Multiple café au lait spots in familial patients with MAP2K2 mutation

Abstract

Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple café au lait spots and Noonan syndrome-like facial features suggested a diagnosis of neurofibromatosis-Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS/MAPK signaling cascade results in multiple café au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated.

Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population

“…With the exception of the existence of deep intronic mutations in SPRED1 and NF1 , some of these mutation-negative patients most likely harbor a segmental or mosaic variant of the NF1 and the affected tissue must be therefore analyzed to identify the mutation. Others may be disorders that overlap with NF1, such as LEOPARD syndrome or neurofibromatosis-Noonan syndrome 24 25 . Unfortunately, corresponding tissues and tests were not available in this study.…”

The Use of Next-Generation Sequencing in Molecular Diagnosis of Neurofibromatosis Type 1: A Validation Study

“…The availability of a mutation analysis panel, like the one presented herein, plays a critical role in differentiating the underlying genetic cause of patients whose diagnosis is uncertain from a clinical standpoint (Takenouchi et al, 2013a(Takenouchi et al, , 2013b. The use of a whole-exome panel would be advantageous because of its comprehensiveness.…”

“…The strength of such a comprehensive approach is the ability to detect atypical presentations of classic syndromes, as illustrated by our recent reports on several patients with atypical presentations of mutations in the causative genes of three classic genetic syndromes: the neonatal progeroid presentation of an FBN1 mutation (Takenouchi et al, 2013a), the Noonan-cafe au lait syndrome-like presentation of a MAP2K2 mutation (Takenouchi et al, 2013b), and Stickler syndrome-like presentation of SOX9 mutation (Takenouchi et al, 2014).…”

Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: Clinical evidence of crosslink between FGFR and RAS signaling pathways

“…A custom‐designed mutation analysis panel (SureSelect XT‐Auto custom; Agilent Technologies, Santa Clara, CA) was run on a next‐generation sequencer (MiSeq; Illumina, Inc., San Diego, CA). The list of genes on this panel comprises most of the causative genes listed in the classic textbook of dysmorphology: Smith's Recognizable Patterns of Human Malformation [Jones, ] (the list of genes is available upon request), including major components in the RAS/MAPK signaling cascade, i.e., NF1 , PTPN11 , SOS1 , RAF1 , SPRED1 , and SHOC2 [Takenouchi et al, ; Takenouchi et al, ]. After we aligned the sequencing reads to the reference human genome sequence (hs37d5) using BWA [Li and Durbin, ], local realignment around indels and base quality score recalibration were performed using Genome Analysis Toolkit software [McKenna et al, ].…”