Diagnosis Of Multiple Endocrine Neoplasia Type Research Articles

Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism

BackgroundPrimary hyperparathyroidism (PHPT) is uncommon in children. The surgical management of PHPT in children has evolved over the past two decades. MethodsA retrospective study of patients who underwent parathyroidectomy for PHPT diagnosed at age <18years and managed at a tertiary referral center for endocrine and familial disorders. ResultsThirty-eight patients met eligibility criteria (1981–2012). Median age at PHPT diagnosis was 15years. Two-thirds of patients were symptomatic (68%, n=26), most commonly from nephrolithiasis. Twenty-six (68%) patients underwent a standard cervical exploration while 32% underwent a focused unilateral parathyroidectomy. Multiple endocrine neoplasia type 1 (MEN1) was diagnosed preoperatively in 22/26 patients. Patients with a preoperative diagnosis of MEN1 were more likely to undergo a complete initial operation (≥3 gland parathyroidectomy with transcervical thymectomy, 13/22, 59% vs. 0/4, 0%; P=0.03) and less likely to have recurrent disease (10/22, 45% vs. 3/4, 75%; P<0.001) during follow up than patients diagnosed postoperatively. ConclusionsChildren with PHPT should raise suspicion for MEN1. Preoperative MEN1 evaluation helped guide the extent of initial parathyroidectomy and was associated with lower rates of recurrence in sporadic and familial PHPT in pediatric patients. Management should occur at a high volume center with experienced clinicians and genetic counseling services.

Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

BackgroundDiagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1.Case presentationThe patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed “adenoma-like” kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence.ConclusionsDespite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked

The morbidity and mortality of individuals with multiple endocrine neoplasia type 1 (MEN1) can be reduced by early diagnosis of MEN1 and related endocrine tumors. To find factors contributing to early diagnosis, we collected clinical information on MEN1 patients through a MEN study group, "MEN Consortium of Japan" and analyzed the time of initial symptom-dependent detection of parathyroid tumors, gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) and pituitary tumors, and that of tumor detection-dependent MEN1 diagnosis in 560 patients. Main tumors were identified up to 7.0 years after symptoms appeared and there was no difference in age at the diagnosis of GEPNETs alone between probands and family members. In patients with typical symptoms (peptic ulcers, urolithiasis, fasting hypoglycemia, bone fracture/loss and amenorrhea), the mean interval between symptom manifestation and tumor detection was extended up to 9.6 years. In particular, 21.7% (5/23) of patients with amenorrhea were diagnosed with pituitary tumors in under one year. In patients with peptic ulcers (from parathyroid tumors or GEPNETs) and urolithiasis (from parathyroid tumors), the interval was positively correlated with age at tumor detection. The interval between tumor detection and MEN1 diagnosis was also prolonged to approximately four years in patients with fasting hypoglycemia (from GEPNETs) and amenorrhea. A substantial delay in the diagnosis of symptom-related tumors and subsequent MEN1 and inadequate screening of GEPNETs in family members were indicated. A greater understanding of MEN1 may assist medical practitioners to make earlier diagnoses, to share patients' medical information and to give family members sufficient disease information.

Application of an intracellular stability test of a novel missense menin mutant to the diagnosis of multiple endocrine neoplasia type 1

Germline MEN1 mutation analysis is a powerful tool for an early diagnosis of multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant familial cancer syndrome characterized by the parathyroid, pituitary and gastroenteropancreatic endocrine tumors. However, the clinical significance of MEN1 gene variants, especially missense and in-frame mutations as well as some splicing mutations, is not always obvious. We have previously shown that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. We also demonstrated by a fluorescent immunocytochemical stability test that the stability of missense and in-frame deletion mutants varies widely but that unstable mutants were found only in MEN1 and related disorders and not in normal polymorphisms. In the present study, we evaluated by this stability test the pathogenicity of a novel MEN1 missense mutation, c.1118C>T, encoding a P373L mutant menin, identified in a suspected MEN1 patient. The results demonstrated that the mutant menin is highly unstable, indicating that this mutation is causative for MEN1. These findings encouraged us to proceed with presymptomatic genetic screening for this mutation among the family members, which resulted in the identification of asymptomatic mutation carriers. Thus, the information from the menin stability test was useful for genetic diagnosis and counseling of MEN1 in the case with a previously unreported MEN1 missense mutation.

A novel splice site mutation of the &lt;i&gt;MEN1&lt;/i&gt; gene identified in a patient with primary hyperparathyroidism

Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome characterized by pituitary, parathyroid and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and its incomplete forms often manifested as familial isolated hyperparathyroidism and apparently sporadic parathyroid tumor. Mutation analysis of the MEN1 gene is a powerful tool for the early diagnosis of MEN1; however, the clinical significance of the identified mutations is not always obvious. In this study, a previously unreported missense MEN1 mutation, c.824G>T was identified in a patient with primary hyperparathyroidism and evaluated for its pathogenicity. This mutation was predicted to generate a putative missense menin protein, R275M. A stability test of the menin protein demonstrated that the stability of R275M mutant was reduced only slightly as compared with wild type menin, and therefore could not preclude the possibility that it was a rare benign polymorphism. However, further analysis of leukocyte mRNA and minigene experiments indicated that the mutant c.824G>T allele gives rise to abnormally spliced menin mRNA, and thereby confirmed that c.824G>T mutation is causative for MEN1. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene.

Multiple endocrine neoplasia type 1- presenting multiple lipomas and hypoglycemia onset

SummaryBackground:Multiple endocrine neoplasia type 1 (MEN1), also called Wermer syndrome, is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the anterior pituitary, and the endocrine pancreas.Case Report:Here, we report a case of MEN1. Our patient was a 44-year-old woman who manifested typical features of MEN1, including insulinoma, pituitary tumors, and parathyroidoma, and exhibited multiple lipomas and a gastrinoma with duodenal ulcers. She was admitted to our hospital because of recurrent massive bleeding of the upper gastrointestinal tract and hypoglycemia. The first operation for pituitary tumors was performed when she was 40 years old. According to these examinations and her clinical course, the patient was diagnosed with insulinoma and gastrinoma. She subsequently underwent surgery for the pancreatic tumors. The majority of these tumor cells were immunohistochemically positive for insulin and negative for glucagon.Conclusions:This case suggests that multiple lipomas, insulinoma and gastrinoma may provide clues for a diagnosis of MEN1.

Presentation and Outcome of Pancreaticoduodenal Endocrine Tumors in Multiple Endocrine Neoplasia Type 1 Syndrome

Aim: To assess presentation and outcome of pancreaticoduodenal endocrine tumors (PDETs) in a single center series of multiple endocrine neoplasia type 1 (MEN1) patients. Methods: Retrospective analysis of prospectively collected data of MEN1 patients observed at the University of Verona. Results: Thirty-one MEN1 patients had PDETs, including 16 nonfunctioning (NF), 6 insulinomas and 9 Zollinger-Ellison syndrome (ZES). In 16 of these patients (52%), PDET was the manifestation which led to the diagnosis of MEN1; among this group, 15 patients (94%) previously had unidentified primary hyperparathyroidism (PHPT), which was asymptomatic in 9 cases (60%). Of the 31 patients, 19 (61%) underwent curativesurgery and 13 (68%, 7 NF-PDETs, 4 insulinomas and 2 ZES) were disease-free after a median follow-up of 3 years (range: 0.5–15). One patient had debulking surgery with stable disease after 2 years of follow-up. Eight patients with NF-PDETs ≤20 mm and 2 with ZES, treated with a conservative approach, showed stable disease. One patient with insulinoma was lost to follow-up. Conclusions: PDET may be the manifestation that leads to MEN1 diagnosis since the almost constant presence of PHPT is very often unrecognized or considered sporadic. Conversely, the presence of PDETs should be looked for in all patients presenting PHPT, even if asymptomatic, particularly before age 50. Surgery may be curative in the majority of insulinomas and can prolong disease-free survival in NF-PDET, but is not proven to be effective in ZES. A conservative approach can be safely reserved for patients with NF-PDETs ≤20 mm.

Simultaneous double thymic carcinoids: a rare initial manifestation of multiple endocrine neoplasia type 1

A 53-year-old man was referred to our hospital for treatment of two anterior mediastinal tumors. The anterior mediastinal tumors were resected by thymectomy under the probable diagnosis of double thymomas. The final pathological diagnosis was multiple thymic carcinoids. Although 20%-25% of patients with thymic carcinoid have a family history of multiple endocrine neoplasia type 1 (MEN-1), radiographic screening just after the operation did not detect any endocrine tumors. However, the patient had a urinary calculus 4 months 7 months after the operation. Endocrinological examination then revealed mild hypercalcemia, hypophosphatemia, hyperinsulinemia, and hyperprolactinemia. Radiologically, a parathyroid tumor and a pancreatic tumor were found. The patient was referred to a university hospital and a mutation of MEN-1 gene was detected. The diagnosis of MEN-1 was confirmed about 1 year after the operation.

Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1)

Phenocopies may confound the clinical diagnoses of hereditary disorders. We report phenocopies in Multiple Endocrine Neoplasia type 1 (MEN1), an autosomal dominant disorder, characterised by the combined occurrence of parathyroid, pituitary and pancreatic tumours. We studied 261 affected individuals from 74 families referred with a clinical diagnosis of MEN1 and sought inconsistencies between the mutational and clinical data. We identified four patients from unrelated families with phenocopies. Patients 1 and 2 from families with MEN1, developed prolactinomas as the sole endocrinopathy but they did not harbour the germline MEN1 mutation present in their affected relatives. Patient 3, had acromegaly and recurrent hypercalcaemia following parathyroidectomy, whilst patient 4 had parathyroid tumours and a microprolactinoma. Patients 3 and 4 and their relatives did not have MEN1 mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium-sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome due to a hyperparathyroidism type 2 deletional-frameshift mutation (c.1239delA), respectively. Phenocopies may mimic MEN1 either by occurrence of a single sporadic endocrine tumour in a patient with familial MEN1, or occurrence of two endocrine abnormalities associated with different aetiologies. Phenocopies arose in >5% of MEN1 families, and awareness of them is important in the clinical management of MEN1 and other hereditary disorders.

Reverse Referral: From Pathology to Endocrinology

Establishing a diagnosis of multiple endocrine neoplasia type 1 (MEN1) especially in children, adolescents, and young adults can be challenging because of phenotypic heterogeneity even among family members. We report an adolescent girl diagnosed to have MEN1 following presentation with multiple collagenomas. Histological evaluation of her cutaneous lesions revealed >70 collagenomas. Hormonal evaluation included calcium, phosphate, and parathormone measurements. Exons 2-10 of the MEN1 gene and flanking intron-exon borders were sequenced and revealed a novel nonsense mutation, Y222X. Following the identification of the cutaneous lesions as collagenomas by the pathologist, the patient was referred for an endocrine evaluation which revealed asymptomatic primary hyperparathyroidism. The patient elected to have surgery at which time she was found to have parathyroid hyperplasia. This case emphasizes the usefulness of cutaneous findings for the diagnosis and management of MEN1.

Pancreatic endocrine neoplasia: familial syndromes

Inherited or familial neuroendocrine tumours of the pancreas are uncommon. The most frequently encountered syndromic form occurs in the setting of multiple endocrine neoplasia type 1 (MEN-1). Sixty per cent of patients with MEN-1 manifest pancreatic endocrine tumours (PETs). These tumours occur in younger patients and tend to be more aggressive than similar sporadic forms. The pancreas displays a range of morphological changes that can assist in making the diagnosis of MEN-1. Ductulo-insular complexes, islet dysplasia and multiple non-functioning microadenomas are typically encountered. If functional, the tumours tend to be gastrin producing. von Hippel-Lindau patients can also have PETs, although benign cysts and serous microcystic adenomas are commoner. Multiple tumours may be encountered and they are characterized by cells with lipid vacuoles. PETs may also be seen in patients with type 1 neurofibromatosis (NF-1) and they are usually somatostatin producing. PETs are less frequently encountered than duodenal tumours in the setting of NF-1. Very few cases of PET are seen in tuberous sclerosis.

MEN1 gene and its mutations: Basic and clinical implications

Heterozygous germline mutations of the tumor-suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by pituitary, parathyroid, and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and related disorders. Neither mutation hot spot nor phenotype–genotype correlation has been established in MEN1 although some missense mutations may be specifically associated with a phenotype of familial isolated hyperparathyroidism. The gene product menin has been implicated in multiple roles, including gene transcription, maintenance of genomic integrity, and control of cell division and differentiation. These multiple functions are likely to be conferred by association with multiple protein factors. Occurrence of MEN1-causing missense mutations throughout menin also suggests the requirement of multiple binding factors for its full tumor-suppressive activity. The effect of menin depletion is highly tissue specific, but its underlying mechanism remains to be elucidated. A DNA test for MEN1 germline mutations is a useful tool for diagnosis of MEN1 although it needs further improvements

Mediastinal Seminoma in a Patient with Multiple Endocrine Neoplasia Type 1

A patient with multiple endocrine neoplasia type 1 (MEN1) developed a mediastinal seminoma. The patient was a 46-year-old man who presented with respiratory symptoms. A diagnosis of mediastinal seminoma was pathologically confirmed and a complete remission was achieved by chemotherapy. During his hospital stay, hyperparathyroidism and multiple pancreatic tumors associated with hypergastrinemia were found. A diagnosis of MEN1 was made genetically. Although patients with MEN1 manifest a variety of neoplastic disorders, no cases of concurrent seminoma and MEN1 have previously been reported. In addition, no etiological relationship between seminoma and MEN1 has yet been reported.

Improved Contemporary Surgical Management of Insulinomas

To determine changes in the management strategy of patients with insulinomas and identify critical factors in patient outcome. Pancreatic insulinomas are rare neoplasms that are present in various ways. The optimal approach to localization, operative management, and follow-up of insulinomas is undetermined. Sixty-one patients with a diagnosis of insulinoma requiring surgery at a tertiary care center between 1983 and 2007 were reviewed. Demographic details, mode of presentation, preoperative localization, operative procedures, and pathology data were assessed. The effect of different factors on survival was determined. Seven of 61 (11%) patients had a diagnosis of multiple endocrine neoplasia-type 1 (MEN-1). Multiple insulinomas were noted in 8% of cases and were more common in MEN-1 patients. The overall rate of malignancy was 8%. Confusion (67%), visual disturbances (42%), and diaphoresis (30%) were the most common presenting symptoms. Weight gain was noted in 44% of patients. The median duration of symptoms before diagnosis was 18 (1-240) months. The sensitivity of preoperative imaging of tumors before 1994 was 75%, compared with 98% after this period, which included use of endoscopic ultrasound scanning (P = 0.012). A combination of palpation and intraoperative ultrasound detected 92% of tumors. Distal pancreatectomy (40%), enucleation (34%), and pancreaticoduodenectomy (16%) were the most common procedures and pancreatic fistula occurred in 18% of patients. Three patients underwent noncurative distal pancreatectomy in the early period. The 10-year disease-specific and disease-free survival was 100% and 90% respectively. There were 5 patients with disease recurrence. Lymph node metastases (P < 0.001), lymphovascular invasion (P < 0.001), and the presence of MEN-1 (P = 0.035) were prognostically significant adverse factors in disease-free survival. Lymphovascular invasion was the only significant factor on multivariate analysis (P = 0.002). Pancreatic insulinomas can be readily localized preoperatively with modern imaging to avoid unsuccessful blind pancreatic resection. Surgical resection is associated with low morbidity and mortality and achieves long-term disease-free survival in the absence of lymphovascular invasion.

THE IMPACT OF CLINICAL AND GENETIC SCREENINGS ON THE MANAGEMENT OF THE MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4% of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.

Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening

Adrenal tumors are a common manifestation of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Prevalence in recent studies varies between 9 and 45%. A genotype-phenotype correlation has been described as well as the development of adrenocortical carcinomas. Long-term prospective data are still lacking. Thirty-eight MEN-1 patients with proven germline mutations have been prospectively observed in a regular screening program in our hospital. Adrenal glands have been screened by biochemical analysis and either by endoscopic ultrasound (EUS) or computed tomography (CT) or both. Median follow-up was 48 months (12-108 months). Age at diagnosis of MEN-1, type of adrenal tumor, genotype, therapy, and clinical characteristics have been analyzed. In 21 (55%) patients, adrenal involvement of the disease was detected. Adrenal lesions were detected in average 6.9 years after the initial diagnosis of MEN-1. Median tumor size was 12 mm (5-40 mm). Tumor size smaller than 10 mm was observed in 11 patients. Twelve patients had unilateral while nine had bilateral adrenal lesions. EUS detected all adrenal tumors, whereas CT failed in seven cases. In three patients, functioning tumors (one pheochromocytoma, one bilateral Cushing adenoma, and one adrenocortical carcinoma) and one nonfunctioning adenoma were diagnosed by histology and biochemical assessment. Two laparoscopic adrenalectomies and one laparoscopic subtotal resection were performed. Nonfunctioning adrenal lesions, not characterized by histology yet, were found in 18 patients. There was no statistical difference with regard to adrenal involvement between patients with germline mutations in exons 2 and 10 (12/21) and those with mutations in exons 3-9 (6/11). MEN-1-associated adrenal tumors are mostly small, benign, and nonfunctioning and much more common than previously reported. EUS was the most sensitive imaging procedure. The genotype-pheotype correlation previously suggested by our group could not be confirmed.

New splicing mutation of MEN1 gene affecting the translocation of menin to the nucleous

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome inherited in an autosomal dominant trait caused by the inactivation of the tumor suppressor gene MEN1. To communicate a family with a new heterozygous germ line mutation in the intronic region of MEN1 gene and to study its influence in the menin expression. We studied 5 members of a family with symptomatic hyperparathyroidism (HPT). One of them had also a neuroendocrine pancreatic tumor, and 2 had non-functional multinodular cortical adrenal hyperplasia compatible with the diagnosis of MEN1. After the mutation was identified, HSP92II restriction enzyme was used to determine both zygosity and segregation of the mutation. RT-PCR from leukocyte's isolated mRNA and western blot from pancreatic tumor tissue were performed. In vitro studies were done in Chinese hamster ovary (CHO) cells transfected with reporter minigenes carrying the coding regions spanning exon (EX)-intron 9 and EX10 with the mutant and the wild type sequences. We identified a heterozygous G-to-T substitution in the intron-EX junction (IVS9-1 G>T) of MEN1 gene in the index case and the family members. The mRNA from patient's leukocytes was larger (934 bp) in comparison to the normal transcript (717 bp). Immunoblot analysis demonstrated that wild type (67 kDa) and two additional mutant proteins (approximately 55 and approximately 90 kDa) were expressed in the pancreatic tissue. The in vitro study showed a 45% nuclear localization of the mutated menin signal and a 95% in the wild type protein. We identified a new intronic heterozygous germ line mutation (IVS9-1G>T) of MEN1 gene in a family affected by MEN1 syndrome. This mutation alters the splice acceptor site of intron 9 that promotes an incorrect splicing, generating aberrant proteins without the nuclear localization signals necessary for the normal menin translocation to the nucleus.

Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing

Diagnostic molecular genetic testing for multiple endocrine neoplasia type 1 (MEN1) has been available since the identification of the MEN1 gene in 1997. Mutation screening of the MEN1 gene has been recommended for patients who meet clinical criteria for MEN1 (at least two of the following: parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma) and those in whom a diagnosis of MEN1 is suspected. We examined the appropriateness of these clinical criteria. A total of 292 patients were referred for diagnostic testing. The coding region of the MEN1 gene was sequenced in 186 index cases and mutation testing was requested for 106 subjects, including 83 asymptomatic relatives. MEN1 gene mutations were identified in 68/186 index cases (37%). Twenty-nine of the 60 MEN1 mutations reported are novel. The likelihood of finding a mutation was correlated with the number of MEN1-related tumours (mutation detection rate of 79%, 37% and 15% in patients with three, two and one main MEN1-related tumours; P < or = 0.00001) and increased in the presence of a family history (mutation detection rate of 91%, 69% and 29%vs. 69%, 23% and 0% in sporadic cases with three, two or one main MEN1-related tumours, respectively; P < or = 0.00001). The pick-up rate in the 83% of subjects who met proposed criteria for diagnostic testing was 42%, but in those who did not meet these criteria this fell to 0%. The likelihood of finding an MEN1 mutation depends on the clinical features of the patient and their family. This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations.

Gonadotroph Tumor Associated with Multiple Endocrine Neoplasia Type 1

Although anterior pituitary tumors constitute a main clinical feature of multiple endocrine neoplasia type 1 (MEN1), and most types of pituitary tumors have been associated with MEN1, gonadotroph tumors have not previously been recognized clinically as part of this syndrome. We report here a woman who presented with ovarian hyperstimulation due to a gonadotroph tumor that was confirmed biochemically and immunohistochemically. She then developed hyperparathyroidism, and she was found to have three hypercellular parathyroid glands. Subsequently, she developed a temporal lobe metastasis of the gonadotroph tumor, demonstrating that it was a gonadotroph carcinoma. The diagnosis of MEN1 was confirmed by finding a deletion mutation (c.307delC) on the second exon of the MEN1 gene that predicts truncation of the resulting menin protein 15 codons downstream from the deletion (p.Leu103fsX15). This case illustrates that gonadotroph tumors, like other pituitary tumors, can be part of MEN1. The clinical implications of this case are that the clinical and biochemical features of gonadotroph tumors should be considered when evaluating patients for MEN1, and MEN1 should be considered in patients who have gonadotroph tumors.

Adrenal involvement in multiple endocrine neoplasia type 1.

Adrenal lesions belong to the spectrum of multiple endocrine neoplasia type 1 (MEN-1) syndrome. However, the prevalence of adrenal involvement, the characteristics, and the clinical management of adrenal lesions have not yet been clearly defined. A total of 66 patients with confirmed MEN1 germline mutations and 1 additional patient with typical manifestations in three organ systems were monitored in a regular screening program that included evaluation of the adrenals (median follow-up 96 months; range 12 to 300 months). Age at the diagnosis of MEN-1 and of adrenal tumors and the clinical characteristics, genotype, treatment, and follow-up of adrenal disease were analyzed. Adrenal lesions were identified in 18 of 67 (26.8%) MEN-1 patients and were diagnosed 5 years later than MEN-1. The median tumor diameter at diagnosis was 3.0 cm (range 1.2-15.0 cm), with most tumors being 3 cm or smaller. Eight patients had bilateral tumors. Ten patients had nonfunctional benign tumors, three had benign adrenal Cushing syndrome, and one patient had a pheochromocytoma. Four patients developed adrenocortical carcinomas (ACCs), three of which were functional. Nine adrenalectomies and one subtotal adrenalectomy were performed in six patients. Three patients with ACC died owing to the tumor. Patients with mutations in exons 2 and 10 developed adrenal tumors significantly more often than patients with other mutations (p <0.01). Adrenal tumors are a common feature of MEN-1 but occur later in the course of the disease. The lesions are often small and nonfunctional and can therefore be managed by close surveillance; others have significant malignant potential and should be considered for surgery when they are 3 cm or larger.