Abstract

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second-hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second-hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second-hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS-MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS-MAPK pathway.