Somatic NF1 loss of heterozygosity associated with NF1-related pectus excavatum deformity: a new insight in pathogenesis?

Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder with a broad spectrum of associated signs and symptoms, including skeletal anomalies. The association of NF1 with anterior chest wall deformities has been recently reported, especially the pectus excavatum (PE). Over the years, several authors have suggested loss of heterozygosity (LOH) as the possible pathogenic mechanism underlying the development of the typical NF1 skeletal features. Here, we report a NF1 patient with severe chest deformity and harboring the germline heterozygous pathogenic NF1 variant NM_001042492.3: c.4271delC p.(Ala1424Glufs*4). Through Next Generation Sequencing (NGS), we investigated the affected cartilage from the PE deformity and identified the additional frameshift variant NM_001042492.3: c.2953delC p.(Gln985Lysfs*7), occurring as a somatic NF1 second hit mutation. Western blot analysis showed the absence of wild-type NF1 protein in the cartilage of the patient, consistent with a somatic LOH. Taken together, our findings support the role of LOH in NF1-related PE, widening the spectrum of the pathophysiological mechanisms involved in NF1-related skeletal features. This mechanism can be studied in the future in our center and applied to other tissues, including non-skeletal tissues (plexiform neurofibromas, vasculopathy and many others). The discovery of this possible pathogenetic mechanism helps us in understanding a varied and complex disease and tells us to pay attention to the possible exposure of patients to sources emitting ionizing radiation, trying to spare exams such as CT and similar.