Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review.

This systematic review was performed to understand better the myriad presentations, various therapeutic options, response to therapy, and its clinical outcomes in hyperphosphatemic tumoral calcinosis (HTC). Full texts were selected according to strict inclusion criteria. All case reports of HTC wherein baseline phosphate was measured, treatment offered was mentioned, and information on follow-up and response to therapy that were available were included. A total of 43 of 188 eligible studies (N = 63 patients) met the inclusion criteria. A list of desired data was extracted and graded for methodological quality. A total of 63 individuals (Males = 33) were included from the 43 eligible case studies. The median age of the patients was 18 (IQR 8-32) years. The most frequently involved sites were the hip/gluteal region (34/63; 53.9%) followed by the elbow/forearm (26/63; 41.2%), and the shoulder (18/63; 28.5%). Three patients had conjunctival calcific deposits. The mean (SD) phosphate was 6.9 (1.1) mg/dL. Among the subjects, 36/63 (57.1%) underwent surgical excision with some form of medical therapy. Two patients underwent only surgical excision (2.1%). One patient was maintained on follow-up (1.6%) and 24/63 (38.1%) patients were treated with medical measures. The median (IQR) follow-up duration was 3 (1-9) years. Regression or reduction in lesion size was reported in 19/63 (30.2%) subjects; 20/63 (31.7%) showed progression, 24/63 (38.1%) had features of stable disease, and mortality was reported in 3 patients (4.7%). We report for the first time a detailed description of the clinical and therapeutic response of HTC. A combination of medical measures aimed at lowering serum phosphate appears to be the cornerstone of treatment, although clinical responses may vary.

Clinical Profile and Mutations Associated with Multiple Endocrine Neoplasia-Type1 (MEN1) and Their First-Degree Relatives at Risk of Developing MEN1: A Prospective Study.

Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.

DXA Measured Visceral Adipose Tissue, Total Fat, Anthropometric Indices and its Association With Cardiometabolic Risk Factors in Mother-Daughter Pairs From India.

Visceral fat is the pathogenic fat depot associated with diabetes, dyslipidemia, and cardiovascular diseases. Estimation of visceral adipose tissue (VAT) by dual energy-X-ray absorptiometry (DXA) is a newer technique with less radiation exposure, shorter scanning time, and lower cost. In this study, we attempted to look at relationship between cardiometabolic risk factors and VAT, total body fat percent (TBF%) and anthropometry. We also studied the changes in body composition and metabolic parameters with menopause. The familial resemblance of VAT and TBF% in mother-daughter pair was also compared. This was a cross sectional community study of 300 women (150 postmenopausal mothers and 150 premenopausal daughters). Body composition indices by DXA and metabolic parameters were assessed. The association between DXA-VAT, TBF%, anthropometric measures, and cardiometabolic risk factors were studied by correlation, receiver operating characteristics curves, and logistic regression analysis. VAT indices were significantly higher and lean indices lower in postmenopausal women as compared to premenopausal women. One fourth of postmenopausal women were categorized as metabolically obese normal weight. DXA-VAT was a better predictor of cardiometabolic risk factors as compared to waist circumference, body mass index, and TF% in postmenopausal women (AUC:0.68 vs 0.62, 0.60 & 0.5, respectively), whereas body mass index had a better prediction in premenopausal women(AUC:0.68). VAT area >100 cm² had a significant association with the presence of ≥2 cardiometabolic risk factors (p = 0.04, OR: 2.2, CI:1.0-4.7) in the postmenopausal women. Daughters of the mothers with higher TBF% were found to have a higher TBF% compared to daughters of mothers with normal TBF% (36.2 ± 4.2 vs 32.2 ± 4.4, p = 0.03), similar resemblance was not seen for VAT. The study showed that the VAT increases and lean mass decreases with age and menopause. DXA measured VAT is a better predictor of cardiometabolic risk in postmenopausal women but not in premenopausal women. Total body fat may have a familial resemblance, but not the VAT which is determined by age, menopause, and probable life style factors.

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.

ECTOPIC CUSHING SYNDROME: A 10-YEAR EXPERIENCE FROM A TERTIARY CARE CENTER IN SOUTHERN INDIA.

OBJECTIVE: Ectopic adrenocorticotropic hormone (ACTH) secretion is a less common cause of Cushing syndrome and is seen in 5 to 10% of cases with endogenous hypercortisolemia. We hereby describe our experience of patients with ectopic ACTH syndrome, who have been managed over the past 10 years at a tertiary care center in Southern India. METHODS: The inpatient and outpatient records of patients from 2006 to 2015 were retrospectively reviewed. The clinical features, clinical history, biochemical values, imaging features, including radiologic findings and positron emission tomography scans, management, details of follow-up, and outcomes, were documented. We compared the biochemical findings in these patients with 20 consecutive patients with Cushing disease (Cushing syndrome of pituitary origin). RESULTS: A total of 21 patients were studied. The median age at presentation was 34 years (range, 19 to 55 years). Seven patients had thymic carcinoid, 7 had bronchial carcinoid, 3 had lung malignancies, 2 had medullary carcinoma thyroid, 1 patient had a pancreatic neuroendocrine tumor, and 1 patient had an occult source of ACTH. The most common clinical features at presentation were muscle weakness (95%), hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%), and striae (52%). Extensive acne was seen in a large number of patients (43%). Only 3 patients (14%) had central obesity. The median 8 am cortisol was 55.5 µg/dL (range, 3.8 to 131 µg/dL), median 8 am ACTH was 207 pg/mL (range, 31.1 to 703 pg/mL), and the median 24-hour urinary free cortisol was 2,484 µg (range, 248 to 25,438 µg). Basal cortisol and ACTH, as well as midnight cortisol and ACTH level, were markedly higher in patients with ectopic Cushing syndrome as compared to patients with Cushing disease. Twelve of 21 patients had developed life-threatening infections by follow-up. Nine patients had undergone surgical intervention to address the primary tumor. However, only 1 patient exhibited a complete cure on follow-up. CONCLUSION: In our series, ectopic Cushing syndrome was most commonly seen in association with intrathoracic tumors such as bronchial or thymic carcinoid. Hyperpigmentation and proximal myopathy were frequent, while central obesity was uncommon. Early and rapid control of hypercortisolemia was important in order to prevent life-threatening infections and metabolic complications. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CT = computed tomography DOTATATE = 68Ga-DOTA-Tyr3-octreotate ECS = ectopic Cushing syndrome FDG = fluorodeoxyglucose MTC = medullary thyroid cancer NET = neuroendocrine tumor PET = positron emission tomography.

Bone turnover markers and bone mineral density in healthy mother-daughter pairs from South India.

Bone turnover markers (BTMs) provide important insights into the dynamics of bone remodelling and are subjected to preanalytical and ethnic variations in addition to influence of genetic and environmental factors. AIM/OBJECTIVES: To derive ethnicity specific reference range for BTMs and to study their correlation with Bone Mineral Density (BMD) in a cohort of healthy postmenopausal women and their premenopausal daughters and to look at the impact of maternal bone mineral status on daughters bone health. MATERIAL AND METHODS: This community based cross sectional study included 300 subjects (150 mother-daughter pairs). Demographic details were collected. Fasting blood and a second void morning urine samples were obtained for measurement of BTMs (sCTX, sPTNP1, sOC and urine DPD respectively) and bone mineral parameters. BMD was measured by DXA scan. RESULTS: Osteoporosis was seen in 44·7% of the postmenopausal women. Ethnicity specific reference ranges of BTMs were derived for the study population. Significant inverse correlation was found between all BTMs (except urine DPD) and BMD(P < 0·05). Daughters of mothers with osteoporosis at spine and femoral neck had lower BMD, compared to daughters of mothers without osteoporosis(P = 0·03 & 0·05). CONCLUSION: Apart from deriving the ethnicity specific reference range for BTMs and finding a significant inverse correlation between BTM and BMD, this study found significantly lower BMD in daughters of mothers with osteoporosis at spine and femoral neck implicating the probable interplay of genetic, epigenetic and similar environmental factors.

Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing.

OBJECTIVE: To establish and utilize a Next-Generation Sequencing (NGS)-based strategy to screen for maturity onset diabetes of the young (MODY) gene mutations in subjects with early-onset diabetes. PATIENTS AND METHODS: Maturity onset diabetes of the young (MODY) genetic testing was carried out in 80 subjects of Asian Indian origin with young onset diabetes to identify mutations in a comprehensive panel of ten MODY genes. A novel multiplex polymerase chain reaction (PCR)-based target enrichment was established, followed by NGS on the Ion Torrent Personal Genome Machine (PGM). All the mutations and rare variants were confirmed by Sanger sequencing. RESULTS: We identified mutations in 11 (19%) of the 56 clinically diagnosed MODY subjects and seven of these mutations were novel. The identified mutations include p.H241Q, p.E59Q, c.-162G>A 5' UTR in NEUROD1, p.V169I cosegregating with c.493-4G>A and c.493-20C>T, p.E271K in HNF4A, p.A501S in HNF1A, p.E440X in GCK, p.V177M in PDX1, p.L92F in HNF1B and p.R31L in PAX4 genes. Interestingly, two patients with NEUROD1 mutation were also positive for the p.E224K mutation in PDX1 gene. These patients with coexisting NEUROD1-PDX1 mutations showed a marked reduction in glucose-induced insulin secretion. All 24 subjects who had not met the clinical criteria of MODY were negative for the mutations. To the best of our knowledge, this is the first report of PDX1, HNF1B, NEUROD1 and PAX4 mutations from India. CONCLUSIONS: Multiplex PCR coupled with NGS provides a rapid, cost-effective and accurate method for comprehensive parallelized genetic testing of MODY. When compared to earlier reports, we have identified a higher frequency and a novel digenic mutation pattern involving NEUROD1 and PDX1 genes.

Inherited fibroblast growth factor 23 excess.

Syndromes of inherited fibroblast growth factor 23 (FGF-23) excess encompass a wide spectrum that includes X-linked hypophosphataemia (XLH), autosomal dominant and recessive forms of rickets as well as various syndromic conditions namely fibrous dysplasia/McCune Albright syndrome, osteoglophonic dysplasia, Jansen's chondrodysplasia and cutaneous skeletal hypophosphataemia syndrome. A careful attention to patient symptomatology, family history and clinical features, supported by appropriate laboratory tests will help in making a diagnosis. A genetic screen may be done to confirm the diagnosis. While phosphate supplements and calcitriol continue to be the cornerstone of treatment, in recent times burosumab, the monoclonal antibody against FGF-23 has been approved for the treatment of children and adults with XLH. While health-related outcomes may be improved by ensuring adherence and compliance to prescribed treatment with a smooth transition to adult care, bony deformities may persist in some, and this would warrant surgical correction.

Disrupted Sleep Architecture Is Associated With Incident Bone Loss in Indian Postmenopausal Women: A Prospective Study.

Inadequate sleep has been shown to be detrimental to several body systems, including the bone. We proposed to study the impact of insomnia on bone health in Indian postmenopausal women. In a 2-year prospective study, ambulant community-dwelling postmenopausal women aged >50 years were recruited through simple random sampling. Sleep duration was recorded based on self-reported sleep duration and sleep quality using the Women's Health Initiative Insomnia Rating Scale (WHIIRS). Anthropometry, bone biochemistry including bone turnover markers (C-terminal telopeptide of type 1 collagen [CTX], N-terminal telopeptide of type 1 pro-collagen [P1NP]), bone mineral density (BMD), and trabecular bone score (TBS) were assessed at baseline and at the end of 2 years. Among 190 postmenopausal women with mean (SD) age of 58.2 (6.9) years, 65/190 (34.2%) had insomnia (WHIIRS ≥ 9) and 20/190 (10.5%) developed osteoporosis at any site on follow-up. The percentage decline over 2 years in BMD in women with insomnia was significantly (p < 0.001) higher at femoral neck (2.9 [1.6] versus 1.2 [1.2]%) and lumbar spine (4.5 [2.0] versus 1.6 [1.1]%). The decrement in TBS was also significantly higher (p < 0.001) in women with suboptimal sleep (1.5 [2.1] versus 0.5 [1.0] %) when compared with those with adequate sleep. The increment in CTX (46.4 [32.2] versus 18.9 [26.4]) and decrement in P1NP (35.4 [9.1] versus 16.7 [18.9]), respectively, were also greater (p < 0.001) in women with insomnia compared with those without. On multivariate analysis, insomnia was the sole factor that was predictive (adjusted odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.9-29.6; p < 0.001) of incident osteoporosis. In conclusion, poor sleep quality was associated with incident osteoporosis in Indian postmenopausal women. Optimal sleep may help to retard ongoing bone loss that results from sleep deprivation and requires further research. © 2022 American Society for Bone and Mineral Research (ASBMR).

Beyond diabetes remission a step further: Post bariatric surgery hypoglycemia.

Postbariatric hypoglycemia is a rare but increasingly recognized complication of bariatric surgery, with significant associated morbidity, and many patients often require multimodal treatment. A mixed meal challenge test is often helpful to diagnose this condition. This manuscript highlights the underlying mechanisms that lead to this condition and the novel emerging therapeutic targets that target these mechanisms.

Utility and validation of bone mineral density measurements at forearm in predicting trabecular microarchitecture and central-site osteoporosis in aging Indian postmenopausal women-a promising surrogate?

Objective: The objective of this paper was to present the results of our study of the utility of bone mineral density (BMD) measurements at various segments of distal forearm in predicting central-site osteoporosis and deteriorated trabecular microarchitecture. Methods: This was a cross-sectional study and BMD at the femoral neck, lumbar spine, and distal forearm were assessed using the dual-energy X-ray absorptiometry (DXA) scanner and bone microarchitecture at lumbar spine by trabecular bone score (TBS). The utility of forearm BMD in predicting osteoporosis as well as the deteriorated TBS was assessed by a receiver operating characteristic analysis. Results: A total of 352 postmenopausal women with mean (SD) age of 60.7 (6.8) years were included. The odds of having osteoporosis at femoral neck [odds ratio (OR) = 14.1, 95% confidence interval (CI): 7.8-25.2] and lumbar spine (OR = 7.5, 95% CI: 4.6-12.1) was highest with the mid-distal radius. A derived T-score cut off ≤ -1.6, -1.9, and -1.7 at any segment of the forearm was elucidated to predict osteoporosis at the central-site, femoral neck, and lumbar spine, respectively, with sensitivity of 80%-88% and specificity of 60%-70%. The T-scores at all three forearm segments ≤ -1.2 showed fair performance in predicting degraded trabecular microarchitecture. The T-scores thus derived were further validated in cohort of 360 Bengali postmenopausal women. Conclusion: BMD assessment at the forearm may be utilized in prediction of trabecular microarchitecture and central site osteoporosis at the femoral neck and lumbar spine in postmenopausal women.

Bisphosphonate-induced atypical femoral fracture in tandem: long-term follow-up is warranted.

Summary: Although bisphosphonates (BPs) are mainly used for the treatment of osteoporosis and are generally safe, long-term use and more dosage as utilised in malignant conditions may be associated with the rare adverse event of an atypical femoral fracture (AFF). Occasionally, the risk of developing an AFF persists long after BPs are withdrawn. A 39-year-old woman who underwent chemotherapy and an autologous stem cell transplantation for multiple myeloma presented to us with history of pain in the left thigh. She had received multiple doses of oral and parenteral BPs for about 10 years in view of the underlying myeloma with osteoporosis. Her investigations showed a suppressed CTX of 192 pg/mL, and radiograph of pelvis displayed thickened cortices with beaking of the left femoral shaft, which was suggestive of an AFF. Following discontinuation of BPs, she underwent prophylactic intra-medullary nailing with which her symptoms improved. Five years later, she presented with similar complaints on the right side. Investigations showed that her bone turnover continued to be suppressed with Cross linked C- Telopeptide of type 1 collagen (CTX) of 165 pg/mL and an X-ray done showed AFF on the right side despite being off BPs. A second intra-medullary nailing was done and on follow-up, she has been symptom-free and independent in her daily activities. Discontinuation of BPs may not prevent the incident second AFF and, therefore, thus warranting long-term follow-up. Learning points: Regular screening and follow-up of patients who receive long-term bisphosphonate (BP) therapy should be done. Discontinuation of BPs does not preclude the possibility of repeated occurrence of a second AFF. Long-term BP therapy warrants regular monitoring and follow-up should an AFF occur.

Does hip structural analysis confer additional benefit to routine BMD assessment in postmenopausal women with hip fracture? A study from a tertiary center in southern India.

This study from southern India showed that proximal hip geometry was significantly impaired in postmenopausal women with femoral neck fracture. The trabecular bone score (TBS), which is reflective of bone microarchitecture, was also significantly impaired in patients with fracture. INTRODUCTION: There is limited information with regard to comprehensive bone health in Indian postmenopausal women with neck of femur fracture. We studied the bone mineral density (BMD), trabecular bone score (TBS), proximal hip geometry, and bone mineral biochemistry in postmenopausal women with and without femoral neck fractures. METHODS: This was a cross-sectional study conducted at a tertiary care center in South India. BMD, TBS, and hip structural analysis (HSA) were assessed using a dual-energy X-ray absorptiometry (DXA) scanner. Bone mineral biochemical profiles were also studied. RESULTS: A total of 90 postmenopausal women with acute femoral neck fracture with mean (SD) age of 63.2 (6.1) years and 90 age-matched controls were included. The prevalence of osteoporosis was higher among cases as compared to controls (83.3% vs 47.8%; P < 0.001). Degraded bone microarchitecture (TBS value < 1.200) was more frequent among women with hip fracture as compared to controls (46.7% vs 31.1%; P = 0.032). Cross-sectional moment of inertia (CSMI) was significantly lower at the narrow neck (NN) and inter-trochanteric (IT) region in cases (P < 0.05) and buckling ratio (BR) was significantly higher at all three sites in postmenopausal women with femoral neck fracture as compared controls. Multivariate logistic regression analysis showed that femoral neck osteoporosis, low CSMI at NN and high BR at NN and femoral shaft emerged as factors significantly associated with femoral neck fractures. CONCLUSION: This study highlights that impaired parameters of proximal hip geometry and a low trabecular bone score may be significantly associated with femoral neck fractures in postmenopausal women.

Dual-Energy X-Ray Absorptiometry Scanning in Practice, Technical Aspects, and Precision Testing.

The last three decades have witnessed considerable progress in the field of bone densitometry. Osteoporosis may be diagnosed in postmenopausal women and in men aged 50 and older if the bone mineral density (BMD) T-scores of the lumbar spine, total hip, or femoral neck are -2.5 or less. For reporting T-scores, the Hologic dual-energy X-ray absorptiometry (DXA) scanner uses the Caucasian (nonrace adjusted) female normative database for women and men of all ethnic groups although reference database used does have an impact on the categorization of BMD and must be chosen judiciously considering the regional and ethnic characteristics of the population. The quality control for DXA systems should be periodically done in accordance with manufacturer guidelines for DXA. Beyond conventional BMD assessment, DXA may also be utilized to assess the trabecular bone score, hip structural analysis, vertebral fractures, and body composition.

Screening Tools for Osteoporosis in India: Where Do We Place Them in Current Clinical Care?

The prevalence of osteoporosis is about 40%-50% in postmenopausal women and 20% in older men. The limited availability of dual-energy X-ray absorptiometry (DXA) scanners across the country calls for the presence of alternate risk assessment tools to identify those at high risk for osteoporosis. Some of the screening tools available for osteoporosis include Simple Calculated Osteoporosis Risk Estimation and Osteoporosis Risk Assessment Tool for Asians (OSTA), and Fracture Risk Assessment Tool to assess fracture risk. Clinical parameters that may serve as surrogates include dentition and anthropometric indices. Although screening tools do not supplant the assessment of bone mineral density by DXA, they help identify individuals at high risk for osteoporosis who may be selectively referred for confirming the same.