ORPHA: 1340; DO: 0111463;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.3 | Cardiofaciocutaneous syndrome 4 | 615280 | Autosomal dominant | 3 | MAP2K2 | 601263 |
A number sign (#) is used with this entry because of evidence that cardiofaciocutaneous syndrome-4 (CFC4) is caused by heterozygous mutation in the MAPK2K2 gene (601263) on chromosome 19p13.
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder in which individuals have characteristic craniofacial features, cardiac defects, ectodermal anomalies, gastrointestinal dysfunction, and neurocognitive delay (summary by Rauen et al., 2010).
For a general phenotypic description and a discussion of genetic heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).
Rodriguez-Viciana et al. (2006) identified 1 patient with CFC4 among 23 CFC patients. The child had characteristic craniofacial features, ectodermal abnormalities, aortic valve defect and nonprogressive ventricular septal hypertrophy, short stature with growth hormone deficiency, scoliosis and pectus deformity, ocular abnormalities (nystagmus, strabismus, myopia, bilateral cataracts and optic nerve hypoplasia), cerebellar hypoplasia, prominence of the lateral ventricles, thinning of the corpus callosum, and moderate developmental delay. Hypotonia, heat intolerance, and excessive sweating were also present.
Rauen et al. (2010) reported the first documented case of vertical transmission of CFC in a 4-generation Caucasian Cajun family. The proband was initially evaluated at age 7.5 months for short stature and mild pulmonic stenosis. He was found to have mildly delayed motor milestones and classic facial features of the disorder, including high forehead with bitemporal narrowing and telecanthus, as well as ectodermal anomalies. The mother had similar facial features and mild pulmonic stenosis, and several family members reportedly had similar facial and ectodermal features, as well as learning delays and disabilities. After another affected boy was born to this mother, molecular genetic testing was undertaken and the mutation in MEK2 identified. Two individuals with mutations in this pedigree developed cancer: the proband's maternal great grandmother developed a large B-cell lymphoma at age 70 and the proband's maternal great uncle died of acute lymphoblastic leukemia (ALL) at age 41 years.
Linden and Price (2011) reported the second family showing vertical transmission of CFC4. The proband was a 46-year-old man with mildly delayed development, pulmonary stenosis as a child, myopia, short stature, tightly curled short hair, absent eyebrows, hyperelastic skin, and multiple lentigines. His 40-year-old brother and 68-year-old mother had similar features. Linden and Price (2011) emphasized the mild cognitive phenotype in these patients, suggesting greater reproductive success.
The transmission pattern of CFC4 in the families reported by Rauen et al. (2010) and Linden and Price (2011) was consistent with autosomal dominant inheritance.
Cardiofaciocutaneous syndrome most commonly occurs as a sporadic disorder, resulting from de novo heterozygous mutations in any of the 4 genes associated with the disorder. Rauen et al. (2010) reported the first documented case of vertical transmission of CFC in a 4-generation Caucasian Cajun family. After another affected boy was born to this mother, molecular genetic testing was undertaken, and a heterozygous mutation in the MEK2 gene (P128Q; 601263.0004) was found. One of the mutation carriers died of acute lymphocytic leukemia (ALL) at age 41 years, which Rauen et al. (2010) postulated may have resulted from increased activity of the RAS pathway.
Linden and Price (2011) reported another family with autosomal dominant transmission of CFC associated with a heterozygous mutation in the MEK2 gene (G132D; 601263.0005).
In 5 of 23 CFC patients screened for BRAF (164757) mutations (22%), Rodriguez-Viciana et al. (2006) identified no BRAF mutation. Three of these individuals had missense mutations in MEK1 (176872) or MEK2 (601263), which encode downstream effectors of BRAF. Two individuals had missense mutations in MEK1 and 1 had a missense mutation in MEK2. One mutation in MEK1 was a phe53-to-ser substitution (F53S; 176872.0001); phe53 is the equivalent position to the codon changed in the MEK2 mutation, phe57 to cys (F57C; 601263.0001). Rodriguez-Viciana et al. (2006) suggested that substitutions of 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.
Schulz et al. (2008) identified 2 different missense mutations in MEK2 in 3 unrelated patients with CFC. Among 51 patients with CFC, Schulz et al. (2008) identified mutations in the BRAF (47%), MAP2K1 (9.8%), MAP2K2 (5.9%), and KRAS (190070) (5.9%) genes. Careful assessment of facial features suggested that patients with MAP2K1 mutations showed macrostomia and horizontal shape of the palpebral fissures, whereas those with MAP2K2 mutations had a long, narrow face with a high forehead, low-set ears, severe ptosis, epicanthal folds, and prominent supraorbital ridges.
Linden, H. C., Price, S. M. Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation. Clin. Dysmorph. 20: 86-88, 2011. [PubMed: 21178588] [Full Text: https://doi.org/10.1097/MCD.0b013e32833ff29d]
Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., Lacassie, Y. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. Am. J. Med. Genet. 152A: 807-814, 2010. [PubMed: 20358587] [Full Text: https://doi.org/10.1002/ajmg.a.33342]
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]