Cardiofaciocutaneous Syndrome 3

A number sign (#) is used with this entry because of evidence that cardiofaciocutaneous syndrome-3 (CFC3) is caused by heterozygous mutation in the MAP2K1 gene (176872) on chromosome 15q22.

For a general phenotypic description and a discussion of genetic heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).

Description

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).

Clinical Features

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.

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.

Molecular Genetics

In 5 of 23 CFC patients screened for BRAF 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.