American Journal of Medical Genetics 95:144 (2000)
Editorial Comment
Heterogeneity of Cardio-facio-cutaneous Syndrome
Giovanni Neri1 and John M. Opitz2
1
Istituto di Genetica Medica, Università Cattolica, Rome, Italy
2
Pediatrics (Medical Genetics), Human Genetics, Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
The accompanying article by Grebe and Clericuzio
[2000] constitutes the latest addition to the controversy
over the nosology of the cardio-facio-cutaneous (CFC)
and Noonan syndromes. The causa proxima for re-
examining this controversy is the presentation of two
typical, severe cases of CFC syndrome, which the au-
thors refer to as “polar” cases, probably to indicate that
they belong to the most severe extreme of the pheno-
typic spectrum of the syndrome. By providing evidence
of the existence of a well-characterized polar pheno-
type, the authors render a good service to the nosology
of the CFC syndrome, reinforcing the concept that it is
a self-standing entity different and distinct from the
Noonan syndrome, a concept to which we subscribe.
The continuation of their line of reasoning is less
clear, since it suggests that nonpolar cases are better
classified as Noonan syndrome, while still milder and
less typical ones probably represent neither syndrome.
If one were to accept this conclusion, the CFC syn-
drome would turn out to be a rara avis, if not a unique
case of a syndrome in which all cases are typical. This
is by itself a contradiction to the literal meaning of the
term syndrome (“running together”), which implies the
concurrence in the same patient of different signs and
symptoms in varying combinations and to variable de-
grees of severity, due to one cause.
To validate their argument, the authors cite the case
of the Sotos syndrome. It is true that there was a time
when most any big boy or girl was earmarked as having
Sotos syndrome and that more stringent criteria have
corrected this state of affairs. This example is not the
most persuasive, however, given that no one can tell
how many patients now excluded from this diagnosis
because of an insufficient diagnostic score do, in fact,
have the gene, yet unknown, of the Sotos syndrome.
This brings us to the proof of the genes, representing
the ultimate forum in this sort of controversy. In the
case of the CFC syndrome, with essentially no familial
case, we can hope to arrive at the gene only through a
Grant sponsor: Primary Children’s Medical Center Foundation.
Correspondence to: G. Neri, Istituto di Genetica Medica, Uni-
versità Cattolica Largo Francesco Vito 1, 00168 Rome, Italy.
E-mail: gneri@rm.unicatt.it
Received 10 July 2000; Accepted 10 July 2000
© 2000 Wiley-Liss, Inc.
candidate region pinpointed by a chromosomal trans-
location or microdeletion in one or more sporadic pa-
tients. In the case of the Noonan syndrome, linkage
studies are possible in families where the syndrome
segregates as an autosomal dominant trait. In fact, a
locus on chromosome arm 12q was detected in a large
Dutch kindred [Jamieson et al., 1994]. Once a gene is in
hand, it will have to be tested on all available patients.
If it was cloned as a Noonan gene, testing will have to
be extended to CFC patients and vice versa. The split-
ting versus lumping debate then will be resolved, at
least to a large extent. Some doubts may linger about
whether in a particular clinical context a clinical diag-
nosis should or should not prevail over a molecular
diagnosis. The question is not an idle one. Think of the
case of the ATRX gene, whose mutations define a num-
ber of phenotypically (somewhat) different conditions,
from the ATRX syndrome itself to the Juberg-Marsidi,
the Holmes-Gang, the Carpenter-Waziri, and the
Smith-Fineman-Meyers syndromes [Chiurazzi et al.,
2000].
In the meanwhile, moving patients whose symptoms
represent the periphery of a given diagnostic category
out of it and into another one with similar character-
istics or into an undefined area seems to be a pointless
exercise of no benefit to the patients. This once again
proves a point that is absolutely critical in situations
such as these, that is, the need to talk to the patients
and their families clearly, repeatedly, and sympatheti-
cally, to make them understand the provisional nature
of their diagnostic status and to provide them with the
right motivation to help the doctors in their effort to
come up with a clear-cut answer. One way of doing that
is by sticking together within family support groups,
which represent the ideal terrain to exchange help and
to stay in close contact with the experts, so that imme-
diate benefit can be derived from scientific break-
throughs as soon as they occur.
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Chiurazzi P, Hamel B, Neri G. 2000. Genes on the X chromosome causing
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Grebe TA, Clericuzio C. 2000. Neurologic and gastrointestinal dysfunction
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type. Am J Med Genet 95:135–143.
Jamieson CR, van der Burgt I, Brady AF, van Reen M, Elsawi MM, Hol F,
Jeffrey S, Patton MA, Mariman E. 1994. Mapping a gene for Noonan
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