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From
the physician-in-chief
Prospects for the future of child
health through research
By Ralph D. Feigin, M.D., for the Journal of the American
Medical Association, Sept. 21,2005 - Vol. 294, p. 1373.
Copyright
© 2005, American
Medical Association. All rights reserved.
The application of the new technologies of genomics, proteomics,
tissue engineering, and molecular imaging techniques will
revolutionize the diagnosis and treatment of childhood
disorders. In addition, the interplay between genetic and
environmental components of disease will be clarified.¹
Many postconceptual intrauterine events, as well as genetic and
environmental influences, have subtle connections with chronic
disease of adult life.² Given the multiple determinants of
health (genetics, intrauterine event, behavioral, environmental,
and social influences), prospects for future research must be
elucidated along a continuum that begins at or prior to
conception and continues throughout childhood. Increasingly,
such clinical research will demand the participation of teams of
investigators who, in the aggregate, possess the appropriate
skills to assess the effect of each of these spheres of
influence upon the health of each child.
Congenital diseases, structural
anomalies, and genetically inherited disorders
Future research will permit expanded prereproductive and
prenatal genetic testing. The use of arrays for comparative
genomic hybridization (array CGH) makes it possible to test, in
a single analysis, for virtually all clinically important
cytogenetic disorders (eg, Di-George, Prader-Willi, Angelman,
Williams syndromes).³ Fetal testing could be offered to
all pregnant women and newborn screening also would be feasible.
Preliminary data suggest that testing of the fetus by array CGH
may be possible using fetal DNA in the maternal plasma.4
A markedly expanded
form of newborn screening will become a national standard based
on the use of tandem mass spectrometry.5
In recent decades, the ability to diagnose genetic disease has
far out-stripped the ability to treat or cure such disease. The
mutant genes for many developmental malformations (eg. Smith-Lemli-Opitz,
cleidocranial dysostosis, coloboma [of eyes], hearing deficit,
choanal atresia, retardation of growth, genital defects [males
only], and endocardial cushion defect [CHARGE] association,
diaphragmatic hernia, holoprosencephaly, and many forms of
congenital heart disease) have been identified. Since many of
these involve new mutations or recessive disorders, it is
usually difficult to anticipate the risk for a first affected
child in a family. Where irreversible injury has not occurred
prior to birth, there is cause for optimism. Enzyme replacement
therapy is now a mainstay for treatment of Gaucher, Fabry, and
other lysosomal storage diseases. It seems likely that somatic
gene therapy will afford opportunities to treat selected genetic
disorders that currently are unapproachable with conventional
therapies. The prospects for beneficial or even curative gene
therapy are strong for hemophilia A and B and for many inborn
errors of metabolism such as ornithine carbamoyl transferase
deficiency and familial hypercholesterolemia. The prospects of
effective gene therapy for cystic fibrosis and Duchenne muscular
dystrophy are more problematic, but long-term success may be
achievable. All of these applications are predicated on
solutions to problems experienced to date, including lack of
gene transfer vector targeting to the diseased cell, low
efficiency of gene transfer, immediate toxicities of some viral
vectors (eg, adenovirus) and delayed toxicities (including
neoplasia) and others. Wider applications to more common
pediatric disorders that are not immediately life threatening
must await the development of mechanisms to regulate transgenes
and to destroy transduced cells should they perform aberrantly.
Therapeutic advances have lagged behind diagnostic capabilities
creating ethical dilemmas concerning which patients and
conditions to screen and how to use most appropriately the
information obtained. It may be possible, in the not-too-distant
future, to predict some genetic or epigenetic factor(s) that
pre-dispose all individuals to 1 or more diseases during life.
Personalized medicine for children based on the genotype of an
individual is most likely to be applied with regard to
pharmacogenetic traits with treatment selection based on
genotype and to preventive health care advice. This type of
approach will not be adopted clinically unless insurance
coverage is assured for individuals with “pre-existing
conditions.”
For the
rest of Dr. Feigin's article, please go to the
JAMA Web site.
Ralph D. Feigin, M.D., is physician-in-chief at Texas
Children’s Hospital and professor and chairman of the Department
of Pediatrics at Baylor College of Medicine.
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