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Paola Giordano,
Gennaro M Lenato,
Patrizia Suppressa,
Patrizia Lastella,
Franca Dicuonzo,
Luigi Chiumarulo,
Maria Sangerardi,
Paola Piccarreta,
Raffaella Valerio,
Arnaldo Scardapane,
Giuseppe Marano,
Nicoletta Resta,
Nicola Quaranta, Carlo Sabbà
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ABSTRACT: OBJECTIVE: To evaluate the clinical features in a large cohort of pediatric patients with genetically confirmed hereditary hemorrhagic telangiectasia (HHT) and to identify possible predictors of arteriovenous malformation (AVM) onset or clinical significance. STUDY DESIGN: Prospective cross-sectional survey of all children subjected to screening for AVMs in the multidisciplinary HHT center. All patients proved to be carriers of endoglin mutations or activin A receptor type-II-like kinase 1 mutations, defined as HHT1 and HHT2, respectively. A full clinical-radiological protocol for AVM detection was adopted, independent from presence or absence of AVM-related symptoms. RESULTS: Forty-four children (mean age, 10.3 years; range, 1-18) were subjected to a comprehensive clinical-radiologic evaluation. This investigation disclosed cerebrovascular malformations in 7 of 44 cases, pulmonary AVMs in 20 of 44 cases, and liver AVMs in 23 of 44 cases. Large visceral AVMs were found in 12 of 44 children and were significantly more frequent in patients with HHT1. Only large AVMs were associated with symptoms and complications. CONCLUSIONS: Children with HHT have a high prevalence of AVMs; therefore, an appropriate clinical and radiological screening protocol is advisable. Large AVMs can be associated with complications in childhood, whereas small AVMs probably have no clinical risk.
The Journal of pediatrics 03/2013; · 4.02 Impact Factor
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Nicoletta Resta,
Daniela Pierannunzio,
Gennaro Mariano Lenato,
Alessandro Stella,
Riccardo Capocaccia,
Rosanna Bagnulo,
Patrizia Lastella,
Francesco Claudio Susca,
Cristina Bozzao,
Daria Carmela Loconte, [......],
Laura Giunti,
Vittoria Stigliano,
Liliana Varesco,
Lucio Bertario,
Maurizio Genuardi,
Emanuela Lucci Cordisco,
Maria Grazia Tibiletti,
Carmela Di Gregorio,
Angelo Andriulli,
Maurizio Ponz de Leon
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ABSTRACT: BACKGROUND: Germline mutations in the STK11/LKB1 gene cause Peutz-Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz-Jeghers syndrome. AIMS: To assess cancer risks in a large homogenous cohort of patients with Peutz-Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation. METHODS: One-hundred and nineteen patients with Peutz-Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype-phenotype correlations were evaluated. RESULTS: 36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk (p<0.001) in females (22.0) than in males (8.6). Highly increased relative risks were present for gastrointestinal (126.2) and gynaecological cancers (27.7), in particular for pancreatic (139.7) and cervical cancer (55.6). The Kaplan-Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60 and 65 years, respectively. CONCLUSION: Peutz-Jeghers syndrome entails markedly elevated cancer risks, mainly for pancreatic and cervical cancers. This study provides a helpful reference for improving current surveillance protocols.
Digestive and Liver Disease 02/2013; · 3.05 Impact Factor
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ABSTRACT: Cardiac hypertrophy/remodeling is a critical condition that if not efficiently contrasted may predispose to fatal heart failure and multiple organ dysfunction as a result of irreversible neuroendocrine, autonomic and immune system imbalances. Indeed, in chronic heart failure (CHF) the over-excitation of sympathetic and/or the breakdown of central parasympathetic tone are believed to be the basis of the persistent immune activation that in part is primed by inflammatory reactions in the Central Nervous System. Moreover, the clinical management of CHF still today requires the identification of molecularly targeted drugs alternative to those considered so far. In this review are focused the possible neuroimmune-mediated pathways involved in CHF and set out the current therapeutic strategies.
Endocrine, metabolic & immune disorders drug targets. 01/2013;
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Paola Pierucci,
Gennaro M Lenato,
Patrizia Suppressa,
Patrizia Lastella,
Vincenzo Triggiani,
Raffaella Valerio,
Mario Comelli,
Daniela Salvante,
Alessandro Stella,
Nicoletta Resta,
Giancarlo Logroscino,
Francesco Resta, Carlo Sabbà
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ABSTRACT: The difficulty in establishing a timely correct diagnosis is a relevant matter of concern for several rare diseases. Many rare-disease-affected patients suffer from considerable diagnostic delay, mainly due to their poor knowledge among healthcare professionals, insufficient disease awareness among patients' families, and lack of promptly available diagnostic tools. Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal-dominantly inherited vascular dysplasia, affecting 1:5,000-10,000 patients. HHT is characterized by high variability of clinical manifestations, which show remarkable overlapping with several common diseases.
To perform a detailed analysis concerning the diagnostic time lag occurring in patients with HHT, defined as the time period spanning from the first clinical manifestation to the attainment of a definite, correct diagnosis.
A questionnaire was administered to the HHT patients previously recruited from 2000 and 2009. Clinical onset, first referral to a physician for disease manifestations, and first correct diagnosis of definite HHT were collected. Eventual misdiagnosis at first referral and serious complications occurring throughout the time elapsing between disease onset and definite diagnosis were also addressed.
In the 233 respondents, the clinical onset of disease occurred at an age of 14.1 yrs, while the age of first referral and the age of first definite diagnosis of HHT were 29.2 yrs and 40.1 yrs, respectively. Only 88/233 patients received a correct diagnosis at first counseling. Thus, the diagnostic time lag, represented by the time elapsing from disease onset and first definite diagnosis of HHT, proved to be 25.7 yrs. Twenty-two patients suffered from severe complications during this time interval. The diagnostic delay was significantly longer (p < 0.001) in index patients (first patients who attained definite HHT diagnosis in a given family) than in non-index patients (relative of index patients). The diagnostic time lag was also significantly associated with education grade (p < 0.001).
Our data report for the first time a systematic inquiry of diagnostic delay in HHT showing that patients receive a definite diagnosis only after nearly three decades from disease onset. Concerted efforts are still to be made to increase awareness of this disease among both families and physicians.
Orphanet Journal of Rare Diseases 06/2012; 7:33. · 5.83 Impact Factor
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ABSTRACT: Familial Adenomatous Polyposis, Cowden's Syndrome, and Peutz-Jeghers Syndrome are well known as Intestinal Polyposis Syndromes, inherited conditions characterized by the development of polyps of the gastro-intestinal tract in association with extra-intestinal manifestations, in particular malignant tumors at different sites. Thyroid carcinoma is sometimes part of the clinical picture of these syndromes. The aim of this paper is to review the literature dealing with the association between differentiated thyroid carcinomas and Intestinal Polyposis Syndromes in order to point out peculiar aspects, providing suggestions for the screening and the management of thyroid tumors in these patients.
Endocrine, metabolic & immune disorders drug targets. 03/2012;
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Vincenzo Triggiani,
Edoardo Guastamacchia,
Giuseppina Renzulli,
Vito Angelo Giagulli,
Emilio Tafaro,
Brunella Licchelli,
Francesco Resta, Carlo Sabbà,
Rosanna Bagnulo,
Patrizia Lastella,
Alessandro Stella,
Nicoletta Resta
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ABSTRACT: Peutz-Jeghers syndrome (PJS) is a rare dominantly inherited disease characterized by the association of gastrointestinal hamartomatous polyposis, mucocutaneous hyperpigmentation, and increased risk of cancer at different target organs. Its occurrence with differentiated thyroid cancer, particularly papillary thyroid carcinoma (PTC), even if rare, has been described.
We here present a case of PTC observed in a PJS patient and a review of the literature aiming at discussing the utility of thyroid surveillance in the management of these patients. A 22-year-old woman presenting with hyperpigmented lesions of the lips and hamartomatous polyps in the stomach, duodenum, jejunum, and ileum, leading to the suspicion of PJS, was submitted to genetic analysis. Mutation scanning of the Liver Kinase B1 (LKB1) gene identified the presence of the truncating mutation E265X, thus confirming the clinical diagnosis. Beside the endoscopic, radiologic, and echographic evaluations required by the standard surveillance guidelines, the patient had a neck ultrasound (US), which showed a 5×4×6 mm hypoechoic nodule in the right thyroid lobe. The nodule contained microcalcifications and a perinodular vascular pattern. The cytological preparations derived from US-guided fine-needle aspiration biopsy of the nodule demonstrated the presence of PTC. The patient underwent a video-assisted total thyroidectomy and the histological examination revealed a follicular variant of papillary microcarcinoma. Radioactive iodine therapy was not performed because of the small size of the lesion. The patient was started on levothyroxine therapy to keep the serum thyrotropin levels suppressed. Both the sequencing and the multiplex ligation-dependent probe amplification analysis could not identify any LKB1 mutation in the tumor specimen, and the methylation-specific polymerase chain reaction assay excluded hypermethylation of the LKB1 promoter as the mechanism of inactivation for the remaining normal allele in the tumor.
Although other mechanisms of LKB1 silencing may be responsible for its inactivation in the thyroid cancer, we cannot rule out that the occurrence of thyroid carcinoma could be a coincidental finding in this patient. However, the case here presented suggests that US of the thyroid could possibly become an integral part of the evaluation and the follow-up program adopted for PJS patients.
Thyroid: official journal of the American Thyroid Association 08/2011; 21(11):1273-7. · 2.60 Impact Factor
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Patrizia Lastella,
Margherita Patruno,
Giovanna Forte,
Alba Montanaro,
Carmela Di Gregorio, Carlo Sabbà,
Patrizia Suppressa,
Adalgisa Piepoli,
Anna Panza,
Angelo Andriulli,
Nicoletta Resta,
Alessandro Stella
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ABSTRACT: Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC-) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutations in hMLH1 and 4 in hMSH2. 4/15 mutations in hMLH1 and 2/4 hMSH2 mutations have not been previously reported. Three previously reported mutations were further investigated for the possibility of a common founder effect. Genetic counseling was offered to all probands and extended to 183 relatives after molecular testing and 85 (46%) mutation carriers were identified. Eighty mutation carriers underwent an accurate clinical and instrumental surveillance protocol. Our results confirm that the identification of LS patients based exclusively on family history may miss patients carrying germline mutations in the MMR genes. Moreover, our results demonstrated that molecular screening and subsequent instrumental surveillance are very effective in identifying CRCs at earlier stages and reducing the number of deaths from secondary cancers in HNPCC patients.
Familial Cancer 02/2011; 10(2):285-95. · 1.30 Impact Factor
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ABSTRACT: Hepatic arteriovenous malformations (HAVMs) in hereditary hemorrhagic telangiectasia (HHT) have long been considered to have scarce clinical significance in most cases. Nevertheless, data are lacking regarding the influence of HAVMs on the liver first-pass effect on drugs in HHT patients. To gain insight into the effect of HAVMs on hepatic drug clearance by means of two specific (13)C-labeled probes, namely the (13)C-methacetin and (13)C-aminopyrine, 46 HHT patients and 44-matched healthy controls were enrolled. The liver first-pass effect was studied by the (13)C-based breath test using methacetin and aminopyrine. The methacetin breath test showed statistically significant reduced metabolism rates (p < 0.0001) in HHT when compared with controls, both in patients with and without CT-detectable HAVMs, and when expressed both as cumulative (13)C-percentage dose per hour and as (13)C-percentage peak after 15 min. In contrast, no significant difference was found between HHT and controls regarding aminopyrin metabolism rates. In HHT, (13)C%-methacetin breath test values are significantly lower than those found in normal subjects, probably due to the effect of hepatic shunts. A reduced perfusion and an impaired hepatic metabolism might affect hepatic drug clearance in HHT. Therefore, an appropriate dosage adjustments should be considered when high-hepatic-metabolism drugs are administered to HHT patients.
Internal and Emergency Medicine 02/2011; 7(4):323-9. · 2.06 Impact Factor
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ABSTRACT: Micronutrients, mostly iodine and selenium, are required for thyroid hormone synthesis and function. Iodine is an essential component of thyroid hormones and its deficiency is considered as the most common cause of preventable brain damage in the world. Nowadays about 800 million people are affected by iodine deficiency disorders that include goiter, hypothyroidism, mental retardation, and a wide spectrum of other growth and developmental abnormalities. Iodine supplementation, under form of iodized salt and iodized vegetable oil, produced dramatic improvements in many areas, even though iodine deficiency is still a problem not only for developing countries. In fact, certain subpopulations like vegetarians may not reach an adequate iodine intake even in countries considered iodine-sufficient. A reduction in dietary iodine content could also be related to increased adherence to dietary recommendations to reduce salt intake for preventing hypertension. Furthermore, iodine intakes are declining in many countries where, after endemic goiter eradication, the lack of monitoring of iodine nutrition can lead to a reappearance of goiter and other iodine deficiency disorders. Three different selenium-dependent iodothyronine deiodinases (types I, II, and III) can both activate and inactivate thyroid hormones, making selenium an essential micronutrient for normal development, growth, and metabolism. Furthermore, selenium is found as selenocysteine in the catalytic center of enzymes protecting the thyroid from free radicals damage. In this way, selenium deficiency can exacerbate the effects of iodine deficiency and the same is true for vitamin A or iron deficiency. Substances introduced with food, such as thiocyanate and isoflavones or certain herbal preparations, can interfere with micronutrients and influence thyroid function. Aim of this paper is to review the role of micronutrients in thyroid function and diseases.
Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 10/2009; 9(3):277-94.
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ABSTRACT: The purpose of this study was to estimate vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 serum levels in children with hereditary hemorrhagic telangiectasia (HHT) type 1 and type 2 and to correlate them to the presence of arteriovenous malformations (AVMs). High VEGF levels were initially found in an infant who had been hospitalized with intestinal bleeding and suspected HHT. This case led to the evaluation of VEGF and TGF-beta1 by standard enzyme-linked immunosorbent assay in 13 children with HHT and familiarity. Patients were divided into 2 groups on the basis of the presence/absence of pulmonary AVMs. No significant difference was found for VEGF and TGF-beta1 levels in HHT patients versus controls. Among HHT patients, serum levels of VEGF in those without AVM were significantly lower than those with AVM and normal controls. No difference for TGF-beta1 levels was found in these patient subgroups. Low VEGF levels may represent a protection factor against the onset of pulmonary AVMs in HHT children. However, neither VEGF nor TGF-beta1 can be used as biochemical markers for an early diagnosis in HHT. The diagnosis of HHT still requires clinical criteria, which permitted to confirm the presence of the disease in the infant with intestinal bleeding.
Journal of Pediatric Hematology/Oncology 09/2009; 31(8):577-82. · 1.16 Impact Factor
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Journal of Hepatology 11/2008; 49(4):659-61. · 9.26 Impact Factor
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ABSTRACT: Hepatic arterio-venous malformations (HAVMs) have been found in 74% of hereditary hemorrhagic telangiectasia (HHT) patients with multislice CT (MSCT). This single-blind study aimed to compare the diagnostic accuracy of echo-color-Doppler with MSCT and identify the most sensitive ultrasound criteria indicating hepatic shunts.
One hundred and fifty-three HHT patients were systematically screened for HAVMs by biological tests, abdominal MSCT and echo-color-Doppler. Twenty-five normal subjects and 15 cirrhotic patients were also included as control groups. Both intrahepatic ("color spots" and hypervascularization) and extrahepatic parameters (diameter, flow velocity and tortuosity of hepatic artery and diameter and flow velocity of portal/hepatic vein) were utilized. "Color-spots" are defined as subcapsular vascular spots with a high-velocity arterial blood flow and low resistivity index and can identify extremely small HAVMs.
CT was positive in 128/153 (84%) patients and Doppler color spots were found in 131/153 (86%) patients. The sensitivity, specificity and diagnostic accuracy of "color spots" compared to MSCT were 95.3%, 68.0% and 91.8%, respectively. The "color-spot" showed a greater correlation to CT (V(index)=0.655; p<0.0001) than extrahepatic criteria (V=0.317). In 20/29 (69%) subjects, echo-color-Doppler, confirmed by CT, identified the third criterion for definite HHT diagnosis.
Intrahepatic criteria was superior to extrahepatic criteria for identification of HAVMs. A new Doppler parameter ("color-spots") with an optimal accuracy for detecting HAVMs is proposed for easy periodic screening of HHT patients.
Journal of Hepatology 06/2008; 48(5):811-20. · 9.26 Impact Factor
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ABSTRACT: A 55-year-old woman with hereditary haemorrhagic telangiectasia (HHT) underwent a left lateral liver bisegmentectomy (removal of segments 2 and 3) for hepatic-based arteriovenous malformations. This lesion determined a progressive fatigue and invalidating effort dyspnoea. The postoperative course was uneventful and the patient is currently doing well at 4 years after surgery. To our knowledge, this is the first case of hepatic-based HHT treated with liver resection. This anecdotal report should promote the evaluation of this approach in order to define its role in the treatment of liver involvement in this rare disease.
Liver international: official journal of the International Association for the Study of the Liver 05/2008; 28(4):574-7. · 3.82 Impact Factor
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ABSTRACT: The acquisition of "Level 3" competencies in the setting of the Emergency Room from StR in Acute Medicine raises the question of the boundaries and competences of Acute Medicine and Emergency Medicine. The possibility that phisycians with a training both in Emergency Medicine and Acute Medicine will be involved in the management of Emergency Admission Units and Emergency Medicine Departments in the future is herein considered.
Acute medicine 01/2008; 7(1):46-7.
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Jan Lerut,
Giuseppe Orlando,
René Adam, Carlo Sabbà,
Robert Pfitzmann,
Jurgen Klempnauer,
Jacques Belghiti,
Jacques Pirenne,
Thierry Thevenot,
Christian Hillert,
Colin M Brown,
Dominique Gonze,
Vincent Karam,
Olivier Boillot
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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a rare disease characterized by the presence of arteriovenous malformations. Hepatic involvement can lead to life-threatening conditions.
Forty patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation in the treatment of the hepatic disease form. Indications for transplantation were classified according to Garcia-Tsao: cardiac failure (14 patients), biliary necrosis causing hepatic failure (12 patients), severe portal hypertension (5 patients), cardiac failure and biliary necrosis (6 patients), cardiac failure and portal hypertension (2 patients), and cardiac failure associated with biliary necrosis and portal hypertension (1 patient). Eighteen (81%) of 22 patients had pulmonary artery hypertension. Twelve (30%) patients had pretransplant hepatic interventions. Follow-up was complete for all patients with a mean of 69 months (range, 0-230 months).
One-, 5- and 10-year actuarial patient and graft survival rates are 82.5%. Six of the 7 pretransplant procedures performed on the hepatic artery were severely complicated. Cardiovascular function documented in 24 patients improved in 18 patients and remained stable in 5 patients; 1 patient died perioperatively of acute heart failure. Twenty-four (60%) patients had post-transplant complications, all but one occurring within the first 4 posttransplant months. Seven (17.5%) patients died perioperatively, 6 of them due to bleeding and 1 due to cardiac failure; 1 (2.5%) patient died late due to chronic rejection. There were 2 possible recurrences. Quality of life markedly improved in all 32 surviving patients.
The results of the largest reported transplant series in the treatment of hepatic-based HHT are excellent. Elimination of hepatobiliary sepsis and reversal of cardiopulmonary changes dramatically improve quality of life of the recipients. LT should be proposed earlier in the course of symptomatic hepatic HHT presenting with life-threatening conditions. Palliative interventions, especially on the hepatic artery, should be avoided in view of their high (infectious) complication rate.
Annals of Surgery 01/2007; 244(6):854-62; discussion 862-4. · 7.49 Impact Factor
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Elisabetta Buscarini,
Henry Plauchu,
Guadalupe Garcia Tsao,
Robert I White, Carlo Sabbà,
Franklin Miller,
Jean Cristophe Saurin,
Jean Pierre Pelage,
Gaetan Lesca,
Marie Jeanne Marion,
Annalisa Perna,
Marie E Faughnan
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ABSTRACT: STUDY PURPOSE: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process. CONSENSUS PROCESS: A nominal group technique was used. A list of main clinical, diagnostic and therapeutic issues about liver involvement in HHT was generated by the organizing committee. Panel members then scored their agreement with each statement; the median score, and standard deviation for each statement were determined for each of the three successive panel rounds. These consensus statements formed the basis for recommendations graded with the strength and quality of supporting evidence. RECOMMENDATION STATEMENTS: Doppler US is sufficiently accurate and suitable for first-line imaging of the liver in the general HHT population. Liver biopsy in any patient with proven or suspected HHT should be avoided. Liver involvement in HHT is generally asymptomatic; in the minority of patients where it is symptomatic, morbidity and mortality can be substantial. The prevalence of focal nodular hyperplasia is much higher in patients with liver involvement by HHT than in the general population. Invasive therapies for liver involvement by HHT (namely liver transplantation) should be considered only in patients who have failed to respond to intensive medical therapy.
Liver international: official journal of the International Association for the Study of the Liver 12/2006; 26(9):1040-6. · 3.82 Impact Factor
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ABSTRACT: Nowadays, the treatment of diabetes mellitus is based on the variable use and combination of diet, antidiabetic oral agents (metformin, sulphanylureas, glynides, acarbose and thiazolidinediones) and insulin or its analogs, depending on the type of diabetes and the needs of the patient. The prevention and treatment of chronic micro- and macrovascular complications, on the other hand, is based on the achievement and maintenance of an optimal glycaemic control and requires the combined use of adjunctive therapy such as antihypertensive drugs and cholesterol-lowering medications. Furthermore, several herbal preparations and dietary supplements, such as antioxidants, essential fatty acids, lipid metabolism activators, vitamins and trace elements, are advertised and prescribed to patients as a useful adjuvant to a diabetic diet and conventional medications in order to improve glycaemic control and reduce the impact of chronic complications. In this regard, we have attempted to review the current concepts dealing with the usefulness of these complementary therapies in treating diabetic patients.
Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 04/2006; 6(1):77-93.
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ABSTRACT: Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation.
Human Mutation 03/2006; 27(2):213-4. · 5.69 Impact Factor
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ABSTRACT: There are few cases described in the world literature reporting an association of thymoma (with myasthenia gravis or not) with hyperparathyroidism. In these cases the hyperparathyroidism was due to the presence of an adenoma or hyperplasic parathyroid tissue either in the cervical region or in an ectopic intrathymic location.(12345) In other cases the syndrome of hypercalcemia was due to the secretion of parathyroid-related protein (PTHRP) (6) or parathyroid hormone (PTH) (7) by the thymoma itself. We report the first case, at the best of our knowledge, of a wide invasive malignant thymoma (type B3), associated with myasthenia gravis and hyperparathyroidism caused by parathyroid adenoma.
Immunopharmacology and Immunotoxicology 02/2006; 28(2):377-85. · 1.83 Impact Factor
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ABSTRACT: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disease characterized by mutations occurring in the endoglin and ALK-1, two receptors of transforming growth factor-beta1. From a pathogenic point of view, a possible involvement of the immune system in HHT has been suggested since a mononuclear cell infiltrate was found around the area of telangiectases. Up until now, no information has been available about the role played by leukocytes in HHT and the mechanisms elicited by secretion of their mediators. However, the fact that a deficit of adaptive immunity in HHT has been reported in a companion paper in this issue will represent a great contribution to the understanding of HHT pathogenesis. The purpose of this study was to evaluate whether patients with HHT manifest also alterations in the innate immune response. Therefore, the phenotype of T, B and natural killer lymphocytes, serum immunoglobulin levels, phagocytosis and oxidative burst activity exerted by polymorphonuclear cells (PMN) and monocytes (MO) were analyzed in 22 patients. Twenty individuals demonstrated single or multiple deficits of PMN and MO functions, while the immunophenotype of lymphocytes and serum concentrations of immunoglobulins were normal. To the best of our knowledge, this is the first demonstration of a reduction in PMN and MO functions in HHT, thus suggesting a higher susceptibility to infectious complications in these patients. The relationship between innate immune deficits and T helper 1 and monocyte-derived cytokine dysfunction in HHT, as previously reported, is discussed.
Current Pharmaceutical Design 02/2006; 12(10):1209-15. · 3.87 Impact Factor
