Cardiofaciocutaneous Syndrome 1

A number sign (#) is used with this entry because cardiofaciocutaneous syndrome-1 (CFC1) is caused by heterozygous mutation in the BRAF gene (164757) on chromosome 7q34.

Description

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and mental retardation (summary by Niihori et al., 2006). The heart defects include pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy. Some patients have ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosis-like condition. Typical facial characteristics include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Most cases occur sporadically, but autosomal dominant transmission has been rarely reported (Linden and Price, 2011).

Roberts et al. (2006) provided a detailed review of CFC syndrome, including a discussion of the phenotypic overlap of CFC syndrome with Noonan syndrome (NS1; 163950) and Costello syndrome (218040).

Genetic Heterogeneity of Cardiofaciocutaneous Syndrome

Other forms of cardiofaciocutaneous syndrome include CFC2 (615278), caused by mutation in the KRAS gene (190070); CFC3 (615279), caused by mutation in the MAP2K1 gene (176872); and CFC4 (615280), caused by mutation in the MAP2K2 gene (601263). The protein products of these causative genes, including BRAF, interact in a common RAS/ERK (see 601795) pathway that regulates cell differentiation, proliferation, and apoptosis (summary by Roberts et al., 2006).

Clinical Features

Reynolds et al. (1986) described 4 males and 4 females, each from a different family, with a previously undefined multiple congenital anomalies/mental retardation syndrome, which they designated the cardiofaciocutaneous syndrome. The manifestations included congenital heart defects, characteristic facial appearance, ectodermal abnormalities, and growth failure. The most common cardiac defects were pulmonic stenosis and atrial septal defect. Typical facial characteristics were high forehead with bitemporal constriction, hypoplasia of the supraorbital ridges, antimongoloid slant of palpebral fissures, depressed bridge of nose, and posteriorly angulated ears with prominent helices. The hair was usually sparse and friable. Skin changes varied from patchy hyperkeratosis to a severe generalized ichthyosis-like condition. There was no history of consanguinity. Neri et al. (1987) reported 2 cases; again, no parental consanguinity was observed. Roberts et al. (2006) provided follow-up on 6 of the patients originally reported by Reynolds et al. (1986). Three had been lost to follow-up, 1 was living independently with family, 1 was in a group home, and 1 had died of heart failure.

Verloes et al. (1988) reported 2 cases and pointed out the similarity to Noonan syndrome. They also suggested that the Noonan-like short stature syndrome with sparse hair described by Baraitser and Patton (1986) is the same disorder. The first of their patients had the habitus of Noonan syndrome associated with keratosis plantaris and nystagmus; the second had a somewhat Noonan-like face, macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy.

Chrzanowska et al. (1989) described an affected girl whose twin brother died shortly after birth and may have had the same malformation syndrome. The father and mother, aged 35 and 36 years, respectively, were healthy and nonconsanguineous. Mucklow (1989) described 1 case, and Sorge et al. (1989) described 3 cases. In addition to high cranial vault, bitemporal frontal constriction was noted.

Gross-Tsur et al. (1990) described what they alleged to be the sixteenth reported case of CFC. Roberts et al. (2006) noted that this child had Lennox-Gastaut encephalopathy.

Fryer et al. (1991) also emphasized the phenotypic overlap between the CFC syndrome and the Noonan syndrome. They presented findings in the patient reported by Navaratnam and Hodgson (1973), published photographs spanning from infancy to age 21 years, and showed the appearance of the pectus carinatum/excavatum and the keratotic skin lesions. Matsuda et al. (1991) described 2 Japanese boys with the CFC syndrome but without hyperkeratosis of the skin. Neri et al. (1991) concluded that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype; other members of the cluster were listed.

Turnpenny et al. (1992) described a 7-year-old girl whose features were thought to satisfy the diagnosis of CFC syndrome. The ectodermal features consisted of fine and sparse hair, thin and opalescent nails, finger tip pads, generalized cutaneous pigmentation, but no hyperkeratosis.

Although CFC syndrome is distinguished from Noonan syndrome by the presence of abnormal hair and hyperkeratotic lesions and by its usual sporadic occurrence, Ward et al. (1994) supported the suggestion of Fryer et al. (1991) that it falls 'within the clinical spectrum of the Noonan phenotype.' They described mother and daughter who had features consistent with the CFC syndrome but had other features which have been reported in the Noonan syndrome but not in the CFC syndrome, namely, hemorrhagic diathesis and ocular abnormalities. They were described as having ulerythema ophryogenes (keratosis pilaris affecting the follicles of the eyebrow hairs, associated with erythema, scarring, and atrophy). Krajewska-Walasek et al. (1996) reported 2 unrelated children (a boy and a girl) with CFC syndrome who had 'Noonan-like' face, sparse, thin, curly hair, and severe mental retardation. The girl also had altered sensation of the distal part of the limbs, which has been described in patients with Noonan syndrome but not in patients with CFC syndrome. Leichtman (1996) described a family suggesting that CFC syndrome is a variable expression of Noonan syndrome. He reported a 4-year-old girl with features sufficient to meet the criteria for CFC, including developmental delay, hypotrichosis, eczematic eruption, and characteristic facial and cardiac anomalies, whose mother demonstrated typical manifestations of Noonan syndrome.

Manoukian et al. (1996) reported the case of a 25-year-old woman with typical features of CFC syndrome but without mental retardation. She had valvular and infundibular pulmonic stenosis, brittle and woolly hair with patchy alopecia, scant body hair, dry and hypohidrotic skin, and characteristic facial traits. At the age of 3 years the patient had shown fullness of periorbital tissues, ectropion of the lower palpebral fissures, malar hypoplasia, bulbous nose, and hyperplasia of the helix and earlobes. At the age of 25 she showed downslanting palpebral fissures with scant eyebrows and absent eyelashes on the nasal side, edematous eyelids, ectropion of the lower eyelids, posteriorly angulated ears with hyperplastic helix and lobes, and webbed neck.

Wieczorek et al. (1997) described 3 patients in whom the diagnosis was considered to be CFC syndrome. They provided a detailed review of previously reported cases and discussed the differences from Noonan and Costello (218040) syndromes.

McGaughran (2003) reported the diagnosis of CFC syndrome in a 52-year-old woman who had short stature, a head circumference below the 50th centile, bilateral ptosis, fine, thin hair with frontal balding, posteriorly angulated ears with tipped-up ear lobes, a high, narrow palate, lax skin, and deep palmar creases. Ptosis and lax skin had been present since childhood. McGaughran (2003) stated that this was the oldest person that had been described with CFC syndrome.

Armour and Allanson (2008) reported the clinical features of 38 patients with genetically confirmed CFC syndrome. Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. Cardiac anomaly was present in 71% of individuals with the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: curly hair (92%), sparse hair (84%), and absent or sparse eyebrows (86%). The most frequent cutaneous features were keratosis pilaris (73%), hyperkeratosis (61%), and nevi (76%). Significant and long-lived gastrointestinal dysmotility (71%), seizures (49%), optic nerve hypoplasia (30%), and renal anomalies, chiefly hydronephrosis (20%), were among the less well known issues reported.

In 17 (52%) of 33 unrelated patients with a clinical diagnosis of CFCS, Sarkozy et al. (2009) identified heterozygous de novo mutations in the BRAF gene. The most common facial features included prominent forehead, bitemporal narrowing, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick lips, and low-set ears with thick helices. Pulmonary stenosis and hypertrophic cardiomyopathy were the most common cardiac defects, occurring in 90% and 55% of patients, respectively. Ectodermal anomalies included absent or hypoplastic eyebrows, curly, sparse hair, hyperkeratosis, and keratosis pilaris; hyperhidrosis was a common feature (78%). About half of patients had short stature, and most had some degree of neonatal growth failure with poor feeding. Most also had moderate to severe mental retardation, although 2 had normal cognition. Many had hypotonia or seizures. Nine of 17 patients had pigmentary skin changes, including 2 with a high number of lentigines.

Goodwin et al. (2013) evaluated the craniofacial features of 32 individuals ranging in age from 2 to 27 years with a clinical diagnosis of CFC who were ascertained from large conferences on the disorder. The most common features included relative macrocephaly (97%), high forehead (84%), bitemporal narrowing (84%), a convex facial profile (74%), and hypertelorism (65%)/telecanthus (100%). About half (52%) had hypoplasia of the superior orbital ridge, and only a few (10%) had micrognathia or a small mandible. Other common features were short nose (71%) and low-set (90%), posteriorly rotated (84%) ears with upturned lobes (52%). The patients also had a recognizable dental phenotype characterized by malocclusion, with open bite in which the anterior teeth were not in contact when the posterior teeth were in occlusion (37%). Many (19%) had a posterior crossbite, in which the maxillary posterior teeth are on the lingual side of the mandibular teeth instead of the buccal side. The majority of patients (80%) had a constricted high-arched palate and many showed tongue thrusting. However, dental development, eruption patterns, and enamel were similar to the general population. Individuals with BRAF mutations had a significantly higher incidence (92%) of high-arched palate compared with MEK1- or MEK2-positive individuals.

Inheritance

Bottani et al. (1991) reported a patient and reviewed the cases, all sporadic, reported to date. In 20 cases for which information was available, the average age of fathers at the birth of the child was 39 years. This evidence of paternal age effect significantly supports autosomal dominant inheritance. Corsello and Giuffre (1991) reported 2 unrelated boys with CFC syndrome. The parents were nonconsanguineous but the fathers were 45 and 50 years old. Lecora et al. (1996) reported that the mother and younger sister of a patient with CFC, originally described by Ghezzi et al. (1992), also had variable phenotypes consistent with CFC syndrome, thus suggesting autosomal dominant inheritance.

Diagnosis

Grebe and Clericuzio (2000) described 2 patients with severe manifestations of cardiofaciocutaneous syndrome. Based on these patients, diagnostic criteria for a severe phenotype of CFC syndrome were proposed. These criteria included macrocephaly; characteristic facial features; growth retardation; cardiac defect; sparse, curly hair; neurologic impairment/developmental delay; gastrointestinal dysfunction; ocular abnormalities/dysfunction; history of polyhydramnios; and hyperkeratotic skin lesions. The authors suggested that these stringent diagnostic criteria be used in future studies aimed at identifying a molecular basis for this condition.

Kavamura et al. (2002) created a clinical and objective method, called the CFC index, for the diagnosis of CFC syndrome. The method also differentiated CFC from Noonan and Costello (218040) syndromes.

Other Features

Van Den Berg and Hennekam (1999) reported a child with CFC who developed acute lymphoblastic leukaemia (ALL). The authors noted that malignancy had not been described previously in patients with CFC but had been in those with Noonan syndrome, and that in this group ALL was the most commonly described malignancy. Van Den Berg and Hennekam (1999) cited the report of Legius et al. (1998) and also noted that on the basis of this single case it remained uncertain whether malignancy was a manifestation of CFC or a coincidence in this child. This patient was found to carry a G469E mutation in the BRAF gene (164757.0014) by Niihori et al. (2006).

Molecular Genetics

The phenotypic overlap among CFC syndrome, Noonan syndrome, and Costello syndrome, and the finding of causative mutations for the latter syndromes in the PTPN11 and HRAS (190020) genes, respectively, suggested to Niihori et al. (2006) that the action of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome and Costello syndrome and, hence, possibly of CFC syndrome. To elucidate the molecular basis of CFC syndrome, Niihori et al. (2006) examined the downstream molecules of RAS in the signaling pathway and sequenced the entire 18 codons of BRAF in 40 individuals with CFC. They identified 8 mutations (e.g., 164757.0012) in 16 individuals. Niihori et al. (2006) also sequenced the entire coding regions of 3 Ras genes, HRAS, KRAS, and NRAS (164790), in genomic DNA from 43 individuals with CFC syndrome and identified 2 KRAS mutations: G60R (190070.0009) and D153V (190070.0010).

Rodriguez-Viciana et al. (2006) screened 23 CFC patients for mutations in BRAF. Eighteen of 23, or 78% of individuals, had mutations in BRAF; 11 distinct missense mutations clustered in 2 regions. Five individuals had a gln257-to-arg missense mutation (164757.0013) in the cysteine-rich domain of the conserved region 1 (CR1). The other cluster of mutations was in the protein kinase domain and involved exons 11, 12, 14, and 15. Five patients had heterogeneous missense mutations in exon 12. All parents and controls, totaling 40 phenotypically unaffected individuals, had none of these mutations, supporting the hypothesis that occurrence of CFC is sporadic. Rodriguez-Viciana et al. (2006) suggested that although the causative mutations in BRAF were heterogeneous, the distribution of mutations was specific and nonrandom. No frameshift, nonsense, or splice site mutations were detected in the cohort of patients; thus, BRAF haploinsufficiency is not a likely causative mechanism of CFC.

In 2 patients originally diagnosed with Costello syndrome but with features overlapping those of CFC, in whom no HRAS mutations were found (Estep et al., 2006), Rauen (2006) identified missense mutations in the BRAF gene (164757.0020 and 164757.0021, respectively). Rauen (2006) stated that Costello syndrome and CFC can be distinguished by mutation analysis of genes in the RAS/MAPK pathway.

In 17 (52%) of 33 unrelated patients with a clinical diagnosis of CFCS, Sarkozy et al. (2009) identified heterozygous de novo mutations in the BRAF gene. The mutations clustered in exon 6, encoding the cysteine-rich domain, and in exons 11 to 17, encoding the kinase domain. In vitro functional expression studies of selected variants showed variable gain of function, but little transforming ability; all mutations had less activating potential than the common V600E mutation (164757.0001).

Exclusion Studies

Because CFC syndrome had been considered to be a more severe variant of Noonan syndrome, Ion et al. (2002) screened for PTPN11 mutations in a series of 28 CFC patients using denaturing high-performance liquid chromatography (DHPLC), but found no abnormalities in the coding region of the gene. In an analysis of the PTPN11 gene in 96 Noonan syndrome patients, Musante et al. (2003) also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene.

Genotype/Phenotype Correlations

Niihori et al. (2006) compared the manifestations of KRAS-positive and BRAF-positive individuals and found similar frequencies of growth and mental retardation, craniofacial appearance, abnormal hair, and heart defects. However, they observed a difference between the 2 groups in manifestations of skin abnormality, including ichthyosis, hyperkeratosis, and hemangioma, which were observed in 13 BRAF-positive individuals but in none of the KRAS-positive individuals (P less than 0.05). That somatic mutations in BRAF have been identified in 60% of malignant melanoma or nevi (Garnett and Marais, 2004) suggested to Niihori et al. (2006) that BRAF has an important role in the skin.

Gripp et al. (2007) reported 13 unrelated patients ages 0 to 8 years with a clinical diagnosis of Costello syndrome (218040), Costello-like syndrome, or thought to have either CFC syndrome or Costello syndrome who were negative for mutations in the HRAS gene. De novo heterozygous BRAF or MEK1 mutations were identified in 8 and 5 patients, respectively. In a comparison to a group of previously published patients with HRAS mutations, Gripp et al. (2007) found several significant clinical differences between the 2 groups. Patients with an HRAS mutation and Costello syndrome tended to have polyhydramnios, ulnar deviation, growth hormone deficiency, and tachycardia more frequently than patients with BRAF or MEK1 mutations. Those with BRAF or MEK1 mutations had more cardiovascular malformations. Although the presence of more than 1 papilloma strongly suggested Costello syndrome over CFC, the authors noted that these lesions typically develop over time and thus may not be very helpful in the differential diagnosis of younger children. Gripp et al. (2007) concluded that the 13 patients in their study had CFC syndrome and not Costello syndrome, based on the clinical and molecular findings. The authors noted the phenotypic overlap between the 2 disorders, but suggested that Costello syndrome be reserved for patients with HRAS mutations.

Among 51 patients with CFC, Schulz et al. (2008) identified mutations in the BRAF (47%), MAP2K1 (9.8%), MAP2K2 (5.9%), and KRAS (5.9%) genes. Careful assessment of facial features suggested that patients with MAP2K1 mutations showed macrostomia and horizontal shape of the palpebral fissures, whereas those with MAP2K2 mutations had a long, narrow face with a high forehead, low-set ears, severe ptosis, epicanthal folds, and prominent supraorbital ridges.

In 6 patients with a clinical diagnosis of CFC, Nystrom et al. (2008) identified mutations in the BRAF (2), KRAS (1), MEK1 (1), and MEK2 (2) genes. A seventh patient with a diagnosis of CFC had a mutation in the SOS1 gene (182530), which is usually associated with Noonan syndrome-4 (NS4; 610733). An eighth patient with a diagnosis of Noonan syndrome was found to have a mutation in the BRAF gene, which is usually associated with CFC. Nystrom et al. (2008) concluded that the molecular and clinical overlap between CFC and Noonan syndrome is complex and suggested that they may even represent allelic disorders. However, Neri et al. (2008) disputed the diagnoses of 2 patients reported by Nystrom et al. (2008). Neri et al. (2008) concluded that the SOS1 mutation-bearing CFC patient actually had typical Noonan syndrome, and that the BRAF-carrying NS patient actually had typical CFC. Neri et al. (2008) stated that NS can be caused by mutations in the PTPN11 (176876), SOS1, and RAF1 genes, that CFC can be caused by mutations in the BRAF, MEK1, and MEK2 genes, and that the diagnosis of Costello syndrome should be restricted to patients with HRAS mutations.

History

Rauen et al. (2000) reported the case of a 19-month-old girl who presented with the phenotype of CFC syndrome, including characteristic minor facial anomalies, cardiac defect, ectodermal anomalies (keratosis pilaris), and developmental delay. The patient was found to have an interstitial deletion at 12q21.2-q22, proximal to the critical region for Noonan syndrome, suggesting that in this patient CFC is genetically distinct from Noonan syndrome. Rauen et al. (2002) reported an additional patient with an interstitial deletion cytogenetically identical to the one reported by Rauen et al. (2000). The patient was of XYY sex chromosome constitution. Microarray-based comparative genomic hybridization confirmed both the deletion and the second Y chromosome. The deletion on 12q spanned at least 14 Mb as indicated by the genomic positions of the 4 BAC clones included in the deletion. While the proband did not have the classic features of CFC, he had some dysmorphic craniofacial characteristics, ectodermal anomalies, and moderate developmental delay which were suggestive of CFC syndrome. Zollino and Neri (2000) looked for 12q21-q22 deletions in 7 patients with classic CFC syndrome using FISH with the same probe used by Rauen et al. (2000) and found no deletions. Based on phenotypic features, Zollino and Neri (2000) and Neri et al. (2003) argued that the patients presented by Rauen et al. (2000, 2002) did not have CFC. Rauen and Cotter (2003) stated that 'controversy exists as to whether CFC represents a separate entity or if CFC is part of the Noonan syndrome (NS) spectrum.' They pointed out the identification of mutations in the PTPN11 gene on chromosome 12q24.1 in patients with Noonan syndrome, which shares phenotypic features with CFC. In an Editor's Note, Carey (2003) stated that the idea that 12q21.2-q22 is a candidate region for CFC is not a conclusion, but a hypothesis.

Animal Model

Anastasaki et al. (2009) expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. Both kinase-activating and kinase-impaired CFC mutant alleles promoted the equivalent developmental outcome when expressed during early development. Treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway could restore normal early development. There was a developmental window in which treatment with an MEK inhibitor could restore the normal early development of the embryo without additional unwanted developmental effects of MEK inhibitor.

Inoue et al. (2014) created heterozygous knockin mice expressing Braf with a gln241-to-arg (Q241R) mutation, which corresponds to the most frequent mutation in CFC syndrome, gln257 to arg (Q257R; 164757.0013). Braf Q241R/+ mice showed embryonic or neonatal lethality, with liver necrosis, edema, craniofacial abnormalities, and heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction, and ventricular septal defects. Braf Q241R/+ embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels. Prenatal treatment with a Mek inhibitor partly rescued embryonic lethality in Braf Q241R/+ embryos, with amelioration of craniofacial abnormalities and edema. One surviving pup was obtained following treatment with a histone-3 demethylase inhibitor. Combined treatment with Mek and histone-3 demethylase inhibitors further increased the survival rate in Braf Q241R/+ embryos and ameliorated enlarged cardiac valves.