ORPHA: 1340; DO: 0111462;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q22.31 | Cardiofaciocutaneous syndrome 3 | 615279 | Autosomal dominant | 3 | MAP2K1 | 176872 |
A number sign (#) is used with this entry because of evidence that cardiofaciocutaneous syndrome-3 (CFC3) is caused by heterozygous mutation in the MEK1 gene (MAP2K1; 176872) on chromosome 15q22.
Cardiofaciocutaneous syndrome (CFC) is a complex developmental disorder involving characteristic craniofacial features, cardiac anomalies, hair and skin abnormalities, postnatal growth deficiency, hypotonia, and developmental delay. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures (Schulz et al., 2008).
For a general description and a discussion of genetic heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).
Rodriguez-Viciana et al. (2006) reported 2 patients with CFC3. The first had characteristic craniofacial features, ectodermal abnormalities (curly hair, hyperkeratosis, hyperkeratosis pilaris, and progressive nevi formation with age), pulmonic stenosis and hypertrophic cardiomyopathy, failure to thrive, scoliosis, pectus excavatum, diffuse skeletal demineralization, ocular nystagmus, focal atrophy of the left cerebral hemisphere with prominence of the lateral ventricles, seizures, and developmental delay. The second patient had characteristic but mild features, including few nevi and hemangiomas and mild thinning of the corpus callosum. Both patients had hypotonia, heat intolerance, and excessive sweating.
Gripp et al. (2007) reported 13 unrelated patients, aged 7 weeks to 8 years, with a clinical diagnosis of Costello syndrome (218040), Costello-like syndrome, or an overlap CFC/Costello syndrome, who were negative for mutation in the HRAS gene (190020), which is known to cause Costello syndrome. De novo heterozygous BRAF (164757) or MEK1 mutations were identified in 8 and 5 patients, respectively. In a comparison to a group of previously published patients with HRAS mutations, Gripp et al. (2007) found several significant clinical differences between the 2 groups. Patients with an HRAS mutation and Costello syndrome tended to have polyhydramnios, ulnar deviation, growth hormone deficiency, and tachycardia more frequently than patients with BRAF or MEK1 mutations. Those with BRAF or MEK1 mutations had more cardiovascular malformations. Although the presence of more than 1 papilloma strongly suggested Costello syndrome over CFC, the authors noted that these lesions typically develop over time and thus may not be very helpful in the differential diagnosis of younger children. All 5 patients with MEK1 mutations had failure to thrive and short stature. The majority had cardiovascular malformations including ventricular septal defects and pulmonic stenosis. One patient developed hepatoblastoma following cardiac transplant for hypertrophic cardiomyopathy, the first reported malignant solid tumor in CFC syndrome. Gripp et al. (2007) concluded that the 13 patients in their study had CFC syndrome and not Costello syndrome, based on the clinical and molecular findings. The authors noted the phenotypic overlap between the 2 disorders, but suggested that the designation Costello syndrome be reserved for patients with HRAS mutations.
In a comparison of 51 individuals with CFC carrying mutations in BRAF (164757), KRAS (190070), or MAP2K1, Schulz et al. (2008) found that MAP2K1 mutation-positive cases showed some specific features, such as macrostomia and horizontal shape of palpebral fissures.
The transmission pattern of CFC3 in the patients reported by Rodriguez-Viciana et al. (2006) was consistent with autosomal dominant inheritance.
In 5 (22%) of 23 patients with CFC screened for BRAF mutations, Rodriguez-Viciana et al. (2006) identified no BRAF mutation. Three of these individuals had heterozygous missense mutations in MEK1 or MEK2 (601263), which encode downstream effectors of BRAF. Two individuals had mutations in MEK1 (F53S, 176872.0001; Y130C, 176872.0002) and 1 had a mutation in MEK2 (F47C; 601263.0001). Phe53 in MEK1 is the equivalent position to phe57 in MEK2, and Rodriguez-Viciana et al. (2006) suggested that substitutions at this residue may have similar functional consequences in the 2 family isoforms. All 3 MEK mutations were found to be more active than wildtype MEK in stimulating ERK phosphorylation.
In 5 patients with CFC3, Gripp et al. (2007) identified heterozygous mutations in the MEK1 gene. Three patients had the previously identified Y130C mutation and 2 had novel mutations (176872.0004 and 176872.0005).
In a patient with CFC3, Schulz et al. (2008) identified a heterozygous mutation in the MAP2K1 gene (G128V; 176872.0003).
Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am. J. Med. Genet. 143A: 1472-1480, 2007. [PubMed: 17551924] [Full Text: https://doi.org/10.1002/ajmg.a.31815]
Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311: 1287-1290, 2006. [PubMed: 16439621] [Full Text: https://doi.org/10.1126/science.1124642]
Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin. Genet. 73: 62-70, 2008. [PubMed: 18042262] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00931.x]