Table 2.
Comparison of clinical features of the cohort of individuals heterozygous for pathogenic NF1 missense variants affecting p.Arg1276 with the cohorts of individuals with pathogenic NF1 missense variants affecting codons 1809 and 844‐848, the NF1 p.Met992del as well as with large‐scale previously reported cohorts of individuals with “classic” NF1
| NF1 feature | N (%) | p Value (two‐tailed Fisher's exact test) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| p.Arg1276 | p.Met992del a | p.Arg1809 b | aa 844‐848 c | Previously reported NF1 cohorts d | p.Arg1276 versus p.Met992del | p.Arg1276 versus p.Arg1809 | p.Arg1276 versus aa 844‐848 | p.Arg1276 versus “classic” NF1 | |
| >5 CALMs | 111/119 (93.3) | 165/182 (90.7) | 157/169 (92.9) | 130/157 (82.8) | 1,537/1,728 (89) | ||||
| Skinfold freckling | 74/112 (66.1) | 105/171 (61.4) | 95/161 (59) | 104/144 (72.2) | 1,403/1,667 (84.2) | <0.0001** ↘ | |||
| Lisch nodules | 19/70 (24.1) | 16/139 (11.5) | 12/120 (10) | 42/98 (42.9) | 729/1,237 (58.9) | 0.0059* ↗ | 0.0038* ↗ | <0.0001** ↘ | |
| Major external plexiform neurofibromas e | 5/64 (7.8) | 0/125 (0) | 0/105 (0) | 36/92 (39.1) | 120/648 (18.5) | 0.0040* ↗ | 0.0070* ↗ | <0.0001** ↘ | |
| Cutaneous neurofibromas f | 14/40 (35) | 0–1/57 (0–1.8) g | 0/57 (0) | 47/69 (68.1) | 656/723 (90.7) | <0.0001** ↗ | <0.0001** ↗ | 0.0012* ↘ | <0.0001** ↘ |
| Subcutaneous neurofibromas f | 21/37 (56.8) | 0–3/36 (0–8.3) g | 0–5/57 (0–8.8) g | 33/65 (50.8) | 297/515 (57.7) | <0.0001** ↗ | <0.0001** ↗ | ||
| Symptomatic spinal neurofibromas | 18/97 (18.6) h | 1/165 (0.6) | 0/76 (0) | 13/127 (10.2) | 36/2,058 (1.8) | <0.0001** ↗ | <0.0001** ↗ | <0.0001** ↗ | |
| Symptomatic OPGs i | 0/97 (0) | 0/170 (0) | 0/139 (0) | 12/136 (8.8) | 64/1,650 (3.9) | 0.0016* ↘ | |||
| Asymptomatic OPGs j | 1/48 (2.1) | 1/41 (2.4) | 0/38 (0) | 18/63 (28.6) | 70/519 (13.5) | 0.0002** ↘ | |||
| Other malignant neoplasms k | 4/94 (4.3) l | 1/126 (0.8) m | 2/155 (1.3) n | 13/139 (9.4) | 18/523 (3.4) | ||||
| Skeletal abnormalities | 32/100 (32) | 30/172 (17.4) | 21/126 (16.7) | 48/144 (33.3) | 144/948 (15.2) | 0.0070* ↗ | 0.0076* ↗ | 0.0001** ↗ | |
| Scoliosis f | 8/35 (22.9) | 7/57 (12.3) | 6/48 (12.5) | 20/64 (31.3) | 51/236 (21.6) | ||||
| Cognitive impairment and/or learning disabilities | 46/105 (43.8) | 58/176 (33) | 80/159 (50.3) | 56/138 (40.6) | 190/424 (44.8) | ||||
| Noonan‐like phenotype o | 22/106 (20.8) | 19/166 (11.5) | 46/148 (31.1) | 10/134 (7.5) | 57/1,683 (3.4) | 0.0037* ↗ | <0.0001** ↗ | ||
| Short stature p | 14/80 (17.5) | 16/118 (13.6) | 32/111 (28.8) | 15/91 (16.5) | 109/684 (15.9) | ||||
| Macrocephaly | 24/76 (31.6) | 30/132 (22.7) | 31/107 (29) | 36/98 (36.7) | 239/704 (33.9) | ||||
| Pulmonic stenosis | 11/92 (12) | 8/160 (5) | 14/132 (10.6) | 2/113 (1.8) | 25/2,322 (1.1) | 0.0034* ↗ | <0.0001** ↗ | ||
| Cardiovascular abnormalities | 22/92 (23.9) | 16/160 (10) | 21/118 (17.8) | 16/113 (14.2) | 54/2,322 (2.3) | 0.0055** ↗ | <0.0001** ↗ | ||
Note: Statistically significant p values with FDR of 0.05 (indicated by *) and 0.01 (indicated by **) after correction for multiple testing using Benjamini–Hochberg procedure (see details in Table S25). After applying the Benjamini–Hochberg correction, p ≤ .0076 and p ≤ .0002 remained statistically significant at FDR of 0.05 and 0.01, respectively. The black arrows indicate the statistically significant differences of the NF1 clinical features prevalence between the p.Arg1276 group and the cohort(s) used for the comparison, with the up and down arrows representing an increase and a decrease of the prevalence in the p.Arg1276 group, respectively.
Abbreviations: CALM, café‐au‐lait macule; FDR, false discovery rate; MPNST, malignant peripheral nerve sheath tumor; MRI, magnetic resonance imaging; OPG, optic pathway glioma.
Based on data from Pinna et al. (2015), Rojnueangnit et al. (2015), Ekvall et al. (2014), Nyström et al. (2009), and Santoro et al. (2015).
Based on data from Koczkowska et al. (2018).
Previous NF1 cohorts used for the comparison: Huson et al. (1988), Huson, Compston, Clark et al. (1989), Huson, Compston, and Harper (1989), Listernick et al. (1994), Friedman and Birch (1997), Cnossen et al. (1998), McGaughran et al. (1999), Thakkar et al. (1999), Lin et al. (2000), Blazo et al. (2004), Khosrotehrani et al. (2005), Plotkin et al. (2012), and/or Blanchard et al. (2016).
In individuals ≥9 years old.
In individuals ≥19 years old.
Individuals with few (2–6) cutaneous and/or subcutaneous “neurofibromas,” none were biopsied and therefore none have been histologically confirmed.
The overall prevalence of symptomatic spinal neurofibromas in all individuals was 18.6% (18/97) but in adults 47.2% (17/36 ≥ 19 years old).
The absence of symptomatic OPGs was determined by ophthalmological examination and/or by MRI.
Including only individuals without signs of symptomatic OPGs who underwent MRI examination.
Only malignant neoplasms, not including OPGs and neurofibromas, have been taken into account.
Astrocytoma (n = 2), colon cancer (n = 1) and MPNST (n = 1) were found in the NF1 p.Arg1276 cohort.
A single case of neuroblastoma (n = 1) was found in the NF1 p.Met992del cohort, no follow‐up information on this individual was available.
Breast cancer (n = 1) and Ewing sarcoma (n = 1) were found in the NF1 p.Arg1809 cohort, no follow‐up information on these individuals was available.
An individual was classified as having a Noonan‐like phenotype when at least two of the following features were present: short stature, low set ears, hypertelorism, midface hypoplasia, webbed neck, pectus abnormality, and/or pulmonic stenosis.
As no specific growth curves are available for the Hispanic and Asian populations, Hispanic and Asian individuals were excluded as having short or normal stature.