PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.

Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing's disease following pituitary surgery.

OBJECTIVE: The performance of late-night salivary cortisol (LNSC) to accurately screen for postoperative recurrence of Cushing's disease (CD) at an early stage is unknown. The aim of this study was to compare the accuracy of multiple sampling strategies to suggest the optimal number of LNSC samples needed for diagnosing post-surgical recurrences of CD at an early stage. DESIGN: Retrospective analysis in a single centre. PATIENTS AND MEASUREMENTS: Thirty-six patients in surgical remission of CD had successive measurements of LNSC, defined as 'sequences', using a locally modified RIA assay as part of long-term follow-up (69·2 ± 10·6 months). Patients underwent an extensive biochemical evaluation within 3 months before or after a sequence of saliva sampling and were classified as being in remission or in early-stage recurrence. The accuracy of three diagnostic strategies combining two, three or four LNSC results from a sequence was estimated using areas under the ROC curves (AUC), sensitivity, specificity and predictive values. RESULTS: Forty-four sequences of LNSC measurements were available. Fifty-two percent of sequences were performed during early-stage recurrence. The intrasequence variability of LNSC was higher during recurrence than during remission (medians of SDs: 2·1 vs 0·5 nm; P < 0·0001). AUCs from ROC curves ranged from 0·93 to 0·96 depending on the strategy. For 90% sensitivities, the best specificities (92·9% and 90·9%) were achieved by strategies taking into account three or four measurements summarized either by their mean or their maximum value. CONCLUSIONS: Increase in LNSC concentration is an early abnormality during post-surgical recurrence of CD. However, due to a major within-patient variability of LNSC from 1 day to another, a screening strategy using three or four samples collected on successive days may be recommended to detect early-stage recurrence of CD with a high accuracy.

Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients.

CONTEXT: Neither precise evaluation of pertinent thresholds nor comparison of the diagnostic performance of late-night salivary cortisol (NSC) between inpatient and outpatient settings has been conducted. The usefulness of NSC for the screening of "subclinical" Cushing's syndrome is still unknown. OBJECTIVES: The aim of the study was to compare the influence of inpatient and outpatient settings on the diagnostic performance of NSC and assess its usefulness as a screening test for subclinical Cushing's syndrome. DESIGN: Consecutive patients were investigated prospectively with two salivary collections, first as inpatients and then as outpatients. PARTICIPANTS: Forty-two obese subjects participated in the study, as well as nine patients cured of Cushing's disease, 13 with overt Cushing's syndrome, 14 showing mild recurrence of Cushing's disease, and 48 with adrenal incidentalomas [23 subclinical cortisol-secreting adenomas (SCSA), 25 nonsecreting adenomas]. MAIN OUTCOME MEASURES: Reproducibility of NSC and diagnostic performance were measured using receiver operating characteristic analysis. RESULTS: NSC in controls was similar between inpatient and outpatient settings. The diagnostic performance of NSC across the different patient groups was similar irrespective of the setting. A threshold of 12 nmol/liter yielded 100% sensitivity and specificity in overt Cushing's syndrome. Optimal performance in subclinical Cushing's syndrome required lower thresholds. NSC showed acceptable performance in diagnosing recurrence of Cushing's disease (90% sensitivity, 91.8% specificity). On the contrary, NSC was similar between patients with SCSA and nonsecreting adenomas. CONCLUSIONS: Our data validate the outpatient bed sampling strategy for NSC with no need for specific outpatient threshold. NSC may be helpful to detect mild recurrence of Cushing's disease after surgery but is of little value in identifying SCSA amongst adrenal incidentalomas.