Paula and Bobby
Parents of Lillie
What is Cardiofaciocutaneous syndrome?
Cardiofaciocutaneous syndrome is a rare genetic disorder that presents with very distinct facial characteristics and a wide range of health conditions that affect the skin and hair of individuals affected. Heart defects are also common with the syndrome.
It belongs to the RASopathies group of conditions distinguished by their genetic causes and features. Other syndromes within this group include Costello and Noonan syndrome.
What gene changes cause Cardiofaciocutaneous syndrome?
The syndrome occurs due to mutations of the following genes: BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), KRAS. The mutations are believed to be mainly spontaneous and not inherited.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
What are the main symptoms of Cardiofaciocutaneous syndrome?
The main symptoms of the syndrome are global developmental delay and intellectual disability.
Feeding problems are also common which in turn triggers a failure to thrive.
Congenital heart defects are another common symptom of the syndrome, specific heart defects associated with the syndrome may include pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy.
Issues with the eyes, vision and sight are also common.
Physical features of the syndrome include a prominent forehead, an abnormal narrowing of both sides of the forehead, a short nose and little or no eyebrows and eyelashes.
Individuals with the syndrome are also characterized by their sparse, brittle and curly hair. Many individuals suffer from skin conditions ranging from dry skin to the more severe hyperkeratosis.
How does someone get tested for Cardiofaciocutaneous syndrome?
The initial testing for Cardiofaciocutaneous syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Cardiofaciocutaneous syndrome
Cardio-facio-cutaneous syndrome has many features in common with Noonan syndrome, but it is a separate entity. The cardiac features are variable, but a pulmonary stenosis is the most common, next being an ASD. The facial features are similar to Noonan syndrome, but the hair is especially sparse, friable and curly. The head is relatively big when compared with height and there is a noticeable bi-temporal constriction. The skin is dry, and hyperkeratotic lesions develop, especially over the extensor surfaces. There might be true ichthyosis. The condition was named by Reynolds et al., (1986). Baraitser and Patton (1986) probably described the same condition. Costello et al., (1977) (qv) described similar cases with nasal papillomata. This is a separate condition.
Ades et al., (1992) reported a case with segmental optic nerve dysplasia and poor development of papillomacular bundles. Young et al., (1993) reviewed the ophthalmological findings in three cases, and the cases from the literature. They found strabismus and ptosis in about 50% and nystagmus in 30%. Dunya et al., (1993) reported a case with a retinal dystrophy. Lorenzetti and Fryns (1996) reported a possible case with overlapping features of Noonan syndrome who had retinitis pigmentosa. Kiss and Torok (1992) reported two likely cases under the designation of Salamon syndrome. No heart defects were mentioned but the other features were characteristic for CFC syndrome. Fryns et al., (1992) and Ward et al., (1994) reported possible dominant families, however, the affected individuals did not have as severe manifestations as some other cases in the literature and these families may suggest further evidence of a 'Noonan-CFC spectrum'. Leichtman (1996) reported a 4 1/2-year-old girl with convincing features of the condition whose mother had classical Noonan syndrome. McDaniel and Fujimoto (1997) reported a case with intestinal malrotation. van den Berg and Hennekam (1999) report a five-year-old girl with features of the condition who developed acute lymphoblastic leukaemia. Two further cases with overlapping features of Noonan and CFC syndromes were reported by Krajewska-Walasek (1996). Manoukian et al., (1996) reported a 25-year-old female with some features of the condition who had normal intelligence. However, she could have had simple Noonan syndrome. The mother and daughter reported by Lecora et al., (1996) may well have had NF1 with features of Noonan syndrome. Sabatino et al., (1997) reported a follow up of two cases revealing significant developmental delay. Legius et al., (1998) reported a family where some cases had features of CFC syndrome (although relatively mildly). The gene mapped to the Noonan region.
Grebe and Clericuzio (2000) reported two patients with features of the condition, and outlined diagnostic criteria. Kavamura et al., (2002) report a CFC index for the diagnosis of the condition. However, application of this index appears to be very time consuming and its validity as a diagnostic tool appears to be unsubstantiated. Ion et al., (2002) could find no evidence of PTPN11 mutations in 28 cases of CFC and neither could Kavamura, in 10 cases or Musante et al., (2003) in five cases, or Troger et al., (2003) in 18 cases of CFC syndrome. Schollen et al., (2003) reported a large family segregating for Noonan syndrome previously reported by Legius et al., (1998) and Fryns et al., (1992). Two brothers in the family are said to have a phenotype suggestive of CFC syndrome with mild mental retardation, dry scaly skin and sparse scalp hair. Rauen et al., (2000) reported an 18-month-old girl, apparently with features of the condition, who had 12q21.2->q22 deletion, not thought to encompass the Noonan syndrome locus. Unfortunately, clinical photographs were not published. The further case with a 12q21.2-q22 deletion reported by Rauen et al., (2002) as having features of CFC syndrome, is somewhat unconvincing. See also comments by Neri et al., (2003) and James et al., (2005). Ishiguro et al., (2002) reported a case associated with moyamoya syndrome. Chan et al., (2002) reported a case with a spontaneous chylothorax. Some cases have rather a coarse facial appearance, and as an enlarged liver and spleen have been found many patients have been investigated for a storage disorder, but nothing has been detected. Most cases have been isolated. Leukaemia might be an occasional manifestation (Makita et al., 2007). An excellent AD family with a MEK2 mutation was reported by Linden and Price (2011). McGaughran et al., (2003) reported a 52-year-old woman with features of the condition. Additional features (islet cell hyperplasia, lymphoid depletion, thymus atrophy and a peripheral neuropathy with onion bulbs) were reported by Manci et al., (2005). The condition has now been mapped, and mutations found in KRAS and BRAF. (Niihori et al., 2006). These are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth and death of cells. Niihori et al., (2006) found that those with BRAF mutations had the classical skin changes, but not those with KRAS mutations. The latter could easily be mistaken for Noonan or Costello syndrome - see elsewhere. Rauen (2006), reported three patients, thought to have Costello syndrome (there were no cardiac lesions and they were HRAS negative), who turned out to have CFC with BRAF mutations (in two). She points out the usefulness of mutation analysis in distinguishing the two conditions. In a series of patients with a KRAS mutation, the clinical phenotype ranged from Noonan, to CFC and even Costello syndrome (Zenker et al., 2007). One of the Costello patients had a Dandy-Walker malformation and although all the CFC patients with KRAS mutations had sparse hair, none had hyperkeratosis or ichthyosis. Tang et al., (2007) reported a patient with a KRAS mutation and an ulcerating hemangioma. The overlap of CFC with Costello was emphasised by Narumi et al., (2007). Between 30-40% of patients with the CFC mutation (BRAF, MAP2K1/2) had wrinkled palms and soles, hyperpigmentation and joint hyperextension, features thought common to Costello syndrome. Nava et al., (2007) suggest, that unlike Costello where patients should have an HRAS mutation, those with BRAF, KRAS, MEK1 and two mutations should be accorded the diagnosis of CFC or Noonan syndrome dependent on the phenotype. SOS1 mutations (see Noonan syndrome) can also cause this phenotype (Narumi et al., 2008).
Note that some patients might early-on be thought to have mitochondrial disease (Kleefstra et al., 2011). A peripheral neuropathy in a mother and son with KRAS mutations was reported by Stark et al., (2012). Four patients were reported by Wright et al., (2011) with 17q21.31 microdeletions who had skin hyperpigmentation, numerous nevi and coarse facial features. Wright et al., (2011), suggest that this microdeletion should be in the differential diagnosis of CFC.
Note the four-generation family with a MEK2 mutation reported by Rauen et al., (2010) and the father and son with mild phenotype (Karaer et al., 2015).
Kimiko et al. (2017) reported patients with craniosynostosis and Noonan syndrome (mutations in PTPN11) and CFC syndrome (mutations in BRAF or KRAS).
Two siblings with heterozygous BRAF c.770A> G (p.Gln257Arg) mutation were reported by Geoghegan et al., (2018). The mutation was not found in parental leukocyte DNA and it was presumed to be a case of gonadal mosaicism.
Bessis et al. (2018) summarized dermatological findings in 45 mutation-positive individuals. Hair abnormalities included scarce/absent eyebrows in 73% and wavy or curly hair in 69%. Skin findings were keratosis pilaris (82%), ulerythema ophryogenes (44%), multiple melanocytic naevi (29%) and palmo-plantar hyperkeratosis (27%). Oral acitretin was beneficial for management of palmo-plantar hyperkeratosis, whereas treatment of ulerythema ophryogenes by topical 1% sirolimus was unsuccessful.
* This information is courtesy of the L M D.
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