Inflammatory bowel disease (IBD) includes a group of chronic intestinal inflammatory conditions with three main clinical subtypes: Crohn's disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U). IBD has a multifactorial pathogenesis, involving genetic susceptibility, environmental factors, intestinal microbiota, and immune system. The contribution of genetic factors has been extensively described; however, the impact of genetics in the development of IBD is variable. The most common form of IBD is a polygenic disorder where the implication of genetic factors can significantly impact on the susceptibility and/or in the development of specific clinical characteristics and complications of the disease (1). So far, more than 230 disease loci related to polygenic IBD have been defined by genome-wide association studies (GWAS) (2). Differences between IBD subtypes, associations with clinical features, and prognosis can be explained, at least partially, by GWAS (3). Conversely, fewer common variants in IBD risk loci have been discovered to have a causative role including NOD2, ATG16L1, IRGM, IL23R, CARD9, RNF186, and PRDM1, with most risk loci containing different candidate genes (4, 5). More recently, monogenic forms of IBD have been identified as a group of diseases characterized by an early onset (generally in children <10 years of age: EO-IBD or very early in children <6 years of age: VEO-IBD) and a severe course, refractory to conventional therapies. More than 70 monogenic defects have been described, with a considerable number of the implicated genes involved in the maintenance of the immune homeostasis (6).

In addition to these groups of IBD (polygenic and monogenic forms), some genetic syndromes, mainly characterized by chromosomal abnormalities (numerical or structural), can present with IBD or are at high risk of development of IBD. These syndromes can be associated with autoimmune comorbidities, with the usual paradigms being represented by Turner syndrome (TS) and trisomy 21 or Down syndrome (DS). IBD has been reported, although sporadically, in other genetic syndromes. Possible mechanisms to explain the risk of autoimmunity in such syndromes include the following: genetic defects of immune regulatory pathways, impaired apoptosis and defense against oxidative stress, and molecular mimicry of viral or bacterial antigens (7). Clinical course of IBD in patients with a genetic syndrome can substantially differ from non-syndromic IBD for several reasons, including the following: the intellectual disability, the difficulties in adherence to treatment, a different response to certain medications, and the presence of comorbidities (Figure 1). So far, no specific protocols or guidelines exist for such vulnerable patients.

We aimed to describe this specific scenario starting by illustrating two challenging pediatric cases of IBD in subjects with a genetic syndrome. We further decided to perform a systematic review of literature to identify the frequency of IBD in specific syndromes and to describe the clinical characteristics of IBD in patients with these genetic conditions.

The systematic research identified a total of 986 articles, of which 58 were considered relevant based upon the established inclusion criteria (selection through title and abstract). Furthermore, four papers were identified through reference snowballing. A total of 62 full-text articles were assessed for eligibility and, after accurate reading, 46 were included in the final review. Sixteen articles were excluded, and the reasons for exclusion were as follows: duplicates (reporting cases described elsewhere), not reporting cases of IBD, or not describing either clinical or epidemiological aspects (Figure 2). The 46 articles reported a total of 67 cases of IBD in 6 different syndromes: 37 in TS, 17 in DS, and 13 in other syndromes including 2 cases in DiGeorge syndrome (DGS), 8 cases in neurofibromatosis type 1 (NF1), 2 cases in Kabuki syndrome (KS), and 1 case in Williams syndrome (WS).

With this systematic review, we aimed to characterize the clinical features and epidemiological aspects of IBD in specific genetic syndromes. Following our inclusion criteria, we identified a total of 69 cases of IBD (considering our two unpublished cases) described in six different genetic syndromes, including DS, TS, NF1, DGS, WS, and KS. DS and TS are conditions related to chromosomal abnormalities (21 and X chromosome, respectively), DGS and WS are chromosomal deletion syndromes (22q and 7q11.23, respectively), while NF1 and KS are related to single-gene mutations (NF1 and MLL2 or KDM6A for NF1 and KS, respectively). All of these are genetic diseases associated with a known risk of autoimmune comorbidities, with the only exception being represented by the NF1, where this association has been rarely described (56–59). The presence of an immunological dysfunction has been widely documented in DS, TS, KS, WS, and DGS. Although the association between these genetic conditions and IBD is known, many confounding factors can delay this diagnosis. In fact, all these syndromes share other relevant features, such as the presence of poor growth or short stature (on a genetic basis) and gastrointestinal symptoms (due to gastrointestinal malformations or comorbidities) that overlap with the main symptoms of IBD. Additionally, a variable degree of intellectual disability is reported in all these syndromes, complicating the symptom reporting and their correct assessment. Therefore, it can be difficult to maintain a high index of suspicion of IBD in this particular scenario, with a possible misdiagnosis or a diagnostic delay. Furthermore, the presence of other comorbidities in all these genetic conditions (e.g., cardiac, renal, hematological, and immunological) can complicate the course of IBD, making the patient more vulnerable to developing drug toxicities, infections, and surgical complications and higher risk of mortality (Figure 1).

The results of our systematic search show that the majority of cases of IBD were described in subjects with TS (38 cases including our novel case). Ten cases were particularly severe, with eight requiring surgery and two treated with biologics. It should be noted that all cases with surgical complications or with a lethal outcome and 50% of cases of TS and IBD were published before the year 2000, when biological treatment was rarely used in IBD. In the biologic era, no mortality for IBD has been recorded in females with TS. No early-onset IBD (before 5 years of age) was reported, apart from our case. We could then speculate that TS is not associated to a particularly severe phenotype of IBD; however, no comparison data with the general IBD population (not affected by TS) is available so far. Interestingly, a case of cardiomyopathy induced by adalimumab in a TS patient with bicuspid aortic valve has been recently presented, suggesting caution when using anti-TNF alpha in this fragile category of patients (33).

Epidemiological data for TS were extracted from six studies. Both prevalence (according to five studies) and incidence (based on two reports) indicated a higher risk of IBD in females with TS compared to the general population. These data undoubtedly indicate the need for a gastroenterological follow-up in subjects with TS.

The link between TS and autoimmune or inflammatory disorders could be mediated by genes located on the X-chromosome (e.g., the MHC-paralogs and the Toll-like receptor 8 signaling) and hormonal imbalance (characterized by elevated FSH and LH) that can activate immune pathogenic mechanisms. Based on a previous review of literature including a total of 15 cases of IBD in TS, it has been suggested that females with the isochromosome Xq (found in 60% of the women with IBD and TS vs. 17% of TS women without IBD) are more susceptible to IBD compared to those with the monosomy X (22). Our review, based on 25 genetically confirmed cases, does not reiterate this data, indicating an equal distribution of monosomy and structurally abnormal X chromosome.

Even if cases of IBD and DS were less frequently reported in literature, with a total of 13 adults and 5 children described (including our case), prevalence data (retrospectively collected) from two cross-sectional studies and from one cross-sectional controlled study show a two- to three-fold increase in the prevalence of IBD in DS compared to the general population (35, 40, 41). No longitudinal study was available, with a lack of data on the incidence of IBD in cohorts of subjects with DS. Plausible reasons for an increased risk of autoimmune disorders in DS include the following: involvement of genes on chromosome 21 implicated in the immune response (such as interferon receptor, CD 18, or the gene AIRE), defective T-cell control mechanisms and a reduced expansion of T-cell precursors in the thymus, a higher representation of immature NK cells with lower intrinsic activity, reduced IL-2 expression, defective phagocyte chemotaxis, and oxygen radical production (55).

Besides our pediatric case, one other case described in literature was particularly complicated due to the pulmonary involvement, which is a very rare complication of CD (43). Our case was challenging for several reasons, specifically, 1. the presence of a previously unrecognized esophageal stricture and a long-standing history of dysphagia with solid food refusal and 2. the poor response to standard treatments. Esophageal involvement in CD is uncommon, and its presentation with an esophageal stricture is even less common. The most frequent symptoms are dysphagia and odynophagia, and a large number of patients (up to 1/3) also have oral lesions. Esophageal CD can present as an erosive–ulcerative esophagitis or with an esophageal stricture (generally in the medium or distal esophagus) or fistula. Histology can be unspecific, adding on diagnostic difficulties (60, 61). Differential diagnoses include congenital stenosis or post esophageal atresia repair, gastroesophageal reflux disease, eosinophilic esophagitis, unknown caustic ingestion, and few other rarer causes. All of these conditions should be investigated in patients with DS and esophageal stricture, considering the high incidence of congenital gastrointestinal malformations, gastrointestinal reflux, and intellectual disability (with possible unrecorded foreign bodies or caustic ingestion) (62). In our case, the proximal esophageal stricture was considered compatible with CD, although histology was not specific and the response to anti-inflammatory treatments was poor, requiring endoscopic dilation. Even if there was no history, an origin related to a previous ingestion of caustics of foreign body cannot completely be excluded in our case, considering the severe intellectual disability, equally a congenital origin.

According to the current CD guidelines (63), our patient was considered at high risk at diagnosis; therefore, upfront infliximab was chosen as induction treatment along with EEN. An immunomodulator (azathioprine) was introduced at the first relapse (3 months after diagnosis) and, despite the optimization of infliximab schedule (10 mg/kg every 4 weeks) and the combination with azathioprine, the response was unsatisfactory with several course of steroids required during the follow-up and the necessity to switch to adalimumab. In other cases of IBD in DS reported in literature, response to standard treatments is described as good, except for one case of UC where colectomy was required and the CD case with pulmonary involvement that was treated with infliximab and methotrexate. Patients with DS are generally prone to drug side effects; this is frequently reported with some antiblastic agents, and toxicities (including cardiotoxicity, myelosuppression, infections, and mucositis) have a multifactorial origin (64–67). The greater risk of side effects with high doses of methotrexate in acute leukemia in patients with DS is a typical example; therefore, specific protocols with dose reduction for subjects with DS are currently used (68–71). In the same subjects, a higher accumulation of thioguanine inside erythrocytes in comparison to non-DS children has also been described (72). No specific reports of toxicities related to IBD medications (including thiopurines, methotrexate, and anti-TNF-α) in subjects with DS have been published so far. The risk of malignancy is another concern dealing with DS. Trisomy 21 is associated with a 10- to 20-fold risk for developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), as compared to non-DS children, while the risk of developing solid tumors is not increased (73, 74). Long-term use of some IBD medications (mainly thiopurines with or without anti TNF-α) has been associated to an increased risk of malignancy, particularly a rare form of lymphoma (hepatosplenic T-cell lymphoma) (75–79). In the absence of specific data on toxicity and carcinogenesis of IBD medications in subjects with DS, caution and close clinical follow-up is recommended, particularly with drugs such as azathioprine, methotrexate, and anti-TNF-α.

Lastly, the systematic research identified sporadic cases of IBD in other genetic syndromes. Interestingly, eight cases (six adults and two children), five with UC, have been described in NF1 with five cases reported since 2009. Unfortunately, there are no longitudinal or controlled studies exploring the link between NF1 and IBD, but as more cases accumulate, a correlation beyond coincidence becomes likely. NF1 is one of the RASopathies, a group of genetic syndromes due to germline mutations in genes that encode protein components of the RAS–mitogen-activated protein kinase (MAPK) pathway. RAS has an essential role in adaptive immunity and normal immune cell function, and the MAPK is crucial in the process of inflammation and apoptosis (80). Activated MAPK pathway has been reported previously in acetic acid-induced colitis (81, 82), and MAPK inhibitors were found to reduce inflammation (83) and specifically to ameliorate colitis in animal models of IBD (84, 85). These evidences can explain the basis for a susceptibility to IBD in patients with NF1. Furthermore, an altered mast cell function has been advocated as a possible common mechanism in the pathogenesis of both NF1 and IBD (particularly UC) and could be a link between the two conditions (86–90). From the systematic review, there is no evidence of an enhanced severity of these cases; however, NF1 is another condition associated to the risk of malignancy; therefore, a particular attention to the treatment choice should be reserved to these patients.

Despite the rigorous methodology followed and the extensive review (including several genetic syndromes), this systematic review has some limitations. The major limitations are related to the quality of the studies under review and the small number of available studies. Our results were necessarily based on case reports and series and few cohort studies; as a result, it was not possible to perform a meta-analysis. These limitations further highlight the need for the following: 1. population-based epidemiological studies for specific syndromes focused on the development of IBD and 2. specific studies or registry data sub-analysis investigating clinical characteristics, outcomes, and drug toxicities in subjects with IBD and a genetic syndrome compared to subjects with IBD without an underlying genetic condition.

In conclusion, we found evidence of IBD in several genetic syndromes, with most of the reported cases in TS and DS. Literature on the coexistence of NF1 and IBD has been accumulating in the last years, suggesting a possible link between these two conditions. Both the prevalence and incidence of IBD seem to be increased in subjects with TS and DS compared to the general population, although there is a paucity of high-quality and longitudinal epidemiological data. Patients with IBD and a genetic syndrome require a particular attention during the follow-up, considering the possible association with gastrointestinal and extra-intestinal comorbidities. A careful choice of the immunosuppressive regimens is necessary, particularly in DS, relating to the high risk of malignancy and the enhanced susceptibility to drug side effects, and the development of targeted protocols is required.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

SG and CC designed the study. SG and GG performed literature search and review, wrote the manuscript, and critically revised it. SG, GG, GC, and CC critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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