Pituitary apoplexy in cushing's disease: a single center study and systematic literature review.

INTRODUCTION: Pituitary apoplexy (PA) in Cushing's disease (CD) is rare with data limited to case reports/series. METHODS: We retrospectively reviewed case records of PA in CD managed at our center from 1987 to 2023 and performed a systematic literature review. RESULTS: We identified 58 patients (44 females), including twelve from our center (12/315 CD, yielding a PA prevalence in CD of 3.8%) and forty six from systematic review. The median age at PA diagnosis was 35 years. The most common presentation was type A (79.3%) and symptom was headache (89.6%), with a median Pituitary Apoplexy Score (PAS) of 2. Median cortisol and ACTH levels were 24.9 µg/dl and 94.1 pg/ml, respectively. Apoplexy was the first manifestation of underlying CD in 55.2% of cases, with 31.1% (14/45) presenting with hypocortisolemia (serum cortisol ≤ 5.0 µg/dl), underscoring the importance of recognizing clinical signs/symptoms of hypercortisolism. The median largest tumor dimension was 1.7 cm (53/58 were macroadenomas). PA was managed surgically in 57.8% of cases, with the remainder conservatively managed. All five PA cases in CD with microadenoma achieved remission through conservative management, though two later relapsed. Among treatment-naïve CD patients with macroadenoma, PA-related neuro-deficit improvement was comparable between surgical and conservative groups. However, a greater proportion of surgically managed patients remained in remission longer (70% vs. 38.5%; p = 0.07), for an average of 31 vs. 10.5 months. CONCLUSION: PA in CD is more commonly associated with macroadenomas, may present with hypocortisolemia, and surgical treatment tends towards higher and longer-lasting remission rates.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.

Nutritional Status of Underprivileged Indian Children and Youth with Type-1 Diabetes - A Multicentre Study.

Background: India has the highest number of prevalent type-1 diabetes (T1D) cases in the under-20-year age population. Data on the anthropometry of underprivileged Indian children with T1D are scarce. In economically disadvantaged countries like India, poor growth in patients with T1D is a major concern due to limited accessibility and affordability. Besides, due to the double burden of malnutrition, the prevalence of obesity is increasing mirroring the global trends, which may lead to the development of insulin resistance. Objectives: This study aims to assess the prevalence of malnutrition in Indian children and youth with T1D and to identify the determinants of short stature. Methods: A registry-based cross-sectional analysis of data collected from various centres across India enrolled in the Changing Diabetes in Children (CDiC) programme. Results: We observed that 6.4% were undernourished (3.4% severe undernutrition) and 17.7% (overweight 13.2%) had combined overweight/obesity. 21.2% of participants had short stature (adjusted for mid-parental height) with 7.4% cases of familial short stature. Longer duration of illness and insulin requirement were significant positive predictors of short stature while glycaemic control, insulin regimen and mid-parental height did not have a significant relationship with short stature. Participants on basal-bolus regimen had significantly higher insulin requirements and better glycaemic control than the ones on mixed-split regimen. Conclusion: We report that around one-fifth of children and youth with T1D were overweight/obese and around a fourth were stunted, especially those with longer duration of diabetes and higher insulin requirements. Close monitoring of anthropometric parameters is necessary for all children with T1D to optimize growth and nutrition.

Genotypic Spectrum and its Correlation with Alopecia and Clinical Response in Hereditary Vitamin D Resistant Rickets: Our Experience and Systematic Review.

Alopecia in hereditary vitamin D resistant rickets (HVDRR) has some correlation with severe rickets and poor overall response. However, these observations are based on small series. Hence, we aim to assess the genotypic spectrum of HVDRR and its correlation with alopecia and clinical response. Seven genetically-proven HVDDR patients from five unrelated families and 119 probands from systematic review were analysed retrospectively for phenotypic and genotypic data and overall response to therapy. In our cohort mean age at rickets onset was 12 (± 3.4) months. Alopecia was present in all patients but one. All patients had poor overall response to oral high-dose calcium and calcitriol and most required intravenous calcium. Genetic analyses revealed four novel variants. On systematic review, alopecia was present in majority (81.5%) and preceded the onset of rickets. Patients with alopecia had higher serum calcium (7.6 vs.6.9 mg/dl, p = 0.008), lower 1, 25(OH)2 D (200 vs.320 pg/ml, p = 0.03) and similar overall response to oral therapy (28.7% vs. 35.3%, p = 0.56). Alopecia was present in 51.4% of non-truncating (NT) ligand-binding domain (LBD) variants, whereas it was universal in truncating LBD and all DNA binding-domain (DBD) variants. Overall response to oral therapy was highest in LBD-NT (46.4%) as compared to 7.6% in LBD-truncating and 19% in DBD-NT variants. Among LBD-NT variants, those affecting RXR heterodimerization, but not those affecting ligand affinity, were associated with alopecia. Both alopecia and overall response have genotypic correlation. Age at diagnosis and overall response to oral therapy were similar between patients with and without alopecia in genetically proven HVDRR.

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.

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.

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

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.

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.

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.

Comparison of 68Ga-DOTA-NaI3-Octreotide/tyr3-octreotate positron emission tomography/computed tomography and contrast-enhanced computed tomography in localization of tumors in multiple endocrine neoplasia 1 syndrome.

The optimum imaging modality for the screening of multiple endocrine neoplasia type 1 (MEN1)-associated tumors is not well established. Here, we compare the performance of contrast-enhanced CT (CECT) versus 68Ga DOTA-NOC/TATE PET/CT in MEN1 patients. The retrospective case record study is conducted at a tertiary health-care center. Thirty-four patients, who have undergone both CECT and 68Ga DOTA-NOC/ TATE PET, were included in the analysis. CECT had higher per-lesion sensitivity than 68Ga DOTA-NOC/TATE PET/CT for the detection of parathyroid lesions, (82.6% vs. 24.6%, P < 0.001). 68Ga DOTA-NOC/TATE PET/CT had higher per-lesion sensitivity than CECT for the detection of metastases (85% vs. 47.5%, P < 0.001) and gastrinomas (90% vs. 10%, P = 0.003). When combined use of the two imaging modalities is compared to CECT alone (63.7% vs. 93.1%, P = 0.00012) and 68Ga-DOTA-NOC/TATE PET/CT alone (74.1% vs. 93.1%, P = 0.0057), it provided significantly higher per-lesion sensitivity for the detection of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). 68Ga-DOTA-NOC/ TATE PET was more sensitive for the detection of gastrinomas and metastases than CECT, whereas it was less sensitive for the detection of parathyroid lesions than CECT. The combined use of both the imaging modalities significantly increases the sensitivity for detection of GEP-NETs.

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.

177Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma.

INTRODUCTION: 177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/or inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/or inoperable PPGL. METHODS: This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (plasma-free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy. RESULTS: A total of 15 patients (4 PCC, 4 sPGL, 5 HNPGL, 1 PCC + sPGL, 1 HNPGL + sPGL) were included. The median duration of follow up was 27 (range: 11-62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53%), partial response in one (7%), and minor response in three (20%) and controlled disease in 12 (80%). On linear regression analysis the presence of PGL (P= 0.044) and baseline SUVmax >21 (P < 0.0001) were significant positive predictors of early response to PRRT. Encouraging safety profiles were noted with no long term nephrotoxicity and hematotoxicity. CONCLUSION: 177Lu-DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic/inoperable PPGL. Although it is not prudent to withhold PRRT in metastatic PPGL with baseline SUVmax < 21, baseline SUVmax >21 can be used to predict early response to PRRT.

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.