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Cardio-facio-cutaneous syndrome (CFCS) is a rare disorder characterized by distinctive craniofacial appearance, cardiac, neurologic, cutaneous, and musculoskeletal abnormalities. It is due to heterozygous mutations in BRAF, MAP2K1, MAP2K2, and KRAS genes, belonging to the RAS/MAPK pathway. The role of RAS signaling in bone homeostasis is highly recognized, but data on bone mineral density (BMD) in CFCS are lacking. In the present study we evaluated bone parameters, serum and urinary bone metabolites in 14 individuals with a molecularly confirmed diagnosis of CFCS. Bone assessment was performed through dual X-ray absorptiometry (DXA); height-adjusted results were compared to age- and sex-matched controls. Blood and urinary bone metabolites were also analyzed and compared to the reference range. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFCS patients showed significantly decreased absolute values of DXA-assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls. BMD z-scores and t-scores (respectively collected for children and adults) were below the reference range in CFCS, while normal in healthy controls. These findings confirmed a reduction in BMD in CFCS and highlighted the importance of monitoring bone health in these affected individuals.

A female patient presented with developmental delay, distinctive facial features, and congenital anomalies, including a heart defect and premature lambdoid synostosis. The patient showed a paternally inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving the mitogen-activated protein kinase kinase 2 gene (MAP2K2), in which mutations cause the cardio-facio-cutaneous (CFC) syndrome. Reports of patients with overlapping 19p13.3 microdeletions of this region describe similar clinical manifestations including distinctive facial features: prominent forehead, horizontal/down-slanting palpebral fissures, long midface, pointed chin/angular jaw, sparse eyebrows, and underdeveloped cheekbones. Some of these findings overlapped to that of the patients with 16p13.11 microduplications and CFC syndrome. Although craniosynostosis was occasionally observed in patients with dominant-negative mutations in RAS/MAP kinase signaling genes (RASopathies) related to CFC syndrome, it was also reported in two patients with 16p13.11 microduplications. Genetic contributions of both chromosomal aberrations were discussed.

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.

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.

Cardiofaciocutaneous syndrome or CFC syndrome is a rare genetic disorder first described in 1986. It is one of the RASopathies involving multiple organs particularly the heart, skin and face affecting males and females equally. The phenotypic features overlap with 2 other conditions, the Noonan and Costello syndrome. We report on a 22-month-old boy with CFC syndrome presenting with typical craniofacial appearance, heart defects, ectodermal abnormalities, growth failure and developmental delay. Estimated population of affected individuals worldwide is a few hundreds.

We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy.

We report on three patients with probable cardio-facio-cutaneous (CFC) syndrome. They present clinical findings of this condition such as: growth failure, heart defects, typical craniofacial appearance, ectodermal abnormalities, and developmental delay. We also give a detailed review of the previously published articles on CFC syndrome and discuss the differences between CFC, Noonan, and Costello syndromes. Other differential diagnoses are considered.

We report on a 25-year-old woman with typical manifestations of the cardio-facio-cutaneous (CFC) syndrome, but without mental retardation. She had valvular and infundibular pulmonic stenosis, brittle and woolly hair with patchy alopecia, scant body hair, dry and hypohydrotic skin, and characteristic facial traits. To our knowledge, this is the first case of CFC syndrome without mental retardation but typical cutaneous findings.

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder that is characterised by facial dysmorphism, cardiac defects, mental retardation, typical ectodermal abnormalities and short stature. It is caused by germline mutations in BRAF, MEK1, MEK2 or KRAS and shows phenotypical overlap with other conditions caused by mutations in the RAS-MAPK pathway such as neurofibromatosis type 1, Noonan, LEOPARD, Costello and Legius syndromes. The identification of the underlying genetic defect opens new windows for therapeutic strategies in these RASopathies including CFC syndrome. Key Concepts: Mutations in genes coding for key components of the RAS-MAPK pathway are responsible for a group of inherited disorders (RASopathies). The RASopathies are clinically and molecularly related disorders characterised by variable cognitive deficits, growth retardation, facial dysmorphy, and congenital cardiopathies. CFC syndrome is characterised by the most severe intellectual disabilities seen in the RASopathies. Correcting cerebral RAS-MAPK signalling is a potential targeted treatment for learning disabilities in patients with a RASopathy. Keywords: CFC syndrome; RASopathies; BRAF; MEK; KRAS

We report on two boys with the cardio-faciocutaneous (CFC) syndrome, but without hyperkeratotic skin involvement. They showed most of the manifestations of the CFC syndrome: growth and developmental retardation, relative macrocephaly, distinct facial appearance, sparse hair, and heart defects. Their skin was not hyperkeratotic, but patient 1 had mild atopic dermatitis and keloid-like depigmented spots.

The author gives a personal account on how he was introduced to the field of clinical genetics as a student of John Opitz in Helena, MT. That process was facilitated by the study of several malformation syndromes. Particularly instructive were the approaches to the cardio-facio-cutaneous, the Perlman, and the FG syndrome. These three conditions are briefly revisited with a critical perspective, made possible by the elapse of 20 years, since the time when the author became acquainted with them.

We present a child with cardio-facio-cutaneous (CFC) syndrome with inadequate weight gain due to inadequate food intake. After correction of hyperemesis due to intestinal malrotation, she continued to fail to feed due to poor suck reflex. A review documented digestive system findings in 26 of 57 reported patients with CFC syndrome. Thus, digestive system dysfunction and malformation may represent an additional manifestation of the CFC syndrome.

Item does not contain fulltext CFC (cardiofaciocutaneous) syndrome (MIM 115150) has been considered by several authors to be a more severe expression of Noonan syndrome. Affected patients present with congenital heart defects, cutaneous abnormalities, Noonan-like facial features and severe psychomotor developmental delay. We have recently demonstrated that Noonan syndrome can be caused by missense mutations in PTPN11(MIM 176876), a gene that encodes the non-receptor protein tyrosine phosphatase SHP-2. In this report, we have evaluated the possible involvement of mutations in PTPN11 in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC based on OMIM diagnostic criteria was examined for mutations in the PTPN11 coding sequence by using DHPLC analysis. The results showed no abnormalities in the coding region of the PTPN11 gene in any CFC patient, nor any evidence of major deletions within the gene suggesting that mutations in other gene(s) are responsible for this syndrome.

An 11-year-old boy affected by mental retardation and seizures demonstrates congenital heart defect, many dysmorphic features and dry skin. His hair is sparse over the vertex with alopecia of the eyebrows and eyelashes. There are horny small papules evident in those areas. The diagnosis of cardiofaciocutaneous syndrome has been made. The relationship between cardiofaciocutaneous and Noonan syndrome is discussed.

We report two new patients, a boy and a girl, who show variable but specific manifestations of CFC syndrome. The patients differ in general appearance, severity of skin changes, cardiac involvement and in behaviour. The girl shows some additional clinical features such as easy bruising and altered sensation of the distal part of the limbs, which have never been observed in CFC syndrome, but have been described in a few patients with Noonan syndrome. We discuss our observations in relation to previous cases of CFC syndrome and the possible relationships between the Noonan and CFC syndromes. There is no doubt that the CFC and Noonan syndromes share many manifestations and it is extremely difficult if not impossible unequivocally to distinguish between these two syndromes.

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation and characteristic dysmorphic features. We, thus, report a rare case of this syndrome in a 1-year-old child who presented with typical features of CFC syndrome.

Summary The cardio-facio-cutaneous (CFC) syndrome has several features in common with the Noonan syndrome, but is distinguished by the presence of hyperkeratotic skin lesions, abnormal hair, and a lack of familial cases. We describe a family who clearly satisfy the criteria for the CFC syndrome, and show other features which have been reported in the Noonan syndrome but not in the CFC syndrome, namely a haemorrhagic diathesis and ocular abnormalities. This supports the concept that the CFC syndrome is a manifestation of the Noonan syndrome.

We describe a 6½-year-old girl with the cardio-facio-cutaneous (CFC) syndrome. She presents with most of the characteristics of this condition: typical facial changes, congenital heart defect, slow growth, ectodermal dysplasia, and developmental delay. Chromosome analysis disclosed a 46,XX,inv(7)(q21.2q 31.2) mat karyotype. © 1993 Wiley-Liss, Inc.

The distinction between the cardio-facio-cutaneous syndrome (CFC) and the Noonan syndrome (NS) has been based on the presence of a characteristic facies, abnormal hair and skin, and sporadic occurrence. However, all reports of the CFC syndrome comment on the similarity between it and NS, and its sporadic nature is now debatable. This report demonstrates the evolution of the clinical phenotype in a patient with the CFC syndrome and prompts us to question the validity of separating CFC from NS.

The clinicogenetic relationship between Noonan syndrome (NS) and Noonan-like syndromes (Costello syndrome (CS), cardio-facio-cutaneous (CFC syndrome) and the disruption of the RAS-ERK pathway makes for a fascinating story that has developed over the past decade, and is still developing. The discovery that the genes causing these syndromes encode proteins that converge on the same metabolic pathway facilitated understanding of the similarities that group these conditions within one family of syndromes.1 Nevertheless, their nosological classification continues to be a challenge. There is general agreement that NS is caused by mutations of PTPN11 (most cases), SOS1 or RAF1 , that CFC syndrome is caused by mutations of BRAF (most cases), MEK1 or MEK2 , and that CS is caused …

We read with interest the report by Lorenzetti and Fryn on a Noonan syndrome patient with retinitis pigmentosa, published in this issue of the Journal. We definitely concur with their diagnosis. Actually, the patient has all of those characteristics that we consider distinctive of Noonan syndrome vis-a-vis CFC syndrome, i.e., thick hair (not as sparse and woolly as in CFC syndrome), bushy eyebrows (not sparse or absent, as in CFC syndrome), absence of skin lesions (only dryness is mentioned by the authors), neck webbing (rarely reported in CFC syndrome), and normal intelligence. 7 refs.

We describe three patients, originating from three different Italian localities, affected by the cardio-facio-cutaneous (CFC) syndrome. In addition to a varying degree of mental retardation, these patients present characteristics consisting of a peculiar face with bitemporal frontal constriction and other anomalies involving the eyes, nose, ears, hair, skin, and heart that are consistent with this diagnosis.

We report on two additional patients with the cardiofaciocutaneous (CFC) syndrome, the first to be reported outside the United States. They have several of the characteristic manifestations of this new multiple congenital anomalies/mental retardation syndrome, namely, mental retardation, growth retardation, relative macrocephaly, unusual face, abnormal hair, skin involvement, heart defect, hernias, and splenomegaly. Similar to all previously reported cases, these also were sporadic and had normal chromosomes.

We describe two new cases of cardio-facio-cutaneous (CFC) syndrome, and underline the clinical variability of the CFC phenotype in our two patients presenting with border-line psychomotor development. The first patient showed some additional clinical manifestations, such as cryptorchidism and scoliosis, and the second one had atypical skin lesions.