|Causes and Mechanisms of Linear Growth Retardation (International Dietary Energy Consultative Group - IDECG, 1993, 216 pages)|
|Is complete catch-up possible for stunted malnourished children?|
By comparing elite peoples from around the world, Martorell has produced convincing evidence that the genetic component of differences in children's height is, on average, trivial in comparison to the environmental influences. Nevertheless, the height potential of an individual is related to the parental height. Before deciding how complete the catch-up growth of an individual is, we need to know that individual's potential. In impoverished communities this can lead to a circular argument. The parents were themselves short because of malnutrition; this then, in part, determines the target that the child is aiming towards (his individual potential). If he reaches this target, has he had complete catch-up? If so, is the child then normal? These questions show two different concepts of catch-up. One is a catch-up to what is expected of the child and the other is catch-up to a standard height derived from a healthy population where there is no secular trend: the two may be very different.
The classical experiments of cross breeding Shire horses with Shetland ponies (Walton & Hammond, 1938) dramatically demonstrate the effect of the mother on the subsequent growth of animals. The progeny, as adults, weighed half as much again when the Shetland was the sire rather than the dam. Similar experiments with embryos transplanted into different breeds of sheep have confirmed these findings (Hammond, 1960). The human equivalent are mono-zygotic twins of different size; the smaller twin will end up as an adult of below average height (Babson & Phillips, 1973). Several years ago Stewart, Preece & Sheppard (1975) divided a colony of rats into two. One half were given a restricted protein diet and the other half a control diet. The progeny of the restricted rats were smaller than the control rats and remained so over many generations on the restricted diet - it was as if they became a different strain of rat altogether. When the restricted rats were returned to the control diet, subsequent generations were larger, but it took three generations for them to attain the size of the control group (Stewart et al., 1980). Inherited effects that gradually wash out have been seen in other functions, apart from growth. Beach, Gershwin & Hurley (1982) subjected mice to a brief period of zinc deficiency whilst pregnant and then cross-fostered the pups at birth to normal dams. The pups were immuno-deficient as adults: their own progeny were also partially immuno-deficient; normality was virtually restored by the third generation.
The usual explanation for the Shire/Shetland phenomenon, and that observed in Stewart's rats, is that the mother's small size deprives the fetus of nutrients because of a small placenta and reduced uterine blood flow. Yet the foals are normal, except for their size - they do not demonstrate the usual stigmata of malnutrition. The 'small placenta' explanation is insufficient to explain the 'inherited' immuno-incompetence. How could an insult to the grandmother during pregnancy affect the immuno-competence of the third generation? It is now becoming clear that the maternal (and paternal) environments affect the degree and timing of expression of developmental genes - an epigenetic phenomenon known as imprinting (Hall, 1991; Solter, 1988). The mechanism of imprinting is through methylation of specific DNA bases (Surani et al., 1990) which switch the genes off, or on, during early development; this switching can persist into adulthood or beyond. For example, although we inherit a gene from both our mother and our father, the one expressed, and the timing and degree of expression, are determined by epigenic modification during early development. Thus, only the gene for insulin-like growth factor II: derived from our father is expressed, whereas only the maternal gene for the receptor of this growth factor is expressed (Haig & Graham, 1991).
We are now beginning to appreciate the importance of interaction between nutrition and genetic expression. For example when Cheviot sheep, a breed that does not have horns, are put on a zinc-deficient diet they grow horns (Mills et al., 1967). This is despite the fact that zinc deficiency severely retards growth itself. Clearly, although this breed of sheep do not normally have horns, the appropriate genes are present. They have been bred to be permanently switched off. However, a nutritional insult, zinc deficiency, changes the expression of the hidden genes.
Variation in imprinting by specific epigenomic modification, perhaps stimulated by poor nutrition, provides a satisfactory explanation for Hammond's and Stewart's experiments, as well as the studies on zinc deficiency. As oogenesis occurs in fetal life, the nutritional plane of the grandparents may indeed influence the grandchild and be as important as the nutrition of the mother. If the meiotic and early in-utero environment changes the pattern of epigenic modification to alter the potential for future somatic development over several generations, it would also offer a satisfactory explanation for the close association between height potential and familial height in societies where there are no racial differences in height. It also provides an explanation for a gradual secular trend in height which clearly transcends the genes in the germ line and yet is familialy inherited.
Clearly, control of base methylation, and the substrates and coenzymes involved in methylation reactions, warrant examination in relation to height 'potential'.
The different controls of growth at different periods of growth (Karlberg, 1989) may indeed mean that, if abnormal growth is programmed by early developmental events to occur during a particular period, there may not be the developmentally programmed stimulus to catch-up when the child enters a further period. Martorell's data on the increments in Guatemalan children from 5 to 18 years of age (Martorell, Rivera & Kaplowitz, 1990), suggest that these subjects do not have an inherent 'drive' for increased growth. As we have seen, this may not be related to post-natal experience at all.
Is this relevant to the discussion of whether catch-up growth can occur in either a person or a chronically malnourished population? If a lower potential is determined during intrauterine life, then any catch-up which occurs in an individual will be to that potential and not to a greater one. To catch up to international standards, we may have to correct the defect over several generations. Indeed, a positive secular trend is a cross-generational catch-up in height. On the other hand, if we observe a short malnourished child who surpasses his potential, defined by parental height, we should say that he has had a complete catch-up for him, even though he fails to reach the NCHS standard. This is not to say that complete individual catch-up produces an individual who will function optimally.
In the Third World there is often an adverse prenatal development; many of the affected children later present with severe stunting. They may have a lower growth potential. The question posed can be narrowed to examining the potential for reversing post-natal malnutrition in a child chat is born with a 'normal' height potential.