Table 2. Clinical features of MEK1/MEK2 mutation-positive CFCS patients included in the study, and comparison with published data.
| Features | CFCS patients with MEK1/MEK2 gene mutations from this study | Present cohort | Literaturea,b | Total CFCS with MEK mutations (%) | BRAF- positive patientsc (%) | CFCS indexd (%) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patients | N.1 | N.2 | N.3 | N.4 | N.5 | N.6 | 6 | 55 | 61 | 32 | 54 |
| Gene | MEK1 | MEK1 | MEK1 | MEK1 | MEK2 | MEK2 | |||||
| Nucleotidic/amino acid change | c.124C>T L42F | c.389A>G Y130C | c.389A>G Y130C | c.388T>C Y130H | c.170T>C F57C | c.186_197del K63_E66del | 4 MEK1/2 MEK2 | 37 MEK1/ 18 MEK2 | 41 MEK1/ 20 MEK2 | 32 BRAF | |
| Sex | F | F | F | F | M | M | 2 M, 4 F/6 | 7 M, 10 F/17 | 9 M, 14 F/23 | 14 M, 18 F/32 | |
| Years | 6.6 | 5.11 | 9y | Neonate | 4 | 2.5 | 4.6/6 | 7.5/26 | 6.9/32 | ||
| Polyhydramnios | Yes | No | Yes | Yes | Yes | No | 4/6 | 16/26 | 20/32 (62) | 19/32 (60) | |
| Fetal macrosomia | No | No | Yes | Yes | No | No | 2/6 | 11/19 | 13/25 (52) | 31/32 (97) | |
| Short stature (<3rd centile) | Yes | Yes | Yes | No | No | Yes | 4/6 | 26/32 | 30/38 (79) | 78 | |
| Macrocephaly | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 20/28 | 26/34 (76) | 78 | |
| Failure to thrive | Yes | Yes | Yes | NA | Yes | Yes | 4/4 | 25/31 | 29/35 (83) | 19/30 (63) | |
| Facial anomalies | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 30/30 | 36/36 (100) | ||
| Prominent supraorbital ridge | No | No | No | No | No | No | 0/6 | 9/14 | 9/20 (45) | ||
| Sparse eyebrows | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 29/32 | 35/38 (92) | 24/29 (83) | 63 |
| Downslanting palpebral fissures | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 15/23 | 21/29 (72) | 8/17 (47)e | 61 |
| Hypertelorism | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 17/24 | 23/30 (77) | 12/17 (71)e | 46 |
| Epicanthal folds | Yes | No | Yes | Yes | Yes | No | 4/6 | 10/20 | 14/26 (54) | 59 | |
| Palpebral ptosis | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 12/21 | 18/27 (67) | 52 | |
| Low-set ears/thickened helix | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 21/24 | 27/30 (90) | 76 | |
| Large, thick ear lobe | No | Yes | Yes | Yes | Yes | Yes | 5/6 | 16/18 | 21/24 (87) | 30 | |
| Flat nasal bridge | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 4/6 | 10/12 (83) | 89 | |
| Thick lips/macrostomia | Yes | Yes | No | No | Yes | Yes | 4/6 | 7/13 | 11/19 (58) | 8/17 (47)e | |
| Long/prominent philtrum | No | No | Yes | Yes | No | Yes | 3/6 | 13/20 | 16/26 (62) | 39 | |
| Micrognathia | Yes | Yes | No | Yes | No | No | 3/6 | 8/17 | 11/23 (48) | 24 | |
| Congenital heart defect | Yes | Yes | No | Yes | No | Yes | 4/6 | 21/33 | 25/39 (64) | 23/32 (72) | 78 |
| Pulmonary valve stenosis | Yes | Yes | No | No | No | Yes | 3/6 | 14/36 | 17/42 (40) | 11/27 (41) | |
| Pulmonary valve dysplasia | No | No | No | No | No | Yes | 1/6 | 0/27 | 1/33 (3) | ||
| Supravalvular PVS | No | No | No | No | No | Yes | 1/6 | 0/27 | 1/33 (3) | ||
| Atrial/ventricular septal defect | No | No | No | No | No | No | 0/6 | 7/32 | 7/38 (18) | 9/27 (33) | |
| HCM | No | No | No | No | No | Mild | 1/6 | 13/36 | 14/42 (33) | 11/28 (40) | |
| Other | ST | AVPR ToF | No | No | 1/6 AVPR, ToF; 1/6 ST | 1/27 BAV 1/27 SVT | 9/27 MVD | ||||
| Skin anomalies | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 37/38 | 43/44 (98) | ||
| Keratosis pilaris facies | No | No | No | No | Yes | Yes | 2/6 | 12/26 | 14/32 (44) | 16/22 (73) | 37 |
| Cavernous angiomata | No | No | Yes | No | No | No | 1/6 | 3/6 | 4/12 (33) | 11/27 (41) | 24 |
| Nevi | No | No | Yes | No | No | No | 1/6 | 10/28 | 11/34 (32) | 23/31 (74) | |
| Cafè-au-lait spots | Yes | No | No | No | No | No | 1/6 | 4/24 | 5/30 (17) | 7/27 (26) | 9 |
| Sparse hair | Yes | Yes | No | No | Yes | Yes | 4/6 | 29/43 | 33/49 (67) | 24/29 (83) | 85 |
| Curly hair | Yes | Yes | Yes | Yes | No | No | 4/6 | 32/37 | 36/43 (84) | 29/32 (91) | 72 |
| Others | No | No | No | No | No | No | 3/15 PP; 7/26 EZ; 8/24 DePP; 3/3 ES, 3/3 DS | 5/21 EZ | |||
| Musculoskeletal abnormalities | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 26/28 | 32/34 (94) | ||
| Short webbed neck | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 20/21 | 26/27 (96) | 50 | |
| Pectus excavatum | No | No | Yes | Yes | Yes | Yes | 4/6 | 19/25 | 23/31 (74) | 14/23 (61) | |
| Joint limitations/hyperextension | No | No | Yes | No | No | No | 1/6 | 13/20 | 14/26 (54) | 14/24 (58) | 13 |
| Others | No | PC | No | No | No | No | 1/6 PC | 1/3 DSD; 1/5 UD | |||
| Cubitus valgus | No | No | Yes | Yes | No | No | 2/6 | 1/2 | 3/8 (37) | ||
| Thoracic anomalies | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 18/23 | 24/29 (82) | ||
| Undescended testes | Yes | Yes | 2/2 | 3/3 | 5/5 (100) | 4/14 (29) | 43 | ||||
| Neurological | Yes | Yes | Yes | NA | Yes | Yes | 5/5 | 42/44 | 47/49 (96) | ||
| Mental retardation | Yes | Yes | Yes | NA | Yes | Yes | 5/5 | 38/41 | 43/46 (93) | 91 | |
| CNS abnormality | No | No | No | No | NA | No | 0/5 | 7/10 | 7/15 (47) | ||
| Seizures | No | No | No | NA | No | No | 0/5 | 16/39 | 16/44 (36) | 15/31 (48) | 15 |
| Development delay | Yes | Yes | Yes | NA | DBA | Yes | 5/5 | 38/40 | 43/45 (96) | 81 | |
| Hypotonia | Yes | Yes | Yes | Yes | Yes | Yes | 6/6 | 34/39 | 40/45 (89) | 29/31 (94) | 28 |
| Ocular abnormalities | No | No | No | No | Yes | Yes | 2/6 | 17/30 | 19/36 (53) | ||
| Photophobia | No | No | No | NA | No | No | 0/5 | 3/6 | 3/11 (27) | ||
| Nystagmus | No | No | No | No | Yes | No | 1/6 | 6/14 | 7/20 (35) | 30 | |
| Strabismus | No | No | No | No | No | No | 0/6 | 17/31 | 17/37 (46) | 25/30 (83) | 33 |
| Myopia | No | No | Astigmatism | No | No | No | 0/6 | 6/21 | 6/27 (22) | 18/23 (78) | |
| Optic nerve hypoplasia | No | No | No | No | No | No | 0/6 | 3/13 | 3/19 (16) | 9/20 (45) | |
| Cataract (bilateral) | No | No | No | No | No | Yes | 1/6 | 1/7 | 2/13 (15) | ||
| Others | 1/20 HB; 3/3 HT | ||||||||||
Abbreviations: AVPR, partial anomalous venous pulmonary return; BAV, bicuspid aortic valve; DBA, delayed bone age; DPP, deep palmar/plantar creases; DS, dry skin; DSD, diffuse skeletal demineralization; ES, excessive sweating; EZ, eczema; HB, hepatoblastoma; HT, heat intolerance; MVD, mitralic valve dysplasia; NA, not available; PC, pectus carinatum; PP, papilloma; ST, sinusal tachycardia; SVT, supraventricular tachycardia; ToF, tetralogy of Fallot; UD, ulnar deviation.
a
This column includes three cases with phenotype apparently fitting NS (see Nava et al16).
b
References: Rodriguez-Viciana et al,4 Niihori et al,2 Nava et al,16 Narumi et al,3 Yoon et al,20 Armour et al,22 Gripp et al,21 Schulz et al,17 Nyström et al.18
c
According to Armour and Allanson.22
d
According to Kavamura et al.23
e
As facial dysmorphisms are not reported among Armour and Allanson's cohort, we compared the MEK-mutated CFCS cohort with our unpublished clinical data of 17 CFC BRAF-mutated positive patients.