Table 3.
Comparison of Clinical Features of the Studied Group with the NF1 Arg1809 Cohort, the NF1 Met992del Cohort, and Large-Scale Previously Reported Cohorts of Individuals with “Classic” NF1
| NF1 Feature |
Number of Individuals (%) |
p Value (2-Tailed Fisher’s Exact Test) |
|||||
|---|---|---|---|---|---|---|---|
| aa 844–848 | Arg1809a | Met992delb | Previously Reported NF1 Cohorts | aa 844–848 versus Arg1809 | aa 844–848 versus Met992del | aa 844–848 versus “Classic” NF1 | |
| >5 CALMs | 130/157 (82.8) | 157/169 (92.9) | 46/47 (97.9) | 1,537/1,728 (89)c | 0.0060∗ ➘ | 0.0067∗ ➘ | 0.0263 ➘ |
| Skinfold freckling | 104/144 (72.2) | 95/161 (59) | 32/47 (68.1) | 1,403/1,667 (84.2)c | 0.0164 ➚ | 0.0007∗∗ ➘ | |
| Lisch nodules | 42/98 (42.9) | 12/120 (10) | 3/38 (7.9) | 729/1,237 (58.9)c | <0.0001∗∗ ➚ | <0.0001∗∗ ➚ | 0.0028∗ ➘ |
| Major external plexiform neurofibromasd | 36/92 (39.1) | 0/105 (0) | 0/41 (0) | 120/648 (18.5)e,f | <0.0001∗∗ ➚ | <0.0001∗∗ ➚ | <0.0001∗∗ ➚ |
| Cutaneous neurofibromasg | 47/69 (68.1) | 0/57 (0) | 0/18 (0) | 656/723 (90.7)f,h,i,j | <0.0001∗∗ ➚ | <0.0001∗∗ ➚ | <0.0001∗∗ ➘ |
| Subcutaneous neurofibromasg | 33/65 (50.8) | 0-5/57 (0-8.8)k | ND | 297/515 (57.7)f,i,j | <0.0001∗∗ ➚ | ||
| Symptomatic spinal neurofibromasd,l | 12/79 (15.2) 13/127 (10.2) |
0/40 (0) 0/76 (0) |
1/41 (2.4) 1/47 (2.1) |
2/119 (1.7)e 36/2,058 (1.8)e,f,m |
0.0080∗ ➚ 0.0022∗ ➚ |
0.0341 ➚ | 0.0004∗∗ ➚ <0.0001∗∗ ➚ |
| Symptomatic OPGs, age ≥ 5 yearsl,n | 11/104 (10.6) 12/136 (8.8) |
0/114 (0) 0/139 (0) |
0/46 (0) 0/47 (0) |
7/180 (3.9)e,o 64/1,650 (3.9)c |
0.0002∗∗ ➚ 0.0002∗∗ ➚ |
0.0186 ➚ 0.0384 ➚ |
0.0404 ➚ 0.0125∗ ➚ |
| Asymptomatic OPGs, age ≥ 5 yearsl,p | 16/52 (30.8) 18/63 (28.6) |
0/35 (0) 0/38 (0) |
ND | 2/45 (4.4)o 70/519 (13.5)q,r,s |
0.0001∗∗ ➚ <0.0001∗∗ ➚ |
0.0012∗∗ ➚ 0.0043∗ ➚ |
|
| Other malignant neoplasmst | 13/139 (9.4) | 2/155 (1.3)u | 0/47 (0) | 18/523 (3.4)f | 0.0023∗ ➚ | 0.0409 ➚ | 0.0061∗ ➚ |
| Skeletal abnormalitiesd,l | 38/91 (41.8) 48/144 (33.3) |
14/72 (19.4) 21/126 (16.7) |
8/41 (19.5) 9/47 (19.2) |
14/96 (14.6)e 144/948 (15.2)e,f,j,v |
0.0025∗ ➚ 0.0020∗ ➚ |
0.0174 ➚ | <0.0001∗∗ ➚ <0.0001∗∗ ➚ |
| Scoliosisg | 20/64 (31.3) | 6/48 (12.5) | 2/18 (11.1) | 51/236 (21.6)h,j | 0.0241 ➚ | ||
| Noonan syndrome features | 10/134 (7.5) | 46/148 (31.1) | 4 (all from 1 family) | 57/1,683 (3.4)c | <0.0001∗∗ ➘ | 0.0276 ➚ | |
| Pulmonic stenosis | 2/113 (1.8) | 14/132 (10.6) | 4/47 (8.5) | 25/2,322 (1.1)w | 0.0076∗ ➘ | ||
| Short stature | 15/91 (16.5) | 32/111 (28.8) | 5/47 (10.6) | 109/684 (15.9)e,i | 0.0451 ➘ | ||
| Macrocephaly | 36/98 (36.7) | 31/107 (29) | 4/45 (8.9) | 239/704 (33.9)e,i | 0.0005∗∗ ➚ | ||
| Cognitive impairment and/or learning disabilities | 56/138 (40.6) | 80/159 (50.3) | 8/47 (17) | 190/424 (44.8)e,f | 0.0042∗ ➚ | ||
Statistically significant p values with false discovery rates of 0.05 (indicated by ∗) and 0.01 (indicated by ∗∗) after correction for multiple testing using Benjamini-Hochberg procedure (see details in Table S10). After applying the Benjamini-Hochberg correction, p ≤ 0.0125 remained statistically significant at FDR of 0.05, while p values ≤ 0.0012 were still be considered as significantly different at FDR of 0.01. The black arrows indicate the statistically significant differences of the NF1 clinical features prevalence between the studied 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 studied group, respectively. Abbreviation: ND, no data
Based on data from Pinna et al.,13 Rojnueangnit et al.,14 Nyström et al.,25 Ekvall et al.,26 and Santoro et al.27
Based on data from Upadhyaya et al.12
Previous NF1 cohort used for comparison: Friedman and Birch.32
In individuals ≥9 years in this study and Arg1809, ≥10 years in Met992del and other studies.
Previous NF1 cohort used for comparison: Huson et al.7
Previous NF1 cohort used for comparison: McGaughran et al.34
In individuals ≥19 years in this study and Arg1809, ≥20 years in Met992del and other studies.
Previous NF1 cohort used for comparison: Khosrotehrani et al.38
Previous NF1 cohort used for comparison: Plotkin et al.39
Five individuals with few (1–6) small, subcutaneous “possible” neurofibromas, none were biopsied and therefore none have been histologically confirmed.14
Second value is the frequency of a particular feature regardless of the individuals’ age.
Previous NF1 cohort used for comparison: Thakkar et al.35
The presence or absence of symptomatic OPGs was determined by ophthalmological examination and confirmed by MRI.
Previous NF1 cohort used for comparison: Van Es et al.31
Including only individuals without signs of symptomatic OPGs who underwent MRI examination.
Previous NF1 cohort used for comparison: Listernick et al.30
Previous NF1 cohort used for comparison: Blazo et al.37
Previous NF1 cohort used for comparison: Blanchard et al.40
Only malignant neoplasms, hence excluding neurofibromas and OPGs, have been taken into account.
Breast cancer (n = 1) and Ewing sarcoma (n = 1) were found in the NF1 Arg1809 cohort, no follow-up information on these individuals was available.14
Previous NF1 cohort used for comparison: Cnossen et al.33
Previous NF1 cohort used for comparison: Lin et al.36