CH has been described by various terms, including nesidioblastosis, persistent hyperinsulinemic hypoglycemia of infancy (PHHI), and persistent hyperinsulinemic and hypoglycemia (PHH). Inadequate treatment of hypoglycemia causes serious brain damage in patients with CH [1, 3, 4]. The estimated incidence of sporadic CH is 1 in 50,000 live births [3, 4]. CH has rarely been reported to be associated with clinical syndromes, including—but not limited to—Beckwith-Wiedemann, Kabuki, Sotos, and congenital central hypoventilation (Ondine) syndrome [4, 5]. Histopathological studies have revealed that there are foal and diffuse types of CH [1, 3,4,5]. Focal-type CH shows focal adenomatous hyperplasia of islet beta-cells associated with enlarged cytoplasm with abnormally large nuclei, and sometimes mutations of the SUR1 and Kir6.2 genes [3, 5]. In diffuse-type CH, hyperplasia of islet beta-cells is observed throughout the pancreas [1, 4,5,6]. These conditions have been rarely reported in adult patients after gastric surgeries [7, 8]. The causes of adult nesidioblastosis remain unknown, although several genetic defects have been reported in CH [3, 4, 9]. In particular, mutations of the SUR1 and Kir6.2 genes are frequently reported as causes of CH and are detected in 40–45% of all cases , although the disease is unrelated to either of these mutations in approximately half of CH patient [3, 9]. In the management of CH, conservative treatment is initially applied with high-dose glucose infusion, glucagon injection, diazoxide, and octreotide [1, 3, 4]. Surgical treatment is used to treat both the diffuse and focal types of CH when medical and dietary therapies are ineffective [1, 3,4,5,6]. In diffuse-type of CH, ≥ 95% subtotal pancreatectomy has been recommended for treating hypoglycemia; however, a high incidence of postoperative diabetes mellitus has been reported in long-term follow-up [4, 6, 7]. Adzick et al. suggested that the incidence of diabetes mellitus increased with long-term follow-up and that 47% of 189 patients who underwent near-total (> 95%) pancreatectomy had diabetes at 10–20 years of age . On the other hand, partial resection of the pancreas is performed for most patients with focal type of CH and postoperative diabetes mellitus has rarely been reported. Recently, focal lesions have been frequently detected by 18-fluoro-dihydroxy phenylalanine (18F-DOPA) PET .
HD is another rare congenital disorder of bowel movement that is characterized by severe constipation and enterocolitis. The incidence of sporadic HD is 1 in 5000 live births [2, 11]. The absence of enteric ganglion cells at both the myenteric and submucosal plexuses, from the rectum to the proximal bowels, causes severe movement disorders in the affected bowel [2, 11]. Preoperatively, HD is definitively diagnosed by immunohistochemical staining of AchE-positive nerve fibers in the rectal mucosal biopsy specimens. In HD, increased AchE-positive fibers are observed in the mucosal lamina propria and muscularis propria and/or submucosa [11, 12]. However, increased AchE-positive fibers are not observed in all HD patients during the neonatal period; thus, AchE staining must be repeated later to obtain the definite diagnosis of HD . Associated anomalies have been reported in HD, including Down syndrome, cardiac anomalies, mental retardation, anorectal malformation, and Ondine’s syndrome [2, 11]. However, no reports have described an association between CH and HD. Meissner et al.  reported one case in which CH was associated with congenital central hypoventilation syndrome (Ondine’s syndrome) and suggested that patients with Ondine’s syndrome might often manifest some clinical symptoms of autonomic nervous dysfunction, including HD and/or severe constipation . Although the present case was not associated with Ondine’s syndrome, CH and HD may have common etiologies that are currently unknown. In addition to dysfunction of the enteric nervous system, as seen in HD, more complex molecular mechanisms may be involved in CH. HD is suggested to be caused by defective neural crest cell development, termed “neurocristopathy,” which causes dysfunction of the autonomic nervous system . The PHOX2B polyalanine repeat mutation has also been identified in HD associated with Ondine’s syndrome . Pancreatic islets cells can also be affected by the autonomic nervous system, as they are richly innervated by parasympathetic, sympathetic, and sensory nerves. Hennewig et al. reported a heterozygote missense mutation (Gly68Cys) in the PHOX2B gene in a rare case of Ondine’s syndrome associated with CH . We speculated that the dysfunction of the autonomic nervous system derived from neurocristopathy may induce CH associated with HD, and an unknown de novo mutation in the PHOX2B gene may be involved in neurocristopathy which causes both HD and CH, without symptoms of CCHS.
In the present case, the focal lesion of CH could not be detected by MRI and/or US preoperatively, and 18F-DOPA PET could not be performed in our hospital at that time. According to the intraoperative examinations, the focal lesion could be outlined in the pancreatic body and subtotal pancreatectomy was performed at the level of the SMV. The pancreatic anatomy varies, and pancreatectomy at the level of the SMV has been suggested to be 53.5–75% pancreatectomy [1, 16]. If a 53.5–75% pancreatectomy had been ineffective, we would have performed additional pancreatic resection. Fortunately, however, the pathological examination revealed that the focal lesions of CH were all included within the resected specimen, and the patient showed normoglycemia without octreotide after surgery. Although postoperative diabetes mellitus and/or bowel movement disorders were not observed for 12 years after the operation, further follow-up is necessary to detect postoperative complications at an early stage.