Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome\'s patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.

BACKGROUND: Children and adolescents with type 1 diabetes mellitus (T1DM) are at high risk for the development of celiac disease (CD) because of the common genetic characteristics of both conditions. The study objectives were to investigate the frequency of the human leukocyte antigen system (HLA) for CD in pediatric T1DM patients and to determine whether HLA testing is suitable for CD screening in that population and is cost-effective as compared to serological screening for CD.
METHODS: A retrospective, descriptive study was conducted in 296 patients (148 girls; 148 boys) with T1DM aged <18 years who attended a Madrid hospital. Data on the frequency of genotypes DQ2/DQ8 in a subgroup of 92 patients and the additional cost of performing HLA typing for screening CD were collected. Only when the risk HLA haplotype (DQ2/DQ8) is negative no further serological screening for CD is required.
RESULTS: Twenty-three patients with T1DM (7.77%) also had CD. Alleles DQ2 or DQ8 were found in 91.3% of patients in whom the HLA haplotype was studied. Thus, only 8.7% with a negative haplotype would have benefited from HLA testing. The additional cost of HLA typing was € 105.2 for each patient with positive DQ2 or DQ8 in our population.
CONCLUSIONS: HLA typing is not a cost-effective screening method for CD in T1DM because of the frequent association of T1DM with risk genotypes for CD.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of gluten sensitivity. The interplay between B cell responses to these 3 transglutaminases in developing the clinical spectrum of disease manifestations is not completely understood. Also, the individual or combined diagnostic and predictive value of the respective autoantibodies is not fully explored. We examined the prevalence of TG6 antibodies in a cohort of patients with DH. TG6 positivity was found in 13/33 (39%), with IgA detected in 11 patients, IgG in 3, and both in 1. This was significantly higher compared to what is seen in the classic CD cases (14%) in a Finnish population. TG6 positive baseline samples constituted 60% of DH patients with no enteropathy (n = 10), as opposed to 17% positivity in those with overt enteropathy (n = 12; Marsh IIIB). Repeat testing after adherence to a gluten-free diet for 1 year showed reduced titers for TG6 antibodies in 11/13 (85%), whereby 7 patients were now TG6 antibody-negative. Four patients seroconverted and tested positive for TG6 antibodies at one year, due to the ongoing exposure to gluten. We report another patient who presented with neurological manifestations (encephalopathy) leading to the diagnosis of CD, who was intermittently adhering to a gluten-free diet. Serological testing at baseline showed him to be positive for antibodies to all 3 transglutaminases. Eleven years later, he developed DH. He also subsequently developed ataxia and peripheral neuropathy. Although TG3 and TG6 autoantibodies are linked to certain disease manifestations, TG2, TG3, and TG6 autoantibodies can be present across the spectrum of GRD patients and might develop years before onset of symptoms of extraintestinal manifestations. This is consistent with gluten-dependent adaptive immunity being a necessary but not sufficient pretext to organ-specific damage. TG6 antibodies appear to develop more frequently in patients where tolerance to gluten was broken but, either there was no development of the molecular state driving the tissue destruction at the level of the gut, or perhaps more likely, there was more resistance to developing this phenotype.

BACKGROUND: Children and adolescents with type1 diabetes mellitus (T1DM) are at high risk for the development of celiac disease (CD) because of the common genetic characteristics of both conditions. The study objectives were to investigate the frequency of the human leukocyte antigen system (HLA) for CD in pediatric T1DM patients and to determine whether HLA testing is suitable for CD screening in that population and is cost-effective as compared to serological screening for CD.
METHODS: A retrospective, descriptive study was conducted in 296 patients (148 girls; 148 boys) with T1DM aged <18years who attended a hospital in Madrid. Data on the frequency of genotypes DQ2/DQ8 in a subgroup of 92 patients and the additional cost of performing HLA typing for screening CD were collected. Only when the risk HLA haplotype (DQ2/DQ8) is negative no further serological screening for CD is required.
RESULTS: Twenty-three patients with T1DM (7.77%) also had CD. Alleles DQ2 or DQ8 were found in 91.3% of patients in whom the HLA haplotype was studied. Thus, only 8.7% with a negative haplotype would have benefited from HLA testing. The additional cost of HLA typing was €105.2 for each patient with positive DQ2 or DQ8 in our population.
CONCLUSIONS: HLA typing is not a cost-effective screening method for CD in T1DM because of the frequent association of T1DM with risk genotypes for CD.

OBJECTIVE: To analyze the development of gliadin-specific immune responses in children with a genetic risk for CD and to determine whether these could be detected before the clinical onset of the disease by using immunological tests.
BACKGROUND: Clinical manifestations of celiac disease (CD) in the first year of life is uncommon, which is due to the suboptimal sensitivity of tissue transglutaminase IgA antibodies (tTG-IgA) at this age and other possible causes of malabsorption in infants. The development of Deamidate gliadin peptide-specific antibodies (in particular DGP-IgG) in young children was poorly considered in the CD diagnosis.
METHODS: We conducted a retrospective cross-sectional study on children between one month and forty-eight months of life, which performed in our health center from 2016 to 2018. Three hundred and fifty children were selected according to strict inclusion criteria: positive for HLA-DQA1 and DQB1 alleles, positive anti tTG-IgA/IgG and/or positive DGP-IgG/IgA. Eighty-two children were selected and divided into two different groups of patients: Group one (forty newborns under twenty-four months of life) and Group two (children from twenty-five months to 48 months of life).
RESULTS: Anti-DGP-IgG antibodies precede anti tTG-IgA seroconversion in children under two years in 80% of cases. Anti-DGP-IgG positive patients had milder symptomatic forms of CD than anti tTG-IgA positive children, characterized by gastrointestinal symptoms in the presence of normal growth, normal serum iron, and low MCH level. At tTG-IgA seroconversion, children present gastrointestinal clinical forms associated with impaired growth. The combined use of tTG-IgA and DGP-IgG antibodies upgrade the diagnostic sensitivity from 50% to 92%.
CONCLUSIONS: Anti-DGP-IgG antibodies precede tTG-IgA seroconversion in newborns and identified two distinct clinical phenotypes. At this point, if you wanted to test your newborn patients for CD serology, how would you proceed?

Autoimmune diseases, such as celiac disease (CD) and diabetes mellitus type 1, tend to co-occur within the same patient. The prevalence of CD in diabetic children is higher than in the general population, and is estimated to be 0.6-16.4%. The diagnosis of CD is based on histopathological examination and serological testing, however, these methods are still imperfect and new diagnostic algorithms should be considered.
The aim of the study was to assess the diagnostic value of serological tests detecting antibodies against deamidated gliadin peptide, endomysium, tissue transglutaminase, neo-epitope tissue transglutaminase and to identify HLA-related genetic predisposition to CD in patients with type 1 diabetes mellitus (DM1).
Autoantibodies were measured in the sera of 392 children suffering from DM1 aged 1-19 years old (mean 11.76 ± 4.14 years old). Additionally, PCR-based assessment of HLA DQ2/DQ8 genotyping was performed.
A positive result of at least one serological test was obtained from 81 children (20.66%). The sensitivity and specificity were 76.47% and 91.67% for anti-DGP IgA, 70.59% and 58.33% for IgG anti-DGP, respectively. A positive predictive value was 100% for the anti-TG IgA at cutoff levels of 5 and 10 times higher than upper limit of reference values. HLA DQ2 and/or DQ8 were found in 97.6% of examined children.
Tests based on anti-TG IgA are more accurate for detecting CD in children with type 1 diabetes than anti-DGP IgA. A high percentage of diabetic children carry HLA alleles predisposing to CD, which indicates that genetic screening in this group of patients is not obligated.

The term gluten-related disorders (GRD) encompasses a spectrum of systemic autoimmune diseases with diverse manifestations. GRD are characterized by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Celiac disease (CD) or gluten-sensitive enteropathy is only one of a number of GRD. Extraintestinal manifestations include dermatitis herpetiformis (DH) and neurologic dysfunction. Furthermore it is only recently that the concept of extraintestinal manifestations without enteropathy has become accepted. In this chapter we review the spectrum of neurologic manifestations in GRD, discuss recent advances in their diagnosis, and look at their possible pathophysiologic mechanisms.