Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS).

INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Hidden hypercortisolism: a too frequently neglected clinical condition.

PURPOSE: Classic Cushing's syndrome (CS) is a severe disease characterized by central obesity, hypertension, easy bruising, striae rubrae, buffalo hump, proximal myopathy and hypertricosis. However, several CS cases have also been reported with unusual or camouflaged manifestations. In recent years, several authors investigated the prevalence of "hidden hypercortisolism" (HidHyCo) among subjects affected with bone fragility, hypertension and type 2 diabetes mellitus (DM2). The prevalence of the HidHyCo is estimated to be much higher than that of classic CS. However, similarly to classic CS, HidHyCo is known to increase the risk of fractures, cardiovascular disease and mortality. METHODS: We reviewed all published cases of unusual presentations of hypercortisolism and studies specifically assessing the HidHyCo prevalence in diabetic, osteoporotic and hypertensive patients. RESULTS: We found 49 HidHyCo cases, in whom bone fragility, hypertension and diabetes were the presenting manifestations of an otherwise silent hypercortisolism. Amongst these cases, 34.7%, 32.7%, 6.1% and 19.0%, respectively, had bone fragility, hypertension, DM2 or hypertension plus DM2 as the sole clinical manifestations of HidHyCo. Overall, 25% of HidHyCo cases were of pituitary origin, and bone fragility was the very prevalent first manifestation among them. In population studies, it is possible to estimate that 1-4% of patients with apparent primary osteoporosis has a HidHyCo and the prevalence of this condition among diabetics ranges between 3.4 and 10%. CONCLUSION: These data indicate that patients with resistant or suddenly worsening hypertension or DM2 or unexplainable bone fragility should be screened for HidHyCo using the most recently approved sensitive cut-offs.

Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility.

Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone fragility fractures compared to nondiabetic subjects. This increased fracture risk may occur despite normal or even increased values of bone mineral density (BMD), and poor bone quality is suggested to contribute to skeletal fragility in this population. These concepts explain why the only evaluation of BMD could not be considered an adequate tool for evaluating the risk of fracture in the individual T2DM patient. Unfortunately, nowadays, the bone quality could not be reliably evaluated in the routine clinical practice. On the other hand, getting further insight on the pathogenesis of T2DM-related bone fragility could consent to ameliorate both the detection of the patients at risk for fracture and their appropriate treatment. The pathophysiological mechanisms underlying the increased risk of fragility fractures in a T2DM population are complex. Indeed, in T2DM, bone health is negatively affected by several factors, such as inflammatory cytokines, muscle-derived hormones, incretins, hydrogen sulfide (H2S) production and cortisol secretion, peripheral activation, and sensitivity. All these factors may alter bone formation and resorption, collagen formation, and bone marrow adiposity, ultimately leading to reduced bone strength. Additional factors such as hypoglycemia and the consequent increased propensity for falls and the direct effects on bone and mineral metabolism of certain antidiabetic medications may contribute to the increased fracture risk in this population. The purpose of this review is to summarize the literature evidence that faces the pathophysiological mechanisms underlying bone fragility in T2DM patients.

Epidemiology of the vascular assessment and correlation of the WIfI Classification in lower limb amputee patients at Martinique university hospital in 2018.

BACKGROUND: The precise epidemiological evaluation of amputations is difficult. It is a serious public health and economic problem with a high death rate. The proportion of amputees with pre-amputation vascular status remains unknown. The main objective of our study was to evaluate the proportion of patients with lower limb amputation who had a pre-procedural vascular assessment. The secondary objectives were to evaluate the risk of amputation at the admission of these patients, estimate the incidence of amputations in Martinique, and to collect epidemiological data on this category of patients. MATERIAL AND METHODS: We conducted an epidemiological, retrospective, and observational study, over the year 2018 between January 01 and December 31, including all adults' patients who underwent an amputation of the lower limb at the university hospital center of Martinique. RESULTS: Among the 170 included patients, 79 (46%) patients had a major lower limb amputation. The incidence of amputations in 2018 was estimated at 48.9/100,000 inhabitants. The vascular assessment was performed for 110 (65%) patients. For the other 60 (35%) patients who did not have a vascular assessment, 53 (88%) had a severe infection. This assessment was significantly related to the amputation level: a vascular assessment was performed in 97 (70%) patients with below the knee amputation versus 13 (41%) patients with above the knee amputation (P<0.01). The WIfI classification system found a high risk of amputation for 152 (89%) of patients but also a benefit of revascularization ranked high for 138 (81%) of them. The origin of amputation was limb ischemia for 125 (68%) patients. CONCLUSION: A significant number of patients who underwent lower limb amputation did not have a pre-procedural vascular assessment. Many improvements in the health care are therefore to be implemented. The upcoming M@diCICAT project in Martinique will contribute in the improvement of patient management. The incidence of amputation in Martinique is considered high compared to other countries (French national incidence in 2003=24.8/100,000 inhabitants), and it seems to have remained stable since 2008. Our population is considered to be at high risk of amputation by the SVS-WIfI classification. This score seems adapted to anticipate the evolution of these patients and could be useful in daily practice.

Efficacy and safety of abaloparatide for the treatment of post-menopausal osteoporosis.

INTRODUCTION: Osteoporosis is a skeletal disorder characterized by loss of bone mass and strength affecting up to 30-50% of postmenopausal women worldwide. Current therapeutic options include antiresorptives such as aminobisphosphonates or denosumab and osteoanabolic compounds such as teriparatide. Areas covered: In this review, the authors summarize the clinical development, safety and efficacy profile of abaloparatide, a new osteoanabolic agent recently marketed in the US for the treatment of postmenopausal osteoporosis in women who are at high risk for fracture or who fail antiresorptive therapy. Expert opinion: Abaloparatide is a 1-34 PTH related peptide-like molecule that has been modified in order to potentiate the osteoanabolic effect. In its pivotal phase 3 trial in postmenopausal women with osteoporosis, subcutaneous abaloparatide 80 mcg/day reduced the risk of vertebral, nonvertebral, major osteoporotic, and clinical fractures compared with placebo and reduced the risk of major osteoporotic fractures compared with teriparatide. These results, together with a reduced prevalence of hypercalcemia and a lower cost of the marketed compound, point toward improved cost effectiveness with abaloparatide versus teriparatide. However, some concerns have been raised due to a somewhat higher occurrence of adverse effects (particularly with palpitations and increased heart rate) or the resultant discontinuation due to these adverse effects when compared to teriparatide.

Association of vitamin D and vitamin B12 with cognitive impairment in elderly aged 80 years or older: a cross-sectional study.

BACKGROUND: The present study aimed to assess the association of vitamin D and vitamin B12 with cognitive impairment in elderly people. METHODS: The data were obtained from a cross-sectional study that included individuals aged 80 years or older living in the urban and rural areas of the cities of Siderópolis and Treviso in the state of Santa Catarina, Brazil. In total, 165 elderly people were included in the analysis. The outcome of cognitive decline was assessed by the Mini-Mental State Examination. Vitamin D and vitamin B12 levels were measured from blood samples. The socio-demographic, anthropometric and health variables used in the analysis were collected from a questionnaire. Crude and adjusted analyses of the relationship between vitamins D and B12 and cognitive decline were performed using a Poisson regression model. RESULTS: The prevalence of cognitive decline was 35.2%. In the adjusted model, individuals who had vitamin D levels >19 ng mL-1 showed a lower prevalence of cognitive decline (prevalence ratio = 0.59; 95% confidence interval = 0.39-0.87). Those participants who had vitamin B12 levels of ≥496 pg mL-1 had a higher prevalence of cognitive decline (prevalence ratio = 1.90; 95% confidence interval = 1.08-3.36). CONCLUSIONS: The present study showed that individuals aged ≥80 years who had vitamin D levels of ≤18 ng mL-1 had a higher prevalence of cognitive decline even after adjustment for potential confounders. In addition, the study demonstrated that vitamin B12 levels of ≥496 pg mL-1 in this population were also a risk factor for cognitive decline. A cross-sectional analysis does not enable the inference of a cause-effect relationship and additional studies are needed to understand these relationships.

Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults

Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.

Fragility fractures: clinical and therapeutic aspects.

Osteoporosis is the most important bone metabolic disorder characterized by reduction of bone mass and micro-architectural deterioration associated to an increased risk for fragility fractures. It involves millions of worldwide-dispersed individuals of both sexes and, consequently, the elevated morbidity and mortality of fractured subjects and the increased socio-economic costs suggest it must be faced as a major health problem. Thus, there is a need for either a precocious identification of subjects with fragile “bones” or the institution of specific diagnostic-therapeutical strategies. Improvement in bone pathophysiology knowledge, together with progress in pharmaceutical development has led to an opportunity for early identification and therapy of subjects at high risk of fragility fractures. In this review, we briefly describe the recent acquisitions in bone pathophysiology as well as in the anti-fracture drug development with a brief excursus on those already well established.

[Left laparoscopic adrenalectomy for pheochromocytoma in MEN 2B: case report]. / Surrenectomia laparoscopica sinistra per feocromocitoma in MEN 2B: caso clinico.

INTRODUCTION: Multiple endocrine neoplasia syndromes (MEN) are genetic disease with many pathologic models. MEN 2B is a autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal ganglioneuromatosis and marfanoid habitus. Laparoscopic surgery is the gold standard for the treatment of pheochromocytoma. CASE REPORT: Woman 25 years old, suffering from medullary thyroid carcinoma in MEN 2B syndrome, underwent total thyroidectomy, with emptying of the lymphonodal central and lateral cervical (bilaterally) compartments and radioreceptor therapy. The patient was then submitted to four plastic surgery for cervical keloid. In January 2010, follow-up blood and instrumental tests show, in the lower portion of left adrenal gland, a round lesion, with smooth margins 17 mm diameter, attributable to pheochromocytoma. In March 2010 the patient underwent laparoscopic surgery for left adrenalectomy. DISCUSSION: The benefits of laparoscopic adrenalectomy for a single lesion are well documented in the literature; this type of intervention is indicated in cases of pheochromocytoma in patients with MEN 2B. Our case demonstrates the feasibility of this technique.

Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the occurrence of tumors of parathyroids, neuroendocrine cells of the gastro-enteropancreatic tract and anterior pituitary. MEN1 gene encodes menin-oncosuppressor protein. Loss of heterozygosity at 11q13 is typical of MEN1 tumors. We have analyzed the MEN1 mRNA and menin expression in fibroblasts from normal skin biopsies and from MEN1 patients (two with a frameshift 738del4 (exon 3) mutation, introducing a premature stop codon, and an individual with an R460X (exon 10) nonsense mutation). The expression of full-length menin protein did not differ between MEN1 and normal fibroblasts. Wild-type alleles mRNAs were expressed in MEN1 patients, whereas mutant alleles were partially degraded by nonsense-mediated mRNA decay pathway, suggesting a mechanism of compensation for allelic loss by the up-regulation of wild-type menin expression at a post-transcriptional level. Small-interfering RNA silencing of the wild-type mRNA allele abolished menin compensation, whereas the ribozyme silencing of the MEN1-mutated mRNA allele resulted in strongly enhanced wild-type menin expression. Gel-retardation analysis showed that in vitro-specific RNA-protein complexes bound to MEN1 mRNA. These findings contribute to the understanding of tumorigenesis in MEN1, offering the basis for the development of RNA-based therapies in MEN1 gene mutation carriers.

DNA-based test: when and why to apply it to primary hyperparathyroidism clinical phenotypes.

Several cancer-related genes have been discovered and molecular test for the cancer genetic risk assessment has been widely increasing. Disorders such as Multiple Endocrine Neoplasia syndromes have received benefits from the identification of the responsible genes whose mutations account for the genetic susceptibility to develop endocrine tumours. Primary hyperparathyroidism (PHPT)is a clinical phenotype frequently associated to Multiple Endocrine Neoplasia syndromes, but it can also represent the unique endocrinopathy recurring as a familial cluster. In recent years, care options have been made available to patients and families with hereditary PHPT, and the process of systematically assessing the genetic risk has been becoming increasingly important. This review aims to help health providers not frequently dealing with genetic testing use and it will introduce some general concepts concerning genetic diagnosis issues. As an example the role and the practical usefulness of DNA-based diagnosis in patients affected by different forms of congenital PHPT is described, with a close look on why, when and how genetic testing should be performed in these subjects and their relatives. Some practical recommendations and suggestions concerning on how to deal when a suspect or known case of familial PHPT has to be faced conclude this manuscript.

A novel recessive mutation of fibroblast growth factor-23 in tumoral calcinosis.

BACKGROUND: Tumoral calcinosis is a rare disease characterized by hyperphosphatemia due to hypophosphaturia and by ectopic calcifications. Phosphatonins are important hormones that regulate phosphorus homeostasis. Tumoral calcinosis is a rare congenital disorder in which the differential diagnosis from other syndromes associated with extraskeletal calcifications may be difficult. Mutations in the UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 (GALNT3) and fibroblast growth factor-23 (FGF23) genes have been described. Mutational analysis is important for the early recognition of the disorder, for prevention of its complications, and for family screening strategies. We examined two unrelated white patients affected by tumoral calcinosis. METHODS: The first patient was a woman with a history of an ectopic calcification in the left shoulder. The second patient was a man with a history of an ectopic calcification in the right buttock. Routine biochemistry and FGF-23 assays were performed on serum samples. Genomic DNA was extracted from peripheral blood. The FGF23 and GALNT3 genes were analyzed by direct sequencing. RESULTS: A new homozygous H41Q codon 41, C-->A transversion at position 123 (c.123C>A) in exon 1 of the FGF23 gene was evidenced in both patients. No mutation of the GALNT3 gene was detected in these patients. As determined by an ELISA assay, intact FGF-23 circulating protein was low in both patients. CONCLUSIONS: This is the fourth mutation of the FGF23 gene described in subjects with tumoral calcinosis.

The genetic ascertainment of multiple endocrine neoplasia type 1 syndrome by ancient DNA analysis.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited endocrine cancer syndrome characterised by parathyroid, pancreas, and anterior pituitary tumors. The disease responsible gene, MEN1, was identified in 1997 and localizes to chromosome 11q13 in a minimal 600 kb interval between PYGM and D11S449 loci. About 10-20% of MEN1 patients do not have any mutation in the coding region and/or in the exon-intron junctions of the MEN1 gene. In this case, familial haplotype analysis of the 11q13 region, in at least two generations of affected members, is the only possible genetic ascertainment of the disease. We performed a microsatellite haplotype analysis at 11q13 region in 8 living and 1 deceased member of a MEN1 Italian family without any detected germline mutation of the MEN1 gene. The application of forensic techniques for ancient DNA analysis made it possible to identify the familial disease-associated haplotype and demonstrated that MEN1 disease haplotype family history can be reconstructed even when one or more family members are deceased. Identification of MEN1 disease haplotype is helpful in the clinical management of patients and relatives in families without any mutation of the MEN1 gene. Genetic screening allows the identification of individuals who are at risk before the development of clinical symptoms, limiting invasive annual cancer surveillance only to genetically positive individuals and making it possible to avoid further clinical screenings in non-carriers.

Silent familial isolated pituitary adenomas: histopathological and clinical case report.

Familial isolated pituitary adenoma (FIPA) is a rare condition independent of Carney Complex or MEN1. An international multicenter study recently described 28 nonfunctioning pituitary adenomas in 26 families with only two homogeneous nonsecreting phenotype families consistent of silent GH and silent gonadotroph adenomas, respectively. We present the clinical, genetic, and morphological analysis of two silent pituitary adenomas occurring in a man and his daughter, and discuss the differential diagnosis associated with their histological, immunohistochemical, and ultrastructural features. The patients developed invasive nonsecreting macroadenomas manifesting only with compressive symptoms. Genetic analysis in the father showed no MEN-1 germ-line mutation. Tissue samples obtained after paraseptal trans-sphenoidal surgery were studied by immunohistochemistry for adenohypophyseal hormones, low molecular weight cytokeratins (CAM 5.2), proliferation markers, and anterior pituitary transcription factors (Pit-1 and SF-1) and by electron microscopy for secretory granules. The clinical, histological, and immunohistochemical features of the lesions posed a differential diagnosis between a null cell adenoma and a silent corticotroph adenoma (Type II); on the basis of immunohistochemical stains for cytokeratin and adenohypophysis cell lineage markers, tumor behavior and ultrastructural studies we concluded for the second. The reported cases represent an as yet undescribed example of homogeneous family with silent corticotroph adenomas (Type II). Our observations support the trend for more aggressive behavior in nonsecreting FIPAs as compared with sporadic adenomas.

[Italian guidelines for the diagnosis and treatment of Paget's disease of bone]. / Linee guida per la diagnosi e la terapia del morbo di Paget.

Paget's disease of bone is a chronic focal abnormality of bone turnover that remains totally asymptomatic over a very long period of time but that eventually ensue in bone pain and skeletal deformities. Although, in the last decade new insights have been obtained on its etiology, this remains largely obscure. Effective medical treatment (based on the use of bisphosphonates) has become available and the diagnostic procedures are now well defined. However, there remains considerable controversy regarding the hierarchy of diagnostic procedures and the medical treatment threshold. In the last few years different institution have published national guidelines, reflecting local national health systems and the available medical treatment. In this review, a working group derived from members of the SIOMMMS has examined the information available regarding the diagnosis and treatment of Paget's disease in order to develop guidelines to assist in the management of this condition. The first draft was then extensively reviewed by experts derived from the most representative scientific societies of rheumatology, internal medicine, and orthopaedic surgery. The document provides the most updated recommendations based primarily on the "evidence-based- medicine" but also on the Italian regulation for the diagnostic procedures and on the available medical treatments.

Relationship of volumetric bone mineral density and structural parameters with ERalpha gene polymorphisms.

Bone mineral density (BMD) contributes to bone strength, and methods for clinical assessment of bone quality characteristics beyond what can be gathered by BMD are awaited. Peripheral quantitative computed tomography (pQCT) allows for separate assessments of cortical and trabecular bone, providing information on bone geometry. Previous studies examining the relationship between estrogen receptor alpha (ERalpha) gene polymorphisms and BMD have been performed in large populations. However, only limited information is available on the possible segregation of ERalpha gene polymorphisms with bone structural properties. The aim of our study was to evaluate the association of XbaI and PvuII ERalpha gene polymorphisms with QCT parameters. We studied 900 subjects (541 women, 449 men) participating to the InCHIANTI study. By tibial pQCT we evaluated trabecular volumetric BMD, cortical volumetric BMD, cortical bone area, and cortical thickness (CtTh). Subjects were genotyped for ERalpha gene PvuII and XbaI polymorphisms. Analysis of variance was used for statistical analysis. Male subjects with PP and XX genotypes had higher geometric parameters, and female subjects with XX and PP genotypes showed higher densitometric parameters than other genotypes; however, the differences did not reach statistical significance. After adjustment for potential confounders, we found a significant (P = 0.002) CtTh difference across PvuII polymorphism in male subjects, with higher CtTh values in PP genotypes with respect to Pp and pp genotypes. These results show a relationship between the presence of the P allele and higher values of CtTh in male subjects, indicating for ERalpha a role in the control of tibial bone geometry.

FokI polymorphism of the vitamin D receptor gene correlates with parameters of bone mass and turnover in a female population of the Italian island of Lampedusa.

One of the most promising genetic approaches to dissecting a multifactorial disease is represented by genetically isolated population studies. We studied a genetic marker in a cohort of women living on the Mediterranean island of Lampedusa, a geographically isolated population. Lampedusa, located between the African coast and Sicily, consists of a young genetic isolate (<20 generations) with an exponential growth in the last generations. We analyzed the association between the FokI vitamin D receptor (VDR) gene polymorphism, previously proposed as a predictor of bone mass, with parameters of bone mass and turnover in a cohort of pre- and postmenopausal women living on Lampedusa. In 424 women (277 postmenopausal and 147 premenopausal), allelic frequencies were 49% for the F allele and 51% for the f allele. Using analysis of covariance, we found that subjects with ff genotype exhibited a significantly (P < 0.001) lower lumbar spine bone mass, by dual-energy X-ray absorptiometry, and lower values of bone ultrasonographic parameters (speed of sound and broadband ultrasound attenuation) relative to those with Ff and FF genotypes. Conversely, osteocalcin and serum cross-laps were significantly higher in ff and Ff compared to FF genotype. Our data suggest that FokI VDR polymorphism may contribute to the determination of bone mass and turnover in both pre- and postmenopausal women in this geographically isolated population.

TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.

The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor-node-metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients.

MEN1 family with a novel frameshift mutation.

Multiple endocrine neoplasm type 1 (MEN1) syndrome predisposes to the development of endocrine and non-endocrine tumors with an autosomal dominant pattern of inheritance. Different mutations have been found throughout the gene with a variable phenotype expression. The proband, a Caucasian man, was admitted to our department in 2001, at the age of 51 because of a 1-yr history of diarrhoea and hypertension. He reported a previous intestinal resection for bowel occlusion with a histological diagnosis of unspecified mesenchymal neoplasia. He had also undergone a left adrenalectomy for a large nonfunctioning adrenal adenoma. Subsequently, he had suffered from gastralgia and melena; a gastroduodenoscopy showed an erosive gastritis. His family history was negative for endocrine disorders. On physical examination, multiple abdominal cutaneous lipomas and facial angiofibromas were observed. Biochemical screening revealed a primary hyperparathyroidism and an increase in circulating levels of PRL, chromogranin-A, gastrin and glucagon. The whole body computed tomography (CT) scan, the 111In-octreotide scan and the pituitary magnetic resonance imaging (MRI) did not reveal any abnormality. The presence of small neuroendocrine tumors was suspected by a positron emission tomography uptake in the epigastric region. The endoscopic ultrasound revealed a pancreatic lesion sized 1.1 cm that is under evaluation. Direct DNA sequencing analysis of the proband MEN1 gene revealed the 579delG frameshift mutation in the exon 3. The genetic screening of the family revealed the same mutation in 3 out of 5 offspring. The biochemical screening revealed some features of the MEN1 syndrome in all three of them. In conclusion, a novel frameshift MEN1 mutation was found in kindred with an apparently negative family history. Our experience confirms that MEN1 syndrome is a complex and underestimated condition, unless specifically investigated by trained specialists.