Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions.

OBJECTIVE: To determine the spectrum of MEN1 mutations in Portuguese kindreds, and identify mutation-carriers. PATIENTS, DESIGN AND RESULTS: Six unrelated MEN1 families were studied for MEN1 gene mutations by single-strand conformational polymorphism (SSCP) and DNA sequence analysis of the coding region and exon-intron boundaries of the MEN1 gene. These methods identified 4 different heterozygous mutations in four families: two mutations are novel (mt 1539 delG and mt 655 ims 11 bp) and two have been previously observed (mt 735 del 46p and mt 1656 del C) all resulting in a premature stop codon. In the remaining two families, in whom no mutations or abnormal MEN1 transcripts were detected, segregation studies of the 5' intragenic marker D11S4946 and codon 418 polymorphism in exon 9 revealed two large germline deletions of the MEN1 gene. Southern blot and tumour loss of heterozygosity analysis confirmed and refined the limits of these deletions, which spanned the MEN1 gene at least from: exon 7 to the 3' untranslated region, in one family, and the 5' polymorphic site D11S4946 to exon 9 (obliterating the initiation codon), in the other family. Twenty-six mutant-gene carriers were identified, 6 of which were asymptomatic. CONCLUSIONS: These results emphasize the importance of the detection of MEN1 germline deletions in patients who do not have mutations of the coding region. Important clues indicating the presence of such deletions may be obtained by segregation studies using the intragenic polymorphisms D11S4946 and at codon 418. The detection of these mutations will help in the genetic counselling of clinical management of the MEN1 families in Portugal.

Percutaneous occlusion of patent foramen ovale in patients with paradoxical embolism.

INTRODUCTION: A patent foramen ovale can be found in about one quarter of adults and in a small percentage it is a wide opening and may be associated with aneurysmal formation. The association between a wide patent foramen ovale and paradoxical embolism is well established. In such cases percutaneous closure is indicated, as an alternative to life-long anticoagulant therapy or surgery. Percutaneous closure is an attractive technique and is more advantageous than other methods. METHODOLOGY: We describe the first cases of percutaneous occlusion of patent foramen ovale performed in Portugal, using the Amplatzer PFO occluder, in three female patients with documented cerebrovascular accidents due to paradoxical embolism. We also analyze the rationale for using this technique in such patients and its preliminary results. RESULTS: All three patients submitted to percutaneous occlusion of patent foramen ovale had a similar history of ischemic cerebrovascular accident. Transesophageal echocardiography showed a wide-open foramen ovale ranging from 9 to 12 mm, with spontaneous right-to-left shunt in all patients, and one of them also had an aneurysmal formation. Total procedure time ranged from 30 to 55 minutes and fluoroscopic time from 9 to 12 minutes. There were no complications and during the short follow up all patients are asymptomatic and free of recurrent events. CONCLUSIONS: Percutaneous closure of patent foramen ovale is a safe and promising technique in the prevention of recurrent systemic thromboembolism in appropriately selected patients. Prospective studies comparing antithrombotic therapy or surgery with percutaneous closure should clarify its efficacy and therapeutic value.

[The sinus venosus type of interatrial communication: its diagnosis by transesophageal echocardiography]. / Comunicação interauricular tipo sinus venosus: diagnóstico por ecocardiografia transesofágica.

Transthoracic echocardiography has important limitations in the diagnosis of sinus venosus atrial septal defects in adults because of the posterior location of the defect. We review the role of transesophageal echocardiography in the diagnosis of this congenital heart disease in nine patients, as well as in the identification of associated abnormal pulmonary venous connections.

[Biological prostheses in the tricuspid position. The immediate and follow-up results]. / Próteses biológicas em posição tricúspide: resultados imediatos e no follow-up.

The results of bioprostheses in the tricuspid position were analysed in 42 patients. 79% were in NYHA class III-IV and 43% had previous cardiac surgery. Concomitant surgical procedures were performed in 86% of the cases. Surgical mortality was 14.3%. Mean follow-up was 54 +/- 31 months. Eight patients were reoperated (5.1%/patient/year), but only 3 for the tricuspid prosthesis. Four patients, with left-sided mechanical prostheses, had systemic thromboembolic events (3.8%/patient/year) and 3 on oral anticoagulation had major haemorrhage (2.8%/patient/year). Primary tricuspid valve dysfunction occurred in two patients (1.2%/patient/year). There were no cases of tricuspid valve thrombosis. For hospital survivors, 5 and 8 years survival was 91.4 +/- 10.3% and 76.2 +/- 10.4%, respectively. The only preoperative predictor of decreased survival was pulmonary artery systolic pressure > or = 50 mmHg. Tricuspid valve replacement with a bioprosthesis was usually performed in the set of multiple-valve operation, with previous cardiac surgery in a high percentage of patients, carrying a significant surgical mortality. However, the long-term survival and the low rate of events related to the tricuspid bioprosthesis favours its use, when conservative surgery is not feasible.

The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

[Clinical manifestations and therapeutic of isolated infective endocarditis of the tricuspid valve]. / Manifestações clínicas e terapêutica da endocardite infecciosa isolada da válvula tricúspide.

We reviewed the records of patients admitted to our centre with the diagnosis of isolated tricuspid valve infective endocarditis and analysed the clinical presentation, etiopathogenic agent, echocardiographic features and therapeutic approach, namely the indication for cardiac surgery. Between 1988 and 1996, 11 cases of confirmed tricuspid valve endocarditis were identified, corresponding to 5% of the cases of endocarditis admitted to our centre in the same period. A predisposing factor was found in ten of the patients, half of them intravenous drug addicts and Staphylococcus aureus was the most frequent agent isolated. Fever and pleuro-pulmonary manifestations were predominant clinical features. Transthoracic echocardiography had a crucial role in the diagnosis and transesophageal echocardiography was important to characterize vegetations. Four patients underwent cardiac surgery, for persistent infection. In two cases, excision of the vegetations and ring annuloplasty was performed. In two patients not addicted to drugs, the tricuspid valve was replaced with a bioprosthesis, since the extension of the damage to the valve did not allow repair. One patient, with early endocarditis of a tricuspid bioprosthesis died before surgery was attempted.

[A review of infectious endocarditis due to Candida]. / Revisão de endocardite infecciosa a cândidas.

OBJECTIVE: As fungal endocarditis is a serious disease, frequently requiring cardiac surgery, a review was made of the experience of our Departments in this pathology. DESIGN: A retrospective analysis of clinical, echocardiographic and surgical data. SETTING: Patients studied in a tertiary care Hospital with cardiac surgery available. PATIENTS: Between 1984 and 1994 there were ten cases of candida endocarditis in nine patients, four male and five female, mean age--45 +/- 12 years (31-65). INTERVENTIONS: The following parameters were analysed: clinical (predisposing factors, clinical evolution, complications, therapy and mortality), echocardiographic (presence of vegetations, abscesses, valvular regurgitations). Patients studied in other Centres and referred to our Department only for examination (echocardiograms) were excluded from this analysis. RESULTS: Eight cases in seven patients were prosthetic valve endocarditis and two native valve endocarditis. No patient was drug addicted. Seven cases of prosthetic valve endocarditis developed less than one year after surgery and another had a gynecological fungal infection as the cause of the endocarditis. Four patients had had previous endocarditis. There were four embolic events and three developed heart failure. There were three perivalvular infections, six valvular regurgitations and only one case with huge vegetations on echocardiography. Nine patients were treated with amphotericin B, in five fluocytosin was added and in four ketoconazol, which was replaced by flukonazol in one patient. Therapy was continued for at least eight weeks. Six patients were operated during the acute stage and one died. One patient was operated on late after the infection. Three patients died during the active stage. In a follow up of 5.2 +/- 4.8 years (8 months to 8 years) there was one fatal candida endocarditis relapse, one fatal candida sepsis, one non cardiac death, one patient developed a periprosthetic leak and one had recurrent systemic embolization. Abscesses/pseudoaneurysms were found in five out of seven patients submitted to surgery. CONCLUSION: Candida infective endocarditis has a bad prognosis, specially in those patients not operated early; it develops in patients with predisposing factors, which in our series were a previous infective endocarditis (four patients) and/or a prosthetic valve implantation less than one year before; it has important morbidity with multiple embolic events, perivalvular involvement, valvular regurgitation and heart failure.

[Mitral prosthesis dysfunction--report of 3 clinical cases with unusual ultrasonography features]. / Disfunção protésica mitral--a propósito de três casos clínicos com aspectos ecocardiográficos pouco frequentes.

Prosthetic valve obstruction is one of the most serious complications of mechanical cardiac valves. Clinicians must be aware of this diagnosis in patients with a worsening of functional NYHA class. Over the past years, echocardiography has imposed itself as the method of choice to diagnose and evaluate patients with suspected prosthetic valve obstruction. We present three clinical reports of prosthetic valve malfunction that have unusual echocardiographic features.

[TSH anti-receptor antibodies in Graves' disease]. / Anticorpos anti-receptor da TSH na doença de Graves.

The purpose of this study was to evaluate the sensitivity, specificity and predictive value of thyrotropin receptor antibody (TRAb) in the diagnosis of Graves disease. TRAb was tested by an isotopic receptor assay-TRAK Henning-in 80 newly diagnosed, untreated Graves disease patients (group I), 63 with other thyroid diseases (group II) and 60 controls (group III). In group I, 11 patients were TRAb negative and 7 were considered in the gray area (TRAb between 9 and 14 U/L). In group II, only 2 patients had TRAb 9 U/l and all controls were TRAb negative. For statistical analysis patients with TRAb in gray area were excluded. Sensitivity and specificity for this assay were 84.5 and 100% respectively. Predictive value of 100% affords certainty that a hyperthyroid patient with a positive TRAb has Graves disease, not sequining a scintigram.

[Heart failure due to a postlaminectomy arteriovenous fistula]. / Insuficiência cardíaca por fístula arteriovenosa pós-laminectomia.

The authors report a case of congestive heart failure as a consequence of traumatic postlumbar laminectomy arteriovenous fistula. A 49 years old female with the diagnosis of atrial septal defect was admitted at the hospital, complaining of dyspnea and peripheral edema. A hemodynamic study was performed and an arteriovenous fistula was detected between the iliac artery and vein, and arterial septal defect was excluded. Surgery for fistula closure was performed with great clinical improvement.

[Holt-Oram syndrome. Review and report of 2 familial cases]. / Síndrome de Holt-Oram. Revisão a propósito de 2 casos clínicos numa família.

In 1960 Holt and Oram reported a family in which upper extremity malformations were associated with a secundum atrial septal defect. Since then, more than 200 cases have been reported with a wide spectrum of phenotypes. The authors present the cases of one mother and daughter with Holt-Oram Syndrome (SHO).

[Myocardial infarct and coronary fistula. A rare combination]. / Enfarte do miocárdio e fístula coronária. Uma associação rara.

We report an unusual case of a 39-years-old male patient, with previous inferior and anterior non Q wave myocardial infarctions, in whom the coronary arteriography showed an arteriovenous fistula between the left anterior descending coronary artery and the pulmonary artery, without any other coronary lesions. We make a revision of this disease and discuss the mechanisms of ischemia.

[Coronary fistula --clinical and angiographic review]. / Fístulas coronárias--revisão clínica e angiográfica.

OBJECTIVE: To evaluate clinical and angiography date of patients (pts) in whom coronary arteriovenous fistula were detected. STUDY DESIGN: Retrospective study of diagnostic coronary angiographies done between 1988 and 1993 in whom coronary arteriovenous fistula were detected. SETTING: Patients submitted to cardiac catheterisation in the Cardiology Department of Santa Marta Hospital in whom coronary arteriovenous were detected. PATIENTS: Fourteen pts, 10 male and 4 female, with a mean age of 49 years (21-72). INTERVENTIONS: A retrospective analysis of clinical data and coronary artery anomalies was done. Whenever available, the Pulmonary Artery and the shunt (calculated through oximetries) were evaluated. RESULTS: The following pathologies were associated: rheumatic valve heart disease (3 pts), Tetralogy of Fallot (2 pts), atrial septal defect--ostium primum (1 pt), dilated cardiomyopathy (1 pt), hypertrophic cardiomyopathy (1 pt), atherosclerotic coronary artery disease (2 pts). Four pts were in atrial fibrillation and the others in sinus rhythm. Four pts had normal ECG. In 6 pts there was cardiomegaly on the chest X-rays. The fistula was single in 11 pts, double in one and multiple in 2 other pts. The fistula originated from the right coronary artery in 6 pts, the left anterior descending coronary artery in 5 pts, the circumflex coronary artery in 3 pts and the left main coronary artery in one pt. Eight drained to the pulmonary artery (or its branches), 2 to the coronary sinus, one directly to the right atrium, one to the right ventricle and one to the left atrium. In only 2 pts the fistula was closed. In 6 pts the associated anomalies were corrected. With a mean follow up of 24 months (1-72), 8 pts are asymptomatic, 4 complain of slight heart failure, 3 of angina pectoris and the pt with dilated cardiomyopathy died 1 year after being studied. CONCLUSION: A male predominance was found. Most fistulae were single. The artery mostly involved was the right coronary artery and the fistula drained more often to the pulmonary artery or its branches.

[The pulsed Doppler evaluation of patients with dilated cardiopathy]. / Avaliação por Doppler pulsátil de doentes com cardiopatia em fase dilatada.

OBJECTIVE: To evaluate, by 2D-Doppler echocardiography, the patterns of left ventricular filling in groups of patients with left ventricular systolic disfunction and different pulmonary wedge pressures. STUDY DESIGN: perspective study of different indexes of left ventricular diastolic filling measured by Doppler echocardiography and compare them with a normal group. SETTING: Patients studied in the Cardiology Department of the Santa Marta Hospital with a diagnosis of dilated cardiopathy and submitted to cardiac catheterisation. PATIENTS: Twenty-four patients, aged 39 years old, submitted to hemodynamic study (group A) and nineteen subjects, aged 34 years old (group B). Pulmonary capillary wedge pressure (PWP) was determined in group A and the patients were divided in two groups: group A1 (with PWP < 16 mmHg) and group A2 (with PWP > or = 16 mmHg). INTERVENTIONS: Every patient was submitted to cardiac catheterisation. The echocardiographic study showed global decrease of left ventricular systolic function. With pulsated Doppler left ventricular diastolic flow indexes were determined. The following parameters were studied: peak protodiastolic flow velocity (Vel E), peak telediastolic flow velocity (Vel A), E/A ratio, protodiastolic acceleration time (O-E) and diastolic flow time (O-C). MEASUREMENTS AND RESULTS: There were no statistical differences between group A as a whole and group B. However in group A1, with a lower PWP there was a decrease of E flow velocity in relation to the control group (54.6 cm/sec +/- 14 vs 66.4 cm/seg +/- 12.8 p < 0.05) or to the group A2 (75.3 cm/sec +/- 29.9 p < 0.05). In the group A1 there was an increase of the flow velocity A in relation to group B (56.1 cm/sec +/- 15.9 vs 36.4 cm/sec +/- 7.3 p < 0.05) and to the group A2 (56.1 cm/sec +/- 15.5 vs 28.2 +/- 9.1 p < 0.05). The relation E/A in group A1 was deceased in relation to group B (1.0 +/- 0.4 m vs 1.8 +/- 0.6 p < 0.05) and in group A2 its increased in relation to B (2.6 +/- 0.9 vs 1.8 +/- 0.6 p < 0.05). The E-D time was increased in group A1 in relation to group B (162.1 +/- 8.7 cm/sec vs 140.5 +/- 42.0 cm/sec p < 0.05) and slightly reduced in group A2 (134.5 +/- 78 msec vs 140.5 +/- 42.0 msec NS). All the patients with mitral regurgitation belonged to group A2. There was only statistical difference in the velocity between the patients in group A with and without mitral regurgitation (29.6 +/- 17.4 cm/sec vs 26.4 +/- 8.5 cm/sec p < 0.05). CONCLUSIONS: In spite of some limitations, Doppler echocardiography is useful in the evaluation of left ventricular filling of patients with dilated cardiomyopathy. It shows different patterns that vary according to the hemodynamic states of the patient.

[Successful operation of aortic abscess ruptured into left atrium. Diagnostic importance of color coded Doppler echocardiography]. / Abcesso aórtico com rotura para a aurícula esquerda, operado com sucesso. Importância diagnóstica do eco-Doppler codificado a cor.

Myocardial abscesses are a serious complication of infectious endocarditis. A 60 years old male patient with subaortic ring abscess is reported. A fistula developed between the left ventricular outflow tract and the left atrium. Doppler echocardiography was of outmost importance for diagnosis. Surgery was successfully performed.

[Myxedema coma]. / Coma mixedematoso.

Five patients, 4 female and 1 male, aged 45 to 73, were observed in myxedema coma between 1984 and 1992. In three patients hypothyroidism was not known. Depressed consciousness, hypothermia, bradycardia and no goiter were common to all and a precipitating factor could be identified in 3 of them. Therapy included L-thyroxine and/or triiodothyronine by nasogastric tube, hydrocortisone and supportive measures. Outcome was good in the 2 patients with known precipitating event, less impaired consciousness and normalization of body temperature by the third day of treatment.

[Persistent ductus arteriosus in the adult--report of a case]. / Persistência do canal arterial no adulto--a propósito de um caso.

The authors describe a case of congenital heart disease no longer frequent in adults, due to an early diagnosis and surgical treatment. The patent ductus arteriosus in adults who received no therapy can present several forms of evolution, depending on its own hemodynamic profile. The present case is an example of a congenital heart disease not diagnosed during the childhood, that developed pulmonary hypertension and congestive heart failure. These clinical situations have a bad prognosis and place this patient in a group of high surgical risk. Thus, surgery is not advisable considering the bad prognosis and early high mortality rate.