Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Assessment of suspected insulinoma by 48-hour fasting test: a retrospective monocentric study of 23 cases.

OBJECTIVE: Insulinoma causes fasting hypoglycaemia due to inappropriate insulin secretion. The diagnosis of insulinoma is based on Whipple's triad during a supervised fasting test. The aim of our study was to evaluate retrospectively the percentage of positive 48-hour fasting tests in a large series of patients with insulinoma. DESIGN, PATIENTS AND METHODS: In a retrospective study, we identified 39 patients (24 females, 15 men; average age 47 years [range 12-78 years]) with insulinoma. Sixteen patients were diagnosed by spontaneous hypoglycaemia. Twenty-three patients with insulinoma were tested with a 48-hour fasting test and compared to 31 healthy controls who had a negative fasting test and were followed up for at least two years. RESULTS: The fast was terminated due to neuroglycopenic symptoms in 4 patients (17.4%) at the 12th hour, in 17 patients (73.9%) at the 24th hour, and in 22 patients (95.7%) at the 48th hour. One patient with insulinoma had no neuroglycopenic symptoms, but was diagnosed by glucose and insulin levels during the 48-hour fast. Healthy controls had significantly higher blood glucose and lower insulin levels, and a lower insulin-glucose ratio than patients with insulinoma at the end of the fast. CONCLUSIONS: In conclusion, the 48-hour fasting test was successful in the diagnosis of insulinoma in 95.7% of patients. In this series we did not observe a need for fasting beyond 48 hours.

[Endovascular therapy of non-aneurysmatic infrarenal aortic rupture]. / Endovaskuläre Therapie bei nicht-aneurysmatischer infrarenaler Aortenruptur.

INTRODUCTION: Endovascular therapy is being used increasingly also to treat ruptured infrarenal aortic aneurysms. Non-traumatic rupture of non-aneurysmatic infrarenal aorta is an absolute rarity. METHODS: The feasibility of endovascular repair of infrarenal aortic rupture is demonstrated with a case history and a literature review. RESULTS: A 58-year-old male developed spontaneous rupture of his infrarenal aorta after successful chemotherapy resulting in regression of a periaortic tumor. The patient suffered from a sepsis for several days before aortic rupture was discovered during computed tomography for focus search. Immediate endovascular stent-graft repair was performed under emergency conditions. There is no recurrence and the patient is doing well with the stent-graft in place without any pathological finding after a follow-up of 24 months. So far only three further cases have been reported of endovascular repair for penetrating atherosclerotic ulcer with rupture of the infrarenal aorta. DISCUSSION: This is the first report of endovascular repair of aortic rupture due to successful chemotherapy of a periaortic mesothelioma. Furthermore, this is the fourth case of successful stent-graft placement to treat non-aneurysmatic rupture of the infrarenal aorta. Minimally invasive endovascular therapy should become a standard treatment option for aortic rupture.

Improved assessment of body cell mass by segmental bioimpedance analysis in malnourished subjects and acromegaly.

BACKGROUND: Estimation of body cell mass (BCM) has been regarded valuable for the assessment of malnutrition. AIM: To investigate the value of segmental bioelectrical impedance analysis (BIA) for BCM estimation in malnourished subjects and acromegaly. METHODS: Nineteen controls and 63 patients with either reduced (liver cirrhosis without and with ascites, Cushing's disease) or increased BCM (acromegaly) were included. Whole-body and segmental BIA (separately measuring arm, trunk, leg) at 50 kHz was compared with BCM measured by total-body potassium. Multiple regression analysis was used to develop specific equations for BCM in each subgroup. RESULTS: Compared to whole-body BIA equations, the inclusion of arm resistance improved the specific equation in cirrhotic patients without ascites and in Cushing's disease resulting in excellent prediction of BCM (R(2) = 0.93 and 0.92, respectively; both P<0.001). In acromegaly, inclusion of resistance and reactance of the trunk best described BCM (R(2) = 0.94, P<0.001). In controls and in cirrhotic patients with ascites, segmental impedance parameters did not improve BCM prediction (best values obtained by whole-body measurements: R(2)=0.88 and 0.60; P<0.001 and <0.003, respectively). CONCLUSION: Segmental BIA improves the assessment of BCM in malnourished patients and acromegaly, but not in patients with severe fluid overload.

[Gastric polyps in pernicious anemia: indications for polypectomy]. / Magenpolypen bei perniziöser anämie--Indikation zur Polypektomie.

HISTORY AND CLINICAL FINDINGS: A 54-year-old man was admitted to hospital with dyspnoea, giddiness, lack of appetite and burning sensation in the tongue for 3 years. Gastritis was known from his history. Clinical examination showed jaundice, glossitis, systolic murmur and pallhypesthesia of both legs. INVESTIGATIONS: Blood and bone marrow investigations revealed pernicious anaemia. At gastroscopy, fundal gastritis was diagnosed and two small polyps of the fundus were removed. Histologically, one of the two polyps turned out to be a gastric carcinoid type 1 (according to [16]). Additional investigations (x-ray, ultrasound of the abdomen, somatostatin-receptor scintigraphy) did not find any metastases. TREATMENT AND COURSE: With the diagnosis of a pernicious anaemia the patient was treated with vitamin B12. The original symptoms and the anaemia disappeared. Additional therapy of the gastric carcinoid was not necessary. One year after beginning of the treatment, no signs of the gastric carcinoid were found. CONCLUSION: In gastric polyps of patients with pernicious anemia neoplastic transformations will often be found. That is why polypectomy should always be done. The best therapy of the gastric carcinoids type 1, which are the most frequently gastric carcinoids, is endoscopic tumour removal. Surgery is the treatment of choice only for gastric carcinoids type 2 to 4. Concerning quality of life and costs, endoscopic treatment is better for patients with gastric carcinoids type 1 than conventional surgical therapy.

[Unusual localization in primary hyperparathyroidism]. / Ungewöhnlicher Lokalisationsbefund bei primärem Hyperparathyreoidismus.

BACKGROUND: Cystic degenerations of parathyroid adenoma appear in 4 to 5% of all cases. These tumors might be localized in the mediastinum. Until now very few cases of cystic parathyroid adenoma have been published. Difficulties in the diagnosis are common because these adenomas are often thought to belong to other anatomic structures. Persistence of hyperparathyroidism and elevated surgical complications can be the consequences. CASE REPORT: We report on the case of a 76-year-old patient with primary hyperparathyroidism. Pre-operative ultrasound revealed a suspicious lesion near the left upper lobe of the thyroid and an unclear cystic structure in the upper posterior mediastinum, suspected as cervical cyst or dysontogenetic cyst. Additional investigations concerning the cystic mediastinal lesion suggested the following differential diagnoses: goiter (X-ray), bronchogenic cyst, cervical cyst or esophageal diverticulum (CT). During the operation no adenoma could be found on the left side, but when the cystic mediastinal lesion was finally removed it turned out to be a giant cystic activated parathyroid adenoma. Postoperatively calcium, phosphate and PTH levels returned to normal. CONCLUSION: In patients with primary hyperparathyroidism, unclear cystic mediastinal masses should be taken into consideration.

[Prevalence of diabetes in acromegaly and Cushing syndrome]. / Diabetes-Häufigkeit bei Akromegalie und Cushing-Syndrom.

In a retrospective study glucose metabolism was investigated in 206 patients with acromegaly and 131 patients with Cushing's disease. 40.5% of the patients with hypersomatotropism and 32.0% of the patients with hypercortisolism suffered from overt diabetes mellitus. Impaired glucose tolerance was present prior to therapy in 28.2% and 30.6% of the patients, respectively. In acromegaly the incidence of overt diabetes mellitus was higher in women than in men, but no difference existed in the distribution of impaired glucose tolerance between both sexes. No correlation was found between growth hormone levels and occurrence of diabetes. In acromegaly and Cushing's disease overt diabetes increased with advanced age. Diabetes mellitus occurred independently from the etiology of hypercortisolism.

[Food-dependent Cushing syndrome of long standing with mild clinical features]. / Nahrungsabhängiges Cushing-Syndrom mit langer Anamnese und moderater Klinik.

HISTORY AND CLINICAL FINDINGS: A 40-year-old woman complained of weight gain for 10 years. Because of this, she yearly went on a excessive weight reduction diet with weight loss of up to 12 kg. Nevertheless, a total weight gain of 15 kg as well as changing degrees of hypertension, muscular weakness and severe depression were registered during this long period. For 5 years ecchymosis and for 2 years oligomenorrhoea as well as oedema had become evident. Recently large macronodular adrenal glands were found on routine abdominal ultrasound. At the time of clinical investigation early this year she presented with relatively mild Cushing features, such as moon face, central obesity, hirsutism, ecchymosis and hypertension. INVESTIGATIONS: Endocrine testing demonstrated suppressed plasma ACTH, low to normal plasma cortisol after overnight fasting and an inverse diurnal rhythm. During 24 hours of fasting plasma cortisol levels and free urinary cortisol excretion were within normal range, but highly elevated under normal food intake. Plasma cortisol levels increased dramatically in response to a lipid-rich meal (5.6-fold), to a protein-rich meal (6.6-fold) and to oral glucose (3.7-fold). Increases in plasma cortisol were closely correlated to increases of gastric inhibitory polypeptide (GIP) concentrations. Subcutaneous injection of octreotide completely inhibited the plasma cortisol and GIP response to oral glucose. Plasma ACTH and cortisol levels did not increase after CRH administration, but fasting plasma cortisol promptly increased after ACTH stimulation. Non-fasting plasma cortisol levels and free urinary cortisol excretion were not suppressed by high doses of dexamethasone. Abdominal computed tomography showed macronodular enlargement of both adrenal glands. TREATMENT AND COURSE: The patient underwent bilateral adrenalectomy. Postoperatively, she was treated with replacement doses of hydrocortisone and fludrocortisone. All Cushing features have regressed, a normal menstrual cycle and normal plasma ACTH concentrations have become evident. CONCLUSION: This case report not only presents a very rare cause of Cushing's syndrome--food-dependent or gastric inhibitory peptide (GIP)-dependent hypercortisolism--but it also demonstrates a special course of this disease of relatively long duration. Severe adrenal hyperplasia contrasted with mild clinical symptoms obviously caused by frequent periods of weight reduction diet. Considering this moderate clinical course it might well be that food-dependent hypercortisolism is more frequent than supposed, but not diagnosed owing to relatively mild clinical symptoms.

Diagnosis of Cushing's syndrome: re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group.

We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with Cushing's syndrome and 144 patients in whom this diagnosis had been excluded. These patients were hospitalized in our department from 1975 to 1996. Additionally, we measured these parameters in 20 healthy volunteers and in 5 patients with nonendocrine disease. Corresponding data of urinary free cortisol and low-dose dexamethasone suppression testing were included in the evaluation. Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range 165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76 nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119-812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg dexamethasone. Values of the healthy volunteers respectively patients with non-endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651) respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete dexamethasone suppressors. The diagnostic value of these parameters was examined based on various cutoffs. We recommend determination of midnight plasma cortisol as an efficient and simple additional procedure for the diagnosis of Cushing's syndrome. The sensitivity and specificity of this procedure is similar to urinary free cortisol and slightly above the low-dose dexamethasone suppression testing in our hospitalized patients.

McCune-Albright syndrome: clinical and molecular evidence of mosaicism in an unusual giant patient.

Molecular genetics recently uncovered the mystery of the protean picture of McCune-Albright syndrome by identification of the somatic gain of function mutations in the GNAS1 gene. Here we present an adult patient with fibrous dysplasia and an endocrinopathy resulting in unusual giant height. The clinical diagnosis in the patient could be confirmed by molecular investigations in tissues involved in the process of fibrous dysplasia.

[Improvement of diabetes mellitus after excision of a parathyroid adenoma]. / Besserung eines Diabetes mellitus nach Exstirpation eines Parathyreoidea-Adenoms.

Disturbances of glucose metabolism with hyperinsulinism and peripheral insulin resistance are frequently observed in patients with hyperparathyroidism. The mechanism of how hyperparathyroidism affects glucose metabolism is not known. Hypercalcemia, hypophosphatemia and the parathyroid hormone itself seem to be involved. However, parathyroidectomy exerted rather variable effects on glucose metabolism: In patients with fully developed diabetes mellitus both, a complete normalisation of glucose tolerance as well as no change in the metabolic situation have been observed. We report a 64-year old female patient with primary hyperparathyroidism and diabetes mellitus. The patient had severe insulin resistance with insulin requirements of 200 IU/day. Fasting insulin and C-peptide levels were elevated. After successful operation of a parathyroid adenoma there was a marked improvement in diabetes, and the patient's insulin requirement decreased to one third of the preoperative dose. This case further illustrates the association between primary hyperparathyroidism and diabetes mellitus and the potential improvement of the metabolic situation after parathyroidectomy.

[The long-term therapy of hypothalamic-hypophyseal Cushing's syndrome with mitotane (o,p'-DDD)]. / Langzeit-Therapie des hypothalamisch-hypophysären Cushing-Syndroms mit Mitotan (o,p'-DDD).

BACKGROUND AND OBJECTIVE: Drug treatment of hypothalamic-pituitary Cushing's syndrome is indicated if standard surgical intervention is not possible or has failed. The question arises whether, after unsatisfactory treatment with various adrenostatic drugs, mitotane (o,p'-DDD), used against adrenal cortical cancer, is efficacious and free of significant side effects when used long-term. PATIENTS AND METHODS: The results of long-term administration of mitotane to six patients, including one pregnant woman, were analysed retrospectively. After a moderate initial dosage of 3.0 g daily a maintenance dose of minimally 0.5 g per week was given or the treatment temporarily interrupted. The concentration of urinary free cortisol served as the main criterion of efficaciousness, together with the clinical course. The plasma concentrations of cortisol, aldosterone and ACTH were also determined, as well as routine clinicochemical parameters. RESULTS: Cortisol excretion became normal in all patients between the 2nd and 10th treatment month, falling from 919 +/- 621.3 nmol daily in the six months before treatment to 162 +/- 93.0 nmol daily in the third six-month treatment period (mean +/- standard deviation). Normal cortisol excretion and regression of symptoms was noted, dose-dependent, as long as the 12th year after start of treatment. Adrenocortical insufficiency occurred in one patient and at times required hormone substitution, followed by lasting remission without special treatment. Significant side effects were not observed other than a reversible increase in gamma-glutamyl transpeptidase. CONCLUSION: Mitotane proved to be an efficacious drug which in exceptional cases can be used without significant side effects in low dosage for the long-term treatment of hypothalamic-pituitary Cushing disease.

[Pregnancy in hyperprolactinemic patients]. / Schwangerschaften bei hyperprolaktinmischen Patientinnen.

In a retrospective study we analysed the outcome of 27 pregnancies in 17 hyperprolactinaemic patients. Cranial CT or MRI scans showed a microadenoma in 9, a macroadenoma in 7 and no change in 1 case. In 5 patients macroadenomas were surgically removed but a residual hyperprolactinaemia remained. In 2 patients with selectively removed microadenomas through the transsphenoidal route only in one case normal prolactin levels could be achieved. This patient became two times pregnant. In 24 patients pregnancy was induced by dopaminergic treatment whereas another patient with microadenoma became spontaneously pregnant after surgery and treatment with bromocriptine. The treatment was discontinued as soon as the pregnancy was recognised. 19 pregnancies were finished by spontaneous delivery and 3 by Caesarean section. Termination of pregnancy was artificially induced in 3 patients. One miscarriage was observed. Another patient was suffering from an extrauterine pregnancy. During pregnancy prolactin levels increased in comparison to basal levels. After delivery and lactation the same prolactin level was found compared to basal levels in patients with microprolactinomas. In patients suffering from macroadenomas prolactin levels decreased in comparison to basal levels. CT of MRI scan evaluations performed after delivery revealed a clinical not relevant increase as well as a decrease of tumor size in 2 cases, respectively. During pregnancy there was no complication due to tumor found in treated patients for hyperprolactinaemia. Only about one half of mothers were able to perform regular breast feeding.

[Sellar germinoma with lung metastases]. / Selläres Germinom mit Lungenmetastase.

Reported in this paper is the case of a boy aged 15 years with sellar germinoma which led to one singular pulmonary metastasis, three years after subtotal surgical removal and subsequent successful irradiation of the tumor rest. The primary tumor together with the lung metastasis were characterised as germinoma with trophoblastic giant cells as additional elements. Interpretation of the pulmonary tumour was somewhat difficult, since diagnosis of the primary tumor had encouraged assumption of a chromophobic hypophyseal adenoma with polymorphic manifestation, with no relationship between the intracranial and pulmonary tumors being presumed by the surgeon. The true nature of the metastasis and, consequently, the histogenetic identity of both tumors was cleared up by immunohistochemical detection of beta-HCG in almost all syncytiotrophoblasts. Comprehensive analysis of the literature on metastasising intracranial germinomas may be helpful in disclosing possible relationships between the histological type of a primary tumor or neurosurgical action and the metastatic potential of tumors.

[Cushing's syndrome in CRF-producing mediastinal carcinoid]. / Cushing-Syndrom bei CRF-produzierendem mediastinalem Karzinoid.

A 36-year-old patient developed marked pigmentation, marked myopathy and severe hypokalaemic alkalosis which at first pointed towards an ectopic ACTH syndrome. The dexamethasone test at a high dose indicated cortisol suppression. A mediastinal tumour was seen radiologically, but the sella was of normal size. Computed tomography provided indirect signs of a sellar space-occupying lesion which suggested an ectopic production of corticotropin-releasing factor (CRF) as cause of the Cushing's syndrome. CRF concentration in antecubital venous blood was markedly elevated to 280 ng/l. The mediastinal tumour was excised and proved to be a carcinoid histologically. Postoperatively the CRF concentration fell to 70 ng/l. An extract of the carcinoid contained 15.5 ng/g wet-weight of CRF and 254 ng/g wet-weight of beta-endorphin. The patient died 5 weeks postoperatively of sepsis with bilateral pneumonia. At autopsy the hypophysis was of normal size but showed nodular ACTH-cell hyperplasia. This was thus a case of Cushing's syndrome resulting from ectopic CRF production in a mediastinal carcinoid tumour.

Fabry-Perot interferometer with personal computer control.

To record weak light scattering spectra with a Fabry-Perot interferometer, long measuring times are often necessary. For long term stability of the parallel alignment of the mirrors, a microcomputer controlled interferometer system has been developed for both single and multipass operation. The three piezo stacks, which are responsible for the alignment of the mirrors, are supplied from three digital-to-analog converters controlled by a personal computer. The test and correction steps of the mirror alignment are performed around two independent axes perpendicular to each other. A special function generator provides a nonlinear scanning ramp for the piezostacks, thereby allowing a temporally linear scanning of the Fabry-Perot.

Paradoxical response of plasma beta-endorphin to combined administration of TRH and GnRH in adrenal disorders.

The combined intravenous injection of TRH and GnRH elicited paradoxical responses of plasma beta-endorphin in active and successfully treated pituitary dependent Cushing's disease as well as in ectopic ACTH syndrome and in congenital adrenal hyperplasia. No response was observed in Cushing's syndrome due to adrenal tumours. It is concluded that an abnormal response to inappropriate releasing hormones cannot verify the existence of a pituitary corticotrophic microadenoma.

[The immunohistochemistry of pituitary adenomas]. / Immunhistochemie der Hypophysenadenome.

A great deal of progress has been achieved in recent years in the field of immunohistochemistry of pituitary adenoma. Continued use of more new antisera and monoclonal antibodies against numerous hormones in the adenohypophysis have resulted in new approaches to classification of pituitary adenoma. However, new problems have been discovered, on the other hand, by large-scale studies in recent years. The great number of multihormonal pituitary adenomas and possible change of the immunohistochemically detectable hormone status in cases of recurrent tumours have particularly re-emphasised the need for new thinking about patterns of classification. It would appear somewhat problematic, in this context, to uncritically accept terms, such as ACTH cellular adenoma or GH cellular adenoma. Reference is also made to the distribution pattern of cell and tissue markers in pituitary adenomas. The paper is based on thorough literature screening as well as on experience obtained by the authors from 450 cases of pituitary adenoma of which 260 had been analysed by immunohistochemistry, 131 by morphometry, and 80 by electron microscopy.