Molecular characterization of a novel p.R118C mutation in the insulin receptor gene from patients with severe insulin resistance.

CONTEXT: Mutations of the insulin receptor gene (INSR) can cause genetic syndromes associated with severe insulin resistance. OBJECTIVES: We aimed to analyse INSR mutations in Saudi patients with severe insulin resistance. DESIGN: Ten patients with Type A insulin resistance syndrome from five unrelated Saudi families were investigated. The entire coding region of INSR was sequenced. The founder effect was assessed by microsatellite haplotype analysis. The functional effect of the mutation was investigated by in vitro functional assays. RESULTS: A novel biallelic c.433 C>T (p.R118C) mutation was detected in all patients. The c.433 C>T (p.R118C) sequence variation was not found in 100 population controls. The arginine residue at position 118 is located in the ligand-binding domain of INSR and is highly conserved across species. Microsatellite haplotype analysis of these patients indicated that p.R118C was a founder mutation created approximately 2900 years ago. The wild-type and mutant (R118C) INSR were cloned and expressed in CHO cells for functional analysis. Specific insulin binding to the mutant receptor was reduced by 83% as compared to wild-type (WT), although the mutant receptor was processed and expressed on the cell surface. Insulin-mediated receptor autophosphorylation was also significantly reduced in CHO(R118C) cells. CONCLUSIONS: Biallelic c.433 C>T (p.R118C) mutation of INSR causes significant damage to insulin binding and insulin-mediated signal transduction. p.R118C is a founder mutation frequently present in the Saudi patients with severe insulin resistance.

The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing's disease.

Despite the high resolution of magnetic resonance imaging (MRI) of the pituitary gland, up to 40% of cases of Cushing's disease (CD) have normal MRI. Fused images of positron emission tomography and computed tomography (PET-CT) may have a potential diagnostic role in CD in general and in such cases in particular. Objective of this study is to explore the diagnostic potential of PET-CT for localization of adrenocorticotropin-secreting pituitary adenomas in CD. PET-CT was performed in 12 cases with de novo (7 cases) or persistent CD (5 cases) that were proven to have CD on biochemical, radiological and/or histopathological findings. These cases had a definite CD confirmed on histopathological and immunostaining examination of the subsequent transphenoidal surgical specimens (10 cases) and/or bilateral inferior petrosal sinus sampling (IPSS, 4 cases). PET-CT was positive in 7 of the 12 cases of CD (58%) showing a focal area of uptake in the pituitary gland. In these seven cases, MRI was positive in six (85.7%) but negative in one case (14.3%). In the other five cases with negative PET-CT, MRI was positive in two and negative in three cases. Of four cases with negative MRI, PET-CT was positive in one case (25%). We conclude that PET-CT is positive in around 60% of the cases of CD. Although the majority of cases with positive PET-CT had positive MRI, PET-CT may detect some cases with negative MRI and thus provides important diagnostic information. If these findings are confirmed in larger studies, PET-CT might become an important diagnostic technique, especially when the more invasive and technically demanding procedure of IPSS is not available or inconclusive.

Serum thyroglobulin predicts thyroid remnant ablation failure with 30 mCi iodine-131 treatment in patients with papillary thyroid carcinoma.

BACKGROUND: Most patients with differentiated thyroid cancer are treated with radioiodine (131-I) after thyroidectomy. The characteristics predictive of successful remnant ablation with low activities of 131-I are ill defined and could help stratify patients into those who should receive higher activities. METHODS: In a case series of 193 consecutive patients with papillary thyroid cancer who underwent total thyroidectomy and received 30 mCi (1110 MBq) of 131-I, we assessed the percentage of successful radioremnant ablation as defined by a composite of scintigraphic and biochemical endpoints. Clinical, histological, scintigraphic, and biochemical covariables were analyzed to identify associations with treatment failure. RESULTS: Successful radioremnant ablation with low-activity 131-I was obtained in 78% of the entire cohort of patients. The presence of limited microscopic extrathyroidal extension, nodal micrometastases, or an elevated stimulated ablation was associated with failure to ablate the remnant. While accounting for other factors in a multivariable analysis, patients with an ablation thyroglobulin of at least 6 µg/l were at a more than five times greater risk (P<0.001) to fail 30 mCi 131-I remnant ablation. CONCLUSION: The majority of patients with papillary thyroid carcinoma experienced successful ablation. However, elevated-stimulated ablation thyroglobulin levels were strongly predictive of ablation failure, suggesting that this biochemical marker correlates with a more aggressive tumor profile and identifies those patients who might benefit from additional therapy.