ABSTRACT
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.
Subject(s)
Intestinal Volvulus , Megacolon , Multiple Endocrine Neoplasia Type 2b , Thyroid Neoplasms , Humans , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/diagnosis , Multiple Endocrine Neoplasia Type 2b/pathology , Multiple Endocrine Neoplasia Type 2b/surgery , Male , Intestinal Volvulus/surgery , Intestinal Volvulus/complications , Adolescent , Megacolon/complications , Megacolon/surgery , Megacolon/etiology , Thyroid Neoplasms/complications , Thyroid Neoplasms/surgery , Thyroid Neoplasms/pathology , Thyroid Neoplasms/diagnosis , Constipation/etiology , Proto-Oncogene Proteins c-ret/genetics , Carcinoma, Neuroendocrine/complications , Carcinoma, Neuroendocrine/surgery , Carcinoma, Neuroendocrine/pathology , Ganglioneuroma/complications , Ganglioneuroma/surgery , Ganglioneuroma/pathology , Ganglioneuroma/diagnosis , Intestine, Small/pathologyABSTRACT
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.
Subject(s)
Multiple Endocrine Neoplasia Type 2a , Multiple Endocrine Neoplasia Type 2b , Multiple Endocrine Neoplasia , Thyroid Neoplasms , Humans , Child , Female , Male , Multiple Endocrine Neoplasia Type 2a/complications , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/diagnosis , Hyperplasia , Multiple Endocrine Neoplasia/complications , Multiple Endocrine Neoplasia/genetics , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/epidemiology , Thyroid Neoplasms/surgerySubject(s)
Colonic Polyps/diagnostic imaging , Colonic Polyps/pathology , Digestive System Neoplasms/diagnostic imaging , Digestive System Neoplasms/pathology , Ganglioneuroma/diagnostic imaging , Ganglioneuroma/pathology , Multiple Endocrine Neoplasia Type 2b/diagnostic imaging , Multiple Endocrine Neoplasia Type 2b/pathology , Abdominal Pain/etiology , Colonic Polyps/complications , Colonoscopy , Digestive System Neoplasms/complications , Female , Ganglioneuroma/complications , Humans , Multiple Endocrine Neoplasia Type 2b/complications , Young AdultABSTRACT
BACKGROUND: The occurrence of multiple endocrine neoplasia type 2B (MEN2B) in Asians is very rare. In particular, patients with intractable constipation as the main clinical manifestation are even rarer. Atypical clinical manifestations are likely to lead to a diagnostic delay. In this report, we described a case of a delayed diagnosis of MEN2B, and the first clinical manifestation was intractable constipation. CASE PRESENTATION: A female teenager had suffered from intractable constipation since infancy. Because the colonoscopy and biopsy results from local hospitals did not confirm the presence of congenital megacolon, the girl had been followed up at a local clinic for a long time. The diagnosis was not confirmed until thyroid masses were found in the Pediatric Department of Shanghai Ruijin Hospital when she was 12 years old. According to our detailed evaluation, she suffered from Hirschsprung disease (HD), growth retardation, medullary thyroid carcinoma (MTC) and mucosal neuroma due to a mutation in the RET gene. Thus, the diagnosis of MEN2B was confirmed. Afterward, the girl underwent several surgeries and was still being followed up before the article was published. CONCLUSION: MEN2B has atypical clinical symptoms in the early stage. Refractory constipation may be the only clinical manifestation that lasts for several years. Therefore, we recommend that early screening and gene sequencing should be performed for patients with severe constipation due to HD to determine the cause of the disease and to improve the survival outcome.
Subject(s)
Multiple Endocrine Neoplasia Type 2b , Adolescent , Child , China , Constipation/etiology , Delayed Diagnosis , Female , Humans , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/diagnosis , Multiple Endocrine Neoplasia Type 2b/genetics , Proto-Oncogene Mas , Proto-Oncogene Proteins c-ret/geneticsSubject(s)
Adrenal Gland Neoplasms/diagnosis , Multiple Endocrine Neoplasia Type 2b/complications , Pituitary ACTH Hypersecretion/complications , Thyroid Neoplasms/diagnosis , Adrenal Gland Neoplasms/pathology , Adult , Humans , Lymph Nodes/pathology , Male , Pituitary ACTH Hypersecretion/diagnosis , Thyroid Neoplasms/pathologyABSTRACT
OBJECTIVE: To report a case of a patient affected by multiple endocrine neoplasia type 2B (MEN 2B) with imaging of conjunctival neuromas by in vivo confocal microscopy (IVCM). METHODS: Case report. RESULTS: A 48-year-old patient affected by MEN2B complained of progressive visual loss in his right eye and severe red, dry and itchy eyes. Best-corrected visual acuity was 20/63 OD and 20/25 OS. Slit lamp exam showed thickened and turned out lid margins, significant blepharitis, conjunctival injection, multiple presumed subconjunctival neuromas at the bulbar conjunctiva and at the limbus, marked prominence of corneal nerves, exposure keratopathy due to incomplete blinking and corneal hypoesthesia, subepithelial corneal neovascularization and scarring in the mid inferior part of both corneas and bilateral iris nodules. We performed IVCM on conjunctival neuromas, revealing large, thick bundles of nerves with disorganization, prominent loops, bifurcations and dilations measuring as much as 1 mm. The IVCM of corneal nerves demonstrated hypertrophic sub basal plexus. CONCLUSIONS: To date, this is the first report which documents conjunctival neuromas by confocal microscopy in MEN2B.
Subject(s)
Conjunctiva/innervation , Conjunctival Neoplasms/diagnosis , Cornea/innervation , Corneal Diseases/diagnosis , Microscopy, Confocal/methods , Multiple Endocrine Neoplasia Type 2b/complications , Ophthalmic Nerve/pathology , Conjunctiva/pathology , Conjunctival Neoplasms/complications , Cornea/pathology , Corneal Diseases/etiology , Humans , Male , Middle Aged , Nerve Fibers/pathology , Slit Lamp , Visual AcuityABSTRACT
ABSTRACT Background: RET proto-oncogene mutations are responsible for familial thyroid medullary carcinoma and multiple endocrine neoplasia (MEN) type 2A and 2B. These syndromes develop specific biomarkers and, in the case of MEN2B, clinically observable stigmas. However, the diagnosis of patients with MEN2B is usually delayed. Because of the close genotype-phenotype correlation, molecular testing is the final approach for the diagnosis to establish preventive care and therapeutic behaviors. Discussion: pM918T is classified as ''highest risk'' for medullary carcinoma with a 50% of lifetime risk for developing pheochromocytoma. Most cases of MEN2B are due to a de novo mutation. Even with the increased risk of developing pheochromocytoma, our 24-year-old patient does not yet present one. Other factors may be involved in the modulation of the phenotype in different populations. Case report: We present the case of a woman diagnosed with a thyroid nodule at the age of nine. She underwent a total thyroidectomy plus radical cervical lymph node dissection, with a diagnosis and initial management of papillary thyroid carcinoma. During the evolution of the disease, she developed pulmonary metastases. At the age of 24, after her first endocrinological evaluation, typical physical manifestations of MEN2B were observed. A re-evaluation of the original thyroidectomy revealed a medullary carcinoma, with positive manifestation CEA and calcitonin. The analysis of RET proto-oncogene identified a de novo mutation in exon 16 (pM918T). Conclusion: The timely diagnosis of MEN2B offers opportunities to make appropriate preventive and therapeutic decisions that may change the natural evolution of the disease and its complications.
Subject(s)
Humans , Female , Adult , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/diagnosis , Multiple Endocrine Neoplasia Type 2b/prevention & control , Diagnosis, Differential , Proto-Oncogene Proteins c-ret/analysisABSTRACT
Diffuse intestinal ganglioneuromatosis is a rare condition associated with MEN2B. It is also seen in conditions like neurofibromatosis type 1 and Cowden syndrome. This is a report of a patient who underwent total colectomy with end ileostomy creation for a megacolon. He was diagnosed to have diffuse ganglioneuromatosis on histological examination of the resected segment of colon. The definitive management of diffuse ganglioneuromatosis is to resect and anastomose.
Subject(s)
Constipation/diagnosis , Megacolon/pathology , Multiple Endocrine Neoplasia Type 2b/complications , Adult , Aftercare , Constipation/etiology , Diagnosis, Differential , Digestive System Neoplasms/pathology , Ganglioneuroma/pathology , Humans , Laparotomy/methods , Male , Megacolon/diagnostic imaging , Megacolon/surgery , Multiple Endocrine Neoplasia Type 2b/diagnosis , Multiple Endocrine Neoplasia Type 2b/pathology , Rare Diseases , Sri Lanka/ethnology , Treatment OutcomeSubject(s)
Digestive System Neoplasms/complications , Ganglioneuroma/complications , Gastrointestinal Hemorrhage/diagnosis , Gastrointestinal Stromal Tumors/diagnostic imaging , Multiple Endocrine Neoplasia Type 2b/complications , Neurofibromatosis 1/complications , Acute Disease , Aged , Anastomosis, Surgical , Calbindin 2/metabolism , Digestive System Neoplasms/pathology , Digestive System Neoplasms/surgery , Ganglioneuroma/pathology , Ganglioneuroma/surgery , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/surgery , Humans , Male , Multiple Endocrine Neoplasia Type 2b/pathology , Multiple Endocrine Neoplasia Type 2b/surgery , Neurofibromatosis 1/metabolism , Neurofibromatosis 1/pathology , Neurofibromatosis 1/surgery , S100 Proteins/metabolism , Tomography Scanners, X-Ray Computed , Treatment OutcomeABSTRACT
Context: Multiple endocrine neoplasia type 2B (MEN2B) is characterized by early-onset medullary thyroid cancer in virtually all cases and a 50% lifetime risk of pheochromocytoma (PHEO) development. The literature on PHEO in patients with MEN2B is limited with most data being reported from adult studies that primarily address MEN2A. Objective: The aim of the current study is to describe PHEO development in a cohort of pediatric patients with MEN2B. Design: Retrospective chart review of patients with MEN2B evaluated at the National Institutes of Health in the period between July 2007 and February 2018. Results: A total of 38 patients were identified (21 males and 17 females). Mean age at MEN2B diagnosis was 10.6 ± 3.9 years. Eight patients (21%) developed PHEO in the course of follow-up to date, all of whom were sporadic cases with the classic M918T RET mutation. PHEO was diagnosed based on biochemical and/or imaging screening studies in five patients, whereas three patients presented with symptoms of excess catecholamines. PHEO was diagnosed at a mean age 15.2 ± 4.6 (range, 10 to 25) years and 4.0 ± 3.3 years after MEN2B diagnosis. Only one patient was diagnosed with PHEO as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea. Conclusion: Undiagnosed PHEO can be associated with substantial morbidity. Current American Thyroid Association guidelines recommend PHEO screening starting at age 11 for the high-/highest risk group. The youngest patient diagnosed with PHEO in our cohort was an asymptomatic 10-year-old, suggesting that PHEO development may begin before the screening-recommended age of 11, though remains clinically undetectable and thus the current screening guidelines seem appropriate.
Subject(s)
Adrenal Gland Neoplasms/etiology , Multiple Endocrine Neoplasia Type 2b/complications , Pheochromocytoma/etiology , Adolescent , Adrenal Gland Neoplasms/diagnosis , Adrenal Gland Neoplasms/mortality , Adult , Age of Onset , Catecholamines/metabolism , Child , Cohort Studies , Disease Progression , Female , Follow-Up Studies , Humans , Male , Mass Screening , Multiple Endocrine Neoplasia Type 2a/genetics , Multiple Endocrine Neoplasia Type 2b/genetics , Multiple Endocrine Neoplasia Type 2b/mortality , Pheochromocytoma/diagnosis , Pheochromocytoma/mortality , Retrospective Studies , Young AdultSubject(s)
Lip/physiopathology , Multiple Endocrine Neoplasia Type 2b/diagnosis , Puberty, Delayed/diagnosis , Adolescent , Exons , Female , Genes, Dominant , Humans , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/genetics , Multiple Endocrine Neoplasia Type 2b/surgery , Neoplasm Metastasis , Puberty, Delayed/complications , Thyroid Neoplasms/complications , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Thyroid Neoplasms/surgery , Thyroidectomy , Tongue/physiopathologySubject(s)
Adenocarcinoma/secondary , Carcinoma, Neuroendocrine/pathology , Multiple Endocrine Neoplasia Type 2b/complications , Prostatic Neoplasms/secondary , Thyroid Neoplasms/pathology , Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Adult , Carcinoma, Neuroendocrine/diagnosis , Carcinoma, Neuroendocrine/genetics , Germ-Line Mutation , Humans , Male , Multiple Endocrine Neoplasia Type 2b/diagnosis , Multiple Endocrine Neoplasia Type 2b/genetics , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Young AdultSubject(s)
Carcinoma, Neuroendocrine/diagnosis , Edema/etiology , Lip Diseases/etiology , Multiple Endocrine Neoplasia Type 2b/diagnosis , Neuroma/diagnosis , Thyroid Neoplasms/diagnosis , Tongue Neoplasms/diagnosis , Carcinoma, Neuroendocrine/complications , Child , Female , Humans , Multiple Endocrine Neoplasia Type 2b/complications , Neuroma/complications , Thyroid Neoplasms/complications , Tongue Neoplasms/complicationsABSTRACT
Context: The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Design: Retrospective analysis. Setting: International collaboration. Patients: Included were 13 A883F carriers. Intervention: The intervention was thyroidectomy. Main Outcome Measures: Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. Results: One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. Conclusions: MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level.
Subject(s)
Adrenal Gland Neoplasms/genetics , Carcinoma, Neuroendocrine/genetics , Multiple Endocrine Neoplasia Type 2b/genetics , Pheochromocytoma/genetics , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Adolescent , Adrenal Gland Neoplasms/etiology , Adult , Carcinoma, Neuroendocrine/etiology , Carcinoma, Neuroendocrine/surgery , Child , Female , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Male , Multiple Endocrine Neoplasia Type 2b/complications , Mutation , Penetrance , Pheochromocytoma/etiology , Proto-Oncogene Mas , Retrospective Studies , Risk Assessment , Survival Rate , Thyroid Neoplasms/etiology , Thyroid Neoplasms/surgery , Thyroidectomy , Young AdultABSTRACT
Mucosal neuromas of the larynx in the setting of multiple endocrine neoplasia type 2B (MEN-2B) are extremely rare; to the best of our knowledge, only 2 other cases have been previously reported in the world literature. We describe a new case, which occurred in a 30-year old woman who presented with dysphagia, dysphonia, and cough. On examination, she was found to have multiple laryngeal mucosal neuromas throughout the glottis and supraglottis. She underwent surgical resection of these lesions with resolution of her symptoms.
Subject(s)
Laryngeal Neoplasms/pathology , Multiple Endocrine Neoplasia Type 2b/pathology , Neuroma/pathology , Adult , Female , Humans , Laryngeal Neoplasms/complications , Laryngeal Neoplasms/surgery , Laryngoscopy/methods , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/surgery , Neuroma/complications , Neuroma/surgeryABSTRACT
One of the components of trethe classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. The prevalence is more rare in gene carriers as these frequently have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, codon 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis after the 3rd decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation.
Subject(s)
Hyperparathyroidism, Primary/etiology , Multiple Endocrine Neoplasia Type 2a/complications , Multiple Endocrine Neoplasia Type 2b/complications , Biomarkers, Tumor/genetics , Calcium/blood , Genetic Predisposition to Disease , Humans , Hyperparathyroidism, Primary/blood , Hyperparathyroidism, Primary/diagnosis , Hyperparathyroidism, Primary/surgery , Multiple Endocrine Neoplasia Type 2a/diagnosis , Multiple Endocrine Neoplasia Type 2a/genetics , Multiple Endocrine Neoplasia Type 2b/diagnosis , Multiple Endocrine Neoplasia Type 2b/genetics , Mutation , Parathyroidectomy , Phenotype , Proto-Oncogene Proteins c-ret/geneticsABSTRACT
A 33-year-old healthy woman with a family history of hyperlipidemia presented with asymptomatic skin-colored yellowish linear transverse plaques and papules on the trunk and forearms for a period of 6 months (Figure 1). She noticed that the lesions during this period have been gradually increasing in size and number. The initial clinical impression was eruptive xanthomas. A serum lipid profile showed a total serum cholesterol level of 406 mmol/L (high-density lipoprotein, 1.38 mmol/L; low-density lipoprotein, 2.73 mmol/L) and a triglyceride level of 1.1 mmol/L, which is within the normal range. A 4-mm punch biopsy was performed from the skin lesion on the patient's forearm, and findings showed the presence of bundles of mature nerve fibers in the papillary dermis (Figure 2) with a normal overlying epidermis. No abnormalities were seen in the subcutaneous tissue. There was no evidence of lipid deposition. A diagnosis of cutaneous hyperneury was made.