ONLINE MUTATION REPORT A 17p11.2 germline deletion in a patient with Smith- Magenis syndrome and neuroblastoma

N euroblastoma is the most frequently occurring extracranial tumour type in children. It arises from the undifferentiated neural crest derived cells destined to become the sympathetic nervous system, and primary tumours typically occur in the adrenal medulla and paraspinal location in the abdomen or chest. At diagnosis, most children of .1 year of age have metastases, commonly in lymph nodes, bones, or bone marrow. However, in addition to potential lethal progression, neuroblastomas occasionally mature into benign ganglioneuromas or spontaneously regress, even without treatment. 2 Several acquired genetic changes have been described in neuroblastoma, the most frequent being MYCN oncogene amplification, 1p deletion, and 17q amplification. These alterations have been associated with aggressive forms of the disease; MYCN amplification in particular is used as a prognostic marker. In addition, chromosome number changes, translocations, and deletions in several other parts of the genome have been identified, but the significance of these changes needs further clarification. A small subset of neuroblastoma cases have a family history of the disease and are diagnosed at a younger age with multifocal primary tumours. Hence Knudson and Strong postulated that the two hit model of cancer initiation could be applied to neuroblastoma, and that the mode of inheritance was consistent with autosomal dominant Mendelian pattern with incomplete penetrance. Some linkage studies have been performed on familial neuroblastomas, and linkage to 4p16 and 16p12-13 has been suggested in families from Europe and North America, respectively. 6 However, the chromosome 16p region was tested for linkage with negative results in Italian and British families. In addition, the known candidate neuroblastoma loci that are frequently altered sporadically have been excluded in some neuroblastoma families. 7 Thus, despite extensive studies into neuroblastoma susceptibility, the putative predisposing genetic changes have remained unidentified, and additional analyses are required to further elucidate the mechanisms behind hereditary neuroblastoma development. We report the genetic analyses of a Finnish girl who was diagnosed with neuroblastoma at the age of 2 years and 10 months. At diagnosis, she had advanced stage neuroblastoma, but with extensive therapy, she was cured of the disease. She was subsequently diagnosed with a psychomotor retardation/multiple congenital anomaly syndrome, SmithMagenis syndrome (SMS), which was confirmed by karyotyping; the patient displayed a 17p11.2 germline deletion, characteristic of this syndrome. Because of the possible association of the neuroblastoma and the germline deletion, 17p11.2 was further evaluated in the patient’s normal tissue DNA by performing microsatellite marker analyses and array comparative genomic hybridisation (CGH). In addition, data from serial analysis of gene expression (SAGE) of neuroblastoma cell lines was analysed to identify those 17p11.2 genes that could have a role in neuroblastoma differentiation pathways. We also analysed sporadic neuroblastomas for loss of heterozygosity (LOH) in the 17p11.2 region.