Marked increase in bone mineral density with oral phosphate and calcitriol in tumour-induced osteomalacia.

Patients with osteomalacia have a low bone mineral density (BMD) and are often misdiagnosed as osteoporosis. A marked increase in BMD is noticed following successful treatment of osteomalacia. The biochemical hallmark of tumour-induced osteomalacia (TIO) is hypophosphatemia. Patients with TIO often have severe hypophosphatemic osteomalacia and dual-energy X-ray absorptiometry may demonstrate low BMD. Surgical removal of the phosphatonin-secreting lesion restores serum phosphate, corrects osteomalacia and is associated with a dramatic increase in BMD. We report two patients with TIO and low BMD, who were treated with oral phosphate and calcitriol supplementation. The percentage increase in BMD at 33 months was as high as 94.3% in areas with the lowest BMD at baseline. The BMD at 33 months was higher than the +2SD of the population-specific reference ranges, a finding not reported in surgically treated patients with TIO. An intermittent rise in parathyroid hormone following oral phosphate supplementation might have resulted in such findings.

Rickets in proximal renal tubular acidosis: a case series of six distinct etiologies.

OBJECTIVES: Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. CASE PRESENTATION: We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. CONCLUSIONS: Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Glial Cell Missing Homolog 2 Mutation Causing Severe Hypoparathyroidism: Report of Two Cases With Novel Mutations.

Hypoparathyroidism is a common encounter in endocrinology practice. A thorough search for the etiology is generally futile, and most cases are labeled as idiopathic. Familial idiopathic hypoparathyroidism is a large chunk of these idiopathic cases. Here we present 2 cases who presented with features of hypocalcemia and were eventually diagnosed with hypoparathyroidism. Our first case is that of a middle-age woman who presented with spontaneous tetany and perioral numbness. She had very low serum calcium values, low serum magnesium, hypokalemia, hypercalciuria, and undetectable parathormone levels. She was initially managed with parenteral calcium, magnesium, and oral potassium chloride, which was shifted to oral replacements once stabilized. Focused exome sequencing for causes of hypoparathyroidism and hypocalcemia revealed a frameshift mutation in glial cell missing homolog 2 (GCM2) (NM_004752.4) on chromosome 6, c737dupA variant (p. Asp246Glufs*25) located at exon 5. The second case presented is that of a 1-month-old infant presenting with hypocalcemic seizures, severe hypocalcemia, hyperphosphatemia, and low parathormone levels. The infant was stabilized with parenteral calcium and trial of subcutaneous teriparatide for further improvement. Oral calcium and calcitriol were instituted once stabilized, and teriparatide was tapered off. Focused exome sequencing revealed a homozygous mutation involving GCM2 (ENST0000379491.5) on chromosome 6, variant CM2 chr6:10876558_10877139insT located on exon1-2. Both of these mutations are novel and underscore the profound effect of GCM2 on parathyroid gland development in infants and maintenance in adults.

Clinical and Biochemical Characteristics of Patients with Renal Tubular Acidosis in Southern Part of West Bengal, India: A Retrospective Study.

PURPOSE OF THE STUDY: Reversible proximal tubular dysfunction associated with distal renal tubular acidosis (dRTA) mimics type 3 RTA, a condition classically associated with features of both proximal RTA (pRTA) and dRTA. Proximal tubulopathy has been reported in children with primary dRTA, but the data in adults are lacking. STUDY DESIGN: In this hospital record-based retrospective study, data from 66 consecutive cases of RTA, between January 2016 to December 2018, were retrieved and analyzed. RESULTS: Mean age of the study population was 25.3 years (range: 3 months to 73 years). Six (9.1%) of them had pRTA, 58 (87.9%) had dRTA, 1 (1.5%) had type 3 RTA, and the remaining 1 (1.5%) had type 4 RTA. Ten patients (17.2%) with dRTA and 3 patients of pRTA (50%) had underlying secondary etiologies. Data on proximal tubular dysfunction were available for 30 patients with dRTA, of whom 1 had isolated dRTA, and the rest 29 patients had accompanying completely reversible proximal tubular dysfunction. Among the 10 cases of secondary dRTA, 6 were not evaluated for proximal tubular dysfunction. Of the remaining 4, 3 had reversible form of proximal tubular abnormality. Fifty-two patients with dRTA came from a population, indigenous to the "Rarh" region of India. CONCLUSIONS: Proximal tubular dysfunction often accompanies dRTA; 75% of the children with primary dRTA, at least 29% of adults with primary dRTA, and at least 30% of adults with secondary dRTA manifest such completely reversible form of proximal tubulopathy. "Rarh' region of India probably is a hotspot for endemic dRTA.

Indian Expert Review on Use of Teneligliptin in patients with Diabetes and its Safety and Efficacy (INTENSE).

INTRODUCTION: Management of diabetes in India remains less than satisfactory despite a huge prevalence of type 2 diabetes (T2D). Associated obesity, inadequate lifestyle modifications and burden of treatment costs are certain major issues contributing to inadequate management of diabetes in India. AIM: To evaluate the use of Teneligliptin in patients with diabetes and its safety, efficacy and cost effectiveness especially in Indian patients with T2D. METHODS: A detailed analysis of the best available scientific evidence (clinical trials, meta-analyses and real-world experience) was performed to create an evidence driven understanding of teneligliptin's efficacy, safety and cost effectiveness. Fourteen leading endocrinologists contributed as experts and the modified Delphi process was followed. Evidences and clinical questions were discussed over a series of web and in a live meeting. Final draft was created based on the opinions endorsed by the experts. RESULTS: Teneligliptin is the most commonly used gliptin in India and exhibits pharmacokinetic and pharmacodynamic advantages as well as greater cost effectiveness compared to other gliptins. It has been recognized as an efficacious and well tolerated antidiabetic agent both as monotherapy and in combination based on multiple clinical trials, meta-analyses and real world studies. Teneligliptin as add on therapy to other antidiabetic drugs (OADs) or insulin has provided significant reductions in HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels and is generally well tolerated with low risk of hypoglycemia both in short term and long term. Studies have also proven its efficacy in ameliorating glucose fluctuations, reducing post prandial insulin requirement, increasing active incretin levels and improving pancreatic ß cells function. Efficacy and safety has also been proven in all age groups, all stages of renal disease and mild to moderate hepatic disease. QT prolongation is not seen even with maximum recommended dose of 40 mg/day. CONCLUSION: Teneligliptin has firmly positioned itself as a very important drug in the armamentarium for managing T2D. It offers efficacy, safety and cost-effective therapeutic choice in Indian patients with T2D.

Chronic inflammation in polycystic ovary syndrome: A case-control study using multiple markers.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and elevated risk of cardiovascular disease and diabetes. Chronic inflammation has been observed in PCOS in several studies but there is also opposing evidence and a dearth of research in Indians. OBJECTIVE: To estimate chronic inflammation in PCOS and find its relationship with appropriate anthropometric and biochemical parameters. MATERIALS AND METHODS: Chronic inflammation was assessed in 30 women with PCOS (Group A) and 30 healthy controls (Group B) with highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), and platelet microparticles (PMP). In group A, the relationship of chronic inflammation with insulin resistance, waist hip ratio (WHR) serum testosterone, and serum glutamate pyruvate transaminase (SGPT) were examined. RESULTS: In group A, the hsCRP, TNFα, and PMP were significantly elevated compared to group B. However, IL-6 level was similar between the groups. In group A, PMP showed a significant positive correlation with waist-hip ratio and serum testosterone. IL-6 showed a significant positive correlation with insulin sensitivity and significant negative correlation with insulin resistance and serum glutamate pyruvate transaminase. CONCLUSION: PCOS is associated with chronic inflammation and PMP correlates positively with central adiposity and biochemical hyperandrogenism in women with PCOS.

Phenotypic and genotypic spectrum of CTSK variants in a cohort of twenty-five Indian patients with pycnodysostosis.

BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia with easily recognizable clinical features and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 25 Indian patients with pycnodysostosis from 20 families. METHODS: Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the CTSK gene. Novel variants were systematically assessed by prediction softwares and protein modelling. The pathogenicity of variant was established based on ACMG-AMP criteria. An attempt was also made to establish a genotype-phenotype correlation and devise a diagnostic scoring system based on clinical and radiological findings. RESULTS: Consanguinity and positive family history were present in 65% (13/20) and 45% (9/20) of the families respectively. Short stature and fractures were the predominant presenting complaints and was evident in 96% (24/25) and 32% (8/25) of affected individuals respectively. Gestalt facial phenotype and acro-osteolysis were present in 76% (19/25) and 82.6% (19/23) of the individuals respectively. Hepatosplenomegaly was present in 15% (3/20) of the individuals with one of them having severe anaemia. Causative sequence variations were identified in all of them. A total of 19 variants were identified from 20 families amongst which 10 were novel. Homozygous variants were identified in 90% (18/20) families. Amongst the novel variants, there was a considerable proportion (40%) of frameshift variants (4/10). No significant genotype-phenotype correlation was noted. Scoring based on clinical and radiological findings led to the proposal that a minimum of 2 scores in each category is required in addition to high bone density to diagnose pycnodysostosis with certainty. CONCLUSION: This study delineated the genotypic and phenotypic characterisation of Indian patients with pycnodysostosis with identification of 10 novel variants. We also attempted to develop a clinically useful diagnostic scoring system which requires further validation.

Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement.

Diabetic kidney disease (DKD) occurs in approximately 20-40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (- 21.0%, confidence interval [CI] - 34.1 to - 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52-0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48-0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

A Cross-sectional Study of Stretched Penile Length in Boys from West Bengal, India.

INTRODUCTION: Short penile length is a commonly encountered problem in clinical practice. Detection of abnormal stretched penile length (SPL) warrants appropriate endocrine evaluation. Ethnicity-specific SPL data are required to detect these abnormalities. There is a dearth of such data in India. This study aims to establish normative values of SPL in boys from West Bengal. MATERIALS AND METHODS: This is a cross-sectional study. SPL, testicular volume (TV), height/length, and weight were measured in 460 boys aged 1 to 13 years from the schools located at urban, suburban, and rural areas in the state of West Bengal, India. Similar data were collected from 36 healthy neonates within 1-3 days of full-term delivery at IPGME and R and SSKM Hospital, Kolkata, West Bengal, India. RESULTS: The 5th percentile, median, and 95th percentile of SPL were 1.7, 2.0, and 2.7 cm for neonates; 3.5, 4.4, and 6.4 cm for the children aged 1 Y-2 Y 11 M; 4.0, 5.5, and 7.0 cm for the age group 3 Y-4 Y 11 M; 4.2, 6.0, and 7.2 cm for the age group 5 Y-6 Y 11 M; 4.3, 6.0, and 7.6 cm for the age group 7 Y-8 Y 11 M; 4.4, 6.5, and 9.0 cm for the age group 9 Y-10 Y 11 M; and 4.8, 7.0, and 11.0 cm for the age group 11 Y-12 Y 11 M, respectively. SPL showed significant positive correlation with TV [r = 0.365, P < 0.0005] and height of the children [r = 0.516, P < 0.0005], but not with BMI. CONCLUSION: Our study provides normative data of SPL in neonate and children aged 1 to 13 years from the eastern part of India. SPL value correlated positively with TV and height of children.

FSH ß-subunit mutations in two sisters: the first report from the Indian sub-continent and review of previous cases.

Isolated FSH deficiency due to mutations in the gene for ß-subunit of FSH is an extremely rare autosomal recessive disease of which only eleven cases have been reported so far. The clinical features include absent breast development and primary amenorrhea in females and azoospermia with normal testosterone levels in males. In this study we report two Kashmiri sisters born to native Kashmiri consanguineous parents with failure of onset of puberty. Hormonal evaluation revealed undetectable serum FSH and estradiol and high LH. Genetic analysis of FSH ß-gene identified one nonsense mutation (c.343C > T:p. Arg115Stop) in exon 3. The two sisters were homozygous for this nonsense mutation while the parents were heterozygous. Incorporation of a stop codon at 115 codon position is predicted to result in the formation of truncated FSH ß protein, lacking 14 amino acid from the carboxy-terminus (p.Arg115Stop). Very recently, this same mutation was reported for the first time in a Chinese male. Ours is the first ever report of any FSH ß-subunit mutation from the Indian sub-continent and this particular mutation in any female from anywhere in the world. We conclude and emphasize that this diagnosis should be considered in girls with delayed puberty and selective deficiency of FSH.

Reversible Secondary Osteolysis in Diabetic Foot Infection.

Osteolysis, caused by active resorption of bone matrix by osteoclasts, can be primary or can develop secondary to a variety of disease processes. An elevated level of inflammatory cytokines in the local milieu and increased blood flow secondary to infection or autonomic neuropathy stimulate the osteoclasts and cause bone loss in the diabetic foot. Charcot's neuroarthropathy and osteomyelitis are well-known foot complications of diabetes, and secondary osteolysis has largely been underappreciated and, hence, underreported. Plain radiographs, an initial component in the evaluation of the diabetic foot, may not successfully differentiate secondary osteolysis from osteomyelitis. We describe a patient with phalangeal osteolysis secondary to soft-tissue infection in whom a correct and timely diagnosis helped avoid unnecessary surgical interventions.

Effects of thyroid status on glycated hemoglobin.

INTRODUCTION: Glycated hemoglobin (HbA1c) can be altered in different conditions. We hypothesize that HbA1c levels may change due to altered thyroid status, possibly due to changes in red blood cell (RBC) turnover. OBJECTIVES: The objective of this study was to determine the effects of altered thyroid status on HbA1c levels in individuals without diabetes, with overt hyper- and hypo-thyroidism, and if present, whether such changes in HbA1c are reversed after achieving euthyroid state. METHODS: Euglycemic individuals with overt hypo- or hyper-thyroidism were selected. Age- and sex-matched controls were recruited. Baseline HbA1c and reticulocyte counts (for estimation of RBC turnover) were estimated in all the patients and compared. Thereafter, stable euthyroidism was achieved in a randomly selected subgroup and HbA1c and reticulocyte count was reassessed. HbA1c values and reticulocyte counts were compared with baseline in both the groups. RESULTS: Hb A1c in patients initially selected was found to be significantly higher in hypothyroid group. HbA1c values in hyperthyroid patients were not significantly different from controls. HbA1c reduction and rise in reticulocyte count were significant in hypothyroid group following treatment without significant change in glucose level. Hb A1c did not change significantly following treatment in hyperthyroid group. The reticulocyte count, however, decreased significantly. CONCLUSION: Baseline HbA1c levels were found to be significantly higher in hypothyroid patients, which reduced significantly after achievement of euthyroidism without any change in glucose levels. Significant baseline or posttreatment change was not observed in hyperthyroid patients. Our study suggests that we should be cautious while interpreting HbA1c data in patients with hypothyroidism.

Efficacy and safety of low dose oral prednisolone as compared to pulse intravenous methylprednisolone in managing moderate severe Graves' orbitopathy: A randomized controlled trial.

BACKGROUND: High dose oral prednisolone (100 mg/day) in Graves' orbitopathy (GO) is limited by lesser response, and greater side-effects compared to intravenous (iv) methylprednisolone. Low dose oral prednisolone has not been evaluated in GO. This study aimed to evaluate the safety and efficacy of low dose oral prednisolone in GO. MATERIALS AND METHODS: A total of 114 consecutive GO patients were screened of which 65 patients with previously untreated moderate-severe GO, clinical activity score (CAS) >2, without co-morbid states were randomized into treatment Group-A (iv methylprednisolone 0.5 g for 3 days/month for 4 months) and Group-B (oral prednisolone 1 mg/kg/day for 6 weeks then tapered stopped), and followed-up. Thirty-one patients in each group with at least 1-year follow-up were analyzed. Responders were defined as improvement in ≥ 1 major response criteria or ≥ 2 minor response criteria. The trial is registered at ctri.nic.in (CTRI/2013/12/004264). RESULTS: At 1-year, 27/31 (87.10%) patients were responders in Group-A compared to 17/31 (54.84%) in Group-B (P = 0.005). There was a greater improvement in CAS score in patients of Group-A as compared to Group-B (P < 0.001). Responders (n = 44) had significantly higher baseline intra-ocular pressures and left eye proptosis as compared to nonresponders. Cox-regression revealed baseline T4 levels, diplopia, and smoking history were predictive of remission. Low dose prednisolone was well tolerated, and the occurrence of adverse events were comparable in both groups. CONCLUSIONS: Low dose oral prednisolone is inferior to iv pulse methylprednisolone in managing GO, having a comparable side-effect profile. It can be a safe second line alternative in patients intolerant to pulse iv methylprednisolone.

Precocious puberty: A blessing in disguise!

Germ cell tumors may lead to incomplete isosexual male precocity and are commonly located in the pineal gland. Germinomas of the basal ganglia are almost always unilateral and precocious puberty is a rare manifestation in them. We report a 9.5-year-old boy who presented with incomplete isosexual precocity due to bilateral basal ganglia germinoma.

Thyroid associated orbitopathy with ocular myasthenia in primary hypothyroidism: Keep those eyes open.

Thyroid associated orbitopathy, although seen most commonly with thyrotoxicosis, is also known to occur in primary hypothyroidism. Myasthenia gravis is an autoimmune condition with an established association with autoimmune thyroid disease. We report the case of a patient who presented with recent onset unilateral ptosis that was fatigable with a history of proptosis since a year. On examination, she had a goiter, bilateral proptosis, restriction of upward gaze and adduction both eyes and normal pupils. Investigations revealed primary hypothyroidism with anti-thyroid peroxidase positive and anti-acetylcholine receptor antibody positive. Computerized tomography orbit showed thickening of medial and inferior rectus characteristic of thyroid orbitopathy. A diagnosis of primary hypothyroidism with thyroid orbitopathy with ocular myasthenia gravis was made. Patient is on Levothyroxine and anticholinesterase medications and is on follow-up. We present this case to highlight that the presence of ptosis in a patient with thyroid orbitopathy should alert the clinician to the possible coexistence of myasthenia gravis.