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Colonic Lymphoid Nodular Hyperplasia in an Adolescent

Vossenkämper, Anna*; Fikree, Asma; Fairclough, Peter D.; Aziz, Qasim; MacDonald, Thomas T.*

Journal of Pediatric Gastroenterology and Nutrition: December 2011 - Volume 53 - Issue 6 - p 684–686
doi: 10.1097/MPG.0b013e318223650a
Case Reports

*Centre for Immunology and Infectious Disease

Neurogastroenterology Group, Centre for Digestive Diseases, Barts and the London School of Medicine and Dentistry

Barts and The London NHS Trust, Gastroenterology, London, UK.

Address correspondence and reprint requests to Anna Vossenkämper, MD, Centre for Immunology and Infectious Disease, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London E1 2AT, UK (e-mail:

Received 18 February, 2011

Accepted 1 May, 2011

Anna Vossenkämper is funded by the Medical Research Council, UK.

The authors report no conflicts of interest.

Lymphoid nodular hyperplasia (LNH) of the lower gastrointestinal tract is of unclear significance, but is often found in children with food allergy, for example, cow's-milk allergy (1). Several studies have highlighted a possible connection among LNH, refractory constipation, and food allergy in adults and children (2,3). Furthermore, LNH is more prevalent in children with juvenile idiopathic arthritis and connective tissue disease (4). LNH also has been observed in healthy children and adults and is of uncertain significance (5).

Ehlers-Danlos syndrome (EDS) includes several different forms of collagen abnormalities and is characterised by hypermobile joints and flexible skin. It is divided into 7 subtypes based on the underlying collagen abnormality. EDS type III is a relatively benign form of the disease and characterised by hypermobile joints, flexible skin, and musculoskeletal symptoms (6), and patients have a high prevalence of gastrointestinal symptoms, which include dysphagia and constipation (7). Gastrointestinal abnormalities previously described in EDS subtypes include spontaneous bowel perforation, bleeding, and herniation (8). LNH is not a feature usually linked to EDS type III, and colonoscopy in these patients is usually reported to be normal. This report describes the extensive LNH in the colon of an adolescent patient who experienced severe constipation and EDS type III.

A 17-year-old female patient with EDS type III received upper gastrointestinal endoscopy because of dysphagia and a colonoscopy because of anaemia and unexplained weight loss in combination with chronic constipation. The patient used a wheel-chair and had a percutaneous endoscopic gastrostomy for nutritional reasons. The patient experienced arthralgias and autonomic neuropathy with bladder dysfunction and had antibiotic treatment for a urinary tract infection 2 weeks before endoscopy. She also experienced autonomic symptoms and was diagnosed with postural orthostatic tachycardia syndrome. The patient exhibited the classical features associated with EDS type III, including hypermobile joints and hyperextensible skin. Medication included diclofenac, paracetamol, fludrocortisone, midodrine, amytriptyline, domperidone, and VSL#3 probiotics. The patient was not atopic and did not experience eczema.

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A barium swallow revealed a slight mucosal irregularity of the anterior cervical oesophagus, likely to represent a small venous plexus. The cervical and thoracic oesophagus was otherwise unremarkable, with undisturbed passage of barium. A magnetic resonance image of the abdomen showed no abnormalities of the bowel and solid organs. No lymphadenopathy was seen. Evaluation of laryngeal function by video fluoroscopy showed reduced laryngeal elevation.

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Physiological Tests

High-resolution manometry of the oesophagus showed occasional weak-amplitude contraction, but clearance was normal, thus excluding a dysmotility.

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Blood Tests

One week before endoscopy, the patient was anaemic with a haemoglobin of 9.4 g/dL (normal range 11.5–16.5 g/dL) and a haematocrit of 0.30 (normal range 0.37–0.47). Mean cell haemoglobin concentration was decreased to 31.8 g/dL (normal range 32–34.5 g/dL). Lymphocyte count was decreased to 1.2 × 109/L (normal range 1.3–3.5 × 109/L). Other leukocyte counts were within the normal range. C-reactive protein was elevated at 28 mg/mL (normal range <5 mg/L) 2 weeks before endoscopy and was 9 mg/mL 1 week later. Immunoglobulin (Ig) G, IgA, and IgM were within the normal range. Serum IgE concentration was not determined.

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Endoscopic Examinations

Endoscopy of the upper intestinal tract showed no abnormalities in the oesophagus, stomach, or duodenum. Colonoscopy revealed an extensive number of prominent lymphoid follicles throughout the colon, with a particularly high number in the distal colon, starting in the rectum. In most areas, follicles were aligned along ridges associated with blood vessels (Fig. 1). Individual follicles showed a circular plexus of vessels in the dome (white square, Fig. 1A). The colon appeared otherwise normal, and no macroscopic inflammation, malignancies, strictures, or polyps were seen. Prominent Peyer patches and single lymphoid follicles were observed in the terminal ileum (Fig. 2).





Histopathological examination of the oesophageal biopsies (n = 5) showed no inflammatory infiltrate and eosinophils. No metaplasia or malignancy was present. Biopsies from the colon (n = 10) showed preservation of glandular architecture and goblet cells. The follicles had the architecture of Peyer patches. No significant chronic inflammatory infiltrate was seen; however, focal mild inflammatory activity with neutrophils in the surface epithelium and focal cryptitis was observed. No crypt abscesses, granulomas, or malignancies were seen. The terminal ileal biopsies (n = 3) were normal with intact villous architecture, and the absence of inflammatory infiltrates, granulomas, and parasites was noted.

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The patient experienced oropharyngeal dysphagia caused by depressed laryngeal elevation, which may be caused by the neuropathy in addition to connective tissue involvement. The most striking feature in this patient was the dramatic LNH in the colon. It has been estimated that there are approximately 300 Peyer patches in the normal human small intestine and 100,000 isolated lymphoid follicles scattered along the small bowel and colon (9). Endoscopically, lymphoid follicles are easily seen in the bowel, especially in children. In some children, the follicles become enlarged and prominent. LNH has been linked to refractory constipation (2,3) and food allergies (1,2); however, it can be observed in a small number of healthy children and adults (5). The exact mechanism underlying LNH is still unknown, but an increased activation of the intestinal immune system, for example, caused by allergies (1) or infections (10), has been proposed. Also, rheumatoid conditions that affect organs other than the intestine are sometimes associated with LNH (4). Therefore, it seems likely that various disorders of the immune system can result in the formation of prominent intestinal follicles.

Peyer patches and follicles are connected to a dense vascular network (11). The colonic follicles observed in this patient were unusual in that they were surrounded by macroscopically visible blood vessels, and indeed blood vessels were visible in the follicles themselves. This network of vessels almost certainly represents the planar capillary plexus identified in mouse Peyer patches (12). Second, and most intriguing, the follicles in the caecum, colon, and rectum were aligned along mucosal ridges, which, to the authors’ knowledge, has not been reported before. Usually in LNH, the protuberant follicles appear randomly in the mucosa as prominent “bumps.” We were therefore wondering whether this unusual linear feature could be a manifestation of the underlying connective tissue abnormality and whether defects in structural collagens in the mucosa or underlying tissues lead to unusual folds in the lining of the gut, so that the follicles at the top of the folds are exposed to luminal contents and become hyperplastic. Constipation is most likely associated with straining efforts, some degree of retro passage of luminal content, and bacterial overgrowth. Whether or to what extent these factors contribute to the unusual appearance of the lining and the LNH is unknown.

The patient in our report showed no signs of an eosinophilic enteropathy, which would have been indicative of a food allergy or parasitic infection. The histological examination of the colonic biopsies showed unspecific mild inflammation; therefore, the diagnosis of LNH was made entirely endoscopically. In fact, the histology of LNH is usually unremarkable and does not show any inflammation. It is therefore advisable that such an endoscopic finding should be completed by histological studies. The increased level of C-reactive protein, a strong marker of inflammation and/or infection, was most likely caused by the bladder infection. This infection and the antibiotic treatment were considered unlikely to be the reason for the observed LNH, because such treatment and urinary, respiratory, or other infections outside the gut are fairly common, but such a degree of enlarged LNH is an unusual finding in patients who undergo colonoscopy. The patient was, however, severely constipated. There is reasonably strong evidence that LNH can be associated with chronic constipation. For example, developmentally normal children with constipation have LNH (13). There are also sound immunological reasons why constipation, stasis of intestinal contents, and impaction may cause LNH. Chronic antigen exposure may cause a generalised lymphoid hyperplasia. Likewise, in diverted colon, in which there is intestinal stasis, a classic finding is enlargement of lymphoid follicles (14).

Although no specific treatment for the patient was advocated, the focus remains on an improved diet to avoid further weight loss and to improve anaemia. The patient also continues to take probiotic supplements to alleviate her constipation.

The patient experienced autonomic neuropathy with bladder dysfunction and dysmotility of the intestinal tract. LNH is not a feature of EDS type III; we speculate, however, that the autonomic neuropathy related to the underlying condition of EDS may be at least partly responsible for the chronic constipation, which could have subsequently led to the extensive LNH in this patient.

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