About 77 % of neonates affected by Down syndrome (DS ) present with or develop GI abnormalities [16]. Cleves et al., in a recent cohort study, showed an elevated relative risk for GI malformations (OR 67.07) in infants with DS [17]. The most frequent GI malformation associated with DS is Hirschsprung disease ; however, esophageal atresia, tracheoesophageal fistula, duodenal atresia or stenosis, and imperforate anus are all well-described associations. Some of the most commonly GI symptoms reported by patients with DS are dysphagia for liquids and solids, vomiting/GER, and heartburn, as well as other esophageal dysmotility symptoms [18]. Children affected by DS are at high risk of GERD [19] and its serious complications such as oropharyngeal aspiration and pneumonia. Much like in other conditions with neurological impairment such as CP, treatment of GERD in DS should combine optimization of antisecretory therapy and behavioral interventions including feeding and positional changes. Despite correct and aggressive medical therapy, some patients with DS, especially patients with respiratory complications of GERD, need antireflux surgery [20]. It has been observed that neurological impairment and GI disease necessitating surgery are independently associated with poorer developmental outcome [21]. In regard to esophageal motor disorders, different cases of association between achalasia and DS have been described, and although achalasia remains a rare entity, it should be considered in any patient with DS who presents with dysphagia [22]. Severe chronic constipation is also highly prevalent [23]. In children with chronic constipation, it is important to exclude Hirschsprung disease (HSCR), observed in approximately 1 out of 200–300 patients with DS [24]. About 30 % of HSCR patients have a recognized chromosomal abnormality, a recognized syndrome, or additional congenital anomalies, the most frequent of which being indeed DS [25]. Moore et al., studying a population of 408 HSCR patients, reported a prevalence of 3.2 % of DS [26], suggesting a possible role for chromosome 21 in the etiology of HD. Nevertheless, the existence of trisomy 21 although seemingly increasing the risk of developing HSCR does not invariably lead to its occurrence. Several studies investigating the role of chromosome 21 as a potential candidate area for a modifying gene in HSCR exist [27], but in the last few years, the possible role of genes mapping outside chromosome 21 (such as SOD1, ITGB2, protein s-100 beta) is emerging. Also, well studied has been the relationship between the major susceptibility genes associated with HSCR (RET and EDNRB) and DS. Arnold et al. [28] demonstrated that the RET enhancer polymorphism RET 19.7 at chromosome 10q11.2 is associated with HSCR in individuals with DS. Interestingly, the RET19.7T allele frequency is significantly different between individuals with DS alone (0.26 ± 0.04), HSCR alone (0.61 ± 0.04), and HSCR and DS (0.41 ± 0.04), demonstrating an association and interaction between RET and chromosome 21 gene dosage. Similarly, a novel EDNRB variant was identified in DS patients with HSCR [29]. There appears to be a significantly higher overall incidence of both pre- and postoperative enterocolitis in DS with HSCR [30].

Williams syndrome (WS ), also known as Williams-Beuren syndrome , is due to a homozygous deletion of a contiguous gene on the long arm of chromosome 7 (7q11.23) [31]. The estimated prevalence of WS is 1 in 7500 live births [32]. Most individuals with WS (99 %) have a 1.5 megabase deletion in 7q11.23 encompassing the elastin gene (ELN ) and 25–35 other genes, all of which are detectable by fluorescent in situ hybridization (FISH) [33]. Clinical features of WS include distinctive facial anomalies; congenital heart defects, in particular supravalvular aortic stenosis; slight to severe mental retardation; hernia; growth deficiency; and infantile hypercalcemia [34]. Gastrointestinal symptoms such as chronic abdominal pain, feeding problems, constipation, and GERD are seen relatively frequently in children with WS [35]. Hypercalcemia may contribute to irritability, vomiting, constipation, and muscle cramps; it is more common in infancy but may recur in adults [36].

Autism spectrum disorder (ASD ) is a neurodevelopmental condition that unfolds in the first few years of life and involves severe impairments in social interaction and communication, with restriction in interests and extreme attachment to routine or to repetitive or perseverative behaviors [37]. The term includes autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified [37]. Estimates of ASD in pediatric populations have dramatically increased over the past decade, with ~1 in every 88 children meeting diagnostic criteria in the United States [38]. GI dysfunction is frequently reported among children with ASD, and many causal and therapeutic theories of ASD involve the GI system [39]. This includes the hypothesis that a specific GI pathology is associated with ASD, triggered by abnormal immune function or elevated intestinal permeability. A great amount of controversy has surrounded this issue since a publication in 1998 naming a new pathologic entity, “autistic enterocolitis,” as responsible for developmental regression in 12 children after administration of the measles-mumps-rubella (MMR) vaccine [40]. Ultimately, this research was retracted for several reasons, including questionable research practices, as found by the General Medical Council of the United Kingdom [41]. Although the presence of a unique GI pathophysiology specific to ASDs has yet to be identified, elevated risk for GI symptoms in this population remains a critical issue in pediatric settings, because this population is significantly more likely to use GI agents and experience hospitalizations related to GI disturbances. The prevalence of GI symptoms in children with ASDs is poorly understood, and it is still unclear whether it is increased when compared with control subjects. Indeed, prospective well-controlled studies are unavailable. To date, prevalence has been reported with a wide range from 9 to 70 % [42–44]. A recent meta-analysis investigating GI symptoms among children with ASD concluded that ASD patients experience significantly more general GI symptoms than comparison groups (mean difference: 0.82, OR: 4.42) [45]. The most common GI symptoms reported in children with ASDs are chronic constipation, abdominal pain with or without diarrhea, and encopresis as a consequence of constipation [39]. Other gastrointestinal motility abnormalities that have been described for individuals with ASDs include GERD and abdominal bloating [39]. In children with ASDs, gastrointestinal conditions can present typically or atypically as non-gastrointestinal manifestations, including behavioral changes. Horvath et al. reported disturbed sleep and nighttime awakening in 52 % of children with ASDs who had gastrointestinal symptoms (vs 7 % of age-matched healthy sibling) [42]. Children with ASDs who had reflux esophagitis exhibited unexplained irritability more frequently (43 %) than those who did not (13 %) [42]. Behavioral changes may be markers of abdominal pain or discomfort in individuals with ASDs [46]. Nevertheless, a consensus report on the evaluation, diagnosis, and treatment of GI disorders in individuals with ASDs published in 2010 concluded that the existence of a gastrointestinal disturbance specifically correlated with ASDs has not been established [39]. Well-designed trials are therefore needed in order to develop evidence-based recommendations for optimal diagnostic and treatment strategies in children with ASDs. Until then, current consensus is that application and, when necessary, adaptation of conventional recommendations for the general pediatric population are also relevant to children with ASDs [39].

Turner’s syndrome (TS ) affects about 1 in 2000 live births females [47]. In about 50 % of cases, karyotype analysis of peripheral lymphocytes reveals the complete loss of one X chromosome (karyotype 45,X) whereas the remaining patients display a multitude of chromosomal abnormalities, including part absence of one X chromosome or mosaicism [47]. In the early 1980s, Chen et al. reported a high incidence of feeding difficulties in early childhood in children affected by TS, associated with regurgitation and vomiting [48]. In 1992, Mathisen and colleagues investigated 10 infants affected by TS and 10 control girls in order to detect oral-motor dysfunction and feeding disorders [49]. Through the use of video recording of routine meals and the administration of the Feeding Assessment Schedule (FAS), the authors clearly demonstrated that patients affected by TS presented considerable and persistent early feeding problems correlated with a characteristic range of oral-motor dysfunctions [49]. Breast-feeding as well as introduction of solid foods was especially difficult for the mothers of case infants. In addition, most of the case-group mothers reported vomiting and regurgitation, suggesting that some children with Turner’s syndrome may have some dysfunction of the lower gastroesophageal tract [49]. Following these findings, Staiano and colleagues evaluated upper gastrointestinal motility in patients with Turner’s syndrome in order to detect the presence of GI motor dysfunctions [50]. The study population consisted of 13 girls with TS and two comparison groups: seven girls with familial short stature and eight control girls. All the subjects underwent a scintigraphic gastric emptying study. In addition, six girls with TS and eight control children also underwent esophageal manometry [50]. The percentage of retention of solids at 60 and 90 min was significantly greater in patients with TS than in control subjects and in children with familial short stature. Five of the 13 girls with Turner’s syndrome had a gastric emptying at 60 min exceeding the mean plus 2 standard deviations of the results in control children. Conversely, esophageal manometry did not show significant differences in TS children when compared with controls group. The authors concluded that the impaired gastric motility represented a novel gastrointestinal finding of this syndrome. To the best of our knowledge, no further report of motility dysfunction in TS children has successively been published.

Noonan’s syndrome (NS) is an autosomal dominant disorder characterized by short stature, typical face dysmorphology, and congenital heart defects. The incidence of NS is reported to be between 1 in 1000 and 1 in 2500 live births [51]. Severe feeding difficulties are commonly described in children with NS, although the prevalence and underlying cause are poorly understood [52]. In 1992, Sharland and colleagues reported the clinical characteristics of 151 children affected by NS. Feeding histories were obtained in 144 children. Significant feeding difficulties were reported in 75 % of children [52]. In 24 % of these patients, these difficulties were defined as severe, requiring tube feeding for 2 weeks or longer. In 38 % of cases, feeding difficulties were moderate, defined as very poor suck, with slow feeding and recurrent vomiting [52]. Following these early reports, in 1999 Shah et al. conducted a study in order to characterize gastrointestinal motility in children affected by NS [53]. Twenty-five children with NS were consecutively enrolled. Poor feeding described as poor suck or refusal to drink or eat solids, and recurrent vomiting were present in 16 patients. Eight of 16 infants with gastrointestinal symptoms had evidence of gastroesophageal reflux [53]. The children with the most severe symptoms were further investigated by surface electrogastrography (EGG ) and antroduodenal manometry (ADM). Four of the five patients who underwent EGG had evidence of abnormal gastric myoelectrical activity. ADM showed an immature contractile activity rather than neuropathological in appearance, reminiscent of that seen in neonates of 32–35 weeks’ gestation [53].

Rett syndrome is a neurodevelopmental disorder characterized by a period of developmental regression at approximately 6–18 months with loss of hand and communication skills, development of hand stereotypies, and impaired gait [54]. Most cases are caused by a mutation in the MECP2 gene [54]. As with other neurodevelopmental conditions, disorders of GI motility such as GERD, constipation, and abdominal bloating are common [55]. Recently, a group of experts published a systematic review of the literature in order to provide some practical recommendations for the management of GI motility disorders in children with Rett syndrome [56]. GERD has been reported up to 39 % of girls and women affected by Rett syndrome [57]. According to the experts’ panel, common presenting symptoms include vomiting, rumination, regurgitation, and respiratory signs, and unexplained weight loss [56]. The diagnostic approach should not differ from other patients with GERD, including pH-monitoring and upper GI endoscopy. Regarding the treatment, the majority of the panel agreed that conservative strategies such as small frequent feeds and the use of more upright positions in combination with pharmacological management should be adopted [56]. Laparoscopic fundoplication should only be advised in case of refractory GERD. Despite the frequency reported to be up to 80 % of girls and women in a recent US family survey [57], there remains a paucity of evidence as to how constipation should be best diagnosed and treated. Diagnosis is often difficult due to the communication challenges. A stepwise plan for management was identified with a high rate of agreement from the panel members on the use of various laxative agents [56]. Abdominal bloating, as a result of aerophagia, has been reported in almost half of the cases in a population-based sample [58]. In some case reports, severe aerophagia has been associated with gastric perforation [59]. Use of simethicone or magnesium sulfate or selective serotonin reuptake inhibitors has been suggested. There was no consensus on the use of magnesium sulfate; its use has only been supported by case reports. Where symptoms are severe, a gastrostomy may be considered [56].

Prader-Willi syndrome (PWS ) is a multisystemic genetic disease which was first described in 1956 [60]. The incidence of PWS is 1:15,000–30,000 newborns. The syndrome is characterized by muscular hypotonia, feeding difficulties, failure to thrive, developmental delay, short stature, and hypogonadism [60]. Gastrointestinal motility in children with PWS has been sparsely investigated. Following case reports describing gastric rupture in PWS children [61, 62], Arentz and colleagues measured the gastric emptying in eight pediatric patients with PWS through nucleotide scintigraphy after a standardized test meal [63]. In contrast with adult literature [64], the authors found a delayed emptying in 5 out of 8 children and concluded that this may represent a risk factor for the development of gastric rupture [63]. More recently, Kuhlmann et al. evaluated colorectal function in 21 adult patients with PWS [65]. All enrolled patients underwent a whole assessment for diagnosis of constipation including total gastrointestinal transit time (GITT). Eight out of 21 patients fulfilled diagnostic criteria for functional constipation, and GITT was >3 days in 24 % of PWS and none of the controls. To the best of our knowledge, no pediatric study has evaluated the prevalence of functional constipation among PWS children.