Steroidogenic acute regulatory protein (STAR) deficiency: Our experience and systematic review for phenotype-genotype correlation.

OBJECTIVE: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype-genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype-genotype correlation. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of three genetically proven LCAH patients from our centre and per-patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia). RESULTS: We report three new LCAH probands from India, all diagnosed post-infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two-thirds of LCAH probands were East-Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice-site variants and deletion/insertions were present in Group A. CONCLUSIONS: We report three new cases of LCAH from India. We propose a phenotype-derived genotypic classification of reported STAR variants in 46,XY LCAH.

Correlation between Serum Vitamin D3 Levels and Severity of COVID-19, Experience from a COVID-19-Dedicated Tertiary Care Hospital from Western India.

Context: It is postulated that 25(OH)D deficiency is associated with a worse prognosis of COVID-19. Aims: We aimed to find out whether baseline serum 25-hydroxy vitamin D levels were correlated with COVID-19 disease severity or not in Indian population. Settings and Design: It is a prospective observational study. Methods and Material: We prospectively recruited 200 COVID-19-positive adult patients and measured their baseline vitamin D levels on admission and prospectively followed their clinical course for their outcome and correlated the association. Statistical Analysis Used: The continuous data were represented as mean (±SD) or median (IQR), while the categorical data were represented as proportions. Parametric data were analysed using unpaired T-test and ANOVA for two and more than two groups, and for categorical, nonparametric data, Chi-square test were applied. A two-sided P value of <0.05 was considered as statistically significant with 95% confidence interval. Results: Eighty-six per cent (172/200) of patients had hypovitaminosis D (<30 ng/mL). The prevalence of 25(OH) severe deficiency, deficiency and vitamin D insufficiency was 23%, 41% and 22%, respectively. Clinical severity was graded as asymptomatic (11%), mild (14%), moderate (14.5%), severe (37.5%) and critical (22%). Sixty per cent of patients had clinically severe or critical disease requiring oxygen support with eleven per cent (n = 22) mortality overall. Age (P: 0.001), HTN (P: 0.049) and DM (P: 0.018) were negatively associated with clinical severity. No linear association was found between vitamin D levels and clinical severity. Low vitamin D levels had a significant inverse association with inflammatory markers like neutrophil-lymphocyte ratio (NLR, P: 0.012) and IL-6 (P: 0.002). Conclusions: Vitamin D deficiency was not associated with worse outcomes of COVID-19 infection in Indian population.

Targeting Predialysis Glucose up to 180 mg/dl Reduces Glycemic Variability in End Stage Diabetic Nephropathy.

Context: Glycemic variability plays a major role in the development as well as the progression of cardiovascular disease in diabetes. Aims: We compared the mean plasma glucose and glycemic variability (GV) parameters on and off hemodialysis (HD) in patients with End-Stage Diabetic Nephropathy (ESDN) and End-Stage Renal Disease (ESRD). Settings and Design: Cross-sectional study. Methods and Material: We included 23 ESDN and 6 ESRD patients who underwent continuous glucose monitoring (CGM) (iPro2) for 6 days and a glucose-free dialysate for 4 hours thrice weekly. EasyGV software was used to calculate the variability parameters {mean glucose, Time in range (TIR), Time above and below range (TAR/TBR), CV (Coefficient of Variation) and MAGE}. Statistical Analysis Used: The quantitative data variables were expressed by using mean and SD. Unpaired t-test was used to compare the two groups. P value <0.05 was considered significant. Results: In the ESDN group, TIR was significantly lower whereas TAR and TBR were significantly higher on HD day. MAGE (101.88 ± 40.5 v/s 89.46 ± 30.0, P < 0.007) and CV (29.41% v/s 21.67%) were higher on HD day. Subjects with pre-HD glucose values ≥180 mg/dl (Group B, n = 24) had a rapid drop with a delayed higher rise in glucose values than those with pre-HD glucose values <180 mg/dl (Group A, n = 27). Ten patients had 13 episodes of hypoglycemia. The CGM parameters were not different in the ESRD group. Conclusions: Targeting a pre- HD glucose value <180 mg/dl could be a good strategy to prevent larger fluctuation during and post HD.

Prevalence and predictors of abnormal glucose tolerance and its resolution in acromegaly: Single Centre retrospective study of 90 cases.

Aims The aim of the study was to evaluate the prevalence and predictors of abnormal glucose tolerance (Diabetes + Prediabetes) and its resolution in Acromegaly. SETTINGS AND DESIGN: Retrospective observational study. METHODS AND MATERIAL: Ninety patients with acromegaly and followed up post operatively for 1 year were included. The study cohort was divided into two groups: Group A: abnormal glucose tolerance [AGT: Diabetes + prediabetes (n = 40)] and Group B: normal glucose tolerance (NGT) (n = 50).The impact of the following parameters: age, sex, Waist Circumference(WC), Body Mass Index (BMI), duration of acromegaly, Growth Hormone (GH) levels, Insulin like Growth Factor 1 (IGF1) levels, pituitary tumour size, hypertension, and family history of diabetes as predictors for diabetes were studied pre surgery and post-surgery at 3 months and 1 year affecting glycaemia. Unpaired t-test, chi-square test and binary logistic regression analysis were used for statistical analysis. RESULTS: The prevalence of AGT in our cohort was 44.44% (Diabetes 37.77%, prediabetes 6.66%).Patients with AGT were older (44.2 ± 12.21 years vs. 34.92 ± 11.62 years; p = 0.00040) and had higher WC (in cm) (91.35 ± 7.87 vs.87.12 ± 6.07; p = 0.005) than NGT. Hypertension and family history of diabetes were significantly more frequent in patients with AGT. GH and IGF1 levels were not significantly different between the groups. On binary logistic regression, Sex (p = 0.0105) (OR = 6.0985), waist circumference (p = 0.0023) (OR = 1.2276) and hypertension (p = 0.0236) (OR = 1.632) were found to be significant predictors of AGT in acromegaly. After surgery 42.5% and 62.5% patients became normoglycemic at 3 months and 1 year respectively. On binary logistic regression there were no predictors for achieving normoglycemia at 3 months or 1 year, however the delta change in GH, BMI and tumour size were significant. CONCLUSIONS: The prevalence of AGT was 44.44%. Female sex, WC and hypertension were found to be significant predictors of AGT in acromegaly. Post-surgery normoglycemia was achieved in 42.5% at 3 months and 62.5% at 1 year with no predictors for normalisation of AGT.

Unrecognized Primary Hypothyroidism As a Possible Cause of Hyperreactio Luteinalis.

Hyperreactio luteinalis (HRL) is characterised by benign enlargement of ovaries in pregnancy associated with hyperandrogenism. A 19-year-old primigravida presented with breathlessness, abdominal distension and vomiting in the thirteenth week of gestation. Abdominal examination revealed distension of abdomen disproportionate to the gestational age. Ultrasound was suggestive of bilaterally enlarged multicystic ovaries with a characteristic "spoke-wheel" pattern and a diagnosis of HRL was made. Laboratory investigations revealed primary hypothyroidism and elevated testosterone. She was initiated on levothyroxine therapy. Her respiratory distress worsened on the third day of admission for which she underwent emergency laparotomy with cyst aspiration. Thyroid function tests normalized within six weeks after the initiation of therapy and remained normal for the remainder of pregnancy. Serum testosterone levels returned to normal six weeks postpartum. The elevated thyroid-stimulating hormone levels could have contributed to development of HRL by cross-reacting with human chorionic gonadotropin and follicle-stimulating hormone receptors. Hyperandrogenism and ovarian enlargement regresses with levothyroxine 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.

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.

Current Status of Diagnosis and Management of Functioning Pituitary Tumors: Part II.

Functioning pituitary tumors contribute to significant morbidity and mortality. Proper diagnostic approach and management is essential for optimal outcomes. Prolactinomas, the commonest of these, are the only tumors which can be managed medically. Acromegaly, apart from acral enlargement, can have multiple comorbidities like diabetes, hypertension, and obstructive sleep apnea. The primary treatment is surgical and it can be supplemented by radiotherapy and medications such as somatostatin analogs, growth hormone receptor blockers, or cabergoline. Thyrotropin-secreting tumors are rare and present with hyperthyroidism. Optimal preoperative management followed by surgical resection often leads to cure.

A study of glycemic variability in patients with type 2 diabetes mellitus with obstructive sleep apnea syndrome using a continuous glucose monitoring system.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) in association with Type 2 Diabetes Mellitus (DM) may result in increased glycemic variability affecting the glycemic control and hence increasing the risk of complications associated with diabetes. We decided to assess the Glycemic Variability (GV) in patients with type 2 diabetes with OSAS and in controls. We also correlated the respiratory disturbance indices with glycemic variability indices. METHODS: After fulfilling the inclusion and exclusion criteria patients from the Endocrinology and Pulmonology clinics underwent modified Sleep Apnea Clinical Score (SACS) followed by polysomnography (PSG). Patients were then divided into 4 groups: Group A (DM with OSAS, n = 20), Group B (DM without OSAS, n = 20), Group C (Non DM with OSAS, n = 10) and Group D (Non DM without OSAS, n = 10). Patients in these groups were subjected to continuous glucose monitoring using the Medtronic iPro2 and repeat PSG. Parameters of GV: i.e. mean glucose, SD (standard Deviation), CV (Coefficient of Variation), Night SD, Night CV, MAGE and NMAGE were calculated using the Easy GV software. GV parameters and the respiratory indices were correlated statistically. Quantitative data was expressed as mean, standard deviation and median. The comparison of GV indices between different groups was performed by one-way analysis of variance (ANOVA) or Kruskal Wallis (for data that failed normality). Correlation analysis of AHI with GV parameters was done by Pearson correlation. RESULTS: All the four groups were adequately matched for age, sex, Body Mass Index (BMI), waist circumference (WC) and blood pressure (BP). We found that the GV parameters Night CV, MAGE and NMAGE were significantly higher in Group A as compared to Group B (p values < 0.05). Similarly Night CV, MAGE and NMAGE were also significantly higher in Group C as compared to Group D (p value < 0.05). Apnea-hypopnea index (AHI) correlated positively with Glucose SD, MAGE and NMAGE in both diabetes (Group A plus Group B) and non- diabetes groups (Group C plus Group D). CONCLUSIONS: OSAS has a significant impact on the glycemic variability irrespective of glycemic status. AHI has moderate positive correlation with the glycemic variability.