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.
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.
To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients with cryptorchidism beyond infancy.
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.
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.
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.
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.
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.
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.
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.
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.
Summary
Background
Various techniques have been attempted to increase the yield of magnetic resonance imaging (MRI) for localization of pituitary microadenomas in corticotropin (ACTH)‐dependent ...Cushing's syndrome (CS).
Objective
To compare the performance of dynamic contrast spin echo (DC‐SE) and volume interpolated 3D‐spoiled gradient echo (VI‐SGE) MR sequences in the diagnostic evaluation of ACTH‐dependent CS.
Design
Data was analysed retrospectively from a series of ACTH‐dependent CS patients treated over 2‐year period at a tertiary care referral centre (2009–2011).
Patients
Thirty‐six patients (24 female and 12 male) were diagnosed to have ACTH‐dependent CS during the study period. All patients underwent MRI by both sequences during a single examination. Cases with negative and equivocal pituitary MR imaging underwent corticotropin‐releasing hormone (CRH) stimulated bilateral inferior petrosal sinus sampling (BIPSS) to confirm pituitary origin of ACTH excess state. Thirty patients were finally diagnosed to have Cushing's disease (CD) based on histopathology proof of adenoma and/or remission (partial/complete) of hypercortisolism postsurgery. Six patients were diagnosed to have histopathologically proven ectopic CS.
Results
Of 30 patients with CD, 24 patients had microadenomas and 6 patients had macroadenomas. DC‐SE MRI sequence was able to identify microadenomas in 16 of 24 patients, whereas postcontrast VI‐SGE sequence was able to identify microadenomas in 21 of 24 patients. All six patients of ectopic CS had negative pituitary MR imaging by both techniques (specificity: 100%).
Conclusion
VI‐SGE MR sequence was better for localization of pituitary microadenomas particularly when DC‐SE MR sequence is negative or equivocal and should be used in addition to DC‐SE MR sequence for the evaluation of ACTH‐dependent CS.
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.
Context
Localization of phosphatonin‐producing mesenchymal tumours in patients with primary tumour‐induced osteomalacia (pTIO) is challenging. Functional imaging plays an important role in the ...localization of these tumours.
Objective
We studied the relative performance of different functional imaging modalities (18F‐FDG PET/CT, 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT) in tumour localization in cases of pTIO.
Design and Methods
Retrospective chart evaluation of 16 patients with confirmed TIO treated from 2006 to 2013 was conducted in a tertiary care referral centre.
Results
Of 16, nine patients had pTIO. In these nine, the positivity rates of different functional imaging modalities were 50% for 18 F‐FDG PET/CT (four of eight patients), 100% for 99Tc‐HYNIC‐TOC SPECT/CT (six of six patients) and 100% for 68Ga‐DOTATATE PET/CT (seven of seven patients). Of nine patients, six were subjected to both the 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT and all of them showed coregistration on the two scans.
Conclusions
In patients with pTIO, the somatostatin receptor‐based functional scans performed better than 18F‐FDG PET/CT in tumour localization. Amongst the somatostatin receptor‐based scans, 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT performed equally well for localization of tumours.
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.
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.
