Association between Growth Hormone Deficiency and Celiac Disease among Children with Short Stature

Introduction

Celiac disease is an intestinal problem caused by gluten sensitivity. Its clinical spectrum is broad, ranging from asymptomatic patients to severe gastrointestinal and or extra-intestinal manifestations. Those without clinical features may have latent or silent celiac disease and remain undiagnosed but still at high risk, and sometimes with a serious complications if untreated , one of these symptoms is growth retardation(Alwan, 2014). Many screening researches showed that celiac disease is a very common health problem with an expected prevalence which can reach to 3 % among children(Naredi Scherman et al., 2025). Although impaired growth has long been recognized as a clinical manifestation of celiac disease, the mechanisms underlying growth failure and the factors contributing to it are not yet fully understood. Traditionally, growth impairment has been attributed to severe intestinal mucosal injury resulting in malabsorption of essential nutrients; however, the evidence supporting this explanation remains limited(Caio et al., 2019) . Other proposed mechanisms include disturbances in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and an increased prevalence of anti-pituitary antibodies, which may contribute to impaired endocrine regulation of growth(Nijenhuis-Noort et al., 2024). 

Recent pediatric evidence documents growth stunting in children and adolescents with celiac disease and shows improvement in anthropometric indices during follow up supporting careful assessment of linear growth in affected children (Almahmoud et al.,2024; Krauthammer et al., 2024).

Celiac disease is a common chronic disease among children n USA and European countries. The prevalence of previously undiagnosed coeliac disease from screening histology-based ranged from 0.10% to 3.03% (Roberts et al., 2021). . In the USA , celiac disease may affect 1/104 children by the ages of five years(Popp & Maki, 2019).

Short stature also has a broad pediatric differential diagnosis that includes genetic growth disorders, supporting evaluation for alternative causes when assessing persistent growth failure (Bittmann et al., 2026). Coeliac disease is diagnosed through an overall assessment that integrates the patient’s clinical presentation with disease-specific serological markers and examination of the small intestinal mucosa. In addition, improvement in symptoms and mucosal abnormalities following adherence to a gluten-free diet can support the diagnosis in appropriate clinical settings (Al-Toma et al., 2025). Among the available serological investigations, IgA antibodies directed against tissue transglutaminase (tTG-IgA) are commonly used, together with total serum IgA measurement to detect underlying IgA deficiency. The diagnostic performance of tTG-IgA is high, with reported sensitivity and specificity of approximately 90–95%. When duodenal biopsy is performed, the most typical microscopic findings include shortening or loss of intestinal villi accompanied by crypt hyperplasia. Nevertheless, these mucosal alterations are not unique to coeliac disease and may be observed in a range of other gastrointestinal conditions. Therefore, histological findings should be interpreted in conjunction with clinical and serological evidence (Villanacci et al., 2020).

A recent multicenter survey of pediatric centers found variability in the implementation of guideline-based coeliac disease diagnostic pathways, underscoring the importance of a structured serological and histological approach (Litwin et al., 2025). Despite recognition of both coeliac disease and growth hormone deficiency as causes of impaired growth, their concomitant occurrence and treatment response have not been specifically characterized among children with short stature attending the Anbar GrowthCenter. This local evidence gap provides the basis for evaluating the coexistence of the two conditions and the response to combined dietary and growth hormone therapy in this setting.

This study was aimed to;

1. To diagnose children with short stature.

2. To diagnose children with celiac disease associated with deficiency in growth hormone.

3. To study the response of those children after therapy after one year.

4. To identify the age and gender distribution of coeliac cases and theirdistribution according to response to therapy.

Patient And Method

Study design; the study is prospective analytic cross sectional done on short stature children who visit Ramadi teaching hospital for maternity and children growth center, Anbar, Iraq.

Study Setting and Period; Data were obtained from each child's caregiver.The study period was one year after each child's diagnosis with short stature,beginning in 2017. For all cases evaluated for coeliac disease, the first testperformed was the total serum IgA level as some proportion of population had genetically deficiency in IgA level. If the serum levelsis normal, then serological tests for anti-tissue transglutaminase IgA antibody is performed. In cases with negative results, then coeliac is not to be the etiology of growth retardation, but if the result is positive, then the child need to underwent other test which is serum level of antiendomysial antibody, if also with positively result then the diagnosis of celiac disease is established and the child should began the free gluten diet. Those children with borderline serological levels or those with congenital IgA deficiency were sent to do duodenal biopsy. Children with highly positive anti tissue transglutaminase levels and with negative results of antiendomysial levels, then serological investigations and/or duodenal biopsies were repeated (Branski, 2015). All cases diagnosed with coeliac disease at in this study were also sent for serological levels of growth hormone and sent for , any other expected etiologies of growth retardation, and assessed for bone age by a radiological specialist.

Ethical consideration; permission was taken from all children caregivers, informed consent was taken after explaining to them the purpose of the study . Permission was taken from Anbar research committee.

Data Collection: Questionnaires data form were prepared for each studied child include the following information;

1. Child age, divided into; 4 – 8 years old group, 8 - 12years those older than 12 years.

2. Sex,

Children, who diagnosed as celiac disease and with deficiency of growth hormone after one-hour provocative test, were, checked their height at time of diagnosis, and after one year from starting therapy with injectable growth hormone and free gluten diet.

Another required data included;

1. Listed the height in a special chart at time of diagnosis and after one year from beginning therapy.

2. Child caregiver personal phone number to follow up with them.

3. Height standard deviation scores (SDS) were determined for each child at baseline, at the time of diagnosis, and again following 12 months of treatment. The height SDS was calculated by subtracting the reference mean height for healthy children of the same age and sex from the child's measured height and dividing the resulting value by the corresponding reference standard deviation. Treatment efficacy was assessed based on the change in height SDS during the first year of therapy. In children with growth hormone deficiency, an increase in height SDS of approximately 0.25 or greater is generally considered indicative of a favorable treatment response (Cooke et al., 2016; Gleiss et al., 2025).

Inclusion and Exclusion Criteria;

Inclusion criteria; all children with short stature and celiac disease whose family accept the study.

Exclusion Criteria;

1. Age less than 4 years and more than 15 years.

2. Patients with chronic diseases as renal failure, heart failure, hypothyroidism or any syndrome, which can cause short stature.

3. Patients not attending on time.

The collected data were reviewed to ensure accuracy and completeness before being coded and entered into the Statistical Package for the Social Sciences (SPSS) for analysis. Descriptive statistics were applied to summarize the study variables, while the chi-square test was used to assess associations between categorical variables. Statistical significance was considered at a p-value of less than 0.05.

Results

Between 2017 and 2023, 233 children attending the Anbar Growth Centerfor evaluation of short stature were diagnosed with coeliac disease. Malesrepresented the larger proportion of patients, accounting for 140 (60%)cases, while females accounted for 93 (40%) cases, giving a ratio of 1.5:1.Regarding age distribution, the majority of patients were younger than 12years, with the highest percentages observed among children aged 4—<8years, 86 (37%), and 8-<12 years, 83 (36%), whereas fewer cases werereported among adolescents aged 12 years and above, 64 (27%) as in table 1.

Among all diagnosed patients, 48 cases were found to have concomitantgrowth hormone deficiency in addition to coeliac disease. Table 2 illustratesthe distribution of these patients according to sex and age categories.Following one year of treatment with a gluten-free diet combined withsomatotropin therapy, more than half of the patients demonstrated apositive response based on improvement in the standard deviation score(SDS).Table 2. Distribution of celiac disease diagnosed children associated with deficiency in growth hormone intervals by age and sex.

Among patients with concomitant coeliac disease and growth-hormoneinsufficiency, 58% of that group were considered as responders after starting treatment with injectable growth hormone and free gluten, as documented by changing in measurements of their mean standarddeviation score (SDS). The mean standarddeviation scores as in table (3) presents the values before and aftertreatment for both sexes. Improvement in growth parameters was observedin both boys and girls after one year of therapy, although the difference inresponse between sexes was not statistically significant. The Standard deviation scores were converted from (-2.86) to (-2.28) in boys after a year treatment course. In addition, it was converted from (-3.13) to (-2.73) within girls group. There was no significant difference inresponse according to sex. Table 3. Respond distribution of children with associated celiac and growth hormone deficiency intervals with sex.

P-value = > 0.05. Not significant

According to age groups, Table 4 shows that all categories experienced improvement in SDS following treatment. The standard deviation scores of patients with diagnosed concomitant conditions across different age groups, before and after one year of treatment with injectable growth hormone combined with a gluten-free diet, are presented. The score was shifted from (-3.05) to (-2.45) in patients aged (4 - 8) years, and it was shifted from (-3.05) to (-2.66) among patients aged (8 – 12) years, and it was shifted from (-2.87) to (-2.41) among those with ages above 12 years. In this table, the differences was significantly recorded in between these three age groups.

P-value = < 0.05. Significant

Discussion

The reported prevalence of coeliac disease among children investigated for short stature ranges from 2% to 10% (Muhammad et al., 2022; Singh et al.,2015), emphasising the necessity of evaluating endocrine and growth-related abnormalities in affected patients to prevent persistent short stature and later complications. To date, no previous research has specifically examined this association among children with short stature in Anbar Governorate.

In the current study, males were slightly more frequently affected than females, which is comparable to findings reported in Saudi Arabia (Assiri,2010). Conversely, Singh et al. (2018) demonstrated a higher prevalence among females, while a study in Pakistan (Muhammad et al., 2022) found no significant gender predominance. These discrepancies may reflect differences in cultural and social factors influencing healthcare utilisation and diagnosis. A notable proportion of patients with coeliac disease and short stature also exhibited growth hormone deficiency, demonstrated by growth hormone levels below 10 mcg/L following provocative testing. This coexistence may represent either a coincidental association or a physiological consequence of coeliac disease affecting growth hormone secretion. Similar observations have been documented in studies from Italy (Bozzola et al., 2015) and Iraq(Abdullah & Mahmood, 2024), supporting the relationship between coeliac disease and impaired growth hormone function. Moreover, previous investigations have shown that patients with coeliac disease often have reduced basal and stimulated growth hormone levels as well as decreasedinsulin-like growth factor concentrations (Boguszewski et al., 2015; Qutub &Saadah, 2020). Partial resistance to growth hormone activity has also been suggested in some cases (Guandalini & Assiri, 2014).

Although adherence to a gluten-free diet remains the cornerstone of treatment for coeliac disease, several studies have demonstrated that the addition of injectable growth hormone may induce child growth, improving of growth velocity, and contribute to achieving a normal final height (Witkowska-Sedek et al., 2018). In our growth center, patients received both growth hormone therapy and a excluding gluten from child diet for one year because of the limited availability of diagnostic facilities capable of distinguishing primary growth hormone deficiency from secondary hormonal suppression related to coeliac disease.

The present findings showed that approximately 58% of patients with both conditions responded positively to treatment, as evidenced by improvement in height standard deviation scores. Comparable studies (Bozzola et al., 2005;Meazza et al., 2011) have also reported favourable outcomes with combined hormonal and dietary therapy. Nevertheless, the relatively high proportion ofpoor responders in our centre suggests the need to further evaluate patientadherence to both treatment modalities. In addition, younger childrendemonstrated better therapeutic responses than older age groups after one yearof therapy, a finding consistent with studies from France and the UnitedKingdom, which indicated that earlier treatment initiation is associated withgreater improvement in growth outcomes.The limitations of this study include a relatively small sample size anddifficulties with subsequent measurements

Conclusion

This study identified 233 children with coeliac disease among those referred to the Anbar Growth Registry for evaluation of short stature. Boys constituted a slightly higher proportion than girls. Of the children diagnosed with coeliac disease, 48 also had growth hormone deficiency, demonstrating that the two conditions coexisted in a subset of this short-stature population. Following one-year of treatment with a non-gluten diet and injectable growth hormone,58% of children with assocaited coeliac disease and growth hormone deficiency showed a response according to changes in height SDS. Response rates were similar between boys and girls, indicating no statistically significant difference according to sex. In contrast, response differed significantly across age groups, with the highest proportion of responders among children aged 4—<8 years and the lowest proportion among those older than 12 years. Within the scope of these findings, the results support careful evaluation of children with short stature for coeliac disease and assessment for concomitant growth hormone deficiency when clinically indicated, while highlighting the greater observed treatment response among younger children.

Recommendations1. Screening for all children with short stature for celiac disease is recommended.

2. Further investigation is needed in patients with concomitant coeliac growth hormone deficiency and celiac to distinguish those with primary hormonal deficit and those with hormonal suppression because of coeliac disease.3. Another researches are also necessary to investigate the relation of celiac disease with patients newly diagnosed as type 1 diabetes mellitus.4. Among those patients who not respond to regime therapy, another study is recommended to re-evaluation them for wrong diagnosis or another diagnosisor drug compliance.

Conflict Of Interest

Authors declare that there is no conflict of interest.

Disclaimer

Authors declare that NO generative AI technologies such as Large Language Models (ChatGPT, COPILOT, etc.) and text-to-image generators have been used during the writing or editing of this manuscript.

Acknowledgment

We would like to express our deepest thanks to all the patients and their caregivers who participated in this study, and all the medical staff of growth center in Ramadi Teaching Hospital for Maternity and Children for their help throughout the execution of this study.