Cardiofaciocutaneous syndrome: a rare entity.

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation and characteristic dysmorphic features. We, thus, report a rare case of this syndrome in a 1-year-old child who presented with typical features of CFC syndrome.

Introduction

The cardiofaciocutaneous (CFC) syndrome (OMIM 115150) is a syndrome where patients have multiple congenital anomalies or mental retardation, failure to thrive, psychomotor delay, a characteristic face, congenital heart defects, and abnormalities of the skin, eyes, gastrointestinal tract and central nervous system. Occurrence is sporadic, with men and women equally affected. The syndrome was first described 20 years ago by Reynolds et al[1] in eight children. Additional reports soon followed and, according to a recent review,[2] about 59 patients have been reported, providing the basis for an accurate delineation of the phenotypic spectrum of the syndrome. Nevertheless, a question has lingered for many years whether CFC is a unique and separate condition, or a variant of the Noonan syndrome (OMIM 163950)[3-9] or of the Costello syndrome (OMIM 218040).[10] A useful diagnostic approach was provided with the creation of a CFC index based on 82 clinical traits and their frequencies in the population with the CFC syndrome.[11] However, matters changed radically only with the discovery of different genes whose mutations cause each one of these syndromes: the protein tyrosine phosphatase SHP-2 gene PTPN11 for Noonan syndrome,[12] HRAS for Costello syndrome,[13] and KRAS, BRAF, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2 for CFC.[1415]

Case Report

One-year-old Indian boy was referred to our center at 8 months of age with some dysmorphic features and developmental delay for evaluation. He was a product of a full-term normal delivery with a birth weight of 3.6 kg (more than the 95th percentile). He had transient neonatal jaundice which needed phototherapy but without any complications. Developmental history showed a delay from the beginning with the child unable to crawl, sit or hold objects in hand or produce any sounds like the normal children. Family history revealed the child being the third sibling after two normal children and two early abortions. There was no history of consanguineous marriage. No similar condition existed in the family.

Clinically his weight was 10 kg (90th percentile), height 73 cm (75th percentile), and head circumference 44.5 cm (25th percentile).

Dermatological evaluation showed a dysmorphic child with asymmetrical face, bitemporal narrowing and prominant metopic sutures, epicanthic fold, wide mouth, sparse hair, and absent eye brows [Figures 1a–c]. His skin was dry and mildly hyperkeratotic; eczematous lesions were found on his neck and extremities, keratosis pilaris on his arms [Figure 2], seborrheic dermatitis on his scalp, and miliaria on his back.

Figure 1a

Dysmorphic face with asymmetry, bitemporal narrowing and prominant metopic sutures, epicanthic fold, wide mouth, sparse hair and absent eye brows

Figure 1c

Sparse scalp hair

Figure 2

Dry and mildly hyperkeratotic skin. Eczematous lesions found on his neck and extremities, keratosis pilaris on his arms

Close-up view of facial features

There was an evidence of a vascular hemangiomatous plaque measuring 5 cm×3.5 cm involving the medial aspect of right lower limb [Figure 3].

A vascular hemangiomatous plaque involving the right lower limb

The results of routine hematological examination, blood biochemistry analysis, urinalysis, thyroid function tests, and serum zinc level assessment were within the normal ranges.

Echocardiography was suggestive of small secundum atrial septal defect and patent ductus arteriosus. Ultrasound of the abdomen showed mild hepatosplenomegaly. MRI scanning of the brain showed bifrontal subdural T2 hyperintense areas plus prominence of the frontotemporal subarachnoid space and corpus callosum hypoplasia. There was no evidence of hypoplasia.

Karyotype revealed 46 XY, involving 9p11q21.2 chromosome.

Discussion

CFC syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay.[14]

The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis.[16]

The diagnosis of CFC syndrome is purely clinical.[11]

It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous hemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe.[16]

Neurological involvement in the CFC syndrome is extensive, and can involve functions of the cortex, brain stem and ventricular system. Mental retardation and global developmental delay are found in most (81%) cases.[17]

We established the diagnosis in our patient based on typical dysmorphic features concordant with CFC syndrome. Noonan syndrome and Costello syndrome, especially the former, can be phenotypically similar to CFC syndrome and should be excluded.[18] Noonan syndrome differs by less severe psychomotor delay bordering to normality, low posterior hairline with thick hair, cubitus valgus, neck abnormalities, ectodermal involvement characterized by nevi, café-au-lait spots, familial occurrence.[4] Costello syndrome differs by the presence of ‘coarse’ face, nasal and/or anal papillomata and a predisposition to child tumors such as neuroblastoma, redundant skin of hands and feet with deep palmar and plantar creases, elbow joint limitation.[18]