A. Brew Atkinson

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.

Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance

Objective  There have been a few reports on long‐term remission rates after apparent early remission following pituitary surgery in the management of Cushings disease. An undetectable postoperative serum cortisol has been regarded as the result most likely to predict long‐term remission. Our objective was to assess the relapse rates in patients who underwent transsphenoidal surgery in order to determine whether undetectable cortisol following surgery was predictive of long‐term remission and whether it was possible to have long‐term remission when early morning cortisol was measurable but not grossly elevated. Endocrinological factors associated with late relapse were also studied.

Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis.

CONTEXT The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial. OBJECTIVE Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI. DATA SOURCES We searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators. STUDY SELECTION Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls. DATA EXTRACTION We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios. DATA SYNTHESIS Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P<0.001). CONCLUSIONS Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

Neuroendocrine tumors: A European view

A center in Belfast, Northern Ireland, has established a register for tumors of the gastroenteropancreatic endocrine system. Carcinoid tumors occur most frequently. Of the non-carcinoid tumors, insulinomas, gastrinomas, and unknown types have the highest incidence, with other types being extremely rare. The potentially remediable nature of the tumors is stressed, and frequently a good quality of life can be experienced even in the presence of metastatic disease. The syndromes are probably underdiagnosed as they present with clinical features for which there are more common explanations, and appropriate diagnostic methods are therefore not used. The management of the syndromes is reviewed with particular emphasis on the treatment of patients with inoperable disease. Histamine (H2)-receptor antagonist therapy has made an impact in Zollinger-Ellison syndrome, and streptozotocin and somatostatin analogues can control tumor growth and endocrine syndromes, respectively.

AIP Mutation in Pituitary Adenomas in the 18th Century and Today

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa. We extracted DNA from the patients teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

Assessment of cure after transsphenoidal surgery for Cushing's disease

The best long-term results of transsphenoidal surgery appear to be in those patients who have unmeasurable serum cortisol levels in the immediate post-operative period. This appears to be due to isolated ACTH deficiency in the remaining normal pituitary gland. In our experience, however, long-term clinical remission may be possible with measurable serum cortisol levels post-operatively. The cortisol response to ACTH or CRF appears to provide no greater discrimination than basal measurements and is possibly less helpful than dexamethasone suppression. The prolonged clinical remission that we have seen in some patients with early measurable but low cortisol levels, together with the possible operative morbidity and partial success of repeat surgery, suggests careful assessment before a recommendation is made of an immediate second operation in these patients. The possibility of cyclical secretion of cortisol must be considered both pre and post-operatively. Finally, as experience with transsphenoidal surgery is still relatively short, all these patients need continuing endocrine follow-up in centres with adequate experience of the condition. For the individual patient we recommend that decisions regarding further therapy are based on 0800-0900 h serum cortisol levels, an index of cortisol production (serum cortisol day profiles or 24 hour urinary free cortisol), and the response to low dose dexamethasone suppression in the early post-operative period.

BILATERAL INFERIOR PETROSAL SINUS SAMPLING AS A ROUTINE PROCEDURE IN ACTH‐DEPENDENT CUSHING'S SYNDROME

Bilateral inferior petrosal sinus sampling was successfully performed in 12 of 13 consecutive patients with ACTH‐dependent Cushings syndrome. Ten of the patients subsequently had transsphenoidal pituitary microsurgery. Eight patients in whom the inferior petrosal sinus to peripheral vein ACTH level ratio was 1.5 or greater were found to have a pituitary adenoma. One of the remaining two patients who had ratios < 1.5 had pituitary hyperplasia while the other had no identified abnormality. In five of the patients with pituitary tumour a ratio above 1.5 was present on only one side. Bilateral petrosal sampling is therefore always necessary. Tumour localization within the pituitary was only poorly predicted by either petrosal sinus sampling (four of eight) or computed tomography scanning (three of eight). If petrosal sinus sampling is used early in the differential diagnosis of ACTH‐dependent hypercortisolism, then the use of other differential diagnostic tests may not always be necessary.

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).

The PPAR‐gamma activator rosiglitazone fails to lower plasma ACTH levels in patients with Nelson's syndrome

Backround  Peroxisomal proliferator‐activated receptors (PPAR)‐ γ are expressed abundantly in ACTH‐secreting pituitary tumours. The PPAR‐gamma activator rosiglitazone has been shown to suppress ACTH secretion in human adrenocorticotroph tumour cells in vitro, and prevent and reduce adrenocorticotroph tumour development in mouse models in vivo.

A case of hepatoma associated with hypoglycaemia and overproduction of IGF-II (E-21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma Insulin‐like growth factor II (IGF‐11) was not elevated although 71% of plasma IGF‐II was present as big IGF‐II (molecular weight 11 kDa) which probably represents a non‐glycated form of pro‐IGF‐II. The GH response to hypoglycaemia was Impaired and plasma levels of both IGF‐l and the GH‐dependent IGF binding protein (IGFBP‐3) were low.