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Growth in any species is an extraordinarily com- man growth), deceleration of growth immediately
plex process, but growth in humans is character- after birth, a prolonged growth phase during child-
ized by a number of unique features. These include hood, prepubertal deceleration, and a pronounced
dramatic fetal growth (the most rapid phase of hu- adolescent growth spurt. Although some of these
aspects are shared with other mammalian species, studies in humans, have convincingly demonstrat-
others are characteristic only of Homo sapiens and are ed the critical role of the insulin-like growth factor
not replicated even in other primates. (IGF) system in all phases of mammalian growth,
The intricacy of the human growth curve (see including intrauterine, childhood, and pubertal.
Figure) is the product of an evolutionary process The existence of IGFs was first proposed in 1957
expressing the sum effect of multiple genes whose on the basis of studies indicating that growth hor-
interplay determines a pattern of growth that reflects mone did not directly stimulate the incorporation
the survival needs of our species. Given the complex- of sulfate into cartilage but rather acted through
ity of vertebrate and, especially, human growth, it is a serum factor. This factor was originally termed
reasonable to assume that a large number of genet- sulfation factor, then somatomedin, and ulti-
ic factors are involved in the control of stature, a hy- mately, insulin-like growth factor I (IGF-I) and II
pothesis supported by the existence of multiple clin- (IGF-II). Subsequent investigations demonstrat-
ical disorders characterized by growth failure. It is ed that growth hormone (GH), after binding to its
therefore all the more surprising that a series of ele- transmembrane receptor, initiated a complex sig-
gant investigations in mice, complemented by case naling cascade leading to transcriptional regulation
of the gene for IGF-I and related genes. Thus, the
growth characteristics of patients with severe IGF
Birth deficiency, resulting from homozygous mutations
CrownHeel Length Velocity (cm/4 wk)
tient with combined prenatal and postnatal growth disruptions in the mouse and case studies in hu-
failure who was found to be homozygous for a de- mans has thus established the unequivocal role of
letion in the IGF-I gene. The clinical implications of the IGF system as the main driver of embryonic, fe-
molecular defects of the IGF-I receptor were less tal, and postnatal growth. The prenatal contribution
certain, however. Patients with deletions of chromo- of the IGFs is largely independent of GH, presum-
some 15q and consequent haploinsufficiency for the ably representing the combined influences of pla-
IGF-IR gene generally have growth retardation, but cental sufficiency, fetal nutrition, and insulin, each
the potential contribution of the loss of contiguous of which has been shown to affect fetal IGF concen-
genes has been unclear. Similarly, studies suggest- trations, and a variety of as yet unidentified factors.
ing that IGF resistance has a role in the growth fail- Shortly before birth, GH-dependent IGF-I produc-
ure of the African Efe Pygmy have been inconclu- tion emerges as the critical regulator of skeletal
sive, since no underlying molecular defect has been growth, with minor direct contributions from sex
identified. steroids at the time of puberty.
A report by Abuzzahab et al. in this issue of the Although molecular defects of the IGF system
Journal (pages 22112222) provides the most con- currently appear to be rare causes of intrauterine or
vincing evidence to date that molecular abnormali- postnatal growth failure, the case reports described
ties of the IGF-I receptor can, as in the mouse mod- by Abuzzahab et al. provide incontrovertible evi-
el, result in combined intrauterine and postnatal dence that the IGFs have a key role in mammalian
growth failure. One of 42 children with intrauter- growth. It is likely that they will be followed by re-
ine growth retardation and subsequent short stat- ports of milder phenotypes associated with partial
ure was found to be a compound heterozygote for defects. Even though the original somatomedin hy-
point mutations in the IGF-IR gene; in a second study pothesis has required modification over the 46 years
of children with short stature despite elevated se- since it was published, its fundamental conclusion
rum IGF-I concentrations, one child with a history about the critical role of the IGFs in growth re-
of intrauterine growth retardation was identified mains sound.
with heterozygosity for a nonsense mutation of the
From the Lucile Packard Foundation for Childrens Health, Stan-
IGF-IR gene. ford University, Palo Alto, Calif.; and the Department of Pediatrics,
The combination of data from targeted gene Oregon Health and Science University, Portland.
Incentive-Based Formularies
Cindy Parks Thomas, Ph.D.
While much of the nation has been following the substitutes. For specific drugs, an insured person
deliberations in Congress over a Medicare drug ben- may be asked to pay up to half of the full price; un-
efit, a quiet revolution has been taking place in the der some insurance plans, members commonly
way benefits are managed for the 200 million Amer- contribute one third of their overall prescription
icans who already have insurance for prescription costs. How this transformation in cost sharing af-
drugs. Just 10 years ago, most insured persons were fects patients, their health care providers, and phar-
required to make a standard copayment of $5 or maceutical expenditures has been the subject of sev-
less for a prescription, regardless of the type of med- eral studies. The article by Huskamp and colleagues
ication they purchased. Now, incentive-based for- in this issue of the Journal (pages 22242232) is
mularies are standard, with the amount of copay- the most recent contribution.
ments depending on the type of drug prescribed; The goal of incentive-based formularies is to
the contracts among the insurer, the manufacturer, encourage people to choose lower-cost prescrip-
and the pharmacy; and the price differential be- tion drugs, thereby creating cost savings for the
tween the selected drug and reasonable low-cost health plan, which can, in theory, then be passed on