Familial states of primary hyperparathyroidism: an update.

BACKGROUND: Familial primary hyperparathyroidism (PHPT) includes syndromic and non-syndromic disorders. The former are characterized by the occurrence of PHPT in association with extra-parathyroid manifestations and includes multiple endocrine neoplasia (MEN) types 1, 2, and 4 syndromes, and hyperparathyroidism-jaw tumor (HPT-JT). The latter consists of familial hypocalciuric hypercalcemia (FHH) types 1, 2 and 3, neonatal severe primary hyperparathyroidism (NSHPT), and familial isolated primary hyperparathyroidism (FIHP). The familial forms of PHPT show different levels of PHPT penetrance, developing earlier and with multiglandular involvement compared to sporadic counterpart. All these diseases exhibit Mendelian inheritance patterns, and for most of them, the genes responsible have been identified. DNA testing for predisposing mutations is helpful in index cases or in individuals with a high suspicion of the disease. Early recognition of hereditary disorders of PHPT is of great importance for the best clinical and surgical approach. Genetic testing is useful in routine clinical practice because it will also involve appropriate screening for extra-parathyroidal manifestations related to the syndrome as well as the identification of asymptomatic carriers of the mutation. PURPOSE: The aim of the review is to discuss the current knowledge on the clinical and genetic profile of these disorders along with the importance of genetic testing in clinical practice.

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.

Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic mechanisms in MEN2A.

The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. Mutations that disrupt the disulfide network in the extracellular domain (ECD) of RET drive multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome associated with the development of thyroid cancers. However, structural details of how specific mutations affect RET are unclear. Here, we present the first structural insights into the ECD of the RET(C634R) mutant, the most common mutation in MEN2A. Using electron microscopy, we demonstrate that the C634R mutation causes ligand-independent dimerization of the RET ECD, revealing an unusual tail-to-tail conformation that is distinct from the ligand-induced signaling dimer of WT RET. Additionally, we show that the RETC634R ECD dimer can form complexes with at least two of the canonical RET ligands and that these complexes form very different structures than WT RET ECD upon ligand binding. In conclusion, this structural analysis of cysteine-mutant RET ECD suggests a potential key mechanism of cancer induction in MEN2A, both in the absence and presence of its native ligands, and may offer new targets for therapeutic intervention.

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.

Lived experiences of undergoing regular tumor screening in patients with multiple endocrine neoplasia types 1 and 2 (MEN1/MEN2).

Targeted screening programs for individuals with an increased risk for cancer have become increasingly available. Patients with multiple endocrine neoplasia (MEN), rare genetic conditions associated with the development of tumors in the endocrine glands, undergo intensive surveillance from an early age. Quantitative research has shown that patients with MEN experience fear of disease occurrence in themselves and their family members. However, little is known about the role that intensive, lifelong screening plays in the lives of individuals. This study investigates the lived experiences of patients with MEN undergoing regular tumor screening through an interpretative phenomenological analysis of interviews with 12 patients with MEN1, MEN2A, or MEN2B syndrome. Four experiential group themes are identified: coming to the foreground/fading into the background, relating to uncertainty, experiencing control, and familial context. Screening is characterized as an ambiguous experience that brings MEN to the foreground and may both exacerbate MEN-related uncertainty as well as provide a sense of control over the disease. The experience of undergoing screening is strongly influenced by the familial context, as participants care for and are cared for by family members and understand their disease through familial experiences. Good care according to patients with MEN includes providing family-centered care, addressing the impact on daily functioning and the meaning of illness, support in the interpretation of physical complaints, facilitation of patient experiences of control, and careful attunement to patient needs within a good doctor-patient relationship.

Incidence of medullary thyroid carcinoma and Hirschsprung disease based on the cosmos database.

PURPOSE: Multiple endocrine neoplasia Type 2A (MEN2A) can occur with Hirschsprung disease (HD) due to mutation in the RET proto-oncogene, with the majority developing medullary thyroid carcinoma (MTC). Given the comorbidity, many parents have contacted us to share concerns and unfortunate experiences about the prevalence rates of MEN2A/MTC in patients with HD. The aim is to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma, respectively. METHODS: This is a cross-sectional study of the COSMOS database from January 01, 2017, to March 08, 2023. The database was searched for patients diagnosed with MEN2A, MTC, and HD. IRB exemption was provided (COMIRB #23-0526). RESULTS: The database contained 183,993,122 patients from 198 contributing organizations. The prevalence of HD and MEN2A was 0.00002%, and for HD and MTC was 0.000009%. One in 66 patients (1.5%) with MEN2A also had HD. One in 319 patients (0.3%) in the HD group had MEN2A. One in 839 patients (0.1%) within the HD population had MTC. CONCLUSION: The prevalence of MTC and HD or MEN2A and HD in the study population was low. Considering that almost all MEN2A patients have a positive family history, this data does not support the general genetic testing of HD patients.

Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database.

The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma (MTC) onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature. The classifications for the 166 single unique variants in the MEN2 RET database were reanalyzed using the MEN2 RET specifically modified ACMG/AMP classification guidelines (version 1). Applying these guidelines added two new variant classifications to the database (likely benign and likely pathogenic) and resulted in clinically significant classification changes (e.g., from pathogenic to uncertain) in 15.7% (26/166) of the original variants. Of those clinically significant changes, the highest percentage of changes, 46.2% (12/26), were changes from uncertain to benign or likely benign. The modified ACMG/AMP criteria with MEN2 RET specifications will optimize and standardize RET variant classifications.

Observational study of population genomic screening for variants associated with endocrine tumor syndromes in a large, healthcare-based cohort.

BACKGROUND: In current care, patients' personal and self-reported family histories are primarily used to determine whether genetic testing for hereditary endocrine tumor syndromes (ETS) is indicated. Population genomic screening for other conditions has increased ascertainment of individuals with pathogenic/likely pathogenic (P/LP) variants, leading to improved management and earlier diagnoses. It is unknown whether such benefits occur when screening broader populations for P/LP ETS variants. This manuscript assesses clinical utility outcomes of a large, unselected, healthcare-based genomic screening program by describing personal and family history of syndrome-related features, risk management behaviors after result disclosure, and rates of relevant post-disclosure diagnoses in patient-participants with P/LP ETS variants. METHODS: Observational study of individuals informed of a P/LP variant in MEN1, RET, SDHAF2, SDHB, SDHC, SDHD, or VHL through Geisinger's MyCode Community Health Initiative between June 2016 and October 2019. Electronic health records (EHRs) of participants were evaluated for a report of pre-disclosure personal and self-reported family histories and post-disclosure risk management and diagnoses. RESULTS: P/LP variants in genes of interest were identified in 199 of 130,490 (1 in 656) adult Geisinger MyCode patient-participants, 80 of which were disclosed during the study period. Eighty-one percent (n = 65) did not have prior evidence of the result in their EHR and, because they were identified via MyCode, were included in further analyses. Five participants identified via MyCode (8%) had a personal history of syndrome-related features; 16 (25%) had a positive self-reported family history. Time from result disclosure to EHR review was a median of 0.7 years. Post-disclosure, 36 (55.4%) completed a recommended risk management behavior; 11 (17%) were diagnosed with a syndrome-related neoplasm after completing a risk management intervention. CONCLUSIONS: Broader screening for pathogenic/likely pathogenic variants associated with endocrine tumor syndromes enables detection of at-risk individuals, leads to the uptake of risk management, and facilitates relevant diagnoses. Further research will be necessary to continue to determine the clinical utility of screening diverse, unselected populations for such variants.

Multiple endocrine neoplasia type 2 and autoimmune polyendocrine syndromes (type 1 diabetes mellitus and Graves' disease) in a 16-year-old male with Kabuki syndrome.

Multiple endocrine neoplasia type 2A (MEN2A) is caused by germline pathogenic variants in the RET proto-oncogene and is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and hyperparathyroidism. Autoimmune polyendocrine syndromes (APS) are defined as multiple endocrine gland insufficiency associated with loss of immune tolerance. APS type 2 (APS-2) consists of at least two of the following diseases: type 1 diabetes mellitus (T1DM), autoimmune thyroid disease, and Addison's disease. We describe the clinical, molecular, and biochemical findings of MEN2A, APS-2, and Kabuki syndrome (KS) in a 16-year-old male. Whole exome sequencing was performed to identify the genetic cause of the pheochromocytoma and syndromic features including facial dysmorphism, developmental delay, and epilepsy. RET pathogenic variant and KMT2D pathogenic variant were identified, and he was diagnosed with MEN2A and KS. This is the first case of association between MEN2 and APS in adolescence and the second proven case in humans. In addition, this is the first report of MEN2 and APS in KS.

Impact of gastrointestinal symptoms on quality of life in MEN2.

CONTEXT: Besides medullary thyroid carcinoma and other endocrinopathies, people with Multiple Endocrine Neoplasia Type 2 (MEN2) are at risk of gastrointestinal (GI) symptoms. OBJECTIVE: To investigate the impact of GI symptoms on the daily lives of patients with MEN2. DESIGN: An online survey was conducted among patients with MEN2 via the Association for Multiple Endocrine Neoplasia Disorders (AMEND). METHODS: The survey incorporated two validated questionnaires for the assessment of GI symptoms (SAGIS, PAC-QoL). PARTICIPANTS: There were 91 respondents, MEN2A (n = 57), MEN2B (n = 34). RESULTS: People in the MEN2A group reported a high level of GI symptoms, the most prevalent being abdominal pain 85% (n = 49), diarrhoea 85% (n = 49) and constipation 75% (n = 43) with one patient having a SAGIS score > 10/12 in the constipation domain. People in the MEN2B group reported constipation in 79% (n = 27) with one quarter of these scoring > 10/12 in the constipation domain. Other GI symptoms included diarrhoea 62% (n = 21), excessive gas and flatulence (79%), epigastric pain (59%) abdominal cramps (76%) and dysphagia (41%). The effect of constipation on quality of life was severe in all MEN2 patients as measured by PAC-QOL and all patients reported dissatisfaction of with their current treatment for constipation. There was a trend towards higher severity of GI symptoms in MEN2B. CONCLUSIONS: We report unmet needs of patients with MEN2 syndromes. The GI symptoms, especially constipation, had a severe impact on quality of life in people with MEN2. This suggests that there is room for improvement in the quality of care offered for these patients.

Procalcitonin measured by three different assays is an excellent tumor marker for the follow-up of patients with medullary thyroid carcinoma.

OBJECTIVES: Procalcitonin (PCT) has been suggested as a tumor marker in patients with medullary thyroid carcinoma (MTC). Clinical application data in long term follow-up are missing. METHODS: 210 serum samples of 169 consecutive patients with MTC (92 sporadic, 77 hereditary, 158 postoperative follow-up, 11 preoperative) were collected between 2018 and 2020. Postoperative patients were stratified into three groups according to their disease status at the end of follow-up: cured (n=51, calcitonin (CT) levels < limit of quantitation), minimal residual disease (n=55, detectable CT and no metastases provable by imaging methods), metastatic disease (n=52). In five patients CT and PCT were measured while on therapy with tyrosine kinase inhibitors (TKI). CT was analyzed by the Roche ECLIA, PCT by three assays from Roche, PES, Abbott. RESULTS: The mean ± SD values seen with the three PCT assays in the MTC response groups, cured: <0.06, 0.016 ± 0.007, 0.014 ± 0.007 ng/mL, minimal residual disease: 0.511 ± 0.800, 0.389 ± 0.687, 0.341 ± 0.614 ng/mL, metastatic disease 109 ± 202, 60.4 ± 110, 63.3 ± 115 ng/mL correlate well with the CT results in these groups: cured <1.0 pg/mL, minimal residual disease 91.3 ± 121.5 pg/mL, metastatic disease 14,489 ± 30,772 pg/mL. There was a significant correlation (p<0.001) between the three PCT assays (Roche/PES r=0.970, Roche/Abbott r=0.976, Abbott/PES r=0.995). In the course of treatment with TKI both CT and PCT reflected clinical state. Preoperative PCT in hereditary MTC has the same diagnostic validity than CT. CONCLUSIONS: PCT measured with three different immunoassays is as good as the standard tumor marker CT in the follow-up of MTC but has a superior analytical stability.

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A.

Genetic analysis for germline mutations of RET proto-oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next-generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch-wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87-year-old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as 'likely benign' according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.

Congenital infiltrating lipomatosis of the face with lingual mucosal neuromas associated with a PIK3CA mutation.

We report the case of a 5-year-old girl with congenital right-sided facial hemihypertrophy and right hemi-macroglossia with lingual mucosal neuromas. The segmental presentation of findings suggested the diagnosis of congenital infiltrating lipomatosis of the face (CILF), which belongs within the PIK3CA-related overgrowth spectrum (PROS). This was confirmed by genetic analysis showing a mosaic mutation in PIK3CA H1047R. CILF/PROS should be considered in the differential diagnosis of mucosal neuromas.

Over-diagnosis of potential malignant behavior in MEN 2A-associated pheochromocytomas using the PASS and GAPP algorithms.

PURPOSE: Pheochromocytomas (PCCs) exhibit malignant potential, but current histological modalities for the proper detection of aggressive behavior are debated. The two most widespread algorithms are the "Pheochromocytoma of the Adrenal Gland Scaled Score" (PASS) and the "Grading System for Adrenal Pheochromocytoma and Paraganglioma" (GAPP), both which mostly rely on histological parameters to identify PCC patients at risk of disseminated disease. Since the algorithms are derived from studies using predominantly sporadic PCCs, little is known whether the PASS or GAPP scores can predict malignant potential in hereditary cases. METHODS: PASS and GAPP were applied on 41 PCCs; 13 PCCs were diagnosed in ten multiple endocrine neoplasia type 2A (MEN 2A) patients carrying established germline RET proto-oncogene mutations, as well as 28 assumed sporadic PCCs. RESULTS: Six out of thirteen MEN 2A tumors (46%) exhibited PASS scores ≥ 4, indicative of a potential for aggressive behavior. In addition, 7/13 tumors (54%) exhibited GAPP scores ≥ 3, indicative of a "moderately differentiated type" with risk of future recurrence. All MEN 2A PCCs with an elevated PASS score also displayed an elevated GAPP score. In contrast, 4/28 (14%) sporadic PCCs demonstrated PASS scores ≥ 4, and 9/28 (32%) displayed GAPP scores ≥ 3. Follow-up found all cases in the study are free of metastatic or recurrent disease. CONCLUSIONS: We conclude that the PASS and GAPP scoring systems might be suboptimal for determining true malignant potential in PCCs with constitutional RET mutations and advocate restrictive use of these scores in MEN 2A cases until the results are reproduced in larger numbers.

Next generation immunohistochemistry: Emerging substitutes to genetic testing?

The identification of at-risk kindreds facilitates screening and risk reduction strategies for patients with hereditary cancer predisposition syndromes. Recently, immunohistochemistry (IHC) has emerged as a cost-effective strategy for detecting or inferring the presence of mutations in both tumors and the germline of patients presenting with tumors associated with hereditary cancer predisposition syndromes. In this review we discuss the use of novel IHC markers, including PRKAR1A, ß-catenin, SDHB, fumarate hydratase and 2SC, HRASQ61R, BAP1, parafibromin and glucagon, which have either established applications or show promise for surgical pathologists to complement morphological or clinical suspicion of hereditary cancer predisposition syndromes. Specifically, we focus on Carney complex, familial adenomatous polyposis (FAP)-associated cribriform-morular variant of papillary thyroid carcinoma, familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, hereditary leiomyomatosis and renal cell cancer (HLRCC), medullary thyroid cancer and Multiple Endocrine Neoplasia 2 (MEN2), BAP1 hereditary cancer predisposition syndrome, Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT), and Pancreatic Neuroendocrine Tumor Syndrome (Mahvash disease).

Is new American Thyroid Association risk classification for hereditary medullary thyroid carcinoma applicable to Chinese patients? A single-center study.

OBJECTIVE: The American Thyroid Association (ATA) proposed a new risk classification for hereditary medullary thyroid carcinoma (MTC) in 2015. This study aimed to assess whether the new guidelines are suitable for the Chinese population, and reported our experience on prophylactic thyroidectomy. METHODS: A total of 73 patients from 22 families were screened as rearranged during transfection (RET) mutation carriers from 2010 to 2016 in Cancer Hospital, Chinese Academy of Medical Science; the medical history for each patient was collected. Based on the initial treatment, we identified the risk factors for poor prognosis by univariate and multivariate logistic regression. Then, 4 RET mutation carriers were enrolled for prophylactic thyroidectomy, and their pathological data and follow-up outcomes were recorded. RESULTS: In univariate and multivariate logistic regression analyses, age at initial surgery and risk classification were significant risk factors for stage III/IV hereditary MTC at initial diagnosis. The likelihood was increased by 11.6% per year of age at initial surgery [95% confidence interval (95% CI), 1.040-1.198; P=0.002). It was 7.888 times more likely to have III/IV stage disease for ATA highest risk patients, compared to ATA moderate risk individuals (95% CI, 1.607-38.717; P=0.003). Postoperative pathological results showed all 4 multiple endocrine neoplasia type 2A (MEN2A) patients had C-cell hyperplasia (CCH); multifocal malignancies were detected in 3 of them. All 4 patients were cured biochemically, and none developed permanent hypoparathyroidism. CONCLUSIONS: In Chinese individuals, hereditary MTC aggressiveness is in line with the new ATA risk classification. Germline RET gene mutation carriers should undergo prophylactic thyroidectomy according to basal serum calcitonin levels.

Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer.

Thyroid cancer is the most common endocrine malignancy and accounts for nearly 1% of all of human cancer. Thyroid cancer has four main histological types: papillary, follicular, medullary, and anaplastic. Papillary, follicular, and anaplastic thyroid carcinomas are derived from follicular thyroid cells, whereas medullary thyroid carcinoma (MTC) originates from the neural crest parafollicular cells or C-cells of the thyroid gland. MTC represents a neuroendocrine tumor and differs considerably from differentiated thyroid carcinoma. MTC is one of the aggressive types of thyroid cancer, which represents 3-10% of all thyroid cancers. It occurs in hereditary (25%) and sporadic (75%) forms. The hereditary form of MTC has an autosomal dominant mode of inheritance. According to the present classification, hereditary MTC is classified as a multiple endocrine neoplasi type 2 A & B (MEN2A & MEN2B) and familial MTC (FMTC). The RET proto-oncogene is located on chromosome 10q11.21. It is composed of 21 exons and encodes a transmembrane receptor tyrosine kinase. RET regulates a complex network of signal transduction pathways during development, survival, proliferation, differentiation, and migration of the enteric nervous system progenitor cells. Gain of function mutations in RET have been well demonstrated in MTC development. Variants of MTC result from different RET mutations, and they have a good genotype-phenotype correlation. Various MTC related mutations have been reported in different exons of the RET gene. We proposed that RET genetic mutations may be different in distinct populations. Therefore, the aim of this study was to find a geographical pattern of RET mutations in different populations.

Pheochromocytomas in Multiple Endocrine Neoplasia Type 2.

Pheochromocytoma (PC) is a neuroendocrine tumor that originates from chromaffin cells of the adrenal medulla. The production of catecholamines, including epinephrine, norepinephrine and dopamine, may lead to haemodynamic instability. Over 30% of PCs are associated with germline mutations, including re-arranged in transfection (RET) mutations seen in multiple endocrine neoplasia type 2 (MEN2) syndromes. Around 40% of individuals with MEN2 develop PC, though it is rarely the presenting feature. Compared to sporadic PC, MEN2-associated PC is more likely to be epinephine secreting and demonstrate bilateral adrenal involvement, and is less likely to be malignant. The diagnosis of PC requires clinical suspicion and biochemical testing, followed by imaging studies. Novel nuclear medicine modalities, including FDG positron emission tomography (PET) and 68Ga DOTATATE PET have added to the conventional techniques of 123I-metaiodobenzylguanindine (MIBG) scintigraphy, computer tomography and magnetic resonance imaging. Treatment of PC is surgical and requires peri-operative alpha and, frequently, beta blockade. Novel surgical techniques, such as adrenal sparing surgery and a laparoscopic approach, have decreased peri-operative morbidity. Surveillance for PC is life long, due to the risk of metastatic disease.

Primary Hyperparathyroidism in MEN2 Syndromes.

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.

Histopathology of C Cells and Medullary Thyroid Carcinoma.

The human thyroid gland contains less than 0.01-0.1% calcitonin producing and secreting C cells, which in men are almost exclusively situated in an intrafollicular location; the vast majority of C cells are embryologically derived of remnants of the ultimobranchial body and ultimately of the neural crest, a small subset, however, is presumed to originate from endodermal stem cells. Thyroid tumours with C cell differentiation have been named medullary thyroid carcinoma (MTC); calcitonin is also produced and secreted by MTC which makes this peptide hormone a very useful serum marker both for early detection and clinical follow-up of patients with MTC. About 70-80% of MTC are sporadic tumours, whereas 20-30% are familial MTC which are autosomal-dominant inherited and caused by germline mutations of the RET proto-oncogene located on chromosome 10. This article summarizes the histological, immunhistochemical and molecular genetic features of C cells, C-cell hyperplasia (CCH) and MTC, emphasizing the role of diagnostic pathology.