[Neuroendocrine tumors : Classification, clinical presentation and imaging]. / Neuroendokrine Tumoren : Klassifikation, Klinik und Bildgebung.

CONTEXT: Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms found in all organs. They often present with characteristic clinical syndromes due to hormone hypersecretion. DIAGNOSTICS: In addition to hormone diagnostics molecular-genetic work-up can play an important role. IMAGING: Morphological imaging comprises ultrasound, endoscopy, computed tomography (CT) and magnetic resonance imaging (MRI) scans. Functional imaging of NET relies on radioligands that bind to specific receptors or transporters (Ga-68-DOTATATE-PET-CT, Tc-99-tektrotyd-SPECT/CT, F­18-DOPA-PET/CT). THERAPY: Somatostatin analogs either native or coupled to radionuclides are potent drugs for treating various neuroendocrine tumors. CONCLUSION: The requirements of imaging are determined by clinical presentation, laboratory findings, tumor stage, the presence of a tumor syndrome and the need of a personalized systemic treatment modality.

Phaeochromocytoma in multiple endocrine neoplasia type 2: RET codon-specific penetrance and changes in management during the last four decades.

OBJECTIVES: We describe phaeochromocytoma (phaeo) penetrance in multiple endocrine neoplasia type 2 (MEN2) according to RET protooncogene-specific mutations and report changes in phaeo diagnosis and management from 1968 to 2015. DESIGN: This retrospective chart review included 309 MEN2 patients from one specialized ambulatory care centre. Phaeo patients were categorized by diagnosis date: early, 1968-1996, n=40, and recent, 1997-2015, n=45. RESULTS: Phaeochromocytoma was diagnosed in 85/309 patients with RET mutations in the following exons (phaeos/all carriers, %): exon 11 (56/120, 46.6%); exon 16 (7/17, 41.2%), exon 10 (14/47, 29.8%), and exon 13-15 (2/116, 1.7%). Age at phaeo diagnosis differed according to affected exon: 21.9±1.5 years, exon 16; 34.1±11.6 years, exon 11; and 41.8±8.8 years, exon 10. Age-related phaeo penetrance differed among five amino acid substitutions at codon 634 and was highest for Cys634Arg and Cys634Tyr. Age at diagnosis was 34.4±11.6 years in the early and recent groups. Phaeochromocytoma and medullary thyroid carcinoma (MTC) were diagnosed synchronously in 21/40 (early) vs 8/45 (recent) and metachronously in 19/40 vs 37/45 cases. Diagnostic methods significantly changed from clinical (22/40 vs 4/45) to biochemical and/or imaging based (14/40 vs 35/45). Phaeochromocytoma diameter at diagnosis was 4.6 vs 2.6 cm. CONCLUSION: Phaeochromocytoma penetrance and age of diagnosis are highly correlated with MTC aggressiveness based on RET mutation status, with higher penetrance and younger age of diagnosis associated with more aggressive MTC. Penetrance steadily increases with age. At-risk patients require lifelong follow-up.

A Novel Mutation of the Calcium Sensing Receptor Gene in a Franconian Kindred: Heterozygous Mutation c.1697_1698delTG Exon 6.

Familial hypocalciuric hypercalcemia (FHH) belongs to the disorders of a disturbed calcium homeostasis. Genetically, the disorder is inherited in an autosomal-dominant trait and represents an inactivating mutation of the calcium sensing receptor (CaSR) gene. We identified a Franconian kindred in which 6 individuals could be tested by molecular genetic means. In 5 individuals of 3 generations, the mutation could be classified as c.1697_1698delTG. This novel germline mutation creates a premature stop codon leading to a loss of 510 amino acids of the protein. The detection of CaSR gene mutations is suitable to differentiate states of hypercalcemia and may help to avoid invasive procedures such as parathyroidectomies.

Long-Term Follow-Up and Treatment of Postoperative Permanent Hypoparathyroidism in Patients with Medullary Thyroid Carcinoma: Differences in Complete and Partial Disease.

This study aimed to identify factors influencing long-term outcome in complete or partial postoperative hypoparathyroidism (parathyroid hormone ≤10 or >10 ng/l, respectively) in medullary thyroid carcinoma (MTC). It was designed as retrospective, long-term follow-up with single-center outpatient visits. Quality of treatment, renal calcification, and function were evaluated. In 33 patients with MTC and postoperative hypoparathyroidism, current medication includes: calcium (73%), calcitriol (73%), alfacalcidol (6%), dihydrotachysterol (3%), and cholecalciferol supplements (21%). Mean hypoparathyroidism duration was 15.9±9.4 years. Initially, 15% of patients received high cholecalciferol dosages. Initial calcium dosages were higher (1 542±1 179 mg/day) than final dosages (1 188 ± 595 mg/day) (p<0.05); calcitriol dosages remained constant. Over the median observation period of about 12 years it was found that serum calcium was within the target range (2.0-2.3 mmol/l) in 63% of visits, decreased (<2.0 mmol/l) in 20.4%, high-normal (2.4-2.6 mmol/l) in 15.8%, and increased (>2.65 mmol/l) in 0.9% of visits. Calcitriol dosages were 0.73±0.22 µg/day and 0.47±0.20 µg/day in patients with complete (n=13) and partial (n=20) hypoparathyroidism, respectively (p=0.008). Renal function decreased slightly during follow-up (eGFR: 102±22 vs. 90±27 ml/min). eGFR was negatively correlated with hypoparathyroidism duration (r=-0.35, p=0.05). Of 9 patients with renal calcification, 5 had received high initial cholecalciferol doses. eGFR was lower in patients with than in those without calcification (77±17 vs. 95±29 ml/min) (p=0.07). At least one tetanic episode occurred in 60.6% of patients, and 9% had repeated tetanic complaints. In conclusion, severity of hypoparathyroidism affects treatment: Partial hypoparathyroidism required lower calcitriol dosages than complete hypoparathyroidism. Renal calcifications occurred more frequently in patients treated initially with high cholecalciferol dosages. Impaired renal function was related to hypoparathyroidism duration and renal calcification.

[Multiple endocrine neoplasia (MEN)]. / Multiple endokrine Neoplasie (MEN).

CLINICAL ISSUE: Multiple endocrine neoplasia (MEN) types 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types. STANDARD TREATMENT: Carriers of a MEN1 or RET gene mutation can be identified before manifestation of the disease. Family screening allows the early diagnosis and therapy of gene carriers. TREATMENT INNOVATIONS: Early thyroidectomy in young patients with MEN2 results in a high cure rate of medullary thyroid carcinoma (MTC). Treatment with tyrosine kinase inhibitors (TKI), such as vadetanib and cabozantinib, represents an important new therapeutic option for patients with progressive metastatic MTC. Neuroendocrine tumors (MEN1) are treated surgically and progressive disease is treated with somatostatin or everolimus. DIAGNOSTICS: The most important imaging methods for monitoring of MTC are sonography of the neck and upper abdomen and computed tomography (CT) of the lungs. In cases of MEN1 metastases can be localized by DOTATOC positron emission tomography CT (PET/CT). PERFORMANCE: Using these methods up to 70 % of tumors and metastases can be detected, depending on the localization, size and endocrine activity. Follow-up investigations with CT is an important tool for monitoring changes in tumor mass which are important criteria for decisions concerning TKI therapy. ACHIEVEMENTS: Together with the doubling time of tumor markers, tumor progression monitored by imaging methods or response evaluation criteria In solid tumors (RECIST) are prognostic factors and provide indications for initiating systemic therapy (e.g. TKI) PRACTICAL RECOMMENDATIONS: Patients with MEN syndromes should be treated in specialized centers because of the complexity and rarity.

[Secondary osteoporosis - relevant clinical characteristics in diagnosis and therapy]. / 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]. / Hereditäre Formen des primären Hyperparathyreoidismus. 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.

Rapid response to sorafenib in metastatic medullary thyroid carcinoma.

OBJECTIVE: To investigate the efficacy of sorafenib in progressive metastatic Medullary Thyroid Carcinoma (MTC), for which there is currently no effective treatment. DESIGN: Off-label observational study. METHODS: Sorafenib 400 mg twice daily was evaluated. The primary endpoint was the objective Response Evaluation Criteria in Solid Tumours (RECIST) score assessed on day 28 and every 12 weeks thereafter. Additional endpoints were time to response, duration of tumour response, tumour-related symptoms, and changes in tumour markers, calcitonin, and CEA measured initially, at 2 weeks, and then every 4 weeks. Therapy duration was 2 weeks, and 3-12 months. RESULTS: The 5 patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. 2 patients showed a partial response with tumour regression of -46% and -36% after 6 and 9 months, respectively, and 2 patients exhibited tumour regression of -14% and -29%, respectively (stable disease). Ultrasound-documented regression of -37% within 2 weeks occurred in 1 patient. Calcitonin decreased within 2 weeks in all patients by -69, -90, -75, -96, and -39%, respectively. 1 patient died because of progressive ascites from acute renal and hepatocellular failure. 2 patients developed grade 3 hand-foot syndrome within the first month, so that sorafenib was interrupted or reduced; other side effects were rash, fatigue, and hair loss. 3 patients remain on sorafenib, 2 at a reduced dosage (600 mg/d). CONCLUSION: These data suggest a possible role for sorafenib in the treatment of progressive metastatic MTC.

Are commonly recommended dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D levels--an observational study during clinical practice conditions.

UNLABELLED: Vitamin D deficiency is associated with increased fracture risk. The observational study aimed to investigate vitamin D status and supplementation in ambulatory patients. Only 20% of patients had optimal serum 25-hydroxyvitamin D [25(OH)D] levels. Commonly recommended dosages were insufficient to achieve clinically relevant increase of 25(OH)D levels. Higher dosages were safe and effective under clinical practice conditions. INTRODUCTION: Vitamin D deficiency is associated with adverse health outcome. The study aimed to investigate vitamin D status and supplementation in ambulatory patients. METHODS: Nine hundred seventy-five women and 188 men were evaluated for bone status from January 2008 to August 2008 within an observational study; 104 patients (n = 70 osteoporosis) received follow-up after 3 months. Dosage of vitamin D supplementation was documented and serum 25(OH)D and parathyroid hormone (PTH) determined. RESULTS: In all patients (age, 60.4 ± 14.1 years), distribution of 25(OH)D was 56.3 ± 22.3 nmol/L (normal range, 52-182 nmol/L) and PTH 53.8 ± 67.5 ng/L (normal range, 11-43 ng/L). The proportion of patients with 25(OH)D < 25, 25 to <50, 50 to <75, ≥75 nmol/L was 7.5%, 33.3%, 38.9% and 20.2% in the total group and 20.1%, 38.5%, 30.8%, 10.6% at baseline in the follow-up group, respectively. After 3 months, 3.9% had still 25(OH)D < 25 nmol/L; only 12.5% achieved 25(OH)D ≥ 75 nmol/L. In osteoporosis patients, 25(OH)D increased more in those taking ≥1,500 (median, 3,000) IU vitamin D per day (33.1 ± 14.7 nmol/L) compared with ≤1,000 (median, 800) IU/day (10.6 ± 20.0 nmol/L) (p < 0.0008). PTH decreased more in patients taking ≥1,500 IU/day (-13.2 ± 15.2 ng/L) compared with ≤1,000 IU/day (-7.6 ± 19.2 ng/L; p = 0.29). 25(OH)D was negatively correlated to PTH (r = -0.49, p < 0.0001). An increase of 25(OH)D ≥ 75 nmol/L resulted in normalised PTH. CONCLUSION: Supplementation with higher vitamin D dosages (2,000-3,000 IU/day) is required to achieve a relevant increase of 25(OH)D and normalisation of PTH.

New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour.

UNLABELLED: Clinical studies are needed to classify rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC) into one of the clinical risk groups. Here we describe two new RET mutations/variants, R770Q and L881V, in patients with MTC and analyzed genotype-phenotype correlations associated with these RET mutations in the gene carriers. FAMILY 1: Calcitonin screening in a 42-year-old female patient with multinodular goiter showed elevated levels. RET mutation analysis revealed a new variant in exon 13 R770Q (CGA>CAA) in the patient. A thyroidectomy with central and lateral node dissection was done. Histology showed MTC in a mixed variance with follicular cancer of 2 cm diameter (T2N0M0). Postoperatively there was no increase of calcitonin after pentagastrin stimulation. The patient is biochemically cured concerning MTC and FTC after radioiodine therapy. In the sister of the index patient surprisingly another, previously not described amino-acid substitution Y791N (TAT><) in the RET protooncogene was found. In the parents the R770Q variant was detected in the mother, the Y791N mutation in the father. Another sister carries the R770Q variant. In all other gene carriers (aged 44-70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed. FAMILY 2: In a 46-year-old female patient with nodular goiter thyroidectomy, central and left lateral lymph node dissection was done because of elevated calcitonin levels. Histology revealed a microcarcinoma with one lymph node metastasis (T1N1(1/8)Mx). RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). The L881V mutation was detected in five other family members. In the first generation stimulated calcitonin levels were in the normal range, therefore thyroidectomy had not yet been performed. In the sons of the index case thyroidectomy revealed CCH in the older one, no MTC in both. In a cousin thyroidectomy is intended because of elevated basal and stimulated calcitonin. CONCLUSION: Our clinical findings indicate that the L881V mutation may be associated with late-onset nonaggressive disease. If the germline RET R770Q variant has a causative role in the pathogenesis of the mixed medullar/follicular derived histology of the thyroid tumour in the index patient of family 1 has to be proven. The recommendations for prophylactic thyroidectomy in these mutations should be individualized depending on basal and stimulated calcitonin levels until more data are available.

Mutational analysis of the PHEX gene: novel point mutations and detection of large deletions by MLPA in patients with X-linked hypophosphatemic rickets.

X-Linked hypophosphatemic rickets (HYP, XLH) is a disorder of phosphate homeostasis, characterized by renal phosphate wasting and hypophosphatemia, with normal to low 1,25-dihydroxy vitamin D3 serum levels. The purpose of our study was the detection of inactivating mutations in the PHEX gene, the key enzyme in the pathogenesis of XLH. The 16 patients, representing eight families, presented with suspected XLH from biochemical and clinical evidence. All 16 were referred for mutational analysis of the PHEX gene. We detected three novel disease-causing mutations, C59S, Q394X, and W602, for which a loss of function can be predicted. A G28S variation, found in two healthy probands, may be a rare polymorphism. Another mutation, A363 V, is localized on the same allele as the C59S mutation, thus its functional consequences cannot be proven. Furthermore, we detected a deletion of three nucleotides in exon 15 which resulted in the loss of amino acid threonine 535. Heterozygosity of this mutation in a male patient without any chromosomal aberrations suggests its presence as a mosaic. Novel large deletions were detected using multiplex ligation-dependent probe amplification (MLPA) analysis. Two of these deletions, loss of exon 22 alone or exons 21 and 22 together, may result in the translation of a C-terminal truncated protein. Two large deletions comprise exons 1-9 and exons 4-20, respectively, and presumably result in a nonfunctional protein. We conclude that molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA.

Relapsing pheochromocytoma in a Chinese women caused by a novel mutation in exon 6 of the SDHB gene: a case report.

Pheochromocytomas are rare catecholamine-secreting, chromaffin tumors of the autonomic nervous system. Most pheochromocytomas are sporadic, but up to 24% of pheochromocytomas are part of a familial disorder. Here we describe a female patient, who presented to our outpatient clinic 18 years after removal of a pheochromocytoma of the left adrenal gland in China. Now she reported flank pain on the left side and elevated blood pressure. 24-hour urinary catecholamines, metanephrines, and normetanephrines as well as plasma-norepinephrine were elevated. The transabdominal ultrasonography revealed a tumor with reduced echogenicity in the left suprarenal region, which was suspected to be a recurrent pheochromocytoma. This finding was confirmed by MRT and J (123)-MIBG-scan. Parathyroid hormone (PTH) and calcitonin were in the normal range. After surgical excision, histological examination of the adrenal mass proved to be a pheochromocytoma. Molecular genetic analysis with sequencing of the succinate dehydrogenase type B (SDHB) gene revealed a formerly unknown mutation of codon 214 (CAG-->TAG) leading to an amino acid change of glutamine to a stop-Codon (Q214X-mutation) in exon 6. This case report highlights the necessity of re-evaluating patients with nonsyndromic pheochromocytoma who are diagnosed without genetic testing to estimate the risk of a relapse and to initiate testing of first-degree relatives.

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.

[Hyperparathyroidism-jaw tumor syndrome. A hereditary form of primary hyperparathyroidism with parathyroid carcinoma]. / Hyperparathyreoidismus-Kiefertumor-Syndrom. Eine hereditäre Form des primären Hyperparathyreoidismus mit Nebenschilddrüsenkarzinom.

HISTORY: A 29-year-old man presented with a giant cell granuloma of the maxilla that had initially been diagnosed as a "brown tumor" (a bone replacing mass of fibrous tissue containing hemosiderin-pigmented macrophages and multinucleated giant cells). Because serum calcium and PTH were elevated, primary hyperparathyroidism was diagnosed. Three months later a parathyroid carcinoma and a brown tumour in the left femur were identified and removed surgically. Hyperparathyroidism-jaw tumor syndrome was suspected. INVESTIGATIONS AND DIAGNOSIS: Mutation analysis of the DNA revealed heterozygous nonsense mutation R234X in exon 7 of the HRPT2 gene, a tumor suppressor gene responsible for the HPT-JT syndrome. Subsequent studies indicated that the patient had inherited the HRPT2 mutation from his father who was now 68 years old. He showed no symptoms of the hyperparathyroidism-jaw tumor syndrome; serum calcium and PTH were normal. The R234X mutation was also found in the patient}s sister. She had been diagnosed for primary hyperparathyroidism at the age of 32 years. Serum calcium and PTH levels were within the normal range after subtotal parathyroidectomy. FURTHER COURSE: Follow up over 3 years showed no clinical, morphological or biochemical relapse of primary hyperparathyroidism. CONCLUSION: The identification of the R234X mutation is not only important for the patient himself, but also for other family members who could benefit from being identified as mutation carriers. This information can be used for the early detection and removal of malignant parathyroid tumours.

The role of the extracellular calcium-sensing receptor in health and disease.

The calcium-sensing receptor has a key role in calcium homeostasis, it is involved in the regulation of the serum calcium level within minutes via the secretion and action of parathyroid and the excretion of calcium in the kidney in a negative feedback manner. Mutations of the calcium sensing receptor gene leads to inactivating and activating mutations resulting in diseases with hypercalcaemia and hypocalcaemia. The loss of function mutations are associated with familial benign hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease characterised by lifelong mild hypercalcaemia, low urinary calcium excretion, and inappropriate high parathyroid hormone levels, sometimes difficult to distinguish from mild asymptomatic primary hyperparathyroidism. Patients with FHH did not profit from parathyroidectomy, a calcium lowering therapy is not necessary. The gain of function mutations of the calcium-sensing receptor are associated with autosomal dominant hypocalcaemia (ADH), a disease characterised by a generally asymptomatic hypocalcaemia, inappropriately high urinary calcium excretion and normal PTH levels. A therapy to raise the serum calcium concentration has to be done carefully and is only indicated in symptomatic patients, because of enhancement of hypercalciuria with the risk of nephrocalcinosis and nephrolithiasis. Molecular genetic analysis of the calcium sensing receptor gene facilitates the sometimes difficult diagnosis. The development of compounds modulating the calcium sensing receptor function and thereby the section of PTH may become an important role in treatment of diseases of calcium metabolism.

Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype.

OBJECTIVE: In children with RET proto-oncogene mutation, curative treatment of medullary thyroid carcinoma (MTC) is possible by prophylactic thyroidectomy. Recommendations on the timing and extent of thyroidectomy are based upon a model that utilises genotype-phenotype correlations to stratify mutations into three risk groups. DESIGN: We evaluated the long-term outcome (mean follow-up 6.4 years, 15 patients more than 10 years, 26 patients more than 5 years) of operated gene carriers stratified into two risk groups (levels 1 and 2) based on the biological aggressiveness of MTC. RESULTS: In 46 RET gene carriers, prophylactic thyroidectomy was carried out between the ages of 4 and 21 years. Level 1 mutations were harboured by 11 patients (codons 790, 791, 804 and 891). Histology was completely normal in two patients; in seven patients C-cell hyperplasia (CCH) and in two patients T1 tumours were diagnosed. All patients with level 1 mutations were cured. Level 2 mutations were harboured by 35 patients (codons 618, 620, 630 and 634). Histology of these patients showed CCH in 11 patients, T1 tumours in 21, T2 tumour in 1, T3 tumour in 1 and Tx in 1 patient. Histology showed no lymph node involvement. Five patients with level 2 mutations failed to be cured; in two patients, persistence of MTC was diagnosed directly after thyroidectomy and in three during follow-up. In two patients carrying a 634 mutation, other endocrinopathies (hyperparathyroidism and bilateral pheochromocytoma) manifested during follow-up. CONCLUSIONS: If prophylactic thyroidectomy is done at early ages, cure rate is high. Timing and extent of prophylactic thyroidectomy can be modified by individual RET mutation.

Late diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia results from 21-hydroxylase deficiency in more than ninety percent of cases. The classical form of 21-hydroxylase deficiency presents in the neonatal period with virilization or adrenal insufficiency, with or without concurrent salt wasting. We report on a rare case of classic 21-hydroxylase deficiency diagnosed in late adulthood. A 39-year-old male patient presented for workup of infertility. Urologic investigation revealed small testes, bilateral testicular masses, and asthenozoospermia. The patient's steroid metabolism showed markedly increased levels of adrenal androgens, in particular of 17-hydroxyprogesterone amd 21-deoxycortisol. The gas chromatographic-mass spectrometric (GC-MS) urinary steroid profile was dominated by metabolites of 17-hydroxyprogesterone, while the endogenous glucocorticoid production was subnormally low. ACTH levels in plasma were elevated. These hormonal findings were consistent with 21-hydroxylase deficiency. Therapy with dexamethasone was initiated. The CTP21A2 gene analysis revealed the mutation I172N (ATC --> AAC) in exon 4 of allele 1 and a large gene deletion in allele 2. Cases of 21-hydroxylase deficiency diagnosed in late adulthood are rare; however, clinicians should be alert of this possibility.

Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter. To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.