Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder, classified under the multiple congenital anomalies/mental retardation (MCA/MR) syndromes. The major characteristic of the disease is the distinctive facial appearance, which includes relative macrocephaly, short neck, high and prominent forehead, bitemporal constriction, short nose with depressed nasal bridge, prominent posteriorly angulated pinna, palpebral fissures, ocular hypertelorism, ptosis, and estropia. The patients have unusually sparse, brittle, and curly scalp hair, sparse or absent eyelashes and eyebrows, and display a range of skin abnormalities, ranging from dermatitis and follicular keratosis to hyperpigmentation and generalized ichthyosis. Congenital heart defects, especially valvar pulmonary stenosis and atrial septal defects are common. Affected individuals may show delayed growth, psychomotor retardation, and/or mental retardation.
Diagnosis of the syndrome relies totally on physical examination of the above symptoms. Other diseases like Noonan syndrome and Costello syndrome are very similar to CFC in their phenotypic manifestations, and may pose difficulties in diagnosis. Treatment is symptomatic.
Mutations in any of the three genes- V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), Mitogen-Activated Protein Kinase Kinase 1 (MEK1) and Mitogen-Activated Protein Kinase Kinase 2 (MEK2) have been shown to lead to CFC syndrome. The protein products of these genes are components of the Mitogen Activated Protein Kinase (MAPK) pathway, which is one of the most important molecular mechanisms involved in growth and differentiation. Therefore, disruption of their proper functioning results in developmental defects such as CFC.
Aglan et al. (2003) compared the clinical features of six Egyptian patients (two males and four females) diagnosed with CFC, with patients diagnosed with Noonan syndrome. Analysis involved three generation pedigree construction, clinical examination, anthropometric and IQ measurements, cytogenetic studies, echocardiography, and ultrasound examination. All cases of CFC were sporadic. Parental consanguinity was observed in 50% of the cases. Aglan et al. (2003) showed that in the cases they studied, clinical features could be used to differentiate between CFC and NS The important features which were found in a significantly higher frequency in CFC cases, compared to NS were gastrointestinal problems (66% CFC, 7% NS), bitemporal constriction (66% CFC, absent in NS), short nose (100% CFC, 29% NS), sparse hair (100% CFC, absent in NS), and relative macrocephaly (100% CFC, 7% NS). On the other hand, features like antimongoloid staining (57% NS, 17% CFC), ptosis (50% NS, 17% CFC), neck webbing (71% NS, absent in CFC), and shieldchest (64% NS, 17% CFC) were present in higher frequencies in NS cases. Application of Kavamura's scoring index on the patients diagnosed with CFC showed a high specificity, proving its usefulness. Aglan et al. (2003) proposed that gastro-intestinal manifestations also be added to this scoring index, and their results showed that comprehensive clinical examination and scoring indices are important towards identifying cases of CFC, and differentiating them from other symptoms with overlapping manifestations.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism (IEM) and other genetic disorders. Among the cohort with non-IEM related genetic disorders in whom mutational pathogenicity was confirmed, 1 patient harboring a mutation in BRAF was diagnosed with cardiofaciocutaneous syndrome 1. The patient clinically presented with developmental delay, cortical blindness, seizures, stridor, and constipation.
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