Cardio-facio-cutaneous syndrome: Does genotype predict phenotype?

Department of Genetics at Children’s Hospital of Eastern Ontario.
American Journal of Medical Genetics Part C Seminars in Medical Genetics (Impact Factor: 3.91). 05/2011; 157(2):129-35. DOI: 10.1002/ajmg.c.30295
Source: PubMed


Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10–30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype–phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (approximately 75%), while 46 (approximately 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413–427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype–phenotype correlation, being more common in individuals with a BRAF mutation.

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Available from: Martin Zenker, Oct 04, 2015
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    • "In subjects with cardiofaciocutaneous syndrome (CFCS, MIM 115150), measurements at birth tend to be normal, but postnatally failure to thrive (78%) commonly occurs due to severe feeding difficulties. Two thirds of individuals exhibit stature below the 3rd centile [Allanson et al., 2011], and W is also generally below the normal growth curve [Roberts et al., 2006]. In contrast, prenatal overgrowth with relatively high birth W (>50th centile in 89%) [Hennekam, 2003] is typical of CS, likely caused by fetal hydrops [Lin et al., 2009]. "
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    ABSTRACT: RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2015; DOI:10.1002/ajmg.a.37260 · 2.16 Impact Factor
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    • "It may be by chance that MEK2 mutations predominate among the rare familial cases of CFC syndrome. There is no strict genotype–phenotype correlation when clinical features of CFC patients mutated in the different genes are compared [Allanson et al., 2011]. All mutations reported in familial CFC syndrome represent rare or even private mutations and are associated with only minor neurological and intellectual impairment in affected adults. "
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    ABSTRACT: Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(2). DOI:10.1002/ajmg.a.36429 · 2.16 Impact Factor
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    • "Short stature is one of the cardinal features of CFC syndrome. Allanson et al (1) reported that two-thirds of patients with CFC had a stature under the 3rd percentile. The underlying cause of short stature in CFC and NS may be similar since both of these syndromes are caused by a germline mutation of the same MAPK pathway that regulates cell differentiation, proliferation and apoptosis (16). "
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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.
    Journal of Clinical Research in Pediatric Endocrinology 03/2014; 6(1):55-8. DOI:10.4274/Jcrpe.1151
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