Mosaic copy number variation in a patient with cerebral and pulmonary arteriovenous malformations and recurrent epistaxis

Summary

https://doi.org/10.1093/clinchem/hvae101

A 45-year-old female presented to internal medicine for evaluation and treatment of a cerebral arteriovenous malformation (AVM) with associated partial seizures.

Student Discussion

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Sharri S. Cyrus, Michelle L. Kluge, Cherisse A. Marcou, Erik C. Thorland, Vivek N. Iyer, and Linnea M. Baudhuin

Case Description

A 45-year-old female presented to internal medicine for evaluation and treatment of a cerebral arteriovenous malformation (AVM) with associated partial seizures. The patient reported her first seizure in the year prior to presentation and subsequent brain imaging confirmed the presence of an inferior right temporal cerebral AVM roughly 2.5 cm in diameter. She subsequently underwent definitive treatment of the AVM in a staged manner with initial partial coil embolization and stereotactic guided Gamma Knife radiosurgery performed 1 month later.

In addition to cerebral AVM, her medical history was significant for spontaneous and recurrent nosebleeds (epistaxis) since childhood. Epistaxis occurred multiple times a day with each episode lasting approximately 5 min and not typically gushing in nature. Her epistaxis severity score was calculated at 5.25 (moderate epistaxis severity) and she had previously received multiple nasal cautery treatments. Nasal examination demonstrated significant generalized erythema and anterior rhinoscopy showed bilateral nasal telangiectasias that were treated with bipolar cauterization. Additional telangiectasias were noted, one each on the tip of her tongue and her lower lip.

During the preoperative work-up for possible surgery of the cerebral AVM, a chest X-ray showed nodular densities, suggestive of pulmonary AVMs. Further pulmonary function testing showed normal spirometry values with a reduced diffusion capacity. Subsequent computed tomography (CT) pulmonary angiography showed 2 adjacent middle lobe AVMs and she underwent 2 successful embolization procedures. Notably no other AVMs were found by abdominal CT.

The presence of spontaneous and recurrent epistaxis, along with mucocutaneous telangiectasias and the AVMs noted in her brain and lung, raised the possibility of hereditary hemorrhagic telangiectasia (HHT). A detailed family history obtained was notable for the absence of epistaxis or other manifestations of HHT in her parents (both of whom were deceased at the time of her presentation) as well as her 6 siblings. A blood sample was obtained and an external HHT and a vascular malformation next-generation sequencing (NGS) gene panel was ordered interrogating the genes ACVRL1, ENG, EPHB4, GDF2, RASA1, and SMAD4, but the results were negative. A subsequent in-house gene panel was ordered: the Mayo Clinic HHT and Vascular Malformation Gene Panel, which interrogated the genes outlined previously in addition to BMPR2, CCM2, GLMN, KRIT1, PDCD10, and TEK. This was performed using the IDT xGEN Exome targeted cocapture for library preparation, and Illumina NovaSeq6000 for sequencing. Initial bioinformatics analysis of the sequencing results did not flag any causative variants, but manual inspection of the copy number data raised suspicion of an intragenic ENG duplication.