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:
- Craniofacial dysmorphism with a short webbed neck, relative
macrocephaly, high forehead, bitemporal constriction, supra-orbital
hypoplasia, hypertelorism, epicanthal folds, ptosis, down slanting of
palpebral fissures, low-set ears, and a short nose with a depressed
nasal bridge (9);
- A short stature;
- Neurological involvement such as developmental delay, cognitive
impairment, hypotonia, and epilepsy;
- Gastrointestinal problems such as gastroesophageal reflux, oral
aversion, and gastrointestinal dysmotility (2);
- Congenital cardiac defects;
- Ectodermal abnormalities such as short, thin, and curly hair,
ichthyosis, ulerythema ophryogenes, alopecia of the eyebrows and
eyelashes, follicular hyperkeratosis, palmoplantar hyperkeratosis, and
hyperplastic skin (3, 4, 9);
- Other cutaneous manifestations: slow growth of nails, folding of the
earlobes, acanthosis nigricans, hyperplastic nipples,
hyperpigmentation, and hemangioma (4).
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.