Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000-3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of RASopathies and shares several clinical features with Noonan syndrome. Here, we describe the main clinical characteristics and complications associated with NF1, particularly those occurring in pediatric age. NF1 has complete penetrance and shows wide inter- and intrafamilial phenotypic variability and age-dependent appearance of manifestations. Clinical presentation and history of NF1 are multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. In this scenario of extreme phenotypic variability, some genotype-phenotype associations need to be taken into consideration, as they strongly impact on genetic counseling and prognostication of the disease. We provide a synthetic review, based on the most recent literature data, of all known genotype-phenotype correlations from a genetic and clinical perspective. Molecular diagnosis is fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes.

Keywords: genotype–phenotype correlations; neurofibromatosis type 1 (NF1); pediatric features.

Figure 1

Schematic representation of the RAS/MAPK pathway in RASopathies. Germinal mutations in genes encoding different components of the pathway can cause overlapping phenotypes, color coded according to the legend.

Figure 2

Typical manifestations of neurofibromatosis type 1 (NF1): café au lait macules characterized by linear margins (A,B), homogeneous color, and rounded/oval shape ((A); black arrow), with dimension > 1.5 cm in post-pubertal age; atypical freckles on the abdomen ((A); red arrow); typical freckles in the axillary fold (C); multiple cutaneous neurofibromas typically found in adulthood—note the pinkish color and rounded shape (D); extensive plexiform neurofibroma involving the entire upper limb, with hyperchromic skin lesions in the affected area and secondary deformity (E).

Figure 3

Coronal T2-weighted (A) and T1-weighted MR images after fat suppression contrast (B) showing a thickened optic chiasm (black arrow) with a lobulated mass-effect lesion (asterisk) on the left showing a hyperintense signal and a linear contrast enhancement. T2 axial TSE sequences (C,D) showing a hyperintense rounded focal lesion (black arrow) with minimal marked and homogeneous vasogenic edema (black arrow) in the right middle cerebellar pedicle in line with a likely low-grade lesion. Coronal T2-weighted (E) and sagittal T1-weighted (F) sequences of lumbosacral spine showing a plexiform neurofibroma (black arrows), marked dural ectasia (asterisk) associated with significant scalloping of the posterior lower lumbar vertebral bodies (white arrows). Coronal STIR images with volumetric reconstruction (G,H) showing a voluminous plexiform neurofibroma arising from the lumbo-sacral plexus and extending into the left thigh region.

Figure 4

Sagittal (A) and axial bFFE STIR-FSE (B) MR images of the cervical spine showing at C2-C3 level a focal area of hyperintensity located on the right posterior side of the medulla, compatible with UBO. T2-weighted coronal sequence showing dilation of the frontal and temporal horns of the lateral ventricles (asterisk) (C). T2-weighted sagittal MR image (D) showing aqueduct stenosis (black arrow) with widening of the hypothalamic recess. Angio-MR image in a boy with Moyamoya vasculopathy (E,F): the 3D time-of-flight technique with sagittal and coronal maximum intensity projection reconstructions shows focal stenosis of the M1 segment of the right middle cerebral artery (white arrow); “Moyamoya-type” collateral vessels are visible. Sternum excavatum (G) and profile X-ray showing malformation of the sternum (H).

Figure 5

Genotype–phenotype correlations known to date for NF1. Major phenotypic characteristics significantly more (↑) or less (↓) present, or possibly absent, are listed. Amino acid changes at specific positions are grouped according to the observed phenotypic features.

Figure 6

Graphical distribution of NF1 missense variants currently associated with different classes of mild to severe phenotypes: deletion of methionine 992 (orange); six different substitutions of arginine 1809 (blue); 14 substitutions involving leucine 844, cysteine 845, alanine 846, and glycine 848 (red); 13 substitutions of methionine 1149, arginine 1276, and lysine 1423 (green). All these variants were annotated in Clinvar and refer to the NM_000267.3 isoform.