Delayed appearance of mature ganglia in an infant with an atypical presentation of total colonic and small bowel aganglionosis: a case report

Total colonic aganglionosis (TCA) is a rare form of Hirschsprung’s disease (HD) that affects one in every 50,000 births [1, 2]. TCA involves the entire colon and may extend up to 50 cm proximal to the ileocecal valve. Total colonic and small bowel aganglionosis (TCSA) is a more rare form involving long segments of small bowel (exceeding 50 cm) [1]. In TCSA, non-specific dilatation of small bowel loops is frequently seen. However, a characteristic transition zone can be difficult to identify [3, 4], which may complicate surgery, including the need to re-site a previously created stoma [5].

Here we present a case of apparent TCSA in which serial biopsies over the first year of life revealed de novo mature ganglion cells in previously aganglionic small bowel. This case suggests the possibility of post-natal ganglion maturation and encourages surgeons to consider a more conservative surgical approach.

TCSA occurs in less than 1% of all HD patients and may represent an entirely separate disease process from rectosigmoid HD [1, 5]. Our case introduces new controversy to our understanding of aganglionosis. We believe this is the first case of aganglionosis reported with de novo post-natal appearance of ganglion cells. Furthermore, this is the first case of witnessed propulsive peristalsis in a segment of aganglionic, normal caliber bowel. At the time of the patient’s surgeries, it appeared as though the ganglion cells were developing de novo; in retrospective review of the case, it seems possible the bowel was severely hypoganglionic with delayed maturation of ganglion cells.

The gold standard diagnostic test of HD is intestinal biopsy demonstrating aganglionosis [5, 6]. There are inherent difficulties in relying on frozen section to make definitive diagnoses in HD. Even with permanent sections, diagnosis of TCSA can be confounded by the difficulty of identifying normal intestinal plexus histologically in the small bowel compared with the colon [7]. Neural hypertrophy is absent in cases of TCA and TCSA, further complicating the identification of a potential transition zone. We identified three case reports that describe an unusual form of HD where the patients presented with multiple skip segments of aganglionosis [8‐10]. No reports have identified de novo or delayed appearance of ganglion cells on serial biopsies.

The case presented here adds to the complexity in our incomplete understanding of intestinal aganglionosis and its etiology. Murine models have demonstrated long hypoganglionic segments with increased immaturity of cells [6, 11]. Watanabe et al. described hypoganglionosis as a completely different clinical entity from HD in which there is no clear identification of a transitional zone [12]. Berger et al. introduced three different types of intestinal innervation disturbances including aganglionosis (HD), hypoganglionosis, and intestinal neuronal dysplasia [13]. A transition zone with hypo- or dysganglionosis may lead gradually into normally innervated bowel [13]. It is possible this patient exhibited extreme hypoganglionosis or immature cells that matured into ganglion cells by the subsequent biopsy at 7 months of life.

An alternate explanation is that a long, extended transition zone with very rare ganglion cells escaped detection on previous leveling biopsies, or that the patient was exhibiting skip segments [9, 14]. Shimotake et al. suggested that the type of genetic mutation in HD influences the postnatal distribution and function of enteric ganglion cells. In contrast to patients with RET gene mutation, those with SOX10 mutation show a very long histologic transition extending longer than 100 cm [14]. There also exist a few studies describing acquired aganglionosis caused by inflammation and destruction of intestinal neurons due to herpes virus infection in young adults and animal models [15, 16]. Paraneoplastic syndromes and antitumor inflammatory responses have also been demonstrated to be related to ganglion cell destruction in the myenteric plexus resulting in hypoganglionosis or HD with a long segment transition zone [17]. Though none of these studies involved newborns, these mechanisms cannot be ruled out.

Contrary to the conventional understanding that aganglionosis results in a failure of relaxation in the affected segment, this patient demonstrated effective peristalsis in the aganglionic segment that was confirmed post-operatively with normal transit time on small bowel follow-through radiograph and normal stoma output. Walther et al. described a patient with TCSA who presented with dilated small bowel and visible peristalsis on X-ray despite biopsy-proven absence of ganglion cells distal to the stomach. Intraoperatively, distal small bowel peristalsis was observed; however, that patient died on DOL 80 of septicemia [18].

Currently, the mainstay of treatment for HD is surgery. However, in patients with TCSA, functional outcomes are often poor [19‐21]. In patients with extensive small bowel involvement and less than 20–40 cm of ganglionic bowel, radical resection puts the patient at risk for short bowel syndrome, long term TPN dependency, and TPN-related complications such as liver failure and catheter-associated infections [5, 22]. Intestinal transplant is an emerging option, but is limited to a few centers and fraught with morbidity [23]. To decrease morbidity, partial preservation of aganglionic segments has been reported despite evidence of its association with recurrent episodes of enterocolitis [1, 22]. Others have advocated using aganglionic bowel as an intestinal patch or performing myectomy-myotomy, although these have been met with limited success and are not the standard practice at our institution [24]. Sharif et al. evaluated post-intestinal transplant outcomes of patients with TCSA with or without extensive aganglionic segment resection. Those with previous extensive resection had earlier deterioration of liver function requiring earlier transplantation and increased technical difficulty due to decreased intraabdominal space [25]. Our finding of propulsive peristalsis in apparently aganglionic, but normal caliber bowel may support the practice of preservation of aganglionic bowel in cases of TCSA. Nevertheless, the ideal operative approach remains controversial [26, 27].

TCSA remains a major challenge for pediatric surgeons. We present the first case of TCSA in which mature ganglion cells were subsequently identified in a significant portion of previously aganglionic intestine with effective peristalsis observed in the remaining aganglionic, normal-caliber small bowel. Our observations warrant further research into the possibility of post-natal ganglion maturation in severely hypoganglionic bowel and encourage surgeons to consider a more conservative surgical approach.