Since the original description in 1986, it has taken 20 years to discover genes whose mutations cause the CFC syndrome and to indisputably establish this condition as a distinct genetic entity, with autosomal dominant heritability. The nosological tangle involving the CFC, Noonan and Costello syndromes was partly solved by the discovery in 2001 of PTPN11
as a gene responsible for a large proportion of patients with the Noonan syndrome.15
Reports soon followed, showing that PTPN11
mutations are not found in those with a firm clinical diagnosis of the CFC syndrome.20,27
Further clarifying evidence was provided by the report in 2005 that the Costello syndrome is caused by HRAS
These mutations were also shown not to be involved in the CFC syndrome.54
The final evidence came with the recent discovery that yet other genes cause the CFC syndrome. Rodriguez‐Viciana et al
studying 23 individuals with the CFC syndrome, found 11 different mutations of BRAF
in 18 of them, mutations of MEK1
in two and of MEK2
in one person. All of these were de novo mis‐sense mutations, suggesting a gain‐of‐function effect. Likewise, Niihori et al
studying a non‐overlapping group of 43 patients with the CFC syndrome, found eight different de novo mis‐sense mutations in BRAF
in 16 and also de novo mis‐sense mutations in KRAS
in three of them. All patients from Niihori et al
group testing positive for any one of the reported mutations had a typical CFC phenotype (growth failure, mental retardation, relative macrocephaly, characteristic face, curly and sparse hair, heart defects). On the other hand, not all typical cases of the CFC syndrome have one of the known mutations. Out of 10 bona fide cases described by Kavamura et al
only five tested positive for a mutation (Dr Aoki, personal communication, 2006). With respect to genotype–phenotype correlations, Niihori et al18
found that skin abnormalities were present in BRAF
‐positive patients, but not in KRAS
‐positive ones. No other major differences were noted. By pooling data from the two reports (table 5), there are 13 different BRAF
mutations, Q257R being the most common (n
Table 5Genes involved in the causation of the cardiofaciocutaneous, Noonan and Costello syndromes
The protein products of the CFC genes and those of HRAS
involved in the causation of Costello syndrome,16
and those of PTPN11
in the Noonan syndrome15
(table 5), all have a role in the RAS—extracellular signal‐regulated kinase (ERK) pathway (fig 3). RAS
genes encode guanosine triphosphate‐binding proteins that serve as molecular on–off switches that activate or inhibit downstream molecules. It is a signalling pathway that is important for cell proliferation, growth and death. When dysfunctional, it can cause cancer. A major proportion of mutations are gain‐of‐function mutations, as shown by in vitro assays, and stimulate the RAS–ERK pathway. This might explain the increased incidence of solid tumours (rhabdomyosarcoma, ganglioneuroblastoma, bladder carcinoma, etc) in patients with the Costello syndrome and of haematopoietic malignancies in those with the Noonan syndrome.62
Conversely, no increased incidence of tumours has been noted so far in patients with the CFC syndrome. It is not clear whether acute lymphoblastic leukaemia in one patient with a BRAF
should be considered to be a component manifestation of the syndrome or just a coincidence. However, increased cellular proliferation could explain some of the clinical findings in the CFC syndrome, such as hyperkeratosis and hypertrophic cardiomyopathy. Still, the major effect of all described mutations seems to take place during development, explaining psychomotor retardation and physical anomalies, the common denominator of all three syndromes.
Figure 3RAS–extracellular signal‐regulated kinase (ERK) signalling pathway connecting pathogenetically the cardiofaciocutaneous (CFC), Costello and Noonan syndromes. Inactive HRAS and KRAS (green outline) are activated (red outline) (more ...)
Many important details need further clarification through the discovery of additional causative genes. For instance, a good proportion of patients with the Noonan syndrome do not have a PTPN11
mutation and, although a recent report established that KRAS
mutations can also cause the Noonan syndrome, mutations were found in only a small proportion of cases. These individuals were described to have more severe features than would be expected in typical Noonan syndrome.57
The complexity of the issue is well considered by Bentires‐Alj et al
who dissected the many components of the RAS pathway in relation to the Noonan, CFC, Costello and neurofibromatosis syndromes. At the moment, however, there are more questions than answers in trying to establish why pathogenetically related syndromes display major phenotypic differences.
Yet, we can firmly state that the CFC, Noonan and Costello syndromes are genetically heterogeneous. As they are all caused by mutations in genes whose protein products are part of the RAS–ERK pathway, we also understand, at least partly, why they are phenotypically similar. Further clarification may result from new molecular findings also, but perhaps more likely, and from a more detailed phenotypic description of the various affected patients.
Virtually every well‐defined condition or syndrome in medical genetics (ever more frequently causally identified) has a classic historical precedent as de Lange had in Brachmann, Étienne‐Louis Arthur Fallot (tetratology) in Niels Stensen and Johann Friedrich Meckel the Younger (the latter fully aware of the resulting defect in oxygenation), Turner (45,X) in Ullrich and George Fraser in the German‐speaking cryptophthalmos pioneers Zehender, Chiari and Fuchs64
. The list is endless and the CFC syndrome is no exception.
First published synoptically, after some editorial surgery, upon evaluation of eight patients by Reynolds et al
it was preceded by at least one report by Navaratnam and Hodgson,65
who described the entity ulerythema ophryogenes in patients who obviously had what is now known as the CFC syndrome.
In the same year that saw the publication of Reynolds et al
Baraitser and Patton66
evidently described the same entity—another one of innumerable recent instances of “when the time is right” discoveries of the same condition or phenomenon, independently in one part of the world or another.
All biological entities have two histories: an ontogeny in a specific individual and a species‐specific phylogeny involving a group of individuals. Again, the CFC syndrome is no exception. The ontogeny of the condition is encapsulated in the eight clinical reports by Reynolds et al1
; however, that publication had a phylogeny spanning almost two decades.
The first child with the CFC syndrome studied by JMO was SVH (patient 3 in Reynolds et al1
), born on 20 July 1968 and ascertained on 9 December 1968 at the former Wisconsin Orthopedic Hospital for Children of the University of Wisconsin, Wisconsin, Madison, USA after a visit to the cardiology clinic for probable pulmonic stenosis and atrial septal defect. He was followed up for some years, also studied by FR Grosse and Gerhard Neuhäuser, and then lost to follow‐up. An effort has been initiated to determine his subsequent fate.
The second child from Wisconsin was KAS, patient 2 in Reynolds et al
born on 11 March 1969 and ascertained on 28 July 1969. She was one of two of the original three children with the CFC syndrome with a cavernous hemangioma. She had a heart failure presumably due to an endocardial cushion defect. Her present condition is unknown. Patient 1 in Reynolds et al1
was the third of the children with the CFC syndrome from Wisconsin, born on 5 July 1967 and ascertained on 19 April 1971, also with a hemangioma. An attempt to interest former Wisconsin coworkers in a collaborative publication at that time was unsuccessful.
About 10 years after the Wisconsin group began collaborating with Dr Philip D Pallister in Montana, we studied KL (patient 6 in Reynolds et al
born on 2 September 1974 and first seen by Dr Pallister on 17 December 1976). In west America, especially Montana, families tend to “stay put”; thus, it was no surprise that this young woman's mother called promptly at 08:00 on 1 March 2006 from her original phone of 30 years ago, delighted at the news that no less than four genes had been identified as the cause of the CFC syndrome and to tell us that her daughter was in stable condition, doing well at age 31 years. She had graduated from high school in special education and was now living, self‐sufficiently in an apartment space of her own in the family's original home with her sister, brother‐in‐law and five children. She is able to use her microwave oven, walk up and down stairs, used a lotion for her “rough” skin and glasses for her visual defect—which had remained stable since the first evaluation. She greatly enjoys television and the love and company of her family and considers herself perfectly normal. An incipient menstrual hygiene problem had been solved through a partial hysterectomy; however, her breast hypertrophy still awaits surgical action. Results of her DNA study will be communicated in due time.
Patient 8 of the original report (ARA, born on 23 April 1976) was a patient of Dr James G Coldwell of Tulsa, Oklahoma, USA, where the boy was evaluated in November 1983, as reported in Reynolds et al
In 1999, Dr Coldwell informed us that the young man had developed severe, poorly controlled congestive heart failure at age 18 years, followed by a supraventricular tachycardia at 20 years. This “converted poorly” and was interpreted as an ectopic atrial tachycardia with a “tachycardia‐induced cardiomyopathy”. There was successful radio frequency ablation of one atrial ectopic site but inability to ablate the second ectopic site, and poor adherence to the medical regimen was probably the cause of death at 22 years. The report of the medical examiner was instructive. He (the patient) was described as a short man with an extremely short neck and short and stubby toes and fingers. A marked cardiomegaly (1080 g) was observed, with the right and left ventricles and septum measuring 1.5, 3.0 and 2.0 cm in thickness, respectively. Brain weight was 1750 g. Sections of the heart showed considerable fibre disarray. Before death, he had been found unresponsive by a relative and at a local hospital discovered to have ventricular fibrillation unresponsive to resuscitation. Histological sections transmitted to us were so broken that they did not enable further histological analysis.
JP, patient 5 in Reynolds et al
is now 30 years old, living in a group home and visiting with parents every weekend. Despite being considered “profoundly” mentally retarded, she is reportedly happy and social. She recently came close to death due to pneumonia and intestinal obstruction.
Had an earlier publication been possible (say in 1972), the CFC syndrome would accordingly have been designated the VHSZ syndrome, much to the annoyance of Victor McKusick. As it turned out, it was not until the opportunity of the 1986 David Smith meeting in Vermont presented itself that Reynolds et al1
finally completed their manuscript, initially including 10 patients. In a thoughtful analysis, one reviewer concluded “that the CFC syndrome is [not] a unique genetic MCA/MR [multiple congenital abnormality/mental retardation] syndrome”, perhaps a form or subgroup of the Noonan syndrome, and a second reported that “the cases are too diverse to be sold as a single entity”. Owing to the conflict of interest, we asked Dr John C Carey to edit the manuscript; he had the good sense to recommend deletion of cases 8 and 10 of the original manuscript (who, in retrospect, clearly did not have the CFC syndrome), leaving it with the eight, now clearly bona fide children with the CFC syndrome. Thus, the “heterogeneity” alluded to above actually refers to the phenomenon of variability (a phenotypic attribute); the heterogeneity (a causal attribute) of the CFC syndrome did not become evident until the recent work by Rodriguez‐Viciana et al17
and Niihori et al
The Salt Lake City CFC files include about 78 affected children (and a few adults); many of these are probably not members of the CFC Support Group. Much work remains to be carried out on the CFC syndrome and related conditions.