Long-term remission of disseminated parathyroid cancer following immunotherapy.

PURPOSE: Parathyroid cancer is a rare tumor associated with poor prognosis particularly when disseminated. While chemotherapy and/or radiotherapy are of no clinical value in disseminated disease, immunotherapy should be considered. SUBJECT AND RESULTS: A patient with CDC73-associated metastatic parathyroid carcinoma was treated with combined anti-hPTH immunotherapy and surgery. CONCLUSIONS: Following five courses of anti-hPTH immunotherapy and subsequent surgery, a 12-year long remission of disseminated parathyroid cancer is reported. This case further supports the ever-expanding spectrum of cancers that may benefit from immunotherapy.

Neonatal Severe Hyperparathyroidism: Novel Insights From Calcium, PTH, and the CASR Gene.

CONTEXT: Neonatal severe hyperparathyroidism (NSHPT) is rare and potentially lethal. It is usually from homozygous or heterozygous germline-inactivating CASR variant(s). NSHPT shows a puzzling range of serum calcium and parathyroid hormone (PTH) levels. Optimal therapy is unclear. EVIDENCE ACQUISITION: We categorized genotype/phenotype pairings related to CASRs. For the 2 pairings in NSHPT, each of 57 cases of neonatal severe hyperparathyroidism required calcium, PTH, upper normal PTH, and dosage of a germline pathogenic CASR variant. EVIDENCE SYNTHESIS: Homozygous and heterozygous NSHPT are 2 among a spectrum of 9 genotype/phenotype pairings relating to CASRs and NSHPT. For the 2 NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of maternofetal calcium fluxes. Homozygous dosage of CASR variants was generally more aggressive than heterozygous. Among heterozygotes, high-grade CASR variants in vitro were more pathogenic in vivo than low-grade variants. Fetal calcium insufficiency as from maternal hypoparathyroidism caused fetal secondary hyperparathyroidism, which persisted and was reversible in neonates. Among NSHPT pairings, calcium and PTH were higher in CASR homozygotes than in heterozygotes. Extreme hypercalcemia (above 4.5 mM; normal 2.2-2.6 mM) is a robust biomarker, occurring only in homozygotes (83% of that pairing). It could occur during the first week. CONCLUSIONS: In NSHPT pairings, the homozygotes for pathogenic CASR variants show higher calcium and PTH levels than heterozygotes. Calcium levels above 4.5 mM among NSHPT are frequent and unique only to most homozygotes. This cutoff supports early and robust diagnosis of CASR dosage. Thereby, it promotes definitive total parathyroidectomy in most homozygotes.

New Concepts About Familial Isolated Hyperparathyroidism.

CONTEXT: Familial isolated hyperparathyroidism (FIHP) is defined as familial primary hyperparathyroidism (FH) without a characteristic extraparathyroidal feature of a more complex hyperparathyroid syndrome. New concepts of FIHP have been developed within this definition. FIHP has been difficult to study due to small kindreds and mildly symptomatic cases. EVIDENCE ACQUISITION: Searches were through PubMed for FIHP, other FH syndromes, and the gene(s) mutated in each. EVIDENCE SYNTHESIS: Within its definition, the current concept of FIHP has clinical and mutational components that can include incomplete expressions of multiple endocrine neoplasia type 1 (MEN1) familial hypocalciuric hypercalcemia, hyperparathyroidism-jaw tumor syndromes, or their mutations. Newest concepts of FIHP focus on kindreds without mutation of the MEN1, CASR, or CDC73 genes; 17% have germline activating mutation of the gene for the GCM2 transcription factor. The FIHP kindreds with or without GCM2 mutation contain a median of only two cases of primary hyperparathyroidism. The small kindred size in both subgroups of FIHP is probably caused by a low rate of screening among relatives. Persons with FIHP and GCM2 mutation present as adults with mild hypercalcemia and multiple parathyroid tumors. CONCLUSION: The current concept of FIHP led to a focus on small kindreds without mutation of MEN1, CASR, or CDC73. These assisted in identifying germline activating GCM2 mutations in 17% of kindreds. Clinical and mutational characterization in more cases is needed to determine if there are any unique clinical features of FIHP, with or without mutation of GCM2.

High prevalence of chronic kidney disease in patients with multiple endocrine neoplasia type 1 and improved kidney function after parathyroidectomy.

BACKGROUND: Because chronic kidney disease is an important comorbidity associated with primary hyperparathyroidism, we sought to evaluate the prevalence of chronic kidney disease and effects of parathyroidectomy on kidney function in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. METHODS: We performed a retrospective analysis of 112 patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism who had at least 1 operation for primary hyperparathyroidism at 2 tertiary referral centers. The preoperative and postoperative estimated glomerular filtration rates were compared. The prevalence of chronic kidney disease stage 3 or worse (estimated glomerular filtration rates less than 60 mL/min/1.73m2) in this cohort was compared to the rates in the US population reported by the Centers for Disease Control and Prevention. RESULTS: The median age at the time of parathyroidectomy was 36.5 years (range: 12-76 years). A total of 99 patients had biochemical remission. The rate of chronic kidney disease stage 3 or worse in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism was greater than that observed in the US population for ages 20-39 and 40-59 (5% [n = 2/44] vs 0.39% [n = 18/4565], P = .015 and 10% [n = 4/40] vs 2.31% (n = 89/3848), P = .015, respectively). We observed improved estimated glomerular filtration rates in those with chronic kidney disease stage 3 or worse postoperatively (48 vs 57 mL/min/1.73m2, P = .047). A successful parathyroidectomy normalized all 24-hour urine calcium excretion. CONCLUSION: An indication for early parathyroidectomy should include estimated glomerular filtration rates less than 60mL/min/1.73m2 in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism.

Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.

We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research.

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing.

Background Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.

Recent Topics Around Multiple Endocrine Neoplasia Type 1.

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is complex with regard to clinical expressions, management, and molecular pathways. Advances are being made broadly and in focused aspects. Selected topics are presented for their developments since publication of the most recent MEN1 consensus guidelines 6 years ago. Methods: Topics were selected for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews. Results: The selected topics are as follows: tumor behavior and breast cancer in MEN1; foregut neuroectoderm tumor screening, biomarkers periodically to detect tumor emergence of foregut neuroectoderm tumors, 68Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal neuroectodermal tumor imaging, and glucagon-like peptide-1 receptor scintigraphy for insulinoma; therapy, the size of pancreatic neuroendocrine tumor (NET) as one criterion for surgery, minimally invasive surgery of pancreatic NETs, and 177Lu dotatate therapy; MEN1 gene, the search for the MEN1/menin pathway and MEN1 or GCM2 mutation in familial isolated hyperparathyroidism, and MEN1 mutation-positive vs mutation-negative cases of MEN1 are different. Conclusions: MEN1 topics are a rich and fast-moving area. Important highlights stand out, and major and rapid advances will continue into the near future.

Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease.

OBJECTIVE: Cushing disease (CD) is a rare entity caused by ACTH-secreting pituitary tumours, leading to prolonged hypercortisolism. Most cases are sporadic but can rarely occur in the context of familial predisposition, due to germline mutations in genes such as MEN1, leading to multiple endocrine neoplasia type 1, MEN1. We have reported previously that CD can be the first and only presenting manifestation of MEN1. In this report, we describe a cohort of paediatric patients who presented with CD as the first manifestation of MEN1. MATERIALS AND METHODS: A retrospective analysis of paediatric patients admitted to the National Institutes of Health (NIH) Clinical Center for evaluation of hypercortisolism, between 1997 and 2017. MEN1 was diagnosed on a clinical, familial and/or genetic basis. RESULTS: Of a total of 238 children with CD, six patients were subsequently diagnosed with MEN1, three males and three females with a mean age at diagnosis of CD at 13.4 ± 2.9 years. Five of the six patients had familial MEN1 and one patient was a sporadic case. Additional manifestations of MEN1 included primary hyperparathyroidism in three patients and hyperprolactinemia in two patients. DISCUSSION: This report describes a paediatric patient population with MEN1 in whom CD was the initial manifestation, confirming a previous observation that paediatric patients with MEN1 may present first with an ACTH-producing adenoma. Therefore, germline MEN1 mutations should be sought in paediatric CD and tested for when there is a suggestive family history and/or other manifestations.

Probability of Positive Genetic Testing Results in Patients with Family History of Primary Hyperparathyroidism.

BACKGROUND: Approximately 10% of patients with primary hyperparathyroidism (PHPT) have hereditary disease. Hereditary PHPT may be syndromic (MEN1, 2, and 4 and hyperparathyroidism-jaw tumor syndrome) or non-syndromic (familial isolated PHPT). There are limited data on the probability of testing positive for genetic mutation based on clinical presentation. The aim of this study was to determine potential associations between clinical and biochemical features and mutation in susceptibility genes for PHPT in patients with a family history of PHPT. STUDY DESIGN: A retrospective analysis of 657 patients who had an initial parathyroidectomy for PHPT at a tertiary referral center. Logistic regression analyses were performed in 205 patients with a family history of PHPT to identify factors associated with a positive genetic test. RESULTS: Of 657 patients, 205 (31.2%) had a family history of PHPT. Of those 205 patients, 123 (60%) had a germline mutation detected (91 MEN1, 14 CDC73, and 18 GCM2). In univariate analysis, younger age (45 years and younger), male sex, multigland disease, and parathyroid carcinoma were associated with positive germline mutation; biochemical cure after an initial parathyroidectomy was less frequent in patients with familial PHPT (96.2% vs 89.2%; p = 0.005). In multivariable analysis, age 45 years and younger, male sex, and multigland disease were independent factors associated with positive genetic testing. CONCLUSIONS: In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT.

Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure.

BACKGROUND: Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism. METHODS: We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism. RESULTS: Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P < .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P < .001). CONCLUSION: GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism.

Prognostic Utility of Total 68Ga-DOTATATE-Avid Tumor Volume in Patients With Neuroendocrine Tumors.

BACKGROUND & AIMS: Survival times vary among patients with neuroendocrine tumors (NETs) - even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs because some patients can survive decades without treatment. 68Gallium-DOTATATE positron emission tomography with computed tomography (68Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68Ga-DOTATATE PET/CT-based analysis of tumor volume in patients with NETs. METHODS: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center (Bethesda, MD) from 2013 through 2017. All patients underwent 68Ga-DOTATATE PET/CT image analysis and total 68Ga-DOTATATE-Avid tumor volume (68Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion during the interval between baseline 68Ga-DOTATATE PET/CT scan and follow-up imaging (14.0 ± 6.1 months; range, 1-35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range, 4-35 months). RESULTS: We found an inverse correlation between quartiles of 68Ga-DOTATATE TV and PFS (P = .001) and disease-specific survival (P = .002). A 68Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P = .04). A 68Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P = .01), as well as in subgroup analysis of patients with pancreatic NETs. CONCLUSIONS: In a prospective study, we demonstrated the prognostic utility of 68Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality.

Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Ethnicity of Patients With Germline GCM2-Activating Variants and Primary Hyperparathyroidism.

CONTEXT: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID). OBJECTIVE: We investigated the ethnicity of individuals with germline variants in the GCM2 CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database. DESIGN: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the GCM2 CCID region. Luciferase reporter assays were performed to determine the functional impact of GCM2 variants. SETTING AND PATIENTS: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients. RESULTS: The GCM2 p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with GCM2-activating variants often had multigland involvement or postoperative recurrent or persistent disease. CONCLUSIONS: Specific GCM2-activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT.

Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone-Secretory Tissue.

Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in CASR, GNA11, or AP2S1. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the CASR. 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of MEN1 or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from RET activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in CDC73. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT-JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects GCM2 activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression.

Calcimimetic Use in Familial Hypocalciuric Hypercalcemia-A Perspective in Endocrinology.

Context: Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia that even persists after subtotal parathyroidectomy. Symptoms are usually mild. Past recommendations have often been for monitoring and against surgical or pharmacologic treatments. Methods: Review of publications about FHH, calcium-sensing receptors (CaSRs), and calcimimetics. Results: FHH reflects heterozygous germline mutation of CASR, GNA11, or AP2S1. These mutations inactivate the CaSRs in the parathyroid cell. Thereby, they shift the serum calcium set point to higher values and cause hypercalcemia. Calcimimetic drugs enhance the effects of calcium on the CaSRs and thereby inhibit the parathyroid cell. Calcimimetic drugs are indicated in adults with primary hyperparathyroidism without a good surgical option. Calcimimetic safety and efficacy are not established in children younger than age 18 years. Recent case reports have described treatment of FHH with calcimimetics. Success was classified as combinations of subjective improvements and decreases of serum calcium levels, but not necessarily into the normal range. Treatment was successful in 14 of 16 cases (88%). Conclusion: Deductions based on these case reports have limitations. For example, failures of therapy may not have been reported. Cost of the drug might be rate limiting. Calcimimetics can be offered to adults with FHH and those in whom the serum calcium level is >0.25 mM (1 mg/dL) beyond the upper limit of normal or with possible symptoms of hypercalcemia. Calcimimetics can now be offered to more adults with FHH.

Association between neuroendocrine tumors biomarkers and primary tumor site and disease type based on total 68Ga-DOTATATE-Avid tumor volume measurements.

OBJECTIVE: To determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by 68Ga DOTATATE PET/CT imaging. DESIGN: A retrospective analysis of a prospective database of patients with NETs. METHODS: Fasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total 68Ga-DOTATATE-avid tumor volume (TV) was analyzed. RESULTS: The analysis included 232 patients. In patients with pancreatic NETs (n = 112), 68Ga-DOTATATE TV correlated with CgA (r = 0.6, P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39), 68Ga-DOTATATE TV correlated with glucagon (r = 0.5, P = 0.01) and PP levels (r = 0.5, P = 0.049). In patients with von Hippel-Lindau (n = 24), plasma VIP (r = 0.5, P = 0.02) and PP levels (r = 0.7, P < 0.001) correlated with 68Ga-DOTATATE TV. In patients with small intestine NET (SINET, n = 74), 68Ga-DOTATATE TV correlated with CgA (r = 0.5, P = 0.02) and 5-HIAA levels (r = 0.7, P < 0.001), with 5-HIAA ≥8.1 mg/24 h associated with metastatic disease with high positive (81.8%) and negative (85.7%) predictive values (P = 0.001). 68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8, P = 0.002 and r = 0.7, P = 0.02 respectively). CONCLUSIONS: Our data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET.

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.

A patient with MEN1 typical features and MEN2-like features.

Multiple endocrine neoplasia (MEN) type 1 (MEN1) and 2 (MEN2) rarely co-exist in one case. Here we report a patient with features of both syndromes. The patient presented with typical MEN1 features plus pheochromocytoma and thickened corneal nerves. She had a germline 1132delG frameshift mutation in MEN1, no mutation in CDKN1B (p27) and no RET mutation, but had both RET polymorphisms Gly691Ser and Arg982Cys. This is the first case report of a combination of typical clinical findings of MEN1 harboring a germline MEN1 mutation and the MEN2-like phenotype with negative full RET gene analysis of pathogenic variants. Possible explanations include a previously unrecognized phenotype-genotype association or the influence of potential phenotypic modifying RET variants. Furthermore, the combination observed in this patient may point to a single molecular pathway, and supports the possibility of as yet unrecognized connections between the molecular pathways for MEN1/menin protein and MEN2/RET protein.