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Chirurgie (Heidelberg, Germany) May 2024Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline... (Review)
Review
Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, a tumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on a positive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to a lesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30 years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: a shining example for the success of translational transnational medical research for the benefit of patients.
PubMed: 38806713
DOI: 10.1007/s00104-024-02105-x -
World Journal of Surgical Oncology May 2024In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence...
BACKGROUND
In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence of two genetic diseases, even with partially common symptoms, remains unusual. Therefore, targeted next-generation sequencing (NGS), along with genetic consultation and imaging studies, is essential for every patient with confirmed paraganglioma. In this report, we present two sisters diagnosed with multiple endocrine neoplasia type 2 (MEN2A) and familial paraganglioma syndrome type 1 (FPGL1).
CASE PRESENTATION
After presenting to the clinic with neck tumors persisting for several months, both patients underwent tumor removal procedures following imaging and laboratory studies. Pathological reports confirmed the diagnosis of paragangliomas. Subsequently, genetic testing, including NGS, revealed a mutation in the rearranged during transfection (RET) gene: the heterozygous change (c.2410G > A), (p.Val804Met), and a variant of the succinate dehydrogenase complex subunit D (SDHD) gene: (c.64 C > T), (p.Arg22Ter). Subsequently, thyroidectomy procedures were scheduled in both cases.
CONCLUSION
To the best of our knowledge, this is the first report presenting these two mutations in two related patients, resulting in distinctive genetic syndromes with similar manifestations. This underscores that although infrequent, multiple hereditary disorders may co-occur in the same individual.
Topics: Humans; Female; Multiple Endocrine Neoplasia Type 2a; Siblings; Succinate Dehydrogenase; Adult; Proto-Oncogene Proteins c-ret; Prognosis; Thyroidectomy; Mutation; Genetic Testing; Pedigree; Paraganglioma; High-Throughput Nucleotide Sequencing
PubMed: 38802890
DOI: 10.1186/s12957-024-03418-1 -
AACE Clinical Case Reports 2024Although common in adults, primary hyperparathyroidism (PHPT) is a rare condition in children with the most common etiology being solitary parathyroid adenoma (PTA). The...
BACKGROUND/OBJECTIVE
Although common in adults, primary hyperparathyroidism (PHPT) is a rare condition in children with the most common etiology being solitary parathyroid adenoma (PTA). The typical presentation is symptomatic hypercalcemia. Management of PHTP secondary to PTA requires excision of the adenoma.
CASE REPORT
A 13-year-old adolescent boy presented because of orbital cellulitis and was noted to have hypercalcemia. Despite this, the patient was curiously asymptomatic. Further investigations yielded an elevated parathyroid hormone (PTH) level and a normal urine calcium-to-creatinine ratio making the most likely cause of hypercalcemia PHTP secondary to PTA. Imaging demonstrated PTA. The patient underwent parathyroidectomy with the pathology demonstrating PTA. Postoperatively, the PTH levels were undetectable; hence, the patient was treated with calcitriol and calcium supplementation for 1 month and 4 months, respectively. Genetic work-up for multiple endocrine neoplasia 1 and rearranged during transfection mutations was negative.
DISCUSSION
Solitary PTA is the most common cause of PHPT. Adenomas are mostly sporadic or may be a manifestation of an inheritable syndrome, such as multiple endocrine neoplasia. Although symptomatic disease is more common in children, our patient denied any hypercalcemia symptoms. The distinguishing biochemical feature of PHPT because of PTA is high or inappropriately normal PTH level in the context of high-normal or elevated serum calcium levels. Urinary calcium excretion is usually normal or high. PTAs are localized by ultrasound and Tc-99m-Sestamibi scintigraphy. Management includes parathyroidectomy and monitoring for postoperative hypocalcemia.
CONCLUSION
In a child or adolescent presenting with hypercalcemia and elevated PTH levels, it is important to consider PHPT secondary to PTA, because an early diagnosis will aid in preventing complications from hypercalcemia.
PubMed: 38799050
DOI: 10.1016/j.aace.2024.02.008 -
Gastroenterology May 2024Present in all eukaryotic cells, the integrated stress response (ISR) is a highly coordinated signaling network that controls cellular behavior, metabolism, and survival... (Review)
Review
Present in all eukaryotic cells, the integrated stress response (ISR) is a highly coordinated signaling network that controls cellular behavior, metabolism, and survival in response to diverse stresses. The ISR is initiated when any 1 of 3 stress-sensing kinases (protein kinase R-like endoplasmic reticulum kinase [PERK], general control non-derepressible 2 [GCN2], double-stranded RNA-dependent protein kinase [PKR], heme-regulated eukaryotic translation initiation factor 2α kinase [HRI]) becomes activated to phosphorylate the protein translation initiation factor eukaryotic translation initiation factor 2α (eIF2α), shifting gene expression toward a comprehensive rewiring of cellular machinery to promote adaptation. Although the ISR has been shown to play an important role in the homeostasis of multiple tissues, evidence suggests that it is particularly crucial for the development and ongoing health of the pancreas. Among the most synthetically dynamic tissues in the body, the exocrine and endocrine pancreas relies heavily on the ISR to rapidly adjust cell function to meet the metabolic demands of the organism. The hardwiring of the ISR into normal pancreatic functions and adaptation to stress may explain why it is a commonly used pro-oncogenic and therapy-resistance mechanism in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Here we review what is known about the key roles that the ISR plays in the development, homeostasis, and neoplasia of the pancreas.
PubMed: 38768690
DOI: 10.1053/j.gastro.2024.05.009 -
Endocrine-related Cancer Jul 2024The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30...
The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.
Topics: Humans; Proto-Oncogene Proteins c-ret; Middle Aged; Adult; Multiple Endocrine Neoplasia Type 2a; Adolescent; Male; Female; Thyroid Neoplasms; Young Adult; Pheochromocytoma; Child; Aged; Child, Preschool; Adrenal Gland Neoplasms; Genotype; Infant; Germ-Line Mutation; Carcinoma, Neuroendocrine; Heterozygote; Hyperparathyroidism, Primary; Multiple Endocrine Neoplasia Type 2b; Aged, 80 and over
PubMed: 38753300
DOI: 10.1530/ERC-24-0038 -
Clinical Journal of Gastroenterology May 2024Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like...
Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like fatigue, a peculiar face with thickening of the lips, mucosal neuromas on the lips and tongue, and gastrointestinal phenomena. Most patients harbor pathological variants of the RET gene. Herein, we present the first case of a 14 year-old boy who experienced small intestinal volvulus along with a megacolon, and he was diagnosed with multiple endocrine neoplasia type 2B. The patient complained of constipation since he was 2 years old and slowly progressive abdominal distension at school age. At 14 years of age, he presented with remarkable megacolon mimicking Hirschsprung's disease and complicated with small intestinal volvulus. The volvulus was successfully repaired, and the particularly dilated transverse colon was resected following a rectal biopsy. Histopathological evaluation of the resected transverse colon revealed to be compatible with ganglioneuromatosis. After emergency surgery, the patient was diagnosed with multiple endocrine neoplasia type 2B with medullary thyroid carcinoma, and a de novo variant of RET was confirmed. Gastroenterologists should consider it when treating patients with constipation, especially those with megacolon. Therefore, timely diagnosis may lead to appropriate treatment of medullary thyroid carcinoma and improve mortality.
PubMed: 38753051
DOI: 10.1007/s12328-024-01979-y -
The Kaohsiung Journal of Medical... Jun 2024Pheochromocytoma is a tumor that usually originating from adrenal medullary chromaffin cells and producing one or more catecholamines, can manifest as hereditary or... (Comparative Study)
Comparative Study
Pheochromocytoma is a tumor that usually originating from adrenal medullary chromaffin cells and producing one or more catecholamines, can manifest as hereditary or sporadic. While the majority pheochromocytomas are sporadic, hereditary forms are often associated with genetic syndromes such as von Hippel-Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. This study aims to analyze data from our series of surgically excited pheochromocytoma patients and compare the characteristics between hereditary and sporadic cases. We retrospectively evaluated 33 diagnosed pheochromocytoma patients, documenting clinical features, surgical complications, and tumor characteristics in both hereditary and sporadic cases. Among the patients, 21% (7 individuals) had hereditary pheochromocytoma, while 79% (26 individuals) had sporadic cases. During diagnosis, hereditary pheochromocytoma patients exhibited a significantly lower mean age compared to the sporadic group (26.4 ± 9.9 years vs. 50.4 ± 14.0 years; p < 0.001). The maximum tumor size was also lower in hereditary cases compared to sporadic cases (p = 0.004). Adrenal tumor localization analysis showed that 63.6% were right-sided, 24.2% were left-sided, and 12.1% were bilateral. Laboratory analysis revealed significantly higher urinary norepinephrine levels in hereditary pheochromocytoma patients (p = 0.021). Our findings suggest that hereditary pheochromocytoma cases are characterized by a younger age at diagnosis, smaller tumor size, and a higher prevalence of multiple bilateral adrenal adenomas. We recommend genetic testing for all pheochromocytoma patients, particularly those with early-onset disease and bilateral adrenal tumors.
Topics: Humans; Pheochromocytoma; Female; Male; Adult; Middle Aged; Adrenal Gland Neoplasms; Retrospective Studies; Adolescent; Young Adult; Aged
PubMed: 38747189
DOI: 10.1002/kjm2.12836 -
ACG Case Reports Journal May 2024Insulinomas are rare neuroendocrine tumors characterized by episodic hypoglycemia. Typically, insulinomas are benign, solitary, intrapancreatic, and measure less than 2...
Insulinomas are rare neuroendocrine tumors characterized by episodic hypoglycemia. Typically, insulinomas are benign, solitary, intrapancreatic, and measure less than 2 cm in diameter. When insulinomas are multicenter or recurrent, they are often associated with genetic conditions such as multiple endocrine neoplasia type 1, neurofibromatosis type 1, or von Hippel-Lindau disease. Most insulinomas can be resolved with surgery. Multicenter and recurrent insulinomas, known as insulinomatosis, may require additional medical and surgical management. We report a distinctive case involving recurrent multicenter insulinomatosis devoid of any identified genetic familial predisposition. The patient's complex medical history spans nearly 2 decades, marked by unsuccessful attempts at resolution through surgical enucleation and noninvasive medical management, culminating in the decision for total pancreatectomy.
PubMed: 38746622
DOI: 10.14309/crj.0000000000001350 -
Radiology Case Reports Aug 2024Pheochromocytoma, a neuroendocrine tumor, represents a rare medical condition characterized by the excessive secretion of catecholamines. These tumors often exhibit...
Pheochromocytoma, a neuroendocrine tumor, represents a rare medical condition characterized by the excessive secretion of catecholamines. These tumors often exhibit distinctive features on imaging studies, notably appearing hypervascular. Furthermore, they may present as cystic masses with thin walls, a characteristic that becomes more evident following the administration of contrast medium. The cystic form of adrenal pheochromocytoma, as exemplified in our case, is particularly uncommon, thus underscoring the importance of recognizing its atypical presentation. Accurate diagnosis hinges on a thorough understanding of both the clinical manifestations and radiological findings suggestive of pheochromocytoma. However, definitive confirmation typically necessitates histological examination of the surgical specimen post-adrenalectomy. By shedding light on this rare variant, our case emphasizes the critical role of comprehensive diagnostic approaches in managing such complex medical conditions. Additionally, it underscores the significance of multidisciplinary collaboration among clinicians, radiologists, and pathologists to ensure timely and accurate diagnosis, ultimately guiding appropriate treatment strategies and optimizing patient outcomes.
PubMed: 38741687
DOI: 10.1016/j.radcr.2024.03.079 -
The Journal of Medical Investigation :... 2024Pancreatic GHRHomas (pGHRHomas) with acromegaly have unique conditions, harboring the existence of multiple endocrine neoplasia type 1 (MEN 1). Moreover, pituitary... (Review)
Review
Pancreatic GHRHomas (pGHRHomas) with acromegaly have unique conditions, harboring the existence of multiple endocrine neoplasia type 1 (MEN 1). Moreover, pituitary lesions are affected by both protracted ectopic GHRH and loss of menin function. Of significance is the clarification of clinicopathological aspects of pGHRHomas in patients with or without MEN 1. From 1977-2016, thirty-six patients with pGHRHomas were reported. Twenty-two out of 36 patients (61%) had pGHRHomas with MEN 1 and 14 patients did not. The former had a tendency of male predominance, benign tumor behavior and fewer metastasis rather than the latter. The latter is a single pGHRHoma accompanied by pituitary enlargement with somatotroph hyperplasia (hyperplasia) caused by protracted ectopic GHRH. Nine patients with MEN 1 underwent transsphenoidal surgery (TSS). The hyperplasia associated with various pituitary adenomas (PAs) including three GH-related adenomas was observed in seven subjects (32%). In these patients, the resection of their pGHRHomas was feasible. Furthermore, all patients with acromegaly due to pGHRHomas without MEN 1 had non-TSS, whereas approximately 70% of those with MEN 1 had unnecessary TSS. The association with hyperplasia and various PAs suggested that formation of the three GH-related adenomas may be induced by the foundations of MEN 1 gene mutations. J. Med. Invest. 71 : 1-8, February, 2024.
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Male; Female; Acromegaly; Middle Aged; Adult; Aged
PubMed: 38735704
DOI: 10.2152/jmi.71.1