Motility Problems in the Intellectually Challenged Child, Adolescent, and Young Adult

Down Syndrome

Down syndrome (DS) is the most common chromosomal abnormality occurring in humans. In Europe, DS accounts for 8% of all registered cases of congenital anomalies. Throughout the world, the overall prevalence of DS is 10 per 10,000 live births, although in recent years this figure has been increasing. DS is characterized by several dysmorphic features, delayed psychomotor development, and low muscle tone in early infancy. DS is associated with dysfunctions that might affect almost every organ and system, including the gut. It has been reported that more than 77% of DS affected neonates have, or develop, associated gastrointestinal (GI) disorders. These conditions can be classified into mechanical and functional disorders and can be primary or secondary.

Next to the most common associated congenital malformations, such as tracheo–esophageal fistula, duodenal atresia/stenosis, and imperforate anus, the most frequently occurring GI disorders in DS are characterized by motor disturbances, particularly encountered in the esophagus and colon. DS affected infants have been reported to be at 100-fold increased risk for Hirschsprung disease (HSCRD). In addition, gastroesophageal reflux disease (GERD), achalasia, and unexplained chronic constipation often complicate the clinical course of DS children. According to a recent report by Van Trotsenburg and colleagues, GI disorders and feeding difficulties represent a very frequent cause of hospitalization (19%) in patients affected by DS. Unfortunately, the inherent difficulties of DS patients to express themselves could hamper clinical evaluation and delay the diagnosis, increasing the risk of related complications. The likelihood of the involvement of the enteric nervous system (ENS) in these associations, although not yet completely understood, is generally accepted.

Role of the Enteric Nervous System

The anomalous central nervous system (CNS) development, function, and intellectual impairment in DS has always been related to the genetic imbalance, resulting from the presence of an extra copy of chromosome 21. However, the underlying pathogenetic mechanisms are still unclear. Whether chromosome 21 trisomy determines a malfunction of dosage-sensitive genes or results in a more generalized alteration of homeostasis in a critical development period is still not clarified. In this context, it is not surprising to observe a high frequency of enteric nervous system alterations, as both embryonic brain and GI tract development are regulated by similar neural growth factors, under the control of the same genes. A link between brain and ENS development is well demonstrated by the high prevalence of cerebral dysgenesis in patients affected by neurocristopathies, such as HSCRD. The ENS develops from the colonization of neural crest cells, which migrate to populate the GI tract. This mechanism is regulated by a complex signaling system, which appears to be altered in DS. Decreased neuronal migration, as well as alterations of dendritic development, has been shown in an animal model of DS. At the same time, alterations in ENS structure and function have been demonstrated in DS patients. Nakazato and Landing showed a reduced number of neurons in esophageal plexus ganglia in DS patients. Hypothetically, this decrease, described in the esophagus, could occur throughout the entire gut. Further studies are needed to better clarify these fundamental pathogenetic mechanisms.

Esophageal Motor Dysfunction

In a recent prospective analysis, Zarate and colleagues reported that the most common functional GI symptoms described in DS patients are dysphagia for liquids and solids, vomiting, regurgitation, and heartburn. GERD remains one of the most frequent causes of esophageal symptomatology in DS. Previous studies described a high prevalence of severe GERD with the occurrence of serious complications, such as oropharyngeal aspiration and pneumonia, in 43% of DS patients. In one case report, GERD was associated with the development of pulmonary arterial hypertension in a 2-month-old DS-affected boy.

As is the case with all children with a neurologic impairment, many factors could contribute to the high prevalence of reflux and impaired esophageal clearance and, consequently, lead to the development and progression of GERD among DS patients. For example, abnormal swallowing, delayed gastric emptying, abnormal muscle tone, obesity, and constipation are commonly reported in this patient population. The severity of GERD may also result from poor self-protective mechanisms and delayed diagnosis caused by difficulties in obtaining an accurate history of symptoms. In addition, it seems that the severity of GERD correlates directly to the severity of neurologic impairment. For all these reasons it seems extremely important to investigate esophageal function in all patients with typical or such atypical GERD symptoms as food rejection, frequent vomiting, coughing, and failure to thrive. Early diagnosis is essential to prevent respiratory problems, growth retardation, and all other GERD complications. According to the latest European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)–North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) guidelines on GERD, the evaluation of children with neurologic impairment, such as DS, should be based on a high index of suspicion and must not only confirm the diagnosis but also rule out alternative diagnoses. Contrast GI radiographic studies, upper GI endoscopy and biopsy, metabolic and drug toxicity screening, and pH/impedance studies may be required. Treatment should associate optimized antisecretory therapy to behavioral measures, including feeding and positional changes. Given the morbidity and high failure rates of antireflux surgery, patients whose symptoms are well controlled on medical therapy may not derive additional benefit from antireflux surgery. Despite optimized medical therapy, some DS patients affected by GERD need antireflux surgery. However, this should be considered only in highly selected cases, as antireflux surgery has been independently associated with poorer developmental outcome. In addition, it has been shown that preexisting esophageal dysmotility in DS patients could complicate the postoperative clinical course after corrective surgical procedures.

Next to GERD, esophageal motor disorders, such as achalasia, are not infrequent in DS patients. A number of instances of the association between achalasia and DS have been described in adult and pediatric DS populations ( Fig. 1 ). In a study conducted by Zarate and colleagues, the authors evaluated esophageal clearance in adult DS patients and controls, using scintigraphy. Patients with abnormal scintigraphic studies and suggestive symptoms proceeded to undergo radiologic and manometric examinations. Results clearly showed a significantly greater retention of both liquid and semisolid boluses in DS. Achalasia was diagnosed in two patients, providing an astonishingly high prevalence (2/58 patients enrolled) compared with the general population (prevalence 8/100,000). Further, another patient had total body aperistalsis and two had a nonspecific motor disorder. The same authors, in 1999, reported five cases of DS associated with achalasia. Two of the five reported cases were children. Why does DS carry a higher risk of achalasia?