Publications by authors named "Tushar Bandgar"

160 Publications

Giant prolactinoma in children and adolescents: a single-center experience and systematic review.

Pituitary 2022 Jul 18. Epub 2022 Jul 18.

Department of Endocrinology and Metabolism, Seth G S Medical College & KEM Hospital, Parel, Mumbai, 400012, Maharashtra, India.

Purpose: Giant prolactinoma (GP) in childhood and adolescence is a rare entity with scarce literature. We aimed to describe clinical features, biochemistry, radiology, genetics, management, and outcome in pediatric (≤ 20 years) GP.

Methods: Retrospective record review of 18 pediatric GP patients from our center and systematic review including these and 77 from the literature (total cohort: 95).

Results: GP constituted 20% of our pediatric prolactinoma cohort. In the total cohort (age: 15.4 ± 3.5 years), the majority (77, 82.8%) were males. Mass effect symptoms (88.6%), and pubertal delay/arrest in males (82.1%) were frequent. Median basal prolactin was 8649 (3246-17,532) ng/ml and the maximum tumor dimension was 5.5 ± 1.5 cm. MEN1 and AIP mutations were noted in 7 (21.9%) and 6 (18.8%) patients, respectively. Males with central hypogonadism had baseline bi-testicular volume of 20.2 ± 8.4 cc, lower LH than FSH (-2.04 ± 0.9 vs. -0.7 ± 1.6 SDS, p = 0.0075), and mostly, normal inhibin B. Majority (49/76, 64.5%) received dopamine agonist (DA) as first-line treatment with additional therapy in 35% (17/49). DA monotherapy arm had less frequent central hypothyroidism (42.9% vs 87.1%, p = 0.002) and central adrenal insufficiency (7.1% vs 66.7%, p = 0.0003) than multimodal therapy. A smaller tumor dimension (4.7 vs. 5.7 cm, p = 0.04) was associated with normoprolactinemia on DA monotherapy and AIP mutations (33.3% vs. nil, p = 0.02) with multimodal therapy.

Conclusion: GP is characterized by male predominance with frequent delay/arrest of puberty (82%), but relative sparing of the FSH-inhibin B axis in boys. DA monotherapy may be preferred as the first-line therapy in pediatric GP.
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http://dx.doi.org/10.1007/s11102-022-01250-yDOI Listing
July 2022

Pituitary stalk interruption syndrome: phenotype, predictors, and pathophysiology of perinatal events.

Pituitary 2022 Aug 24;25(4):645-652. Epub 2022 Jun 24.

Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India.

Purpose: There is limited data regarding Pituitary Stalk Interruption Syndrome (PSIS) from India. Moreover, the pathophysiological link between perinatal events and PSIS is unclear. We aim to elucidate the predictors of PSIS among patients with growth hormone deficiency (GHD) and perinatal events in PSIS by comparing cohorts of PSIS and genetically proven GHD without PSIS.

Methods: Among 179 GHD patients, 56 PSIS and 70 genetically positive GHD (52-GHRHR, 15-POU1F1, and 3-PROP1) patients were included. Perinatal events, clinical anomalies, pituitary hormone deficiency, and imaging findings were recorded. We compared PSIS-isolated GHD (PSIS-IGHD) subgroup with GHRHR-IGHD and PSIS-combined pituitary hormone deficiency (PSIS-CPHD) subgroup with POU1F1/PROP1-CPHD.

Results: PSIS patients (45 males, median age: 12.5 years) most commonly presented with short stature. At last follow-up (median age: 17.35 years), gonadal (during pubertal-age), thyroid and cortisol axes were affected in 81.6%, 62.5%, and 62.5%. 10/13 (77%) of PSIS children with initial IGHD diagnosis manifested hypogonadism during pubertal age. Male predominance, sporadic presentation, and clinical anomalies were significantly higher in both PSIS subgroups than in the respective genetic subgroups. Breech presentation was higher in PSIS-CPHD than POU1F1/PROP1-CPHD (44.4% vs 5.5%, p = 0.004). Neonatal hypoglycemia (22% vs. 0%, p = 0.05) and jaundice (42 vs. 5%, p = 0.004) were higher in PSIS-CPHD than PSIS-IGHD.

Conclusion: Later age at presentation and frequent hypogonadism were observed in our PSIS cohort. Male sex, sporadic presentation, clinical anomalies, and breech presentation predicted PSIS at presentation. Breech presentation in PSIS is likely due to stalk interruption rather than hormonal deficiency.
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http://dx.doi.org/10.1007/s11102-022-01243-xDOI Listing
August 2022

Role of Preoperative Blockade in Pheochromocytoma-Paraganglioma: A Clinician's Perspective.

Indian J Endocrinol Metab 2022 Jan-Feb;26(1):30-31. Epub 2022 Apr 27.

Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, Maharashtra, India.

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http://dx.doi.org/10.4103/2230-8210.343877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162254PMC
April 2022

Percentage arterial enhancement on 2D CT in the diagnosis of primary hyperparathyroidism: A prospective validation study and potential pitfalls.

Head Neck 2022 08 31;44(8):1849-1856. Epub 2022 May 31.

Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India.

Background: Parathyroid lesions are identified by subjective enhancement and washout patterns on computed tomography (CT). We have previously proposed "percentage arterial enhancement" (PAE) as an objective index and now aim to validate its performance prospectively.

Methods: Dual-phase CT was performed in 40 consecutive primary hyperparathyroidism patients. PAE was calculated as [{arterial phase Hounsfield unit (HU)-unenhanced phase HU}/unenhanced phase HU] × 100. PAE > 128.9% was considered parathyroid.

Results: PAE had 94.2% sensitivity, 100% positive predictive value (PPV) in lateralization, and sensitivity and PPV of 93.9% in quadrant localization of single-gland disease. PAE failed to identify two lesions: an intrathyroidal parathyroid carcinoma in the background of multinodular goiter and another lower enhancing cystic parathyroid adenoma. PAE had 60% sensitivity, and 100% PPV to identify multigland disease. The mean effective dose was 2.74 mSV.

Conclusions: PAE is a specific CT index for parathyroid lesions with less radiation exposure. Areas of caution include intrathyroidal and cystic lesions.
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http://dx.doi.org/10.1002/hed.27108DOI Listing
August 2022

Genotype-Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism.

Calcif Tissue Int 2022 May 14. Epub 2022 May 14.

Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, 400012, India.

Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.
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http://dx.doi.org/10.1007/s00223-022-00985-xDOI Listing
May 2022

Luteinizing hormone β-subunit deficiency: Report of a novel LHB likely pathogenic variant and a systematic review of the published literature.

Clin Endocrinol (Oxf) 2022 Apr 25. Epub 2022 Apr 25.

Department of Endocrinology, Seth G. S. Medical College & KEM Hospital, Mumbai, India.

Context: Selective deficiency of β-subunit of luteinizing hormone (LHB) is a rare disease with scarce data on its characteristics.

Objectives: To describe a male with LHB deficiency and systematically review the literature.

Design And Patients: Description of a male patient with LHB deficiency and a systematic review of LHB deficiency patients published to date (10 males and 3 females) as per PRISMA guidelines.

Results: A 36-year-old Asian Indian male presented with infertility. On evaluation, he had sexual maturity of Tanner's stage 3, low testosterone (0.23 ng/ml), low LH (0.44 mIU/ml), high follicle-stimulating hormone (FSH, 22.4 mIU/ml), and a novel homozygous missense likely pathogenic variant (p.Cys46Arg) in LHB. In the molecular dynamics simulation study, this variant interferes with heterodimerization of alpha-beta subunits. Eleven males with pathogenic variants in LHB reported to date, presented at a median age of 29 (17-38) years, most commonly with delayed puberty. Clinical and biochemical profiles were similar to those of our patient. In the majority, testosterone monotherapy modestly increased testicular volume whereas human chorionic gonadotropin (hCG) monotherapy also improved spermatogenesis. In females, oligomenorrhoea after spontaneous menarche was the most common manifestation. Ten pathogenic/likely pathogenic variants (three in-frame deletions, three missense, two splice-site, one nonsense, and one frameshift variants) have been reported in nine index patients.

Conclusion: We report a novel likely pathogenic LHB variant in an Asian Indian patient. The typical phenotype in male patients with LHB deficiency is delayed puberty with low testosterone, low LH, and normal to high FSH and hCG monotherapy being the best therapeutic option.
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http://dx.doi.org/10.1111/cen.14749DOI Listing
April 2022

Gonadal dysfunction in male patients with Budd Chiari syndrome and its reversibility with treatment.

Hepatol Int 2022 Jun 17;16(3):640-648. Epub 2022 Mar 17.

Department of Gastroenterology, Seth G S Medical College and KEM Hospital, Parel, Mumbai, 400012, India.

Background And Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s12072-022-10316-9DOI Listing
June 2022

The Utility of Ga-DOTATATE PET/CT in Localizing Primary/Metastatic Pheochromocytoma and Paraganglioma: Asian Indian Experience.

Indian J Endocrinol Metab 2021 Sep-Oct;25(5):410-417. Epub 2022 Jan 12.

Department of Endocrinology, Seth G.S Medical College and KEM Hospital, Mumbai, Maharashtra, India.

Purpose: Pheochromocytoma and paraganglioma (PGL), together called PPGL, are rare tumors with a limited number of studies on the diagnostic performance of Ga-DOTA (0)-Tyr (3)-octreotate positron emission tomography-computed tomography (Ga-DOTATATE PET/CT) from the Asian-Indian subcontinent.

Materials And Methods: In this retrospective study, PPGL suspects ( = 87) who had undergone at least contrast-enhanced computed tomography (CECT) and Ga-DOTATATE PET/CT, were included. Lesion-wise, patient-wise, and region-wise sensitivities of Ga-DOTATATE PET/CT, F fluorodeoxyglucose positron emission tomography CT (F-FDG PET/CT, = 53), I-metaiodobenzylguanidine (I-MIBG, = 37), and CECT were compared, and diagnostic performance of Ga-DOTATATE PET/CT in the detection of PPGL was calculated.

Results: Ga-DOTATATE PET/CT had significantly higher lesion-wise sensitivity than I-MIBG for both primary (94% vs 75%, = 0.004) and metastatic disease (85% vs 59%, = 0.001) and higher sensitivity than CECT for metastatic lesions (83% vs 43%, = 0.0001). The lesion-wise sensitivity of Ga-DOTATATE PET/CT was similar to F-FDG PET/CT for both primary tumors (94% vs 85%, = 0.08) and metastatic lesions (82% vs 84%, = 0.76) in the whole cohort but tended to be inferior in the head to head comparison.

Conclusion: Ga-DOTATATE PET/CT had higher sensitivity for detection of PPGL than I-MIBG (primary and metastatic) and CECT (metastatic) but similar to F-FDG PET/CT (primary and metastatic).
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http://dx.doi.org/10.4103/ijem.ijem_307_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923324PMC
January 2022

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature.

J Endocr Soc 2022 Mar 29;6(3):bvac011. Epub 2022 Jan 29.

Department of Endocrinology, Seth G S Medical College & KEM Hospital, Mumbai 400012, India.

Context: There are more than 100 pathogenic variants in that have been identified in patients with 17α-hydroxylase/17,20-lyase deficiency (17OHD).

Objective: We aimed to describe 46,XY patients with 17OHD from our center and review the literature.

Methods: We retrospectively analyzed genetically proven index cases of 17OHD from our 46,XY disorders of sex development cohort and reviewed similar cases from the literature (n = 150). Based on the phenotype, 17OHD probands were classified into combined severe deficiency (n = 128) and combined partial deficiency (n = 16). Additionally, patients with the apparent isolated 17,20-lyase deficiency (n = 7, from 6 families) were noted. Residual enzyme activities with the observed mutant enzymes were divided in 2 categories as < 1% and ≥ 1%, each for hydroxylase and lyase.

Results: We present 4 index cases of 46,XY 17OHD with a complete spectrum of undervirilization and 2 novel variants in . In the review, the combined severe deficiency was the most common form, with more frequent female sex of rearing, hypertension, hypokalemia, suppressed renin, higher plasma corticotropin, lower serum cortisol, and androgens. Immunoassay-measured serum aldosterone was frequently (68.2%) unsuppressed (>5 ng/dL). Elevated serum progesterone had high sensitivity for diagnosis of combined 17OHD, even in combined partial deficiency (83.3%). Among patients with clinical phenotype of combined severe deficiency, 11.5% had partial 17α-hydroxylase and complete 17,20-lyase deficiency (>1%/<1%) and had significantly higher serum cortisol than those with < 1%/<1% activity.

Conclusion: We report the first monocentric case series of Asian Indian 46,XY patients with 17OHD. We propose that a phenotype of severe undervirilization with milder cortisol deficiency may represent a distinct subtype of combined severe 17OHD with residual 17α-hydroxylase activity but severe 17,20-lyase deficiency (>1%/<1%), which needs further validation.
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http://dx.doi.org/10.1210/jendso/bvac011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845120PMC
March 2022

17β hydroxysteroid dehydrogenase 3 deficiency in 46,XY disorders of sex development: Our experience and a gender role-focused systematic review.

Clin Endocrinol (Oxf) 2022 Jul 27;97(1):43-51. Epub 2022 Feb 27.

Department of Endocrinology, Seth G S Medical College & KEM Hospital, Mumbai, Maharashtra, India.

Objectives: To describe Asian Indian patients with 17β hydroxysteroid dehydrogenase 3 (17βHSD3) deficiency and to perform a systematic review to determine the factors influencing gender role in 46,XY disorder of sex development (DSD) due to 17βHSD3 deficiency.

Patients And Design: We present the phenotypic and genotypic data of 10 patients (9 probands and 1 affected family member) with 17βHSD3 deficiency from our 46,XY DSD cohort (N = 150; Western India) and a systematic review of 152 probands with genetically proven, index 17βHSD3 deficiency patients from the world literature to identify the determinants of gender role.

Results: 17βHSD3 deficiency was the third most common (6%) cause of non-dysgenetic 46,XY DSD in our cohort. Five patients each had prepubertal (atypical genitalia) and pubertal (primary amenorrhoea) presentations. Six patients were initially reared as female of whom two (one each in prepubertal and pubertal age) changed their gender role. Ten pathogenic molecular variants (six novel) were observed. In the systematic review, initial male sex of rearing was uncommon (10.5%) and was associated with atypical genitalia, higher testosterone/androstenedione (T/A) ratio and Asian origin. Gender role change to male was seen in 10.3% of patients with initial female sex of rearing and was associated with Asian origin but unrelated to pubertal androgens or molecular variant severity. It has not been reported in patients of European origin.

Conclusions: We report the first Indian case series of 17βHSD3 deficiency, the third most common cause of 46,XY DSD, with six novel molecular variants. Distinct geographical differences in the frequency of initial male sex of rearing and gender role change to male in those initially reared as females in 17βHSD3 deficiency were noted which needs further evaluation for the underlying molecular mechanisms.
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http://dx.doi.org/10.1111/cen.14694DOI Listing
July 2022

Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review.

Pituitary 2022 Jun 8;25(3):444-453. Epub 2022 Feb 8.

Department of Endocrinology, Seth G S Medical College and KEM Hospital, Parel, Mumbai, 400012, Maharashtra, India.

Purpose: 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.

Methods: 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.

Result: 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.

Conclusion: (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.
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http://dx.doi.org/10.1007/s11102-022-01209-zDOI Listing
June 2022

Clinical Spectrum of Adrenal Cushing's Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience.

Horm Metab Res 2022 Feb 7;54(2):57-66. Epub 2022 Feb 7.

Department of Endocrinology, Seth G. S. Medical College and KEM Hospital, Mumbai, India.

To describe the differences in presentation, biochemistry, and radiological evaluation of various etiologies of adrenal Cushing's syndrome (CS) from a single center. To emphasize caution for interpretation of plasma adrenocorticotropic hormone (ACTH), as a spuriously unsuppressed ACTH level by immunometric assay may lead to therapeutic misadventures in adrenal CS.

Design:  Retrospective, single-center, observational study.

Methods:   Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed.

Results:   Cortisol secreting ACC presented at 38(1-50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9-40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state.

Conclusions:   Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.
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http://dx.doi.org/10.1055/a-1735-3232DOI Listing
February 2022

GNRH1 Variants in Congenital Hypogonadotropic Hypogonadism: Single-Center Experience and Systematic Literature Review.

Neuroendocrinology 2022 17;112(8):723-732. Epub 2021 Dec 17.

Department of Endocrinology, Seth G S Medical College and KEM Hospital, Mumbai, India.

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 gonadotropin therapy and fertility in 1 proband. We included 19 probands from 12 studies after the literature review. Ten CHH probands (inclusive 2 from this study) with biallelic GNRH1 variants had severe reproductive phenotype, low gonadotropin levels, low/normal prolactin, normal pituitary imaging, and no extra-reproductive phenotype. Of seven biallelic variants reported, three were frameshift, two were splice-site, and two were missense mutations. All of them were pathogenic/likely pathogenic without oligogenicity. Of seven monoallelic GNRH1 variants reported in 11 probands, 4 had nonreproductive phenotype, 3 were benign/likely benign, and 4 were oligogenic.

Conclusion(s): GNRH1 biallelic variants lead to severe reproductive phenotype, with low gonadotropin levels without nonreproductive features or oligogenicity. However, the role of GNRH1 monoallelic variants in CHH pathophysiology for reported variants remains questionable.
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http://dx.doi.org/10.1159/000521558DOI Listing
August 2022

Octreotide-LAR is a Useful Alternative for the Management of Diazoxide-Responsive Congenital Hyperinsulinism.

Horm Metab Res 2021 Nov 5;53(11):723-729. Epub 2021 Nov 5.

Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India.

The data on the congenital hyperinsulinism (CHI) in Asian Indian patients is limited. Diazoxide is often unavailable in India, which poses challenge in managing CHI. The study was aimed to present our experience with CHI with a special focus on the effectiveness and cost-effectiveness of octreotide long-acting release (OCT-LAR) among diazoxide-responsive CHI. The data of 14 index cases with CHI registered at our center were retrospectively analyzed. The diagnosis of CHI was based on elevated serum insulin (3.4-32.5 μIU/ml) and C-peptide (0.58-1.98 ng/ml) at the time of symptomatic hypoglycemia (BG≤41 mg/dl). Fourteen patients (13 males) presented at a median (range) age of 3 (1-270) days, seizures being the most common mode of presentation (78.6%). Ten patients were diazoxide-responsive, two were partially responsive, while two were unresponsive. Genetics was available for eight patients; (n=3, 1 novel) and (n=2, both novel) were the most commonly mutated genes. OCT-LAR was offered to eight patients including four with diazoxide-responsive disease and was universally effective. We propose a cost-effective approach to use OCT-LAR in the management of CHI, which may also make it more cost-effective than diazoxide for diazoxide-responsive disease. Five of the 11 (45.5%) patients had evidence of neurological impairment; notably, two patients with mutations had intellectual disability despite diazoxide-responsiveness. We report three novel mutations in CHI-associated genes. We demonstrate the effectiveness of and propose a cost-effective approach to use OCT-LAR in diazoxide-responsive CHI. Mutations in may be associated with abnormal neurodevelopmental outcomes despite diazoxide-responsiveness.
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http://dx.doi.org/10.1055/a-1654-8542DOI Listing
November 2021

Exonic WT1 pathogenic variants in 46,XY DSD associated with gonadoblastoma.

Endocr Connect 2021 Nov 25;10(12):1522-1530. Epub 2021 Nov 25.

Department of Endocrinology, Seth G S Medical College & KEM Hospital, Mumbai, India.

Objective: The literature regarding gonadoblastoma risk in exonic Wilms' tumor suppressor gene (WT1) pathogenic variants is sparse. The aim of this study is to describe the phenotypic and genotypic characteristics of Asian-Indian patients with WT1 pathogenic variants and systematically review the literature on association of exonic WT1 pathogenic variants and gonadoblastoma.

Design: Combined retrospective-prospective analysis.

Methods: In this study, 46,XY DSD patients with WT1 pathogenic variants detected by clinical exome sequencing from a cohort of 150 index patients and their affected relatives were included. The PubMed database was searched for the literature on gonadoblastoma with exonic WT1 pathogenic variants.

Results: The prevalence of WT1 pathogenic variants among 46,XY DSD index patients was 2.7% (4/150). All the four patients had atypical genitalia and cryptorchidism. None of them had Wilms' tumor till the last follow-up, whereas one patient had late-onset nephropathy. 11p13 deletion was present in one patient with aniridia. The family with p.Arg458Gln pathogenic variant had varied phenotypic spectrum of Frasier syndrome; two siblings had gonadoblastoma, one of them had growing teratoma syndrome (first to report with WT1). On literature review, of >100 exonic point pathogenic variants, only eight variants (p.Arg462Trp, p.Tyr177*, p.Arg434His, p.Met410Arg, p.Gln142*, p.Glu437Lys, p.Arg458*, and p.Arg458Gln) in WT1 were associated with gonadoblastoma in a total of 15 cases (including our two cases).

Conclusions: WT1 alterations account for 3% of 46,XY DSD patients in our cohort. 46,XY DSD patients harboring exonic WT1 pathogenic variants carry a small but definitive risk of gonadoblastoma; hence, these patients require a gonadoblastoma surveillance with a more stringent surveillance in those harboring a gonadoblastoma-associated variant.
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http://dx.doi.org/10.1530/EC-21-0289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8679883PMC
November 2021

Metastatic cluster 2-related pheochromocytoma/paraganglioma: a single-center experience and systematic review.

Endocr Connect 2021 Nov 11;10(11):1463-1476. Epub 2021 Nov 11.

Department of Endocrinology, Seth G S Medical College & KEM Hospital, Mumbai, India.

Risk of metastatic disease in the cluster 2-related pheochromocytoma/paraganglioma (PPGL) is low. In MEN2 patients, identification of origin of metastases from pheochromocytoma (PCC) or medullary thyroid carcinoma (MTC) is challenging as both are of neuroendocrine origin. We aim to describe our experience and perform a systematic review to assess prevalence, demographics, biochemistry, diagnostic evaluation, management, and predictors of cluster 2-related metastatic PPGL. Retrospective analysis of 3 cases from our cohort and 43 cases from world literature was done. For calculation of prevalence, all reported patients (n = 3063) of cluster 2 were included. We found that the risk of metastasis in cluster 2-related PPGL was 2.6% (2% in RET, 5% in NF1, 4.8% in TMEM127 and 16.7% in MAX variation). In metastatic PCC in MEN2, median age was 39 years, bilateral tumors were present in 71% and median tumor size was 9.7 cm (range 4-19) with 43.5% mortality. All patients had a primary tumor size ≥4 cm. Origin of primary tumor was diagnosed by histopathology of metastatic lesion in 11 (57.9%), 131I-MIBG scan in 6 (31.6%), and selective venous sampling and CT in 1 (5.3%) patient each. In subgroup of neurofibromatosis 1 (NF1), median age was 46 years (range 14-59) with median tumor size 6 cm and 57% mortality. To conclude, the risk of metastatic disease in cluster 2-related PPGL is low, being especially high in tumors with size ≥4 cm and associated with high mortality. One-third patients of NF1 with metastatic PPGL had presented in second decade of life. Long-term studies are needed to formulate management recommendations.
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http://dx.doi.org/10.1530/EC-21-0455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630763PMC
November 2021

Low-Dose, Low-Specific Activity I-metaiodobenzyl Guanidine Therapy in Metastatic Pheochromocytoma/Sympathetic Paraganglioma: Single-Center Experience from Western India.

Indian J Endocrinol Metab 2021 Mar-Apr;25(2):148-159. Epub 2021 Sep 8.

Department of Endocrinology, Seth G.S Medical College and KEM Hospital, Mumbai, Maharashtra, India.

Introduction: Radionuclide therapy is a promising treatment modality in metastatic pheochromocytoma/paraganglioma (PPGL). There is scarce data on I-metaiodobenzyl guanidine (I-MIBG) therapy from the Indian subcontinent. Hence, we aim to study the safety and effectiveness of low-dose, low-specific activity (LSA) I-MIBG therapy in patients with symptomatic, metastatic PPGL.

Methods: Clinical, hormonal, and radiological response parameters and side effects of LSA I-MIBG therapy in patients with symptomatic, metastatic PPGL were retrospectively reviewed. World health organizations' (WHO) symptomatic, hormonal, and tumor response, and response evaluation criteria in solid tumors (RECIST1.1) criteria were used to assess the response.

Results: Seventeen (PCC: 11, sympathetic PGL: 06) patients (15 with disease progression) received low-dose LSA I-MIBG therapy. Complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) were 18% (3/17), 24% (4/17), 18% (3/17), and 41% (7/17), respectively, for WHO symptomatic response; 20% (2/10), 10% (1/10), 30% (3/10), and 40% (4/10), respectively, for WHO hormonal response; and 19% (3/16), 6% (1/16), 31% (5/16), and 44% (7/16), respectively for tumor response based on RECIST1.1. All patients with symptomatic PD and 50% (2/4) with hormonal PD had progression as per RECIST1.1 criteria. Side effects included thrombocytopenia, acute myeloid leukemia, mucoepidermoid carcinoma, and azoospermia in 6% (1/17) each.

Conclusions: Our study reaffirms the modest efficacy and safety of low-dose, LSA I-MIBG therapy in patients with symptomatic, metastatic PPGL. Symptomatic, but not hormonal, progression after I-MIBG therapy correlates well with tumor progression and should be further evaluated with imaging. In resource-limited settings, anatomic imaging alone may be used to assess tumor response to I-MIBG therapy.
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http://dx.doi.org/10.4103/ijem.IJEM_52_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477742PMC
September 2021

Prevalence of primary aldosteronism in type 2 diabetes mellitus and hypertension: A prospective study from Western India.

Clin Endocrinol (Oxf) 2022 04 27;96(4):539-548. Epub 2021 Sep 27.

Department of Endocrinology, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra, India.

Objective: Type 2 diabetes mellitus (T2DM) and hypertension commonly coexist; however, underlying primary aldosteronism (PA) can lead to worsening of hypertension, glycemia and cardiovascular risk. We aim to screen patients with T2DM and hypertension for PA by conducting a prospective monocentric study from Western India, which included adults with T2DM and hypertension from the outpatient diabetes clinic.

Design: Prospective study.

Patients And Measurements: Patients with an aldosterone renin ratio of ≥1.6 ng/dl/µIU/ml with plasma aldosterone concentration (PAC) ≥ 10 ng/dl were considered to be positive on a screening test. A PAC ≥ 6 ng/dl on seated saline suppression test (SST) was used to confirm the diagnosis of PA.

Results: Four hundred and eighty-six patients were included in this study. Seventy-six (15.6%, 95% confidence interval [CI]: 12.7%-19.1%) patients had a positive screening test with positive confirmatory test in 20 of the 36 (55.5%, 95% CI: 39.3%-71.7%) screen-positive patients who underwent SST. Patients with positive screening test had a higher proportion of females (65.8% vs. 50%; p = .011), frequent history of hypertensive crises (21.1% vs. 8%; p = .001), uncontrolled blood pressure (51.3% vs. 34.6%; p = .006), diagnosis of hypertension before diabetes (32.9% vs. 21.7%; p = .035) and higher systolic (137.6 ± 6.9 vs. 131.2 ± 17.8 mmHg; p = .004) and diastolic (85.3 ± 11.1 vs. 81.7 ± 10.7 mmHg; p = .007) blood pressures. Patients with positive confirmatory test had longer duration of diabetes (108 [60-162] vs. 42 [24-87] months; p = .012), hypertension (84 [42-153] vs. 36 [15-81] months; p = .038) and higher creatinine (1.16 [1.02-1.42] vs. 0.95 [0.84-1.12] mg/dl; p = .021).

Conclusions: PA is prevalent (at least 4.1%) in Asian Indian patients with T2DM and hypertension. Further studies are needed to assess the cost-effectiveness of routine screening.
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http://dx.doi.org/10.1111/cen.14598DOI Listing
April 2022

Ga-DOTATATE PET/CT imaging in endogenous hyperinsulinemic hypoglycemia: A tertiary endocrine centre experience.

Clin Endocrinol (Oxf) 2022 02 8;96(2):190-199. Epub 2021 Sep 8.

Department of Endocrinology, Seth GS Medical College & KEM Hospital, Mumbai, India.

Objective: Literature regarding utility of Ga-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 Ga-DOTATATE PET/CT was compared with contrast-enhanced computed tomography (CECT) and Ga-NODAGA-Exendin-4 PET/CT (whenever available) in an endogenous hyperinsulinemic hypoglycemia (EHH) cohort.

Design: Retrospective audit.

Patients: EHH patients [N = 36, lesions (n) = 49, final diagnosis: benign sporadic insulinoma (BSI) (N = 20), malignant insulinoma (N = 4, n = 14), MEN-1 syndrome associated insulinoma (N = 9, n = 15), Munchausen syndrome (N = 2) and drug-induced hypoglycemia (N = 1)] having both preoperative imaging modalities (CECT and Ga-DOTATATE PET/CT).

Measurements: Per-lesion sensitivity (Sn) and positive predictive value (PPV) for histopathological diagnosis of insulinoma.

Results: Sn and PPV of Ga-DOTATATE PET/CT were 67.3% and 89.2%; 55% and 100%; 85.7% and 100%; and 66.7% and 77% for overall EHH, BSI, malignant, and MEN-1 syndrome associated insulinoma cohorts respectively. Despite having comparatively lower sensitivity in BSI cohort, Ga-DOTATATE PET/CT localized a pancreatic tail lesion missed by other modalities. Ga-DOTATATE PET/CT had comparatively higher sensitivity in malignant insulinoma than BSI cohort. Ga-DOTATATE PET/CT also paved the way for successful response to Lu-based peptide receptor radionuclide therapy (PRRT). In MEN-1 cases, lower PPV as compared with BSI was due to uptake in non-insulinoma pancreatic neuroendocrine tumours (Pan-NET).

Conclusions: Ga-DOTATATE PET/CT has supplemental role in selected cases of BSI with negative and/or discordant results with CECT and Ga-NODAGA-Exendin-4 PET/CT. In malignant insulinoma, Ga-DOTATATE-PET/CT has an additional theranostic potential. Interference due to uptake in non-insulinoma Pan-NET in MEN-1 syndrome may hinder insulinoma localization with Ga-DOTATATE-PET/CT.
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http://dx.doi.org/10.1111/cen.14586DOI Listing
February 2022

Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review.

J Pediatr Endocrinol Metab 2021 Dec 8;34(12):1505-1513. Epub 2021 Sep 8.

Department of Endocrinology, Seth G.S Medical College and KEM Hospital, Mumbai, Maharashtra, India.

Background: Vitamin D dependent rickets type 1 (VDDR1) is a rare disease due to pathogenic variants in 1- hydroxylase gene. We describe our experience with systematic review of world literature to describe phenotype and genotype.

Methods: Seven patients from six unrelated families with genetically proven VDDR1 from our cohort and 165 probands from systematic review were analyzed retrospectively. The clinical features, biochemistry, genetics, management, and long-term outcome were retrieved.

Results: In our cohort, the median age at presentation and diagnosis was 11(4-18) and 40(30-240) months. The delayed diagnoses were due to misdiagnoses as renal tubular acidosis and hypophosphatemic rickets. Four had hypocalcemic seizures in infancy whereas all had rickets by 2 years. All patients had biochemical response to calcitriol, however two patients diagnosed post-puberty had persistent deformity. Genetic analysis revealed two novel (p.Met260Arg, p.Arg453Leu) and a recurring variant (p.Phe443Profs*24). Systematic review showed that seizures as most common presentation in infancy, whereas delayed motor milestones and deformities after infancy. Diagnosis was delayed in 27 patients. Patients with unsatisfactory response despite compliance were >12 years at treatment initiation. Inappropriately normal 1,25(OH)2D may be present, however suppressed ratio of 1,25(OH)2 D/25(OH)D may provide a clue to diagnosis. Various region specific and hot-spot recurrent variants are described. Patients with truncating variants had higher daily calcitriol requirement and greatly suppressed ratio of 1,25(OH)2D/25(OH)D.

Conclusion: Delayed diagnosis may lead to permanent short stature and deformities. Truncating variants tend to have severe disease as compared to non-truncating variants. Diagnostic accuracy of 1,25(OH)2 D/25(OH)D ratio needs further validation.
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http://dx.doi.org/10.1515/jpem-2021-0403DOI Listing
December 2021

Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India.

Sex Dev 2021 30;15(4):253-261. Epub 2021 Jul 30.

Department of Endocrinology, Seth G S Medical College & KEM Hospital, Mumbai, India.

The study aimed to analyze clinical and hormonal phenotype,and genotype in patients with genetically proven androgen insensitivity syndrome (AIS) from Western India. Index patients with pathogenic variants in the androgen receptor (AR) gene were identified from a consecutive 46,XY DSD cohort (n = 150) evaluated with clinical exome sequencing, and their genetically-proven affected relatives were also included. In sum, 15 index cases (9 complete AIS [CAIS] and 6 partial AIS [PAIS]) were identified making AIS the second most common (10%) cause of 46,XY DSD, next to 5α-reductase 2 deficiency (n = 26; 17.3%). Most patients presented late in the postpubertal period with primary amenorrhoea in CAIS (89%) and atypical genitalia with gynecomastia in PAIS (71.4%). All CAIS were reared as females and 83.3% of PAIS as males with no gender dysphoria. Four of 6 patients with available testosterone to dihydrotestosterone ratio had a false elevation (>10). Metastatic dysgerminoma was seen in 1 patient in CAIS, while none in the PAIS group had malignancy. Fifteen different (including 6 novel) pathogenic/likely pathogenic variants in AR were found. Nonsense and frameshift variants exclusively led to CAIS phenotype, whereas missense variants led to variable phenotypes. In this largest, monocentric study from the Asian Indian subcontinent, AIS was the second most common cause of 46,XY DSD with similar phenotype but later presentation when compared to cases in the rest of the world. The study reports 6 novel pathogenic variants in AR.
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http://dx.doi.org/10.1159/000517763DOI Listing
March 2022

Complete Resolution of Disease After Peptide Receptor Radionuclide Therapy in a Patient of Metastatic Insulinoma.

Clin Nucl Med 2022 Jan;47(1):e77-e78

Department of Endocrinology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India.

Abstract: A 48-year-old man, a case of metastatic insulinoma, who failed transarterial chemoembolization of liver metastases underwent multiple cycles of peptide receptor radionuclide therapy with 177Lu-DOTATATE, following which a complete morphologic and metabolic response was demonstrated on 68Ga-DOTATATE PET/CT. Patient had a remarkable improvement in his quality of life as intractable hypoglycemic episodes resolved after treatment. Peptide receptor radionuclide therapy is a promising targeted radionuclide therapy in patients of metastatic insulinomas that can result in reduced tumor burden and improved quality of life, particularly those who fail the conventional treatment modalities as seen in the present case.
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http://dx.doi.org/10.1097/RLU.0000000000003831DOI Listing
January 2022

Gonadotropins for testicular descent in cryptorchid congenital hypogonadotropic hypogonadism males beyond infancy.

J Pediatr Endocrinol Metab 2021 Jul 26;34(7):917-924. Epub 2021 Apr 26.

Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India.

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, respectively. In two pediatric cases, testicular descent occurred with isolated hMG therapy. At the last follow up (median: 23.5, IQR: 10.5-38.7 months), all the descended testes remained in scrotal position. In four pubertal/postpubertal age patients, continuous CGT (18-60 months) yielded T and inhibin-B levels of 16.64 ± 1.46 nmol/l and 106 ± 32.6 pg/mL, respectively. All the three patients with available semen analysis had sperm concentration of ≥5 million/mL and one of them achieved paternity.

Conclusions: A trial of CGT before orchiopexy may be considered in CHH males with cryptorchidism even beyond the narrow age-window of infancy. CGT may also have beneficial effects on future spermatogenesis and fertility outcomes in these patients.
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http://dx.doi.org/10.1515/jpem-2020-0683DOI Listing
July 2021

Prostate-Specific Membrane Antigen Expression in Patients With Differentiated Thyroid Cancer With Thyroglobulin Elevation and Negative Iodine Scintigraphy Using 68Ga-PSMA-HBED-CC PET/CT.

Clin Nucl Med 2021 Aug;46(8):e406-e409

From the Radiation Medicine Centre, Bhabha Atomic Research Centre.

Purpose Of The Report: Prostate-specific membrane antigen (PSMA) is a member of superfamily of zinc-dependent exopeptidases that is robustly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature including microvessels of thyroid tumors. Its expression in differentiated thyroid cancer (DTC) has been confirmed in many recent studies, but systematic studies exploring PSMA expression in patients with DTC with thyroglobulin elevation and negative iodine scintigraphy (TENIS) are lacking. The aim of the present study was to evaluate the role of PSMA scan in TENIS patients with DTC.

Methods: Nine consecutive patients with DTC with proven TENIS syndrome (6 men and 3 women with age range 29-68 years and mean age of 48 years) underwent 18F-FDG PET/CT as per the institution protocol. Thereafter, they were subjected to 68Ga-PSMA-HBED-CC PET/CT as per the institution protocol within a week of FDG PET imaging. Prostate-specific membrane antigen expression (SUVmax) in the lesions was compared with 18F-FDG PET and CT scan findings.

Results: In 5 of 9 patients with TENIS, the metastatic lesions showed PSMA expression. A total of 14 lesions were seen on the CT scan. Prostate-specific membrane antigen PET detected 9 of 14 lesions (64.28%) (SUVmax ranging from 10.1 to 45.67; median SUVmax of 16.31), whereas FDG PET was positive in 11 of 14 lesions (78.57%). The lesions that showed PSMA uptake was localized to bones (5 of 9) and lungs (4 of 9). Two lesions that were localized to iliac crest and acetabulum were missed on FDG PET but were seen on CT and PSMA PET scan.

Conclusions: The results of this pilot study indicate that 68Ga-HBED-CC-PSMA PET/CT demonstrates PSMA expression in TENIS patients with lesions being localized to the bones and lungs. 68Ga-PSMA PET/CT could be useful for the identification of TENIS patients who might benefit from PSMA-targeted radionuclide therapy.
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http://dx.doi.org/10.1097/RLU.0000000000003655DOI Listing
August 2021

Preoperative Amlodipine Is Efficacious in Preventing Intraoperative HDI in Pheochromocytoma: Pilot RCT.

J Clin Endocrinol Metab 2021 07;106(8):e2907-e2918

Department of Endocrinology, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra 400012,India.

Context: Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce.

Objective: We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL.

Methods: In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure).

Results: The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ± 18.4% vs 2.44 ± 2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine).

Conclusion: Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted.
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http://dx.doi.org/10.1210/clinem/dgab231DOI Listing
July 2021

Preoperative prediction of parathyroid carcinoma in an Asian Indian cohort.

Head Neck 2021 07 10;43(7):2069-2080. Epub 2021 Mar 10.

Department of Endocrinology, Seth GS Medical College & KEM Hospital, Mumbai, India.

Background: Parathyroid carcinoma (PC) requires preoperative prediction for appropriate surgical management. Differentiation from symptomatic primary hyperparathyroidism (sPHPT) cohort is difficult.

Methods: Patients with sPHPT from a tertiary-care center, Western India, including Cohort-A (n = 19 [10/M; 9/F]) with PC and Cohort-B (n = 93 [33/M; 60/F] with benign parathyroid lesions) were compared to derive predictors for differential diagnosis.

Results: There were no differences in clinical or biochemical parameters between the two cohorts. Comparison of CECT parameters showed that irregular shape, tumor heterogeneity, infiltration, short/long-axis ratio >0.76, and long-diameter >30 mm had high negative-predictive value and intratumoral calcification had 100% positive-predictive value to diagnose PC; whereas there were no differences in contrast-enhancement patterns. Long diameter, short/long-axis ratio, and heterogeneity were significant predictors on multivariate analysis.

Conclusion: It is difficult to predict diagnosis of PC in an Indian sPHPT cohort based on clinical and biochemical parameters, whereas CECT parathyroid-based parameters can aid in diagnosis.
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http://dx.doi.org/10.1002/hed.26677DOI Listing
July 2021

Early Pulse Glucocorticoid Therapy and Improved Hormonal Outcomes in Primary Hypophysitis.

Neuroendocrinology 2022 19;112(2):186-195. Epub 2021 Mar 19.

Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India.

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%) patients. Panhypophysitis (PH) was the most common radiological subtype (n = 33, 84.6%). Resolution of mass effects was similar in both groups. Overall and complete AP hormonal recovery was significantly higher in the GTG than in the COG (12/14 [85.7%) vs. 6/14 [42.8%], p = 0.02; 10/14 [71.4%] vs. 1/14 [7.7%], p = 0.0007, respectively). Proportion of cases with empty sella were significantly higher in the COG (9/20 [45%] vs 1/17 [5.9%], p = 0.001). Among PH patients in the GTG (n = 17), we found duration from symptoms onset to treatment as the predictor of recovery.

Conclusion: In a PH subtype-predominant PAH cohort, a standardized high-dose glucocorticoid regimen resulted in higher overall and complete AP hormonal recovery than that in the COG. Initiation of glucocorticoids in the early disease course may have been contributory.
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http://dx.doi.org/10.1159/000516006DOI Listing
March 2022

POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature.

Pituitary 2021 Oct 20;24(5):657-669. Epub 2021 Mar 20.

Department of Endocrinology, IndiaSeth G.S. Medical College & KEM Hospital, Parel, Mumbai, Maharashtra, 400012, India.

Context: POU1F1 mutations are prevalent in Indian CPHD cohorts. Genotype-phenotype correlation is not well-studied.

Aim: To describe phenotypic and genotypic spectrum of POU1F1 mutations in our CPHD cohort and present systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in world literature.

Methods: Retrospective study of POU1F1 mutation-positive patients from a western-Indian center. PRISMA guidelines based pubmed search of published literature of all mutation-positive patients.

Results: Our cohort had 15 POU1F1 mutation-positive patients (9 index, 6 relatives). All had severe GH, TSH and prolactin deficiencies (GHD, TSHD and PD). TSHD was diagnosed earliest followed by GHD (median ages: TSHD-6 months, GHD-3 years), while PD was more variable. Two sisters had central precocious puberty at 7 years of age. Pubic hair was deficient in all post-pubertal patients (females: P1-P2, males: P3-P4). Splice-site/intronic/frameshift mutations were most common, while missense/nonsense mutations were less frequent (33%). Review of world literature yielded 114 patients (82 index patients) from 58 studies. GHD was present in all patients. TSHD was spared in 12.5% and PD in 4.4% patients. Missense/nonsense mutations accounted for 75% of spectrum. Phenotype-genotype analysis revealed higher mean peak-GH levels (1.1 vs 0.2 ng/ml, p = 0.008) and lower prevalence of anterior-pituitary hypoplasia (63.6% vs 86.3%, p = 0.03) in patients with heterozygous than homozygous and compound heterozygous mutations.

Conclusions: We present largest series of POU1F1 mutation-positive patients. Precocious puberty and defective pubarche are lesser-appreciated phenotypic features. Our mutation spectrum is different from that of world literature. Patients with heterozygous mutations have milder phenotype.
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http://dx.doi.org/10.1007/s11102-021-01140-9DOI Listing
October 2021

Hereditary medullary thyroid carcinoma syndromes: experience from western India.

Fam Cancer 2021 07 4;20(3):241-251. Epub 2021 Jan 4.

Department of Endocrinology, Seth G.S Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, 4000012, India.

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 (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35 years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.
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http://dx.doi.org/10.1007/s10689-020-00219-9DOI Listing
July 2021

Exendin-4-based imaging in insulinoma localization: Systematic review and meta-analysis.

Clin Endocrinol (Oxf) 2021 08 21;95(2):354-364. Epub 2021 Jan 21.

Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.

Background And Context: Glucagon-like peptide-1 receptor (GLP-1 R) based imaging has shown higher sensitivity for insulinoma localization as compared to other anatomic/functional imaging.

Methodology: We reviewed the published English literature for GLP-1 R targeted imaging in insulinoma in PubMed until August 2020 in accordance with PRISMA guidelines using the MeSH terms "((Exendin-4 PET/CT) OR (Exendin-4 SPECT/CT) OR (GLP-1 R imaging)) AND (Insulinoma)". An individual patient data-metanalysis (IPD-MA) was performed, and performance parameters were calculated for the histopathological diagnosis of insulinoma.

Main Outcome Measures: True-positive (TP), false-positive (FP), false-negative (FN), true-negative (TN), sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for insulinoma localization.

Results: A total of 179 cases (316 lesions) from 16 publications were included for IPD-MA. For insulinoma localization, exendin-4-PET/CT (Sn & PPV: 94%) performed better than exendin-4-SPECT/CT (Sn: 63%, PPV: 94%). The Sn was lower in malignant insulinoma cases whereas the Sp was higher in cases with MEN-1 syndrome. With exendin-4-based imaging, FP uptakes in Brunner's gland, normal pancreas, and other β-cell pathologies and FN results in pancreatic tail lesions and malignancy were seen in a few patients. TN results suggested the correct diagnosis of other endogenous hyperinsulinemic hypoglycaemia (EHH) subtypes.

Conclusion: For insulinoma localization, exendin-4 PET/CT should be preferred over exendin-4 SPECT/CT because of higher sensitivity and specificity. FP uptakes in Brunner's gland, normal pancreas, and other β-cell pathologies and FN results in tail lesions, and malignant insulinomas are limitations. Higher specificity for insulinoma localization is particularly useful in patients with MEN-1 syndrome.
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http://dx.doi.org/10.1111/cen.14406DOI Listing
August 2021
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