Hypomagnesemia with Secondary Hypoparathyroidism and Hypocalcemia due to Novel Variants in the Transient Receptor Potential Cation Channel Subfamily M Member 6 ( TRPM6 ) Gene.

HOMG1 (hypomagnesemia 1, intestinal) or hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder of magnesium metabolism, characterized by impaired magnesium absorption. This disorder may mimic other conditions presenting with neonatal seizures. Here, we report an infant diagnosed to have hypomagnesemia with secondary hypocalcemia due to novel variants in TRPM6 gene.

Bone microarchitecture and bone mineral density in Graves' disease.

Objectives: Graves' disease (GD) is the most common cause of thyrotoxicosis. There are many studies that have evaluated bone mineral density (BMD) in Graves' disease. However, the strength of a bone also depends on its microarchitecture which can be assessed by various techniques. Trabecular bone score (TBS) is a new method for assessing bone microarchitecture that is non-invasive and easily performed. Methods: The present study was a cross-sectional study that involved 50 patients with active GD and 50 healthy controls. Both groups were subjected to an assessment of biochemical parameters followed by measurement of BMD and TBS on the same dual energy X-ray absorptiometry (DXA) machine. Results: The mean age of patients with active GD (N = 50) was 31.9 ± 10.9 years while that of controls was 31.2 ± 4.9 years (P = 0.640). The female: male ratio was the same for both groups (F = 31, M = 19). The mean lumbar spine BMD, femoral neck BMD, total hip BMD, and distal radius BMD were significantly reduced in GD when compared to that in controls. The mean absolute lumbar spine TBS in GD was 1.263 ± 0.101 while that in controls was 1.368 ± 0.073 (P < 0.001). On multivariate regression analysis, the factors that predicted TBS were serum thyroxine (T4) and L1-L4 BMD. Conclusions: Patients with Graves' disease had reduced bone density at all sites and degraded microarchitecture. Long-term studies are required to understand the pattern of recovery of bone microarchitecture after the restoration of euthyroidism.

Trabecular bone score and bone mineral density as indices of skeletal fragility in endogenous Cushing's syndrome.

OBJECTIVE: Endogenous Cushing's syndrome (CS) is a known cause of secondary osteoporosis. Vertebral fractures (VFs) in endogenous CS may occur despite normal bone mineral density (BMD). Trabecular bone score (TBS) is a relatively new, non-invasive technique to assess bone microarchitecture. The objective of our study was to analyse the BMD and bone microarchitecture using TBS in endogenous CS and compare it with a group of age and sex-matched healthy controls, and also analyse the factors predicting BMD and TBS. DESIGN: Cross-sectional study of cases and controls. PATIENTS AND MEASUREMENTS: We included 40 female patients with overt endogenous CS, out of which 32 were adrenocorticotropic hormone (ACTH)-dependent CS and 8 were ACTH-independent. We also included 40 healthy, female controls. Both patients and controls were subjected to an assessment of biochemical parameters and BMD and TBS. RESULTS: Patients with endogenous CS had significantly lower BMD at the lumbar spine, femoral neck, and total hip and significantly lower TBS than healthy controls (all p < .001), while no significant difference was noted in the distal radius BMD (p = .055). In endogenous CS, a large proportion of patients, n = 13 (32.5%) had normal BMD for age (BMD Z-score ≥ -2.0) with low TBS (L1 -L4 TBS ≤ 1.34). TBS correlated negatively with HbA1c (p = .006), and positively with serum T4 (p = .027). CONCLUSION: TBS should be considered an important complementary tool in addition to BMD for the routine assessment of skeletal health in CS.

Isochromosome Xq and the risk of metabolic comorbidities in Turner syndrome.

BACKGROUND AND AIM: Subjects with Turner syndrome (TS) are at increased risk of metabolic disorders. The objective of this study is to evaluate the prevalence of metabolic abnormalities in TS and compare the metabolic profiles of subjects with respect to their X chromosome dosage. METHODS: Sixty-four TS subjects with a mean age of 19 ± 4.9 years were included, and the prevalence of metabolic abnormalities was assessed. Out of these, 54 age and body mass index-matched TS subjects were divided into two groups based on karyotype: 45,X and 45,X/46,XX (group I; n = 33) and 46,X,i(X)(q10) and 45,X/46,X,i(X)(q10) (group II; n = 21). They were compared for blood pressure, fasting plasma glucose, homeostasis model assessment (HOMA) of insulin resistance (IR) and ß cell function (HOMA-ß), lipid profile, and percent total body fat mass (PTBFM) to assess if an extra copy of Xq contributes to a different metabolic profile. RESULTS: The prevalence of impaired fasting glucose was 7.8%. 12% of subjects had higher systolic blood pressure (SBP), and 16% had higher diastolic blood pressure for age. 53% had a deranged lipid profile. Significant differences were noted in the two groups, with higher prevalence in group II vs. group I for SBP (p = 0.03), low-density lipoprotein cholesterol (LDL-c) (p = 0.03), and PTBFM (p = 0.02). When we applied a multiple regression analysis for these outcome variables while adjusting for potential confounders known to influence the cardiometabolic risk profile in TS, karyotype no longer remained a significant independent variable. CONCLUSION: Extra copies of Xq do not contribute to an adverse metabolic risk profile.

Continuous glucose monitoring and Rituximab treatment in insulin autoimmune syndrome.

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare cause of hypoglycemia. It is characterized by hyperinsulinemic hypoglycemia, elevated insulin autoantibody titers, no prior exposure to exogenous insulin and no pathological abnormalities of pancreatic islets. Hypoglycemia usually occurs in the post prandial and post absorptive state. Most cases of IAS are self-limiting, with resolution of symptoms within six months to one year. In intractable cases, treatment modalities include low-carbohydrate meals; acarbose; diazoxide; glucocorticoids; immune-suppressants like Azathioprine, cyclophosphamide, mycophenolate mofetil; plasmapheresis and partial pancreatectomy. Rituximab, an anti CD20 monoclonal antibody, was first used in 2016 in a patient with IAS who did not respond to glucocorticoids. Subsequently, there have been three more case reports of IAS where Rituximab was used along with other modalities of treatment. Here, we report the case of a 64-year old Asian Indian woman who presented with recurrent episodes of severe post prandial hypoglycemia and was diagnosed with insulin autoimmune syndrome. She was managed with continuous glucose monitoring and two doses of Rituximab 10 weeks apart, that resulted in resolution of hypoglycemia. This case report underlies the role of Rituximab as a first line agent for treatment of hypoglycemia in IAS.

Idiopathic juvenile osteoporosis in a child: a four-year follow-up with review of literature.

OBJECTIVES: Childhood osteoporosis is an uncommon condition that usually develops secondary to underlying disease states. Idiopathic juvenile osteoporosis or early onset osteoporosis is a rare cause of primary osteoporosis in childhood associated with mutations in "bone fragility" genes. CASE PRESENTATION: The index case presented with upper back pain and was detected to have multiple vertebral fractures. Further workup for the cause revealed a homozygous benign mutation in low-density lipoprotein receptor-related protein 5, which was also detected in the mother who remained asymptomatic till presentation. The child was successfully treated with intravenous zoledronate. CONCLUSIONS: The case report describes the management approach and four-year follow-up of the child.

Insulin Autoimmune Syndrome - A Case Series.

Insulin autoimmune syndrome, or Hirata's disease, is a rare cause of hypoglycaemia. It is characterised by spontaneous episodes of hypoglycaemia, without any exposure to exogenous insulin. The majority of cases are seen in the Japanese population and it is rarely found to affect other ethnicities. The recognition of this disease is important to avoid unnecessary investigations and procedures. Here, we report two cases of insulin autoimmune syndrome, which were diagnosed and managed in our institute.

Impact of parental origin of X-chromosome on clinical and biochemical profile in Turner syndrome.

Objectives To evaluate if the parental origin of X-chromosome has an impact on the phenotype and biochemical profile in Turner syndrome (TS). Result of the previous studies have been equivocal and could be attributable to the multicentric study design with different experts examining heterogeneous TS population of various ethnic background. Methods A cross-sectional single center study from Northern India. Fifty nine diagnosed subjects of TS and their parents participated in the study. Parental origin of intact X-chromosome was determined using 12 highly polymorphic short tandem repeats (STR) on X-chromosome. For the evaluation of parent-of-origin effects, typical phenotypic traits including congenital malformations, anthropometry, body composition by dual energy X-ray absorptiometry (DXA) and biochemical profile were compared. Clinical stigmata of TS in all subjects were examined by a single expert. Results The intact X-chromosome was of maternal origin (Xm) in 49.1% subjects while 50.9% had paternal origin (Xp). Skeletal anomalies were more common in Xm group, out of which prevalence of short neck and short fourth metatarsal reached statistical significance (p=0.04 and 0.01 respectively). A strong correlation was observed between subject's baseline height standard deviation score (Ht SDS) and paternal height (r=0.593, p<0.001), maternal height (r=0.564, p<0.001) and mid-parental height (MPH) (r=0.372, p=0.047) in Xp group. This effect was not seen in Xm subjects whose baseline Ht SDS showed no significant correlation with maternal height, paternal height or MPH. No differences were detected between the groups with regard to biochemical profile or body composition. Conclusions We speculate that the differences in skeletal anomalies and height correlations between Xm and Xp groups could be due to the modifying effect of epigenetic signature on short stature homeobox (SHOX) gene of Xm. SHOX gene is not modified on Xp thereby explaining the paucity of skeletal changes and height correlations in Xp subjects.

Severe hyperandrogenism due to ovarian hyperthecosis in a young woman.

Hyperandrogenism is a relatively common clinical problem. However, severe hyperandrogenism causing virilisation is rare. A 27-year-old woman presented with generalised hirsutism, clitoromegaly, breast atrophy and secondary amenorrhoea. She had serum testosterone levels elevated to the adult male range. Administration of gonadotropin-releasing hormone (GnRH) analogue resulted in >50% suppression of serum testosterone which was suggestive of luteinising hormone-dependent ovarian hyperandrogenism. Imaging studies of abdomen and pelvis were normal, and ovarian venous sampling failed to show a gradient between the two sides. A presumptive diagnosis of ovarian hyperthecosis was, therefore, considered. Medical treatment with GnRH analogue and combined oral contraceptive pills was initiated to which an excellent clinical and biochemical response was noted. This case highlights a rare presentation of ovarian hyperthecosis in a young woman with severe hyperandrogenism mimicking a virilising neoplasm.

Achieving Core Indicators for HIV Clinical Care Among New Patients at an Urban HIV Clinic.

Following the release of the 2010 National HIV/AIDS Strategy for the United States, the Institute of Medicine (IOM) issued core clinical indicators for measuring health outcomes in HIV-positive persons. As early retention in HIV primary care is associated with improved long-term health outcomes, we employed IOM indicators as a guide to examine a cohort of persons initiating HIV outpatient medical care at a university-affiliated HIV clinic in the Southern United States (January 2007-July 2012). Using indicators for visit attendance, CD4 and viral load laboratory testing frequency, and antiretroviral therapy initiation, we evaluated factors associated with achieving IOM core indicators among care- and treatment-naïve patients during the first year of HIV care. Of 448 patients (mean age = 35 years, 35.7% white, 79.0% male, 58.4% education beyond high school, 35.9% monthly income > $1,000 US, 47.3% uninsured), 84.6% achieved at least four of five IOM indicators. In multivariable analyses, persons with monthly income > $1,000 (ORadj. = 3.71; 95% CI: 1.68-8.19; p = 0.001) and depressive symptoms (ORadj. = 2.13; 95% CI: 1.02-4.45; p = 0.04) were significantly more likely to achieve at least four of the five core indicators, while patients with anxiety symptoms were significantly less likely to achieve these indicators (ORadj. = 0.50; 95% CI: 0.26-0.97; p = 0.04). Age, sex, race, education, insurance status, transportation barriers, alcohol use, and HIV status disclosure to family were not associated with achieving core indicators. Evaluating and addressing financial barriers and anxiety symptoms during the first year of HIV outpatient care may improve individual health outcomes and subsequent achievement of the National HIV/AIDS Strategy.

Disparate associations of HLA class I markers with HIV-1 acquisition and control of viremia in an African population.

BACKGROUND: Acquisition of human immunodeficiency virus type 1 (HIV-1) infection is mediated by a combination of characteristics of the infectious and the susceptible member of a transmission pair, including human behavioral and genetic factors, as well as viral fitness and tropism. Here we report on the impact of established and potential new HLA class I determinants of heterosexual HIV-1 acquisition in the HIV-1-exposed seronegative (HESN) partners of serodiscordant Zambian couples. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the relationships of behavioral and clinically documented risk factors, index partner viral load, and host genetic markers to HIV-1 transmission among 568 cohabiting couples followed for at least nine months. We genotyped subjects for three classical HLA class I genes known to influence immune control of HIV-1 infection. From 1995 to December 2006, 240 HESNs seroconverted and 328 remained seronegative. In Cox proportional hazards models, HLA-A*68:02 and the B*42-C*17 haplotype in HESN partners were significantly and independently associated with faster HIV-1 acquisition (relative hazards = 1.57 and 1.55; p = 0.007 and 0.013, respectively) after controlling for other previously established contributing factors in the index partner (viral load and specific class I alleles), in the HESN partner (age, gender), or in the couple (behavioral and clinical risk score). Few if any previously implicated class I markers were associated here with the rate of acquiring infection. CONCLUSIONS/SIGNIFICANCE: A few HLA class I markers showed modest effects on acquisition of HIV-1 subtype C infection in HESN partners of discordant Zambian couples. However, the striking disparity between those few markers and the more numerous, different markers found to determine HIV-1 disease course makes it highly unlikely that, whatever the influence of class I variation on the rate of infection, the mechanism mediating that phenomenon is identical to that involved in disease control.

Association of chemokine receptor gene (CCR2-CCR5) haplotypes with acquisition and control of HIV-1 infection in Zambians.

BACKGROUND: Polymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have been associated with HIV-1 infection and disease progression. We investigated the impact of CCR2-CCR5 haplotypes on HIV-1 viral load (VL) and heterosexual transmission in an African cohort. Between 1995 and 2006, cohabiting Zambian couples discordant for HIV-1 (index seropositive and HIV-1 exposed seronegative {HESN}) were monitored prospectively to determine the role of host genetic factors in HIV-1 control and heterosexual transmission. Genotyping for eight CCR2 and CCR5 variants resolved nine previously recognized haplotypes. By regression and survival analytic techniques, controlling for non-genetic factors, we estimated the effects of these haplotypic variants on a) index partner VL, b) seroconverter VL, c) HIV-1 transmission by index partners, d) HIV-1 acquisition by HESN partners. RESULTS: Among 567 couples, 240 virologically linked transmission events had occurred through 2006. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta = -0.58, log10 P = 0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta = 0.54, log10 P = 0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by the HESNs (HR = 2.0, 95% CI = 1.20-3.43, P = 0.008), after adjustments for index partner VL and the presence of genital ulcer or inflammation in either partner in Cox multivariable models. The HHD/HHE effect was stronger in exposed females (HR = 2.1, 95% CI = 1.14-3.95, P = 0.018). CONCLUSIONS: Among Zambian discordant couples, HIV-1 coreceptor gene haplotypes and diplotypes appear to modulate HIV-1 VL in seroconverters and alter the rate of HIV-1 acquisition by HESNs. These associations replicate or resemble findings reported in other African and European populations.

Impact of a functional KIR2DS4 allele on heterosexual HIV-1 transmission among discordant Zambian couples.

Killer cell immunoglobulin-like receptors (KIRs) and their HLA ligands interact to regulate natural killer (NK) cell function. KIR gene content and allelic variations are reported to influence human immunodeficiency virus (HIV)-1 infection and pathogenesis. We investigated the impact of KIR genes on heterosexual HIV-1 transmission among 566 discordant couples from Lusaka, Zambia. KIR2DS4*001, the only allele of KIR2DS4 known to encode a functional activating receptor, was associated with relatively high viral load for HIV-1 in index (HIV-1 seroprevalent) partners (ß [standard error (SE)], .17 [.8] log10; P = .04) and with accelerated transmission of HIV-1 to cohabiting seronegative partners (relative hazard [RH], 2.00; P = .004). The latter association was independent of the direction of transmission (male-to-female or female-to-male), genital ulcers, and carriage of the putative ligand (HLA-Cw*04). No KIR-gene variant in the initially seronegative partners was associated with HIV-1 acquisition or early viral load following seroconversion. Further analysis of NK cell function should clarify the role of KIR2DS4*001 in HIV-1 transmission.

Human leukocyte antigens and HIV type 1 viral load in early and chronic infection: predominance of evolving relationships.

BACKGROUND: During untreated, chronic HIV-1 infection, plasma viral load (VL) is a relatively stable quantitative trait that has clinical and epidemiological implications. Immunogenetic research has established various human genetic factors, especially human leukocyte antigen (HLA) variants, as independent determinants of VL set-point. METHODOLOGY/PRINCIPAL FINDINGS: To identify and clarify HLA alleles that are associated with either transient or durable immune control of HIV-1 infection, we evaluated the relationships of HLA class I and class II alleles with VL among 563 seroprevalent Zambians (SPs) who were seropositive at enrollment and 221 seroconverters (SCs) who became seropositive during quarterly follow-up visits. After statistical adjustments for non-genetic factors (sex and age), two unfavorable alleles (A*3601 and DRB1*0102) were independently associated with high VL in SPs (p<0.01) but not in SCs. In contrast, favorable HLA variants, mainly A*74, B*13, B*57 (or Cw*18), and one HLA-A and HLA-C combination (A*30+Cw*03), dominated in SCs; their independent associations with low VL were reflected in regression beta estimates that ranged from -0.47+/-0.23 to -0.92+/-0.32 log(10) in SCs (p<0.05). Except for Cw*18, all favorable variants had diminishing or vanishing association with VL in SPs (p