Table 2.
Frequency of Clinical Features in Cohorts of Individuals with a Missense Mutation Affecting Leu844, Cys845, Ala846, Leu847, and Gly848
| NF1 Feature |
Number of Individuals (%) [95% Confidence Interval] |
||||
|---|---|---|---|---|---|
| Leu844 | Cys845 | Ala846 | Leu847 | Gly848 | |
| >5 CALMs | 25/25 (100) [86.7–100] | 9/11 (81.8) [52.3–94.9] | 8/10 (80) [49–94.3] | 73/77 (94.8) [87.4–98] | 15/34 (44.1) [28.9–60.6] |
| Skinfold frecklinga | 10/12 (83.3) [55.2–95.3] | 5/7 (71.4) [35.9–91.8] | 6/6 (100) [61–100] | 44/47 (93.6) [82.8–97.8] | 11/23 (47.8) [29.2–67] |
| Lisch nodules | 7/17 (41.2) [21.6–64] | 1/3 (33.3) [6.2–79.2] | 2/4 (50) [15–85] | 24/47 (51.1) [37.2–64.7] | 8/27 (29.6) [15.9–48.5] |
| Plexiform neurofibromasa | 5/14 (35.7) [16.3–61.2] | 4/7 (57.1) [25–84.2] | 2/3 (66.7) [20.8–93.9] | 22/46 (47.8) [34.1–61.9] | 8/22 (36.4) [19.7–57] |
| Cutaneous neurofibromasb | 7/9 (77.8) [45.3–93.7] | 3/4 (75) [30.1–95.4] | 4/5 (80) [37.6–96.4] | 28/33 (84.9) [69.1–93.4] | 5/18 (27.8) [12.5–50.9] |
| Subcutaneous neurofibromasb | 6/8 (75) [40.9–92.9] | 1/4 (25) [4.6–69.9] | 3/5 (60) [23.1–88.2] | 17/30 (56.7) [39.2–72.6] | 6/18 (33.3) [16.3–56.3] |
| Symptomatic spinal neurofibromasa | 0/11 (0) [0–25.9] | 1/6 (16.7) [3–56.4] | 0/2 (0) [0–65.8] | 3/40 (7.5) [2.6–19.9] | 8/20 (40) [21.9–61.3] |
| Spinal neurofibromas by MRIa,c | 0/5 (0) [0–43.5] | 2/3 (66.7) [20.8–93.9] | 0/1 (0) [0–79.4] | 5/22 (22.7) [10.1–43.4] | 12/14 (85.7) [60.1–96] |
| Symptomatic OPGs, age ≥5 yearsd | 1/21 (4.8) [0.9–22.7] | 0/7 (0) [0–35.4] | 2/5 (40) [11.8–76.9] | 5/47 (10.6) [4.6–22.6] | 3/24 (12.5) [4.3–31] |
| Asymptomatic OPGs, age ≥5 yearse | 4/10 (40) [16.8–68.7] | 0/4 (0) [0–49] | 0/3 (0) [0–56.2] | 11/25 (44) [26.7–62.9] | 1/10 (10) [1.8–40.4] |
| Other neoplasmsf | 2/23 (8.7) [2.4–26.8] | 0/7 (0) [0–35.4] | 0/6 (0) [0–39] | 15/72 (20.8) [13.1–31.6] | 4/31 (12.9) [5.1–28.9] |
| Skeletal abnormalities | 9/25 (36) [20.3–55.5] | 5/10 (50) [23.7–76.3] | 0/8 (0) [0–32.4] | 23/67 (34.3) [24.1–46.3] | 11/34 (32.4) [19.1–49.2] |
| Noonan syndrome features | 2/22 (9.1) [2.5–27.8] | 1/7 (14.3) [2.6–51.3] | 0/7 (0) [0–35.4] | 6/66 (9.1) [4.2–18.5] | 1/32 (3.1) [0.6–15.8] |
| Pulmonic stenosis | 1/19 (5.3) [0.9–24.6] | 1/5 (20) [3.6–62.5] | 0/8 (0) [0–32.4] | 0/56 (0) [0–6.4] | 0/25 (0) [0–13.3] |
| Short statureg | 1/13 (7.7) [13.7–33.3] | 1/5 (20) [3.6–62.5] | 1/4 (25) [4.6–69.9] | 7/42 (16.7) [8.3–30.6] | 5/27 (18.5) [8.2–36.7] |
| Macrocephaly | 4/17 (23.5) [9.6–47.3] | 1/4 (25) [4.6–69.9] | 2/4 (50) [15–85] | 20/49 (40.8) [28.2–54.8] | 9/24 (37.5) [21.2–57.3] |
| Cognitive impairment and/or learning disabilities | 6/21 (28.6) [13.8–50] | 4/10 (40) [16.8–68.7] | 4/9 (44.4) [18.9–73.3] | 29/65 (44.6) [33.2–56.7] | 13/33 (39.4) [24.7–56.3] |
| Severe phenotype, age ≥19 yearsh | 7/9 (77.8) [45.3–93.7] | 4/6 (66.7) [30–90.3] | 1/6 (16.7) [3–56.4]i | 32/36 (88.9) [74.7–95.6] | 12/18 (66.7) [43.8–83.7] |
In individuals ≥9 years.
In individuals ≥19 years.
The frequency of both symptomatic and asymptomatic spinal neurofibromas in individuals who had undergone MRI examination.
The presence or absence of symptomatic OPGs was determined by ophthalmological examination and confirmed by MRI.
Including only individuals without signs of symptomatic OPGs who underwent MRI examination.
Including benign and malignant neoplasms, except for OPG and neurofibromas.
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.
Individual was classified as having a severe phenotype if at least one of the following features was observed: plexiform and/or symptomatic spinal neurofibroma, symptomatic OPG, malignant neoplasm, or osseous lesions.
Among individuals with a missense mutation affecting codon 846, the status of plexiform and spinal neurofibromas was known only for 2/6 individuals (UG-R0781-S and UG-R665-F), thus a severe phenotype cannot be excluded in the remaining four individuals with missing data.