A novel clustering of down syndrome and coeliac disease complicated by enteritis and small intestinal strictures: a case series

Abstract

Down syndrome (DS) increases risk for autoimmune conditions, including coeliac disease (CeD). Here, we report five adults with DS and biopsy-proven CeD who developed enteritis and symptomatic small bowel stricturing, a clustering not previously described in this population. All five patients had confirmed DS and CeD, and despite apparent adherence to a gluten-free diet, all developed small bowel strictures requiring endoscopic intervention, most commonly at the duodenal D1/D2 junction. Stricture histology demonstrated active CeD with varying degrees of inflammation and fibrosis. Three patients had elevated faecal calprotectin without consistent colonic pathology, suggesting enteritis as an important inflammatory driver. Two patients responded well to open capsule budesonide with symptom resolution and histological improvement. One patient showed no sustained benefit from multiple immunosuppressive agents, including corticosteroids, azathioprine, and infliximab, requiring repeated endoscopic dilatations. Differential diagnoses, including Crohn’s disease, tuberculosis, nonsteroidal anti-inflammatory drug (NSAID) enteropathy, refractory CeD, and cryptogenic multifocal ulcerating stenosing enteritis were excluded based on clinical history, imaging, and histological findings. No granulomas or aberrant T-cell populations were identified. We propose this clustering may reflect a shared pathogenic mechanism linked to the interferonopathy of DS. Trisomy 21 causes overexpression of interferon receptors, creating heightened interferon signalling. Combined with CeD-triggered interferon production from gluten exposure, this may drive amplified immune activation, chronic enteritis, and fibrotic stricture formation. This hypothesis warrants further investigation through transcriptomic and immunohistochemical studies. Clinicians should consider this clustering in DS patients with CeD who present with persistent gastrointestinal symptoms. Given the underlying biology, JAK inhibitors may represent a promising therapeutic option for this phenotype and merit future study.

Plain language summary

Reporting a new association between Down syndrome, coeliac disease, and inflammation with narrowing of the bowel

People with Down syndrome have a higher risk of autoimmune diseases like coeliac disease. In this report, we describe five adults with Down syndrome and coeliac disease who developed inflammation and narrowing (strictures) of the small intestine. The response to immune-suppressing treatment was variable, and all needed procedures to treat the strictures. We postulate that the combination of Down syndrome, coeliac disease, and small bowel strictures could be due to a shared underlying cause, such as higher levels of specific kinds of immune receptors in people with Down syndrome. Doctors should think about this possibility when Down syndrome patients have ongoing gut symptoms.

Keywords

coeliac disease Down syndrome intestinal strictures trisomy 21

Introduction

Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with intellectual disability.^1,2 It has a global prevalence of approximately 1 in 800 live births, and epidemiological data indicate that its prevalence is rising worldwide.^1,2 DS exhibits phenotypic variability and is associated with a broad spectrum of clinical manifestations, including intellectual disability, characteristic craniofacial features, short stature, congenital heart defects, muscular hypotonia, and an increased risk of autoimmune diseases.¹ Gastrointestinal disorders are common in DS, affecting up to half of patients in some cohorts, and include chronic constipation, gastroesophageal reflux, congenital malformations such as duodenal atresia, imperforate anus, annular pancreas, and Hirschsprung’s disease, and coeliac disease (CeD).³

The risk of developing CeD is significantly elevated in DS.^4
–6 A meta-analysis indicated a prevalence of CeD in DS of 5.8% (95% CI: 4.7%–7.2%),⁵ substantially higher than the 1.4% observed in the general population.⁷ CeD is an immune-mediated enteropathy triggered by dietary gluten from wheat, barley and rye, causing a wide range of intestinal and extra-intestinal manifestations.^8,9 In CeD, gluten triggers a CD4+ T-cell response and the liberation of proinflammatory cytokines, including interleukin-2 and interferon-γ, culminating in the characteristic small intestinal lesion of villous atrophy, crypt hyperplasia, and raised intraepithelial lymphocytes and the production of antibodies to transglutaminase and gluten.^10,11 In contrast, while individuals with DS have a higher risk of developing inflammatory bowel disease (IBD) compared to the general population, this association is much less commonly reported.^12
–14 This rarity is notable given the increased risk of other autoimmune and inflammatory conditions in DS, and highlights a significant knowledge gap regarding the clinical spectrum and pathogenesis of IBD in the DS population.

The pathogenesis of immune dysregulation in DS is complex, differing from classic monogenic immunodeficiencies. DS is characterised by global transcriptional dysregulation and gene dosage effects, with multiple genes on chromosome 21, such as the autoimmune regulator (AIRE) and four interferon receptors (IFN-Rs), implicated in immune homeostasis.¹⁵ Overexpression of IFN-R genes in DS leads to heightened sensitivity to IFNs and a mild, chronic interferonopathy, which is increasingly recognised as a central driver of immune-mediated comorbidities in DS, including autoimmune thyroiditis, CeD, and type 1 diabetes.^15
–18

Here, we describe five adult patients with DS and CeD who developed small intestinal strictures with enteritis without granulomas. Small bowel strictures are very uncommon in uncomplicated CeD.¹⁹ When they do occur, it is typically in the setting of refractory CeD (RCD), a complicated form of CeD that does not respond to a gluten-free diet and is associated with a higher risk of malignant complications, particularly the development of enteropathy-associated T-cell lymphoma.²⁰ We hypothesise that the clustering of DS, CeD, and enteritis with intestinal strictures represents a unique manifestation of immune dysregulation in DS driven by interferon-mediated pathways. We discuss the scientific rationale for this association and its implications for clinical care.

Case summaries

We present five cases of DS with biopsy-confirmed CeD and small bowel enteritis and stricturing disease. The reporting of this study conforms to the CARE Guidelines: Consensus-based Clinical Case Reporting Guideline Development.²¹ These patients were all obtained following referral to one CeD specialist (JT-D) for management. All five cases had biopsy-confirmed CeD based on positive CeD serology and consistent duodenal villous atrophy and raised intraepithelial lymphocytosis. Notably, intestinal histology and CeD serology improved in all patients on a gluten-free diet, fully normalising in four. While a history of adherence to the gluten-free diet was obtained in all patients, it is acknowledged that monitoring dietary adherence can be difficult in individuals with DS. HLA genetic susceptibility for CeD was confirmed in four, and not performed in the fifth.

As this represents a selectively referred population, it is not possible to comment on the incidence or prevalence of this DS-CeD-enteritis clustering in the general population. Table 1 summarises the key demographic and clinical features that could be extracted from the medical records.

Table 1.

Demographic and clinical features of the five patients with DS, CeD and duodenal strictures.

Clinical feature	Case 1	Case 2	Case 3	Case 4	Case 5
Current age in years/(Gender)	22 (F)	43 (M)	35 (M)	37 (M)	31 (M)
Age at CeD diagnosis (years)	5	18	16	23	27
Presenting symptoms	Vomiting	Nausea, vomiting and weight loss	Abdominal pain, weight loss	Diarrhoea	Abdominal pain, diarrhoea, weight loss
HLA-DQ genotype	Not available	HLA-DQ2.2/8	HLA-DQ2.5/2.2	HLA-DQ2.5/2.2	HLA-DQ7
Serology at CeD diagnosis	Positive	Positive	Positive	Positive	Positive
Serology on a GFD	Negative	Negative	Negative	Improved but not fully normalised	Negative
Coeliac disease histology (on a GFD)	Not done	Not done	Marsh 0	Marsh 0	Improved but Marsh 1/2
Age and symptom(s) at first stricture presentation	20; Vomiting	41; Colicky abdominal pain	16; Postprandial abdominal pain	31; Symptom history unclear	27; Abdominal pain
Endoscopic findings	Duodenal stricture located at D1/2	Multifocal stricturing in the pylorus, duodenum & jejunum	Duodenal stricture located at D1/D2	Duodenal stricture located at D1/D2	Duodenal stricture located at D1/D2
Stricture and small bowel histology during acute flare	Stricture: Acute duodenitis Duodenum: Marsh 3 Terminal ileum: Marsh 3	Stricture: Ulceration with patchy intraepithelial neutrophilic infiltrate, granulation tissue and fibrosis. No raised IELs. Duodenum: Marsh 3	Stricture: Acute ulcerative duodenitis Duodenum: Marsh 3	Stricture: Surface epithelial erosion, neutrophil- laden exudate and epithelium lined by neutrophils. No raised IELs. Duodenum: Marsh 3	Stricture: Blunting of villi, focal crypt branching and raised IELs. Increased chronic inflammatory cells within the lamina propria. Duodenum: Marsh 3 Terminal ileum: Marsh 1
Colitis	Yes; focal active right-sided colitis	No	CT imaging and raised faecal calprotectin suggesting focal colitis. Colonoscopy was delayed 2 years and was normal.	No	Yes; lymphocytic colitis on colonoscopy. CT imaging showed no signs of colitis.
Faecal calprotectin (n < 50)	900	1220	210	Not done	Not done
Treatment response (steroids, endoscopic dilatation	Excellent symptom and histological response (full healing) to open capsule budesonide; Symptomatic response to dilatation	Poor response to multiple immunosuppressants; symptomatic response to dilatations	Several dilatations to good effect	Multiple dilatations to good effect; not willing to take open capsule budesonide	Responsive to dilatation

CeD, coeliac disease; D1, first part of duodenum; D2, second part of duodenum; D3, third part of duodenum; DS, down syndrome; GFD, gluten-free diet; HLA-DQ, human leucocyte antigen-DQ genotype; IEL, intraepithelial lymphocytes; Marsh 1, raised intraepithelial lymphocytes; Marsh 3, villous atrophy with crypt hyperplasia and raised intraepithelial lymphocytes.

In each case, we evaluated for alternative diagnoses using clinical and medication history, gastric and intestinal histology, total immunoglobulins and stool PCR, and in selected cases, intestinal flow cytometry, abdominal imaging, QuantiFERON-TB Gold testing and specific histological stains and immunohistochemistry, including periodic acid–Schiff (PAS), Ziehl-Neelsen and cytomegalovirus (CMV) and herpes simplex virus (HSV) immunostains. This allowed us to assess for infections, including tuberculosis, norovirus, Whipple’s disease, giardiasis and other causes for enteropathy, including Crohn’s disease, autoimmune enteropathy, common variable immunodeficiency (CVID), RCD type 2, enteropathy-associated T-cell lymphoma, tropical sprue, collagenous sprue and medication-related enteropathy, including olmesartan and NSAIDs.

Case 1

A 22-year-old woman with DS and CeD, diagnosed at age 5, presented at the age of 20 with abdominal pain attributed to duodenal stricturing and ulceration. Her comorbidities included type 2 diabetes, reactive arthritis, Kawasaki disease and Sjogren’s syndrome. She was strictly adherent to a gluten-free diet and had normal transglutaminase-IgA levels.

At the age of 20, she first presented with abdominal pain and constipation. A gastroscopy revealed a tight stricture at the transition between the first and second parts of the duodenum (D1/D2 junction) that was successfully dilated endoscopically. Biopsies of this area confirmed active CeD (Marsh 3C), and biopsies of the terminal ileum at colonoscopy confirmed similar Marsh 3C changes, indicating a widespread enteropathy. There were no aberrant T cells on flow cytometry to suggest RCD type 2 and no granulomas to suggest Crohn’s disease. Other causes of villous atrophy, including NSAID or sartan use, common variable immunodeficiency and tropical sprue were excluded based on testing or history. Faecal calprotectin was elevated to 900 µg/g, and while a colonoscopy was macroscopically normal, colonic biopsies showed mild focal active right-sided colitis and mild focal active proctitis. MRI enterography was normal. Following the initial dilatation, the patient was managed conservatively. However, 2 years later, recurrent abdominal pain prompted repeat endoscopy, which revealed a tight angulation at the D1/D2 junction, necessitating further balloon dilatation. Histology at D1/D2 again demonstrated active CeD (Marsh 3). She was treated with 3 months of open capsule budesonide,²² which led to a resolution of her abdominal pain and better sleep within a month. A follow-up gastroscopy after treatment showed persistent D1/D2 angulation; however, the duodenal mucosa was entirely normal with no villous atrophy or raised IELs. She remained well on the budesonide but has developed recurrent pain since the dose was reduced.

Case 2

A 43-year-old man with DS, diagnosed with CeD at age 18 and maintained on a strict gluten-free diet, presented at age 41 with recurrent colicky abdominal pain. His medical history included venous sinus thrombosis, iron deficiency, chronic constipation and Hirschsprung’s disease managed with multiple bowel surgeries.

At age 41, he experienced several hospital admissions for colicky abdominal pain initially attributed to constipation. Gastroscopy revealed severe gastritis and a distorted duodenal bulb with ulceration and stricturing. Duodenal histology demonstrated severe villous atrophy, increased intraepithelial lymphocytes and a mixed inflammatory infiltrate (Marsh 3c). One month later, he re-presented with colicky abdominal pain and vomiting; abdominal CT showed massive gastric distension secondary to duodenal stricturing. Repeat gastroscopy identified a pinhole pyloric stricture. Histology from the stricture showed non-specific ulceration, granulation tissue, chronic active inflammation and fibrosis. CeD serology and serum gastrin were normal, and flow cytometry confirmed a normal T-cell phenotype. He underwent laparoscopic gastrojejunostomy and received total parenteral nutrition.

Over the subsequent 2 years, he continued to experience progressive small bowel stricturing (Figure 1), affecting multiple segments from the duodenum and jejunum to the ileum (Figure 2). Although treatment with hydrocortisone and open capsule budesonide provided transient symptomatic benefit, this was not sustained. Azathioprine and dose-intensified infliximab were also ineffective, and frequent endoscopic dilatations have been required. Throughout this period, faecal calprotectin remained elevated (up to 1220 µg/g), but colonoscopy was unremarkable. The diagnosis of Crohn’s disease became less likely over time due to the lack of response to standard therapies. JAK inhibitor therapy has been considered but not commenced due to his history of venous sinus thrombosis and ongoing anticoagulation.

Figure 1.

Illustrative endoscopic images of one of the multiple jejunum strictures from Case 2 pre (a) and post (b) dilatation.

Figure 2.

Illustrative histological image from Case 2 showing jejunal stricture biopsy.

Case 3

A 35-year-old man with DS was diagnosed with CeD at age 16. He has a history of Ollier disease and his father also has CeD. At diagnosis, gastroscopy revealed extensive mucosal ulceration distal to the duodenal bulb. The following year, repeat gastroscopy showed persistent ulcers and a tight, fibrotic-appearing duodenal stricture, which was successfully dilated with a balloon. Histology from the stricture demonstrated acute ulcerative duodenitis, while separate duodenal biopsies showed active coeliac disease (Marsh 3b) with increased chronic inflammation in the lamina propria.

Following endoscopic dilatation, he remained symptom-free, and follow-up gastroscopies at 6 months showed no significant stricturing. However, despite strict adherence to a gluten-free diet and negative coeliac serology, by 12 months he developed recurrent circumferential ulceration at the D1/D2 junction with luminal narrowing. Because of the onset of abdominal pain, a CT scan was performed, which suggested colitis, and faecal calprotectin was elevated at 210 µg/g. Colonoscopy was delayed by 2 years; when eventually performed, it was unremarkable, with normal findings on both ileal and colonic biopsies. He has remained well at his 12-month review.

Case 4

A 37-year-old man with DS and CeD, diagnosed at age 23 and maintained on a strict gluten-free diet, has a history of Graves’ disease. At age 31, he presented to the emergency department with vomiting and abdominal pain. While some symptoms were attributed to dental sepsis, abdominal CT revealed duodenal fluid distension with numerous intraluminal bead-like structures. Gastroscopy demonstrated retained fluid and food proximal to a suspected third-part duodenal stricture, initially thought to be a web, which was managed conservatively.

Over the past 2 years, repeated endoscopies have identified recurrent pinhole duodenal strictures at the D1/D2 junction and significant proximal duodenitis, necessitating repeated balloon dilatations (three in the last year). Due to limited communication capacity, establishing a clear relationship between strictures and overt symptoms has been challenging. Histology from the strictures demonstrated surface epithelial erosion, neutrophilic exudate, lamina propria expansion by lymphoplasmacytic cells and pyloric metaplasia. Duodenal biopsies away from the stricture showed minor villous atrophy and patchy, mildly increased intraepithelial lymphocytes (Marsh 3b). Coeliac serology has remained positive throughout. Flow cytometry confirmed a normal T-cell phenotype. The patient has declined open capsule budesonide but has used a regular proton pump inhibitor.

Case 5

A 27-year-old man with DS and no comorbidities or regular medications underwent upper endoscopy for abdominal pain. A pyloric stricture required balloon dilatation. Gastric biopsies identified Helicobacter pylori. Duodenal biopsies showed villous atrophy without increased intraepithelial lymphocytes and were attributed to H. pylori-associated disease and not CeD at the time. After dilatation and eradication therapy, H. pylori clearance was confirmed by urea breath test and symptoms resolved.

Four years later, he re-presented with lethargy, 2 weeks of diarrhoea and progressive weight loss of more than 10 kg over 12 months (57–47 kg), with severe hypoalbuminaemia (10 g/L; normal range 33–46 g/L). Repeat upper endoscopy demonstrated an inflamed chronic stricture at the D1/D2 junction that was dilated with a balloon, and an atrophic, scalloped duodenum and proximal jejunum. Biopsies from the stricture and non-strictured duodenum and proximal jejunum showed severe villous blunting and flattening with increased intraepithelial lymphocytes, crypt architectural change and chronic lamina propria inflammation (Marsh 3C), without persisting H. pylori, granulomata, parasites, dysplasia, or features of lymphoma. Ileal biopsies showed milder Marsh 1-type changes. Colonic biopsies showed lymphocytic colitis. CT and CT enterography showed no additional small bowel inflammation or stricturing. Stool testing was negative for enteric pathogens, serum immunoglobulins and HIV serology were normal and there was no NSAID exposure.

Coeliac serology showed positive transglutaminase-IgA elevation (25 IU/mL, normal less than 7) that subsequently normalised on a strict gluten-free diet. On treatment there was rapid clinical improvement, 5 kg weight gain, and albumin rise to 16 g/L within 1 month. Open capsule budesonide was added, and by 2 months, he had returned to baseline weight and albumin improved to 31 g/L. Over 3 years, serial endoscopies showed resolution of stricturing and improved histology to Marsh 1/2 changes, and he has remained clinically well with albumin 30 to 35 g/L. Repeat CT abdomen and CT enterography have continued to show no other small or large bowel pathology to suggest inflammatory bowel disease.

Discussion

We report five cases of individuals with DS, CeD and enteritis with small bowel stricturing, a clustering that, to our knowledge, has not been previously described in the literature. These cases illustrate several distinct features: the recurrent and chronic nature of small bowel strictures, often necessitating repeated dilatations; the presence of florid enteritis often accompanied by elevated faecal calprotectin; and the limited, short-term efficacy of conventional immunosuppressive therapies. Although the co-occurrence of these conditions could be coincidental, we propose a plausible biological rationale for a shared pathogenic mechanism, centred on immune dysregulation and interferonopathy associated with DS, that could drive their co‑existence (Figure 3). While this is still conjectural, future work should test whether a common pathogenic pathway exists.

Figure 3.

Clinico-pathologic features of stricturing enteritis in DS and CeD and speculated pathogenic mechanism.

Differential diagnosis

A thorough diagnostic work-up is essential in patients with DS, CeD and small bowel strictures as the differential diagnosis is broad. In the first instance, it is important that the diagnosis of CeD is secure: the presence of typical enteropathy and positive CeD serology that improves or normalises on a GFD is important, and is further supported by the presence of HLA genetic susceptibility. Next, it is important to consider other causes for this presentation, such as Crohn’s disease, tuberculosis, medication-induced enteropathy and the rare disorder cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). While diagnosis can be challenging, distinguishing these entities is crucial, as management strategies and prognoses differ significantly. For example, Crohn’s disease is characterised histologically by transmural inflammation and granulomas, while CMUSE typically presents with chronic, recurrent small bowel stenoses of unclear aetiology, often lacking the classic features of CeD or Crohn’s.^23,24 Tuberculosis and NSAID overuse must be carefully excluded, particularly in high-risk populations or in the presence of atypical histological features.

Advances in genetics have identified key susceptibility genes in Crohn’s disease, such as NOD2, and highlighted the role of genetic polymorphisms in NSAID-related enteropathy, although the latter remains less well understood.²⁵ In hereditary forms of CMUSE, pathogenic variants in PLA2G4A and SLCO2A1 have been described. Given the clinical similarities between stricturing disease in DS and CMUSE, targeted genetic testing for PLA2G4A and SLCO2A1 mutations may be useful in selected cases to exclude this rare but important differential, when available. While this testing is not currently accessible in Australia, it is being considered for Case 2 via referral to an overseas laboratory due to that individual’s ongoing disease activity. Incorporating genetic testing into the diagnostic work-up may one day improve diagnostic accuracy.

A further diagnostic challenge lies in distinguishing duodenal inflammation attributable to active CeD, refractory coeliac disease (RCD) and enteritis with strictures. Duodenal biopsies in both active CeD (due to ongoing gluten exposure) and RCD (inflammation in the absence of gluten intake) typically demonstrate varying degrees of villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes. In our patients, several features argue against a diagnosis of RCD: the presence of enteritis as opposed to enteropathy, the absence of diarrhoea or a malabsorptive phenotype, the rarity of strictures in RCD,²⁰ and, when assessed, the lack of aberrant T-cell populations characteristic of RCD type 2. While we cannot entirely exclude RCD in our five cases, we believe their clinical phenotype is sufficiently distinct from RCD. Recent work has identified somatic mutations in duodenal T cells from patients with RCD type 2 and, importantly, RCD type 1 as well, that could serve as biomarkers to distinguish RCD from other causes of persistent enteropathy.²⁶

While active CeD is in keeping with an ongoing inflammatory process, the presence of enteritis and stricturing suggests an additional, possibly overlapping, inflammatory mechanism beyond what is typically observed in CeD or RCD. Unlike active CeD and RCD, strictures often show varying degrees of fibrosis, chronic inflammation and sometimes prominent neutrophilic infiltration. While histological characterisation can theoretically guide therapy (fibrotic strictures may benefit from dilatation and inflammatory ones from immunosuppression), most strictures contain both elements, limiting the utility of this distinction. This highlights the need for better diagnostics and treatments targeting both inflammatory and fibrotic components.

Clinical challenges

For clinicians, the coexistence of DS and CeD presents unique and complex challenges. Monitoring adherence to the gluten-free diet can be particularly difficult, as individuals with DS may experience varying degrees of cognitive impairment, communication difficulties and a high degree of reliance on caregivers. These factors can complicate accurate dietary assessment and management. The challenge is further compounded by the absence of reliable biomarkers of dietary adherence, and it is well established that CeD serology is a poor guide.²⁷ Furthermore, the clinical manifestations of CeD in DS are often atypical or may be obscured by other comorbidities common in DS, such as gastrointestinal dysmotility or hypothyroidism, resulting in diagnostic delays or misattribution of symptoms. It is also important to recognise that individuals with DS may not always be able to clearly express or localise symptoms associated with strictures or enteritis. Given the potential for recurrent strictures in this clinical clustering, consideration should be given to regular endoscopic surveillance in selected cases, especially where there is uncertainty regarding ongoing symptoms.

Restrictive eating behaviours are prevalent in DS and may be further exacerbated by the introduction of a gluten-free diet.²⁸ Sensory processing difficulties can contribute to a limited dietary repertoire, increasing the risk of micronutrient deficiencies. Therefore, regular screening for micronutrient status is recommended as part of routine care. Engagement with a dietitian experienced in both CeD and DS is essential, with a focus on individualised dietary planning that accounts for sensory preferences and nutritional adequacy.

Finally, robust support structures are critical for effective management. Education and ongoing involvement of family members and caregivers are necessary to ensure understanding and implementation of the gluten-free diet. Regular follow-up with a multidisciplinary team, including a dietitian, can help address challenges, reinforce dietary adherence, and monitor for potential complications. Tools such as urine or stool gluten immunogenic peptide (GIP) assays may provide a sensitive and objective readout of dietary adherence to support the dietary history but are not widely available or utilised in clinical practice at the present point in time.

Pathophysiological considerations: Down syndrome as an interferonopathy

DS is characterised by trisomy of chromosome 21, which encodes four of the six IFN-R genes: IFNAR1, IFNAR2, IFNGR2 and IL10RB. This genetic alteration leads to increased expression of these IFN-Rs across various cell types, including monocytes, T cells, fibroblasts and B cells.²⁹ The resulting gene dosage effect creates an ‘interferonopathy’, marked by heightened expression of interferon-stimulated genes and increased cellular responsiveness to both type I and type II interferons. Individuals with DS have been shown to exhibit up to seven-fold enhanced sensitivity to interferon signalling, which may drive both pro-inflammatory and anti-inflammatory immune processes depending on the context. This immune environment fosters the expansion of atypical B cell populations and the production of diverse autoantibodies, predisposing individuals with DS to autoimmune and inflammatory complications.¹⁸

Within the gastrointestinal tract, interferons, especially IFN-γ, play a pivotal role in regulating tissue damage, immune responses and fibrogenesis. Notably, IFN-γ is the most prominent cytokine in the chronic lesion of active CeD.³⁰ Persistent activation of interferon signalling leads to downstream induction of other pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α). TNF-α is a key mediator of tissue inflammation and fibrosis in conditions such as IBD. In IBD and related stricturing diseases, excessive TNF-α production, often driven by upstream interferon signalling, contributes to abnormal collagen deposition, tissue remodelling and stricture formation through the activation of macrophages and T cells. Thus, anti-TNF agents are often employed as first-line therapy to target this inflammatory cascade and manage stricturing complications.

The association between interferon signalling and intestinal inflammation in DS is further supported by observations of elevated faecal calprotectin levels, which were markedly increased in three of our cases. Notably, colitis was not consistently demonstrated on histological or endoscopic assessment despite these elevations, raising the possibility that enteritis, rather than colitis, was the primary driver of intestinal inflammation. As active CeD is typically not associated with increased faecal calprotectin levels,³¹ these findings suggest that such elevations may reflect DS-related, interferon-driven immune activation, even in the absence of classical IBD.

In IBD, IFN-γ can promote abnormal collagen deposition and stricture formation through macrophage and T-cell activation and downstream TNF-α signalling. The precise contribution of interferon pathways to stricturing disease in DS and CeD remains to be elucidated. However, current evidence supports a model in which interferon-driven immune dysregulation may potentiate both inflammatory, for example, stricturing, enteritis, colitis and fibrotic processes in the gut. Interferon signalling activates downstream pathways such as JAK-STAT, which are central to the propagation of both inflammation and fibrosis.

Establishing a mechanistic basis for this clinical clustering is important as it carries therapeutic implications. If confirmed, it would provide a strong rationale for the use of JAK inhibitors, which broadly block interferon and other pro-inflammatory cytokine signalling. JAK inhibitors have demonstrated efficacy in reducing intestinal inflammation in IBD and case reports have described beneficial effects in patients with inflammatory Crohn’s disease strictures.³² Further, emerging data suggest they can also interfere with the fibrotic processes underlying stricture formation in IBD, offering a dual therapeutic benefit.³³ Collectively, these findings suggest that targeting the interferon-JAK-STAT axis may represent a promising strategy for managing both inflammatory and fibrotic complications in DS, CeD and IBD and warrants further research.

A practical implication of viewing DS as an interferonopathy is that the marked clinical heterogeneity observed in DS likely reflects additional genetic modifiers. We speculate that duodenal stricturing in DS-CeD may represent an extreme phenotype arising from interaction between DS-driven interferon hyper-responsiveness and (i) common variants influencing fibrostenotic intestinal inflammation, given the clinical overlap with stricturing Crohn’s disease and the plausibility of convergent pathways involving genes such as NOD2, IL23R and ATG16L1 and/or (ii) rare monogenic ‘second-hit’ disorders affecting interferon/JAK-STAT signalling. In support of the latter possibility, STAT1 gain-of-function has been reported in individuals with DS and severe immune phenotypes, including upper gastrointestinal stenosis requiring dilatation.³⁴ This does not necessarily imply occult Crohn’s disease, but rather suggests convergent inflammatory and fibrotic pathways that may contribute to stricture formation across distinct conditions.

Notably, genetic testing was not undertaken in this case series. Future studies incorporating genomic evaluation, for example with targeted immune dysregulation/monogenic IBD panels including interferon/JAK-STAT pathway genes such as STAT1, with escalation to WES/WGS when panel testing is negative or suspicion remains high, will be required to assess the contribution of genetic modifiers or rare monogenic disorders. This may be particularly important because broader genomic approaches can identify structural, splice-altering and non-coding variants that are not captured by standard panel-based or coding-focused analyses, thereby increasing diagnostic yield in rare disease settings.³⁵ Broader genomic testing may also help evaluate for CMUSE-associated genes, including PLA2G4A and SLCO2A1. More broadly, integrated approaches that combine genomic, clinical and multi-omic data have been proposed as a useful framework for monogenic IBD diagnostics and for generating mechanistic disease hypotheses.³⁶ In this context, integrating genomic data with RNA-seq/transcriptomic profiling of blood and duodenal tissue, alongside functional studies using patient-derived samples, such as interferon-stimulated gene signatures and assessment of responsiveness to type I and type II interferons, could help distinguish DS-CeD stricturing from Crohn’s-like fibrostenosis and clarify whether an interferonopathy-driven programme is central to the observed phenotype.

Our case series offers an important hypothesis-generating framework for future research linking interferon signalling to gut inflammation and upper gastrointestinal stricturing. For example, transcriptomic or immunohistochemical studies could evaluate local overexpression of interferon-stimulated genes or receptors within strictures. In addition, comparative studies of stricture histology between DS-associated cases and other aetiologies such as Crohn’s disease or CMUSE may clarify distinct pathological features and guide targeted therapies.

Conclusion

Our case series highlights a novel clustering of DS, CeD and small bowel enteritis with recurrent stricturing disease. We speculate that DS-interferonopathy is a potential unifying mechanism. Clinicians should be aware of the increased propensity for inflammatory comorbidities in individuals with DS and specifically consider the possibility of this clustering in patients with both DS and CeD who present with gastrointestinal symptoms when CeD is being managed. Accurate diagnosis requires exclusion of other causes of stricturing, including Crohn’s disease, tuberculosis, NSAID enteropathy and CMUSE. Although mechanical dilatation can provide symptomatic relief, there remains a significant unmet need for effective medical therapies to address the disease process. Given the underlying biology, JAK inhibitors may represent a promising therapeutic option for this clinical phenotype.

Supplemental Material

sj-pdf-1-tag-10.1177_17562848261446854 – Supplemental material for A novel clustering of down syndrome and coeliac disease complicated by enteritis and small intestinal strictures: a case series

Supplemental material, sj-pdf-1-tag-10.1177_17562848261446854 for A novel clustering of down syndrome and coeliac disease complicated by enteritis and small intestinal strictures: a case series by Cynthia Kanagasundaram, Joanna Efklides, Elaine Koh, Sarah Ryan, Tim Elliott, Lani Prideaux, Xiao-Fei Kong, Sern Wei Yeoh, Jaycen Cruickshank and Jason A. Tye-Din in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

The authors thank the patients and their families for their participation and for generously sharing their clinical information for this case series.

Declarations

ORCID iD

Jason A. Tye-Din

Supplemental material

Supplemental material for this article is available online.

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