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Three Part Question

In [children with short stature and no gastrointestinal symptoms] what is the [prevelance] of [coeliac disease]?

Clinical Scenario

An 8-year old girl is referred to the paediatrician because of her stunted growth. Her height SDS is -2.3 (~1st centile), her weight for height ratio is + 0.9 SDS (~80th centile). At the age of 3 years, her height SDS was + 0.3 (~60th centile). Her weight for height ratio had not changed considerably. At the age of 4-5 years, she had several episodes of constipation and anaemia. There were no other complaints. A diagnostic work-up was performed: IgA anti-endomysium (IgA EmA) antibodies were positive. A small intestinal biopsy (gold standard) showed total villous atrophy, consistent with coeliac disease. During follow-up, she fulfilled the ESPGAN criteria for coeliac disease (finding of characteristic small bowel mucosa abnormalities in a small bowel biopsy, and a clinical remission when placed on a gluten free diet).

Search Strategy

Pubmed. Embase - same search strategy - no additional relevant references
Cochrane database - same search strategy - none relevant
(body height AND (short OR little OR small OR abnormal) OR short stature OR dwarfism) OR failure to thrive AND coeliac disease (limited by: Ages: All child 0-18 year, Language: English)

Search Outcome

120 references of which 11 relevant and of sufficient quality (see table).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Knudtzon et al, 1991, Norway	168 children (50 girls; 93 boys; age 0.5 – 17.2 years) with short stature without significant abdominal symptoms	Prospective cohort study (level 2b)	Proportion of coeliac disease in the study group	2.9% (5/168) of the children with short stature were diagnosed as having coeliac disease.	'Short stature' was not defined Results are not internally consistent Diagnosis was not based on ESPGAN criteria
Stenhammer L et al, 1986, Sweden	87 children (32 girls, 55 boys; age 1.0-16.5 years) with short stature (height more than 2SD below the mean for age and sex) and no gastrointestinal symptoms, signs of systemic disease or malabsorption	Prospective cohort study (level 1b)	Proportion of coeliac disease in the study group	5% (4/87) children with short stature were diagnosed as having coeliac disease. There is an overrepresentation of coeliac disease among short children admitted to hospital for examination	Diagnosis was made based on ESPGAN-criteria Gold standard was applied to all children Results are not fully described
Cacciari E et al, 1985, Italy	108 patients (30 girls, 78 boys; age 2.8 – 16.7 years) with short stature (height below third centile) and no gastrointestinal symptoms	Prospective cohort study (level 1b/2b)	Proportion of coeliac disease in study group	8.3% (9/108) patients with short stature were diagnosed as having coeliac disease	Gold standard was applied to all patients Diagnosis of coeliac disease was not according to ESPGAN-criteria Possible overlap in patients in the two studies of Cacciari?
Cacciari E et al, 1983, Italy	60 children (21 girls, 39 boys) with short stature (height below third centile) and no gastrointestinal symptoms	Prospective cohort study (level 1b/2b)	Proportion of coeliac disease in study group	8.3% (5/60) patients with short stature were diagnosed as having coeliac disease	Gold standard applied to all patients Diagnosis of coeliac disease was not according to ESPGAN criteria
Rossi et al, 1993, USA	117 children (age: 2 – 17 years) with height more than 2SD below the mean for age. Of these children, 57 were diagnosed with GH-deficiency. All children were clinically and chemically euthyroid	Prospective cohort study (level 2b)	Proportion of coeliac disease in a group of children with short stature	1.7% (2/117) of children with short stature had biopsy proven coeliac disease. There is an association between idiopathic short stature and coeliac disease	Basic data are not adequately described (no sex differentiation) Gold standard was not applied to all patients Diagnosis of coeliac disease was not according to ESPGAN criteria
Bonamico et al, 1992, Italy	49 children (27 girls, 22 boys; mean age 112 months (SD: 39)) with short stature (height below the third centile) and no gastrointestinal symptoms. None of the 49 patients showed somatic, cardiac, renal or chromosomal disorders	Prospective cohort study (level 1b)	Proportion of coeliac disease in the study group	59.1% (29/49) children with short stature were diagnosed as having coeliac disease	Gold standard was applied to all patients Diagnosis of coeliac disease was made according to ESPGAN criteria
Groll et al, 1980, UK	34 children (16 girls, 18 boys; age 2.5 – 17.0 years) with short stature (more than 2SD below the mean for age) and no gastrointestinal symptoms. There were no dysmorphic features, and endocrine investigations were normal.	Prospective cohort study (level 1b/2b)	Proportion of coeliac disease in the study group	21% (8/34) children with short stature were diagnosed as having coeliac disease	Diagnosis was not according to ESPGAN criteria
Rosenbach et al, 1986, Israel	23 children (12 girls, 11 boys; age 6-16 years) below third centile for age and a bone age delay of at least 25%. Extensive preliminary work up (including hypothalamic, pituitary, adrenal, and gonadal functions, sweat test, stool examination for ova and parasites) was found to be negative	Prospective cohort study (level 2b)	Proportion of coeliac disease in the study group	48.7% (11/23) of the patients with short stature were diagnosed as having coeliac disease	Gold standard was applied to all patients Diagnosis was not according to the ESPGAN criteria
Lecea A de et al, 1996, Spain	118 children (49 girls, 69 boys; age 11 months to 14 years), with height less than third centile for age. Preliminary work up (absorption, hormonal and genetic studies, sweat test, X-ray for bone age, serum IgA AGA) was performed	Prospective cohort study (level 2b)	Proportion of coeliac disease in the study group	18.6% (22/118) of children with short stature had biopsy proven coeliac disease	Results were not presented Numbers do not add up properly Gold standard was not applied to all children Diagnosis was not according to ESPGAN criteria Basic data were not adequately described
Altuntas et al, 1998, Turkey	47 patients (18 girls, 29 boys; age 4-16 years) of short stature (below third centile for height) without gastrointestinal tract symptoms or endocrinologic, cardiac, renal or chromosomal disorders. There were no symptoms associated with coeliac disease or signs of cow's milk allergy	Cross-sectional study (level 1b/2b)	Proportion of coeliac disease in the study group	55.3% (26/47) of the short children had biopsy proven coeliac disease	All children were biopsied Results are not presented clearly; the reader cannot make his own conclusions Diagnosis of coeliac disease was not according to ESPGAN criteria
Tumer L et al, 2001, Turkey	84 children (46 girls, 38 boys; age 16 months – 14 years) with height less than third centile for age; preliminary work-up to evaluate other causes of short stature was found to be negative	Prospective cohort study (level 2b)	Proportion of coeliac disease in the study group	Proportion of coeliac disease was found to be 8.3% (7/84). There is an association between coeliac disease and idiopathic short stature	The IgA EmA test was not verified by a gold standard test (biopsy) in all patients Diagnosis of coeliac disease was not according to ESPGAN criteria

Comment(s)

Growth retardation in childhood may be one of the earliest signs of an underlying disease, such as coeliac disease. In the Netherlands, the growth of nearly every child is monitored. When growth is retarded, the child is referred to secondary health care. After referral it has been advised to perform a diagnostic work-up containing routine laboratory tests to search for diagnostic clues for, among others, coeliac disease. The tests presently used for coeliac disease are IgA EmA and IgA antitissue transglutaminase antibodies. The total immunoglobulin A count is determined as well, because coeliac disease is associated with IgA deficiency. It was questioned if diagnostic investigations for coeliac disease should be performed in all children with short stature, even without gastrointestinal complaints. Some studies (Knudtzon, Stenhammar, Cacciari, Cacciari, Rossi) were based on study groups, in which no preliminary (endocrine) work-up to exclude other causes for short stature had been performed. The proportion of coeliac disease in children with short stature and no gastrointestinal symptoms in these studies ranged from 1.7% to 8.3%. When a group of children was studied, in which endocrine causes for short stature had been excluded (studies Radzikowski, Bonamico, Groll, Rosenbach, de Lecea, Altuntas), the proportion of coeliac disease increased to a range of 18.6% to 59.1%. The characteristics of the preliminary work-up used in Tumer's study were not described. The wide range of these percentages is probably mainly caused by the different methods of selecting the patients. The true variation in prevalences of coeliac disease throughout the world appears to be limited (Csizmadia). Screening on coeliac disease in the general population shows a prevalence of 1:300 to 1:100. About 50% of these children are completely symptomless (Csizmadia). In two British population-based studies on short stature (Voss, Ahmed), where coeliac disease was not specifically investigated, the prevalence of coeliac disease was respectively 2:180 (one patient was already known with coeliac disease) and 0:149. In children with short stature and no gastrointestinal symptoms investigated for coeliac disease, the prevalence increases to 2-8%. When other (endocrine) causes for short stature are excluded, the prevalence might rise to even 59%.

Clinical Bottom Line

In 2% to 8% of children with short stature and no gastrointestinal symptoms, coeliac disease may be the underlying cause. Excluding other causes for short stature increases the risk of having coeliac disease by 19% to 59%. Children with short stature should be evaluated for coeliac disease.

References

1. Knudtzon J, Fluge G, Aksnes L. Routine measurements of gluten antibodies in children of short stature. J Pediatr Gastroenterol Nutr 1991;12(2):190-194.
2. Stenhammar L, Fallstrom SP, Jansson G, et al. Coeliac disease in children of short stature without gastrointestinal symptoms. Eur J Pediatr 1986;145(3):185-186.
3. Cacciari E, Salardi S, Volta U et al. Can antigliadin antibody detect symptomless coeliac disease in children with short stature? Lancet 1985; 1(8444):1469-1471.
4. Cacciari E, Salardi S, Lazzari R, et al. Short stature and celiac disease: a relationship to consider even in patients with no gastrointestinal tract symptoms. J Pediatr 1983;103(5):708-711.
5. Rossi TM, Albini CH, Kumar V. Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus. J Pediatr 1993 123(2):262-264.
6. Radzikowski T, Zalewski TK, Kapuscinska A, et al. Short stature due to unrecognized celiac disease. Eur J Pediatr 1988;147(3):334-335.
7. Bonamico M, Scire G, Mariani P, et al. Short stature as the primary manifestation of monosymptomatic celiac disease. J Pediatr Gastroenterol Nutr 1992;14(1):12-16.
8. Groll A, Candy DC, Preece MA, et al. Short stature as the primary manifestation of coeliac disease. Lancet 1980;2(8204):1097-1099.
9. Rosenbach Y, Dinari G, Zahavi I, et al. Short stature as the major manifestation of celiac disease in older children. Clin Pediatr (Phila) 1986;25(1):13-16.
10. de Lecea A, Ribes-Koninckx C, Polanco I, et al. Serological screening (antigliadin and antiendomysium antibodies) for non-overt coeliac disease in children of short stature. Acta Paediatr Suppl 1996;412:54-55.
11. Altuntas B, Kansu A, Ensari A, et al. Celiac disease in Turkish short-statured children and the value of antigliadin antibody in diagnosis. Acta Paediatr Jpn 1998;40(5):457-460.
12. Tumer L, Hasanoglu A, Aybay C. Endomysium antibodies in the diagnosis of celiac disease in short-statured children with no gastrointestinal symptoms. Pediatr Int 2001;43(1):71-73.
13. Csizmadia CGDS, Mearin ML, von Blomberg BM, et al. An iceberg of childhood coeliac disease in the Netherlands. Lancet 1999;353(9155):813-814.
14. Voss LD, Mulligan J, Betts PR, et al. Poor growth in school entrants as an index of organic disease: the Wessex growth study. BMJ 1992;305(6866):1400-1402.
15. Ahmed ML, Allen AD, Sharma A, et al. Evaluation of a district growth screening programme: the Oxford Growth Study. Arch Dis Child 1993;69(3):361-365.