Identification of Novel PROP1 and POU1F1 Mutations in Patients with Combined Pituitary Hormone Deficiency.

Growth hormone deficiency (GHD) results from variations affecting the production and release of growth hormone (GH) and is of 2 types: isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). IGHD results from mutations in GH1 and GHRHR while CPHD is associated with defects in transcription factor genes PROP1, POU1F1, and HESX1. The present study reports on screening of POU1F1, PROP1, and HESX1 in CPHD patients and the novel variations identified. Fifty-one CPHD patients from 49 unrelated families clinically diagnosed on the basis of biochemical and imaging investigations along with 100 controls were enrolled. Detailed family history was noted from all participants and 5 ml blood samples drawn were processed for DNA isolation followed by direct sequencing of POU1F1, PROP1, and HESX1genes. Of the 51 patients, 8 were females and 43 were males. Mean height standard deviation score (SDS) and weight SDS were -5.50 and -2.76, respectively. Thirty-six of the 51 patients underwent MRI of which 9 (25%) had normal pituitary structure and morphology while 27 (75%) showed abnormalities. Molecular analysis revealed 10 (20%) patients to have POU1F1 and PROP1 mutations/variations of which 5 were novel and 2 previously reported. No mutations were identified in HESX1. The novel variations identified were absent in the 100 healthy individuals screened and the control database Exome Aggregation Consortium (ExAC). Reported POU1F1 and PROP1 mutation hotspots were absent in our patients. Instead, novel POU1F1 changes were identified suggesting existence of a distinct mutation spectrum in our population.

Diabetes mellitus in pheochromocytoma and paraganglioma: Prevalence, dynamics of insulin secretion / sensitivity and predictors of remission.

BACKGROUND AND AIMS: Pheochromocytoma and paraganglioma (PPGL) are associated with dysglycemia and diabetes mellitus (DM) much of which improves post operatively. In this study, we set out to ascertain pre and post-operative prevalence of DM in patients with PPGL based on oral glucose tolerance test (OGTT) and HbA1c and to evaluate effect of insulin secretion and sensitivity indices on DM pre-operatively. METHODS: Clinical and anthropometric data collection, HbA1c, 75 g OGTT with serum insulin estimation were done pre-operatively (n = 34) and at follow-up after successful surgery (n = 24) in patients with PPGL. RESULTS: Pre and post-operative prevalence of DM were 48%(18/37) and 17% (4/24) respectively. Comparison of patients with highest (Q4) and lowest (Q1) quartiles of insulinogenic index (IGI),a parameter of insulin secretion, revealed trends towards higher prevalence of DM in patients with lower IGI (Q4 to Q1: 29% versus 71%,n = 28, p = 0.24)but no association was observed with HOMA-IR (Q4 to Q1:50% versus 57%, n = 28, p = 1.00), an insulin sensitivity index. DM remitted in 77% patients post-operatively, predicted by duration of DM of<3 years. CONCLUSION: There is high prevalence of DM in PPGL, with marked remission post-operatively, especially predicted by shorter duration of DM. Impaired insulin secretion is more strongly associated with pre-operative DM than increased insulin resistance.

Clinical and laboratory profile of primary hyperparathyroidism in India.

AIM: To assess 25-hydroxyvitamin D (25OHD) concentrations in patients with primary hyperparathyroidism and to study the relationship, if any, between vitamin D concentration and bone disease. METHODS: Consecutive patients with diagnosed primary hyperparathyroidism were enrolled in the study. Clinical and biochemical details, including serum calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH) and 25OHD levels, were recorded. An abbreviated skeletal survey and preoperative localisation with ultrasound/CT scan of the neck and tetrofosmin/technetium-99m hexakis(2-methoxyisobutylisonitrile) parathyroid scan was performed. RESULTS: 39 patients with primary hyperparathyroidism were identified (mean (SD) age 38.4 (15.0) years (range 12-72)). The most common presenting features were bone pain (80%), fatigue (80%) and proximal muscle weakness (78%). Brown tumours were present in 58% of cases, renal calculi in 42% and nephrocalcinosis in 12%. The mean (SD) corrected serum calcium concentration was 12.47 (1.58) mg/dl (3.2 (0.4) mmol/l). Serum 25OHD concentration was <5 ng/ml in 11 patients (28%), 5-10 ng/ml in nine (23%), 10-20 ng/ml in 14 (36%), and >20 ng/ml in five (13%). Serum alkaline phosphatase, PTH and gland weight were higher, whereas serum 25OHD was lower, in patients with skeletal disease. Patients with 25OHD concentrations

Serum Cortisol Level in Indian Patients with Severe Sepsis/Septic Shock.

BACKGROUND: The relationship between cortisol level and sepsis is not known in Indian patients of severe sepsis/septic shock. AIMS: The study was done to determine the optimal range of cortisol levels, defining the adrenocortical response, and predicting the mortality, if possible, in the above type of patients. SETTINGS AND DESIGNS: The study was a single-centered prospective cohort study, conducted in a tertiary referral center, North India. MATERIALS AND METHODS: Sixty patients with severe sepsis (n = 30) and septic shock (n = 30) were recruited. Basal and postcosyntropin (1 µg)-stimulated cortisol levels were measured, and all patients were closely monitored with daily assessments of clinical and laboratory variables. Western diagnostic criteria were followed for defining adrenal insufficiency (AI). The end point was the survival assessed at day 28 or death, whichever came earlier. RESULTS: The mean basal (T0) and poststimulation (T30) cortisol levels were 31.77 ± 15.9 µg/dL and 37.58 ± 17.31 µg/dL, respectively. In all sepsis patients, 48.33% qualified as AI at T0 ≤ 24 µg/dL, 61.67% at delta cortisol (Δ = T30-T0) ≤7 µg/dL, and 78.33% at Δ ≤9 µg/dL. Using receiver operating characteristic curve, the area under the curve (AUC) was 0.4954, signifying poor prediction to death. CONCLUSIONS: Indians have completely different characteristics of cortisol levels in sepsis patients, in comparison to the Western data. They have higher range of basal cortisol levels, higher percentage of AI, and an inability to predict mortality with the cortisol levels. Hence, there is requirement of an international study to confirm the dichotomy of the results.

Novel multiple endocrine neoplasia type 1 variations in patients with sporadic primary hyperparathyroidism.

BACKGROUND AND OBJECTIVES: Primary hyperparathyroidism (PHPT) can occur either as a sporadic case or in association with syndromes such as multiple endocrine neoplasia. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal-dominant disease resulting from mutations in MEN1 gene encoding a 621 amino acid long tumor suppressor protein "menin." We report here the results of MEN1 screening in 31 patients diagnosed with sporadic PHPT. MATERIALS AND METHODS: Diagnosis of sporadic PHPT was made when blood urea and serum creatinine were normal, serum parathyroid hormone was high, and parathyroid enlargement could be localized on ultrasound and/or parathyroid scan. A total of 31 patients and 50 healthy volunteers were recruited for molecular analysis after taking informed consent. RESULTS: Major symptoms at presentation were bone pain, fatigue, muscle weakness, and renal stones. Molecular genetic analysis revealed the presence of two novel intronic variations, c. 913-79T>A and c. 784-129T>A which by human splicing finder are predicted to cause potential alteration of splicing by either activating an intronic cryptic acceptor site or converting a conserved exonic splicing silencer sequence to an exonic splicing enhancer site. Apart from these, two reported polymorphisms rs144677807 and rs669976 were seen only in patients and none of the controls. Other reported polymorphisms rs2071313 and rs654440 were identified both in controls and patients. CONCLUSIONS: This is the first study of MEN1 gene screening in sporadic PHPT in India reporting on the clinical and genetic findings, wherein two novel intronic variations c. 913-79T>A and c. 784-129T>A were identified showing their possible role in disease causation.

Rare association of insulin autoimmune syndrome with ankylosing spondylitis.

UNLABELLED: Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycaemia, which is known to occur in association with the use of sulfhydryl-containing drugs and autoimmune disorders. We describe a patient with hitherto an unreported association of IAS with ankylosing spondylitis. We have also performed and described a simplified method of polyethylene glycol (PEG) precipitation of an insulin bound antibody in the serum. LEARNING POINTS: IAS should be considered in differential diagnosis of endogenous hyperinsulinemic hypoglycaemia.Ankylosing spondylitis can be associated with IAS apart from several other autoimmune diseases.Very high serum insulin levels (100-10 000 µU/ml) are frequently seen in IAS.When faced with very high serum insulin before suspecting insulinoma, it is advisable that PEG precipitation of serum be done to identify antibody bound insulin.A clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.

Cranial irradiation--an unusual cause for diabetes insipidus.

Central diabetes insipidus frequently occurs due to tumours in the region of pituitary or hypothalamus or following surgical trauma to these regions. Rarely it has been reported following cranial irradiation. We report the case of a middle aged woman who underwent surgical removal of a frontal capillary hemangioblastoma and received cranial irradiation. She presented ten months later with features of diabetes insipidus which was confirmed to be of central origin. She responded well to desmopressin nasal spray. Radiation induced damage to the hypothalmo-pituitary axis presents usually with anterior pituitary hormone deficiencies, most commonly that of growth hormone. Presentation as central diabetes insipidus is very uncommon.

Clinical and biochemical profiles of young diabetics in North-Eastern India.

OBJECTIVE: We compared the clinical and biochemical profiles of young diabetics in North Eastern India. METHODS: Seventy diabetics who were detected at less than 30 years of age were studied. Patients with ketoacidosis or ketonuria on insulin withdrawal were grouped as insulin dependent diabetes mellitus (IDDM), patients with history of chronic abdominal pain with or without exocrine pancreatic dysfunction who either on ultrasonography (USG) or endoscopic retrograde cholangiopancreaticoduodenography (ERCP) revealed pancreatic calcification and/or ductal dilatation were grouped as fibrocalculous pancreatic diabetes (FCPD), those having BMI < 19 kg/m2 with history or stigmata of childhood malnutrition and who were ketosis resistant were taken to be protein deficient diabetes mellitus (PDDM)/malnutrition modulated diabetes mellitus (MMDM) and those who neither had ketonuria nor history of chronic abdominal pain, malabsorption or stigmata of malnutrition were grouped as NIDDM of young (NIDDY). RESULTS: Amongst the young diabetics studied FCPD constituted 32.9%, IDDM 28.6%, MMDM 21.4% and NIDDY 17.11%. USG abnormalities were observed in 21 of the 23 patients of FCPD. Seven out of these showed pancreatic head calcification on X-ray while 14 showed pancreatic duct dilatation and calcification or calculi on USG. In the two remaining patients, ERCP revealed tortuousity of main pancreatic duct and calcification which were not detected on USG. Majority of FCPD and MMDM patients revealed insulin resistance on insulin tolerance test (ITT). HDL was significantly lower in NIDDY, while VLDL and triglycerides were significantly higher in FCPD and MMDM as compared to controls. Microvascular complications of diabetes were seen in all these groups, with peripheral neuropathy being more common in FCPD (43.5%) and background diabetic retinopathy in NIDDY (41%). CONCLUSIONS: We conclude that FCPD and MMDM together form majority (54.29%) of young diabetics at our center and a sizeable proportion of them may have microvascular complications, even at the time of diagnosis.

Completion report: Effect of Comprehensive Yogic Breathing program on type 2 diabetes: A randomized control trial.

BACKGROUND: Yoga has been shown to be beneficial in diabetes in many studies, though randomized control trials are few. The aim of this randomized control trial was to see the effect of Sudarshan Kriya and related practices (comprehensive yogic breathing program) on quality of life, glycemic control, and cardiac autonomic functions in diabetes. Diabetes mellitus is a risk factor for sudden cardiac death. Cardiac autonomic neuropathy has been implicated in the causation of sudden cardiac death. Therefore, a maneuver to prevent progression of cardiac autonomic neuropathy holds significance. MATERIALS AND METHODS: A total of 120 patients of diabetes on oral medication and diet and exercise advice were randomized into two groups: (1) Continued to receive standard treatment for diabetes. (2) Patients administered comprehensive yogic breathing program and monitored to regularly practice yoga in addition to standard treatment of diabetes. At 6 months, quality of life and postprandial plasma glucose significantly improved in the group practicing yoga compared to baseline, but there was no significant improvement in the fasting plasma glucose and glycated hemoglobin. RESULTS: On per protocol analysis, sympathetic cardiac autonomic functions significantly improved from baseline in the group practicing comprehensive yogic breathing. CONCLUSION: This randomized control trial points towards the beneficial effect of yogic breathing program in preventing progression of cardiac neuropathy. This has important implications as cardiac autonomic neuropathy has been considered as one of the factors for sudden cardiac deaths.

Postmenopausal hormonal therapy: Current status.

Many trials of the pros and cons of postmenopausal hormone replacement therapy have been done and this treatment has evolved over time. Here, we present a review and current status of this therapy.

An obese young man with uncontrolled diabetes and insatiable hunger: Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare cause of obesity. With the rising incidence of obesity, clinicians need to be aware of genetic causes of obesity and when to suspect them. A case of PWS, which was diagnosed in adulthood, has been discussed. This case is special because of lack of history of floppiness in infancy and predominance behavioral problems.

Bilateral thecoma presenting as premenopausal hirsutism: Laproscopic removal.

Hyperandrogenism is a common disorder among women in the reproductive age group. One of the rare causes for androgen excess is sex cord- stromal tumors of the ovary. These are usually unilateral. Here we report case of a 48 year old woman who presented with hyperandrogenism due to bilateral ovarian thecoma. Androgen levels normalized following resection of the tumor. This, to the best of our knowledge, is the first case of bilateral thecoma presenting as hirsutism in a premenopausal woman.

Profile of type 2 diabetes mellitus without overt complications of diabetes mellitus at a tertiary care center.

INTRODUCTION AND OBJECTIVES: Internal audit of an aspect of a disease at repeated intervals helps in predicting the new emerging trends. This study was planned to assess the profile of patients with diabetes mellitus (DM) without overt complications. MATERIALS AND METHODS: Patients with HbA1c between 6% and 9% on oral hypoglycemic agents and who did not have clinically overt complications of diabetes were recruited from outpatient clinic of Department of Endocrinology and Metabolism at All India Institute of Medical Sciences (AIIMS) from April 2009 to October 2011. RESULTS: A total of 91 patients (53 males and 38 females) were recruited over 3 years of period. Their mean age was 49.65 ± 11.22 years (range in years) and mean duration of diabetes was 48.09 ± 41.44 (range: 1-180) months. Biochemical evaluation revealed mean fasting blood sugar (FBS): 126.69 ± 25.80 mg/dl and mean HbA1c: 7.12 ± 0.81%. Family history of DM was present in 60.43% of patients, 6.59% were active smokers and 46.15% were obese (waist circumference ≥90 cm in males and ≥80 cm in females). All but 6.59% (n = 6) of patients were dyslipidemic and only 25 of these were on antidyslipidemic treatment. Isolated low HDL was most common abnormality (25.27%, n = 23), followed by combination of low HDL and raised LDL (17.58%, n = 16). Evaluation of complications showed retinopathy in just one patient, nephropathy in 17.68%, and neuropathy in 10.97%. MINI neuropsychiatric scale for depression was positive in four patients and four patients were on antidepressants. CONCLUSION: Type 2 diabetes mellitus (T2DM) patients have very high prevalence of dyslipidemia even in patients with good glycemic control. This study allowed us to realize lacunae in our clinical practice regarding need for better care of lipid parameters.

Effect of Cushing's syndrome - Endogenous hypercortisolemia on cardiovascular autonomic functions.

Cushing's syndrome is associated with increased cardiovascular morbidity and mortality. It's also associated with other cardiac risk factors like hypertension, diabetes mellitus and obesity. Cardiovascular autonomic function impairment could predict cardiovascular morbidity and mortality. Twenty five patients with Cushing's syndrome without diabetes and twenty five age matched healthy controls underwent a battery of cardiovascular autonomic function tests including deep breath test, Valsalva test, hand grip test, cold pressor test and response to standing from lying position. The rise in diastolic blood pressure on hand grip test and diastolic BP response to cold pressor test in Cushing's patients were significantly less compared to healthy controls (9.83 ± 3.90 vs 20.64 ± 9.55, p<0.001 and 10.09 ± 4.07 vs 15.33 ± 6.26, p<0.01 respectively). The E:I ratio on deep breathing test was also less in the patients in comparison to controls (1.36 ± 0.21 vs 1.53 ± 0.19, p<0.01). Seven patients underwent the same battery of tests 6 months after a curative surgery showing a trend towards normalization with significant improvement in expiratory to inspiratory ratio and sinus arrhythmia delta heart rate. To conclude, this study showed that chronic endogenous hypercortisolism in Cushing's is associated with an impaired sympathetic cardiovascular autonomic functioning. After a curative surgery, some of the parameters tend to improve.