Medscape

eMedicine

Medscape CME
Physician Connect
The Medscape Journal

CLOSE [X]

SPECIALTY SITES
Allergy & Clinical Immunology
Cardiology
Critical Care
Dermatology
Diabetes & Endocrinology
Emergency Medicine
Family Medicine
Gastroenterology
General Surgery
Hematology-Oncology
HIV/AIDS
Infectious Diseases

Internal Medicine
Lab Medicine
Nephrology
Neurology & Neurosurgery
Ob/Gyn & Women's Health
Oncology
Ophthalmology
Orthopaedics
Pathology & Lab Medicine
Pediatrics
Psychiatry & Mental Health
Public Health & Prevention
Pulmonary Medicine

Radiology
Rheumatology
Surgery
Transplantation
Urology
Women's Health

OTHER SITES
Business of Medicine
Medscape Today
Med Students
Nurses
Pharmacists

All    Medscape    eMedicine    Drug Reference    MEDLINE

Dr. A Tang
Account Settings  |  Log Out  |  Newsletters

Pediatrics

Latest
News
Conferences

Journals
Resource Centers
Viewpoints

Printer-Friendly
Email This

Selection from: Small for Gestational Age: Issues in 2008

Genetic Determinants of Size at Birth (Slides With Transcript)  CME

Ken K. Ong, MD, PhD, MRCP   Disclosures

Slide 1.

Welcome and Introduction

Slide 2.

Anita Hokken-Koelega, MD: I would like to welcome you to this symposium on "Small for Gestational Age." This symposium will discuss the genetic determinants of size at birth, also the risk of insulin resistance and the metabolic syndrome, and also review the treatments with growth hormone of children born with SGA, who remain short.

Slide 3.

Genetic Determinants of Size at Birth

Ken Ong, MD: Thank you very much.

Slide 4.

First of all, why is size at birth important? I have three reasons here. To start off life, size at birth is predictive for perinatal mortality and morbidity. This graph shows one of the earliest studies to show this relationship between birth weight, lower birth weight, and increased mortality. While, of course, the absolute mortality rates are much lower these days, the same associations with birth weights are also seen.

Slide 5.

Secondly, at the end of childhood, low birth weight is important for adult height, and particularly, low-birth-weight children who do not catch up within the first few years of life remain small as adults. This is clearly exemplified by the control groups of recent, very long-term published results of growth hormone trials. Here you can see the control group does not show any spontaneous catch-up at all from early childhood through to adult life.

Slide 6.

In the next talk, you will hear much more about the association between low birth weight and increased risk of adult diseases, such as coronary heart disease and type 2 diabetes.

Slide 7.

What regulates birth weight? I am sure it will be no surprise to you at all to hear that both maternal factors and fetal factors are important. An example of maternal factors which can be either discrete conditions, such as maternal hypertension, which is associated with lower birth weights of offspring,

Slide 8.

and the maternal factors can be continuous. Here you can see maternal glucose levels clearly influence birth weight. Infants of first pregnancies have lower birth weight compared with second and third pregnancies. But in all cases, you can see a clear, positive, linear trend between birth weight and increasing maternal glucose levels.

Slide 9.

Then fetal factors; fetal genes are important, and this is a very recent example, mutations in HNF4a are a rare cause of maturity onset diabetes or MODY. But peculiarly, the phenotype in the neonatal period is one of hypoglycemia due to hyperinsulinemia. In utero, this increase in insulin levels leads to higher birth weights in those infants who carry a copy of the mutation.

Slide 10.

These maternal factors and fetal factors do not operate independently, but of course, are interlinked. This cartoon here shows the interactions. The maternal-uterine factors determine the nutrition, the placental transfer of nutrients to the fetus, which then stimulates insulin and IGF-I and promotes fetal growth. The fetal genes, specifically those that regulate insulin metabolism and the insulin-like growth factors, may modify the fetal responses to the level of nutrition. This explains very schematically the hormonal control of fetal growth. But it does not tell us much about the balance between maternal factors or fetal factors.

Slide 11.

What I want to do is to go through three questions: firstly, is the mother in change of fetal growth? Or can the fetus regulate the mother? Then finally, what are the implications of these factors for postnatal growth and early infancy?

Slide 12.

First, here is a list of independent significant factors that impact birth weight. This came from a study of normal children, about 1000 children born in Bristol in the ALSPAC study. First of all, there aren't any paternal factors on this list, but rather a large number of maternal factors, birth weight, mother's current weight, weight gain, height, smoking, are all independently related to birth weight, in addition to blood pressure and glucose that we mentioned earlier.

Slide 13.

Certainly in terms of direct environmental effects, the maternal uterine environment does have a very large influence on fetal growth and birth weight. Furthermore, the maternal uterine environment impacts and modifies whether fetal genes are expressed or modified or are manifested.

Slide 14.

This study confirmed a finding we published earlier, that a common variant in the insulin gene, the INS VNTR, was associated with infants who carried two copies of the class 3 allele had larger size at birth, than those with class 1 allele. But you can see that this effect of fetal genotype is only seen in these larger second and third pregnancies, whereas in first pregnancies, where the infants are smaller and possibly more restrained by the mother, the effect of fetal genotype is abolished. The test for interaction importantly confirms that the effect of fetal genotype is significantly different between these different pregnancies. This is a common variant in the insulin gene.

Slide 15.

Similar interactions can be seen with rare mutations, here in the glucokinase gene. This is glucokinase, controls beta cell insulin secretion and is -- mutations are another cause of MODY or mature onset diabetes by reducing insulin secretion and elevating glucose levels.

Slide 16.

Andrew Hattersley and colleagues in Exeter showed that if the offspring carried the mutation, this exposes the fetus to lower insulin levels, and therefore lower birth weight; whereas if mother carries the mutation, the offspring -- the fetus is exposed to higher glucose levels in utero, and therefore birth weight is heavier.

Slide 17.

Put together, you can see this graph, in the middle, the wild type or normal birth weight offspring, in red the lower birth weight if the fetus carries the mutation that has lower insulin levels, and dark blue, the effects if just the mother carries the mutation and has higher glucose levels, provides more nutrient to the fetus. You can see in the middle here, that the effect of a fetal mutation can be completely abolished simply by raising glucose levels in the mother. This is a very rare mutation in the glucokinase,

Slide 18.

but similar to the insulin gene, a common variant in glucokinase, which does not cause diabetes, but it increases glucose levels very slightly, again, due to lower insulin secretion. These authors looked at the effects separately of maternal genotype or offspring glucokinase genotype from birth weight, and they found an effect of maternal genotype, but no effect of the offspring genotype.

Slide 19.

An identical finding is shown with another common variant in this gene TCF7L2, which is a recently confirmed susceptibility variant for type 2 diabetes. These authors looked at both maternal and fetal genotypes, and I have only shown you here the effect of maternal genotype, which, again through promoting higher glucose levels in the mother, increased birth weight by 30 grams. I have not shown you the fetal genotype effect, because there were no independent effects of fetal genotype.

Slide 20.

Overall, mother's genotype seems to have a more predominant effect than fetal genotype, as well as modifying the effects of fetal genes. The third way mother can control things is actually by directly influencing which specific genes are expressed in the infant through transmission of her genes.

Slide 21.

This is a schematic diagram of the effects of insulin-like growth factors, IGF-I and IGF-II, which promote growth by acting on the type 1 IGF receptor. There is a second IGF receptor, the type 2 receptor, which does not promote growth, but rather binds IGF-II and degrades it, and therefore it inhibits growth.

Slide 22.

Here is the effect of Igf2. If Igf2 is knocked out, then the infants are smaller at birth, about 60% of the normal birth weight. Placental size is also reduced to about 60% of normal, and identical phenotype is seen, whether you knock out both copies of Igf2 or just the father's copy of Igf2. It just seems to be that father's Igf2 gene is specifically expressed to promote growth.

Slide 23.

In contrast, the type 2 IGF receptor that inhibits growth is exclusively expressed by mother's transmitted copy, and so knocking out this inhibitory type 2 receptor leads to a fourfold increase in circulating Igf2 levels in the fetus, and then larger birth weight. It is an effect specifically to the maternal transmitted allele to the fetus.

Slide 24.

This difference between paternally-transmitted and maternally-transmitted alleles has led to this Haig Hypothesis, that the mother may be more interested in survival, thus passes on genes to restrain fetal growth such as the Igf2r; whereas the father is more interested in promoting fetal growth through exclusively paternally-expressed genes, such as Igf2.

Slide 25.

In summary, my first question, certainly there does seem to be a predominant effect of maternal factors, first through direct effects of the maternal-uterine environment, although, as we have seen, this term maternal environment itself can relate to the effects of maternal genes acting on mother's metabolism, and therefore controlling the nutrient to the offspring. Secondly, this maternal-uterine environment can modify the expression or the manifestation of fetal genotype. Thirdly, the mother can also directly influence expression of genes in the fetus through maternally-transmitted genes.

Slide 26.

In the face of this seemingly overwhelming effect by the mother, is it possible that the fetus can influence maternal metabolism? There is some growing evidence for this.

Slide 27.

I think the first evidence also came from the Igf2 gene model in the mouse. Igf2 is quite a complex gene. There are a range of promoters, which lead to a number of varying length mRNA transcripts, which are expressed in specific tissues. There is a further promoter upstream, which is specific to the placenta, and leads to a very long mRNA transcript which, again, is specifically expressed in the placenta.

Slide 28.

Interestingly, if you knock out just this P0 placental-specific promoter, so you only knock out Igf2 in the placenta, you get identical phenotype to knocking Igf2 completely in the fetus, the placenta is reduced to 60%, and birth weight is also reduced to 60%. This shows the placental weight is reduced in the mutations throughout pregnancy. But curiously, fetal weight is preserved until very late pregnancy, and the authors proposed that there was a compensation by this small placenta to safeguard or protect fetal growth until the end.

Slide 29.

Indeed, that is what they found. Compared with the wild type allele, they found that this mutant small placenta was actually upregulating active transport of nutrients across the placenta, as illustrated by these labeled markers of glucose and amino acid transport across the placenta, compared with the wild type. This upregulation of active transport of glucose and amino acids was driven by Igf2 in the fetus.

Slide 30.

If you then further knock out Igf2 in the fetus, we no longer see this upregulated active transport. That is quite a complex story, so this cartoon summarizes that. If you knock out Igf2 specifically in the placenta, then fetal Igf2 produces a signal to increase efficiency in the active function of the placenta. In this paper, published about 3 years ago now, the authors summarize that this is the first direct evidence that the fetal genetic growth potential can demand placental supply of nutrients.

Slide 31.

Of course, we do not have such experimental data in humans, but in this naturally occurring experiment of Igf2 overexpression in humans is the Beckwith-Wiedemann Syndrome, where infants are larger at birth and have hypertrophy of various organs.

Slide 32.

It has been noted that mothers carrying Beckwith-Wiedemann Syndrome fetuses -- so these are mothers who are otherwise completely normal -- they are carrying a fetus that overexpresses Igf2. These pregnancies have higher rates of preterm delivery, polyhydramnios, and hypertension, so that there appear to be effects of fetal genome on the mother's metabolism.

Slide 33.

These are some data we have had from Cambridge showing that fetal number also impacts mother's glucose levels during pregnancy, so that glucose levels increase from singletons to twins, to triplets; again suggesting that fetal load of genetic potential does impact mother's metabolism. These are just a few examples, and there are many more potential ways whereby the fetus can regulate metabolism.

Slide 34.

There is a list of hormones, which are all secreted from the placenta, potentially the control from fetal genetic variants, and which influences mother's metabolism, affecting insulin resistance and mother's blood pressure, and which can therefore control nutrients to the fetus. It is an area where we may see many more examples, and which may have relevance not only to birth weight, but also to risk of various gestational diseases in the mother.

Slide 35.

Finally, how do these things affect the infant in early postnatal growth?

Slide 36.

We have seen the regulation of prenatal growth. In postnatal growth, nutrition obviously changes, and the nutrition is supplied by infant feeding, infant appetite, and parental choice of feeding. But the fetal genes remain the same, at least during early infancy. So it is no surprise then that the fetal genes which impact antenatal growth also impact on postnatal growth.

Slide 37.

Here a severe deletion of IGF-I, very rare, led to a very low birth weight, 1.4 kg, but also very severely impaired postnatal growth. That was IGF-I.

Slide 38.

This is the Igf1 receptor (Igf1R), and again a mutation here also leads to low birth weight, 2.4 kg, and a very poor postnatal growth pattern with a final height of 134 cm. These are rare mutations.

Slide 39.

Also copy number, chromosomal imbalances, which lead to either one copy of the Igf1R or three copies, also have concordant effects on growth. So presumably underexpression of Igf1R leads to low birth weight and poor postnatal growth, whereas three copies or overactive Igf1R leads to high birth weight and ongoing rapid postnatal growth.

Slide 40.

Similarly for Igf2, there is some evidence that infants with Beckwith-Wiedemann Syndrome are not only larger at birth, but they continue to grow rapidly, particularly in height, postnatally.

Slide 41.

The exact opposite, at genetic level to the Beckwith-Wiedemann Syndrome is the Silver-Russell Syndrome, which is now identified to be due to Igf2 underexpression. This is, as you know, associated with low birth weight and also very poor infant weight gain and subsequent growth.

The effects of fetal genes certainly appear to continue into postnatal life, whereas the effect of the mother's environment seems to wear off.

Slide 42.

Here are data from the ALSPAC study. In red is the growth trajectory of mothers who smoked during pregnancy. The weight is expressed as a standard deviation score, where at any age from birth to age 5, the population average is represented by this horizontal line through 0. You can see that the infants of mothers who smoked had lower birth weights, but caught up appropriately during the first year of life.

Slide 43.

We have already talked about birth order, so first-born children being smaller at birth, and again, they show a catch-up, compensatory catch-up growth during the first year of life.

Slide 44.

These are some preliminary data we have from our Cambridge cohort. On the right panel, this shows the correlation coefficient between mother's glucose level and the infant's skin folds at birth. And you can see a positive correlation, as we have shown before, between higher mother's glucose levels and larger skin folds at birth. But if you follow these infants up into the first 2 years of life, this association rapidly disappears, even by age 3 months, as these infants catch down in growth. In contrast, mother's BMI independent of glucose levels does not actually influence skin folds at birth. If we follow these infants up, we see a rapidly emerging correlations with mother's BMI.

Slide 45.

Another maternal trait that appears to have a rapid effect on growth in the early postnatal period is mother's age at menarche. Age at menarche is a highly heritable trait, and is strongly associated with increased weight and BMI both in childhood and adult life. Mother's earlier age at menarche seems to confer a more rapid postnatal growth pattern, even particularly in the first 2 years of life. In contrast, in the lower panel shows infants of mothers with later menarche. They show the opposite pattern of particularly slow growth again in this crucial first 2 years of life.

Slide 46.

These are apparent transgenerational effects of maternal traits, and I suspect that the specific genes that influence these traits also are susceptibility genes for obesity. This is the leptin-deficient mouse, who was identified about 10 to 15 years ago.

Slide 47.

This is the growth chart of a human individual with leptin deficiency. You can see a marked effect of leptin treatment when this child was age 5. But particularly, I want to point out that the period of most rapid deviation from the normal growth charts is in infancy, showing the marked effects of these appetite genes, particularly on infant weight gain.

Slide 48.

Leptin deficiency is exceedingly rare, but the common variation that leads to obesity was reported last year, result from a genome-wide association study. This was in the fatso gene, or FTO. You see remarkable data in nearly 40,000 individuals showing a very consistent increased effect on BMI. This study was largely in adults,

Slide 49.

but data from Lourdes Ibáñez in Barcelona has shown that this gene particularly confers rapid growth, even in the first 2 weeks of life. There was no effect on birth weight, but the infants who were with the predisposing alleles for obesity put on more weight in the first 13 days of life. On DEXA scans at age 2 weeks of life, these infants were already fatter than infants with the wild type allele.

Slide 50.

So to summarize the last area, fetal growth genes also impact on postnatal growth. The effects of the maternal-uterine environment largely appear to disappear during infancy, allowing catch-up growth. Then thirdly, further parental genetic effects do impact on postnatal weight gain and infant growth very soon after birth. I think that these concepts are robust, but the examples I was showing you so far are quite limited and we are unable yet to use these for prediction of which infants are going to have low birth weight and which infants are going to catch up postnatally.

Slide 51.

But you may have heard about the results of the genome-wide association scans, which really have revolutionized the discovery of common genetic variants. This is through genotyping, not just handfuls of SNPs at a time, but hundreds of thousands of genetic markers at a time. In this month's edition of Nature Genetics, there is a report on 30 or 40 new genes for adult height, and a further 6 new genes for type 2 diabetes, and many more are on their way. So watch this space.

Slide 52.

Thank you very much to several of my colleagues at Cambridge, and to the ALSPAC team in Bristol. And thank you very much for your attention.

Go to CME Test Questions »

Contents of: Small for Gestational Age: Issues in 2008
All sections of this activity are required for credit.

Genetic Determinants of Size at BirthKen K. Ong, MD, PhD, MRCPCHAvailable As: Slides/Audio | Slides/Transcript
Assessing the Risk of Insulin Resistance and Metabolic SyndromeClaire Lévy-Marchal, MDAvailable As: Slides/Audio | Slides/Transcript
The Treatment of Growth Failure in SGA ChildrenAnita Hokken-Koelega, MDAvailable As: Slides/Audio | Slides/Transcript
Panel DiscussionAnita Hokken-Koelega, MD; Ken K. Ong, MD, PhD, MRCPCH; Claire Lévy-Marchal, MDAvailable As: Slides/Audio | Slides/Transcript

Go to CME Test Questions »

Copyright © 2008 Scherer Clinical Communications.

CME Information
Earn CME Credit »

All    Medscape    eMedicine    Drug Reference    MEDLINE

About Medscape
Privacy & Ethics
Terms of Use
WebMD Health
WebMD Corporate
Help
Contact Us

All material on this website is protected by copyright, Copyright © 1994-2008 by Medscape. This website also contains material copyrighted by 3rd parties.