Rare and aggressive metastatic pheochromocytoma recurrence in a patient with MEN 2A syndrome.

An adult male in his early 30s diagnosed with multiple endocrine neoplasia type 2A syndrome, confirmed through genetic testing, presented as bilateral pheochromocytoma in a metachronous fashion, primary hyperparathyroidism and medullary thyroid carcinoma. Left and right adrenalectomy was done 9 years and 3 years ago, respectively. He was also subjected to total thyroidectomy with neck dissection and left inferior parathyroidectomy. During surveillance monitoring, 24-hour total urine metanephrines were elevated 13.977 mg (Normal value 0-1 mg) 1 year after right adrenalectomy. Adrenal CT scan demonstrated a 2.1 cm ovoid focus in the right suprarenal region, and functional imaging (131I meta-iodobenzylguanidine (MIBG scan) showed an avid uptake on the right frontal bone. Excision of the right adrenal bed and the right frontal bone tumour was performed, and metastatic pheochromocytoma was confirmed histologically. The patient achieved clinical and biochemical remission postoperatively and is currently receiving steroid and thyroxine replacement.

Pediatric head and neck manifestations associated with multiple endocrine neoplasia syndromes.

INTRODUCTION: Multiple endocrine neoplasia (MEN) syndromes are a group of hereditary cancer syndromes that can predispose children to endocrine neoplasms developing within the head and neck. OBJECTIVE: To examine the neoplastic manifestations of MEN type 1 (MEN1) and MEN type 2 (MEN2) in the pediatric head and neck. METHODS: Single-institution, retrospective review of pediatric MEN between 2005 and 2022. RESULTS: Fifty-three children were genetically confirmed with MEN (15 MEN1, 34 MEN2A, and 4 MEN2B), while three patients received clinical diagnoses of MEN1. The male to female ratio was essentially equal (1.15:1), and a documented family history of cancer was present in 89% (50/56). After multidisciplinary evaluation, a familial MEN diagnosis was confirmed in 91% (51/56). The mean ages of initial presentation and surgical intervention were 8.9 years (SD 5) and 9.8 years (SD 4.8), respectively. Although patients with MEN2 received surgery earlier than patients with MEN1 (8.7 vs 12.7 years), surgical patients with MEN2 in this cohort were older relative to current American Thyroid Association (ATA) guidelines primarily due to late presentation. Thyroid malignancies were identified in 36% (9/25) of thyroidectomy specimens (21 MEN2A, 4 MEN2B), with medullary thyroid carcinoma (MTC) present in five MEN2A patients and three MEN2B patients (89%), and papillary thyroid carcinoma (PTC) present in one MEN2A patient (11%). Nearly 90% (8/9) of thyroid malignancies were occult, with some occurring earlier than predicted by current guidelines (ATA-MOD and ATA-H). Central neck dissections were performed in 24% (2 MEN1, 2 MEN2A, and 4 MEN2B), with two MEN2B (50%) demonstrating cervical lymph node (LN) metastases. Additional histopathologic findings included C-cell hyperplasia in 57% (12/21) of MEN2A thyroidectomy patients. Of the eight MEN1 parathyroidectomy patients, four demonstrated parathyroid hyperplasia and four presented with parathyroid adenoma. CONCLUSION: Nearly 60% required head and neck procedures. While MEN1 guidelines were appropriate for our cohort, we identified patients with MEN2 that developed MTC earlier than expected based on current ATA guidelines, including children in categories considered lower risk. In conjunction with a multidisciplinary approach, pediatric head and neck surgeons should be aware of the potential need for earlier surgical intervention in the pediatric MEN2 population.

[Pheochromocytoma associated with primary hyperparathyroidism and type 1 neurofibromatosis]. / Feokhromotsitoma v sochetanii s pervichnym giperparatireozom i neirofibromatozom tipa 1.

Neurofibromatosis type 1 (NF-1) is a predominantly inherited genetic disease with prevalence of 1 per 2500-3000 newborns and based on clear clinical criteria. In addition to common neurofibromas and gliomas of the visual pathways, these patients have a higher risk of various benign and malignant tumors throughout their lives including tumors of the central nervous system, membranes of peripheral nerves, gastrointestinal stromal tumors and leukemia. Endocrine diseases and neoplasms also occur in patients with NF-1 and can include extrarenal paraganglioma, primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumors, thyroid tumors and other adrenal neoplasms. We demonstrate multiple neuroendocrine neoplasia (MEN 2A) of neurofibromatosis type 1 combined with pheochromocytoma and primary hyperparathyroidism in a woman with a long history of palpitations, paroxysmal hypertension and osteoporosis. Biochemical analysis revealed severe hypercalcemia with elevated parathyroid hormone indicating primary hyperparathyroidism, as well as high fractionated normetanephrine and metanephrine in the urine as a sign of catecholamine-releasing pheochromocytoma/paraganglioma. Further scintigraphy revealed signs of solitary parathyroid adenoma causing primary hyperparathyroidism and right-sided pheochromocytoma. Clinical diagnosis of MEN-2 syndrome is based on combination of at least two major MEN-2-associated endocrine tumors. Resection of parathyroid adenoma and pheochromocytoma normalized biochemical parameters and blood pressure. Combination of pheochromocytoma with primary hyperparathyroidism and type 1 neurofibromatosis is discussed.

Case Report: A Case of Moyamoya Syndrome Associated With Multiple Endocrine Neoplasia Type 2A.

To the best of our knowledge, we report a case of MEN2A complicated by moyamoya syndrome. A 52-year-old woman presented with vertigo. Magnetic resonance angiography (MRA) revealed bilateral supraclinoid stenosis of the internal carotid artery and abnormal moyamoya-like vessels around the basal ganglia. She had a heterozygous variant of RNF213, which is the susceptibility gene for moyamoya disease. She had also previously received diagnoses of medullary thyroid carcinoma (MTC) at age 23 and left-sided pheochromocytoma (PHEO) at age 41. Genetic testing revealed heterozygosity for a mutation at codon 634 in exon 11 (TGC-TTC mutation; p.Cys634Phe) of the Ret gene. Intracranial vascular stenosis may have been caused by a genetic mutation of RNF213 and hypersecretion of catecholamines by MEN2A. Physicians should recognize that MEN2A can be present with moyamoya syndrome.

Pheochromocytoma: A three-decade clinical experience in a multicenter study.

OBJECTIVE: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC). DESIGN AND METHODS: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals. RESULTS: A total of 106 patients (61 [57.5%] women, mean age 52.3 ±â€¯14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ±â€¯14.2 years vs 54.5 ±â€¯13.9 years, p < .001). Familial PCCs were more frequently associated with MEN2A (n = 8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3 cm (3-6 cm); 27.7% of the patients had tumors ≥6 cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4 cm [2.4-5.0 cm] vs 5.6 cm [4.0-7.0 cm], p < .001). Scintigraphy by ¹²³I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%). CONCLUSIONS: PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low.

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.

Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2.

Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1-2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.

Effect of Lenvatinib on a Patient with Medullary Thyroid Carcinoma Liver Metastasis Caused by Multiple Endocrine Neoplasia Type 2A.

A 61-year-old female was diagnosed with multiple endocrine neoplasia type 2A (MEN2A), caused by a heterozygous point mutation in the RET gene (TGC to TAC at codon 634) resulting in the substitution of cytosine with leucine (C634Y). The patient had pheochromocytoma (PCC) in the left adrenal gland and medullary thyroid carcinoma (MTC) with liver metastasis. Primary hyperparathyroidism (PHP) was not evident. Family history data suggested that the RET gene mutation was inherited from the father. The PCC was removed laparoscopically, but the MTC was observed conservatively for 7 years because the status of the MTC was compatible with T1N1M1 and stage IVC; therefore, it was not curable with surgery. The MTC liver metastasis increased in size. Lenvatinib, an oral multi-tyrosine kinase inhibitor, was administered until the patient had received a total dose of 1336mg, and then administration was stopped because of nausea. The reduction rate of the MTC liver metastasis was 31%, which was considered partial response. At this point, the patient was doing well, suggesting that lenvatinib was effective in treating the MTC liver metastasis and may be one of the treatment for advanced MTC caused by C634Y mutation in the RET gene.

Use of Dexmedetomidine in a Parturient With Multiple Endocrine Neoplasia Type 2A Undergoing Adrenalectomy and Thyroidectomy: A Case Report.

Dexmedetomidine is a selective α2-agonist, frequently used in perioperative medicine as anesthesia adjunct. The medication carries a Food and Drug Administration pregnancy category C designation and is therefore rarely used for parturients undergoing nonobstetric surgery. We are reporting the use of dexmedetomidine in the anesthetic management of a parturient undergoing minimally invasive unilateral adrenalectomy for pheochromocytoma during the second trimester of pregnancy. Additionally, because of the multiple endocrine neoplasia type 2A constellation with diagnosis of medullary thyroid cancer, the patient underwent a total thyroidectomy 1 week after the adrenalectomy.

[Pheochromocytoma in multiple endocrine neoplasia 2A associated with pulmonary tuberculosis presenting as abdominal pain: a case report and literature review]. / Feocromocitoma en neoplasia endocrina múltiple IIA asociado a tuberculosis pulmonar presentada como abdomen agudo: reporte de caso y revisión de la literatura.

Pheochromocytoma is a catecholamine-producing neoplasm that may occur sporadically or associated with hereditary diseases, such as multiple endocrine neoplasia. The classic symptoms are headache, sweating, and palpitations and are attributed to the sympathetic nervous system activity, usually presenting as paroxysms. On the other hand, pulmonary tuberculosis is an infectious disease considered a public health problem in many countries, whose incidence depends on risk factors such as immunosuppression. It is well known that endocrine-tumor diseases such as multiple endocrine neoplasia can predispose to chronic inflammation and immunosuppression. We report the case of a 38-year-old male patient who had an episode of arterial hypertension and abdominal pain as the first symptoms of a pheochromocytoma associated with multiple endocrine neoplasia type 2A. The patient developed pulmonary tuberculosis simultaneously, but we managed to treat both entities and achieve a favorable clinical course.

El feocromocitoma constituye una neoplasia productora de catecolaminas que se presenta de forma esporádica o asociada a enfermedades de transmisión hereditaria, como la neoplasia endocrina múltiple. Los síntomas clásicos como la cefalea, sudoración y palpitaciones son atribuidos a la actividad del sistema nervioso simpático y suelen presentarse en forma de paroxismos. La tuberculosis pulmonar es una enfermedad infecciosa que constituye un problema de salud pública en muchos países, cuya incidencia depende de algunos factores incluyendo la inmunosupresión que generan las enfermedades endocrino-tumorales como la antes descrita. Presentamos el caso de un paciente masculino de 38 años que acude a emergencia por presentar un paroxismo de hipertensión arterial y dolor abdominal, como manifestaciones iniciales de un feocromocitoma en el contexto de una neoplasia endocrina múltiple de tipo IIA. El paciente desarrolló de forma concomitante tuberculosis pulmonar; no obstante, se logró tratar ambas entidades consiguiendo una evolución clínica favorable.

Quality of life in multiple endocrine neoplasia type 2A compared with normative and disease populations.

BACKGROUND: Patient-reported outcomes are measured in chronic disease states to inform intervention and management decisions while minimizing negative outcomes. We hypothesized that health-related quality of life in patients with multiple endocrine neoplasia type 2A would be worse than the general US population but similar to other chronic diseases. METHODS: Adults ≥18 years with multiple endocrine neoplasia type 2A were recruited to complete the Patient-Reported Outcomes Measurement Information System 29-item questionnaire (n = 45). Scores based on the Patient-Reported Outcomes Measurement Information System T-score metric were compared with the general US population and with cohorts with low back pain, cancer, congestive heart failure, chronic obstructive pulmonary disease, major depressive disorder, rheumatoid arthritis, neuroendocrine tumors, primary hyperparathyroidism, and MEN1. RESULTS: Compared with US normative data, multiple endocrine neoplasia type 2A patients reported worse anxiety (58.2 ± 12.0, P < .0001), depression (55.4 ± 12.0, P < .01), fatigue (61.4 ± 10.8, P < .0001), pain interference (54.0 ± 11.5, P < .05), and sleep disturbance (56.9 ± 2.7, P < .001), as well as significantly lower physical functioning (45.7 ± 9.3, P < .01) and ability to participate in social roles (46.4 ± 9.7, P < .05). Multiple endocrine neoplasia type 2A patients reported greater fatigue than patients with cancer (P < .0001), chronic obstructive pulmonary disease (P = .01), rheumatoid arthritis (P = .0002), neuroendocrine tumors (P = .0007), and primary hyperparathyroidism (P < .0001) but higher physical functioning compared with patients with rheumatoid arthritis (P = .02), low back pain, congestive heart failure, and chronic obstructive pulmonary disease (P < .0001). CONCLUSIONS: This study is the first to use the Patient-Reported Outcomes Measurement Information System to compare patient-reported outcomes between multiple endocrine neoplasia type 2A and other chronic conditions. Individuals with multiple endocrine neoplasia type 2A reported worse health-related quality of life in all 7 domains compared with US normative data. Multiple endocrine neoplasia type 2A patients reported greater fatigue but greater physical function compared with several other conditions. Prospective longitudinal evaluation of patient-reported outcomes in multiple endocrine neoplasia type 2A should be conducted to identify treatments associated with the highest health-related quality of life.

The Clinical Spectrum of Multiple Endocrine Neoplasia Type 2A with Cutaneous Lichen Amyloidosis in Ethnic Han Chinese.

This study systematically reviewed previous literatures and analyzed the genotype-phenotype relationship between the multiple endocrine neoplasia type 2A (MEN 2A)-cutaneous lichen amyloidosis (CLA) and RET/OSMR/IL31RA mutations. RET/OSMR/IL31RA screening was performed on 8 RET-carriers from 3 independent Chinese MEN 2A families. Besides, 51 MEN 2A-CLA patients in 116 RET carriers from literatures were clustered and analyzed. Our results indicated that almost all MEN 2A-CLA patients exhibited CLA which was located in the scapular region and carried RET mutation at codon 634. Meanwhile, we firstly described MEN 2A-CLA here in Chinese Han patient with RET p.C634F mutation.

Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism.

While primary hyperparathyroidism (PHPT) generally represents a common endocrine disorder, being the more frequent cause of hypercalcemia in outpatients, familial forms of PHPT (FPHPT) account for no more than 2-5% of the overall PHPT. In the last decades, many technical progresses in both molecular and biochemical-radiological evaluation have been made, and substantial advancements in understanding these disorders have been reached. Differences both in the pathogenesis and clinical presentation exist among the various hyperparathyroid syndromic forms, and, since FPHPT is frequently associated to other endocrine, proliferative and/or functional disorders, as also non-endocrine tumours, with varying clinical spectrum of occurrence in each syndrome, its early clinically detection for appropriately preventing complications (i.e. kidney and bone disorders) is strictly advised. In this review, the clinical-biochemical features and diagnostic procedures of each FPHPT form will be summarized and a general overview on surgical and pharmacological approaches to FPHPT has been also considered.

Feocromocitoma en neoplasia endocrina múltiple IIA asociado a tuberculosis pulmonar presentada como abdomen agudo: reporte de caso y revisión de la literatura / Pheochromocytoma in multiple endocrine neoplasia 2A associated with pulmonary tuberculosis presenting as abdominal pain: a case report and literature review

El feocromocitoma constituye una neoplasia productora de catecolaminas que se presenta de forma esporádica o asociada a enfermedades de transmisión hereditaria, como la neoplasia endocrina múltiple. Los síntomas clásicos como la cefalea, sudoración y palpitaciones son atribuidos a la actividad del sistema nervioso simpático y suelen presentarse en forma de paroxismos. La tuberculosis pulmonar es una enfermedad infecciosa que constituye un problema de salud pública en muchos países, cuya incidencia depende de algunos factores incluyendo la inmunosupresión que generan las enfermedades endocrino-tumorales como la antes descrita. Presentamos el caso de un paciente masculino de 38 años que acude a emergencia por presentar un paroxismo de hipertensión arterial y dolor abdominal, como manifestaciones iniciales de un feocromocitoma en el contexto de una neoplasia endocrina múltiple de tipo IIA. El paciente desarrolló de forma concomitante tuberculosis pulmonar; no obstante, se logró tratar ambas entidades consiguiendo una evolución clínica favorable.

Pheochromocytoma is a catecholamine-producing neoplasm that may occur sporadically or associated with hereditary diseases, such as multiple endocrine neoplasia. The classic symptoms are headache, sweating, and palpitations and are attributed to the sympathetic nervous system activity, usually presenting as paroxysms. On the other hand, pulmonary tuberculosis is an infectious disease considered a public health problem in many countries, whose incidence depends on risk factors such as immunosuppression. It is well known that endocrine-tumor diseases such as multiple endocrine neoplasia can predispose to chronic inflammation and immunosuppression. We report the case of a 38-year-old male patient who had an episode of arterial hypertension and abdominal pain as the first symptoms of a pheochromocytoma associated with multiple endocrine neoplasia type 2A. The patient developed pulmonary tuberculosis simultaneously, but we managed to treat both entities and achieve a favorable clinical course.

La chirurgie d'épargne surrénalienne : du cortex à la médulla: Cortical sparing surgery: from cortex to medulla.

The 2017 Endocrine Society annual meeting included several communications and debates on the conservative adrenal surgery in bilateral hereditary pheochromocytomas (BHP), bilateral adrenal macronodular hyperplasia (BAMH) and primary hyperaldosteronism (PHA). The general principle is to preserve a part of the adrenal cortex to prevent the occurrence of a definitive adrenal insufficiency. In BHP, cortical sparing surgery allows more than 50% of patients to maintain normal corticotropic function at 10 years with a low recurrence rate (~ 10%). Since the adrenal medulla cannot be removed entirely, recurrence seems inevitable and long-term follow-up is essential. Individual risk of malignancy must be taken into account. In BAMH responsible for Cushing syndrome, unilateral adrenalectomy induces a normalization of urinary free cortisol in 92 to 100% of cases and even corticotropic insufficiency in 40 to 100% of cases. This is most often transient. Late recurrences of Cushing's syndrome may occur in 13 to 60% of cases. Prolonged patient monitoring is therefore essential. In PAH with lateralized aldosterone production, minimally invasive partial adrenal surgery, which consists of removing only the adrenal adenoma visualized at TDM, allows an improvement blood pressure in about 94% of patients. However, failure or recurrence may occur. Its place therefore remains marginal in the treatment of the lateralized PAHs.

Dermal Hyperneury and Multiple Sclerotic Fibromas in Multiple Endocrine Neoplasia Type 2A Syndrome.

Importance: Multiple endocrine neoplasia type 2 (MEN 2) syndrome is an autosomal dominant, hereditary cancer disorder caused by germline mutations in the RET (formerly MEN2A, MEN2B) proto-oncogene located on chromosomal band 10q11.21. Two distinct clinical forms have been described as the following phenotypes: multiple endocrine neoplasia type 2A (MEN 2A) and multiple endocrine neoplasia type 2B (MEN 2B) syndromes. The common and necessary nexus that defines these 2 phenotypes is the presence of medullary thyroid carcinoma (MTC). The familial MTC type of MEN 2 syndrome was included within the spectrum of MEN 2A syndrome. Cutaneous manifestations of MEN 2A syndrome include macular amyloidosis, whereas MEN 2B syndrome is traditionally linked to multiple mucosal neuromas. Objectives: To describe a family with cutaneous manifestations not previously described in patients with MEN 2A syndrome and to discuss the association of this disorder with Cowden syndrome. Design, Setting, and Participants: Clinicopathologic correlation of cutaneous lesions and genetic studies in 11 members of a family with familial MTC. Interventions: Cutaneous lesions were histopathologically and immunohistochemically studied. Genetic screening for a germline mutation at the RET gene was performed in 11 family members. Main Outcomes and Measures: Identification of cutaneous lesions not previously described in patients with MEN 2A syndrome. Results: This family of 11 individuals with familial MTC type of MEN 2A syndrome demonstrated the moderate risk RET p.Val804Met (protein valine at residue 804 replaced by methionine) genetic mutation, with 2 of the relatives presenting with dermal hyperneury, cutaneous lesions classically described in MEN 2B syndrome, and 1 relative also showing multiple sclerotic fibromas, a cutaneous manifestation of PTEN (phosphatase and tensin homologue) hamartoma-tumor syndrome. Conclusions and Relevance: Dermal hyperneury and multiple sclerotic fibromas should be added to the list of cutaneous manifestations of patients with the familial MTC type of MEN 2A syndrome.