Impact of Early Diagnostic and Therapeutic Interventions and Clinical Course in Children and Adolescents with Multiple Endocrine Neoplasia Types 1 and 2.

PURPOSE: Multiple endocrine neoplasia types 1 (MEN1) and 2 (MEN2) are inherited endocrine tumor syndromes caused by mutations in the MEN1 or RET genes. This study aimed to investigate clinical outcomes and molecular characteristics among children with MEN. METHODS: This study included eight patients from seven unrelated families. Data on clinical course, biochemical findings, and radiologic studies were collected by retrospective chart review. All diagnoses were genetically confirmed by Sanger sequencing of MEN1 in three MEN1 patients and RET in four patients with MEN2A and one patient with MEN2B. RESULTS: Three patients with MEN1 from two families presented with hypoglycemia at a mean age of 11±2.6 years. Four patients with MEN2A were genetically diagnosed at a mean of 3.0±2.2 years of age by family screening; one of them was prenatally diagnosed by chorionic villus sampling. Three patients with MEN2A underwent prophylactic thyroidectomy from 5 to 6 years of age, whereas one patient refused surgery. The patient with MEN2B presented with a tongue neuroma and medullary thyroid carcinoma at 6 years of age. Subsequently, he underwent a subtotal colectomy because of bowel perforation and submucosal ganglioneuromatosis at 18 years of age. CONCLUSION: This study described the relatively long clinical course of pediatric MEN with a mean follow-up duration of 7.5±3.8 years. Insulinoma was the first manifestation in children with MEN1. Early diagnosis by family screening during the asymptomatic period enabled early intervention. The patient with MEN2B exhibited the most aggressive clinical course.

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.

Tumor-to-Tumor Metastasis of Medullary Thyroid Carcinoma to Paraganglioma in a Multiple Endocrine Neoplasia Type 2B Patient: A Case Report and Literature Review.

Tumor-to-tumor metastasis is a rare phenomenon in which primary tumor cells metastasize to other tumors. Herein, we report an extremely rare case of tumor-to-tumor metastasis of medullary thyroid carcinoma to a paraganglioma in a patient with multiple endocrine neoplasia type 2B. Based on genetic examination, a 36-year-old woman was diagnosed with multiple endocrine neoplasia type 2B when she was 24 years old. She had a history of total thyroidectomy for medullary thyroid carcinoma and bilateral adrenalectomy for pheochromocytomas, which were performed when she was 15 years and 29 years old, respectively. Follow-up computed tomography demonstrated a retroperitoneal tumor of 30 mm in diameter beside the left kidney and a liver tumor of 16 mm in diameter located in segment 6. The retroperitoneal and liver tumors were surgically resected and examined by a pathologist. Histological examination revealed the classic Zellballen pattern in the retroperitoneal tumor, rendering the diagnosis of a paraganglioma recurrence. Inside the tumor, a white nodule positive for carcinoembryonic antigen, weakly positive for calcitonin, and negative for tyrosine hydroxylase, was identified and diagnosed as a metastatic medullary thyroid carcinoma with high malignant potential. The liver lesion was diagnosed as a metastasis of the medullary thyroid carcinoma. This is the first report of tumor-to-tumor metastasis of medullary thyroid carcinoma to paraganglioma in a patient with multiple endocrine neoplasia type 2B twenty years after total thyroidectomy.

Prominent corneal nerves in pure mucosal neuroma syndrome, a clinical phenotype distinct from multiple endocrine neoplasia type 2B.

BACKGROUND: Pure mucosal neuroma syndrome (MNS), an autosomal dominant neurocutaneous disorder, is a rare discrete subgroup in multiple endocrine neoplasia (MEN) type 2B, which present without associated endocrinopathies of MEN2B but with typical physical features such as prominent corneal nerves. Case presentation This report describes a 41-year-old patient with complaint of itchy eyes and irritation, presenting with blocked gland orifices in the upper and lower eyelids, light conjunctival hyperemia, a semitransparent neoplasm measuring 2 mm*2 mm on the nasal limbus suggestive of neuromas, and prominent corneal nerves. In vivo confocal microscopy (IVCM) revealed structural alterations-namely a prominent hyperreflective, thickened nerve plexus and a normal endothelium-in both eyes. Testing for SOS1 mutation was positive. This patient may represent a discrete subgroup termed pure mucosal neuroma syndrome (MNS), which presents with the characteristic appearance of MEN2B but without RET gene mutations. CONCLUSION: Prominent corneal nerves have been described in some diseases, such as multiple endocrine neoplasia (MEN) type 1 and type 2A and 2B, congenital ichthyosis, Refsum's disease, leprosy, etc. Ophthalmic assessment including prominent corneal nerves has proven valuable in asymptomatic individuals of MEN2B. Our case illustrates the importance of recognizing the ocular features of MNS, a rare presentation of MEN2B, in order to prevent prophylactic thyroidectomy in these patients for prophylactic thyroidectomy is not mandatory in MNS. However, regular monitoring and genetic counseling are still necessary.

["Graded early warning system" of RET germline mutation carriers in MEN2A/MEN2B families and total thyroidectomy (report of 7 cases)].

Objective: To explore the reasonable time of prophylactic thyroidectomy for RET gene carriers in multiple endocrine neoplasia(MEN) 2A/2B families. Methods: From May 2015 to August 2021, RET gene carriers in MEN2A/MEN2B families were dynamically followed up at the Department of Thyroid Head and Neck Surgery, Beijing Tongren Hospital of Capital Medical University. The high-risk patients were encouraged to undergo prophylacitc total thyroidectomy according to the principle of "graded early warning system", namely the evaluation of gene detection, calcitonin value and ultrasound examination successively. Seven cases underwent the surgery, including 3 males and 4 females, aged from 7 to 29 years. According to the risk stratification listed in the guidelines of the American Thyroid Association in 2015, there were 2 cases of the highest risk, 2 cases of the high risk and 3 cases of the modest risk. Calcitonin index remained within the normal range in 3 cases and elevated in 4 cases before operation. All 7 patients underwent thyroidectomy with lymph node dissection of the level Ⅵ performed in 4 patients. Results: The time from suggestion to operation was 2 to 37 months, with an average of 15.1 months. The 6 patients were medullary thyroid carcinoma and 1 case with C-cell hyperplasia. The follow-up time was 2 to 82 months, with an average of 38.4 months. Postoperative serum calcitonin levels of all cases decreased to normal level, with biochemical cure. There was no sign of recurrence on ultrasound examination. All 7 patients had no serious complications, no obvious thyroid dysfunction. Their height, weight and other indicators of pediatric patients were similar to those of their peers, with normal growth and development. Conclusion: For healthy people with MEN2A/MEN2B family history, prophylactic thyroidectomy can be carried out selectively based on the comprehensive evaluation of "graded early warning system" with strict screening and close monitoring.

Frequency and impact of musculoskeletal symptoms on quality of life in MEN2B.

OBJECTIVE: To investigate the impact of musculoskeletal (MSK)-related symptoms on the quality of life of patients with multiple endocrine neoplasia Type 2b (MEN2B). DESIGN: An online survey was distributed by the Association for Multiple Endocrine Neoplasia Disorders (AMEND) to their members and worldwide via a social media group for MEN2B patients. METHODS: The survey consisted of a detailed questionnaire analysing the MSK-related symptoms and structural deformities of MEN2B patients and their impact on patient's lives. PARTICIPANTS: Forty-eight participants completed the survey. RESULTS: Participants reported several musculoskeletal complaints; the most prevalent being musculoskeletal weakness at 73% (n = 35) and pain 58% (n = 28). The median pain score was 7 (interquartile range [IQR]: 5-8) and the frequency of pain was daily in 44% (n = 15) and constant in 21% (n = 7). Structural complaints were common with 63% (n = 30) stating their physique was 'different' and 40% (n = 19) describing marfanoid body features. Spinal curvature and foot deformities were the commonest structural abnormalities with scoliosis 70% (n = 16) and pes cavus 63% (n = 22) prevailing. Dental problems were mentioned by 69% (n = 33) with interdental spacing being the most common complaint at 61% (n = 20). The musculoskeletal symptoms of MEN2B had a median impact of 6 (IQR: 3-9) on quality of life (QOL) with structural deformities 53% (n = 18) and pain 26% (n = 9) listed as having the highest impact. Poor MSK health affected exercise, work and mobility. CONCLUSIONS: We report a high prevalence of musculoskeletal-related complaints in MEN2B which significantly affects QOL. This suggests a need to provide better holistic care including a multidisciplinary team with physiotherapist, orthopaedic and dental specialist input.

[Intestinal ganglioneuromatosis as an early extra-endocrine manifestation of type 2B multiple endocrine neoplasia].

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare variant of hereditary tumor syndromes caused by germinal mutations in the proto-oncogene RET. One of the components of the syndrome is multiple neurinomas, the early detection of  which is not always given due attention. We present a description of the case of MEN 2B, manifested in the first months of life by intestinal ganglioneuromatosis. The disease presented with chronic constipation, including episodes of intestinal obstruction that required repeated surgical interventions. MEN 2B was suspected at the age of 15. At the time of diagnosis, an increase in serum calcitonin levels was noted (1041 pg/ml, norm <9.5 pg/ml), and a node in the thyroid gland was also determined (1,3*1,0*1,2 see, TIRADS 5), subsequently verified as a neoplasm of C-cells. By DNA analysis, a pathogenic variant p.Met918Thr, typical for MEN2 B, was detected in the RET gene. No signs of pheochromocytoma were found at the time of investigation. The patient underwent a thyroidectomy with lymphadenectomy. The difficulties of early diagnosis of sporadic cases of MEN 2B due to the nonspecificity of gastrointestinal manifestations of the disease are discussed.

Fracture Risk in Pediatric Patients With MEN2B.

CONTEXT: The skeletal phenotype of patients with MEN2B has been described but fracture risk in these patients has not yet been evaluated. OBJECTIVE: This work aims to better delineate fracture risk in patients with multiple endocrine neoplasia type 2B (MEN2B). METHODS: This case series with chart review was conducted at the National Institutes of Health, Pediatric Oncology Branch. A total of 48 patients with MEN2B were identified, with an age range of 5 to 36 years, median of 19; 24 of 48 (50%) patients were female. Medical records, demographic information, available imaging, and laboratory results were reviewed. History up to age 19 was included in the statistical analyses. RESULTS: Of the 48 patients with MEN2B, 20 patients experienced at least one fracture. The majority (n = 18) experienced their first fracture at or before age 19. The observed frequency of fracture occurrence throughout childhood (0-19 years) was 38%, with very little difference between males and females. This frequency is higher than the 9.47 to 36.1 fractures per 1000 persons per year that has been reported in healthy pediatric cohorts in the United States. Less common sites of fracture including vertebral compression fracture and pelvic fractures were observed in patients with MEN2B. CONCLUSION: In this group of patients with MEN2B, there was an increased overall risk of fracture compared to general pediatric cohorts in the United States. Less common sites of fracture were also observed. This suggests a possible effect of an activating RET mutation on bone physiology and warrants further investigation.

Amphicrine Medullary Thyroid Carcinoma - a Case-Based Review Expanding on Its MUC Expression Profile.

Amphicrine phenotype in medullary thyroid carcinoma (MTC) is a rare phenomenon characterized by tumor cells that show both endocrine differentiation (calcitonin secretion) and exocrine differentiation (mucin production and secretion). Not much is known about the pathobiology of amphicrine MTCs. This report undertook a case-based review approach by discussing the cytological, histopathological, and ultrastructural features of this rare enigmatic entity, expanding on the radiological and novel MUC immunohistochemistry findings from a 28-year-old MEN2B syndrome patient with C cell hyperplasia and multifocal MTC with amphicrine features. The patient had widespread hematogenous metastases at presentation. MUC immunoexpression analysis revealed evidence of micro-lumina formation, and unique to-date unreported expression patterns of MUC1, MUC5AC, and MUC6 in an amphicrine subtype of MTC. Review of the literature identified five other MTC cases with well-documented amphicrine features. Of these six cases, two were associated with MEN2B syndrome, and four had metastatic disease. Follow-up was available in three patients, and two died of disease. Recognition of this rare subtype of MTC may be of clinical interest given their frequent link to MEN2B syndrome and biological aggressiveness.

Simultaneous unilateral laparoscopic adrenalectomy for pheochromocytoma and thyroidectomy in MEN 2A and MEN 2B syndrome.

Not required for Clinical Vignette.

Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Cystic ovarian teratoma as a novel tumor and growth hormone deficiency as a new condition presenting in Multiple Endocrine Neoplasia type 2B: Case reports and review of the literature.

BACKGROUND: We describe early and typical nonendocrine symptoms of Multiple Endocrine Neoplasia type 2B (MEN2B) presented in our patients with de novo M918T mutation in the RET proto-oncogene in early childhood, however, the diagnosis of MEN2B and medullary thyroid carcinoma (MTC) was confirmed late, in the second decade of life. In this paper, we emphasize the possibility of growth retardation, growth hormone (GH) deficiency and ovarian teratoma as a new symptom of MEN2B. CASE REPORTS: Advanced MTC with palpable mass on the neck and nonendocrine symptoms such as marfanoid habitus, thickened lips, mucosal neuromas led to the diagnosis in case 1 at the age of 13 years and GH deficiency and nonendocrine symptoms in case 2 at the age of 11 years. The earliest feature of MEN2B was alacrima and constipation. Patient 1 was operated on for a slipped femoral capital epiphysis and for a cystic ovarian teratoma. CONCLUSIONS: Improved awareness of nonendocrine signs of MEN2B could lead to earlier diagnosis, when surgical cure of MTC is possible. Alacrima is the first sign of MEN2B. We confirmed the possibility of growth retardation and GH deficiency in MEN2B, which had been previously rarely described. We suggest that patients with MEN2B may develop cystic ovarian teratoma, to the best of our knowledge, which has never been described so far in the literature. The results of this study could be used to guide further diagnosing of MENB2 at the early stage for better clinical outcome. We emphasize that MEN2B carries a risk for development of cystic ovarian teratoma as a novel tumor in this disease.

[Pediatric Multiple Endocrine Neoplasia Type 2B with Pheochromocytoma Diagnosed after Perforation of a Colonic Diverticulum : A Case Report].

A 12-year-old girl was found to have decending colon diverticulum perforation and retroperitoneal abscess on computed tomography (CT) carried out to determine the cause of fever and stomachache. CT-guided drainage tube placement was performed. She was suspected of having MEN2B from her specific facial appearance, Marfan-like body shape and lingual mucosa neuroma. Cervical ultrasonography and serum tumor marker revealed medullary thyroid carcinoma and metastasis to cervical lymph node. Genetic examination revealed a mutation of RET gene codon 918. Therefore, she was diagnosed as having MEN2B. Laboratory data showed elevated urinary catecholamines. Metaiodobenzylguanidine (MIBG) adrenal scintigraphy showed bilateral adrenal uptake and a definitive diagnosis of bilateral adrenal pheochromocytomas was made. Discharge from the drainage tube persisted and it was difficult to continue conservative treatment. Therefore, laparoscopic bilateral adrenalectomy and transverse colon colostomy were performed. Subsequently, total thyroidectomy and cervical lymph node dissection were performed. At five years of follow up, bilateral lung metastases were observed, but the serum calcitonin level was normal and the patient is under observation.

Children with multiple endocrine neoplasia type 2B: Not tall and marfanoid, but short with normal body proportions.

OBJECTIVE: Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood. DESIGN: It is a retrospective case series. METHODS: Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height. RESULTS: Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI. CONCLUSIONS: This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus.

Isolated intestinal Ganglioneuromatosis: case report and literature review.

BACKGROUND: Intestinal Ganglioneuromatosis (IG) is a rare disorder of the enteric nervous system. In pediatric age it is often associated with genetic syndromes such as Neurofibromatosis 1 (NF1), multiple endocrine neoplasia type 2B (MEN2B) and Cowden syndrome (PTEN mutation), and ganglioneuromas (GNs) may be sometimes the first sign of the disease. Isolated GNs are rare and sporadic. Clinical symptom vary and depend on the size and on the location of the GNs. This disorder affects intestinal motility and it, consequently, causes changes in bowel habits, abdominal pain, occlusive symptoms and rarely lower gastrointestinal bleeding secondary to ulceration of the intestinal mucosa. On the other hand, patients can remain asymptomatic for many years. CASE PRESENTATION: We describe a 9-year-old boy referred to our emergency department for right lower quadrant abdominal pain. No familial history for gastrointestinal disorders. No history of fever or weight loss. At physical examination, he had diffused abdominal pain. Abdominal ultrasonography showed a hypoechoic formation measuring 41.8 mm by 35 mm in the right lower quadrant of the abdomen. Routine blood tests were normal, but fecal occult blood test was positive. Abdominal TC confirmed the hypodense formation, of about 5 cm in transverse diameter, in the right hypochondrium that apparently invaginated in the caecum-last ileal loop. Colonoscopy showed in the cecum an invaginated polypoid lesion of the terminal ileal loop. Laparoscopic resection of the polypoid lesion was performed. Histological diagnosis of the large neoplasm observed in the terminal ileum was diffuse ganglioneuromatosis. NF1, RET and PTEN gene tests resulted negative for specific mutations. At the 1 year follow-up, the patient presented good general condition and blood tests, fecal occult blood test, esophagogastroduodenoscopy, colonoscopy and MR-enterography were negative. CONCLUSIONS: Only few cases are reported in literature of IG in pediatric age. Although rare, the present case suggests that this disorder must be taken in consideration in every patient with GI symptoms such as abdominal pain, constipation, lower intestinal bleeding, in order to avoid a delayed diagnosis.

Late diagnosis of metastatic pheochromocytoma in multiple endocrine neoplasia 2B with rapid clinical decline.

Multiple endocrine neoplasia type 2B (MEN2B) is the rarest and most aggressive of the MEN syndromes. It is characterised by medullary thyroid cancer (MTC), pheochromocytoma, marfanoid body habitus, mucosal neuromas and colonic dysfunction. Patients typically present with chronic constipation and MTC in early childhood. We discuss an atypical late presentation of MEN2B in a 19-year-old man with chronic constipation since childhood admitted with acute spinal cord compression. He underwent emergent neurosurgical intervention followed by postoperative radiotherapy. Bone biopsy revealed metastatic pheochromocytoma. Thyroid nodule biopsy showed MTC. MIBG scan confirmed pheochromocytoma as the dominant malignancy. Germline testing revealed a RET mutation (p.M918T). He received one cycle of cyclophosphamide, vincristine and dacarbazine and subsequently developed a pathological right femur fracture requiring repair. Postoperative course was complicated by hypoxic respiratory failure requiring intubation. Imaging showed lymphangitic spread of disease in the lungs. He unfortunately did not respond to a short trial of sunitinib and transitioned to comfort care.

Timely diagnosis of multiple endocrine neoplasia 2B by identification of intestinal ganglioneuromatosis: a case series.

BACKGROUND: Medullary thyroid carcinoma (MTC) in childhood is rare and has an unfavorable prognosis. To improve outcome, early diagnosis is essential. In patients with multiple endocrine neoplasia type 2B (MEN2B), MTC can occur already before the age of 1 year. Recognition of non-endocrine features of MEN2B may lead to timely diagnosis. PURPOSE: To describe how early recognition of non-endocrine features can lead to a timely diagnosis of MEN2B as well as the effect of recognition of premonitory symptoms on prognosis. METHODS: A retrospective case series from the University Medical Center Utrecht/Wilhelmina Children's Hospital, a Dutch national expertise center for MEN patients. All eight MEN2B patients in follow-up between 1976 and 2020 were included and medical records reviewed. RESULTS: Intestinal ganglioneuromatosis (IGN) as the cause of gastrointestinal (GI) symptoms was detected in seven patients. In three of them within months after birth. This led to early diagnosis of MEN2B, which allowed subsequent curative thyroid surgery. On the contrary, a MEN2B diagnosis later in childhood-in three patients (also) triggered by oral neuromas/neurofibromas-led to recurrent, persistent, and/or progressive MTC in five patients. CONCLUSIONS: Neonatal GI manifestations offer the most important window of opportunity for early detection of MEN2B. By accurate evaluation of rectal biopsies in patients with early onset severe constipation, IGN can be timely detected, while ruling out Hirschsprung's disease. MEN2B gene analysis should follow detection of IGN and-when confirmed-should prompt possibly still curative thyroid surgery.

Hereditary medullary thyroid carcinoma syndromes: experience from western India.

The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35 years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.