Neurofibromatosis type 2 with mild Pierre-Robin sequence showing a heterozygous chromosome 22q12 microdeletion encompassing NF2 and MN1.

Pierre-Robin sequence (PRS) is a rare, congenital defect presenting with micrognathia, glossoptosis, and airway obstruction with variable inclusion of a cleft palate. Overlapping PRS with neurofibromatosis type 2 (NF2) is a syndrome caused by a chromosome 22q12 microdeletion including NF2. We describe a patient with severe early-onset NF2 overlapping with PRS that showed micrognathia, glossoptosis, and a mild form of cleft palate. We detected a de novo chromosome 22q12 microdeletion including MN1 and NF2 in the patient. Previous cases of overlapping PRS and NF2 caused by the chromosome 22q12 microdeletions showed severe NF2 phenotypes with variable severity of cleft palate and microdeletions of varying sizes. Genotype-phenotype correlations and comparison of the size and breakpoint of microdeletions suggest that some modifier genes distal to MN1 and NF2 might be linked to the cleft palate severity.

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes.

Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK. Here, we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, either somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele. The second hits differed among DSAP lesions but were identical in those of congenital LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP to a single second hit in the embryonic period. In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second hit keratinocytes. DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis.