Delineation of the clinical phenotype associated with non-mosaic type-2 NF1 deletions: two case reports

Abstract

Introduction: Large deletions of the NF1 gene and its flanking regions are frequently associated with a severe clinical manifestation. Different types of gross NF1 deletion have been identified that are distinguishable both by their size and the number of genes included within the deleted regions. Type-1 NF1 deletions encompass 1.4 Mb and include 14 genes, whereas the much less common type-2 NF1 deletions span 1.2 Mb and contain 13 genes. Genotype-phenotype correlations in patients with large NF1 deletions are likely to be influenced by the nature and number of the genes deleted in addition to the NF1 gene. Whereas the clinical phenotype associated with type-1 NF1 deletions has been well documented, the detailed clinical characterization of patients with non-mosaic type-2 NF1 deletions has not so far been reported.

Case presentation: In the present report we characterized two Caucasian European patients with non-mosaic (germline) type-2 NF1 deletions. Our first patient was a 13-year-old girl with dysmorphic facial features, mild developmental delay, large hands and feet, hyperflexibility of the joints, macrocephaly and T2 hyperintensities in the brain. A whole-body magnetic resonance imaging scan indicated two internal plexiform neurofibromas. Our second patient was an 18-year-old man who exhibited dysmorphic facial features, developmental delay, learning disability, large hands and feet, hyperflexibility of the joints, macrocephaly and a very high subcutaneous and internal tumor load as measured volumetrically on whole-body magnetic resonance imaging scans. At the age of 18 years, he developed a malignant peripheral nerve sheath tumor and died from secondary complications. Both our patients exhibited cardiovascular malformations.

Conclusions: Our two patients with non-mosaic type-2 NF1 deletions exhibited clinical features that have been reported in individuals with germline type-1 NF1 deletions. Therefore, a severe disease manifestation is not confined to only patients with type-1 NF1 deletions but may also occur in individuals with type-2 NF1 deletions. Our findings support the concept of an NF1 microdeletion syndrome with severe clinical manifestation that is caused by type-1 as well as type-2 NF1 deletions.

Figure 1

Schema of the NF1 gene region and relative extents of the different deletion types. The 14 genes located within the NF1 gene region, and included within the type-1 deletion region, are indicated by horizontal arrows. The direction of each arrow denotes the transcriptional orientation of the corresponding gene. The relative locations of the low-copy repeats, termed NF1-REPa, NF1-REPb and NF1-REPc are also indicated by vertical bars. Cen, centromeric; tel, telomeric.

Figure 2

Whole body MRI of our first patient indicated a superficial plexiform neurofibroma (pn) of the left calf (A, B) and an internal plexiform neurofibroma above the right ankle (C).

Figure 3

(A) Funnel chest and cutaneous neurofibromas on the trunk of our second patient, and multiple subcutaneous neurofibromas on the back of our patient (B).

Figure 4

Internal tumor load of our second patient. Whole body MRI (A) indicated multiple tumors along the lumbar nerves (ln), the sciatic nerves (sn) and within the lumbar plexus (lp). Nodular neurofibromas (nd) were also detected. A coronal image of his head (B) indicated multiple spinal neurofibromas (sp), which were also detected on MRI images of his trunk (C) as well as neurofibromas within the brachial plexus (bp) and along the intercostal nerves (in). MRI also showed a high tumor density in the lesser pelvis of our patient (D), including a malignant peripheral nerve sheath tumor (MPNST) as confirmed by positron emission tomography - computed tomography (PET-CT) (E).