Germline Mutation of <i>CBL</i> Is Associated With Moyamoya Disease in a Child With Juvenile Myelomonocytic Leukemia and Noonan Syndrome‐Like Disorder

Hyakuna, Nobuyuki; Muramatsu, Hideki; Higa, Takeshi; Chinen, Yoshiaki; Wang, Xinan; Kojima, Seiji

doi:10.1002/pbc.25271

Cited by 37 publications

(27 citation statements)

References 14 publications

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“…Arita et al () described a 14‐year‐old Japanese boy that was incidentally diagnosed with thalamic glioblastoma during a radiological follow‐up after a surgical treatment for MMS. A more recent report described a patient with MMD that carried a germline CBL mutation, and had juvenile myelomonocytic leukemia and neovascular glaucoma (Hyakuna et al, ). Thus, other genetic factors, in addition to NF1 , might explain the cancer association, and might also play a role in MMS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Moyamoya syndrome in children with neurofibromatosis type 1: Italian–French experience

Santoro

Rocco

Kossorotoff

et al. 2017

American J of Med Genetics Pt A

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Moyamoya syndrome (MMS) is the most common cerebral vasculopathy among children with neurofibromatosis type 1 (NF1). In this study, we clinically, radiologically, and genetically examined a cohort that was not previously described, comprising European children with NF1 and MMS. The NF1 genotyping had been registered. This study included 18 children. The mean age was 2.93 ± 3.03 years at the NF1 diagnosis and 7.43 ± 4.27 years at the MMS diagnosis. In seven patients, MMS was diagnosed before or at the same time as NF1. Neuroimaging was performed in 10 patients due to clinical symptoms, including headache (n = 6), cerebral infarction (n = 2), and complex partial seizures (n = 2). The remaining eight children (47%) had MMS diagnosed incidentally. Sixteen children were characterized molecularly. The features of MMS were similar between patients with and without NF1. Additionally, the NF1 phenotype and genotype were similar between children with and without MMS. Interestingly, three children experienced tumors with malignant histology or behavior. The presence of two first cousins in our cohort suggested that there may be potential genetic factors, not linked to NF1, with an additional role respect of NF1 might play a role in MMS pathogenesis. The incidental diagnosis of MMS, and the observation that, among children with NF1, those with MMS were clinically indistinguishable from those without MMS, suggested that it might be worthwhile to add an angiographic sequence to brain MRIs requested for children with NF1. A MMS diagnosis may assist in properly addressing an NF1 diagnosis in very young children who do not fulfill diagnostic criteria.

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Section: Discussionmentioning

confidence: 99%

Moyamoya syndrome in children with neurofibromatosis type 1: Italian–French experience

Santoro

Rocco

Kossorotoff

et al. 2017

American J of Med Genetics Pt A

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“…First, they were both referred for a haematological condition strongly suggestive of a CBL mutation. One of them had a JMML, in addition to dysmorphic features suggestive of Noonan syndrome 26. The second one was referred for the association of splenomegaly, mild monocytosis and juvenile xanthogranuloma 22.…”

Section: Discussionmentioning

confidence: 99%

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy

et al. 2017

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“…Germline CBL mutations have been associated with Noonan-like syndrome, moyamoya, and vasculitis (12). Our patient displays many of the phenotypic features consistent with germline CBL mutations.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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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Germline Mutation of CBL Is Associated With Moyamoya Disease in a Child With Juvenile Myelomonocytic Leukemia and Noonan Syndrome‐Like Disorder

Cited by 37 publications

References 14 publications

Moyamoya syndrome in children with neurofibromatosis type 1: Italian–French experience

Moyamoya syndrome in children with neurofibromatosis type 1: Italian–French experience

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy

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

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