Cardiofaciocutaneous Syndrome Phenotype in a Case with de novo Pathogenic Variant.

Cardiofaciocutaneous (CFC) syndrome is one of the developmental disorders caused by a dysregulation of the Ras/mitogen-activated protein kinase (MAPK) pathway. RASopathies share overlapping clinical features, making the diagnosis challenging, especially in the newborn period. The majority of CFC syndrome cases arise by a mutation in the , or (rarely) genes. Germline mutations are identified in a minority of CFC and Noonan syndrome cases. Here, we describe a patient with a mutation presenting with a CFC syndrome phenotype. The female patient was referred for genetic testing because of congenital exophthalmos. Her facial appearance is distinctive with a coarse face, exophthalmos, ptosis, downslanting palpebral fissures, hypertelorism, deep philtrum, downturned corners of the mouth, and a short neck. She suffered from feeding difficulties, poor weight gain, and developmental delay. The sequencing of the genes involved in the MAPK pathway () identified a heterozygous de novo NM_004985.4:c.173C>T (p.Thr58Ile) in the gene. Germline mutations have been identified in approximately 2% of the reported NS cases and less than 5% of the reported CFC syndrome cases. Because CFC and Noonan syndrome share clinical overlapping features, the phenotype caused by mutations is often difficult to assign to one of the 2 entities. The mutation that we detected in our patient was previously reported in a patient with an Noonan syndrome phenotype. However, our patient predominantly exhibits CFC clinical features. In our case, coarse facial appearance and severe developmental delay help discriminate CFC from Noonan syndrome. Thus, patient follow-up, especially for delayed motor milestones suspected from RASopathies, is important for the discrimination of overlapping conditions as in the abovementioned syndromes.