Discussion:
Cardiofaciocutaneous (CFC) syndrome was first described by Reynolds et al. in 1986 (2). This syndrome is a genetic disorder with autosomal dominant transmission caused by germline pathogenic variants in theBRAF (75%), mitogen-activated protein kinase kinase 1 (MAP2K1 ), mitogen-activated protein kinase kinase 2 (MAP2K2 ), or KRAS genes (3). No epidemiological studies accurately estimate the worldwide prevalence of the CFC syndrome (4).
The syndrome is a member of a family of syndromes referred to as RASopathies. RASopathies are caused by germline mutations in genes encoding the RAS/MAPK signaling pathway and share overlapping clinical features. It is difficult to make a diagnosis based solely on the physical examination (7); therefore, a molecular genetics study is necessary for a definitive diagnosis.
Various organs can be involved in CFC syndrome. Clinical features include:
The clinical findings of CfC syndrome often overlap with other RASopathies, particularly Noonan syndrome. However, substantial mental disorders and cutaneous ectodermal abnormalities like ulerythema ophryogenes (seen in our case) suggest CFC syndrome (8). Other differential diagnoses that CFC syndrome can be mistaken with include Noonan syndrome, Costello syndrome, Leopard syndrome, Noonan-like syndrome with loose anagen hair, and Turner syndrome (7).
The RAS/MAPK pathway plays an essential role in regulating cell proliferation, differentiation, survival, and death. Therefore, somatic mutations in genes encoding proteins from this pathway can be oncogenic. Unlike other RASopathies, CFC syndrome does not increase the risk of malignancy (5). However, the potential risk should not be ignored, and patients should be followed up.
Ulerythema ophryogenes, also known as keratosis pilaris atrophicans faciei, is a rare dermatologic disorder presenting with inflammatory keratotic papules in the outer portion of the eyebrows. It has been associated with several genetic syndromes caused by dysfunction of the MAPK/Ras–signaling pathways, such as cardio-facio-cutaneous syndrome and Noonan syndrome. Treatment of ulerythema ophryogene is challenging, and topical medications have been used including topical steroids, tacrolimus, and pimecrolimus, retinoids, and topical keratolytics such as such as urea, lactic acid, or salicylic acids had little effect (6).
As CFC syndrome is a developmental condition, abnormalities in vital organs may present from infancy to adulthood, so making the diagnosis is crucial in planning the patient’s management and monitoring (10). Therefor, in childrens presenting with ulerythema ophryogenes, if there are any suspicious findings, clinicians should consider several genetic syndromes such as CFC syndrome and refer the patient for further workup. In our case, a multidisciplinary team consisting of a dermatologist, geneticist, cardiologist, and orthopedist and ophthalmologist evaluated the patient and devised the management and follow-up plan.