p.Ala541Thr variant of MEN1 gene: a non deleterious polymorphism or a pathogenic mutation?

CONTEXT: Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers. OBJECTIVE: The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes. PATIENTS AND METHODS: We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1- heterozygous knock-out mice, and compared with wild type (WT). RESULTS: The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein. CONCLUSION: Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.

Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome.

CONTEXT: HIF2A germline mutations were known to cause congenital polycythemia. Recently, HIF2A somatic mutations were found in several patients with polycythemia and paraganglioma, pheochromocytoma, or somatostatinoma, suggesting the occurrence of a de novo postzygotic HIF2A mutation that has not been demonstrated clearly. PATIENTS: Patient 1 is a woman suffering from polycythemia diagnosed at the age of 16 years. She was operated on for a pheochromocytoma at 45 years and for two abdominal paragangliomas at 59 years. She was also diagnosed with somatostatinoma. Patient 2 is a young boy who suffered from polycythemia since infancy. He underwent surgery for a nonfunctional adrenal paraganglioma at the age of 9 years. METHODS: We sequenced by Sanger and next-generation sequencing the HIF2A gene in DNA extracted from tumors, leukocytes, and buccal cells. RESULTS: In patient 1, we identified a somatic HIF2A mutation (c.1586T>C; p.Leu529Pro) in DNA extracted from both paragangliomas. The mutation was detected as a somatic mosaic in DNA extracted from somatostatinoma and was absent from germline DNA. In patient 2, we found an HIF2A heterozygous mutation (c.1625T>C; p.Leu542Pro) in the paraganglioma, but the mutation was also present as a mosaic in leukocyte DNA and in DNA extracted from buccal cells (3.3 and 8.96% of sequencing reads, respectively). Both mutations disrupt the hydroxylation domain of the HIF2α protein. CONCLUSIONS: Our study shows that HIF2A-related tumors are caused by postzygotic mutations occurring in early developmental stages. Potential germline mosaicism should be considered during the familial genetic counseling when an individual has been diagnosed with HIF2A-related polycythemia-paraganglioma syndrome.

The clinical spectrum of RET proto-oncogene mutations in codon 790.

OBJECTIVE: Due to a strong genotype-phenotype correlation, the timing of prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers is usually dictated by genetic analysis. SUBJECTS AND METHODS: We report a nationwide retrospective study of the clinical data of 77 French patients from 19 families with a mutation in codon 790 of the RET proto-oncogene. RESULTS: The average age at diagnosis was 35.6 years ± 20.5. Thirty-nine patients were women. Fifty-five patients underwent operations for the treatment of medullary thyroid carcinoma (MTC) at the mean age of 38 years (4-82 years). The mean follow-up duration was 89 months. TNM staging was as follows: T0NxMx in 19, TxNxMx in 1, T1NxMx in 22, T1N1Mx in 8, T2N1Mx in 1 and T3N1Mx in four patients. In the T1/x-Nx group, 96% were considered cured after surgery. In the N1 group (n=13), six patients had multifocal disease and five patients were cured. Age and gender were not significant predictors of remission. Twenty-two patients did not undergo an operation (age 1.5-78 years); among them, 11 patients had a mean basal calcitonin (CT) level of 9.8 pg/ml (2-24) after 53 months of follow-up. One patient had been operated on for phaeochromocytoma (PHEO), and their CT level remained normal for 262 months. CONCLUSIONS: This study confirms that RET 790 mutation is associated with a non-aggressive form of multiple endocrine neoplasia type 2, as 28% of the patients were followed up without thyroidectomy, 25% had been thyroidectomised with no tumour being detected and even patients with MTC had slow-evolving disease. Moreover, only one patient had PHEO, and no-one had primary hyperparathyroidism.

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism.

CONTEXT: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant syndrome with incomplete penetrance that can associate in a single patient parathyroid adenoma or carcinoma, fibro-osseous jaw tumor, cystic kidney lesion, and uterine tumor. Germline mutations of the HRPT2 gene (CDC73) coding for parafibromin are identified in approximately 50%-75% of HPT-JT cases and in approximately 14% of familial isolated hyperparathyroidism. A whole deletion of this gene has recently been reported in 1 sporadic case and in a family presenting with HPT-JT. OBJECTIVE: The objective of the study was to report molecular abnormalities of the HRPT2 gene in patients with primary hyperparathyroidism in a French National cohort from the Groupe d'Étude des Tumeurs Endocrines. METHODS: Patients' genomic DNA was screened by PCR-based sequencing for point mutations affecting HRPT2 and real-time quantitative PCR analysis for gross deletions. RESULTS: We report 20 index patients with a germinal HRPT2 abnormality. Median age at diagnosis of primary hyperparathyroidism was 23 years (range 14-65 years). Median serum total calcium level at diagnosis was 3.19 mmol/L (range 2.8-4.3 mmol/L). Thirteen different mutations were identified by routine sequencing, including 7 mutations never reported. Seven patients (35%) carried a gross deletion of this gene (3 complete and 4 partial deletions). No genotype-phenotype correlation could be identified. A gross deletion of the HRPT2 gene was identified in 7% of patients for whom a routine screening by direct sequencing came up as negative. CONCLUSION: Gross deletion analysis of the HRPT2 gene is indicated for all patients negative for mutation, presenting with HPT-JT or familial isolated hyperparathyroidism, parathyroid carcinoma, or in patients with apparently sporadic parathyroid adenoma diagnosed at a young age, having a severe hypercalcemia.

Is basal ultrasensitive measurement of calcitonin capable of substituting for the pentagastrin-stimulation test?

OBJECTIVE: To evaluate a second-generation assay for basal serum calcitonin (CT) measurements compared with the pentagastrin-stimulation test for the diagnosis of inherited medullary thyroid carcinoma (MTC) and the follow-up of patients with MTC after surgery. Recent American Thyroid Association recommendations suggest the use of basal CT alone to diagnose and assess follow-up of MTC as the pentagastrin (Pg) test is unavailable in many countries. DESIGN: Multicentric prospective study. PATIENTS: A total of 162 patients with basal CT <10 ng/l were included: 54 asymptomatic patients harboured noncysteine 'rearranged during transfection' (RET) proto-oncogene mutations and 108 patients had entered follow-up of MTC after surgery. MEASUREMENT: All patients underwent basal and Pg-stimulated CT measurements using a second-generation assay with 5-ng/l functional sensitivity. RESULTS: Ninety-five per cent of patients with basal CT ≥ 5 ng/l and 25% of patients with basal CT <5 ng/l had a positive Pg-stimulation test (Pg CT >10 ng/l). Compared with the reference Pg test, basal CT ≥ 5 ng/l had 99% specificity, a 95%-positive predictive value but only 35% sensitivity (P < 0.0001). Overall, there were 31% less false-negative results using a 5-ng/l threshold for basal CT instead of the previously used 10-ng/l threshold. CONCLUSION: The ultrasensitive CT assay reduces the false-negative rate of basal CT measurements when diagnosing familial MTC and in postoperative follow-up compared with previously used assays. However, its sensitivity to detect C-cell disease remains lower than that of the Pg-stimulation test.

Molecular profiling of pancreatic neuroendocrine tumors in sporadic and Von Hippel-Lindau patients.

PURPOSE: Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutations in the VHL tumor suppressor gene, predisposing to a variety of neoplasms including pancreatic neuroendocrine tumors (PanNET). In VHL disease, PanNET probably progress according to a specific pathway of carcinogenesis. Our aim was to characterize by molecular quantitative analysis a panel of molecules implicated in the VHL pathway and in tumor progression in the PanNET of patients with VHL. EXPERIMENTAL DESIGN: The expression of 52 genes was studied by quantitative reverse transcriptase PCR in 18 patients with VHL operated on for PanNET and compared with 16 non-VHL PanNET. The VHL and non-VHL tumors were matched according to their size and cell proliferation. For some genes, we looked for differences in the protein expression in VHL PanNET (n = 31), microadenomas (n = 22), and non-VHL PanNET (n = 16), included in tissue microarray blocks. RESULTS: Nineteen (36%) genes were significantly upregulated and three (6%) downregulated in VHL PanNET. The upregulated genes were related to (i) hypoxia-inducible factor (HIF) molecules (CA9, HIF2A, and GLUT1), (ii) angiogenesis (CDH5, VEGFR1, EDNRA, ANGPT2, CD34, VEGFR2, VEGFA, and ANGPT1), (iii) the processes of epithelial-mesenchymal transition (VIM) and/or metastasis (LAMA4 and CXCR4), (iv) growth factors and receptors (PDGFB, IRS1, and ERBB1), or (v) cell cycle (CCND1 and CDKN2A). The downregulated genes were related to (i) EMT (OCLN) and (ii) signaling pathways (RPS6KB1 and GADD45B). CONCLUSION: This study shows that the progression of PanNET in patients with VHL tumors follows a specific pathway and supports that targeting molecules specifically involved may be of therapeutic importance.

Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH): a French nationwide series of 21 cases.

CONTEXT: Ectopic GHRH secretion is a rare cause of acromegaly, and case reports are mainly isolated. SETTING: From the registry of the sole laboratory performing plasma GHRH assays in France, we identified cases of ectopic GHRH secretion presenting with acromegaly between 1983 and 2008. PATIENTS: Twenty-one patients aged 14-77 yr were identified from 12 French hospitals. Median GHRH was 548 (270-9779) ng/liter. MAIN OUTCOME MEASURES: Outcome measures included description of tumor features and outcome and the relation between plasma GHRH values and tumor site, size, and spread. RESULTS: The primary neuroendocrine tumor was identified for 20 of 21 patients (12 pancreatic, seven bronchial, one appendicular). Tumors were large (10-80 mm), identified on computed tomography scan in 18 cases and by endoscopic ultrasound and somatostatin receptor scintigraphy in two. Somatostatin receptor scintigraphy had a similar sensitivity to computed tomography scan (81 vs. 86%). Tumors were all well differentiated; 47.6% had metastasized at the time of diagnosis of acromegaly. After a median follow-up of 5 yr, 85% of patients were alive. Ninety-one percent of patients whose tumor was completely removed were considered in remission, and most had normalized plasma GHRH. The remaining patients were treated with somatostatin analogs: IGF-I normalized except for one patient who required pegvisomant, but GHRH levels remained elevated. No correlations were found between GHRH levels and tumor site or size or the existence of metastases. Identification of increased plasma GHRH during follow-up was an accurate indicator of recurrence. CONCLUSIONS: The prognosis of endocrine tumors responsible for GHRH secretion appears relatively good. Plasma GHRH assay is an accurate tool for diagnosis and follow-up.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. DESIGN: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Magnetic resonance imaging versus endoscopic ultrasonography for the detection of pancreatic tumours in multiple endocrine neoplasia type 1.

OBJECTIVE: In multiple endocrine neoplasia type 1, the main risk factor for metastases is pancreatic tumour size. We and others recommend limiting surgery to non-functioning pancreatic tumors ≥20 mm or growing, based on their size measured with endoscopic ultrasonography. Because endoscopic ultrasonography is invasive, we compared endoscopic ultrasonography (EUS) to non-invasive magnetic resonance imaging (MRI) for the detection of pancreatic tumours ≥10 mm in multiple endocrine neoplasia type 1 patients. METHODS: A prospective study was performed in nine participating centres; 90 patients with multiple endocrine neoplasia type 1 underwent EUS and MRI with gadolinium infusion. Gastroenterologists and radiologists were blinded to the results, magnetic resonance images were reviewed centrally. RESULTS: EUS detected 86 tumours ≥10 mm, and 48 (53.3%) patients had at least one tumour ≥10 mm. MRI detected 67 tumours ≥10 mm, and 46 (51.1%) patients had at least one tumour ≥10 mm. EUS and MRI agreement was moderate for detection of tumours ≥10 mm (Kappa coefficient=0.49), and for selection of patients with tumours ≥10 mm (Kappa coefficient=0.55). EUS and MRI missed 11/24 and 4/24 lesions ≥20 mm, respectively. EUS failed to identify 9/57 (15.7%) patients with pancreatic tumours ≥10 mm, and MRI failed to identify 11/57 (19.3%) patients with pancreatic tumours ≥10 mm. CONCLUSIONS: EUS and MRI are complementary and should be performed at initial evaluation in multiple endocrine neoplasia type 1 patients. Whether follow-up should be based on either technique or both, requires further evaluation.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients.

BACKGROUND: The natural history of multiple endocrine neoplasia type 1 (MEN1) is known through single-institution or single-family studies. We aimed to analyze the risk factors and causes of death in a large cohort of MEN1 patients. METHODS: Overall, 758 symptomatic MEN1 patients were identified through the GTE network (Groupe d'étude des Tumeurs Endocrines), which involves French and Belgian genetics laboratories responsible for MEN1 diagnosis and 80 clinical reference centers. The causes of death were analyzed. A frailty model, including time-dependent variables, was used to assess the impact of each clinical lesion, except for hyperparathyroidism, on survival. RESULTS: The median follow-up was 6.3 years. Female gender, family history of MEN1, and recent diagnosis were associated with a lower risk of death. Compared with nonaffected patients, those with thymic tumors (hazard ratio [HR] = 4.64, 95% CI = 1.73-12.41), glucagonomas-vipomas-somatostatinomas (HR = 4.29, 95% CI = 1.54-11.93), nonfunctioning pancreatic tumors (HR = 3.43, 95% CI = 1.71-6.88), and gastrinoma (HR = 1.89, 95% CI = 1.09-3.25) had a higher risk of death after adjustment for age, gender, and diagnosis period. The increased risk of death among patients with adrenal tumors was not significant, but three patients died from aggressive adrenal tumors. Pituitary tumors, insulinomas, and bronchial tumors did not increase the risk of death. The proportion of MEN1-related deaths decreased from 76.8 to 71.4% after 1990. CONCLUSIONS: The prognosis of MEN1 disease has improved since 1980. Thymic tumors and duodenopancreatic tumors, including nonsecreting pancreatic tumors, increased the risk of death. Rare but aggressive adrenal tumors may also cause death. Most deaths were related to MEN1. New recommendations on abdominal and thoracic imaging are required.

A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

CONTEXT: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). OBJECTIVE: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. DESIGN AND PATIENTS: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. RESULTS: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. CONCLUSION: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.

The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas.

CONTEXT: Germline mutations in SDHx genes cause hereditary paraganglioma. OBJECTIVE: The aim of the study was to assess the indications for succinate dehydrogenase (SDH) genetic testing in a prospective study. DESIGN: A total of 445 patients with head and neck and/or thoracic-abdominal or pelvic paragangliomas were recruited over 5 yr in 20 referral centers. In addition to classical direct sequencing of the SDHB, SDHC, and SDHD genes, two methods for detecting large genomic deletions or duplications were used, quantitative multiplex PCR of short fluorescent fragments (QMPSF) and multiplex ligation-dependent probe amplification (MLPA). RESULTS: A large variety of SDH germline mutations were found by direct sequencing in 220 patients and by QMPSF and MLPA in 22 patients (9.1%): 130 in SDHD, 96 in SDHB, and 16 in SDHC. Mutation carriers were younger and more frequently had multiple or malignant paraganglioma than patients without mutations. A head and neck paraganglioma was present in 97.7% of the SDHD and 87.5% of the SDHC mutation carriers, but in only 42.7% of the SDHB carriers. A thoracic-abdominal or pelvic location was present in 63.5% of the SDHB, 16.1% of the SDHD, and in 12.5% of the SDHC mutation carriers. Multiple paragangliomas were diagnosed in 66.9% of the SDHD mutation carriers. A malignant paraganglioma was documented in 37.5% of the SDHB, 3.1% of the SDHD, and none of the SDHC mutation carriers. CONCLUSIONS: SDH genetic testing, including tests for large genomic deletions, is indicated in all patients with head and neck and/or thoracic-abdominal or pelvic paraganglioma and can be targeted according to clinical criteria.

Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines).

BACKGROUND: Thymic neuroendocrine tumors (Th-NET) present a poor prognosis for patients with multiple endocrine neoplasia type 1 (MEN1). The purpose of this article was to study the clinical, biological, and pathological features of Th-NET in a large cohort of patients with MEN1. METHODS: The 761-patient MEN1 cohort from the GTE registry was used (Groupe des Tumeurs Endocrines). RESULTS: The actuarial probability of occurrence was 2.6% (range, 1.3-5.5%) at aged 40 years. All, except one, Th-NET patients were men. Four patients had no other associated lesions. The youngest patient was aged 16 years. Mean age at the time of diagnosis was 42.7 (range, 16.1-67.5) years. The 10-year probability of survival was 36.1% (range, 11.5-62%). Seven patients (33%) belonged to clustered MEN1 families. The spectrum of associated lesions in patients with Th-NET was not statistically different from the spectrum of the remainder of the cohort. Various endocrine markers were high, but none were sensitive or specific enough to be useful for Th-NET detection. CT-scan and MRI were always positive at the time of diagnosis. No particular mutation was found to be associated with Th-NET. Five cases underwent prophylactic thymectomy without success. CONCLUSIONS: Several end points may be helpful for future guidelines: (1) earlier detection of Th-NET in MEN1 patients is required; (2) screening of both sexes is necessary; (3) a prospective study comparing MRI vs. CT scan in yearly screening for Th-NET is needed; (4) a reinforced screening program must be established for patients who belong to clustered families; and (5) thymectomies must be performed in specialized centers.

Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations.

CONTEXT: Kallmann's syndrome (KS) is a genetically heterogeneous disorder consisting of congenital hypogonadotropic hypogonadism (CHH) with anosmia or hyposmia. OBJECTIVE: Our objective was to compare the reproductive phenotypes of men harboring KAL1 and FGFR1/KAL2 mutations. DESIGN AND PATIENTS: We studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 and 18 in FGFR1/KAL2, but none had additional mutations in PROK-2 or PROKR-2 genes. RESULTS: Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete CHH. Three patients with FGFR1/KAL2 mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent (14 of 21 vs. 3 of 15; P<00.1) and testicular volume (2.4+/-1.1 vs. 5.4+/-2.4 ml; P<0.001) was smaller in CHH subjects with KAL1 mutations than in subjects with FGFR1/KAL2 mutations. The mean basal plasma FSH level (0.72+/-0.47 vs. 1.48+/-0.62 IU/liter; P<0.05), serum inhibin B level (19.3+/-10.6 vs. 39.5+/-19.3 pg/ml; P<0.005), basal LH plasma level (0.57+/-0.54 vs. 1.0+/-0.6 IU/liter; P<0.01), and GnRH-stimulated LH plasma level (1.2+/-1.0 vs. 4.1+/-3.5 IU/liter; P<0.01) were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and seven subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. CONCLUSION: KAL1 mutations result in a more severe reproductive phenotype than FGFR1/KAL2 mutations. The latter are associated with a broader spectrum of pubertal development and with less severe impairment of gonadotropin secretion.

Therapeutic impact of 18FDG-PET/CT in the management of iodine-negative recurrence of differentiated thyroid carcinoma.

BACKGROUND: 18-F-fluoro-2-deoxyglucose positron emission tomography ((18)FDG-PET) is useful in the detection of iodine-negative differentiated thyroid carcinoma (DTC). The aim of this prospective study was to assess therapeutic impact of (18)FDG-PET imaging using a PET/computed tomography (CT) system in patients with iodine-negative recurrence of DTC. METHODS: From 2002 to 2006, patients with recurrence of DTC diagnosed by elevated thyroglobulin level and negative 131-I whole-body scan were included. RESULTS: Forty-five patients (31 women, 14 men), with a mean age of 55 years, with 36 papillary, 5 follicular, and 4 Hürthle carcinomas, were studied. All patients had previously undergone total thyroidectomy and postoperative thyroid remnant ablation with 131-I. The findings of (18)FDG-PET/CT were positive in 31 patients (68.8%) and negative in 14 (32.2%). Results were true positive in 24 of 31 patients. The sensitivity, positive predictive value, and accuracy of (18)FDG-PET/CT were 63%, 77%, and 53%, respectively. Twenty patients were operated on, 19 had neck surgery with mediastinal lymph node dissection (1 case) and lung resection (1 case), and 1 underwent lung resection. Seven patients had a stimulated thyroglobulin level <1 ng/mL. CONCLUSION: (18)FDG-PET/CT is able to select patients who can benefit from surgery. Normalization of thyroglobulin is observed in one third of operated patients.

Sensitivity and prognostic value of positron emission tomography with F-18-fluorodeoxyglucose and sensitivity of immunoscintigraphy in patients with medullary thyroid carcinoma treated with anticarcinoembryonic antigen-targeted radioimmunotherapy.

CONTEXT: Patients with progressive medullary thyroid carcinoma (MTC) undergo multiple imaging procedures for diagnosis of relapse and staging. OBJECTIVE: Our objective was to assess the sensitivity and prognostic value of 18F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and the imaging sensitivity of pretargeted iodine-131-radioimmunotherapy (RIT) in patients with progressive MTC. DESIGN/SETTING/PATIENTS: We performed a prospective multicenter study in high-risk patients with rapidly progressing MTC enrolled in a phase-II pretargeted RIT study, as documented by short serum calcitonin (Ct) or carcinoembryonic antigen (CEA) doubling time (DT). INTERVENTIONS/MAIN OUTCOME MEASURES: Patients underwent neck-thoracic-abdominal CT, spine and pelvic magnetic resonance imaging, whole-body post-RIT immunoscintigraphy (IS) with iodine-131, and whole-body 18F-FDG-PET/CT imaging. Imaging sensitivity and the correlation between FDG uptake and biomarkers DT were evaluated. RESULTS: A total of 33 patients with mean CEA and Ct DTs of 1.90 yr (range 0.21-8.50) and 1.52 yr (range 0.09-6.01), respectively, were evaluated. Sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone metastases; overall sensitivity was 76%. Median standardized uptake value (SUVmax) was 5.23 (2.06-13.90). SUVmax correlated significantly with Ct DT (P = 0.011) and minimal DT (minimal value between CEA DT and Ct DT) (P = 0.027). Overall sensitivity of post-RIT IS, CT, and bone magnetic resonance imaging were 94, 74, and 85%, respectively. CONCLUSIONS: These results demonstrate the value of FDG-PET/CT for staging of patients with progressive MTC, especially in the neck and mediastinum, with possible prognostication by SUV quantification. Post-RIT IS was the most sensitive of the imaging modalities studied prospectively.

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis.

In a new cohort of 141 unrelated patients affected by Kallmann syndrome we identified FGFR1 sequence variants in 17 patients, all in the heterozygous state. The fifteen novel variants consist of 10 missense (p.N77K, p.C101F, p.R250W, p.G270D, p.P283R, p.S332C, p.H621R, p.S685F, p.I693F, p.R822C), two nonsense (p.E324X, p.R661X), a frameshift (p.S439fs), and two splice site (c.1081G>C and c.1977+1G>A) changes. However, the p.N77K and p.R822C changes were also found in two and one out of 150 healthy control individuals, respectively, and therefore, their pathogenic effect is questionable. Notably, three alterations (p.E324X, p.S332C, c.1081G>C) are located in the alternative exon 8B that codes for the FGFR1c isoform, thus indicating that this isoform plays a crucial role in the development of the olfactory system in man. Moreover, the presence of cleft palate in a patient carrying the p.E324X change shows that FGFR1c is important for palate morphogenesis too.