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Revista chilena de pediatría

Print version ISSN 0370-4106

Rev. chil. pediatr. vol.90 no.6 Santiago Dec. 2019

http://dx.doi.org/10.32641/rchped.v90i6.925 

ORIGINAL ARTICLE

Celiac disease in children with Down syndrome

Carlos Alberto Velasco-Benítez1  2 

Lina Johanna Moreno-Giraldo3 

1 Department of Pediatrics, Universidad del Valle, Hospital Universitario del Valle, Cali, Colombia.

2 Universidad de Granada. Granada, Spain.

3 Universidad Santiago de Cali. Cali, Colombia.

Abstract:

Introduction:

Celiac disease (CD) in children with Down syndrome (DS) has been published by several countries, without available data for Colombia.

Objective:

To determine the frequency and related factors of CD in children with DS, compared with a group of children without DS, analyzing the clinical, im munological, and genetic manifestations.

Patients and Method:

A total of 209 children between 1-18 years of age (8.4 ± 4.1 years, 55.5% female) were studied, 97 with DS and 112 without DS, using anti-transglutaminase antibodies as serological marker (tTG2). Variables of age, gender, race, ori gin, weight, height, and digestive symptoms were studied. Children with positive tTG2 underwent duodenal biopsy and genotype. The proportion of children with DS, without DS, and CD was esti mated and their 95% CI; measures of central tendency, univariate and bivariate analysis, considering a p < 0.05 significant.

Results:

Eight children with DS (8.2%) and five children without DS (4.5%) were tTG2 positive (p = 0.200). None presented serum IgA deficiency. One child with DS presented CD with Marsh II (1.0%), and two children with DS (2.1%) and two without DS (1.8%), presen ted potential CD (p = 0.432). Three children were HLA-DQ2. CD was more likely in the preschool group (OR = 6.14 95%CI = 0.41-87.35 p = 0.0462).

Conclusions:

The CD frequency due to intestinal biopsy in children with DS is much lower than that reported in the literature, being associated with preschool, and having DQ2 as its main allele. These findings are similar to those described worldwide.

Keywords: Genotype; celiac disease; potential celiac disease; Down syndrome; children

Introduction

Celiac disease (CD) is an immune system-mediated systemic disorder caused by gluten and related prolam ins in genetically susceptible individuals, characterized by a combination of variable clinical manifestations dependent on gluten, CD-specific antibodies, HLA- DQ2 or HLA-DQ8 haplotypes, and enteropathy1.

The CD prevalence worldwide is between 0.1% and 5.6%2. A systematic and meta-regression review con ducted in Colombia concludes that CD seems to be a rare condition in Colombians3, however, a 7.1% of prevalence is reported in a group of children with type 1 diabetes mellitus, with no symptoms that suggest a risk of developing CD4.

Some genetic syndromes are recognized for their association with CD, such as Down syndrome (DS)5. The first case of a patient with DS and CD was described in 19756. A prevalence between 1.6% and 13.0%7-21 of CD is reported in children with DS diagnosed through biopsy, with an increased risk of up to 6 times of CD in these patients22. The American Academy of Pediatrics (AAP) Guidelines on DS and CD recommend scree ning for CD in children with symptomatic DS23, and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines also recommend it in asymptomatic children and ado lescents at genetic risk of developing CD, such as DS1. The CD diagnosis is made through blood analyses of specific antibodies (IgA anti-tG2, IgA EMA, or IgA/ IgG anti-DGP), HLA-DQ2/HLA-DQ8 haplotypes, and duodenal biopsy1. Early CD detection decreases the risk of both lymphoma24,25 and mortality26. Although the presence of CD in children with DS has already been published by several countries, there are no data on these two conditions in Colombia. The objective of this work is to determine the frequency and related factors of CD in children with DS, compared with a group of children without DS, analyzing the clinical, immunological, and genetic manifestations.

Patients and Method

Down syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21 (or part of it), rather than the usual two (trisomy 21), characterized by a variable degree of intellectual disa bility and characteristic physical features that give it a recognizable appearance27. The CD diagnosis is confir med when the IgA anti-transglutaminase (anti-tTG2) is positive, haplotype HLA-DQ2 and HLA-DQ8 are compatible, duodenal histopathology shows intestinal villi abnormality with a Marsh II score or higher, and a variable combination of gluten-dependent clinical ma nifestations is presented; and potential CD when tTG2 is positive, HLA compatible, and without histological abnormalities in the duodenal biopsy, with or without signs and symptoms1.

A descriptive observational comparative study was conducted between May 9, 2014 and May 23, 2018 on children diagnosed with DS who attended the Pedia tric Outpatient Consultation of the Hospital Univer sitario del Valle ‘Evaristo García’ (HUV) in Cali, Co lombia, a tertiary level facility in the southwest of the country, and the Fundar Humanos Down Foundation (Fundown) in Bucaramanga, Colombia, an institution where the children with DS from the northeast of the country are treated. The inclusion criteria were chil dren with DS diagnosis, of both sexes, aged between 6 months who had already intake gluten in their com plementary diet and up to 18 years; and the exclusion criteria were children with DS with type 1 diabetes me llitus, with autoimmune diseases such as hypothyroi dism, with previous diagnosis of CD, with inflamma tory bowel disease, and no gluten users. A randomly selected group of children, of both sexes, aged between 6 months and 18 years, gluten users, asymptomatic, with no DS or pathologies, and no family history of CD who attended the Pediatric Outpatient Consultation of the HUV in Cali, Colombia and two Public Educatio nal Institutions in Cali and Floridablanca, Colombia were considered as controls. Sociodemographic varia bles such as age, sex, race, and origin were considered as well as anthropometric variables such as weight and height. The clinical digestive variables considered were constipation, vomiting, abdominal distension, steato rrhea, diarrhea, abdominal pain, flatulence, and weight loss.

All children were screened with an IgA anti-trans glutaminase (anti-tTG2) BiocardTM Celiac Test (Ani Biotech Oy, Vantaa, Finland) which has 97.4% of sen sitivity and 96.9% specificity28,29. Children with total IgA absence in the Celiac Test BiocardTM, a blood sam ple was taken to analyze serum IgG anti-transglutami nase for CD. The tTG2-positive children underwent upper endoscopy with biopsy collections and HLA- DQ2/HLA-DQ8 haplotypes analysis. A minimum of 4 biopsies of the bulb and the second portion of the duo denum were collected. The biopsy material evaluation was carried out by the same pathologist after hema toxylin and eosin staining. The immunohistochemistry of the leukocyte common antigen was used for the evaluation of the intraepithelial leukocyte count, and the presence of more than 30 intraepithelial lympho cytes versus 100 epithelial cells detected by the leuko cyte common antigen was considered as intraepithelial lymphocytosis30,31. According to the Marsh-Oberhuber classification, the histopathology was classified as Mar sh I when observing ‘infiltrative lesion’, as Marsh II when observing ‘infiltrative-hyperplastic lesion’, and as Marsh III when observing ‘villous atrophy’ (partial IIIa, subtotal IIIb, and total IIIc)32. The HLA-DQ2 and HLA-DQ8 genotyping were performed through poly merase chain reaction33.

According to age groups, they were classified as in fants (< 2 years of age), preschoolers (> 2 and up to 5 years of age), schoolchildren (> 5 and up to 12 years of age), and adolescents (> 12 and up to 18 years of age). The race was classified as mixed-race, of African descent, white, and indigenous. For children without DS, according to WHO, they were classified as mal nourished when the BMI-for-age and sex were affec ted (obesity > +2 SD, overweight between +1 and +2 SD, moderate malnutrition between -2 and -3 SD, and severe malnutrition > or = -3 SD), and altered height when height-for-age (H/A) was affected (high height > +3 SD, low height between -2 and -3 SD, and severe low height > -3 SD)34. For children with DS, the growth charts of The Down Syndrome Growing Up Study by the U.S. Centers for Disease Control and Prevention35 were considered.

In order to elaborate (Table 3) of the results, a search was made in the ProQuest, OvidSP, and EBS- COHOST platforms of the Electronic Library of the HUV in Cali, Colombia. Original articles between 2000 and 2017 were included whose research de signs were meta-analyses, controlled clinical trials, analytical (cases and controls, and cohorts), and non- analytical (prevalence) with diagnosis of CD and DS with keywords in English (celiac disease and Down syndrome) and in Spanish (enfermedad celiaca and síndrome de Down).

By signing the informed consent and assent, pa rents or guardians and children over the age of 7, res pectively, accepted to participate in this study, which was approved by the Ethics Committee of the HUV.

Convenience sampling was used where all chil dren with and without DS participated, who met the study inclusion criteria, agreed to participate in the study and attended the Pediatric Outpatient Consul tation at the HUV in Cali, Colombia, the Fundown in Bucaramanga, Colombia, and the Public Educational Institutions in Cali and Floridablanca, Colombia. The proportion of children with and without DS, and CD was estimated and its corresponding 95% confidence interval (CI). Out of the total of participating children, we estimated percentiles, averages, medians, and the other descriptive measures with their corresponding standard deviations and ranges, and to evaluate the possible associations, we initially carried out a univa riate analysis between each of the exposure variables of interest and the effect variable. In addition, the possible association between the exposure variables of greatest interest and other covariates, and between the result variable of interest (CD) and the other covariates, was explored in order to assess possible confusion. To this end, graphs and 2x2 tables were made, and the ORs with their respective CI (95%) were estimated. To as sess statistical significance, Fisher’s exact test was used, and a 2-tailed p <0.05value was considered as statisti cally significant.

Results

97 children with DS from the HUV in Cali, Colom bia and from the Fundown in Bucaramanga, Colombia were included as controls, and 112 children without DS from the HUV in Cali, Colombia and from two Pu blic Educational Institutions in Cali and Floridablanca, Colombia. (Table 1) shows demographic, anthropome tric, and clinical data of study participants. Overall, the nutritional status of children with DS was more affected than children without DS in BMI (p=0.000) and H/A (p=0.000). Although tTG2 had more positive cases in children with DS compared with control chil dren without DS, there were no significant differences, as well as in the frequency of diagnosing CD (Table 1).

Table 1 Characteristics of children with and without Down Syndrome (N=209). 

Out of the 209 children included, none presented serum IgA deficiency, 13 had positive tTG2 (6.2%), and 11 of them underwent upper endoscopy with intestinal biopsies and haplotypes HLA DQ2 and HLA DQ8; and finally, five children (3 with DS and 2 without DS) presented findings in intestinal biopsies compatible with positive immunohistochemistry and Marsh between 0 and II (Figure 1 and Table 2). These 5 children with CD diagnosed by immunohistochemis- try presented in the CD3, CD8 and CD45 antibodies a number and location concordant with CD compared with appropriate controls. The patient with the biggest lesion in the biopsy was a 3-year-old girl with Marsh II score (infiltrative hyperplastic lesion) who presented 30%-40% of the lamina propria (LP) CD3 cells, up to 45 intraepithelial cells per 100 enterocytes; 10% of the LP CD8 cells, up to 40 intraepithelial cells per 100 enterocytes, and in the CD45 total lymphocytes, up to 50 intraepithelial cells per 100 enterocytes.

Figure 1 Enrollment flowchart and inclusion of children with and without Down syndrome. DS=Down syndrome; tTG2=anti-transglutaminase antibodies; UDTE=upper digestive tract endoscopy; HLA=antigens of histocompatibility; DQ=serotyping system; CD=disease celiac; n=number. 

Table 2 Characteristics of children with Celiac disease (n = 5). 

(Table 3) shows the prevalence of CD in children with DS in different countries worldwide8-20. In the association analysis, comparing children with DS (n = 97) and children without DS (n = 112), there was a greater odds ratio in infants with DS (OR = 4.54 95%CI = 1.51-16.32 p = 0.0022), males (OR = 3.00 95%CI = 1.64-5.51 p = 0.0001), and of African des cent (OR = 7.76 95%CI = 1.64-72.65 p = 0.0023); and comparing children with CD (n = 5) and children without CD (n = 204), there was a greater odds ratio in preschoolers with CD (OR = 6.14 95%CI = 0.41-87.35 p = 0.0462).

Table 3 Prevalence of Celiac disease in children with Down syndrome.(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) 

Discussion

This is the first study that shows the CD frequen cy in children with and without DS in Colombia. Although there is a higher CD frequency (including potential CD) diagnosed by both tTG2 (8.2% vs 4.5%, p=0.334) and histopathology (3.1% vs 1.8%, p=0.432) in children with DS compared with children without DS, this cannot be inferred nor confirmed through the results of this study.

When comparing this frequency with the prevalen ce in other Latin American countries, it is possible to observe that it is very similar to the results of Rumbo et al21, who reported 3.6% of prevalence in Argentine children with DS, however, their histopathological description is defined as a severe enteropathy and they do not use the Marsh classification nor do they report the control group data, and it is much lower than that described by Gomes et al7 in Brazilian children with DS, who reported 13.0% of prevalence. Globally, the CD prevalence in children with DS diagnosed by biop sy ranges from 1.6% to 11.0% (Table 3)8-20.

There were no significant differences in screening to identify CD through tTG2 (8.2% children with DS versus 4.5% children without DS; p=0.200). These findings are different from those reported by Nisihara et al36, who in Brazilian children with DS found a 17.5% seroprevalence of tTG2 versus 0.0% in children without DS (p<0.001). This positive tTG2 seropreva lence in other countries ranges from 5.2% to 31.8% (Table 3) in children with DS8,9,12-17,37. When analyzing the 5 children without DS and positive tTG2, we found that when asked about digestive symptoms, 3 of them presented constipation, 2 abdominal pain, and 1 dia rrhea with steatorrhea which could indicate selection bias and that this population of children without DS was not completely asymptomatic. However, when studying the intestinal biopsies and haplotype of these 5 children without DS, only in 2 of them it was possi ble to identify CD, and were classified as potential CD, which by definition according to ESPGHAN, are chil dren who do not present intestinal villi atrophy, who may or may not present symptoms, and who may or may not develop CD in the future1. Regarding other serological markers, such as AGA and EMA, CD sero-prevalence in children with DS ranges from 6.7% to 41.0%89,12-17,37 and 0.0% to 14.3%, respectively (Table 3)8,ii-2o.38. Some authors recommend the use of tTG2 to identify CD in children with DS16,39,40, as was done in this study, however, it should be stressed that the AAP suggests screening for CD in symptomatic chil dren with DS23, while ESPGHAN recommends it in asymptomatic children and adolescents at genetic risk of developing it1.

Most of the children with DS and CD in this stu dy present positive HLA-DQ2, similar to that reported by Book et al38 in the United States, by Wouters et al15 in the Netherlands, and by Rodríguez et al13 in Spain, from which we are descendants (Table 3). It should be noted that in southwestern Colombia, one of the re gions where this study was carried out, the allele most frequently found is HLA-DQ2 at 25.3%41 which are the most common in the Colombian population42-44.

The results of frequency, tTG2 seropositivity, and CD genotype variability in children with DS in this study, in Latin American and worldwide, may be due, among others, to regional differences, age and sex distributions, genetic characteristics, indications, symptoms, the timing and repetition of screening tests performed on these children, and the different criteria used for the CD diagnosis.

In this study, despite reporting 1.8 times more likely to have CD in children with DS than in children without DS (95%CI 0.19-21.30), it was not statistically significant (p=0.5374). Other authors have reported increased risk of CD in individuals with DS compared with individuals without DS, such as Marild et al22 in Sweden (OR=6.2 95%CI=5.09-7.43 p<0.05), whose national study included 65,636 individuals. We do not seek associations between CD, DS, and heart diseases or diet, however, some authors have failed in finding these associations as Noori et al37 in children with DS with and without congenital heart disease, and as Ro driguez et al13 in children with CD with and without DS, regarding the beginning and continuity of breast feeding or the gluten introduction.

In Colombia, there is no national program for the CD detection in children with DS, which requires a higher awareness and screening of these two entities, and thus reduce their morbidity and mortality45 as pro posed by authors such as Csizmadia et al46 and Sharr et al47.

The strengths of the study are that all in-hospital children are treated by the same health care professio nals (endocrinologist, gastroenterologist, and patho logist) for several years of follow-up and that all chil dren belong, since some years, to the same foundation. Among the limitations of the study, despite describing the population of a tertiary hospital attended by a large number of children in southwestern Colombia, and of a foundation where most children with DS in the nor theastern part of the country belong, the sample size is considered limited, therefore, the results cannot be reported as prevalence, but rather as frequency, and cannot be generalized throughout Colombia, nor to each city from which the children were included. Simi larly, no questions were asked about other possible risk factors such as quality of life, psychological, social, nutritional, and environmental, among others, that could explain the multifactorial model of this entity. Finally, our data were obtained from an in-hospital environ ment, from a foundation, and from Public Educational Institutions, which allows for some degree of selection bias.

In conclusion, the CD frequency diagnosed by in testinal biopsy in these children with DS is much lower than that reported in the literature. Also, it is associa ted with preschoolers, and its main allele is DQ2, fin dings similar to that described worldwide.

Ethical Responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed ac cording to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regu lations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the patients and/or subjects referred to in the article. This docu ment is in the possession of the correspondence author.

Conflicts of Interest: Authors declare no conflict of interest regarding the present study.

Financial Disclosure: Authors state that no economic support has been asso ciated with the present study.

Referencias:

1. Husby S, Koletzko S, Korponay-Szabó IR, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136-60. doi: 10.1097/MPG.0b013e31821a23d0. [ Links ]

2. Lionetti E, Gatti S, Pulvirenti A, Catassi C. Celiac disease from a global perspective. Best Pract Res Clin Gastroenterol. 2015; 29(3):365-79. doi: 10.1016/j.bpg.2015.05.004. [ Links ]

3. Parra-Medina R, Molano-Gonzalez N, Rojas-Villarraga A, et al. Prevalence of celiac disease in Latin America: a systematic review and meta-regression. PLoS One. 2015;10(5):e0124040. doi: 10.1371/journal.pone.0124040. [ Links ]

4. Velasco-Benitez CA, Matallana-Rhoades AM, Ruiz-Extremera A, Saps M. First Epidemiological Study on Celiac Disease in Children in Colombia. A Study on the Prevalence of Celiac Disease in Children With Type I Diabetes and Controls. Gastroenterology. 2016;150(4):S688 (Abstract). [ Links ]

5. Morris M, Yiannakou J, King A, et al. Coeliac disease and Down syndrome: associations not due to genetic linkage on chromosome 21. Scand J Gastroenterol. 2000;35:177-80. [ Links ]

6. Bentley D. A Case of Down’s Syndrome Complicated by Retinoblastoma and Celiac Disease. Pediatrics. 1975;56(1):131-3. [ Links ]

7. Gomes RC, Maia JC, Arrais RF, et al. The celiac iceberg: from the clinical spectrum to serology and histopathology in children and adolescents with type 1 diabetes mellitus and Down syndrome. Scand J Gastroenterol. 2016;51(2):178-85. doi: 10.3109/00365521.2015.1079645. [ Links ]

8. AlRuwaily F, Kattan HA, AlMehaidib AM, AlDekhail W. Prevalence of celiac disease in Saudi children with Down syndrome: A retrospective study. Int J Pediatr Adolesc Med. 2017;4(2):51-3. doi: 10.1016/j.ijpam.2016.12.002. [ Links ]

9. Szaflarska-Poplawska A, Soroczynska- Wrzyszcz A, Barg E, Józefczuk J, et al. Assessment of coeliac disease prevalence in patients with Down syndrome in Poland - a multi-centre study. Gastroenterol Rev. 2016;1(1):41-6. doi: 10.5114/pg.2016.57794. [ Links ]

10. Stordal K, Bakken IJ, Surén P, Stene LC. Epidemiology of coeliac disease and comorbidity in Norwegian children. J Pediatr Gastroenterol Nutr. 2013;57(4):467-71. doi: 10.1097/MPG.0b013e3182a455dd. [ Links ]

11. Bhat AS, Chaturvedi MK, Saini S, et al. Prevalence of celiac disease in indian children with down syndrome and its clinical and laboratory predictors. Indian J Pediatr. 2013;80(2):114-7. doi: 10.1007/s12098-012-0838-1. [ Links ]

12. Pavlovic M, Arsie B, Kazic B. Coeliac disease in children with Down syndrome in Serbia. Serbian J Exp Clin Res. 2012;13:9-14. doi: 10.5937/SJECR13-1538. [ Links ]

13. Rodríguez Martínez A, Espín Jaime B, González-Meneses López A, González Fernández-Palacios M, Pizarro Martín A, Gómez de Terreros Sánchez I. Coeliac disease profile in Down syndrome patients. Int Med Rev Down Syndr. 2010;14(1):3-9. doi: 10.1016/S2171-9748(10)70002-7. [ Links ]

14. Cerqueira RM, Rocha CM, Fernandes CD, Correia MR. Celiac disease in Portuguese children and adults with Down syndrome. Eur J Gastroenterol Hepatol. 2010;22(7):868-71. doi: 10.1097/MEG.0b013e3283328341. [ Links ]

15. Wouters J, Weijerman ME, van Furth AM, et al. Prospective Human Leukocyte Antigen, Endomysium Immunoglobulin A Antibodies, and Transglutaminase Antibodies Testing for Celiac Disease in Children with Down Syndrome. J Pediatr. 2009;154(2):239-42. doi: 10.1016/j.jpeds.2008.08.007. [ Links ]

16. Hartman C, Pollack S, Hujerat M, et al. Tissue transglutaminase antibodies are a useful serological marker for the diagnosis of celiac disease in patients with down syndrome. J Pediatr Gastroenterol Nutr. 2007;44(5):583-6. doi: 10.1097/MPG.0b013e3180320679. [ Links ]

17. Uibo O, Teesalu K, Metsküla K, et al. Screening for celiac disease in Down’s syndrome patients revealed cases of subtotal villous atrophy without typical for celiac disease HLA-DQ and tissue transglutaminase antibodies. World J Gastroenterol. 2006;12(9):1430-4. doi: 10.3748/wjg.v12.i9.1430. [ Links ]

18. Cogulu O, Ozkinay F, Gunduz C, et al. Celiac disease in children with Down syndrome: importance of follow-up and serologic screening. Pediatr Int. 2003;45:395-9. [ Links ]

19. Bonamico M, Mariani P, Danesi H, et al. Prevalence and clinical picture of celiac disease in Italian down syndrome patients: A multicenter study. J Pediatr Gastroenterol Nutr. 2001;33(2):139-43. doi: 10.1097/00005176-200108000-00008. [ Links ]

20. Zachor DA, Mroczek-Musulman E, Brown P. Prevalence of celiac disease in Down syndrome in the United States. J Pediatr Gastroenterol Nutr. 2000;31(3):275-9. [ Links ]

21. Rumbo M, Chirdo F, Ben R, Saldungaray I, Villalobos R. Evaluation of coeliac disease serological markers in Down syndrome patients. Dig Liver Dis. 2002;34:116-21. [ Links ]

22. Mârild K, Stephansson O, Grahnquist L, Cnattingius S, Söderman G, Ludvigsson JF. Down Syndrome Is Associated with Elevated Risk of Celiac Disease: A Nationwide Case-Control Study. J Pediatr. 2013;163(1):237-42. doi: 10.1016/j.jpeds.2012.12.087. [ Links ]

23. Bull MJ. Health Supervision for Children With Down Syndrome. Pediatrics. 2011; 128: 393-406. doi Available from: 10.1542/peds.2011-1605. [ Links ]

24. Baecklung E, Smedby KE, Sutton LA, Askling J, Rosenquist R. Lymphoma development in patients with autoimmune and inflammatory disorders - What are the driving forcesa. Semin Cancer Biol. 2014;24:61-70. doi: 10.1016/j.semcancer.2013.12.001. [ Links ]

25. Elfström P, Granath F, Ekström Smedby K, et al. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst. 2011;103(5):436-44. [ Links ]

26. Ludvigsson JF, Montgomery SM. Small-intestinal histopathology and mortality risk in celiac disease. JAMA. 2009;302(11):1171-8. doi: 10.1001/jama.2009.1320. [ Links ]

27. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and Down syndrome: From genomics to pathophysiology. Nat Rev Genet. 2004;5(10):725-38. doi: 10.1038/nrg1448. [ Links ]

28. Brusca I, Carroccio A, Tonutti E, et al. The old and new tests for celiac disease: Which is the best test combination to diagnose celiac disease in pediatric patients?. Clin Chem Lab Med. 2012;50(1):111-7. doi: 10.1515/CCLM.2011.714. [ Links ]

29. Brusca I. Overview of Biomarkers for Diagnosis and Monitoring of Celiac Disease. Adv Clin Chem. 2015;68:1-55. doi: 10.1016/bs.acc.2014.12.006. [ Links ]

30. Sergi C, Shen F, Bouma G. Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease). World J Gastroenterol. 2017;23(4):573-89. [ Links ]

31. Mubarak A, Wolters VM, Houwen RHJ, Ten Kate FJW. Immunohistochemical CD3 staining detects additional patients with celiac disease. World J Gastroenterol. 2015;21(24):7553-7. [ Links ]

32. Marsh MN. Gluten, Major Histocompatibility and the Smal1 Intestine Complex. Gastroenterol Latinoam. 1992;102(1):330-54. [ Links ]

33. Olerup O, Aldener A, Fogdell A. HLA-DQBl and -DQAl typing by PCR amphfication with sequence-speci f l C pruners ( PCR-SSP ) in 2 hours. Tissue Antigens. 1993;41:119-34. [ Links ]

34. de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. BWHO. 2007;85(9):660-7. [ Links ]

35. Zemel BS, Pipan M, Stallings VA, et al. Growth Charts for Children With Down Syndrome in the United States. Pediatrics. 2015;136(5):e1204-11. doi: 10.1542/peds.2015-1652. [ Links ]

36. Nisihara RM, Kotze LMS, Utiyama SRR, Oliveira NP, Fiedler PT, Messias-Reason IT. Celiac disease in children and adolescents with Down syndrome. J Pediatr (Rio J). 2005;81(5):373-6. doi: 10.2223/JPED.1381. [ Links ]

37. Noori NM, Phil ATM, Ph D, Nakhaee M, Shahraki T. The Prevalence of Celiac Disease in Down syndrome Children with and without Congenital Heart Defects. Int J Pediatr. 2016;4(7):2143-52. [ Links ]

38. Book L, Hart A, Black J, Feolo M, Zone JJ, Neuhausen SL. Prevalence and clinical characteristics of celiac disease in Downs syndrome in a US study. Am J Med Genet. 2001;98(1):70-4. [ Links ]

39. Hansson T, Dahlbom I, Rogberg S, et al. Antitissue transglutaminase and antithyroid autoantibodies in children with Down syndrome and celiac disease. J Pediatr Gastroenterol Nutr. 2005;40(2):170-4. doi: 10.1097/00005176 200502000-00016. [ Links ]

40. Paul SP, Sandhu BK, Spray CH, Basude D, Ramani P. Evidence Supporting Serology- based Pathway for Diagnosing Celiac Disease in Asymptomatic Children from High-risk Groups. J Pediatr Gastroenterol Nutr. 2018;66(4):641-4. [ Links ]

41. Arrunategui AM, Villegas A, Ocampo LA, Rodriguez LM, Badih A. Frecuencias alélicas , genotípicas y haplotípicas del sistema HLA clase i y ii en donantes de una población del suroccidente colombiano. Acta Medica Colomb. 2013;38(1):16-21. [ Links ]

42. Rodríguez LM, Giraldo MC, García N, et al. Frecuencias alélicas, genotípicas y haplotípicas. 2007; 537-47. [ Links ]

43. Ossa H, Manrique A, Quintanilla S, Peña A. Polimorfismos del sistema HLA (loci A*, B* y DRB1*) en población colombiana. Nova. 2007;5(7):25-30. [ Links ]

44. Bermeo S, Guerra MT, Alfonso HO. Frecuencias de HLA-A, B y DRB1 en una población de Huila-Colombia. Rev Factulad Salud. 2010;2(1):9-19. [ Links ]

45. Ludvigsson JF, Lebwohl B, Green PHR, Chung WK, Mârild K. Celiac disease and Down syndrome mortality: a nationwide cohort study. BMC Pediatr. 2017;17:1-6. doi: 10.1186/s12887-017-0801-4. [ Links ]

46. Csizmadia CGDS, Mearin ML, Oren A, et al. Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome. J Pediatr. 2000;137(6):756-61. doi: 10.1067/mpd.2000.110421. [ Links ]

47. Sharr C, Lavigne J, Elsharkawi IMA, Ozonoff A, Baumer N, Brasington C, et al. Detecting celiac disease in patients with Down syndrome. Am J Med Genet. 2016;170(12):3098-105. doi: 10.1002/ajmg.a.37879. [ Links ]

Received: October 09, 2018; Accepted: May 23, 2019

Correspondence: Carlos Alberto Velasco-Benítez. E-mail: carlos.velasco@correounivalle.edu.co.

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