ID #18 CHD7-associated CHARGE Syndrome and a spinal schwannoma with a SH3PXD2A::HTRA1 fusion: A case report

Background

CHARGE syndrome is a genetic malformation disorder with a wide range of phenotypes. Most commonly, the syndrome is characterized by colobomas, heart disease, choanal atresia, growth delay, intellectual disabilities, genital anomalies, and ear malformations.[1] It is associated with CHD7 gene mutations.[2]The CHD7 gene is part of the chromodomain helicase deoxyribonucleic acid-binding protein family and helps to regulate chromatin organization, which is key for the development of organ systems.[2] Alterations of the CHD7 gene are not classified as a cancer predisposition syndrome, though changes in the gene are reported to be oncogenic.[3] Despite this, CHARGE syndrome is not commonly associated with tumors or malignancies. Schwannomas are benign peripheral nerve sheath tumors, which have genetic drivers outside of associations with NF2-related schwannomatosis, including CHD7::VGLL3 and SH3PXD2A::HTRA1 fusions.[4-6]

Case

We are reporting on a case of a 19-year-old male with CHARGE syndrome who developed a spinal schwannoma. His presentation was characterized by worsening pain and weakness over 6 months. An MRI identified a 3cm3 mass at the level of thoracic spine vertebrae T10 and T11, which was resected. A SH3PXD2A::HTRA1 fusion was identified, which is a novel finding in the setting of CHD7-mutated CHARGE syndrome. Post-operative surveillance imaging has been stable for 4 years.

Conclusion

VGLL3 is a common rearrangement in hybrid schwannoma-perineuriomas, including fusions of CHD7::VGLL3.[7] The SH3PXD2A::HTRA1 fusion, which acts to promote tumorigenesis and cell proliferation likely via the MEK-ERK pathway, is a relatively recent finding.[5,8] In some preclinical studies, the growth of fusion-positive cells was suppressed by a MEK inhibitor.[5] The hope is that ultimately, the fusion could serve as a therapeutic target. Further research is important to better understand the identified SH3PXD2A::HTRA1 fusion and its implications for schwannomas and CHARGE syndrome, specifically the possible need for routine cancer surveillance and the possibility of targeted treatments.

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