An 18-month-old boy presents to the emergency department with a 3-month history of diarrhea and 1 month of weight loss. He was in his usual state of health until 3 months earlier when he began having liquid stools approximately 4 times a day. The stools have increased in frequency, and at the time of presentation he is having up to 20 stools per day. They are reported to be watery, nonbloody, and nonfrothy. Parents deny fever, sick contacts, recent travel, or ingestion of raw meat or unpasteurized dairy products. Oral intake has been unchanged; he eats a varied diet that includes small amounts of juice and occasional cow milk. He was seen by his pediatrician 2 months earlier for a similar complaint and was trialed on a lactose-free diet without improvement. Stool testing was negative for ova and parasites, Giardia, and fecal occult blood.Physical examination is notable for a well-appearing but thin toddler with extremity wasting. His weight is 22.3 lb (10.1 kg) (8th percentile), down from 26.5 lb (12 kg) (72nd percentile) 10 weeks ago. He is afebrile with normal vital signs, moist mucous membranes, and normal skin turgor. His abdomen is distended but soft, without appreciable mass or hepatosplenomegaly. He has an erythematous diaper rash surrounding the gluteal cleft. The remainder of his examination findings are normal. Initial laboratory tests are significant for a serum sodium level of 129 mEq/L (129 mmol/L), potassium level of 2.2 mEq/L (2.2 mmol/L), chloride level of 94 mEq/L (94 mmol/L), and bicarbonate level of 12 mEq/L (12 mmol/L). Complete blood cell count, C-reactive protein level, and erythrocyte sedimentation rate are normal. Human immunodeficiency virus screen, celiac antibody profile, and gastrointestinal viral panel are negative. Stool culture grows normal flora. Abdominal radiograph is normal, and upper and lower endoscopy is grossly normal. Further laboratory and imaging studies reveal the diagnosis.Diarrhea is defined as the passage of 3 or more loose or liquid stools in a 24-hour period (or more frequent passage than normal for the individual) and can be further defined based on the duration of symptoms. Although these definitions may vary among authors, those provided by the World Health Organization are the most commonly used according to a systematic review by Johnston et al. (1) According to the World Health Organization guidelines, acute diarrhea lasts several hours to days, and persistent or chronic diarrhea is defined as lasting 14 days or longer. (2) In addition, some authors use the term prolonged diarrhea to describe an episode of diarrhea that lasts 7 days or more but less than 14 days. (3)Although acute diarrhea is usually due to self-limited infections, chronic diarrhea may encompass many other diagnoses. A thorough history and examination can narrow the differential diagnosis and help guide further diagnostics. For example, a detailed dietary history may reveal excessive juice intake, which can contribute to functional diarrhea (or toddler’s diarrhea) due to poor absorption of carbohydrates. A history of chronic diarrhea in any child on a gluten-containing diet warrants screening for celiac disease given the relatively high prevalence, approximately 0.5% to 1% in the United States. (4) Persistent diarrhea after an episode of acute gastroenteritis suggests a postinfectious diarrhea due to mucosal injury and transient lactose intolerance. A history of diarrhea since birth raises suspicion for congenital diarrheas and enteropathies, a group of rare but severe inherited enteropathies that typically present in the neonatal period. The presence of weight loss or poor weight gain is concerning for a malabsorptive process such as celiac disease, cystic fibrosis, exocrine pancreatic insufficiency, and bile acid malabsorption or, especially in the presence of bloody stools, inflammatory bowel disease. Anal fissures and soiled underwear may be due to constipation with overflow incontinence. An itchy vesicular rash may represent dermatitis herpetiformis, which, although rare in children, is the most common skin manifestation of celiac disease.To help guide diagnostics and management, diarrhea can be classified by its mechanism: osmotic, secretory, inflammatory, or motility abnormality (Table 1). A 24-hour fast with intravenous hydration may be necessary to identify osmotic (or substrate-induced) diarrhea, with resolution of the diarrhea on fasting. Continuation of the diarrhea during fasting suggests a secretory pathophysiology. Stool osmotic gap can also help distinguish between osmotic and secretory diarrhea:Stool osmotic gap (mOsm/kg) = stool osmolality (mOsm/kg) − (2*[Stool Na (mEq/L) + stool K (mEq/L)])If the osmotic gap is greater than 100 mOsm/kg, the diarrhea is osmotic in nature. If the osmotic gap is less than 100 mOsm/kg, the diarrhea is presumed to be secretory.Because our patient continued to have profuse watery stools during a prolonged period of fasting while hospitalized, his diarrhea was categorized as secretory. Certain infections are known to cause secretory diarrhea, including cholera, enterotoxic Escherichia coli, Clostridium difficile, and cryptosporidiosis. However, no pathogens were identified on stool culture or ova and parasite examination, making an infectious etiology less likely. Although rare, immunoregulatory defects such as agammaglobulinemia, isolated immunoglobulin A deficiency, and IPEX (immune dysregulation, polyendocrinopathy and enteropathy, X-linked) syndrome, a disorder caused by mutations in the FOXP3 gene leading to regulatory T-cell dysfunction, were considered. Congenital diarrheas such as congenital chloride deficiency typically present in infancy, but milder forms may present at an older age, so these remained on the differential diagnosis. (6) Finally, given the chronicity and severity of the patient’s diarrhea, a neuroendocrine tumor was highly suspected.Oncology was consulted and laboratory studies were sent to screen for a neuroendocrine tumor, including those listed in Table 2. These laboratory tests were significant for an elevated plasma dopamine level of 422 pg/mL (2,755 pmol/L) (reference range, 0–20 pg/mL [0–131 pmol/L]) and an elevated plasma vasoactive intestinal peptide (VIP) level of 222 pg/mL (65.7 pmol/L) (reference range, <75 pg/mL [<22.2 pmol/L]). Neuron-specific enolase (NSE) and urine homovanillic acid levels were also elevated. Urine vanillylmandelic acid, plasma metanephrine, and gastrin levels were normal. Abdominal ultrasonography revealed a mass in the right lower quadrant, prompting a computed tomographic scan of the abdomen and pelvis, which confirmed a 7.8 × 3.0 × 3.7–cm retroperitoneal mass with internal calcifications (Fig). He was taken to the operating room for gross total resection of the mass. Surgical pathology confirmed a diagnosis of ganglioneuroblastoma.Neuroblastoma is a term often used generically to describe a spectrum of neuroblastic tumors, ranging from neuroblastoma (the most immature and undifferentiated) to ganglioneuroma (the most mature and differentiated). Ganglioneuroblastoma lies in the middle, as it has both mature gangliocytes and immature neuroblasts. These tumors arise from primitive sympathetic ganglion cells and are distinguished by their ability to synthesize and secrete catecholamines.These tumors can arise wherever sympathetic tissue exists. The most common site is the adrenal gland (40%), followed by abdominal, thoracic, cervical, and pelvic sympathetic ganglia. Symptoms vary based on tumor site and extent. Patients with localized disease may be asymptomatic, and children with metastatic disease may have more pronounced symptoms, such as abdominal pain, abdominal mass, “raccoon eyes” (periorbital ecchymosis from metastases), Horner syndrome (if the cervical paravertebral sympathetic chain is involved), hypertension, fever, and weight loss. Several paraneoplastic syndromes have been associated with neuroblastoma, including opsoclonus-myoclonus syndrome and, as in this patient, secretion of VIP. VIP secretion is quite rare and more often associated with the more mature neuroblastic tumors, namely, ganglioneuroblastomas and ganglioneuromas, than with neuroblastomas. (7)VIP has many functions in the body, including stimulation of intestinal mucus secretion, vasodilation of the splanchnic and systemic vessels, and inhibition of gastric secretion. Patients with a VIP-secreting ganglioneuroblastoma typically present with watery diarrhea, hypokalemia, and achlorhydria syndrome. However, because it is quite rare for patients with a neuroblastoma to present with diarrhea as the main symptom, diagnosis is often delayed. As described in a variety of case reports, time from diarrhea initiation to diagnosis can range from 4 months to 1 year, indicating how difficult it can be to diagnose. (7)(8)(9)(10) For example, Leleiko et al (11) describes the case of an 18-month-old girl who had 6 months of watery diarrhea before being diagnosed as having a VIP-secreting ganglioneuroma. The mainstay of treatment is complete surgical resection, with subsequent symptom resolution and good prognosis.After tumor resection, the patient’s diarrhea resolved and electrolyte levels stabilized. His plasma dopamine and VIP levels returned to normal, and his NSE level decreased. A meta-iodobenzylguanidine scan was obtained in addition to a chest computed tomographic scan and confirmed lack of metastases. The final pathology was consistent with ganglioneuroblastoma, nodular subtype, N-Myc nonamplified status. He continues to be followed with surveillance examinations, tumor markers (serum catecholamines, VIP, and NSE), and serial imaging. One and a half years later, he has remained asymptomatic with excellent weight gain.