CHRISTINA L. MASTER
HISTORY OF PRESENT ILLNESS
The patient is a 15-month-old boy who presents with watery diarrhea for the last 3 months associated with weight loss. At 12 months of age he developed diarrhea characterized by six to eight watery brown stools per day accompanied by significant flatulence. There was no associated emesis or blood in the stool. He continued to have a good appetite despite frequent stooling. Dietary changes including bananas, rice, apples, toast diet (BRAT diet) as well as a lactose-free diet were introduced, without any improvement in the diarrhea. Occasional low-grade fevers were noted. There was no history of foreign travel or ill contacts. There are two cats and one dog in the home. He has lost three pounds in the last 3 months.
The boy was a full-term infant with a birth weight of 3900 g who was fed cow’s milk-based commercial formula without any problems. He had normal weight gain and developmental milestones. He was introduced to rice cereal, baby foods, and adult table foods without any problems. He was taking no medications.
T 36.8°C; RR 26/min; HR 100 bpm; BP 102/53 mmHg
Weight below 5th percentile; 50th percentile for a 6-month old; Height 10th percentile
The initial examination revealed a quiet, gaunt-appearing child. His eyes were sunken but the rest of the head, eyes, ears, nose, mouth, and throat examination was unremarkable. His cardiac and respiratory examinations were normal. His abdominal examination revealed no masses; his liver edge was palpable at the right costal margin. There was no clubbing of his fingers. He had dry skin around his nose and lips. He had very little subcutaneous fat. His neurologic examination was nonfocal.
Laboratory analysis revealed 11 100 WBCs/mm3 with 29% segmented neutrophils, 66% lymphocytes, 5% monocytes. The hemoglobin was 12.2 g/dL and there were 492 000 platelets/mm3. Electrolytes were significant for serum potassium of 2.8 mmol/L, serum bicarbonate 16 mmol/L. His erythrocyte sedimentation rate was 4 mm/h. Urinalysis was negative with a urine specific gravity of 1.005. Serum alkaline phosphatase was low at 115 U/L, while alanine aminotransferase was elevated at 59 U/L, aspartate aminotransferase at 64 U/L, and lactate dehydrogenase at 845 U/L.
COURSE OF ILLNESS
The patient was admitted and started on hyperalimentation for his nutritional status and to correct his hypokalemia. Blood culture and stool culture were both negative. A sweat test was normal. Stool sample tested negative for Clostridium difficile toxins. Stool for ova and parasites revealed Indian meal moth larvae. Colonoscopy was performed on the sixth day of hospitalization that revealed nonspecific lymphoid hyperplasia. Despite taking nothing by mouth, he continued to have mucousy diarrhea which became heme positive. Stool osmolality was normal at 298 mOsm/kg H2O. Chest radiograph (Figure 17-4) suggested a diagnosis that was confirmed by biopsy.
FIGURE 17-4. Chest radiograph similar to that of the patient’s. (Reproduced, with permission, from Swischuk LE. Imaging of the Newborn, Infant, and Young Child. 4th ed. Baltimore: Williams & Wilkins; 1997, p. 144.)
DISCUSSION CASE 17-4
The chronic nature of his diarrhea for the last 3 months, associated with weight loss, moves the differential diagnosis away from the diagnosis of acute infectious diarrhea, due to either bacterial or viral causes. A prolonged bout of postinfectious diarrhea due to disaccharidase deficiency is possible, but unlikely. Chronic diarrhea due to infection with C. difficile or ova and parasites is a possibility even without history of antibiotic use, bloody diarrhea, foreign travel, or use of untreated water sources. The key observation in making this diagnosis occurred while in the hospital: the patient took nothing by mouth but continued to produce profuse voluminous watery diarrhea. This finding indicates the presence of secretory, rather than osmotic, diarrhea. In this differential diagnosis, the list is rather brief, including rare congenital and paraneoplastic conditions. Congenital defects in chloride or sodium transport are more likely to present in infancy. Infectious causes of secretory diarrhea include small bowel overgrowth or infection with immunoadherent Escherichia coli stimulating gastrointestinal secretions. Any cause of villous atrophy, whether congenital, autoimmune, or secondary to immune deficiency, such as severe combined immunodeficiency (SCID) or HIV may also present with this picture. Neuroblastoma, or other tumors of neural crest origin, such as ganglioneuroma, may secrete vasoactive intestinal peptide, resulting in secretory diarrhea.
Chest radiograph revealed a large posterior mediastinal mass (Figure 17-4). Computed tomography of the chest performed on the seventh day of hospitalization confirmed a 4 cm × 4 cm right posterior mediastinal mass. The urine vanillylmandelic acid level was 498 mg/g of creatinine and the homovanillic acid level was 245 mg/g of creatinine, which were both extremely elevated. Surgical excision revealed neuroblastoma with a favorable histology. These findings were consistent with the diagnosis of neuroblastoma causing secretory diarrhea.
INCIDENCE AND EPIDEMIOLOGY OF NEUROBLASTOMA
The incidence of neuroblastoma is approximately eight per million per year in children younger than 15 years of age. The median age at diagnosis is 22 months and 95% of cases are usually diagnosed by the age of 10 years. Neuroblastoma accounts for approximately 6% of all pediatric tumors. There is a slight male preponderance with a boy:girl ratio of 1.2:1. There also appear to be familial cases, which present at a younger age (median age, 9 months). These tumors derive from postganglionic sympathetic cells found in the paraspinal sympathetic ganglia and the adrenal chromaffin cells. Neuroblastoma and ganglioneuroblastoma represent the malignant forms of these neural crest tumors, while ganglioneuroma represents the most benign form, with no metastatic potential. The primary tumor is located in the abdomen in most (approximately two-thirds) children with neuroblastoma.
Most pediatric patients with neuroblastoma are diagnosed by 5 years of age and most are intraabdominal in location. Signs and symptoms as well as outcomes vary with the site of presentation. Patients diagnosed in the first year of life have a higher incidence of intrathoracic and cervical tumors compared with those diagnosed after 1 year of age. Seventy-five percent of cases in children older than 1 year of age present with a disseminated advanced stage of disease; children presenting at this late stage account for a significant proportion of neuroblastomaassociated mortality. Infants younger than 1 year tend to present with lower stage disease, resulting in high cure rates. Some tumors in this latter group even undergo spontaneous regression. One percent of patients will have no detectable primary tumor. Neuroblastoma metastases occur in 35% of children to the regional lymph nodes which then qualifies as disseminated disease. Hematogenous spread to bone, bone marrow, liver, and skin also occurs. Late metastases are seen in the brain and lung. Patients may present with a large abdominal mass or respiratory distress secondary to the intraabdominal mass. Intrathoracic tumors are often incidentally found. Opsoclonus-myoclonus is a well-defined but uncommon presenting syndrome for neuroblastoma; fewer than 2% of cases present with opsoclonus-myoclonus syndrome. Presentation as severe secretory diarrhea, as in the case of our patient, is known as Verner-Morrison syndrome.
Clinical observation. The observation of continued, intractable watery diarrhea while the patient takes nothing by mouth is key to the ultimate diagnosis. Whether this is accomplished by obtaining a very thorough history or by observation while in the hospital, this piece of information is vital to making the ultimate diagnosis.
Radiographs. Radiographs may localize calcifications and often provide the first indication of the presence of such a tumor as an incidental finding. Skeletal surveys may show bone involvement and are used in tumor staging.
Computed tomography or magnetic resonance imaging. Three-dimensional imaging more accurately delineates the location of the tumor, which is usually retroperitoneal or adrenal and also assists in staging. Occasionally, tumors may be found along the sympathetic chain in the thoracic or cervical region.
Vasoactive intestinal peptide level. Elevated plasma vasoactive intestinal peptide levels may be elaborated by tumors of neural crest origin and may cause secretory diarrhea.
Urinary (or serum) catecholamine levels. Elevation of urinary homovanillic or vanillylmandelic acid in conjunction with diagnostic pathologic features is diagnostic of neuroblastoma. These levels may also be used to follow disease activity.
Surgical removal. Complete surgical excision provides a pathologic specimen for further identification and characterization of the tumor and is also therapeutic, especially with regard to the secretory diarrhea. It is also important in the staging process, especially in assessing lymph node involvement.
Bone scintigraphy. A bone scan is important in detecting possible metastases and is used in the staging process.
Radionuclide scan. Radiolabeled metaiodobenzylguanidine is taken up by catecholamine-secreting cells and is useful for staging in detecting bone and soft tissue involvement.
Surgical resection is usually performed in all patients. Low-risk patients may not need any additional therapy. Radiotherapy and chemotherapy are used depending on the stage of the disease. Patients with high-risk disease may have some improvement in short-term survival with autologous bone marrow transplantation, but longer term outcome is still poor. Surgical removal of the tumor usually cures the secretory diarrhea. The use of somatostatin analogs also has a therapeutic effect on the secretory diarrhea, but the definitive therapy for the diarrhea remains surgical removal of the primary tumor.
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