The following may be noted in patients with neuroblastoma:
Signs and symptoms of neuroblastoma vary with site of presentation. Generally, symptoms include abdominal pain, emesis, weight loss, anorexia, fatigue, and bone pain. Hypertension is an uncommon sign of the disease and is generally caused by renal artery compression, not catecholamine excess. Chronic diarrhea is a rare presenting symptom secondary to tumor secretion of vasoactive intestinal peptide secretion.
Because more than 50% of patients present with advanced stage disease, usually to the bone and bone marrow, the most common presentation includes bone pain and a limp. However, patients may also present with unexplained fever, weight loss, irritability, and periorbital ecchymosis secondary to metastatic disease to the orbits. The presence of bone metastases can lead to pathologic fractures.
Approximately two thirds of patients with neuroblastoma have abdominal primaries. In these circumstances, patients can present with an asymptomatic abdominal mass that usually is discovered by the parents or a caregiver. Symptoms produced by the presence of the mass depend on its proximity to vital structures and usually progress over time.
Tumors that arise from the paraspinal sympathetic ganglia can grow through the spinal foramina into the spinal canal and impinge on the spinal cord. This may result in the presence of neurologic symptoms, including weakness, limping, paralysis, and even bladder and bowel dysfunction.
Thoracic neuroblastomas (posterior mediastinum) may be asymptomatic and are usually diagnosed by imaging studies obtained for other reasons. Presenting signs or symptoms may be insignificant and involve mild airway obstruction or chronic cough, leading to chest radiography.
Thoracic tumors extending to the neck can produce Horner syndrome. Primary cervical neuroblastoma is rare but should be considered in the differential diagnosis of masses of the neck, especially in infants younger than 1 year with feeding or respiratory difficulties.
In a small proportion of infants younger than 6 months, neuroblastoma presents with a small primary tumor and metastatic disease confined to the liver, skin, and bone marrow (stage 4S). If this type of tumor develops in neonates, skin lesions may be confused with congenital rubella, and, if the patient has severe skin involvement, the term "blueberry muffin baby" may be used.
Approximately 2% of patients present with opsoclonus and myoclonus a paraneoplastic syndrome characterized by the presence of myoclonic jerking and random eye movements. These patients often have localized disease and a good long-term prognosis. Unfortunately, the neurologic abnormalities can persist or progress and can be devastating.
Finally, intractable diarrhea is a rare paraneoplastic symptom and is associated with more differentiated tumors and a good prognosis.
The following may be noted in patients with neuroblastoma:
Children are usually referred to a pediatric oncologist by primary care providers who have identified a persistent unexplained symptom or sign, either upon physical examination or based on screening test findings.
In patients with suspected neuroblastoma, performing a thorough examination with careful attention to vital signs (eg, blood pressure), neck, chest, abdomen, skin, and nervous system is essential.
Metastatic lesions of the skin are common in infants younger than 6 months and may represent stage 4S disease.
Examination of the abdomen may reveal an abdominal mass, leading to the appropriate workup.
Neurologic examination may reveal Horner syndrome. In the case of dumbbell tumors, compression of the spinal cord may produce lower extremity weakness or paraplegia. Patients with neurologic involvement by tumor should be treated emergently, secondary to the risk of permanent neurologic sequelae.
The cause of neuroblastoma is unknown, and no specific environmental exposure or risk factors have been identified.
Because of young age of onset with this disease, investigators have focused on events before conception and during gestation.
According to SEER data, factors investigated for which evidence is limited or inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol or tobacco use, and paternal occupational exposures.
The vast majority of neuroblastoma arises sporadically without family history of the disease. However, 1-2% of newly diagnosed cases do have a family history of neuroblastoma. Patients with familial neuroblastoma often present at earlier age or with several distinct primary tumors.
Neuroblastoma has been known to occur in the setting of other disorders that are linked to abnormal development of neural crest tissues, such as Hirschsprung disease or central congenital hypoventilation syndrome. Genome-wide analysis of neuroblastoma from these rare familial cases has identified a genetic defect involved in these cases. Cases of neuroblastoma that accompany other congenital abnormalities of the neural crest have been associated with a germline mutation in PHOX2B. This gene is a homeobox gene that acts as a regulator of autonomic nervous system development.
In familial neuroblastoma cases that are not associated with other congenital disorders of neural crest development, ALK mutations have been identified in the germline.  These mutations largely occur in the kinase domain causing activation of ALK signaling. Efforts are ongoing to investigate the incidence of ALK mutations across all subsets of neuroblastoma, but initial evidence indicates that somatic mutations of the ALK gene are also present in some cases of sporadic neuroblastoma.
A 2014 study reported that deep-sequencing techniques can identify new ALK mutations at relapse of neuroblastoma, suggesting that patients would benefit from repeated tumor sampling. 
De Brouwer et al illustrate the occurrence of the ALK mutation specifically in neuroblastomas. Although they studied a small proportion of cases, mutations were found in similar frequencies in favorable and unfavorable outcome cases. The F1174L mutant was found more frequently in the poor outcome subgroup.  This example illustrates the heterogeneity of cancer and the likely possibility that targeted therapies to the ALK gene may be of benefit in a subset of ALK cancers, which may possibly include a small subset of MYC -amplified neuroblastomas. The challenge for drug development in neuroblastoma is to identify upfront high-risk cases that may benefit from ALK -directed therapy.
Genome-wide association studies (GWAS) have been used to discover numerous genetic variations associated with neuroblastoma. Variations in LMO1, BARD1, and FLJ22536 have all been associated with aggressive forms of neuroblastoma. [12, 13, 14] Genomic variations within DUSP12, DDX4, IL21RA, and HSD17B12 are associated with low-risk forms of neuroblastoma. 
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