Abstract
Individuals with Turner syndrome (TS) are prone to develop autoimmune conditions such as coeliac disease (CD), thyroiditis and type 1 diabetes (T1DM). The objective of the present study was to examine TS of various karyotypes for autoantibodies and corresponding diseases. This was investigated in a prospective cross-sectional study of Danish TS patients (n = 107, median age 36·7 years, range: 6–60 years). A medical history was recorded and a blood sample was analysed for autoantibodies against gliadin, transglutaminase, adrenal cortex, intrinsic factor, anti-thyroid peroxidase (anti-TPO) and glutamic-acid-decarboxylase 65 (GAD-65). Autoantibodies were present in 58% (n = 61) of all patients, whereof 18% (11) had autoantibodies targeting more than one organ. Patients with autoantibodies were significantly older than those without (P = 0·001). Anti-TPO was present in 45% (48) of patients, of whom 33% (16) were hypothyroid. Overall, 18% (19) presented with CD autoantibodies, of whom 26% (five) had CD. Anti-TPO and CD autoantibodies co-existed in 9% (10). Immunoglobulin A deficiency was found in 3% (three) of patients, who all had CD autoantibodies without disease. Among four patients with anti-GAD-65 none had T1DM, but two were classified as having T2DM. One patient had adrenocortical autoantibodies but not adrenal failure. Autoantibodies against intrinsic factor were absent. Anti-GAD-65 was increased in isochromosomal karyotypes (3/23 versus 1/84, P = 0·008) with no other association found between autoantibodies and karyotype. In conclusion, TS girls and women face a high prevalence of autoimmunity and associated disease with a preponderance towards hypothyroidism and CD. Thus, health care providers dealing with this patient group should be observant and test liberally for these conditions even before clinical symptoms emerge.
Keywords: autoimmunity, coeliac disease, karyotype, thyroid, Turner syndrome
Introduction
Turner syndrome (TS) occurs in 50 per 100 000 live-born girls [1] with the cardinal stigmata including reduced final height, cardiovascular malformations and premature ovarian failure [2]. Morbidity secondary to autoimmunity ranks among the more prominent syndrome-associated characteristics, where an estimated 50% of the middle-aged patients suffer from Hashimoto's thyroiditis, and the prevalence increases with age [3,4]. The incidence of coeliac disease (CD) is increased 11-fold [5]. Other diseases of possible autoimmune aetiology also prevail with an increased risk of type 1 diabetes (T1DM) [6,7], alopecia areata [8] and inflammatory bowel disease [9]. Furthermore, an increased frequency of cobalamin deficiency was reported recently, although this was not shown as secondary to pernicious anaemia with autoantibody production [3]. The underlying pathophysiological mechanism leading to the increased risk of morbidity secondary to autoimmune hyperreactivity is unknown. Discrete disturbances in both humoral and cellular immune responses have, however, been reported [10–17] and a genetic basis has been proposed, although not established uniformly [3,4].
No study has investigated the prevalence of multiple forms of autoimmunity in TS and it is not known whether the diseases co-segregate. The aim of the present study thus was to investigate: (i) the prevalence of autoantibodies related to organ-specific disease; (ii) the prevalence of disease; and (iii) the association of autoimmunity with the karyotypes of TS. Emphasis was on autoimmune diseases related to thyroid, adrenocortical and intestinal organs. A further aim was to study the prevalence of cobalamin deficiency and intrinsic factor autoantibody.
Materials and methods
Subjects
In a cross-sectional study 107 Danish TS patients aged 6–60 years (median 36·7 years) were recruited from the National Society of Turner Contact Groups in Denmark (advertisement), the Medical Department M (Endocrinology and Diabetes) at Aarhus University Hospital, the Paediatric Unit at Hilleroed Hospital and Children's Hospital at Glostrup Hospital. All interested patients were included. All patients had undergone chromosome analysis previously. The karyotypes were: 45,X (n = 64); 45,X/46,XX (n = 8); karyotypes with isochromosomes (IsoXq) (n = 23) and deletions (n = 2); karyotypes with Y chromosomal material (n = 5); and karyotypes with marker or ring chromosomes (n = 5). The study was approved by the Aarhus County Committee on Biomedical Research Ethics (no. 20030116) and the Danish Data Protection Agency.
Methods and assays
An interview was performed by questionnaire completed by the participant or interview (adhering to the questionnaire) concerning any medical history of previously diagnosed autoimmune diseases (thyroid disease, adrenal failure, diabetes or coeliac enteropathy). A venous blood sample was drawn. All blood tests were analysed prospectively in the same laboratory. Total immunoglobulin (Ig) A was measured followed by IgA anti-gliadin and anti-transglutaminase. In the case of IgA deficiency (IgAD), anti-gliadin and anti-transglutaminase IgG were measured. IgG anti-thyroid peroxidase (anti-TPO) and anti-glutamic-acid-decarboxylase 65 (anti-GAD-65) were determined using conventional enzyme-linked immunosorbent assay (ELISA). Autoantibodies against the adrenal cortex were determined by indirect immunofluorescence using monkey adrenal gland tissue. The intrinsic factor antibody level was measured with an in-house ELISA assay, as described previously [18]. Plasma levels of cobalamin were determined on the ACS Centaur™ Automated Chemiluminescence System (Bayer A/S Diamond Diagnostics, Holliston, MA, USA) by a competitive protein binding assay, with analytical imprecision <10%. Serological testing was successful in 106 of 107 patients in all assays except those of cobalamin and intrinsic factor, where 107 results were obtained. If CD-related autoantibodies were found, subjects were referred to endoscopic examination with biopsies to confirm or exclude CD. The presence of other autoantibodies without a related medical history resulted in contact with the study subject (or her parents) and her professional caretaker in order to enable further investigations outside the study setting.
Statistics
All statistical calculations were performed with spss for Windows version 15·0 (SPSS, Inc., Chicago, IL, USA). Data were tested for parametric distribution. Means were calculated by standard method and expressed as mean ± standard deviation and compared using Student's independent t-test when appropriate. Distributions among groups were tested by χ2 test or Fisher's exact test (when n < 6). P < 0·05 was considered statistically significant.
Results
Overall, 58% (61 of 107) of TS patients were positive for one or more autoantibodies. In 18% (11 of 61) of patients two or more organ-specific autoantibodies were found, of these 91% (10 of 11) had a combination of CD autoantibodies with anti-TPO, while the remaining case had anti-GAD-65 IgG together with anti-TPO. The youngest patient with autoantibodies was 11 years old. Autoantibodies were absent in the four youngest patients (age 6–11 years). Patients with autoantibodies were significantly older than those without (38·0 ± 13·5 versus 29·4 ± 13·0 years, P = 0·001). The age distribution of antibody-positive patients is depicted in Fig. 1.
Fig. 1.
Turner syndrome (TS) patients (n = 107) with positive serology for organ-specific autoantibody across age-groups.
In 19 of 106 patients, anti-transglutaminase, anti-gliadin or both were present (Table 1). The serum IgA level was within normal range in 97% (103 of 106) of patients. IgAD presented in three patients, of whom: (i) two were anti-gliadin IgG-positive and anti-transglutaminase IgG-negative; and (ii) the remaining IgAD patient was anti-transglutaminase IgG-positive and anti-gliadin-negative. None of the IgAD patients had other antibodies or autoimmune disease and had negative biopsies for CD at endoscopy. The distribution of CD autoantibodies and disease among the IgA-sufficient is depicted in Fig. 2. Overall, no significant differences surfaced between the median ages of those with positive serology when comparing those with CD to those without diagnosis. The age among patients with CD auto-antibody was comparable to those without.
Table 1.
Turner syndrome (TS) girls and women with positive serology for organ-specific antibodies, with antibodies associated with diagnosed target organ disease and with co-existing autoantibody.
| Autoantibody | Positive serology | Autoantibody with disease | Co-existing autoantibody |
|---|---|---|---|
| Anti-TPO (n = 106) | 45% (48/106) | 33% (16/48) had hypothyreosis | 21% (10/48) had CD autoantibody |
| 4% (2/48) had hyperthyreosis | 2% (1/48) had anti-GAD-65 | ||
| CD autoantibody (n = 106) | 18% (19/106) | 11% (2/19) had known CD | 63% (10/16) had anti-TPO |
| 16% (3/19) received the CD diagnosis | |||
| Anti-GAD-65 (n = 106) | 4% (4/106) | 50% (2/4) classified as type 2 diabetes | 25%(1/4) had CD autoantibody |
| None classified as type 1 diabetes | 25% (1/4) had anti-TPO | ||
| Adrenocortical autoantibody (n = 107) | 1%(1/107) | None | None |
Anti-GAD-65, anti-glutamic-acid-decarboxylase 65 immunoglobulin (Ig) G; anti-TPO, thyroid peroxidase autoantibody; CD, coeliac disease; CD autoantibody, coeliac disease autoantibody (including anti-transaminase and -gliadin IgG and IgA); n, the number with successful serological testing of the autoantibody in question.
Fig. 2.
Coeliac disease (CD) in relation to anti-transglutaminase and anti-gliadin immunoglobulin (Ig)A in Turner syndrome (TS), focusing upon those without IgA deficiency.
Of all TS patients, 45% (48 of 106) tested positive for anti-TPO, of whom 33% (16 of 48) were clinically hypothyroid and 4% (two of 48) had Graves disease (Table 1). Only one hypothyroid patient had no anti-TPO. Those with anti-TPO were significantly older compared with those without such antibodies (38·0 ± 12·8 versus 31·3 ± 14·3 years, P = 0·01), as were patients with hypothyroidism when compared with those without (40·7 ± 7·1 versus 33·4 ± 13·7 years, P = 0·045). No statistically significant difference was found between the average age of patients with anti-TPO-associated hypothyroidism and those with anti-TPO without thyroid disease. Anti-TPO and CD autoantibodies co-existed in 9% (10 of 106). The distribution of autoimmunity and disease is depicted in Table 1.
Anti-GAD-65 was found in 4% (four of 106) of patients. The medical histories revealed one patient classified as T1DM (one of 106) and two T2DM (two of 106). Anti-GAD-65 was present in both cases of T2DM and in two without previously diagnosed diabetes, whereas the T1DM patient was not positive for anti-GAD-65.
All but one patient tested negative for adrenocortical autoantibodies, which complied with the total absence of adrenocortical disease. All tested negative for intrinsic factor antibodies and the level of cobalamines was 165–1064 pmol/l (median: 344, normal range: 200–600 pmol/l). In 8% (eight of 107) of patients cobalamin was slightly below the normal level, whereas it was above the upper limit in 13% (14 of 107). No records were made of vitamin intake.
The distribution of autoimmunity among karyotypes is as summarized in Table 2. Compared with the pooled group of other karyotypes, no statistically significant association was present between 45,X and the overall prevalence of autoimmunity (P = 0·9), anti-TPO (P = 0·4), anti-GAD-65 (P = 0·2) or CD autoantibody (P = 0·4). When comparing IsoXq with the pooled group of other karyotypes, statistically significant associations between IsoXq and an increased prevalence of anti-GAD 65 were found (P = 0·03), whereas none surfaced between this karyotype and the prevalence of anti-TPO (P = 0·5), CD autoantibody (P = 0·9) or overall autoimmunity (P = 0·3). Neither karyotypes involving Y-material, mosaicism, deletions nor marker or ring chromosomes were associated at statistically significant levels with the presence of autoimmunity.
Table 2.
Distribution of karyotype in Turner syndrome (TS) patients and the corresponding allocation of autoimmunity defined as antibodies directed at thyroid, adrenal, endocrine pancreatic and intestinal cells.
| Karyotype | Autoimmunity | Anti-TPO | Anti-GAD-65* | CD autoantibody | Adrenocortical autoantibody |
|---|---|---|---|---|---|
| 45,X (n = 64) | 58% (37/64) | 48% (31/64) | 2% (1/64) | 20% (13/64) | 2% (1/64) |
| 45,X/ 46, XX (n = 8) | 63% (5/8) | 63% (5/8) | None | None | None |
| Ring or marker chromosome (n = 5) | 40% (2/5) | 20% (1/5) | None | 20% (1/5) | None |
| Y chromosome material (n = 5) | 60% (3/5) | 40% (2/5) | None | 20% (1/5) | None |
| Isochromosomes (n = 23) | 65% (15/23) | 39% 9/23 | 13% (3/23) | 17% (4/23) | None |
| Deletions (n = 2) | None | None | None | None | None |
P = 0·03 by Fisher's exact test. Anti-GAD-65, anti-glutamic-acid-decarboxylase 65 immunoglobulin (Ig) G; anti-TPO, thyroid peroxidase auto-antibody; autoimmunity, presence of one or more autoantibody directed thyroid, adrenal, pancreatic or intestinal organs; CD, coeliac disease; CD autoantibody, coeliac disease autoantibody (including anti-transaminase and -gliadin IgG and IgA).
Discussion
The principal result of the present study is a highly increased risk of autoimmunity being present in 57% of all TS patients, with important increases in frequency with age. Although these syndrome-associated autoantibodies target different organs, the preponderance to intestinal and especially thyroid autoreactivity is unambiguous.
A propensity towards autoimmunity in TS is indicated by a prevalence of anti-TPO of 48% in TS in comparison with an estimated prevalence of 13% in the general population [19]. Further, a prevalence of hypothyreosis in one of every five TS patients in this Danish cohort confirms such disease as a significant contributor to the increased morbidity in both paediatric [20] and adult [3] TS populations. The current finding of anti-TPO in 94% of the hypothyroid TS patients indicates a causative relationship between autoimmune reactivity and hypothyroidism in TS. In previous studies of TS the prevalence of autoimmune disease has been reported to increase with age [3], which is in line with anti-TPO producers and the hypothyroid patients being older than those without such features in current cohort. Anti-TPO did not present before the age of 12 years, but we have refrained from specific deductions because of a relatively low number of paediatric TS subjects in the study. However, these findings may support earlier findings of thyroiditis in TS as emerging in the beginning of the second decade [20] and remaining a significant issue in adulthood [3]. It was not the aim of the present study to evaluate thyroid hormone status and this fact, together with the cross-sectional design, therefore limits interpretation of onset of disease. It may also be that cases of hypothyroidism are under-reported because of subclinical presentation [21] and an associated diagnostic delay [3] in TS. This limitation results from the use of questionnaires to obtain information on previously diagnosed disease rather than renewed serological screening.
The prevalence of CD was 5% in this Danish TS cohort, corroborating earlier findings in TS [5] that also documented a tendency towards additional autoimmunity co-segregating with CD, and further revealed a considerable number of clinically silent cases with considerable diagnostic delay. Taken together, these data point towards a markedly increased risk of CD in TS when compared with the European general population, where a prevalence of 1% of disease and detectable autoantibodies has been reported [22,23]. Furthermore, the lack of correct diagnosis in three of five CD patients emphasizes the importance of increased attention to the disease in TS, where poor physical thriving remains a common denominator. The presence of CD autoantibodies was as high as 18% in the cohort, but it remains to be determined if this implies that a large proportion of these patients will develop CD.
Anti-GAD-65 was present in 4%, which is somewhat above the general population prevalence of 1·1% as reported across adult age-groups [24]. Overall, three patients had been diagnosed as diabetics, of whom two were classified as T2DM (both anti-GAD-65-positive) and one T1DM (anti-GAD-65-negative). Although a relatively small cohort, these findings point towards an increased risk of diabetes in TS, as shown previously [7], and it may be speculated that the non-diabetic anti-GAD-65-positive patient might eventually develop diabetes. Further, the presence of anti-GAD-65 in four patients could be interpreted as indicative of more patients than anticipated previously suffering from T1DM misclassified as T2DM. This would be in line with recent findings from our hands, where normal levels of insulin sensitivity but early signs of β cell dysfunction prevailed in non-diabetic adult TS patients, indicating a propensity towards T1DM with atypical presentation rather than T2DM (submitted data). It is therefore proposed that all patients with TS and newly developed diabetes are tested for GAD-65 antibodies.
One case was identified with autoantibody directed at the adrenocortical cortex with a resulting prevalence of 1%, which compares with general population levels between zero and 0·6% [25]. The single patient with autoantibody did not have Addison's disease. These findings are in agreement with results from an adult Swedish TS cohort, where none were positive for antibodies related to autoimmune polyendocrine syndrome types I and II or Addison's disease [26]. Furthermore, adrenal failure has not been reported with increased frequency in TS, although in some cases autoimmune premature ovarian failure and adrenal failure appear to be linked [27]. Addison's disease is, however, a rare occurrence, as is TS, and it may therefore take large cohorts of females with TS to conclude that Addison's disease does not occur with increased frequency in TS.
Overall, the extent of cobalamin deficiency was smaller than reported by others [3] with the average level within the normative range, and those deviating were both below and above this range. Furthermore, autoimmunity towards intrinsic factor was not present. Another finding was that of a prevalence of IgAD as high as 2·9%, which was estimated to occur in 0·2% of the general Caucasian population, and is associated with an increased risk of CD [28]. In this cohort, however, all IgAD patients had autoantibodies directed against gliadin or transglutaminase, although none were diagnosed with CD despite endoscopy with a biopsy.
The increased risk of autoimmune disease in TS remains an enigma. Previously an association was reported between the IsoXq karyotype and increased prevalence of anti-TPO [4], while other investigators were unable to confirm such findings [3]. In this Danish cohort, no association surfaced between specific karyotypes and the presence of autoimmunity in general, TPO-autoantibodies or CD-related autoantibody. This may reflect the size of the cohort, but it could also result from differences in investigated autoantibodies in different studies. However, a higher prevalence of anti-GAD-65 in IsoXq was present, which corroborates the previously reported increased risk of autoimmunity associated with this specific karyotype. Nevertheless, numbers were small and the reported associations should be interpreted with caution.
In conclusion, TS girls and women face a high prevalence of autoimmunity and associated disease, with a preponderance towards hypothyroidism and CD. Thus, health care providers dealing with this patient group should be observant and test liberally for these conditions even before clinical symptoms emerge, regardless of comorbidity and karyotype.
Acknowledgments
Lone Svendsen and Joan Hansen are thanked for their expert technical help.
Acknowledgments
Dronning Louise Børnehospitals Forskningsfond is thanked for unrestricted financial support.
Declaration of interest
None.
References
- 1.Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006;91:3897–902. doi: 10.1210/jc.2006-0558. [DOI] [PubMed] [Google Scholar]
- 2.Gravholt CH. Epidemiological, endocrine and metabolic features in Turner syndrome. Eur J Endocrinol. 2004;151:657–87. doi: 10.1530/eje.0.1510657. [DOI] [PubMed] [Google Scholar]
- 3.El-Mansoury M, Bryman I, Berntorp K, Hanson C, Wilhelmsen L, Landin-Wilhelmsen K. Hypothyroidism is common in Turner syndrome: results of a five-year follow-up. J Clin Endocrinol Metab. 2005;90:2131–5. doi: 10.1210/jc.2004-1262. [DOI] [PubMed] [Google Scholar]
- 4.Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syndrome in women with Turner's syndrome – the association with karyotype. Clin Endocrinol (Oxf) 2001;55:223–6. doi: 10.1046/j.1365-2265.2001.01296.x. [DOI] [PubMed] [Google Scholar]
- 5.Bonamico M, Pasquino AM, Mariani P, et al. Prevalence and clinical picture of celiac disease in Turner syndrome. J Clin Endocrinol Metab. 2002;87:5495–8. doi: 10.1210/jc.2002-020855. [DOI] [PubMed] [Google Scholar]
- 6.Bolar K, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in turner syndrome. J Clin Endocrinol Metab. 2008;93:344–51. doi: 10.1210/jc.2007-1723. [DOI] [PubMed] [Google Scholar]
- 7.Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51:147–58. doi: 10.1016/s0895-4356(97)00237-0. [DOI] [PubMed] [Google Scholar]
- 8.Rosina P, Segalla G, Magnanini M, Chieregato C, Barba A. Turner's syndrome associated with psoriasis and alopecia areata. J Eur Acad Dermatol Venereol. 2003;17:50–2. doi: 10.1046/j.1468-3083.2003.t01-1-00502.x. [DOI] [PubMed] [Google Scholar]
- 9.Elsheikh M, Dunger DB, Conway GS, Wass JA. Turner's syndrome in adulthood. Endocr Rev. 2002;23:120–40. doi: 10.1210/edrv.23.1.0457. [DOI] [PubMed] [Google Scholar]
- 10.Gupta S, Chiplunkar S, Gupta A, Gollapudi S. Increased spontaneous, tumor necrosis factor receptor- and CD95 (Fas)-mediated apoptosis in cord blood T-cell subsets from Turner's syndrome. Genes Immun. 2003;4:239–43. doi: 10.1038/sj.gene.6363945. [DOI] [PubMed] [Google Scholar]
- 11.Jensen K, Petersen PH, Nielsen EL, Dahl G, Nielsen J. Serum immunoglobulin M, G, and A concentration levels in Turner's syndrome compared with normal women and men. Hum Genet. 1976;31:329–34. doi: 10.1007/BF00270862. [DOI] [PubMed] [Google Scholar]
- 12.Lorini R, Ugazio AG, Cammareri V, et al. Immunoglobulin levels, T-cell markers, mitogen responsiveness and thymic hormone activity in Turner's syndrome. Thymus. 1983;5:61–6. [PubMed] [Google Scholar]
- 13.Cacciari E, Masi M, Fantini MP, et al. Serum immunoglobulins and lymphocyte subpopulations derangement in Turner's syndrome. J Immunogenet. 1981;8:337–44. doi: 10.1111/j.1744-313x.1981.tb00938.x. [DOI] [PubMed] [Google Scholar]
- 14.al Attas RA, Rahi AH, Ahmed E. Common variable immunodeficiency with CD4+ T lymphocytopenia and overproduction of soluble IL-2 receptor associated with Turner's syndrome and dorsal kyphoscoliosis. J Clin Pathol. 1997;50:876–9. doi: 10.1136/jcp.50.10.876. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Robson SC, Potter PC. Common variable immunodeficiency in association with Turner's syndrome. J Clin Lab Immunol. 1990;32:143–6. [PubMed] [Google Scholar]
- 16.Kurabayashi T, Yasuda M, Fujimaki T, Yamamoto Y, Oda K, Tanaka K. Effect of hormone replacement therapy on spinal bone mineral density and T lymphocyte subsets in premature ovarian failure and Turner's syndrome. Int J Gynaecol Obstet. 1993;42:25–31. doi: 10.1016/0020-7292(93)90441-x. [DOI] [PubMed] [Google Scholar]
- 17.Hochberg Z, Aviram M, Rubin D, Pollack S. Decreased sensitivity to insulin-like growth factor I in Turner's syndrome: a study of monocytes and T lymphocytes. Eur J Clin Invest. 1997;27:543–7. doi: 10.1046/j.1365-2362.1997.1640702.x. [DOI] [PubMed] [Google Scholar]
- 18.Nexo E, Nooroya B, Hvas AM, Christensen AL, Waters H. Autoantibodies against intrinsic factor (IF) measured with an ELISA using recombinant human IF as both catching and detecting reagent. Clin Chem Lab Med. 2005;43:351–6. doi: 10.1515/CCLM.2005.064. [DOI] [PubMed] [Google Scholar]
- 19.Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III) J Clin Endocrinol Metab. 2002;87:489–99. doi: 10.1210/jcem.87.2.8182. [DOI] [PubMed] [Google Scholar]
- 20.Livadas S, Xekouki P, Fouka F, et al. Prevalence of thyroid dysfunction in Turner's syndrome: a long-term follow-up study and brief literature review. Thyroid. 2005;15:1061–6. doi: 10.1089/thy.2005.15.1061. [DOI] [PubMed] [Google Scholar]
- 21.Chiovato L, Larizza D, Bendinelli G, et al. Autoimmune hypothyroidism and hyperthyroidism in patients with Turner's syndrome. Eur J Endocrinol. 1996;134:568–75. doi: 10.1530/eje.0.1340568. [DOI] [PubMed] [Google Scholar]
- 22.Kolho KL, Farkkila MA, Savilahti E. Undiagnosed coeliac disease is common in Finnish adults. Scand J Gastroenterol. 1998;33:1280–3. doi: 10.1080/00365529850172368. [DOI] [PubMed] [Google Scholar]
- 23.West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut. 2003;52:960–5. doi: 10.1136/gut.52.7.960. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rolandsson O, Hagg E, Hampe C, et al. Glutamate decarboxylase (GAD65) and tyrosine phosphatase-like protein (IA-2) autoantibodies index in a regional population is related to glucose intolerance and body mass index. Diabetologia. 1999;42:555–9. doi: 10.1007/s001250051194. [DOI] [PubMed] [Google Scholar]
- 25.Betterle C, Dal PC, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: auto-antibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002;23:327–64. doi: 10.1210/edrv.23.3.0466. [DOI] [PubMed] [Google Scholar]
- 26.Stenberg AE, Sylven L, Hedstrand H, Kampe O, Hultcrantz M. Absence of autoantibodies connected to autoimmune polyendocrine syndrome type I and II and Addison's disease in girls and women with Turner syndrome. J Negat Results Biomed. 2007;6:10. doi: 10.1186/1477-5751-6-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Conway GS. Premature ovarian failure. Br Med Bull. 2000;56:643–9. doi: 10.1258/0007142001903445. [DOI] [PubMed] [Google Scholar]
- 28.Latiff AH, Kerr MA. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem. 2007;44:131–9. doi: 10.1258/000456307780117993. [DOI] [PubMed] [Google Scholar]