Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
Bibliographical noteFunding Information:
We thank the individuals and their families for participating in this study. This work was supported by the Children’s Tumor Foundation by the Isaac and Sadie Fuchs Genotype–Phenotype Study (to L.M.M.) and by internal funds from the Medical Genomics Laboratory at UAB. M.K. is also affiliated with the Department of Biology and Medical Genetics at the Medical University of Gdansk in Poland. We thank our collaborators: Gail Graham (Children’s Hospital of Eastern Ontario in Ottawa), Stephanie M. Morris (Washington University in St. Louis), Dmitriy M. Niyazov (Ochsner Clinic Foundation in New Orleans), Catherine Ward-Melver (Akron Children’s Hospital), Lawrence Wong (Kaiser Permanente South Bay Medical Center in Harbor City), Katie Farmer (Tallahassee Memorial HealthCare), Monisha Samanta Kisling (Children’s National Medical Center in Washington), and Taylor Warner (University of Iowa Hospitals and Clinics) for confirming the accuracy of clinical information originally provided for their individuals as well as Ender Karaca (UAB) for performing targeted NF1 testing for UAB-R1873 family.
© 2018, American College of Medical Genetics and Genomics.
- genotype–phenotype correlation
- learning difficulties