Steve Ball

Tumor Risks and Genotype-Phenotype-Proteotype Analysis in 358 Patients With Germline Mutations in SDHB and SDHD

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype–phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH‐associated HNPGL and pheochromocytoma. Hum Mutat 31:41–51, 2010.

Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.

Hyponatremia Following Mild/Moderate Subarachnoid Hemorrhage Is Due To SIAD and Glucocorticoid Deficiency and not Cerebral Salt Wasting

CONTEXT Hyponatremia is common after acute subarachnoid hemorrhage (SAH) but the etiology is unclear and there is a paucity of prospective data in the field. The cause of hyponatremia is variously attributed to the syndrome of inappropriate antidiuresis (SIAD), acute glucocorticoid insufficiency, and the cerebral salt wasting syndrome (CSWS). OBJECTIVE The objective was to prospectively determine the etiology of hyponatremia after SAH using sequential clinical examination and biochemical measurement of plasma cortisol, arginine vasopressin (AVP), and brain natriuretic peptide (BNP). DESIGN This was a prospective cohort study. SETTING The setting was the National Neurosurgery Centre in a tertiary referral centre in Dublin, Ireland. PATIENTS One hundred patients with acute nontraumatic aneurysmal SAH were recruited on presentation. INTERVENTIONS Clinical examination and basic biochemical evaluation were performed daily. Plasma cortisol at 0900 hours, AVP, and BNP concentrations were measured on days 1, 2, 3, 4, 6, 8, 10, and 12 following SAH. Those with 0900 hours plasma cortisol<300 nmol/L were empirically treated with iv hydrocortisone. MAIN OUTCOME MEASURES Plasma sodium concentration was recorded daily along with a variety of clinical and biochemical criteria. The cause of hyponatremia was determined clinically. Later measurement of plasma AVP and BNP concentrations enabled a firm biochemical diagnosis of the cause of hyponatremia to be made. RESULTS Forty-nine of 100 developed hyponatremia<135 mmol/L, including 14/100<130 mmol/L. The cause of hyponatremia, and determined by both clinical examination and biochemical hormone measurement, was SIAD in 36/49 (71.4%), acute glucocorticoid insufficiency in 4/49 (8.2%), incorrect iv fluids in 5/49 (10.2%), and hypovolemia in 5/49 (10.2%). There were no cases of CSWS. CONCLUSIONS The most common cause of hyponatremia after acute nontraumatic aneurysmal SAH is SIAD. Acute glucocorticoid insufficiency accounts for a small but significant number of cases. We found no cases of CSWS.

Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non‐syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma

Research studies have reported that about a third of individuals with phaeochromocytoma/paraganglioma (PPGL) have an inherited predisposition, although the frequency of specific mutations can vary between populations. We evaluated VHL, SDHB and SDHD mutation testing in cohorts of patients with non‐syndromic PPGL and head and neck paraganglioma (HNPGL).

Medical Therapy of Macroprolactinomas in Males: I. Prevalence of Hypopituitarism at Diagnosis. II. Proportion of Cases Exhibiting Recovery of Pituitary Function

Hyperprolactinaemia frequently causes secondary hypogonadism through central suppression of gonadotropin secretion. Macroprolactinomas (>1 cm diameter) are more common in males and may additionally cause more generalised hypopituitarism. Recovery of the thyrotropic and/or corticotropic axes is well described following selective adenomectomy, but remains poorly defined in relation to medical (dopamine-agonist) therapy of macroprolactinomas. We therefore performed a retrospective examination of case records of male patients who had received medical therapy alone for macroprolactinoma between 1980–2001 (n = 35) and in whom tumor shrinkage was documented by interval pituitary imaging (reported throughout by a single neuroradiologist).Mean prolactin level at baseline was 59,932 mU/L (median 31,400; range 3,215–332,000); mean period of follow up was 4.2 years (median 2.6; range: 1.0–15). Defects of the following axes were evident at diagnosis: LH/FSH-testosterone (n = 27; 77%), TSH-T4 (n = 14; 41%-not including one case with pre-existing 1° hypothyroidism), ACTH-cortisol (n = 8; 23%). Overall, 14 men (40%) were deficient in 1 axis, seven (20%) in 2 axes and seven (20%) in 3 axes. Growth hormone secretory status was not systematically evaluated. In all but 6 patients, prolactin levels fell to normal or near-normal levels (mean 764 mU/L; median 260; range: <10–4,833). Of the patients in whom adequate reassessment had been performed, thyrotroph function recovered in 4/9, corticotroph function in 4/6 and gonadotroph function in 16/26 cases. In four cases (11%) previously described, development of visual impairment as a result of the chiasmal traction syndrome necessitated a dose reduction in medical therapy to allow a degree of controlled tumor re-expansion.The prevalence at diagnosis of TSH and ACTH deficiency in men with macroprolactinomas was 41% and 23%, respectively. Among eight patients with insufficiency of TSH and/or ACTH secretion who underwent complete interval reassessment over several years of treatment, recovery of at least one axis occurred in six cases (75%). This study highlights the importance of screening ACTH- and/or TSH-deficient men during dopamine agonist therapy in order to identify cases where hypopituitarism has resolved.

Guía de práctica clínica sobre el diagnóstico y tratamiento de la hiponatremia

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic. The prevalence of hyponatremia in a wide variety of conditions and the fact that hyponatremia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and specialty-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed clinical practice guidelines on the diagnostic approach and treatment of hyponatremia as a joint venture of 3societies representing specialists with a natural interest in hyponatremia. In addition to a rigorous approach to the methodology and evaluation of the evidence, the document focuses on patient-positive outcomes and on providing a useful tool for clinicians involved in everyday practice. In this article, we present an abridged version of the recommendations and suggestions for the diagnosis and treatment of hyponatremia extracted from the full guide.

MEN2 screening dilemmas in a family with a novel RET mutation in the MEN2 susceptibility region of the gene, a family history of Hirschsprung disease, and no family history of MEN2-related tumours.

RET mutations are causative of the tumour predisposition syndrome – multiple endocrine neoplasia type 2 (MEN2), with its subtypes MEN2A (lifetime risk – medullary thyroid carcinoma 95%, phaechromocytoma 50%, parathyroid adenoma/hyperplasia 20%–30%), MEN2B (lifetime risk – medullary thyroid carcinoma 100%, phaeochromocytomas 50%, plus associated phenotype including facial neuromas, bowel ganglioneuromas and marfanoid habitus) and familial medullary thyroid cancer (FMTC), which is characterized by a family history of medullary thyroid carcinoma alone. 1

Anti-neutrophil cytoplasmic antibody (ANCA) associated small-vessel vasculitis in a patient with diabetic nephropathy and autoimmune polyendocrinopathy syndrome (APS) Type 2: a case report.

We present a 42-year-old woman with pre-existing autoimmune polyendocrinopathy syndrome (APS) Type 2 and chronic kidney disease due to Type 1 diabetic nephropathy, who developed a rapid deterioration in renal function due to perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-associated vasculitis. Although possibly a chance occurrence, ANCA have been detected more frequently in patients with a history of certain autoimmune diseases. Such an association may simply reflect an underlying tendency to immune system dysfunction in these patients and the finding of positive ANCA serology does not reliably herald the development of ANCA-associated vasculitis. However, our case illustrates that positive ANCA serology in such circumstances is not always a benign phenomenon and should still be interpreted within the clinical context. Moreover, clinicians managing patients with pre-existing autoimmune disease should maintain a low threshold for appropriate assessment should such patients develop evidence suggestive of vasculitis.

Contents Vol. 3, 2014

Maria Alevizaki, Athens Ana Aranda, Madrid Rebecca Bahn, Rochester, Minn. Paul Banga, London Luigi Bartalena, Varese Bernadette Biondi, Naples Anita Boelen, Amsterdam Georg Brabant, Lübeck Henning Dralle, Halle Creswell J. Eastman, Westmead, N.S.W. Murat Erdogan, Ankara Valentin Fadeyev, Moscow Ulla Feldt-Rasmussen, Copenhagen Laszlo Hegedus, Odense George J. Kahaly, Mainz Rui Maciel, São Paolo Ana Luiza Maia, Porto Alegre Jens Mittag, Stockholm Ralf Paschke, Leipzig Simon Pearce, Newcastle-upon-Tyne Robin Peeters, Rotterdam Kris Poppe, Bruxelles Samuel Refetoff , Chicago, Ill. Jacques Samarut, Lyon Pilar Santisteban, Madrid YoungKee Shong, Seoul Jan Smit, Leiden Weiping Teng, Shenyang Mark Vanderpump, London Th eo Visser, Rotterdam Paolo Vitti, Pisa Graham Williams, London Shunichi Yamashita, Nagasaki Mariastella Zannini, Naples Luca Persani, Milan (Translational Th yroidology)

Quality assessment of clinical practice guidelines: who watches the watchmen?

Guidance was once such a simple thing: provided by a valued few to those who sought to learn. Knowledge, experience and wisdom were rare commodities, the topics to be discussed limited. The world has turned. Information is now abundant, healthcare data are widespread. Gradually, it has become impossible to read, appraise and interpret all published material, even within subspecialty fields. In an attempt to deal with this issue, guidelines have increasingly found their way into clinical practice and regulatory decision-making. As defined by the Institute of Medicine, clinical guidelines are ‘systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances’. In other words, guidelines should safeguard users and patients from wrong decisions. Although research supports their ability to do just that, in reality, there have been many that were contradictory, of poor quality, impractical or simply not evidence based. It has caused clinicians to be wary of them. Indeed, they have brought forth a new dilemma: if the guideline declares who is right and who is wrong, how then do we assure that the guideline itself is right? In this month’s Journal, Hazlehurst et al. provide a comparative assessment of guidelines produced by five major professional societies in endocrinology. The authors assessed a basic aspect of guideline quality: the methodology by which individual guideline groups rated the level of evidence underpinning their recommendations. They found that of the 58 guidelines published between 1995 and now, only 29 explicitly mentioned that a grading system was used at all. Overall, only 6 5% of recommendations were based on ‘high level’ evidence. In addition, different organizations used different systems, with different criteria for ratings of quality of evidence, leading to potential confusion and misunderstanding in the clinicians using them. Clearly, a valid, standardized system that is applied consistently would be the ideal. So what is the problem? Simply, we need to distinguish between the grading of the evidence supporting a recommendation and the grading of the recommendation itself. Not all grading systems separate decisions regarding the quality of the evidence from the strength of the recommendations. Those failing to do so create confusion. In this respect, Hazlehurst et al. highlight the utility of the grading of recommendations, assessment, development and evaluation (GRADE) system, which is increasingly accepted as the preferred framework by organizations worldwide. The idea behind GRADE is that although recommendations may arise from large, rigorous randomized controlled trials that show consistent and impressive benefits, this need not be the case. If data on appreciable harms of a treatment come from suboptimal observational studies, the availability of a harmless alternative may be enough to prompt a strong recommendation against it. The evidence for benefit of a treatment may be statistically overwhelming, and yet clinically so small and at such cost, that panels would be reluctant to attach a strong statement in favour or against. This has important consequences as it places emphasis on ‘choice’. Presented with the facts, clinicians must still weigh the desirable and undesirable effects of alternative management strategies carefully. They must do so according to their own values and preferences and particularly according to those of their patients. So, when the evidence is of high quality and the advantages of an intervention clearly outweigh the disadvantages, this will lead to a strong recommendation based on high-quality evidence (1A). But even if the evidence is of high quality, if different clinicians or patients might choose different strategies based on their balancing of the pros and cons, this would lead to a weak recommendation (2A). A simple, transparent grading of the recommendation can indeed effectively convey this key information. Perhaps unsurprisingly, Hazlehurst et al. found that guidance in endocrinology often did not rely on ‘high’ quality evidence and that little has changed over the past 15 years. Alas, we face a catch-22 here: if for a certain topic there is a good systematic review containing several large, well performed randomized controlled trials (and hence, the level of evidence is high), it is unlikely that clinicians will need explicit guidance as they can mostly interpret the evidence by themselves. In addition, both the generation, collection and/or interpretation of evidence may be influenced by other drivers: funding bodies – often industry. Indeed, industry only invests in stud*See related paper on pages 183–190 of this issue.