Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or MEK2 and rarely in KRAS, a small GTPase. CFC is a multiple congenital anomaly disorder in which individuals may have craniofacial dysmorphia, heart issues, skin and hair anomalies, and delayed development. Pathogenic variants for CFC syndrome are usually considered de novo because vertical transmission has only been reported with MEK2 and KRAS. The index case was a 3-year-old male with features consistent with the clinical diagnosis of CFC. Sequencing revealed a previously reported heterozygous likely pathogenic variant BRAF p.G464R. Upon detailed family history, the index case\'s pregnant mother was noted to have similar features to her son. Targeted familial testing of the BRAF pathogenic variant was performed on the mother, confirming her diagnosis. Prenatal genetic testing for the fetus was declined, but postnatal molecular testing of the index case\'s sister was positive for the familial BRAF p.G464R variant. Functional analysis of the variant demonstrated increased kinase activity. We report the first identified vertically transmitted functional BRAF pathogenic variant. Our findings emphasize the importance of obtaining a comprehensive evaluation of family members and that activating pathogenic variants within the canonical MAPK cascade mediated by BRAF are compatible with human reproduction.

Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. \"RASopathies\" is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a \"RASopathy\" to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS.

OBJECTIVE: The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome), neurofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings.
METHODS: Review of the literature.
RESULTS: Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics.
CONCLUSIONS: Careful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development.

De novo germline mutations in HRAS cause Costello syndrome, with >95% of the mutations causing Costello syndrome affecting amino acid position 12 (p.Gly12) or 13 (p.Gly13). We report on a patient with de novo missense mutation causing an amino acid change at codon 146 of HRAS, c.436G > C:p.Ala146Pro, who presented with subtle dysmorphic features, failure to thrive, global developmental delay, and hypertrophic obstructive cardiomyopathy. Mutations affecting codon 146 are observed in <1% of patients with Costello syndrome. From literature search, there were only two other patients reported with mutations involving the same location. We summarized and updated their findings, and discussed evidence to show that these patients with less obvious signs of Costello syndrome may not necessarily run a more benign clinical course.

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis.

Costello syndrome is characterized by constitutional mutations in the proto-oncogene HRAS, causing dysmorphic features, multiple cardiac problems, intellectual disability, and an increased risk of neoplasia. We report a male infant with dysmorphic features, born prematurely at 32 weeks, who, during his 3-month life span, had an unusually severe and ultimately fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia. Molecular studies in this patient demonstrated the uncommon Q22K mutation in the HRAS gene, diagnostic of Costello syndrome. The major autopsy findings revealed hypertrophic cardiomyopathy, congenital myopathy, and a 1.4-cm pancreatic nodule that was positive for insulin expression and morphologically identical to a focal lesion of congenital hyperinsulinism. Sequencing of KCNJ11 and ABCC8, the 2 most commonly mutated genes in focal lesion of congenital hyperinsulinism, revealed no mutations. While hyperinsulinism is a recognized feature of RASopathies, a focal proliferation of endocrine cells similar to a focal lesion of hyperinsulinism is a novel pathologic finding in Costello syndrome.