What endocrinologists can do to prevent cardiovascular complications in adults with Prader-Willi syndrome: Lessons from a case series.

Context: Prader-Willi syndrome (PWS) is a complex rare genetic syndrome. Mortality in patients with PWS is 3% per year. In nearly half of the patients, the cause of death is of cardiopulmonary origin. Prevention, diagnosis and treatment of cardiovascular (CV) disease in PWS adults is complicated by the behavioral phenotype, reduced ability to express physical complaints, high pain threshold and obesity. Objective: To describe the challenges in prevention, diagnosis and treatment of CV disease in PWS adults, in order to increase awareness and improve medical care. Methods: Retrospective study of medical records of adults visiting the Dutch PWS reference center. Results: We describe the challenges encountered during diagnosis and treatment of four PWS adults with heart failure. All had pre-existent peripheral edema. CV risk factors in these patients were obesity (n=4), type 2 diabetes mellitus (n=2), hypertension (n=2), hypogonadism (n=3) and sleep apnea (n=2). Remarkably, all patients were younger than 40 years during their first cardiac decompensation. All patients presented with progressive shortness of breath and/or orthopnea and progressive pitting edema. In 117 controls with PWS without CV problems, 31% had leg edema. Conclusion: Diagnosing CV problems in PWS adults is challenging. Peripheral edema is common in PWS adults without CV morbidity, which makes edema in general a poor marker for heart failure. However, when edema is of the pitting kind and progressive, this is a strong predictor of cardiac decompensation. We provide practical recommendations for diagnosing and treating CV problems in this vulnerable patient population.

[Prevalence of gestational diabetes in high-risk pregnancies: screened using an oral glucose tolerance test]. / Prevalentie van diabetes gravidarum bij risicozwangeren: screening met behulp van orale glucosetolerantietest.

OBJECTIVE: To determine the prevalence of gestational diabetes mellitus in high-risk pregnancies during the second or third trimester diagnosed by screening with the 75-gram oral glucose tolerance test (75 g-OGTT) and, to determine the prevalence of the need for insulin therapy after an initial dietary intervention. DESIGN: Prospective cohort study. METHODS: Pregnant women at high-risk for gestational diabetes mellitus were challenged with the 75 g-OGTT in the second or third trimester, ideally between the 24th and the 28th week of pregnancy. The diagnosis of gestational diabetes mellitus was established when the fasting plasma glucose was ≥ 7.0 mmol/l or when the plasma glucose was ≥ 7.8 mmol/l two hours after the oral ingestion of 75 g glucose. The women with gestational diabetes were initially treated with a dietary regime. Insulin treatment was added if the hyperglycaemia persisted. RESULTS: A total of 471 pregnant women were included. Of these women, 75.8% underwent the 75 g-OGTT between the 24th and 28th week of pregnancy; 24.2% underwent the test between the 28th and 35th week. The diagnosis of gestational diabetes mellitus was established in 24.2% of the pregnant women. Dietary intervention was successful in normalising the blood glucose levels in 77.2% of the cases. The remaining 22.8% needed the additional insulin treatment. CONCLUSION: We ascertained that the prevalence of gestational diabetes mellitus in high-risk pregnancies was high. In most cases, the gestational diabetes mellitus could be managed by diet. A multidisciplinary approach involving obstetricians, gynaecologists, dieticians and internists is needed to ensure a timely diagnosis and adequate treatment during pregnancy.

Functional imaging in hyperinsulinemic hypoglycemia after gastric bypass surgery for morbid obesity.

CONTEXT: Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass (RYGB) has been increasingly reported. It is induced by ß-cell hyperplasia often referred to as nesidioblastosis. Positron emission tomography (PET) with [11C]-5-hydroxytryptophan ((11)C-HTP) and 6-[18F]fluoro-3,4-dihydroxy-l-phenylalanine ((18)F-DOPA) has been successfully applied to image neuroendocrine tumors. No data are available of the usefulness of these functional imaging techniques in post-RYGB in this new endocrine disorder, neither for diagnostic purposes nor for follow-up. OBJECTIVE: We present a patient with post-RYGB hypoglycemia who underwent (11)C-HTP and (18)F-DOPA PET scintigraphy for diagnostic purposes and to evaluate the effect of additional laparoscopic adjustable banding of the pouch as a surgical therapy for this disorder. PATIENT: We describe a woman with biochemically confirmed post-RYGB hypoglycemia who showed diffuse uptake of the (11)C-HTP and (18)F-DOPA tracers in the entire pancreas. After failure of dietary and medical treatment options, she underwent a laparoscopic adjustable banding for pouch dilatation. Subjective improvement was noted, which coincided with decreased uptake of (18)F-DOPA and (11)C-HTP in the head of the pancreas. CONCLUSIONS: Functional imaging by (18)F-DOPA- and (11)C-HTP-PET can accurately visualize diffuse endocrine pancreatic activity in post-gastric bypass hyperinsulinemic hypoglycemia. Both (11)C-HTP- and (18)F-DOPA-PET imaging appear to have a similar diagnostic performance in the presented case, and uptake of both tracers potentially relates to disease activity after surgical intervention.

Circulating vascular endothelial growth factor is unaffected by acute hyperglycemia and hyperinsulinemia in type 1 diabetes mellitus.

BACKGROUND: Circulating levels of vascular endothelial growth factor (VEGF) may predict microvascular complications in type 1 diabetes mellitus and are elevated when metabolic control is poor. We tested whether serum VEGF is influenced by prevailing glucose and insulin levels. METHODS: In 15 type 1 diabetic patients, serum VEGF, plasma von Willebrand factor antigen (vWF-Ag), and serum soluble intercellular adhesion molecule-1 (s-ICAM) levels were measured after 210 min of hyperglycemia (blood glucose target 12.0 mmol/l) and hyperinsulinemia (insulin infused at 120 mU/kg/h), alone and in combination. These were then compared with the levels obtained at the end of a 210-min normoglycemic (blood glucose target 5.0 mmol/l) standard insulin clamp (insulin infused at 30 mU/kg/h). RESULTS: VEGF (p>0.60) as well as vWF-AG (p>0.80) and s-ICAM (p>0.20) remained unchanged at the end of the three intervention periods. CONCLUSION: These findings suggest that no special precautions, in terms of concurrent measurement of glucose or timing of insulin administration, are necessary when interpreting circulating VEGF in this patient category.

Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.

BACKGROUND: Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II). METHODS: Using conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing to analyse genomic DNA from peripheral blood lymphocytes, here we describe the mutation analysis of the SDHB and SDHC genes in 37 patients with sporadic (i.e. no known family history) head and neck paraganglioma and five pheochromocytoma and/or paraganglioma families. RESULTS: Two sporadic patients were found to have a SDHB splice site mutation in intron 4, c.423+1G>A, which produces a mis-spliced transcript with a 54 nucleotide deletion, resulting in an 18 amino acid in-frame deletion. A third patient was found to carry the c.214C>T (p.Arg72Cys) missense mutation in exon 4 of SDHC, which is situated in a highly conserved protein motif that constitutes the quinone-binding site of the succinate: ubiquinone oxidoreductase (SQR) complex in E. coli. Together with our previous results, we found 27 germline mutations of SDH genes in 95 cases (28%) of sporadic head and neck paraganglioma. In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X. CONCLUSION: In conclusion, these data indicate that germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma and further underline the importance of germline SDHB mutations in cases of familial pheochromocytoma-paraganglioma.