Congenital Adrenal Hyperplasia - A Comprehensive Review of Genetic Studies on 21-Hydroxylase Deficiency from India.

Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by mutations in the CYP21A2 gene resulting in 21-hydroxylase (21-OH) deficiency (21-OHD). The genetics of 21-OH CAH is complexed by a highly homologous pseudogene CYP21A1P imposing several limitations in the molecular analysis. Therefore, genetic testing is still not a part of routine CAH diagnosis and is mainly dependent on 17-hydroxy progesterone (OHP) measurements. There are very few reports of CYP21A2 gene analysis from India and there is no comprehensive review available on genetic testing and the spectrum of CYP21A2 mutations from the country. This review focuses on the molecular aspects of 21-OHD and the genetic studies on CYP21A2 gene reported from India. The results of these studies insist the compelling need for large-scale CYP21A2 genetic testing and newborn screening (NBS) in India. With a high disease prevalence and consanguinity rates, robust and cost-effective genetic testing for 21-OH CAH would enable an accurate diagnosis in routine clinical practice. Whereas establishing affordable genotyping assays even in secondary care or resource-poor settings of the country can identify 90% of the mutations that are pseudogene derived, initiatives on reference laboratories for CAH across the nation with comprehensive genetic testing facilities will be beneficial in those requiring extended analysis of CYP21A2 gene. Further to this, incorporating genetic testing in NBS and carrier screening programmes will enable early diagnosis, better risk assessment and community-based management.

Role of Genetic Testing in the Management of Indeterminate Thyroid Nodules in the Indian Setting.

The increased detection of thyroid nodules in the human population has led to an increase in the number of thyroid surgeries without an improvement in survival outcomes. Though the choice for surgery is straightforward in malignant thyroid nodules, the decision is far more complex in those nodules that get categorized into indeterminate thyroid nodules (ITN) by fine needle aspiration. Therefore, there is a pressing need to develop a tool that will aid in decision-making among the ITN. In this context, the development of various molecular testing (MT) panels has helped to confirm or rule out malignancy, reducing unnecessary surgeries and potentially guiding the extent of surgery as well. Currently, such tests are widely used among the Western population but these MT panels are not used by the South Asian population because of non-availability of validated panels and the high cost involved. There is a need to develop a suitable panel which is population-specific and validate the same. In this review, we would focus on current trends in the management of ITN among the South Asian population and how to develop a novel MT panel which is cost-effective, with high diagnostic accuracy obviating the need for expensive panels that already exist.

Do Bone Mineral Density, Trabecular Bone Score, and Hip Structural Analysis Differ in Indian Men with Parkinson's Disease? A Case-Control Pilot Study from a Tertiary Center in Southern India.

Objective: Parkinson's disease (PD) is a neurodegenerative condition that is characterized by bradykinesia, rigidity, and gait instability. Inherent to this condition is an increased predisposition to falls and fractures. Bone health in Parkinson's disease in India has not been studied thus far. This study aimed to assess the bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA) in Indian men with PD and compare them with matched controls. Methodology: A case-control study done at a tertiary care center from southern India. Bone biochemistry, BMD, TBS, and HSA were assessed. Results: Among 40 cases and 40 age, gender, and body mass index (BMI)-matched controls, there was no significant difference in BMD between both groups. The mean (SD) TBS at the lumbar spine [1.349 (0.090)] was significantly (P = 0.019) lower in men with PD as compared to matched controls [1.401 (0.089)]. Among the parameters of HSA, the buckling ratios were significantly higher at the femoral neck [11.8 (2.2) vs 9.4 (2.2); P = 0.001] and inter-trochanteric region [9.4 (2.1) vs 7.8 (1.4); P = 0.002] among cases as compared to matched controls. Vitamin D deficiency was significantly higher in this cohort of patients as was bone turnover marker indicating bone loss and a high bone turnover state. Conclusion: A comprehensive bone health assessment comprising BMD, TBS, and HSA may be required to capture all aspects of bone strength in Indian men with PD as BMD assessment as a stand-alone tool may not suffice to obtain all information pertaining to fracture risk in these individuals.

The prevalence of vertebral fractures among Indian perimenopausal women and its association with ovarian biomarkers.

INTRODUCTION: There is dearth of data on prevalent vertebral fractures in perimenopausal women in India and limited literature on the utility of FSH, AMH and estradiol in evaluating bone health them. The objective was to study the prevalence of vertebral fractures (VF) and to assess the utility of FSH, estradiol and AMH in predicting them in Indian perimenopausal women MATERIALS AND METHODS: It was a cross-sectional study. Perimenopausal women aged 40-49 years underwent assessment for prevalent vertebral fractures, bone mineral density (BMD) and trabecular bone score (TBS). Utility of serum FSH, estradiol and AMH in predicting prevalent vertebral fractures was also assessed. RESULTS: A total of 300 perimenopausal women with mean (SD) age of 43.2 (2.8) years was recruited and 18% had moderate-severe VF. Mean (SD) serum AMH was lower in perimenopausal women with VF as compared to those without fractures [0.752 (0.594) vs 1.023 (0.704) P = 0.006]. AMH showed significant positive correlation with TBS (r = 0.3; P < 0.001) and BMD at the femoral neck (r = 0.2; P < 0.001) and lumbar spine (r = 0.3; P < 0.001).On ROC analysis, AMH demonstrated good performance in predicting prevalent VF with an AUC of 0.800 (95% CI 0.705-0.880) and a sensitivity of 85% and specificity of 60% at a cut-off of 1.12 ng/mL. On an exploratory multivariate logistic regression analysis, AMH significantly predicted prevalent fractures with an adjusted OR (OR) of 1.85 (95% CI: 1.03-3.00; P = 0.04). The performance of FSH and estradiol in predicting prevalent fractures was sub-optimal. CONCLUSION: About one-fifth of the study subjects had prevalent vertebral fractures. AMH may be a menstrual cycle independent biomarker and may reflect bone loss in perimenopausal women. Further prospective studies are needed to validate these findings.

Bone Mineral Density and Body Composition in Males with Motor Neuron Disease: A Study from Teaching Hospital in Southern Part of India.

BACKGROUND: Osteoporosis and sarcopenia are important aspects of motor neuron disease (MND). Individuals with amyotrophic lateral sclerosis (MND-ALS) have an increased risk of falls and fractures. Currently, the standard of care does not involve a routine assessment of bone mineral density (BMD) and body composition in these patients. We aimed to assess BMD, bone mineral parameters and body composition in men with MND and compared them with healthy controls. METHODS: Consecutive males between 50 and 80 years of age diagnosed as MND-ALS by revised El Escorial criteria and able to walk unassisted attending Neurology outpatient clinic were recruited into the study. Age, gender and body mass index (BMI) matched healthy controls were recruited from the local community. BMD and body composition were assessed by dual-energy x-ray absorptiometry (DXA). Bone mineral parameters and bone turnover markers (BTMs) were also assessed in them. RESULTS: A total of 30 subjects with MND-ALS and 33 controls were recruited. The mean age (years) was 59.2 in cases and 61.2 in controls. The mean BMD (g/cm2) between the two groups was similar; however, BTMs were significantly higher in the MND group (P < 0.05). Subjects with MND-ALS had significantly lower mean appendicular lean mass (ALM) (19.9 versus 22.4 kg; P = 0.007) and ALM corrected for BMI than the healthy control group (0.858 versus 0.934 kg/kg/m2; P = 0.034). Sarcopenic obesity (Percentage fat mass >27% + ALM/BMI <0.786 kg/kg/m2) was more prevalent in MND-ALS compared to controls (44.5% versus 16.7%; P = 0.03). CONCLUSION: Although BMD was not significantly different between subjects with MND-ALS and healthy controls, BTMs were significantly higher in the MND group indicating a high bone turnover state. Sarcopenia and sarcopenic obesity were also more in MND-ALS group than controls. Routine assessment for bone health parameters and body composition indices may be included in management of the patients with MND.

The utility of Problem Areas in Diabetes (PAID) scale amongst patients with Type 2 diabetes (T2DM): An experience from a teaching hospital in Southern India.

OBJECTIVES: The purpose of this study was to establish the prevalence of diabetes-specific psychological distress (DSPD) among patients with type 2 diabetes mellitus (T2DM) using the "Problem areas in diabetes" (PAID) scale at a teaching hospital in southern India. Other objectives included observing the relationship between socio-demographic factors and DSPD and, finally exploring the level of acceptance of the PAID scale by Asian-Indian patients. METHODS: The patients with T2DM aged >18 years attending the diabetes outpatient clinic were recruited. They completed two sets of questionnaires; PAID and a satisfactory questionnaire, which included socio-demographic characteristics and questions relating to the acceptance of PAID. Statistical analysis was performed using Stata 13.1 and Excel. RESULTS: A total of 253 questionnaires were completed, including 157 (62.1%) male and 96 (37.9%) female patients. The prevalence of DSPD was 32.8% (83/253). Younger age (OR 3.65, 95% CI 1.36-9.80) and presence of retinopathy (OR 2.60, 95% CI 1.12-6.04) were significantly associated with DSPD. However, it was observed that one-third of the patients had an elevated level of distress regardless of socio-demographic or clinical factors. PAID was well accepted by the participants and 84.6% (214/253) were pleased to complete it again. CONCLUSION: About one-third of the patients with T2DM had DSPD. Psychological distress was higher in the younger age group and those with retinopathy. PAID is an easy, well-accepted questionnaire and would serve as a useful tool to screen for DSPD.

Idiopathic systemic capillary leak syndrome - An often missed diagnosis.

Idiopathic systemic capillary leak syndrome (ISCLS) is a potentially fatal disorder characterised by 'attacks' of varying intensity of hypovolemic shock in association with haemoconcentration and hypoalbuminaemia. It is a disease of exclusion, and the severity of attacks may mimic sepsis at presentation. We report a case of a lady with recurrent attacks of ISCLS with at least two life-threatening episodes, having been treated elsewhere as a case of steroid insufficiency. The diagnosis is often challenging, and treatment of an acute episode involves the judicious use of fluids and vasopressors, as required. Prophylaxis to prevent further attacks is of varied success.

Functioning Endocrine Tumors in Pregnancy: Diagnostic and Therapeutic Challenges.

The occurrence of endocrine tumors in pregnancy poses several diagnostic and therapeutic challenges. Although rare, functioning tumors involving the pituitary, thyroid, adrenal, and pancreas are reported in the literature. Timely diagnosis and management of these tumors are essential as they might lead to adverse maternal and fetal outcomes if left untreated. This review is an attempt to characterize various functioning tumors that could occur in pregnancy, their clinical features, diagnosis, and management.

FRAX® with or without BMD and TBS predicts fragility fractures in community-dwelling rural southern Indian postmenopausal women.

This study from southern India showed that FRAX® with or without BMD or TBS predicted fragility vertebral fractures at a cut-off of ≥ 9% for major osteoporotic fracture and ≥ 2.5% for hip fracture with sensitivities of 77-88% and specificities of 55-72%. PURPOSE: There is limited information available with regard to utility of Fracture Risk Assessment Tool (FRAX® tool) in predicting fragility fractures in Indian postmenopausal women. We studied the performance of 3 categories: FRAX® (without BMD), FRAX® (with BMD), and FRAX® (with BMD and TBS) in predicting fragility vertebral fractures in rural postmenopausal women. MATERIAL AND METHODS: It was a cross-sectional study conducted at a south Indian tertiary care center. Rural postmenopausal women (n = 301) were recruited by simple random sampling. The risk for major osteoporotic fracture (MOF) and hip fracture (HF) was calculated individually for the 3 categories. The BMD (at lumbar spine and femoral neck) and vertebral fractures were assessed by a DXA (dual energy X-ray absorptiometry) scanner and TBS by TBS iNsight software. ROC curves were constructed, and area under curve (AUC), sensitivity and specificity of FRAX® scores, which would best predict prevalent vertebral fractures (moderate to severe), was computed. RESULTS: The mean (SD) age was 65.6(5.1) years. The prevalence of osteoporosis at spine was 45%, and femoral neck was 32.6%. Moderate to severe vertebral fractures was seen in 29.2% of subjects. The performance of all 3 categories for FRAX® (MOF) and FRAX® (HF) were good (AUC was 0.798, 0.806, and 0.800, respectively, for MOF) at a cut-off score of ≥ 9, and at a cut-off of ≥ 2.5 for HF, it was 0.818, 0.775, and 0.770, respectively. At these cut-offs, sensitivities were 77-89%, and specificities were 55-72% for predicting prevalent vertebral fractures. CONCLUSION: All three categories of FRAX® showed good performance in predicting fractures in Indian postmenopausal women. Thus, it may be utilized for decision regarding treatment and referral for osteoporosis.

Utility of anthropometric indicators in predicting osteoporosis in ambulant community dwelling rural postmenopausal women from southern India.

Osteoporosis is characterised by low bone mineral density (BMD) and is a significant public health problem in India. This cross-sectional study was done to assess the relationship between various anthropometric measures and BMD in 308 rural dwelling South Indian postmenopausal women. Anthropometric variables such as weight, body mass index (BMI), waist circumference (WC), hip circumference (HC) and neck circumference (NC) were measured. BMD was assessed by dual-energy X-ray absorptiometry (DXA) scan at the lumbar spine (LS) and femoral neck (NOF). The mean age ± SD of study participants was 60.7 ± 7.8 years. All anthropometric variables showed positive correlation with BMD at NOF and LS (P < 0.05). Weight showed the best correlation (r = 0.482 for NOF and 0.412 for LS; P < 0.001). On multivariate logistic regression, age and weight remained significant for predicting femoral neck osteoporosis while weight and WC were the best predictors for LS osteoporosis. These anthropometric measures may serve as surrogate markers for osteoporosis and thus be used to screen postmenopausal women for referral to a centre with fewer limited resources.

Does Baseline PTH Influence Recovery of Bone Mineral Density, Trabecular Bone Score and Bone Turnover Markers? A Prospective Study Following Curative PArathyroidectomy in Primary Hyperparathyroidism.

OBJECTIVE: This prospective study was carried out to assess trabecular bone score, bone mineral density (BMD), and bone biochemistry in Indian subjects with symptomatic primary hyperparathyroidism (PHPT), and to study the influence of baseline parathyroid hormone (PTH) on recovery of these parameters following curative surgery. METHODS: This was a 2-year prospective study conducted at a tertiary care centre in southern India. Baseline assessment included demographic details, mode of presentation, bone mineral biochemistry, BMD, trabecular bone score (TBS), and bone turnover markers (BTMs). These parameters were reassessed at the end of the first and second years following curative parathyroid surgery. RESULTS: Fifty-one subjects (32 men and 19 women) with PHPT who had undergone curative parathyroidectomy were included in this study. The mean (SD) age was 44.6 (13.7) years. The TBS, BTMs, and BMD at lumbar spine and forearm were significantly worse at baseline in subjects with higher baseline PTH (≥250 pg/mL) when compared to the group with lower baseline PTH (<250 pg/mL). At the end of 2 years, the difference between high versus low PTH groups (mean ± SD) persisted only for forearm BMD (0.638±0.093 versus 0.698±0.041 g/cm2; P =.01). However, on follow-up visits in the first and second year after curative parathyroidectomy, there was no significant difference in BTMs, BMD at the femoral neck, lumbar spine, and TBS between the 2 groups stratified by baseline PTH. CONCLUSION: The BMD at the forearm remained significantly worse in individuals with high baseline PTH even at 2 years after surgery, while other parameters including TBS improved significantly from baseline. ABBREVIATIONS: 25(OH)D = 25-hydroxyvitamin D; BMD = bone mineral density; BMI = body mass index; BTMs = Bone turnover markers; CTX = C-terminal telopeptide of type 1 collagen; DXA = dual energy X-ray absorptiometry; P1NP = N-terminal propeptide of type 1 procollagen; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; TBS = trabecular bone score.

Knowledge gap regarding osteoporosis among medical professionals in Southern India.

RATIONALE, AIMS, AND OBJECTIVES: Osteoporosis is a common health problem in India, which leads to significant morbidity and mortality in elderly individuals. Lack of knowledge and awareness among medical professionals is one of the important barriers in management of these patients. Therefore, this study was conducted to assess knowledge pertaining to diagnosis and treatment of osteoporosis among a group of Indian medical practitioners. METHODS: The study participants included 222 allopathic medical professionals, either graduate or postgraduate working in primary or secondary health care levels. They were assessed using a previously validated Fogelman's multiple choice questionnaire. Out of a total of 18 questions, four questions pertained to knowledge of diagnosis, three questions to treatment decisions, one question to assess knowledge regarding recommended dosage of vitamin D and calcium supplementation, five questions concerned medication use, and the rest to assess attitude and practices. The correct answers were converted into scores and expressed as percentages with a maximum of 100. RESULTS: The mean total score among them was 22.5%, which was quite low. Almost all of them had a score of less than 50%. Medical practitioners performed better in diagnosis-related questions, (19.4% answered all options correctly) than in medication knowledge (no correct response regarding side effects and 2% regarding contraindications). In treatment-related decisions, 37.4% answered correctly for duration of treatment, and 59% answered correctly for treatment goal. Only 1.4% of them were able to answer correctly regarding recommended calcium and vitamin D intake. Professional literature, conferences, and Continuing Medical Education (CME's) were regarded as the main sources of information on the subject by 40% of practitioners. CONCLUSION: This study showed suboptimal knowledge among a group of medical professionals regarding various aspects of diagnosis and management of osteoporosis, and it stipulates the need for escalating the efforts to improve their knowledge regarding various aspects of osteoporosis.

Longitudinal changes in bone mineral density and trabecular bone score following yearly zoledronic acid infusion in postmenopausal osteoporosis-a retrospective-prospective study from southern India.

This study from southern India showed that yearly administration of zoledronic acid demonstrated significant improvement in BMD at lumbar spine following two doses and no decline in BMD at femoral neck or hip and trabecular bone score (TBS) in postmenopausal women. PURPOSE: There is limited information available with regard to the impact of zoledronic acid treatment on bone mineral density (BMD) and trabecular bone score (TBS) in Indian postmenopausal women with osteoporosis. We studied the changes in BMD at femoral neck (FN), hip and lumbar spine (LS), and in TBS following yearly administration of zoledronic acid (ZA) in subjects with postmenopausal osteoporosis. MATERIAL AND METHODS: This was a prospective-retrospective study which included subjects on follow-up after administration of yearly zoledronic acid, over the past 6 years. Postmenopausal women with a T score of ≤ - 2.5 at any site, assessed by dual energy X-ray absorptiometry (DXA), were included. RESULTS: A total of 620 subjects had received ZA during the study period, 197 postmenopausal women were eligible, and follow-up data were available in 164 and 103 at 1st and 2nd follow-up yearly visits respectively. The mean (SD) age and BMI of the women were 63.2 (8.5) years and 25.6 (4.5) kg/m2 respectively. There was significant increment in LS BMD from baseline to the 1st and 2nd follow-up visits, respectively (mean (SD), 0.718 (0.116), 0.734 (0.104), 0.762 (0.127) g/cm2, p = 0.024). No decline in the BMD at FN and hip at first and second follow visit was found. The TBS scores (n = 90) on baseline and follow-up visits were 1.260 (±0.11), 1.256 (± 0.15), and 1.242 (± 0.17) (p value = 0.71). CONCLUSION: Lumbar spine BMD showed significant improvement with zoledronic acid treatment. No decline was noted in femoral neck BMD and TBS with treatment.

The impact of the Hologic vs the ICMR database in diagnosis of osteoporosis among South Indian subjects.

BACKGROUND AND OBJECTIVES: Recently, the Indian Council of Medical Research (ICMR) has published normative data for bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) scanning. However, the impact this has had on the diagnosis of osteoporosis when compared to currently used Caucasian databases has not been analysed. Hence, this study was undertaken to look at agreement between the Hologic Database (HD) based on BMD normative data in Caucasians and the ICMR database (ICMRD) in defining osteoporosis in subjects with or without hip fracture. MATERIALS AND METHODS: It is a cross -sectional study of 2976 subjects (men 341, women 2757) (mean age ± SD = 62·2 ± 7·2 years), including 316 subjects with low impact hip fracture: 2199 were from the hospital database, and 461 were healthy postmenopausal women from the community who underwent (DXA) scanning between January 2010 and March 2013. Recalculated T scores from ICMRD were used for the diagnosis of osteoporosis and compared with HD. RESULTS: An almost perfect agreement existed between the two databases for the diagnosis of osteoporosis at the hip (κ -0·82, P < 0·0001) in all subjects, and a moderate relationship existed in those with hip fracture (κ -0·65, P < 0·0001). Seventy-three of 316 hip fracture subjects (23·5%) defined as osteoporosis according to HD were classified as osteopenia according to ICMRD. CONCLUSION: The threshold of hip BMDT score for treating osteoporosis may have to be redefined if the ICMR reference database is used. Initiation of treatment in these subjects must be based on multiple fracture risk factor assessment in addition to looking at BMD. Further studies with a larger sample size of subjects with fracture are needed to validate our findings.

Thyroid stimulating hormone microadenoma as a rare cause of thyrotoxicosis amenable to surgical cure.

Hyperthyroidism due to a thyroid stimulating hormone (TSH) pituitary adenoma is rare. We report a 29-year-old woman with thyrotoxicosis and elevated serum 3,5,3',5'-tetraiodothyronine and TSH levels that resolved after a transsphenoidal excision of the detected TSH pituitary adenoma. The diagnosis and management options in such patients are reviewed.