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Armour, C. M. & Allanson, J. E. Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. J. Med. Genet. 45, 249-254

Journal of Medical Genetics (Impact Factor: 5.64). 05/2008; 45(4):249-54. DOI: 10.1136/jmg.2007.054460
Source: PubMed

ABSTRACT Cardio-facio-cutaneous syndrome (CFC) is a multiple congenital anomaly/mental retardation syndrome named because of a characteristic facies, cardiac anomalies, and ectodermal abnormalities. While considerable literature describes the main features, few studies have documented the frequencies of less common features allowing a greater appreciation of the full phenotype.
We have analysed clinical data on 38 individuals with CFC and a confirmed mutation in one of the genes known to cause the condition. We provide data on well-established features, and those that are less often described.
Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. 71% of individuals had a cardiac anomaly, the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: 92% had curly hair, 84% sparse hair, and 86% absent or sparse eyebrows. 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.
This study reports a broad range of clinical issues in a large cohort of individuals with molecular confirmation of CFC.

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    • "For many cases neonatal data were also available. Information on prenatal manifestations was assembled for 257 cases including: 94 cases with NS [Witt et al., 1987; Benacerraf et al., 1989; Izquierdo et al., 1990; Donnenfeld et al., 1991; Sonesson et al., 1992; Nisbet et al., 1999; Achiron et al., 2000; Bradley et al., 2001; Menashe et al., 2002; Witters et al., 2002; Eccles et al., 2003; Gandhi et al., 2004; Ragavan and Vause, 2005; Schluter et al., 2005; Becker et al., 2007; Kiyota et al., 2008; González-Huerta et al., 2010; Houweling et al., 2010; Bakker et al., 2011; Baldassarre et al., 2011], 94 cases with CS [Der Kaloustian et al., 1991; Martin and Jones, 1991; Zampino et al., 1993; Johnson et al., 1998; Kerr et al., 1998; van Eeghen et al., 1999; Sigaudy et al., 2000; Gripp et al., 2002; Kaji et al., 2002; Van den Bosch et al., 2002; Estep et al., 2006; Gripp et al., 2006; Levaillant et al., 2006; Lo et al., 2008; Kuniba et al., 2009; Lin et al., 2009; Smith et al., 2009], and 69 cases with CFCS [Reynolds et al., 1986; Chrzanowska et al., 1989; Borochowitz et al., 1992; Somer et al., 1992; Lopez-Rangel et al., 1993; McDaniel and Fujimoto, 1997; Gripp et al., 2007; Armour and Allanson, 2008; Witters et al., 2008].Of these cases neonatal findings were available for 205 cases including: 94 cases of NS, 45 of CS, and 66 of CFCS. Not all subjects had information available about each clinical finding. "
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    ABSTRACT: The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 11/2014; 164A(11). DOI:10.1002/ajmg.a.36737 · 2.05 Impact Factor
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    • "Delayed puberty is expected in cases with CFC, as is true for other RASopathies, NS and CS, due to their genotype-associated phenotypic similarities (10,11). However, cases with early puberty have also been described in all three of these syndromes (12,13,14). Our patient was a CFC case who developed idiopathic central precocious puberty at age 7.5 years. "
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    ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is a rare disorder characterized by craniofacial dysmorphia, ectodermal abnormalities, cardiac malformations, as well as growth and developmental delay. Although some endocrine abnormalities have been reported in this syndrome, very little is known about CFC syndrome-related endocrine disorders. A 7.5-year-old boy was admitted to our endocrinology clinic with the complaint of short stature. He had a height of 103 cm [-4 standard deviation (SD)], a weight of 16 kg (<3th percentile, -1.7 SD), a facial appearance typical for the CFC syndrome, optic nerve hypoplasia and pulmonary stenosis. Genetic investigation revealed a heterozygous mutation in exon 3 of the MEK1 gene, c.389A>G (p. Y130C). During his long-term follow-up, the patient developed a variety of endocrine disorders including precocious puberty, growth hormone deficiency and hyperprolactinemia.
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    • "In particular, BRAF mutants are the most common in CFC syndrome; their gene product is highly expressed in the brain and plays important roles in myelination and hippocampus-dependent learning [3] [4]. A few recent reports have focused on the neurological symptoms of CFC syndrome, describing the complication of epilepsy and neuroradiological findings in this entity [5] [6]. However, detailed information on individual patients, including the treatment course of epilepsy, has not been provided. "
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    ABSTRACT: A girl with cardio-facio-cutaneous (CFC) syndrome due to a BRAF gene mutation (c.1454T→C, p.L485S) experienced repetitive epileptic spasms at the corrected age of 4 months. Electroencephalograms revealed hypsarrhythmia, and magnetic resonance imaging identified delayed myelination and a hypoplastic corpus callosum. Various antiepileptic treatments, including adrenocorticotropic hormone therapy, were ineffective, although transient seizure control was achieved by a ketogenic diet and clorazepate dipotassium. However, seizures with epileptic foci at the bilateral posterior temporal areas re-aggravated and remained intractable; severe psychomotor delay persisted. This case indicated that infantile spasms in CFC syndrome can be difficult to control and may be accompanied by severe psychomotor retardation and abnormal myelination.
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