Can Digenic, Tri-Allelic Inheritance of Variants in STAR and CYP11A1 Give Rise to Primary Adrenal Insufficiency? A Case Report.

An eight-year old South Asian boy presenting with progressive hyperpigmentation was found to have primary adrenal insufficiency (PAI) in the form of isolated glucocorticoid deficiency. Follow up of this boy for nine years, until the age of 17 years showed normal pubertal onset and progression. Molecular evaluation, by targeted next generation sequencing of candidate genes linked to PAI revealed changes in two genes that are intricately linked in the early stages of steroid biosynthesis: compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous rs6161 change in CYP11A1. No variants in other known causal genes were detected. The proband's mother was heterozygous for the c.465+1G>A STAR and rs6161 CYP11A1 variants, while the father was homozygous for the p.(E99K) alteration in STAR but wild-type for CYP11A1. Both parents had normal adrenal cortical function as revealed by short Synacthen tests. The STAR variant c.465+1G>A will lead to abnormal splicing of exon 4 in mRNA and the addition of the p.(E99K) variant, predicted damaging by SIFT and CADD, may be sufficient to cause PAI but this is by no means certain given that the unaffected father is homozygous for the latter change. The rs6161 CYP11A1 variant [c.940G>A, p.(E314K)] has recently been demonstrated to cause PAI in conjunction with a severe rare disruptive change on the other allele, however sequencing of the coding region of CYP11A1 revealed no further changes in this subject. We wondered whether the phenotype of isolated glucocorticoid deficiency had arisen in this child due to tri-allelic inheritance of a heterozygous CYP11A1 change along with the two STAR variants each of which contribute a partial loss-of-function burden that, when combined, is sufficient to cause PAI or if the loss-of-function c.465+1G>A combined with the presumed partial loss-of-function p.(E99K) in STAR could be causative.

Decreased autonomic modulation of heart rate and altered cardiac sympathovagal balance in patients with Cushing's syndrome: role of endogenous hypercortisolism.

BACKGROUND/AIMS: Endogenous Cushing's syndrome is associated with a higher risk of cardiovascular morbidity and mortality. Previous literature suggested multiple possible links by which hypercortisolism may alter the autonomic control of cardiovascular functions. We investigated the impact of chronic endogenous hypercortisolism on the autonomic regulation of cardiac functions by short-term heart rate variability analysis. METHODS: Eighteen patients with endogenous Cushing's syndrome and 20 age-, gender- and BMI-matched controls participated in the study. ECG signal was acquired in lead II configuration for 5 min and heart rate variability assessment was made in both time and frequency domain using the extracted RR interval data. RESULTS: All time and frequency domain measures of heart rate variability were significantly (p < 0.05) lower in the patient group compared to the control group. The patient group had an altered sympathovagal balance with low frequency/high frequency band ratio significantly higher than the control group [1.857 (0.6747-2.610) vs. 0.8581 (0.4779-1.352); p = 0.0253]. A significant negative correlation was obtained between normalized high frequency power of heart rate variability and basal cortisol levels (r = -0.6594; p = 0.0029). Multiple linear regression analysis identified age, disease duration (in months), basal cortisol levels and systolic blood pressure as independent predictors of normalized high frequency power. CONCLUSION: Findings of the study clearly portrayed the diminished autonomic modulation of heart rate in endogenous Cushing's syndrome and its possible relationship with hypercortisolism as the main causative factor. Diminished heart rate variability may be an indicator of the increased risk of cardiac mortality in these patients.

Prevalence of depression among type 2 diabetes compared to healthy non diabetic controls.

AIMS: Successful diabetes management depends on patient behaviour. Diabetes is a significant risk factor for depression which itself is a risk factor for poor metabolic control. Data on this association is scarce from India--which is fast becoming the diabetes capital of the world. This study was done to see the prevalence of depression in adult patients with type 2 diabetes diagnosed within the previous 5 years and treated with oral hypoglycaemic agents compared to healthy persons without diabetes. Also, to evaluate Becks depression inventory (BDI) in terms of Mini International Neuropsychiatric Interview (MINI) as a tool to assess depression in diabetes. METHODS: Patients with diabetes within 5 year of diagnosis and on oral anti-diabetic drugs were included. Controls were healthy relatives of these patients without diabetes. These patients underwent clinical examination, biochemical tests, assessment of depression by BDI and MINI BDI and MINI were used to assess depression in controls as well. Prevalence of depression was found in both groups and compared. BDI was evaluated considering the MINI as gold standard in detecting depression in diabetes. RESULTS: The prevalence of co-morbid depression was 27.05% according to the MINI. In the non-diabetic healthy patient relatives, this was 11.11%. Those having depression had a lower educational attainment and a higher prevalence of retinopathy, compared to subjects without depression. The relative risk for the diabetics to have co-morbid depression was 2.97 (95% confidence interval 1.41-6.24). The BDI score with best sensitivity and specificity for diagnosing depression in diabetes was > or = 21. For healthy controls, a score of > or = 14 had best sensitivity and specificity. Diabetic patients had a higher score of BDI even without a diagnosis of depression on the MINI. CONCLUSION: Prevalence of depression was 27.05% diabetic patients and 11.11% healthy controls. A BDI score of 21 had the best sensitivity and specificity for diagnosing depression in adult type 2 diabetic patients. BDI can be used as a simple screening tool for the detection of depression in diabetic patients.