25-Hydroxy vitamin D (25(OH)D)deficiency is linked with predisposition to autoimmune type 1 diabetes and multiple sclerosis. Our objective was to assess the relationship between serum 25(OH)D levels and thyroid autoimmunity. Subjects included students, teachers and staff aged 16-60 years (total 642, 244 males, 398 females). Serum free thyroxine, thyroid-stimulating hormone (TSH), and thyroid peroxidase autoantibodies (TPOAb), intact parathyroid hormone and 25(OH)D were measured by electrochemiluminescence and RIA, respectively. Thyroid dysfunction was defined if (1) serum TSH $ 5 mU/ml and TPOAb . 34 IU/ml or (2) TSH $ 10 mU/ml but normal TPOAb. The mean serum 25(OH)D of the study subjects was 17·5 (SD 10·2) nmol/l with 87 % having values #25 nmol/l. TPOAb positivity was observed in 21 % of subjects. The relationship between 25(OH)D and TPOAb was assessed with and without controlling for age and showed significant inverse correlation (r 2 0·08, P¼ 0·04) when adjusted for age. The prevalence of TPOAb and thyroid dysfunction were comparable between subjects stratified according to serum 25(OH)D into two groups either at cut-off of #25 or . 25 nmol/l or first and second tertiles. Until recently, vitamin D deficiency was considered to be rare in India because of abundant sunshine (1,2) . However, a systematic study carried out in the year 2000 in Delhi showed the presence of low 25-hydroxy vitamin D (25(OH)D) in a majority of subjects including newborns, their mothers, healthy physicians, nurses, soldiers and those with vitiligo and albinism. Based on these study groups, subnormal serum 25(OH)D levels of Asian Indians could be linked to their skin pigmentation and poor sunshine exposure (1,3) . Subsequently, a series of studies have documented widespread hypovitaminosis D in north as well as south India (3 -5) . Besides bone mineral homeostasis, 25(OH)D deficiency has been associated with a wide range of non-skeletal effects including predisposition towards autoimmune disorders (6 -8) .The demonstration of vitamin D receptor in monocytes, dendritic cells and activated T cells indicates significant interaction between vitamin D and the immune system (6,7) . While the molecular mechanisms linking vitamin D with autoimmunity are under investigation, in vitro studies indicate an immunomodulatory effect of 1,25(OH)D on Th 1 , Th 2 , T regulator and dendritic cells leading to a shift towards activation of Th2 cells (6,7) . Clinical relevance of the mechanism is indicated by a number of studies showing increased prevalence of autoimmune disease such as multiple sclerosis in Canada and the northern part of the USA receiving less sunshine. Vitamin D supplementation resulted in decreased prevalence of autoimmune disorders such as type 1 diabetes and multiple sclerosis. A recent meta-analysis showed 29 % reduction in the risk of type 1 diabetes in children receiving vitamin D supplementation (9,10)

The frequencies of TPOAb and thyroid dysfunction were not significantly higher in patients with SIH than in healthy controls, unlike in patients with T1D and POF.

Thus, spondyloarthropathy is a distinct clinical entity in patients with SIH. Its salient clinical features include presence of syndesmophytes at the thoracic or thoraco-lumbar spine, mild sacroiliitis, calcification at the acetabular margin of hip, preserved bone density, equal distribution in both sexes and lack of HLA-B27 association. Presence of spondyloarthropathy, like basal ganglia calcification, is associated with longer duration of hypoparathyroidism. It is important to differentiate hypoparathyroid-related spondyloarthropathy from ankylosing spondylitis because the management for the two disorders is different.

IP performed the best in detecting CaSRAbs in 12.9% of hypoparathyroid patients. Although CaSRAbs were functionally inert, its clinical relevance remains due to 100% specificity. Limited prevalence of CaSRAb suggests heterogeneity in the etiology of idiopathic hypoparathyroidism or the presence of CaSR epitopes other than those measured in the current study.

The pathogenetic mechanisms involved in the development of sporadic idiopathic hypoparathyroidism are currently under investigation. Although autoantibodies against the calcium-sensing receptor (CaSR) have been implicated to play a role, these could be demonstrated in only 49% of a group of 51 patients with sporadic idiopathic hypoparathyroidism that we previously studied. Therefore, we investigated 49 of these patients further, regardless of their antibody status, and looked for mutations in the section of the PTH gene sequence that coded for prepro-PTH as well as the 3'-untranslated region (3'-UTR) of the gene, which is believed to be involved in the stability of its mRNA. We also examined the relationship between the clinical manifestations of the disease and the occurrences of two commonly observed single nucleotide polymorphisms (SNPs) in the PTH gene. In 49 of the patients with idiopathic hypoparathyroidism and in 55 healthy controls, the SNPs were characterized by restriction analysis using DraII and BstBI enzymes. In a subset of these patients, exons 2 and 3 of the PTH gene (n = 37) and its 3'-UTR region (n = 40) were also sequenced. No mutations were observed in the segment of the PTH gene coding for the signal peptide, prohormone, or the 3'-UTR region. However, three well described SNPs were observed: 1) an A-->G substitution in intron 1 in 35.1% of the patients; 2) a G-->A substitution in intron 2, characterized by BstBI, in one or both alleles in 27%; and 3) a C-->A substitution at codon 52 (CGA) of exon 3, characterized by DraII, in one or both alleles in 59.7% of the patients. There was no significant difference in the frequency of occurrence of these SNPs between the patient and the control groups. Furthermore, the mean age at onset of symptoms, body mass index, frequency of cataract, tetany, convulsion, basal ganglia calcification, serum calcium, inorganic phosphorus, and intact PTH were not significantly different between patients with and without the above-described SNPs. Thus, the data from this report demonstrate that in patients with sporadic idiopathic hypoparathyroidism, neither the clinical manifestations nor the biochemical indexes of the disease are related to the occurrence of mutations or SNPs in the PTH gene. Because neither patient nor control samples exhibited any variations in the sequence of their 3'-UTR regions, it is unlikely that mRNA instability is a factor in the pathogenesis of the disease. Additional studies are required to investigate the role of other genes and autoantigens that may be involved in the genesis of idiopathic hypoparathyroidism.

Hypovitaminosis D is common in Asian Indians. Physicians often prescribe 1500 mg (60 000 IU) cholecalciferol per week for 8 weeks for vitamin D deficiency in India. Its efficacy to increase serum 25-hydroxy vitamin D (25(OH)D) over short (2 months) and long (1 year) term is not known. We supplemented a group of twenty-eight apparently healthy Asian Indians detected to have low serum 25(OH)D (mean 13·5 (SD 3·0) nmol/l) on screening during January -March 2005. Serum parathyroid hormone (PTH) level was supranormal in 30 % of them. Oral supplementation included 1500 mg cholecalciferol per week and 1g elemental Ca daily for 8 weeks. Serum 25(OH)D, total Ca, inorganic P and intact (i) PTH were reassessed in twenty-three subjects (twelve females and eleven males) who had follow up at both 8 weeks and 1 year. At 8 weeks the mean 25(OH)D levels increased to 82·4 (SD 20·7) nmol/l and serum PTH normalized in all. Twenty-two of the twenty-three subjects had 25(OH)D levels . 49·9 nmol/l. At 1 year, though the mean 25(OH)D level of 24·7 (SD 10·9) nmol/l was significantly higher than the baseline, all subjects were 25(OH)D deficient. Hypovitaminosis D is common in India despite its sunny environment (1 -3) . More than 90 % of apparently healthy Indians residing in India have subnormal serum 25-hydroxy vitamin D (25(OH)D) levels with values almost undetectable during winter (1 -3)

Objective: Glial cells missing 2 (GCM2) gene encodes a parathyroid-specific transcription factor. We assessed GCM2 gene sequence in patients with isolated hypoparathyroidism (IH). Design: Case-control study. Methods: Complete DNA sequencing of the GCM2 gene including its exons, promoter, and 5 0 and 3 0UTRs was performed in 24/101 patients with IH. PCR-restriction fragment length polymorphism was used to detect a novel R110W mutation in all 101 IH patients and 655 healthy controls. Significance of the mutation was assessed by electrophoretic mobility shift assay (EMSA) and nuclear localization on transfection.Results: A heterozygous R110W mutation was present in DNA-binding domain in 11/101 patients (10.9%) and absent in 655 controls (P!10 K7 ). Four of 13 nonaffected first-degree relatives for five of these index cases had R110W mutation. Four heterozygous single nucleotide polymorphisms were found in the 5 0 region. One of the 11 patients with R110W also had T370M change in compound heterozygous form. Mutant R110W and T370M GCM2 proteins showed decreased binding with GCM recognition elements on EMSA indicating loss of function. Both wild-type and R110W mutant GCM2 proteins showed nuclear localization. Conclusions: The present study indicates a significant association of R110W variant with IH. Absence of effect of heterozygous R110W mutation on DNA binding and presence of the same mutation in asymptomatic family members indicate that additional genetic (akin to T370M change) or nongenetic factors might contribute to the expression of diseases in IH. Alternatively, it is possible that association of R110W with IH could be due to linkage disequilibrium with the unidentified relevant genes in IH.

IP is currently the best assay to detect clinically relevant NALP5 Ab. Presence of NALP5 Ab in only one patient with IH who also had AIRE gene mutation suggests that these Ab are exceptionally rare in IH (0.69%) and, when present, occur in context of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.