Machine learning for predicting diabetic metabolism in the Indian population using polar metabolomic and lipidomic features.

AIMS: To identify metabolite and lipid biomarkers of diabetes in the Indian subpopulation in newly diagnosed diabetic and long-term diabetic individuals. To utilize the global polar metabolomic and lipidomic profiles to predict the susceptibility of an individual to diabetes using machine learning algorithms. MATERIALS AND METHODS: 87 individuals, including healthy, newly diabetic, and long-term diabetics on medication, were included in the study. Post consent, their serum was used to isolate polar metabolome and lipidome. NMR and LCMS were used to identify the polar metabolites and lipids, respectively. Statistical analysis was done to determine significantly altered molecules. NMR and LCMS comprehensive data were utilized to generate diabetic models using machine learning algorithms. 10 more individuals (pre-diabetic) were recruited, and their polar metabolomic and lipidomic profiles were generated. Pre-diabetic metabolic profiles were then utilized to predict the diabetic status of the metabolome and lipidome beyond glucose levels. RESULTS: Mannose, Betaine, Xanthine, Triglyceride (38:1), Sphingomyelin (d63:7), and Phosphatidic acid (37:2) are some of the top key biomarkers of diabetes. The predictive model generated showed the receiver operating characteristic area under the curve (ROC-AUC) as 1 on both test and validation data indicating excellent accuracy. This model then predicted the diabetic closeness of the metabolism of pre-diabetic individuals based on probability scores. CONCLUSION: Polar metabolic and lipid profile of diabetic individuals is very different from that of healthy individuals. Lipid profile alters before the polar metabolic profile in diabetes-susceptible individuals. Without regard to glucose, the diabetic closeness of the metabolism of any individual can be determined.

Dual-phase computed tomography for localization of parathyroid lesions in children and adolescents with primary hyperparathyroidism.

BACKGROUND: Childhood and adolescent primary hyperparathyroidism (PHPT) is a rare disease caused by single adenomas in 65-94% of patients. In this patient group, there is no data on computed tomography (CT) for pre-operative parathyroid localization that may facilitate focused parathyroidectomy. METHODS: Two radiologists reviewed dual-phase (nonenhanced and arterial) CT images of twenty-three operated children and adolescents [20:single-gland disease(SGD), 3:multi-glandular disease(MGD)] with proven histopathological PHPT. Percentage arterial enhancement (PAE) was calculated as [100*{arterial-phase Hounsfield unit (HU)-nonenhanced phase HU}/nonenhanced HU] of the parathyroid lesion(s), thyroid, and lymph node. RESULTS: Dual-phase CT lateralized 100%, localized to the correct quadrant/site 85% SGD (including 3/3 ectopic), and identified 1/3 MGD. PAE (cutoff ≥ 112.3%) was sensitive (91.3%) and specific (99.5%) in distinguishing parathyroid lesions from local mimics (P<0.001). The average effective dose was 3.16±1.01mSv, comparable to the planar/single photon emission CT (SPECT) Technetium 99m(Tc)-sestamibi and choline positron emission tomography (PET)/CT scans. Solid-cystic morphology identified in 4 patients harboring pathogenic germline variants (3:CDC73, 1:CASR) may serve as a radiological clue to molecular diagnosis. Nineteen out of 20 (95%) patients with SGD who had undergone single gland resection based on pre-operative CT findings were in remission over a median follow-up of 18 months. CONCLUSION: As most children/adolescents with PHPT have SGD, dual-phase CT protocols which reduce the effective radiation dose with high localization sensitivity for single parathyroid lesions may be a sustainable pre-operative imaging modality in this patient group.

Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis.

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 glucocorticoid dose group (0% vs 38.1% vs 57.1%), attaining statistical significance (P = 0.012) with very high-dose. A longer duration of treatment (>6.5 weeks) was associated with better corticotroph and thyrotroph recovery. The need for rescue therapy was lower with i.v. route (38% vs 17.5%, P = 0.012) and with increasing glucocorticoid doses (53.3% vs 34.3% vs 17.3%, P = 0.016). In severe disease, visual field and corticotroph axis recovery were significantly higher with i.v. route and very high-dose steroids. The adverse effects of glucocorticoids were independent of dose and duration of treatment. Conclusions: Very high-dose glucocorticoids by i.v. route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment of severe PAH cases.

Comparison of the Sensitivity of 68 Ga-DOTATATE PET/CT with Other Imaging Modalities in Detecting Head and Neck Paraganglioma: Experience from Western India.

Background This study aimed to compare the sensitivity of 68 Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) with other imaging modalities in the detection of head and neck paraganglioma (HNPGL). Methods The data of consecutive HNPGL patients ( n = 34) who had undergone at least 68 Ga-DOTATATE PET/CT and anatomical imaging (contrast-enhanced computed tomography/magnetic resonance imaging [CECT/MRI]) were retrospectively reviewed. The diagnosis of HNPGL (the primary tumor) was confirmed either by histopathology ( n = 10) or was based on clinical follow-up and correlation of anatomical with functional imaging in whom histopathology was not available ( n = 24). The sensitivities of 68 Ga DOTATATE PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT), 131 I-metaiodobenzylguanidine ( 131 I-MIBG) scintigraphy, and CECT/MRI for primary HNPGL, associated primary pheochromocytoma + sympathetic paraganglioma (PCC + sPGL), and metastatic lesions were analyzed. Results Thirty-four patients (males: 15) [isolated HNPGL: 26, HNPGL + PCC: 04, HNPGL+ sPGL: 03, HNPGL + PCC + sPGL: 01] harboring 50 primary lesions were included. For total lesions, 68 Ga-DOTATATE PET/CT (99.3%) had significantly higher lesion-wise sensitivity than 18 F-FDG PET/CT (81.6%, p = 0.0164), 131 I-MIBG (15.2%, p ≤0.0001), CECT (46.3%, p ≤ 0.0001) but similar sensitivity as MRI neck (97%, p = 0.79). On head-to-head comparison (21 primary HNPGL and 39 metastatic lesions), 68 Ga DOTATATE PET/CT had significantly higher lesion-wise sensitivities for the detection of metastatic (100 vs. 71.9%, p = 0.04) and total lesions (100 vs. 77.2%, p ≤ 0.0001). Conclusion 68 Ga-DOTATATE PET/CT was the most sensitive imaging modality for the detection of HNPGL and related lesions with significantly higher lesion-wise sensitivities than those of 18 F-FDG PET/CT, 131 I-MIBG, and CECT.

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

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.

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

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.

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

OBJECTIVES: To describe Asian Indian patients with 17ß hydroxysteroid dehydrogenase 3 (17ßHSD3) deficiency and to perform a systematic review to determine the factors influencing gender role in 46,XY disorder of sex development (DSD) due to 17ßHSD3 deficiency. PATIENTS AND DESIGN: We present the phenotypic and genotypic data of 10 patients (9 probands and 1 affected family member) with 17ßHSD3 deficiency from our 46,XY DSD cohort (N = 150; Western India) and a systematic review of 152 probands with genetically proven, index 17ßHSD3 deficiency patients from the world literature to identify the determinants of gender role. RESULTS: 17ßHSD3 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 17ßHSD3 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 17ßHSD3 deficiency were noted which needs further evaluation for the underlying molecular mechanisms.

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

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.

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

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.

Low-Dose, Low-Specific Activity 131I-metaiodobenzyl Guanidine Therapy in Metastatic Pheochromocytoma/Sympathetic Paraganglioma: Single-Center Experience from Western India.

INTRODUCTION: Radionuclide therapy is a promising treatment modality in metastatic pheochromocytoma/paraganglioma (PPGL). There is scarce data on 131I-metaiodobenzyl guanidine (131I-MIBG) therapy from the Indian subcontinent. Hence, we aim to study the safety and effectiveness of low-dose, low-specific activity (LSA) 131I-MIBG therapy in patients with symptomatic, metastatic PPGL. METHODS: Clinical, hormonal, and radiological response parameters and side effects of LSA 131I-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 131I-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 131I-MIBG therapy in patients with symptomatic, metastatic PPGL. Symptomatic, but not hormonal, progression after 131I-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 131I-MIBG therapy.

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

BACKGROUND: Vitamin D dependent rickets type 1 (VDDR1) is a rare disease due to pathogenic variants in 1-α 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.

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.

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.

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

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.

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

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.

The utility of 68Ga-DOTATATE PET/CT in localizing primary/metastatic pheochromocytoma and paraganglioma in children and adolescents - a single-center experience.

OBJECTIVES: Pediatric pheochromocytoma and paraganglioma (PPGL) are rare tumors with limited data on the diagnostic performance of 68Ga-DOTA(0)-Tyr(3)-octreotate positron emission tomography-computed tomography (68Ga-DOTATATE PET/CT). We have described our experience of 68Ga-DOTATATE PET/CT in overall and von Hippel Lindau (VHL)-associated pediatric PPGL and compared its sensitivity with that of 131I-meta-iodobenzyl-guanidine (131I-MIBG), 18F-fluorodeoxyglucose PET/CT (18F-FDG PET/CT), and contrast-enhanced CT (CECT). METHODS: Retrospective evaluation of consecutive PPGL patients (age: ≤20 years), who had undergone at least one functional imaging [131I-MIBG, 18F-FDG PET/CT, and/or 68Ga-DOTATATE PET/CT], was done. Composite of anatomical and all the performed functional imaging scans, image comparator (IC), was considered as the gold standard for sensitivity analysis. RESULTS: In a cohort of 32 patients (16 males, age at diagnosis: 16.4 ± 2.68 years), lesion-wise sensitivity of 68Ga-DOTATATE PET/CT (95%) was higher than that of both 18F-FDG-PET/CT (80%, p=0.027) and 131I-MIBG (65%, p=0.0004) for overall lesions, than that of 18F-FDG-PET/CT (100 vs. 67%, p=0.017) for primary PPG, and than that of 131I-MIBG (93 vs. 42%, p=0.0001) for metastases. In the VHL (n=14), subgroup, 68Ga-DOTATATE PET/CT had higher lesion-wise sensitivity (100%) compared to 18F-FDG PET/CT (74%, p=0.045) and 131I-MIBG (64%, p=0.0145). CONCLUSIONS: In our pediatric PPGL cohort, overall lesion-wise sensitivity of 68Ga-DOTATATE PET/CT was higher than that of 18F-FDG PET/CT and 131I-MIBG scintigraphy. Hence, we recommend 68Ga-DOTATATE PET/CT as the preferred modality in pediatric PPGL. 68Ga-DOTATATE PET/CT may evolve as a preferred imaging modality for disease surveillance in VHL.

Prior testosterone replacement therapy may impact spermatogenic response to combined gonadotropin therapy in severe congenital hypogonadotropic hypogonadism.

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.

Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity.

CONTEXT: Regional variation in prevalence of genetic mutations in growth hormone deficiency (GHD) is known. AIM: Study phenotype and prevalence of mutations in GH1, GHRHR, POU1F1, PROP1 genes in GHD cohort. METHODS: One hundred and two patients {Isolated GHD (IGHD): 79; combined pituitary hormone deficiency (CPHD): 23} with orthotopic posterior pituitary were included. Auxologic, hormonal and radiological details were studied. All four genes were analysed in IGHD patients. POU1F1 and PROP1 were studied in CPHD patients. RESULTS: Of 102, 19.6% were familial cases. Height SDS, mean (SD) was - 5.14 (1.63). Peak GH, median (range) was 0.47 ng/ml (0-6.59), 72.5% patients had anterior pituitary hypoplasia (APH). Twenty mutations (novel: 11) were found in 43.1% patients (n = 44, IGHD-36, CPHD-8). GHRHR mutations (n = 32, p.Glu72* = 24) were more common than GH1 mutations (n = 4) in IGHD cohort. POU1F1 mutations (n = 6) were more common than PROP1 mutations (n = 2) in CPHD cohort. With few exceptions, this prevalence pattern is contrary to most studies in world-literature. No patients with peak GH > 4 ng/ml had mutations, signifying it as negative predictor. While many parameters were significant on univariate analysis, only positive family history and lower median peak GH levels were significant predictors of mutations on multivariate analysis in IGHD patients. CONCLUSION: At variance with world literature, we found reverse predominance of GHRHR over GH1 mutations, POU1F1 over PROP1 mutations and predominance of GHRHR p.Glu72* mutations thus re-affirming the regional diversity in GHD genetics. We report positive and negative predictors of mutations in GHD.

Tumour-induced osteomalacia due to an intra-abdominal mesenchymal tumour.

A 50-year-man presented with debilitating lower-limb proximal muscle weakness and hip pain since 3 years. Investigations (serum calcium (8.9 mg/dL), serum phosphorus (1.5 mg/dL), serum albumin (40 g/L), parathyroid hormone (116 pg/mL (12.30 pmol/L)), 25(OH)D3 (25.2 ng/mL (63 nmol/L)) 1,25(OH)2 D3 (19 pg/mL (45.60 pmol/L)), tubular reabsorption of phosphate of 0.22 and elevated serum fibroblast growth factor 23 (FGF23) (387.7 RU/mL)) were consistent with tumour-induced osteomalacia (TIO). Localisation studies (68Ga DOTATATE positron emission tomography (PET)/CT and 18FDG-PET/CT) did not reveal any lesion. Re-evaluation after 2 and 5 years with 68Ga-DOTANOC PET/CT showed 2×1.4 cm progressively increasing rounded soft tissue enhancing mass close to splenic hilum (SUV max: 26.4). Tumour was resected by laparotomy. Both FGF23 (120 RU/mL on day 3) and serum phosphorus (2.5 mg/dL on day 10) normalised with significant clinical improvement after surgery. Histopathology revealed phosphaturic mesenchymal tumour. Here, we report the first case of intra-abdominal mesenchymal tumour causing TIO diagnosed by serial functional imaging.

Tumor induced osteomalacia in head and neck region: single center experience and systematic review.

Tumor-induced osteomalacia in the head and neck region remains a challenging diagnosis to manage. Literature pertaining to management and outcome details remains sparse. We describe two cohorts: cohort 1 included seven patients from a single center in Western India with tumors located in paranasal sinuses (n = 3), intracranial (n = 2) and maxilla (n = 2). The unique features from our series is the management of persistent disease with radiation therapy (n = 2) and peptide receptor radionuclide therapy (PRRT) (n = 1). Cohort two has 163 patients identified from 109 publications for systematic review. Paranasal sinuses, mandible, intracranial disease, maxilla and oral cavity, in descending order, are reportedly common tumor sites. Within this cohort, mean age was 46 ± 14 years at presentation with 44.1% having local symptoms. Duration of symptoms varied from 1 to 240 months. Pre-surgery mean serum phosphorus was 1.4 ± 0.4 mg/dL and median FGF-23 levels were 3.6 (IQR:1.8-6.8) times of normal upper limit of normal. Majority (97.5%) were managed primarily with surgical excision; however, primary radiotherapy (n = 2) and surgery combined with radiotherapy (n = 2) were also reported. Twenty patients had persistent disease while nine patients had recurrence, more commonly noted with intracranial and oral cavity tumors. Surgery was the most common second mode of treatment employed succeeded by radiotherapy. Four patients had metastatic disease. The most common histopathological diagnosis reported is PMT mixed connective tissue, while the newer terminology 'PMT mixed epithelial and connective tissue type' has been described in 15 patients.