Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An
Example of How Genomics Is Changing the Clinical Diagnostic Paradigm
#MMPMID28589114
Seaby EG
; Gilbert RD
; Andreoletti G
; Pengelly RJ
; Mercer C
; Hunt D
; Ennis S
Front Pediatr
2017[]; 5
(?): 113
PMID28589114
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CBL is a tumor suppressor gene on chromosome 11 encoding a multivalent adaptor
protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant.
Pathogenic de novo mutations result in a phenotype that overlaps Noonan syndrome
(1). Some patients with CBL mutations go on to develop juvenile myelomonocytic
leukemia (JMML), an aggressive malignancy that usually necessitates bone marrow
transplantation. Using whole exome sequencing methods, we identified a known
mutation in CBL in a 4-year-old Caucasian boy with atypical hemolytic uremic
syndrome, moyamoya phenomenon, and dysmorphology consistent with a mild
Noonan-like phenotype. Exome data revealed loss of heterozygosity across
chromosome 11q consistent with JMML but in the absence of clinical leukemia. Our
finding challenges conventional clinical diagnostics since we have identified a
pathogenic variant in the CBL gene previously only ascertained in children
presenting with leukemia. The increasing affordability of expansive sequencing is
likely to increase the scope of clinical profiles observed for previously
identified pathogenic variants and calls into question the interpretability and
indications for clinical management.
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