An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation

Abstract

A 5-year-old Mexican girl had a bilateral, systematized epidermal nevus of a non-epidermolytic, non-organoid type covering large parts of her body with the exception of the scalp. Clinically, this nevus was of a soft, velvety type showing affinity to the large body folds. Histopathological examination revealed orthohyperkeratosis and papillomatosis without granular degeneration and without any abnormality of adnexal structures. During infancy she developed seizures, and subsequently a delayed mental development was noted. Computer tomography of the brain revealed cortical and subcortical atrophy, a subdural hygroma in the left frontoparietotemporal region, and hypoplasia of corpus callosum. Molecular analysis of a biopsy specimen obtained from the epidermal nevus revealed a heterozygous R248C hotspot mutation in FGFR3, whereas in normal skin the FGFR3 wild-type allele was exclusively found. The R248C mutation was also present in DNA extracted from blood leukocytes. Because FGFR3 is involved in the development of the central nervous system, the clinical and genetic findings of this case indicate a widespread mosaicism of the FGFR3 mutation. This unusual mosaic phenotype may represent a distinct entity within the group of epidermal nevus syndromes.

Epidermal nevus syndrome associated with unusual neurological, ocular, and skeletal features

“…A widespread mosaicism of the FGFR3 mutation was suggested in a 5-year-old girl with a mosaic phenotype of ENS. [15] A case of discordant monozygotic (MZ) twins with severe ENS, supporting the concept of a postzygotic mutation, is on record. [16] Henceforth, activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development, may be the key event in the pathogenesis of ENS and needs further exploration.…”

Late onset epidermal nevus with hypertrichosis and facial hemihypertrophy

“…Somatic mosaicism for FGFR3 mutations involving skin and other organ systems have been described in patients. [89] If the mutation involves the gonads, such patients are said to be at risk for thanatophoric dysplasia. [9] In many other patients with epidermal nevi, somatic mutations resulting in mosaicism confined to keratinocytes of the affected area have been demonstrated in the FGFR3 gene,[10] specifically at the R248C hotspot, and in the PIK3CA gene.…”

Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma

“…Hernandez et al reported several patients with multiple EN with the same FGFR3 R248C mutation, but without the severe achondroplastic phenotype that is usually associated with R248C germline mutations 18. Of even greater interest, an undoubted mosaic FGFR3 mutation has been reported in a patient showing multiple EN, seizures and mental retardation 6. The higher risk of cancer conferred by mosaic mutations in FGFR3 or PIK3CA is all the more plausible since several cases of young patients harbouring both EN and low-grade bladder cancers have been reported (case report and review by Garcia de Jalon et al 19).…”

“…EN can occasionally be associated with complex developmental abnormalities in so called epidermal nevus syndromes 6. It is also seen in the Proteus syndrome which is related to deleterious PTEN mutations that enhance the PIK3CA activity 7 8.…”