum calcium and iPTH levels in both cases, imaging-confirmed parathyroid adenomas, and additional biochemical markers supporting the diagnosis of MEN 1. Upper G I Endoscopy showing multiple sessile gastric and duodenal polyps ( Figures 1), Key findings included elevated serum calcium, high iPTH levels, and imaging confirming a left lower parathyroid adenoma ( Figures 2) and MRI Brain showing pituitary adenoma (Figure 3).

Figure 1. Upper G I Endoscopy showing multiple sessile gastric and duodenal polyps.

Figure 2. 99mTc-MIBI scan highlighting left lower parathyroid adenoma, which was identified as the cause of hyperparathyroidism in Case 1.

Figure 3. MRI Brain showing pituitary adenoma in Case 1.

Management: The patient was started on medical therapy due to her poor general condition and advanced CKD.

Parathyroid tablet(30 mg BD): To manage hypercalcemia and suppress parathyroid hormone (PTH) secretion.

Surgery was deferred due to her poor general condition. After a week of medical management, significant improvements were observed, as detailed in Table 1.

Figures

Case 2: A 26-Year-Old Female

A 26-year-old female presented with a one-month history of persistent headaches and lower limb pain. She had been evaluated at an external center, where imaging revealed multiple osteolytic lesions in the skull. Fine-needle aspiration cytology (FNAC) of one of these lesions demonstrated no evidence of malignancy. She also reported generalized weakness and unintentional weight loss over the past few weeks.

On physical examination, the patient appeared pale with diffuse tenderness over long bones. Neurological assessment was unremarkable, and no focal deficits were noted.

Investigations and Findings

The diagnostic workup revealed significant biochemical abnormalities, strongly indicative of MEN1 syndrome.

Imaging Findings:

Figure 4. MRI showing osteolytic lesions in the skull, providing evidence of the skeletal manifestations in Case 2.

Figure 5. Tc99 MIBI scan demonstrating right upper parathyroid adenoma, confirming the diagnosis in Case 2.

Figure 6. MRI abdomen revealing a pancreatic tail lesion, consistent with neuroendocrine involvement in MEN 1.

These findings underscored the multisystem involvement characteristic of MEN1, integrating features of hyperparathyroidism and neuroendocrine tumors. A detailed summary of these findings is provided in Table 1.

Management

The patient was initially stabilized for a hypercalcemic crisis with:

Surgical Intervention

The patient underwent a parathyroidectomy, after which:

Diagnostic considerations and multidisciplinary approach

Diagnosing MEN 1 requires integrating clinical symptoms, biochemical findings, and imaging results to identify the involvement of multiple endocrine organs. In both cases, elevated serum calcium and iPTH levels were pivotal in diagnosing primary hyperparathyroidism, the most common manifestation of MEN 1. Imaging modalities like Tc99 MIBI scans and MRI confirmed the presence of parathyroid adenomas and associated neuroendocrine tumors.

The diagnostic process necessitated a multidisciplinary approach:

The combined expertise of these specialties ensured accurate diagnosis, effective treatment, and comprehensive care, highlighting the importance of collaborative management in MEN 1 cases.

Pathophysiology

The MEN1 gene mutation results in the loss of menin function, facilitating unchecked proliferation in endocrine tissues. MEN 1 primarily affects the parathyroid glands, pancreas, and anterior pituitary, though other tissues may also be involved. Hyperparathyroidism is the most common manifestation, present in over 90% of cases, and is often the earliest clinical feature. Tumors in the pancreas and gastrointestinal tract, such as gastrinomas and insulinomas, contribute significantly to morbidity. Pituitary adenomas, observed in about 30-40% of cases, frequently cause hormonal imbalances but may also be asymptomatic.^5,6

In Case 1, hyperparathyroidism and a gastrointestinal neuroendocrine tumor (gastrinoma) were evident, consistent with MEN 1’s hallmark presentations. In Case 2, the combination of skeletal involvement, pancreatic tail lesion, and hyperparathyroidism underscored the syndrome's multisystemic nature.

Diagnostic challenges

The diagnosis of MEN 1 often requires integrating clinical, biochemical, and imaging findings. Symptoms may vary widely depending on the organs involved, and patients may initially present with vague or nonspecific complaints.

Biochemical Markers

Elevated calcium and intact parathyroid hormone (iPTH) levels are critical in diagnosing primary hyperparathyroidism. Additional markers, such as chromogranin A and gastrin, aid in identifying neuroendocrine tumors. In both cases, these markers provided pivotal diagnostic insights. For instance, the markedly elevated chromogranin A and fasting serum gastrin in Case 1 confirmed the presence of a gastrinoma.

Imaging Modalities

Advanced imaging techniques play a central role in localizing tumors and guiding management. Tc99 MIBI scans are highly effective for identifying parathyroid adenomas, as demonstrated in both cases. MRI and CT imaging further delineate the extent of organ involvement and assess for metastatic disease. In Case 2, MRI revealed osteolytic skull lesions and a pancreatic tail neoplasm, underscoring the systemic involvement of MEN 1.⁷

Genetic Testing

While genetic confirmation of MEN 1 is definitive, it is often not immediately necessary for clinical diagnosis. Genetic testing, however, has significant implications for family screening and early detection in asymptomatic carriers. Both cases could benefit from genetic counseling to address familial risk.

Multisystem involvement and management

The multisystem nature of MEN 1 requires a comprehensive and multidisciplinary approach to management, involving endocrinologists, surgeons, radiologists, and oncologists. Each manifestation demands targeted therapeutic strategies:

Hyperparathyroidism

Primary hyperparathyroidism is the most common and earliest manifestation of MEN 1. Parathyroidectomy is the treatment of choice, particularly when symptomatic hypercalcemia or significant bone involvement is present. Case 2 exemplifies the success of this approach, with biochemical normalization post-surgery. Medical therapy with cinacalcet can be valuable in patients unfit for surgery, as in Case 1.

Neuroendocrine Tumors

Neuroendocrine tumors (NETs) in MEN 1 often secrete bioactive peptides, leading to distinct clinical syndromes. Gastrinomas, as seen in Case 1, can result in severe peptic ulcer disease. Management includes proton pump inhibitors, somatostatin analogs like octreotide, and, where feasible, surgical resection. Pancreatic NETs, such as the lesion identified in Case 2, may require surgery or targeted therapies, depending on the tumor’s functional status and metastatic potential.

Pituitary Involvement

Pituitary adenomas in MEN 1 may require medical management with hormone suppression therapies or surgical intervention in cases of significant mass effect or hormonal hypersecretion. Although not prominently featured in these cases, regular screening is essential given the high prevalence of pituitary tumors in MEN 1.

Case-specific insights

Case 1 highlights the challenges of managing MEN 1 in the presence of chronic comorbidities like CKD, which complicate surgical and medical interventions. Conservative management with cinacalcet and octreotide successfully stabilized the patient’s biochemical parameters, delaying the need for surgery. This underscores the importance of individualized treatment strategies.

In contrast, Case 2 demonstrates the more aggressive presentation of MEN 1 in a younger patient. The presence of severe osteoporosis, hypercalcemic crisis, and pancreatic involvement necessitated prompt surgical intervention. The significant improvement in biochemical parameters post-parathyroidectomy illustrates the efficacy of timely surgical management.

Long-term management and surveillance

MEN 1 is a lifelong condition requiring regular surveillance to detect new or recurrent tumors. Annual monitoring of serum calcium, PTH, chromogranin A, and imaging studies is recommended. Early detection of asymptomatic tumors can significantly improve outcomes. Genetic counseling and testing are crucial for first-degree relatives, as early identification in asymptomatic carriers enables proactive monitoring and intervention.⁸

Key observations and trends in MEN1 studies (2010–2025)

Multiorgan Involvement: MEN1 patients frequently develop tumors in multiple endocrine glands, primarily affecting the parathyroid, pancreas, and pituitary glands. Some cases also present with skeletal involvement (osteolytic lesions) or mediastinal masses, underscoring the need for a comprehensive diagnostic approach shown in Table 2.

Diagnostic Markers and Biochemical Evaluation: Elevated serum calcium and intact parathyroid hormone (iPTH) levels are consistent indicators of primary hyperparathyroidism, the most common MEN1 manifestation. For neuroendocrine tumors (NETs), Chromogranin A and Gastrin serve as valuable biomarkers, while fasting insulin and C-peptide levels are crucial for diagnosing insulinomas.

Role of Imaging in MEN1 Diagnosis: A combination of imaging techniques is essential for tumor localization and staging. Tc99 MIBI scans are effective for identifying parathyroid adenomas, whereas MRI and CT scans are preferred for detecting pancreatic and pituitary tumors. PET scans are utilized selectively, particularly in cases of suspected metastatic disease.

Genetic Testing and Family Screening: Given the hereditary nature of MEN1, genetic testing is crucial for confirming diagnoses and screening at-risk family members. Identifying asymptomatic carriers facilitates early detection and preventive care.

Treatment Strategies: Surgery vs. Medical Management: Surgical interventions, such as parathyroidectomy and tumor resection, are standard treatments for MEN1-related tumors. In cases where surgery is not feasible, medical therapies like Cinacalcet and Somatostatin analogs are effective for hormonal control and symptom management.

Follow-up and Long-Term Surveillance: Due to the lifelong risk of tumor recurrence, structured long-term follow-up is essential. Annual biochemical screeningsand routine imaging are recommended to detect early tumor recurrence or new growths. Additionally, genetic counseling is vital for at-risk family members to ensure proactive disease management.