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Eur J Med Genet. 2017 Jul;60(7):374-379. doi: 10.1016/j.ejmg.2017.04.009. Epub 2017 Apr 13.

A case of splenomegaly in CBL syndrome.

Author information

1
Department of Medical Genetics, University of British Columbia, Vancouver, Canada; British Columbia Children's Hospital Research Institute, Vancouver, Canada.
2
Department of Medical Genetics, University of British Columbia, Vancouver, Canada; British Columbia Children's Hospital Research Institute, Vancouver, Canada; Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, Canada; Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada; Institute of Physiology and Biochemistry, Faculty of Biology, The University of Belgrade, Belgrade, Serbia.
3
Department of Medical Genetics, University of British Columbia, Vancouver, Canada; British Columbia Children's Hospital Research Institute, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada.
4
Department of Medical Genetics, University of British Columbia, Vancouver, Canada; British Columbia Children's Hospital Research Institute, Vancouver, Canada; Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, Canada; Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada.
5
British Columbia Children's Hospital Research Institute, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada; Division of Pediatric Hematology, Oncology, and Bone Marrow Transplantation, B.C. Children's Hospital and University of British Columbia, Vancouver, Canada.
6
British Columbia Children's Hospital Research Institute, Vancouver, Canada; Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, Canada; Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada; Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address: cvankarnebeek@cw.bc.ca.

Abstract

INTRODUCTION:

We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting.

CLINICAL REPORT:

A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid erythropoiesis and borderline fibrosis. There were no haematological cytogenetic anomalies or other haematological pathology to explain the splenomegaly. Metabolic testing and chromosomal microarray were unremarkable. Trio whole-exome sequencing (WES) identified a pathogenic de novo heterozygous germline CBL variant (c.1111T > C, p.Y371H), previously reported to cause CBL syndrome and implicated in development of juvenile myelomonocytic leukemia (JMML).

DISCUSSION:

CBL syndrome (more formally known as "Noonan-syndrome-like disorder with or without juvenile myelomonocytic leukemia") has overlapping features to Noonan syndrome with significant variability. CBL syndrome and other RASopathy disorders-including Noonan syndrome, neurofibromatosis 1, and Costello syndrome-are important to recognize as these are associated with a cancer-predisposition. CBL syndrome carries a very high risk for JMML, thus accurate diagnosis is of utmost importance. The diagnosis of CBL syndrome in this patient would not have been possible based on clinical features alone. Through WES, a specific genetic diagnosis was made, allowing for an optimized management and surveillance plan, illustrating the power of genomics in clinical practice.

KEYWORDS:

Case report; Genomics; Myelomonocytic leukemia; RASopathies; Splenomegaly; Whole exome sequencing

PMID:
28414188
DOI:
10.1016/j.ejmg.2017.04.009
[Indexed for MEDLINE]

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