LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis

Abstract

Background: Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1.

Case presentation: A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics.

Conclusions: We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1.

Keywords: LZTR1; Neurofibromas; Noonan syndrome; Whole exome sequencing.

Fig. 1

Timeline of the patient’s diagnosis, symptoms and treatment

Fig. 2

De-identified images of the patient’s plexiform neurofibromas. Panel A shows cornal T1 sequence, with multiple hypodense lesions arising from the sacral nerve roota, in keeping with neurofibromas (white arrows). Panel B shows sagittal T2 sequence, with neurofibromas seen as hyperintense lesions (white arrows)