Third-Generation Thyrotropin Receptor Antibody (TRAb) assay for predicting neonatal thyroid dysfunction in pregnant women with Graves' disease.

PURPOSE: The aim is to validate the third generation Thyrotropin receptor antibody (TRAb) assay for predicting neonatal thyroid dysfunction and adverse pregnancy outcomes in pregnant women with Graves' disease. METHODS: This prospective cohort study was conducted in TRAb positive pregnant women with Graves' disease and their off springs. The primary outcome was to assess different forms of neonatal thyroid dysfunction in relation to maternal and neonatal TRAb levels. The secondary outcome was to predict adverse pregnancy outcomes by using maternal TRAb levels. Serum T3, FT4, TSH, TRAb levels were measured using electrochemiluminescence immunoassay. RESULTS: 51 pregnant women were included. Five women had adverse pregnancy outcomes, TRAb levels of > 19.06 IU/L (10.9 times the upper limit of normal (ULN)) predicted adverse pregnancy outcomes with 100% sensitivity and 93.5% specificity. Among the 46 successful live births, 13 (28.3%) had neonatal thyroid dysfunction. Out of 13 neonates, 7 (32%) had neonatal thyrotoxicosis, 4 (18%) had primary hypothyroidism, and 2 (9%) had central hypothyroidism. Third trimester maternal TRAb levels of > 7.99 IU/L (4.6 times the ULN)and day three neonatal TRAb levels of > 5.03 IU/L (2.9 times the ULN), predicted the neonatal thyrotoxicosis with 100% sensitivity and 97.4% specificity. CONCLUSION: Very high maternal third generation TRAb levels strongly predicted the adverse pregnancy outcomes and neonatal thyroid dysfunction in pregnant women with Graves' disease. Neonatal thyroid function test along with the TRAb levels strongly correlated with different forms of neonatal thyroid dysfunction and is very useful in avoiding inadvertent treatment to neonates.

Clinico-radiological correlation of pituitary stalk interruption syndrome in children with growth hormone deficiency.

PURPOSE: To analyze the clinical, hormonal, and radiological characteristics of Pituitary stalk interruption syndrome (PSIS) in children with growth hormone deficiency (GHD). METHODS: This is a prospective cross-sectional study, conducted over a period of three years in a short stature clinic of tertiary care referral hospital. 57 severe short stature children with proven GHD were included in the study. RESULTS: Among 57 children with GHD, 14 (24%) were diagnosed as PSIS. The mean age at diagnosis was 11.8 ± 2.6years. The male to female ratio was 2.5:1. Nine (64%) children had multiple pituitary hormone deficiency (MPHD) and 5 (36%) had isolated growth hormone deficiency (IGHD). In spite of absent or ectopic posterior pituitary (EPP)in Magnetic Resonance Imaging (MRI) of PSIS cohorts, only one had Arginine vasopressin (AVP) deficiency. EPP was seen near median eminence in 6 (44%), elsewhere in 4 (28%), and absent in 4 (28%)children. The height gain following growth hormone therapy was better in PSIS cohorts as compared to non-PSIS. CONCLUSION: Male gender, breech presentation, external congenital anomalies like cryptorchidism, midline defects and nystagmus were more common in children with PSIS. MPHD were more frequently seen in PSIS whereas IGHD in non-PSIS cohort. AVP deficiency is very rare in PSIS despite of absent or ectopic posterior pituitary in MRI. High index of clinical suspicion in all severe short stature may lead to early diagnosis and prompt initiation of growth hormone treatment for better outcome.

A randomized controlled trial comparing myoinositol with metformin versus metformin monotherapy in polycystic ovary syndrome.

OBJECTIVE: Insulin resistance and hyperinsulinemia plays an important role in pathogenesis of polycystic ovary syndrome (PCOS). Metformin, Myoinositol and d-chiro-inositol acts as insulin sensitizers and exerts a beneficial effects in PCOS. The objective is to compare the effect of metformin monotherapy versus a combination of metformin with Myoinositol and d-chiro-inositol in PCOS. DESIGN: This study is a randomized controlled trial conducted over a period of 6 months. All overweight and obese women with PCOS with the age group between 18 and 35 were included and randomized into two groups, 27 in the metformin monotherapy arm and 26 in the myoinositol combination arm. PATIENTS AND MEASUREMENTS: The variables assessed were duration of menstrual cycle, anthropometric parameters, modified Ferriman Gallwey score, global acne score, Fasting insulin, HOMA-IR, fasting lipid profile, serum testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, anti-Mullerian hormone, and pelvic ultrasound to assess ovarian volume, PCOS Questionnaire score. Changes in the parameters from baseline at the end of 6 months of treatment were assessed and compared between the groups. RESULTS: Menstrual cycle regularity improved in both groups with significantly greater improvement in the group receiving myoinositol-based therapy (p < .001). Pregnancy rate was equal in both the arms. There was a significant improvement in PCOSQ score in myoinositol-based therapy group (p < .001). However, there was no statistically significant difference in other hormonal, metabolic parameters between two groups in spite of symptomatic benefits. CONCLUSIONS: The addition of myoinositol to metformin exerts additional benefits in improving menstrual cycle regularity, and quality of life in women with PCOS.

Epidemiology, Clinical Profile, and Analysis of Risk Factors in COVID Associated Rhino-orbito-cerebral Mucormycosis Patients - An Observational Study.

Aim of Study: To study the clinico-epidemiological profile and identify risk factors for the development of COVID-19-associated mucormycosis (CAM) among the patients treated at our regional mucormycosis center. Materials and Methods: This was a cross-sectional single-centre observational study. All CAM patients admitted to Government Rajaji Hospital, Madurai from April 2021- August 2021 were included in the study. Information regarding clinical features, potential risk factors, diagnostic workup, and comorbid illness was collected. Results: A total of 164 patients of CAM were admitted to our hospital with a mean age of 51.7 years. Out of 164 patients, 12 patients were not covid positive, based on imaging and RT-PCR, however subclinical infection could not be ruled out. Out of the 164 patients studied, 160 patients had diabetes, out of which 66% (n = 105) patients had a previous history of diabetes, and 34% (n = 55) had newly detected diabetes. Most of the patients admitted with mucormycosis had uncontrolled diabetes (94%) and were not on insulin therapy, but were on oral antidiabetic drugs alone. The majority of the patients (68%) have received steroids (IV/oral) during the COVID-19 illness. 74% of these patients were under hospitalization for COVID-19 disease. Only 30% (n = 50) of CAM patients had a history of oxygen therapy and 7% of these patients were treated in ICU during active COVID-19 illness. 59% of patients used cloth masks without adequate hygiene, rest 41% (n = 67) patients reused disposable masks. We also found that 87% of the patients developing mucormycosis had exposure to organic material in the convalescence period of COVID-19 illness. Conclusions: From our study, we found steroid use, poorly controlled diabetes mellitus, reuse of masks, daily steam inhalation, and exposure to organic matter to be more associated with CAM, but oxygen therapy was less associated with CAM. Hence, we could suggest screening for hyperglycemia and daily use of disposable surgical masks to be continued for at least 4 weeks post-COVID-19. It is preferable to continue insulin in titrated doses along with OHA for at least 4 weeks following steroid cessation in the post-COVID-19 period as there is are considerably increased inflammatory cytokine levels in the convalescence phase. Clean environmental hygiene would also help prevent CAM.

Clinical Profile and Molecular Genetic Analysis of Prader - Willi Syndrome: A Single Center Experience.

Aim: The prevalence of childhood and adolescent obesity is increasing worldwide as well as in India. Prader--Willi syndrome (PWS) is one of the most common causes of syndromic obesity with varied clinical manifestations across different lifespan. Herewith, we describe clinical and molecular characteristics of eight PWS who were diagnosed in an obesity clinic of tertiary care hospital. Materials and Methods: Clinically suspected cases of PWS were screened between January 2014 and January 2022. Detailed history and clinical examination were done to look for typical features of PWS like characteristic facial appearance, short stature, obesity, hyperphagia, delayed puberty or hypogonadism, diabetes mellitus, developmental delay, cognitive dysfunction, learning disabilities or abnormal behavior. All were evaluated, with 75 g oral glucose tolerance tests (GTT), HbA1c, Free T4, TSH, LH, FSH, testosterone, and growth hormone level. Intelligent quotient (IQ) of each patient was assessed by a psychiatrist using Binet-Kamat test. Molecular confirmation of clinically suspected PWS was done by either Methylation-specific polymerase chain reaction (MS-PCR) or Fluorescence in situ Hybridization (FISH) methods. Results: Based on clinical and molecular characteristics, eight were diagnosed as PWS. Except one, all were male with characteristic facies, mean age of study cohort was 12 years and mean BMI of 44.58. Obesity, short stature, hyperphagia, hypotonia, and mild to moderate mental retardation were noted in entire (100%) PWS study population. All male PWS patients had cryptorchidism, which was bilateral in six patients and unilateral (right undescended testes) in one. Apart from obesity, short stature, other endocrine associations noted were diabetes mellitus in 50% and subclinical hypothyroidism in 37% of PWS. Molecular characteristics of PWS were confirmed by Methylation-specific PCR in seven and by FISH method in one. Conclusion: Prader-Willi syndrome should be kept in mind in case of childhood or adolescent obesity with short stature, hypotonia, cryptorchidism, and developmental delay or cognitive dysfunction. Judicious use of molecular diagnostic testing should be made in all clinically suspected cases. Early diagnosis and appropriate management of this complex disorder by a multidisciplinary team will improve the quality of life and treatment outcome.

Clinical Profile of Addison's Disease in a Tertiary Care Institute, Southern India - The Changing Landscape.

Aims and Objectives: Clinical, biochemical, and radiological profiles of Addison's disease and to assess the various etiological spectrum of primary adrenal insufficiency (PAI) in adults. Materials and Methods: A retrospective cohort study was carried out in the Department of Endocrinology, Madurai Medical College, Madurai between January 2014 and January 2021 over a 7-year period. Inclusion Criteria: All the patients with clinical symptoms and or signs of suspected PAI, such as hyperpigmentation, weight loss, persistent nausea or vomiting, fatigue, and hypotension, were recruited. All suspected cases underwent measurement of 8-AM plasma ACTH and cortisol levels. In possible cases and equivocal cortisol levels, patients underwent Co-syntropin/ACTH stimulation test. To know the underlying etiology of PAI, 21-hydroxylase autoantibodies (21OHAb), thyroid function test, Anti TPO, calcium, parathyroid hormone (PTH), LH and FSH, CT of chest and abdomen, and sputum AFB based on the clinical pattern of involvement were performed. Exclusion Criteria: Patients with onset of PAI at infancy and childhood, secondary adrenal insufficiency or exogenous Cushing's syndrome, and central hypocortisolism, including Sheehan's syndrome, were excluded. Results: Thirty-six patients were diagnosed with PAI in this study; 19 (53%) were females and 17 were males (47%). The median age of diagnosis was 35 years. Patients were divided into acute presentation and subacute presentation. Twenty-six patients presented with acute presentation and ten were presented with progressive evolved symptoms. Non-tuberculous etiology was the predominant finding noted in our cohort study (87%, 31 out of 36 patients). The other causes of Addison disease included isolated auto-immune PAI, polyglandular autoimmune syndrome type 1 and II, APLA Syndrome, and adrenal metastasis. Conclusion: Non-tuberculous causes of PAI are the leading etiology in our retrospective study. Autoimmune PAI and Polyglandular autoimmune syndromes are increasingly being recognized as the cause of Addison's disease. PAI individuals require lifelong surveillance for possible development of coexisting autoimmune syndromes and need for glucocorticoid/mineralocorticoid therapy.

The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation.

Aim: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the adrenal steroidogenic pathway. The most common form of CAH is due to 21-hydroxylase deficiency resulting from mutations in CYP21A2 gene. The present study aimed to identify CYP21A2 common gene mutations, phenotype correlation, and to analyze the segregation pattern in CAH patients, parents, and siblings. Materials and Methods: Sixteen families having at least one classic CAH child in each family, a total of 58 subjects were recruited. The presence of six most common gene mutations, namely, Intron 2 (c.293-13A/C>G), c.844G>T (p.Val282Leu), c.1019G>A (p.Arg340His), c.92C>T (p.Pro31Leu), c.955C>T (p.Gln319*), and c.518T>A (p.Ile173Asn) in CYP21A2 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using specific primers. Results: Out of 16 classic CAH females analyzed, salt-wasting (SW) form was present in 12 (75%) and simple virilizing form in four (25%) children. Isolated clitoromegaly was the most common clinical presentation followed by ambiguous genitalia. The most common mutation observed in CAH patient population was Intron 2 (c.293-13A/C>G) (100%) followed by p.Pro31Leu (98%), p.Gln319* (93%), p.Val282Leu (91.4%), and p.Ile173Asn (19%). Although p.Arg340His mutation was not observed in this study. Interestingly, Intron 2 (c.293-13A/C>G) homozygous was observed in 31.3% of the entire study cohort and p.Ile173Asn mutation was found to be associated with SW form. Conclusions: Our results suggested a high prevalence of CYP21A2 gene mutations among CAH patients and heterogeneous mutation spectrum in their families of south Indian cohort. The outcomes afford valuable evidence for premarital and prenatal screening as well as planning suitable programs to prevent the development of CAH in Indian population.

HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA: A NOVEL HOMOZYGOUS MUTATION IN SLC34A3 AND LITERATURE REVIEW.

OBJECTIVE: Hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, recessively-inherited form of rickets caused by homozygous or compound heterozygous mutations in the SLC34A3 gene that encodes the renal tubular phosphate transporter protein NaPi2c. The bone phenotype varies from severe rickets to no disease. Accurate diagnosis is important as the treatment differs from other forms of rickets. METHODS: The patient was a 12-year-old boy from the Indian subcontinent with florid hypophosphatemic rickets. A targeted gene panel to search for mutations in genes associated with inherited forms of rickets was performed. We also completed a literature search of published cases of HHRH. RESULTS: The targeted gene panel demonstrated a novel homozygous SLC34A3 mutation: c.1339 G>A (p.Ala447Thr). His parents were heterozygous for the mutation. In our literature review we found that people with homozygous SLC34A3 mutations were more likely to have rickets than those with compound heterozygous mutations (85% versus 45%, p<0.002) and that serum phosphate z scores were lower in those with rickets than those without (-3.3 with a standard deviation of 1.5 versus -2.1 with a standard deviation of 1.5, p<0.005). CONCLUSION: The bone phenotype of HHRH is related to the nature of the mutation and serum phosphate levels. Targeted gene panels can aid in the accurate diagnosis of inherited forms of rickets, and facilitate correct treatment.

Predictors of atypical femoral fractures during long term bisphosphonate therapy: a case series & review of literature.

BACKGROUND & OBJECTIVES: Bisphosphonates (BPs) are the most widely prescribed medicines for the treatment of osteoporosis because of their efficacy and favourable safety profile. There have been, several reports on an increased incidence of atypical femoral fractures after long term treatment with BPs. The objective of this study was to evaluate the clinical presentation including prodromal symptoms, skeletal radiograph findings, type and duration of BPs received and treatment outcome of patients who developed atypical femoral fractures during bisphosphonate therapy. METHODS: In this retrospective study, eight patients with atypical femoral fractures were analysed based on clinical features, biochemical and radiological investigations. RESULTS: Of the eight patients, who sustained atypical femoral fractures, six were on alendronate and two were on zoledronate therapy before the fractures. In addition to BPs, two patients were on long term corticosteroid therapy for rheumatoid arthritis and Addison's disease. Three patients had bilateral atypical femoral fractures. Except one, all of them had prodromal symptoms prior to fracture. Skeletal radiograph showed cortical thickening, pointed (beaking of) cortical margin and transverse fracture in meta-diaphyseal location. Serum calcium, phosphate, alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) concentrations were within the reference range in all patients. INTERPRETATION & CONCLUSIONS: Long term bisphosphonate therapy may increase the risk of atypical femoral fractures. Presence of prodromal pain, thickened cortex with cortical beaking may be an early clue for predicting the atypical fractures. High risk patients need periodical skeletal survey and a close follow up for early detection of cases.

Camurati-Engelmann disease (progressive diaphyseal dysplasia): reports of an Indian kindred.

Camurati-Engelmann disease (CED, OMIM 131300), or progressive diaphyseal dysplasia, is a rare autosomal dominant skeletal dysplasia, caused by mutations in the transforming growth factor-ß1 (TGFß1) gene. We describe the first Indian CED family with genetic confirmation and presenting manifestations. The proband is a 17-year-old woman who presented with lower limb pain and proximal muscle weakness. Skeletal radiographs of the long bones revealed cortical, periosteal, and endosteal thickenings, predominantly affecting the diaphyses of the long bones. On detailed evaluation, there was a strong family history of bone disorder with similar symptoms of pain and radiological findings in several family members. Exon sequencing of the TGFß1 gene was performed in available family members. Based on clinical and radiographic studies and its familial nature, a diagnosis of CED was made and confirmed by mutation analysis. A heterozygous G to A transition in exon 4 of the TGFß1 gene (R218H) was detected in 5 out of 10 available family members, including 4 affecteds and 1 asymptomatic individual. Many of our affected individuals responded to glucocorticoids and cortical windowing. CED is a rare genetic disease with variable clinical manifestations and incomplete penetrance. CED needs to be considered in the differential diagnosis of nonspecific limb pain and waddling gait in all young individuals.

Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study.

OBJECTIVES: Thyroid antibody positivity during pregnancy has been associated with adverse outcomes including miscarriage and preterm delivery. The aim of the study is to evaluate the obstetric outcome in pregnant women with recurrent miscarriage and their response to levothyroxine (l-T4) therapy. STUDY DESIGN AND METHODS: All pregnant and non-pregnant women between 21 and 35 years of age with a history of two or more consecutive miscarriages were included in the study. A third group comprising 100 pregnant women without a history of miscarriage were taken as healthy controls. Thyroid autoimmunity, prevalence of subclinical hypothyroidism and maternal and foetal complications were analysed in all the groups with appropriate statistical methods. RESULTS: The mean age of the patients included in the study was 27.0±3.1 years. Of 100 pregnant patients with previous recurrent miscarriage, thyroid autoimmunity (thyroid peroxidase antibody (TPOAb(+)) >34 U/ml) was found in 31% of the cases. The incidence of subclinical hypothyroidism was higher in TPOAb(+) group than in TPOAb(-) group (52 vs 16%; P=0.0002). There was no difference in the prevalence of miscarriage or obstetric outcomes between recurrent miscarriage and healthy pregnant women group irrespective of TPO status. CONCLUSIONS: The prevalence of thyroid autoimmunity was higher in pregnant women with a history of recurrent abortion compared with healthy pregnant control population. Following l-T4 treatment, there was no difference in prevalence of miscarriage between hypothyroid and euthyroid individuals in TPOAb(+) women.

Macroprolactinemia in hyperprolactinemic infertile women.

Hyperprolactinemia occurs in 15-20 % of women with menstrual disturbances and 30-40 % of infertile women and it can adversely affect the fertility. High molecular weight prolactin (macroprolactin) has long been known in hyperprolactinemic fertile women. However, the prevalence of macroprolactinemia in hyperprolactinemic infertile women is not known. This cross-sectional study was carried out during the period of June 2010 and June 2011 at a single tertiary care centre. All women who attended the infertility clinic during this period were screened for hyperprolactinemia and only women with hyperprolactinemia and infertility were further studied for the presence of macroprolactin by polyethylene glycol precipitation assay. We compared the clinical, hormonal profile and fertility outcome of infertile women with true hyperprolactinemia and macroprolacinemia using appropriate statistical tests. Of 1,163 infertile women, 183 (15.7 %) had hyperprolactinemia [134 (73 %) had primary infertility and 49 (27 %) had secondary infertility]. Out of these 183 women with hyperprolactinemia, one had microadenoma, 161 had true idiopathic hyperprolactinemia and 21 (11.5 %) women had macroprolactinemia. The prevalence of oligomenorrhea and galactorrhea were significantly higher in patients with true hyperprolactinemia than macroprolactinemia (46 vs. 14 %, p < 0.008 and 30 vs. 5 %, p = 0.01 respectively). Twenty-two patients (13.5 %) of true hyperprolactinemia and two (9 %) in macroprolactinemia became pregnant during the study period. Prolactin measurement should be a part of routine evaluation of couples referred to infertility clinics. Macroprolactin screening is mandatory when clinical features and serum PRL assay results are conflicting. Patients with macroprolactinemia should be investigated for causes of infertility other than hyperprolactinemia.

Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: a randomized double-blind placebo-controlled study.

OBJECTIVES: Pioglitazone is an insulin sensitizer used for the management of type 2 diabetes mellitus (T2DM). It has been shown to reduce testosterone level in patients with polycystic ovarian syndrome. However, its effect on testosterone in men has not been studied. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled trial with 6 months follow-up. Fifty (25 in each group) eugonadal men (well virilized and total testosterone ≥ 12 nm) with T2DM, aged 30-55 year and HbA1c of ≤ 7.5% were randomly assigned to receive pioglitazone 30 mg per day or placebo along with existing glimepiride and metformin therapy. RESULTS: As compared to placebo, 6 months of pioglitazone therapy in patients with T2DM resulted in significant reduction in mean total testosterone level (16.1 to 14.9 vs 17.1 to 17.0 nm; P = 0.031), calculated free testosterone (P = 0.001) and bioavailable testosterone (P = 0.000) despite significant increase in sex hormone-binding globulin (P = 0.000). Plasma androstenedione (∆(4) ) level increased (1.5 to 1.9 vs 1.7 to 1.7 ng/ml; P = 0.051) following pioglitazone therapy. The decrease in testosterone was independent of change in body weight, body fat and HbA1c. CONCLUSION: Pioglitazone therapy significantly decreases total, free and bioavailable testosterone in eugonadal men with T2DM. The effects of these alterations need to be determined by further long-term studies.

Anemia and thrombocytopenia improves after curative parathyroidectomy in a patient of primary hyperparathyroidism (PHPT).

CONTEXT: Hematological manifestations are less known in primary hyperparathyroidism (PHPT). Anemia has been recognized as a complication of PHPT in 5-30% of the individuals in various series. OBJECTIVE: Our objective was to identify hematological improvement after the curative parathyroidectomy in a PHPT patient with anemia and thrombocytopenia. PATIENT AND METHODS: A 30-yr-old female presented with recurrent renal stone disease, anemia, and thrombocytopenia diagnosed as PHPT. Bone marrow examination revealed megakaryocytic thrombocytopenia. Two months after the curative parathyroidectomy, her symptoms and hematological parameters were improved. CONCLUSION: Our finding showed a causal association of both anemia and thrombocytopenia with marrow fibrosis in a symptomatic PHPT patient because both anemia and thrombocytopenia improved after the curative parathyroidectomy.