Multifocal Neuroblastoma and Central Hypoventilation in An Infant with Germline <i>ALK</i> F1174I Mutation
Anna Djos,
Diana Treis,
Susanne Fransson,
Lena Gordon Murkes,
Sandra Wessman,
Jurate Ásmundsson,
Agneta Markström,
Per Kogner,
Tommy Martinsson
Affiliations
Anna Djos
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
Diana Treis
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, and Pediatric Oncology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, 141 86 Stockholm, Sweden
Susanne Fransson
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
Lena Gordon Murkes
Department of Pediatric Radiology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, 141 86 Stockholm, Sweden
Sandra Wessman
Department of Clinical Pathology, Karolinska University Hospital, 141 86 Stockholm, Sweden
Jurate Ásmundsson
Pathology Department, Landspitali University Hospital, 101 Reykjavík, Iceland
Agneta Markström
Pediatric Neurology, Department of Women’s and Children’s Health, Karolinska Institute, 171 77 Stockholm, Sweden
Per Kogner
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, and Pediatric Oncology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, 141 86 Stockholm, Sweden
Tommy Martinsson
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic neuroblastoma. Sanger sequencing of ALK and PHOX2B, SNP microarray of three tumor samples and whole genome sequencing of tumor and blood were performed. Genetic testing revealed a germline ALK F1174I mutation that was present in all tumor samples as well as in normal tissue samples from the patient. Neither of the patient’s parents presented the ALK variant. Array profiling of the three tumor samples showed that two of them had only numerical aberrations, whereas one sample displayed segmental alterations, including a gain at chromosome 2p, resulting in two copies of the ALK-mutated allele. Whole genome sequencing confirmed the presence of the ALK variant and did not detect any aberrations in the coding or promotor region of PHOX2B. This study is to our knowledge the first to report a de novoALK F1174I germline mutation. This may not only predispose to congenital multifocal neuroblastoma but may also contribute to the respiratory dysfunction seen in this patient.
