CFC syndrome.

Abstract

With some reluctance and much embarrassment we feel obliged to comment once again on the assignment of a locus on chromosome 12q to the cardiofaciocutaneous (CFC) syndrome. The reason for this writing is the recent publication by Rauen et al. [2002] of yet another deletion of chromosome 12q21.2q22 in an alleged case of CFC syndrome. The previous case, also by Rauen et al. [2000], had already been criticized by us [Zollino and Neri, 2000] based on: (a) a clinical description of the patient which did not fit the criteria for an unquestionable CFC diagnosis, (b) lack of a photograph of the patient, (c) our own demonstration that chromosomes 12q were intact in seven classical CFC patients. Moreover, one of us (M.I.K.) was present at a recent David Smith Workshop (Lake Arrowhead, 2001) where a picture of the patient was shown, attracting much criticism by the audience as to the correctness of the diagnosis. Now, Rauen et al. [2002] report their second case, again highly controversial, in our opinion, given the clinical description and the patient's picture. The following major signs of the CFC syndrome are missing in this patient: short stature, at least relative macrocephaly, sparse and curly hair, typical face with the characteristic gestalt, typical cardiac involvement. In addition, he had normal statural growth, pyloric stenosis, bilateral transverse palmar creases, bitemporal alopecia, which are not commonly seen in the CFC syndrome. In fact, the patient is so unusual that the authors themselves admit that he did not have the classical CFC syndrome: “the patient reported here does not have the classic composite phenotype for CFC syndrome.” On the laboratory side, the authors went to the extreme of doing a sophisticated CGH analysis while it is quite obvious on standard cytogenetics that there is a deletion in chromosome 12q and a simple painting would have excluded either a relocation of the missing portion on another chromosome or insertion within the deleted segment of material from other chromosomes. The source of our embarrassment lays in the support given by the American Journal of Medical Genetics, allowing publication of this second case, to a conclusion which, in our view is entirely unproven, namely, that there is a locus for CFC syndrome in the chromosome region 12q21.2q22. It should be clear to all that the two patients on which this misconception is based simply do not have the CFC syndrome. The prestige of the American Journal of Medical Genetics is such that its published material almost instantly finds its way as an acquired fact into the medical literature (e.g., OMIM) as well as in the current opinion of clinical geneticists and pediatricians, especially those who are less familiar with a particular condition. This will inevitably multiply wrong diagnostic conclusions and, even more importantly, inaccurate counseling. Our intention is to avoid the perpetuation of this state of affairs and we strongly urge a review of the clinical data on both patients by a group of experts on the nosology of the Noonan, CFC, and Costello syndromes.