Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

Abstract

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.

Somatic variants as a cause of drug‐resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis

“…37 The reported germline phenotype includes developmental delay as in our patient, but with focal epilepsy secondary to moyamoya phenomenon and an abnormal MRI scan as well as an atypical hemolytic uremic syndrome (not observed in our patient). 37 ALG13 is an established cause of developmental and epileptic encephalopathy under a germline model. ALG13 is a glycosylation gene that inhibits N-glycosylation, a similar action to SLC35A2.…”

“…The variant is currently absent from germline databases. This being a gene with a known seizure phenotype when observed in the germline, 37 and a gene associated with cancer in the somatic state, 35,36 we hypothesize that this gene may cause epilepsy under somatic as well as germline models, albeit with a different epilepsy phenotype than reported to date for germline CBL variants 37 . The reported germline phenotype includes developmental delay as in our patient, but with focal epilepsy secondary to moyamoya phenomenon and an abnormal MRI scan as well as an atypical hemolytic uremic syndrome (not observed in our patient) 37 …”

Somatic CBL mutation presenting as juvenile myelomonocytic leukemia with vasculitis

“…A report of atypical hemolytic uremic syndrome and CBL mutation suggested an endothelial component as a mechanism of vasculitis. 6 However, vasculitis in our patient with somatic CBL mutation indicates the immune mechanism of vasculitis driven by a dysregulated immune system 7 rather than an endothelial component. It is interesting to note that our patient also had vasculitis involving renal arteries and renal vasculature that is primarily involved in thrombotic microangiopathy.…”

Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants

“…Some patients with JMML due to germline CBL mutations experiencing spontaneous resolution of the myeloproliferative/myelodysplastic disorder have been reported to develop different types of cardiovascular manifestations, including hypertension, cardiomyopathy, Moyamoya disease and Takayasu arteritis [ 6 , 44 ]. Moyamoya disease has also been described in patients harboring de novo CBL mutations [ 10 ], and in CBL syndrome without JMML [ 45 ]. On the contrary, individuals with JMML and homozygous CBL mutations who undergo HSCT seem not to develop vasculitis, suggesting that a normal immune/hematopoietic system could be pivotal in preventing these manifestations [ 6 ].…”