Objectives High-dose glucocorticoids are associated with improved recovery of deficits in primary... more Objectives High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear. Design We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs 6.5–12 vs >12 weeks) of glucocorticoid treatment according to disease severity. Results A total of 153 PAH patients from 83 publications were included. The median age at presentation was 41 (32.5–48) years with a female preponderance (70.3%). Visual field recovery was significantly better with i.v. (91.7%) as compared to oral (54.5%) route and high dose (100%) and very high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in i.v. (54.8% vs 28.1% oral, P = 0.033) route and increasing gluco...
Purpose: To describe phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our cent... more Purpose: To describe phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our center and perform a systematic review of genetic studies using next-generation sequencing (NGS) in KS. Methods: Seventy-eight KS probands from our center and 398 probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG-guidelines. Molecular diagnosis was de ned as the presence of pathogenic or likely pathogenic variant(s) in known CHH gene/s following zygosity status as per the known mode of genetic inheritance. Result: Molecular diagnosis at our center was observed in 20.5% probands (ANOS1:10.2%, FGFR1: 6.4%, PROKR2: 2.5%, and PROK2, SOX10, FGF8, GNRHR: 1.3% each). Molecular diagnosis was reached more often in patients with severe than partial reproductive phenotype (28.3% vs. 4%, p=0.0013). Our center adds eight novel variants. In a per-patient systematic review (including our cohort), the molecular diagnosis was reached in 30.8%, ranging from 16.6-72.2% at different centers. The affected genes were FGFR1 (9.6%), ANOS1 (7.7%), PROKR2 (6.5%), CHD7 (4.6%), oligogenic (1.9%), FGF8 (1%), SOX10 (1%), and others (PROK2, SEMA3A, IL17RD, GNRHR:<1% each). FGFR1 was the most commonly affected gene in most cohorts except Asia and Brazil, where PROKR2 (in China and Japan) and ANOS1 (in India and Brazil) were the commonest. Conclusion(s): The global molecular diagnosis rate was 30.8% in KS cohorts whereas that in our cohort was 20.5% with a higher rate (28.3%) in those with severe reproductive phenotype. The most commonly affected gene in KS patients was FGFR1 globally, PROKR2 in East Asia, and ANOS1 in India and Brazil.
Budd Chiari syndrome (BCS) commonly affects adolescents and adults. With improved survival, impor... more Budd Chiari syndrome (BCS) commonly affects adolescents and adults. With improved survival, important quality-of-life parameters such as sexual life and fertility become more relevant. This study was aimed to assess the gonadal function in male patients with BCS and the effect of treatment on gonadal function. Thirty male patients with newly diagnosed BCS were prospectively assessed for the presence of gonadal dysfunction. Erectile function was assessed using standardized International Index of Erectile Function questionnaire (IIEF). Follicular stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), estradiol, total testosterone (TT), calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), sperm count, and sperm motility were compared at baseline and at 6 months of treatment for the assessment of gonadal function. Sixteen (53.3%) out of 30 patients were sexually active at the time of study and 5/16 (31%) had erectile dysfunction. Hypogonadotropic hypogonadism (HH) was the most common pattern seen in 50% cases followed by hypergonadotropic hypogonadism (HyH) in 23% cases. 27% patients had eugonadism. At 6 months of treatment, 60% of patients in HH group became eugonadal as compared to only 14% in HyH group. Proportion of patients with erectile dysfunction reduced (5/16 vs 1/16) after 6 months of therapy. The improvement in sperm count and sperm motility was not significant. Gonadal dysfunction is common in male patients with BCS. HH remains the most common type of hypogonadism BCS and the type which improves significantly after treatment.
To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogon... more To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic studies using next-generation sequencing (NGS) in nCHH. Sixty-eight nCHH probands from our center, and 370 nCHH probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG guidelines. Molecular diagnosis was defined as presence of a pathogenic or likely pathogenic variant in a known CHH gene following zygosity status as per known mode of genetic inheritance. At our centre molecular diagnosis was observed in 35.3% of probands {GNRHR:16.2%, FGFR1:7.3%, KISS1R:4.4%, GNRH1:2.9%, TACR3:2.9%, CHD7:1.4%}. Molecular diagnosis was observed more often (44.7% vs 14.3%, p = 0.026) with severe than partial reproductive-phenotype. The study adds 12 novel variants and suggests GNRHR p.Thr32Ala variant may have a founder effect. In per-patient systematic review (including our cohort), the molecular diagnosis was reached in 23.2%, ranging from 3.5 to 46.7% at different centers. The affected genes were FGFR1:6.4%, GNRHR:4.3%, PROKR2:3.6%, TACR3:1.8%, CHD7:1.6%, KISS1R:1.4%, GNRH1:1.4% and others (PROK2, SOX3, SOX10, SOX11, IL17RD, IGSF10, TAC3, ANOS1, oligogenic): < 1% each. FGFR1 was the most commonly affected gene in most cohorts except Asia, whereas PROKR2 (in China and Japan) and GNRHR (in India) were the commonest. (s): The global molecular diagnosis rate was 23.2% in nCHH cohorts whereas that in our cohort was 35% with a higher rate (44.7%) in those with severe reproductive-phenotype. The most commonly affected gene in nCHH patients was FGFR1 globally while it was PROKR2 in East Asia and GNRHR in India.
Supplementary tables for the manuscript "GLP-1 receptor based functional imaging in insulino... more Supplementary tables for the manuscript "GLP-1 receptor based functional imaging in insulinoma localization: Learning continues"
Indian Journal of Endocrinology and Metabolism, 2021
Original Article IntRoductIon Pheochromocytomas (PCCs) and paragangliomas (PGL), also known as PP... more Original Article IntRoductIon Pheochromocytomas (PCCs) and paragangliomas (PGL), also known as PPGL together, are rare tumors arising from chromaffin cells in the adrenal medulla and extra-adrenal paraganglia. PCC and sympathetic paraganglioma (sPGL) usually secrete catecholamines, whereas the parasympathetic head and neck paraganglioma (HNPGL) are usually nonsecretory. [1] Mutations (germline or somatic) in more than 20 susceptible genes (divided into three clusters) are associated with PPGL. Cluster 1-related PPGLs (pseudohypoxia pathway) are characterized by upregulation of hypoxia-inducible factor type 2 alpha (HIF-2α), whereas those associated with cluster 2-related PPGLs are associated with the upregulation of kinase pathway. After biochemical confirmation, localization with anatomical imaging [contrast-enhanced computed tomography (CECT)/ magnetic resonance imaging] is the next step in the evaluation of suspected PPGL. Functional imaging is required in patients with high suspicion for PPGL but negative or inconclusive anatomical imaging or to rule out multifocal/metastatic disease. Recently published European society guidelines (2019) have expanded the indications of functional/molecular imaging in PPGL, which include larger tumors (>5 cm), extra-adrenal PGL, normetanephrine-and/or methoxytyramine PPGL, or Purpose: Pheochromocytoma and paraganglioma (PGL), together called PPGL, are rare tumors with a limited number of studies on the diagnostic performance of 68 Ga-DOTA (0)-Tyr (3)-octreotate positron emission tomography-computed tomography (68 Ga-DOTATATE PET/CT) from the Asian-Indian subcontinent. Materials and Methods: In this retrospective study, PPGL suspects (n = 87) who had undergone at least contrast-enhanced computed tomography (CECT) and 68 Ga-DOTATATE PET/CT, were included. Lesion-wise, patient-wise, and region-wise sensitivities of 68 Ga-DOTATATE PET/CT, 18 F fluorodeoxyglucose positron emission tomography CT (18 F-FDG PET/CT, n = 53), 131 I-metaiodobenzylguanidine (131 I-MIBG, n = 37), and CECT were compared, and diagnostic performance of 68 Ga-DOTATATE PET/CT in the detection of PPGL was calculated. Results: 68 Ga-DOTATATE PET/CT had significantly higher lesion-wise sensitivity than 131 I-MIBG for both primary (94% vs 75%, P = 0.004) and metastatic disease (85% vs 59%, P = 0.001) and higher sensitivity than CECT for metastatic lesions (83% vs 43%, P = 0.0001). The lesion-wise sensitivity of 68 Ga-DOTATATE PET/CT was similar to 18 F-FDG PET/CT for both primary tumors (94% vs 85%, P = 0.08) and metastatic lesions (82% vs 84%, P = 0.76) in the whole cohort but tended to be inferior in the head to head comparison. Conclusion: 68 Ga-DOTATATE PET/CT had higher sensitivity for detection of PPGL than 131 I-MIBG (primary and metastatic) and CECT (metastatic) but similar to 18 F-FDG PET/CT (primary and metastatic).
Journal of Pediatric Endocrinology and Metabolism, 2021
Objectives To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spe... more Objectives To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients with cryptorchidism beyond infancy. Methods This retrospective cohort study included CHH patients with cryptorchidism [bilateral (n=5) or unilateral (n=1)] treated with CGT for testicular descent ± pubertal induction. All participants were treated with CGT [human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG)] with hMG pretreatment in three and monitored for changes in testicular volume (TV), serum total testosterone (T), serum inhibin-B, and sperm concentration. Results Complete testicular descent to the scrotal position was achieved in 5/6 patients (10/11 testes) after 4.7 ± 1.6 months of treatment. There was 44 ± 18%, 97.5% (IQR: 44–195), 10-fold (IQR: 3–19.6), and two-fold (IQR: 1.7–9.3) increase in stretched penile length, ultrasound measured TV, T level, and serum inhibin-B from baseline, ...
Objective: As GNRH1 genotype-phenotype correlation in CHH is not well studied, we aim to describe... more Objective: As GNRH1 genotype-phenotype correlation in CHH is not well studied, we aim to describe the GNRH1 variants in our CHH cohort and present a systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in the world literature. Design: This is a retrospective study of GNRH1 mutation-positive patients from a western Indian center. PRISMA guidelines-based PubMed search of the published literature of all GNRH1 mutation-positive patients was conducted. Setting: This study was conducted in an academic medical center. Patient(s): This study included 2 probands from our cohort and 19 probands from the world literature. Main Outcome Measure(s): Demographic details, clinical presentation, biochemistry, imaging, treatment details, and genotypic data were recorded. Result(s): Two probands in our cohort carried two novel pathogenic biallelic GNRH1 variants (p.Glu24Leu, c.238-2A>G). Both had a severe reproductive phenotype. We report successful gonad...
Journal of Pediatric Endocrinology and Metabolism, 2020
Objectives We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe... more Objectives We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe hypophosphatemic rickets with delayed diagnosis and emphasize on timely management of this rare entity. Case presentation A young boy presented with rickets since five years of age. Biochemical evaluation revealed hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase and normal calcium levels. Initially managed as hereditary hypophosphatemic rickets, he was given phosphorus supplements and calcitriol. Despite the therapy, skeletal deformities worsened requiring surgical corrections. Subsequently, he developed iatrogenic tertiary hyperparathyroidism for which he underwent total parathyroidectomy. Later on, he was found to have fibroblast growth factor-23 secreting thoracic mass (10.5 cm in largest dimension) which was excised with significant post operative improvement. Histopathology showed phosphaturic mesenchymal tumor-mixed connective tissue variant, confirming the diagn...
The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocri... more The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJ...
Introduction: The role of glucocorticoids in primary autoimmune hypophysitis (PAH) has been fraug... more Introduction: The role of glucocorticoids in primary autoimmune hypophysitis (PAH) has been fraught with variability in regimens, leading to inconsistent outcomes in terms of anterior pituitary (AP) hormonal recovery. Hence, we aimed to compare the clinical, hormonal, and radiological outcomes of a standardized high-dose glucocorticoid therapy group (GTG) in PAH with a matched clinical observation group (COG). Methods: Thirty-nine retrospective patients with PAH evaluated and treated at a single center in western India from 1999 to 2019 with a median follow-up duration of 48 months were subdivided into the GTG (n = 18) and COG (n = 21) and compared for the outcomes. Results: Baseline demographic, hormonal, and radiological features matched between the groups, except pituitary height, which was significantly higher in GTG. Cortisol, thyroid, and gonadal axes were affected in 25 (64%), 22 (56%), and 21 (54%) patients, respectively, and central diabetes insipidus was seen in 7 (18%) pa...
Introduction: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising th... more Introduction: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/or inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/or inoperable PPGL. Methods: This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (plasma-free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy. Results: A total of 15 patients (4 PCC, 4 sPGL, 5 HNPGL, 1 PCC + sPGL, 1 HNPGL + sPGL) were included. The median duration of follow up was 27 (range: 11–62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53%), partial response in one (7%), and minor response in three (20%) and controlled dis...
Literature regarding utility of 68Ga‐DOTATATE PET/CT in insulinoma localization across various su... more Literature regarding utility of 68Ga‐DOTATATE PET/CT in insulinoma localization across various subgroups [benign/malignant/multiple endocrine neoplasia‐1 (MEN‐1) syndrome associated] remains scarce. In this study, the performance of 68Ga‐DOTATATE PET/CT was compared with contrast‐enhanced computed tomography (CECT) and 68Ga‐NODAGA‐Exendin‐4 PET/CT (whenever available) in an endogenous hyperinsulinemic hypoglycemia (EHH) cohort.
Glucagon‑like peptide‑1 receptor (GLP‐1 R) based imaging has shown higher sensitivity for insulin... more Glucagon‑like peptide‑1 receptor (GLP‐1 R) based imaging has shown higher sensitivity for insulinoma localization as compared to other anatomic/functional imaging.
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Data are limited regarding prevalence, predictors, and mechanisms of persistent hypogonad... more Context Data are limited regarding prevalence, predictors, and mechanisms of persistent hypogonadotropic hypogonadism (HH) in males with a macroprolactinoma who achieve normoprolactinemia on dopamine-agonist therapy. None of the previous studies provide cutoffs to predict the achievement of eugonadism. Objective The objective of this work is to evaluate the prevalence of persistent HH and its determinants in men with a macroprolactinoma who achieve normoprolactinemia on cabergoline monotherapy. Design and Setting This retrospective study with prospective cross-sectional evaluation took place at a tertiary health care center. Patients Study participants included men with a macroprolactinoma and baseline HH who achieved normoprolactinemia on cabergoline monotherapy. Main Outcome Measures Outcome measures of this study included the prevalence of persistent HH and its predictors. Results Thirty participants (age, 38.3 ± 10.1 years) with baseline tumor size of 4.08 ± 1.48 cm and median (...
Objective To study the effect of prior testosterone replacement therapy (TRT) on the spermatogeni... more Objective To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients. Design Retrospective cohort study. Setting Tertiary care center. Patients Patients of CHH without (n = 17) and with prior TRT (n = 18) were subdivided into severe and partial groups, based on mean testicular volume ≤ 3 cc and > 3 cc respectively. Intervention Participants were treated with hMG at a dose of 75-150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of ≥ 3.5 ng/ml was reached. Main outcome measures Final mean TV, trough serum testosterone (T), sperm concentration Results Thirty-five patients (20 severe, baseline mean TV of 3.6 ± 2.7 ml) were started on CGT at 24.8 ± 6.1 years. The median duration of prior TRT was 38 (IQR 10-63.75) months in the exposed group. After 33 ± 12 months, final mean TV was 8.9 ± 5.5 ml, 86% achieved serum testosterone > 3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0-12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior-TRT (median 9 vs 0.05 million/ml, p = 0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p = 0.01). Conclusion Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.
Insulinoma needs accurate preoperative localization for minimally invasive surgery. Exendin‐4‐bas... more Insulinoma needs accurate preoperative localization for minimally invasive surgery. Exendin‐4‐based imaging has shown promising results.
Objectives High-dose glucocorticoids are associated with improved recovery of deficits in primary... more Objectives High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear. Design We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs 6.5–12 vs >12 weeks) of glucocorticoid treatment according to disease severity. Results A total of 153 PAH patients from 83 publications were included. The median age at presentation was 41 (32.5–48) years with a female preponderance (70.3%). Visual field recovery was significantly better with i.v. (91.7%) as compared to oral (54.5%) route and high dose (100%) and very high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in i.v. (54.8% vs 28.1% oral, P = 0.033) route and increasing gluco...
Purpose: To describe phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our cent... more Purpose: To describe phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our center and perform a systematic review of genetic studies using next-generation sequencing (NGS) in KS. Methods: Seventy-eight KS probands from our center and 398 probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG-guidelines. Molecular diagnosis was de ned as the presence of pathogenic or likely pathogenic variant(s) in known CHH gene/s following zygosity status as per the known mode of genetic inheritance. Result: Molecular diagnosis at our center was observed in 20.5% probands (ANOS1:10.2%, FGFR1: 6.4%, PROKR2: 2.5%, and PROK2, SOX10, FGF8, GNRHR: 1.3% each). Molecular diagnosis was reached more often in patients with severe than partial reproductive phenotype (28.3% vs. 4%, p=0.0013). Our center adds eight novel variants. In a per-patient systematic review (including our cohort), the molecular diagnosis was reached in 30.8%, ranging from 16.6-72.2% at different centers. The affected genes were FGFR1 (9.6%), ANOS1 (7.7%), PROKR2 (6.5%), CHD7 (4.6%), oligogenic (1.9%), FGF8 (1%), SOX10 (1%), and others (PROK2, SEMA3A, IL17RD, GNRHR:<1% each). FGFR1 was the most commonly affected gene in most cohorts except Asia and Brazil, where PROKR2 (in China and Japan) and ANOS1 (in India and Brazil) were the commonest. Conclusion(s): The global molecular diagnosis rate was 30.8% in KS cohorts whereas that in our cohort was 20.5% with a higher rate (28.3%) in those with severe reproductive phenotype. The most commonly affected gene in KS patients was FGFR1 globally, PROKR2 in East Asia, and ANOS1 in India and Brazil.
Budd Chiari syndrome (BCS) commonly affects adolescents and adults. With improved survival, impor... more Budd Chiari syndrome (BCS) commonly affects adolescents and adults. With improved survival, important quality-of-life parameters such as sexual life and fertility become more relevant. This study was aimed to assess the gonadal function in male patients with BCS and the effect of treatment on gonadal function. Thirty male patients with newly diagnosed BCS were prospectively assessed for the presence of gonadal dysfunction. Erectile function was assessed using standardized International Index of Erectile Function questionnaire (IIEF). Follicular stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), estradiol, total testosterone (TT), calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), sperm count, and sperm motility were compared at baseline and at 6 months of treatment for the assessment of gonadal function. Sixteen (53.3%) out of 30 patients were sexually active at the time of study and 5/16 (31%) had erectile dysfunction. Hypogonadotropic hypogonadism (HH) was the most common pattern seen in 50% cases followed by hypergonadotropic hypogonadism (HyH) in 23% cases. 27% patients had eugonadism. At 6 months of treatment, 60% of patients in HH group became eugonadal as compared to only 14% in HyH group. Proportion of patients with erectile dysfunction reduced (5/16 vs 1/16) after 6 months of therapy. The improvement in sperm count and sperm motility was not significant. Gonadal dysfunction is common in male patients with BCS. HH remains the most common type of hypogonadism BCS and the type which improves significantly after treatment.
To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogon... more To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic studies using next-generation sequencing (NGS) in nCHH. Sixty-eight nCHH probands from our center, and 370 nCHH probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG guidelines. Molecular diagnosis was defined as presence of a pathogenic or likely pathogenic variant in a known CHH gene following zygosity status as per known mode of genetic inheritance. At our centre molecular diagnosis was observed in 35.3% of probands {GNRHR:16.2%, FGFR1:7.3%, KISS1R:4.4%, GNRH1:2.9%, TACR3:2.9%, CHD7:1.4%}. Molecular diagnosis was observed more often (44.7% vs 14.3%, p = 0.026) with severe than partial reproductive-phenotype. The study adds 12 novel variants and suggests GNRHR p.Thr32Ala variant may have a founder effect. In per-patient systematic review (including our cohort), the molecular diagnosis was reached in 23.2%, ranging from 3.5 to 46.7% at different centers. The affected genes were FGFR1:6.4%, GNRHR:4.3%, PROKR2:3.6%, TACR3:1.8%, CHD7:1.6%, KISS1R:1.4%, GNRH1:1.4% and others (PROK2, SOX3, SOX10, SOX11, IL17RD, IGSF10, TAC3, ANOS1, oligogenic): < 1% each. FGFR1 was the most commonly affected gene in most cohorts except Asia, whereas PROKR2 (in China and Japan) and GNRHR (in India) were the commonest. (s): The global molecular diagnosis rate was 23.2% in nCHH cohorts whereas that in our cohort was 35% with a higher rate (44.7%) in those with severe reproductive-phenotype. The most commonly affected gene in nCHH patients was FGFR1 globally while it was PROKR2 in East Asia and GNRHR in India.
Supplementary tables for the manuscript "GLP-1 receptor based functional imaging in insulino... more Supplementary tables for the manuscript "GLP-1 receptor based functional imaging in insulinoma localization: Learning continues"
Indian Journal of Endocrinology and Metabolism, 2021
Original Article IntRoductIon Pheochromocytomas (PCCs) and paragangliomas (PGL), also known as PP... more Original Article IntRoductIon Pheochromocytomas (PCCs) and paragangliomas (PGL), also known as PPGL together, are rare tumors arising from chromaffin cells in the adrenal medulla and extra-adrenal paraganglia. PCC and sympathetic paraganglioma (sPGL) usually secrete catecholamines, whereas the parasympathetic head and neck paraganglioma (HNPGL) are usually nonsecretory. [1] Mutations (germline or somatic) in more than 20 susceptible genes (divided into three clusters) are associated with PPGL. Cluster 1-related PPGLs (pseudohypoxia pathway) are characterized by upregulation of hypoxia-inducible factor type 2 alpha (HIF-2α), whereas those associated with cluster 2-related PPGLs are associated with the upregulation of kinase pathway. After biochemical confirmation, localization with anatomical imaging [contrast-enhanced computed tomography (CECT)/ magnetic resonance imaging] is the next step in the evaluation of suspected PPGL. Functional imaging is required in patients with high suspicion for PPGL but negative or inconclusive anatomical imaging or to rule out multifocal/metastatic disease. Recently published European society guidelines (2019) have expanded the indications of functional/molecular imaging in PPGL, which include larger tumors (>5 cm), extra-adrenal PGL, normetanephrine-and/or methoxytyramine PPGL, or Purpose: Pheochromocytoma and paraganglioma (PGL), together called PPGL, are rare tumors with a limited number of studies on the diagnostic performance of 68 Ga-DOTA (0)-Tyr (3)-octreotate positron emission tomography-computed tomography (68 Ga-DOTATATE PET/CT) from the Asian-Indian subcontinent. Materials and Methods: In this retrospective study, PPGL suspects (n = 87) who had undergone at least contrast-enhanced computed tomography (CECT) and 68 Ga-DOTATATE PET/CT, were included. Lesion-wise, patient-wise, and region-wise sensitivities of 68 Ga-DOTATATE PET/CT, 18 F fluorodeoxyglucose positron emission tomography CT (18 F-FDG PET/CT, n = 53), 131 I-metaiodobenzylguanidine (131 I-MIBG, n = 37), and CECT were compared, and diagnostic performance of 68 Ga-DOTATATE PET/CT in the detection of PPGL was calculated. Results: 68 Ga-DOTATATE PET/CT had significantly higher lesion-wise sensitivity than 131 I-MIBG for both primary (94% vs 75%, P = 0.004) and metastatic disease (85% vs 59%, P = 0.001) and higher sensitivity than CECT for metastatic lesions (83% vs 43%, P = 0.0001). The lesion-wise sensitivity of 68 Ga-DOTATATE PET/CT was similar to 18 F-FDG PET/CT for both primary tumors (94% vs 85%, P = 0.08) and metastatic lesions (82% vs 84%, P = 0.76) in the whole cohort but tended to be inferior in the head to head comparison. Conclusion: 68 Ga-DOTATATE PET/CT had higher sensitivity for detection of PPGL than 131 I-MIBG (primary and metastatic) and CECT (metastatic) but similar to 18 F-FDG PET/CT (primary and metastatic).
Journal of Pediatric Endocrinology and Metabolism, 2021
Objectives To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spe... more Objectives To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients with cryptorchidism beyond infancy. Methods This retrospective cohort study included CHH patients with cryptorchidism [bilateral (n=5) or unilateral (n=1)] treated with CGT for testicular descent ± pubertal induction. All participants were treated with CGT [human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG)] with hMG pretreatment in three and monitored for changes in testicular volume (TV), serum total testosterone (T), serum inhibin-B, and sperm concentration. Results Complete testicular descent to the scrotal position was achieved in 5/6 patients (10/11 testes) after 4.7 ± 1.6 months of treatment. There was 44 ± 18%, 97.5% (IQR: 44–195), 10-fold (IQR: 3–19.6), and two-fold (IQR: 1.7–9.3) increase in stretched penile length, ultrasound measured TV, T level, and serum inhibin-B from baseline, ...
Objective: As GNRH1 genotype-phenotype correlation in CHH is not well studied, we aim to describe... more Objective: As GNRH1 genotype-phenotype correlation in CHH is not well studied, we aim to describe the GNRH1 variants in our CHH cohort and present a systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in the world literature. Design: This is a retrospective study of GNRH1 mutation-positive patients from a western Indian center. PRISMA guidelines-based PubMed search of the published literature of all GNRH1 mutation-positive patients was conducted. Setting: This study was conducted in an academic medical center. Patient(s): This study included 2 probands from our cohort and 19 probands from the world literature. Main Outcome Measure(s): Demographic details, clinical presentation, biochemistry, imaging, treatment details, and genotypic data were recorded. Result(s): Two probands in our cohort carried two novel pathogenic biallelic GNRH1 variants (p.Glu24Leu, c.238-2A>G). Both had a severe reproductive phenotype. We report successful gonad...
Journal of Pediatric Endocrinology and Metabolism, 2020
Objectives We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe... more Objectives We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe hypophosphatemic rickets with delayed diagnosis and emphasize on timely management of this rare entity. Case presentation A young boy presented with rickets since five years of age. Biochemical evaluation revealed hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase and normal calcium levels. Initially managed as hereditary hypophosphatemic rickets, he was given phosphorus supplements and calcitriol. Despite the therapy, skeletal deformities worsened requiring surgical corrections. Subsequently, he developed iatrogenic tertiary hyperparathyroidism for which he underwent total parathyroidectomy. Later on, he was found to have fibroblast growth factor-23 secreting thoracic mass (10.5 cm in largest dimension) which was excised with significant post operative improvement. Histopathology showed phosphaturic mesenchymal tumor-mixed connective tissue variant, confirming the diagn...
The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocri... more The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJ...
Introduction: The role of glucocorticoids in primary autoimmune hypophysitis (PAH) has been fraug... more Introduction: The role of glucocorticoids in primary autoimmune hypophysitis (PAH) has been fraught with variability in regimens, leading to inconsistent outcomes in terms of anterior pituitary (AP) hormonal recovery. Hence, we aimed to compare the clinical, hormonal, and radiological outcomes of a standardized high-dose glucocorticoid therapy group (GTG) in PAH with a matched clinical observation group (COG). Methods: Thirty-nine retrospective patients with PAH evaluated and treated at a single center in western India from 1999 to 2019 with a median follow-up duration of 48 months were subdivided into the GTG (n = 18) and COG (n = 21) and compared for the outcomes. Results: Baseline demographic, hormonal, and radiological features matched between the groups, except pituitary height, which was significantly higher in GTG. Cortisol, thyroid, and gonadal axes were affected in 25 (64%), 22 (56%), and 21 (54%) patients, respectively, and central diabetes insipidus was seen in 7 (18%) pa...
Introduction: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising th... more Introduction: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/or inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/or inoperable PPGL. Methods: This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (plasma-free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy. Results: A total of 15 patients (4 PCC, 4 sPGL, 5 HNPGL, 1 PCC + sPGL, 1 HNPGL + sPGL) were included. The median duration of follow up was 27 (range: 11–62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53%), partial response in one (7%), and minor response in three (20%) and controlled dis...
Literature regarding utility of 68Ga‐DOTATATE PET/CT in insulinoma localization across various su... more Literature regarding utility of 68Ga‐DOTATATE PET/CT in insulinoma localization across various subgroups [benign/malignant/multiple endocrine neoplasia‐1 (MEN‐1) syndrome associated] remains scarce. In this study, the performance of 68Ga‐DOTATATE PET/CT was compared with contrast‐enhanced computed tomography (CECT) and 68Ga‐NODAGA‐Exendin‐4 PET/CT (whenever available) in an endogenous hyperinsulinemic hypoglycemia (EHH) cohort.
Glucagon‑like peptide‑1 receptor (GLP‐1 R) based imaging has shown higher sensitivity for insulin... more Glucagon‑like peptide‑1 receptor (GLP‐1 R) based imaging has shown higher sensitivity for insulinoma localization as compared to other anatomic/functional imaging.
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Data are limited regarding prevalence, predictors, and mechanisms of persistent hypogonad... more Context Data are limited regarding prevalence, predictors, and mechanisms of persistent hypogonadotropic hypogonadism (HH) in males with a macroprolactinoma who achieve normoprolactinemia on dopamine-agonist therapy. None of the previous studies provide cutoffs to predict the achievement of eugonadism. Objective The objective of this work is to evaluate the prevalence of persistent HH and its determinants in men with a macroprolactinoma who achieve normoprolactinemia on cabergoline monotherapy. Design and Setting This retrospective study with prospective cross-sectional evaluation took place at a tertiary health care center. Patients Study participants included men with a macroprolactinoma and baseline HH who achieved normoprolactinemia on cabergoline monotherapy. Main Outcome Measures Outcome measures of this study included the prevalence of persistent HH and its predictors. Results Thirty participants (age, 38.3 ± 10.1 years) with baseline tumor size of 4.08 ± 1.48 cm and median (...
Objective To study the effect of prior testosterone replacement therapy (TRT) on the spermatogeni... more Objective To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients. Design Retrospective cohort study. Setting Tertiary care center. Patients Patients of CHH without (n = 17) and with prior TRT (n = 18) were subdivided into severe and partial groups, based on mean testicular volume ≤ 3 cc and > 3 cc respectively. Intervention Participants were treated with hMG at a dose of 75-150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of ≥ 3.5 ng/ml was reached. Main outcome measures Final mean TV, trough serum testosterone (T), sperm concentration Results Thirty-five patients (20 severe, baseline mean TV of 3.6 ± 2.7 ml) were started on CGT at 24.8 ± 6.1 years. The median duration of prior TRT was 38 (IQR 10-63.75) months in the exposed group. After 33 ± 12 months, final mean TV was 8.9 ± 5.5 ml, 86% achieved serum testosterone > 3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0-12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior-TRT (median 9 vs 0.05 million/ml, p = 0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p = 0.01). Conclusion Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.
Insulinoma needs accurate preoperative localization for minimally invasive surgery. Exendin‐4‐bas... more Insulinoma needs accurate preoperative localization for minimally invasive surgery. Exendin‐4‐based imaging has shown promising results.
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Papers by RAVIKUMAR SHAH