Friedhelm Raue

Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation.

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.

Sekundäre Osteoporose – praxisrelevante Besonderheiten bei der Diagnostik und Therapie

Osteoporosis is a systemic skeletal disease causing increased fracture risk. According to pathogenesis, primary (70 - 80 %) and secondary osteoporosis (20 - 30 %) are distinguished. Secondary osteoporosis comprises all entities in which osteoporosis is predominantly and causally associated with certain diseases or conditions. The aim of this review article is to put attention to special features in diagnosis, prophylaxis and treatment of secondary osteoporosis in general and to demonstrate some forms of secondary osteoporosis which seem particularly important during clinical practice. The manuscript refers to the guidelines of the DVO 2009 for prevention, diagnosis and therapy of osteoporosis and selective original papers considering the special types of secondary osteoporosis. History, clinical examination and basic laboratory tests are indicative for the diagnosis of secondary osteoporosis. Its clinical presentation is frequently characterized by rapid development and multiple fractures. Therefore, early diagnosis, prophylaxis and causal treatment is decisive. If causal treatment is impossible, risk adaption of bone mineral density (BMD) for osteoporosis specific treatment is essential. Common causes are medications, endocrine, gastrointestinal and hematologic diseases. Glucocorticoid induced osteoporosis, antihormonal therapy (aromatase inhibitor in women with breast cancer, androgen deprivation therapy in men with prostate cancer) and vitamin D deficiency causing secondary hyperparathyroidism are presented in detail. History and basic laboratory testing are decisive to identify possible causes for secondary osteoporosis and to initiate early diagnostic procedures. The risk of severe osteoporosis can be reduced by early and causal treatment or by risk stratified early bone specific medication if causal therapy is impossible.

[Hereditary variants of primary hyperparathyroidism--MEN1, MEN2, HPT-JT, FHH, FIHPT].

OBJECTIVE The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5% of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT. PATIENTS 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up. RESULTS 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85%), followed by HPT-JT (64%), FHH (28.5%), and MEN2 (8%). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5%). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH. CONCLUSION Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.

Hereditäre Formen des primären Hyperparathyreoidismus

OBJECTIVE The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5% of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT. PATIENTS 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up. RESULTS 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85%), followed by HPT-JT (64%), FHH (28.5%), and MEN2 (8%). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5%). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH. CONCLUSION Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.

Update on Multiple Endocrine Neoplasia Type 2: Focus on Medullary Thyroid Carcinoma

Abstract Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome caused by missense gain-of-function mutations in the RET proto-oncogene on chromosome 10. Specific RET mutations can predispose toward a particular phenotype and clinical course, with strong genotype–phenotype correlations. MEN2 is highly penetrant in medullary thyroid carcinoma (MTC), and it can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Two different clinical variants of MEN2 are known: MEN2A, which includes the familial subtype, and MEN2B. Treatment includes early thyroidectomy. Recommendations on the timing and extent of surgery are based on the RET mutation risk categories (moderate-, high-, or highest-risk) regarding the age of MTC onset. Early identification of patients with hereditary MTC has improved treatment outcomes. Previously, MTC was diagnosed based on clinical tumors; in contrast, with genetic screening, MTC can be diagnosed at preclinical disease states. This approach has resulted in a high cure rate and a much better prognosis for MTC. However, classification into one of the three RET mutation risk groups for predicting aggressiveness and prognosis has had limited impact. Increasing evidence has shown that patients with RET mutations in different risk classifications exhibit a broad spectrum of MTC aggressiveness during follow-up, with no relevant difference in survival. The specific germline activating mutation of the RET proto-oncogene appears to be the first determinant of the age of MTC onset, but, presumably, different regulatory events determine long-term tumor behavior.

Empfehlung zum Calcitonin-Screening bei Struma nodosa

Medullary thyroid cancer (MTC) arises from parafollicular C cells of the thyroid gland and is characterized by a calcitonin secretion. Basal calcitonin correlates with the tumor mass and is used as highly sensitive and specific tumor marker for MTC. Based on former assays, unspecific calcitonin increase has frequently been seen in Hashimotos thyroiditis, kidney insufficiency, proton pump inhibitors etc. This phenomenon is now less often seen with modern assays. The consequent use of calcitonin measurement in nodular goiter helps to identify the rare MTC at an early stage. The best cut-off values to differentiate micro-MTC from C-cell hyperplasia and other unspecific calcitonin elevations were achieved by the use of a 30 pg/ml and a 60 pg/ml threshold in women and men, respectively. This approach is not less sensitive than formerly used pentagastrin stimulation. A calcitonin value > 100 pg/ml is nearly 100 % predictive for MTC. Therefore, the Thyroid Section of the German Society of Endocrinology recommends a thyroidectomy in woman with serum calcitonin values > 30 pg/ml (grey zone 20 - 30 pg/ml) and in man with serum calcitonin values > 60 pg/ml (grey zone 30 -60 pg/ml). Lower calcitonin values should be re-evaluated in intervals of 3 - 6 months; rising calcitonin levels may indicate an MTC. In this case, thyroid operation should be performed. The cure rate of MTC with calcitonin values < 100 pg/ml is nearly 100 % done by high volume surgeons.

Molecular Genetics of MEN2-Related Neuroendocrine Tumours

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome with medullary thyroid carcinoma (MTC) as a common manifestation. It is caused by germline missense gain-of-function mutations of the RET proto-oncogene. Two distinct clinical subtypes of MEN2 have been characterized: MEN2A and MEN2B. The specific RET mutation may suggest a predilection toward a particular phenotype and clinical course, with strong genotype–phenotype correlations. Recommendations on the timing of early thyroidectomy and extent of surgery are based on classification of RET mutations into risk levels according to genotype–phenotype correlations as well as on penetrance and aggressiveness of MTC. The excellent prognosis for MTC diagnosed at its earliest stage underscores the importance of prospective calcitonin screening for sporadic MTC and early diagnosis by RET mutation analysis for hereditary MTC. MEN2 provides a unique model for early prevention and cure of cancer and for the roles of stratified mutation-based diagnosis and therapy of carriers. Understanding the molecular basis of both hereditary and sporadic MTC has led to the development of targeted therapy with tyrosine kinase inhibitors.

The Calcium-Sensing Receptor: Physiology and Pathophysiology

The complex control of calcium by the calcium-sensing receptor is the substance of this chapter. It describes the role of this critical receptor at the parathyroid glands and kidneys and focuses on the molecular abnormalities of the receptor and its role in the causation of hypocalcemic and hypercalcemic disorders. It describes how activating and inactivating mutations of the receptor lead to the problems such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and other clinical states. It notes the use of genetic analysis of the calcium sensing receptor gene in the diagnosis of these complex problems and provides some therapeutic options for treatment.

Hereditäre Formendes primären Hyperparathyreoidismus

OBJECTIVE The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5% of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT. PATIENTS 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up. RESULTS 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85%), followed by HPT-JT (64%), FHH (28.5%), and MEN2 (8%). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5%). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH. CONCLUSION Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.

Endokrinologie: Teil II

(Insulin-Hypoglyk-ämie-Test oder Metopiron-Kurztest) angeschlossen werden [8, 9]. Neben der Glukokortikoid(primäre und sekundäre NNR-Insuffizienz) und der Mineralokortikoidsubstitution (nur primäre NNR-Insuffizienz) sollte bei jedem Patienten mit NNRInsuffizienz eine zusätzliche Substitution mit dem NNR-Androgen Dehydroepiandrosteron (DHEA) erwogen werden [10]. Bei Patientinnen mit NNR-Insuffizienz konnte in zwei Studien eindeutig ein verbessertes psychisches Wohlbefinden unter einer Substitution mit 50 mg DHEA/die belegt werden [11, 12]. Da in einer dieser Studien auch männliche Patienten mit NNR-Insuffizienz untersucht und ähnliche Effekte gemessen wurden, wird als Ursache neben der androgenen Wirkung eine zusätzliche „neurosteroidale“ Wirkung des DHEA postuliert [12]. Obwohl weder bei Patienten mit Autoimmunadrenalitis (80–90% der Patienten mit Morbus Addison) noch bei Patienten mit sekundärer NNRInsuffizienz das Nebennierenmark morphologisch verändert ist, findet man sowohl bei primärer [13] als auch bei sekundärer NNR-Insuffizienz [14] eine eingeschränkte Adrenalinsynthese des Nebennierenmarks. Dies wird auf eine funktionelle Einschränkung der Nebennierenmarkenzyme bei fehlendem Glukokortikoidangebot aus der Zona fasciculata zurückgeführt. Hatte man bisher dem daraus resultierenden „Adrenalinmangel“ keine klinische Bedeutung zugeordnet, zeigt eine neuere Studie, dass dies zu einer eingeschränkten „Stressfähigkeit“ führen kann [14]. Ob sich hieraus evtl. eine Indikation zu einer „Ersatztherapie“ des Nebennierenmarks ergibt, ist derzeit bei fehlenden weiterführenden Studien nicht abzusehen, aufgrund der pharmakologischen Voraussetzungen (parenterale Adrenalingabe) aber eher unwahrscheinlich. Nebennierenrinde und -mark