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Cardiofaciocutaneous (CFC) syndrome is a RASopathy phenotypically characterized by facial, cardiac, and ectodermal abnormalities. The extent to which this phenotype is expressed in the affected fetus is unclear, and a better understanding of the fetal autopsy findings in CFC syndrome could facilitate diagnosis and understanding of the developmental effects of dysregulated BRAF activity. Here we describe the fetal autopsy findings in a case of CFC syndrome in a 17-week fetus with a novel BRAF mutation that demonstrates potential similarities and differences with the postnatal presentation of CFC syndrome.

Costello syndrome (CS; MIM 214080) is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac abnormalities, ectodermal and musculoskeletal anomalies, endocrinopathy, developmental delay, and a predisposition to neoplasia both benign and malignant. In this study, we examined a large, well-characterized cohort of patients with the clinical diagnosis of CS. We sequenced HRAS in 36 unrelated individuals with the clinical diagnosis of CS and three sets of parents and 10 normal controls. We screened for HRAS coding region mutations in an effort to define HRAS mutations in CS and attempt to establish a possible genotype-phenotype correlation. In addition, we sequenced HRAS to establish loss of heterozygosity in a rhabdomyosarcoma and fibrosarcoma from a CS patient. HRAS mutations were identified in 33 out of 36 (92%) patients with the clinical diagnosis of CS. Mutations were found in codon 12 or 13. Two different missense point mutations were identified in codon 12: 34G9A and 35G9C, predicting an amino acid substitution of gly12ser and gly12ala, respectively. The 34G9A transition mutation, the most common mutation observed in this cohort of patients, was found in 30 of 33 patients. Two patients were found to have a codon 12 35G9C transversion. One patient in the cohort had a codon 13 mutation: 37G9T transversion, predicting an amino acid substitution of gly13cys. Parental DNA samples from three CS patients with the 34G9A mutation did not harbor a mutation. HRAS was sequenced from DNA isolated from a rhabdomyosarcoma and fibrosarcoma from a patient who had the germline activating mutation 34GA. Sequence analysis demonstrated LOH of the wild-type allele of HRAS as demonstrated by detection of only 34A in exon 1. Our data show that the majority of Costello syndrome patients have de novo heterogeneous HRAS mutations. Furthermore, tumorigenesis in Costello syndrome patients is accompanied by additional somatic changes affecting the HRAS gene.

We evaluated a mildly retarded pregnant young African American whose family history suggested cultural-familial retardation. Dysmorphic features included a long face, epicanthal folds, and down-turned mouth corners. She had a history of serious behavior problems starting in preschool and had been intermittently drug addicted. A high-resolution karyotype revealed a duplication of 4p at 4p16.3, confirmed by FISH with the D4S96 probe. Amniocentesis utilizing interphase FISH found this duplication in her pregnancy and again in two subsequent pregnancies. The two older children have shown normal developmental milestones with borderline speech delay whereas the third child has significant delays. None have striking dysmorphic features and all are > 75% for growth parameters. In her 4th pregnancy the mother sought prenatal diagnosis at 29 weeks9 gestation. Ultrasound revealed ventriculomegaly. Amniocentesis FISH results were equivocal. At birth the female infant was hypotonic and had dysmorphic features similar to her mother9s. FISH and array comparative genomic hybridization (array CGH) studies were undertaken to clarify the prenatal studies. CGH confirmed a duplication of 4p and, interestingly, identified a 22q11.2 duplication. FISH with D4S96 and TUPLE1 probes confirmed both duplications. Family studies utilizing FISH determined that the 22q11.2 duplication was de novo in child #4. No well-defined phenotype has been reported in the few published patients with microduplications of 4p16.1. To date, 21 children with a variable phenotype have been reported with microduplications in the 22q11.2 VCFS region (AJMG 2005;137:47). Most have been discovered incidentally in patients referred for 22q11.2 deletion FISH. In addition to its utility in the detection and confirmation of telomeric deletions, array CGH appears to be useful in the detection of small duplications not easily detectable by FISH. Our experience suggests that the combination of FISH and CGH can be a powerful tool in the evaluation of families with apparent cultural-familial mental retardation. A family history of mental retardation might prompt consideration of array CGH when conventional studies are negative.