Cardiofaciocutaneous Syndrome 2

A number sign (#) is used with this entry because this form of cardiofaciocutaneous syndrome (CFC2) is caused by heterozygous mutation in the KRAS gene (190070) on chromosome 12p12.1.

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

Description

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and mental retardation (summary by Niihori et al., 2006). In a phenotypic comparison of BRAF (164757)-positive and KRAS-positive individuals with CFC, Niihori et al. (2006) observed that patients with KRAS mutations did not have the skin abnormalities, such as ichthyosis, hyperkeratosis, and hemangioma, that were present in patients with BRAF mutation.

Clinical Features

Wieczorek et al. (1997) described a female patient (patient 2) with cardiofaciocutaneous syndrome. She was noted to be hypotonic in the first few weeks of life, and early development was complicated by hypertrophic obstructive cardiomyopathy, atrial septal defect, and pulmonic stenosis. She walked without support and spoke her first word at 18 months of age. At age 2.5 the patient could speak only a few single words. She had short stature, high forehead with bitemporal constriction, bilateral ptosis, sparse eyebrows and eyelashes, short and broad-based nose with anteverted nostrils, low-set posteriorly rotated ears, and sparse, fine, curly hair. The nonconsanguineous mother and father were 34 and 37 years old, respectively, at the time of the patient's birth. Wieczorek et al. (1997) also described 2 other patients, provided a detailed review of previously reported cases, and discussed the differences from Noonan (see 163950) and Costello (218040) syndromes.

Stark et al. (2012) reported 3 patients from 2 families with CFC2. In the first family, vertical transmission of the KRAS mutation occurred from mother to son. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse. She had attended a school for children with special needs. Both patients also showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 (601097) testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The proband of the second family, who had an unaffected dizygotic twin, had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome. Reexamination at age 3.5 years showed coarser facial features more consistent with CFC. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development. Stark et al. (2012) cited rare reports of peripheral neuropathy in CFC (DeRoos et al., 2007; Manci et al., 2005), suggesting that it may be a feature of Ras-pathway associated disorders. Overall, the report emphasized the expanding phenotype of disorders due to germline KRAS mutations.

Molecular Genetics

Niihori et al. (2006) found the same heterozygous missense mutation in the KRAS gene (D153V; 190070.0010) in patient 2 of Wieczorek et al. (1997) and in another patient. They also identified a different KRAS mutation (G60R; 190070.0009) in a third patient, and 8 mutations in BRAF (e.g., 164757.0012) among 16 individuals.

Stark et al. (2012) reported 3 patients from 2 families with novel KRAS mutations (Y71H, 190070.0021 and K147E, 190070.0022, respectively) and a variable phenotype most consistent with a CFC-like syndrome. In the first family, both a son and mother carried the Y71H mutation, which the authors stated was the first documented vertically transmitted KRAS mutation. The proband in the second family, who had a de novo K147E mutation, was 1 of a female dizygotic twin pair; the other twin was unaffected.