Anemia in the pediatric patient

Screening For Cystic Fibrosis Carriers - Health & Wellbeing

by Peter Lavelle

Every year 70 babies are born in Australia with cystic fibrosis, mostly to parents with no family history of this crippling illness. Experts are calling for more widespread screening for carriers.

Published 01/12/2005

Every year, 70 babies are born in Australia with cystic fibrosis. The child suffers serious lung and digestive problems - they don't manufacture a vital protein, which causes secretions to become very sticky and their lungs and pancreas to literally 'gum up'. The lungs become susceptible to infection and digestion doesn't work properly.

Treatment is much more effective than it was 20 years ago. Most children with cystic fibrosis now can expect to survive into adulthood. But the average life expectancy is still only in the mid thirties.

Cystic fibrosis is an inherited condition, but a child has to have an abnormal gene from both parents to get it. When both parents are 'carriers' of the abnormal gene, there is a one-in-four chance of this happening.

About one person in 25 in Australia is a carrier. About one in 2,500 kids will be born with the condition.

At the moment, carriers aren't routinely identified by testing. Instead, newborn babies are routinely screened for the condition (amongst others) and that's how most new cases are diagnosed. Only then do parents become aware they are carriers. Parents are then routinely offered prenatal testing of a foetus in any subsequent pregnancy - and they have the option of then terminating that pregnancy if it turns out to have CF. But it's too late to do anything about the first child.

But genetics centres have developed a test to identify carriers of a cystic fibrosis gene. It's fairly reliable (with an 83 per cent accuracy rate), and it involves a painless cheek swab. It costs about $200. It's offered in some obstetrics clinics as a prenatal test - but only if there's a family history of the condition. The trouble is, most carriers don't know they are carriers, and have no history of the condition. So they don't get offered the test.

A group of doctors from the Royal Children's Hospital, Melbourne, writing in the latest edition of the Medical Journal of Australia, say testing for carriers should be more widely available and offered as a prenatal test, even if there's no family history of CF. They propose that the couple both be tested, and if they are found to be carriers, offered the chance to have the foetus tested (via chorionic villus sampling, in which a portion of the placenta is sampled). If the foetus is found to have both mutations (a one-in-four chance), the parents could then be given the option of terminating the pregnancy.

They then have the option of further prenatal testing, if they have another pregnancy. Or they could opt for in-vitro fertilisation - with the embryo conceived and tested in the lab, and only implanted in the woman's uterus if it was found not to have both mutations.

Ideally, the researchers say, carrier screening should be offered to partners before they conceive, argues Dr John Massie, a paediatric respiratory physician at the Royal Children's Hospital, Melbourne, and one of the authors of the MJA article. He says couples could be tested and if both partners were carriers, they could consider whether they want to conceive in the first place. If they did, they would have the option of conceiving and terminating the pregnancy if the foetus had both mutations, or going down the IVF path.

There is a successful carrier screening program for cystic fibrosis that's been operating along these lines in Edinburgh, Scotland, which has halved the incidence of cystic fibrosis in that community, he says.

At the very least, he argues, it should be offered as part of routine prenatal testing. It should be funded by Medicare, on the grounds of cost-effectiveness (saving the resources otherwise spent treating a child with the condition) not to mention the prevention of future suffering for kids and their families.

But is a little knowledge a dangerous thing? While some parents might prefer not to know, overwhelmingly, parents want as much information about the health of a foetus as early as possible rather than later, when their options are more restricted. 'It's all about choice' says Dr Massie.

Widespread Testing For Cystic Fibrosis Available

WASHINGTON — Gene testing is going mainstream: Starting this month, tens of thousands of white Americans will be offered testing to see if they carry a gene mutation that causes cystic fibrosis even if no one in their family has the disease.

Under new guidelines, obstetricians and gynecologists are supposed to offer the gene test to every Caucasian--or the partner of a Caucasian--who is pregnant or considering having a baby.

It marks the first time gene tests are being offered to the general population. Until now, they have been recommended just for small groups of people who know they're at high risk for a particular inherited disease, such as when an illness runs in the family.

Are we ready for mainstream gene tests? The American College of Obstetricians and Gynecologists is betting that with a little education, Americans will be savvy enough medical consumers that the screening will prove a boon.

To help expectant couples decide whether to accept the test, the group has prepared easy-to-understand educational pamphlets--available from your doctor--explaining cystic fibrosis, how gene testing works, and the relevance of parents-to-be discovering they have the gene mutations that cause it.

Babies must inherit a bad gene from both parents to have the disease, so if the mother has a mutation, the dad must be tested too.

"It's something patients have to decide--do they want it or not," stresses Dr. Michael Mennuti of the University of Pennsylvania, who coauthored the testing guidelines.

About 30,000 American children and young adults are living with cystic fibrosis. It attacks their lungs, clogging them with a thick mucus, and can harm digestion and vitamin absorption by clogging the pancreas and intestines.

Treatment has improved in recent years, lengthening life span. Still, patients typically die in their 30s, most from lung damage or infection.

Why test so many parents? Although it can affect anybody, cystic fibrosis is the most common inherited disease among Caucasians. People can carry the defective gene without knowing it, and more than 10 million Americans do--including one in every 29 whites.

But because there are so many unsuspecting carriers, most babies with the disease are born into families that didn't know they were at risk. If both parents harbor the defective gene, they have a one-in-four chance of having a baby with the incurable disease.

"The vast majority of couples will get reassuring news" that they aren't carriers, notes Dr. Francis Collins of the National Institutes of Health, who co-discovered the gene in 1989.

Testing is best done before a woman gets pregnant, he says. If both parents are carriers, they might opt for in vitro fertilization, for instance, where the resulting embryos can be tested for the disease and only healthy ones are implanted into the mother's uterus.

If parents learn they are carriers early in pregnancy, the fetus can be tested. If the fetus does have it, abortion is one option, but many such parents do as patients of Dr. Debra Baseman recently did: They spent the months of pregnancy learning about top-notch care and lining up specialists for their child. Very early care, especially nutritional care, keeps many patients healthier longer.

"Parents often say, 'The medications are good, the life span is longer, and who knows what medications will be around in 5 or 10 years?' " said Baseman, a Princeton, N.J., obstetrician who has offered routine screening for cystic fibrosis for several years and says about three-fourths of her patients accept it.

The guidelines say the test should not be restricted to Caucasians. Although they are the main target because of their higher risk, the test should be available to anyone who wants it. One in 46 Hispanics carry the bad gene, as do one in 62 blacks and one in 90 Asian Americans.

The test is good but not 100% accurate. There are about 1,000 known mutations in the gene that causes it, and the new guidelines advise test laboratories to check for a minimum of the 25 most common.

Genetic Counseling After Implementation Of Statewide Cystic Fibrosis ...

The intent of the newborn screening program in Massachusetts is to diagnose infants with CF as early in life as possible. A side effect of this program is that some infants, and thus at least one of their parents, are diagnosed as carriers for CF. This diagnosis was not the original intent of the screening program but was believed to be a reasonable trade-off to ensure as few false-negative results as possible. This finding makes genetic counseling of the family more complicated, since the majority of couples do not realize that the newborn screen can also diagnose their child as being a carrier for a CF mutation.

More of the parents seen in our study (82%) decided to have CF carrier testing than has been previously reported in similar circumstances (∼50%).9 Possible factors that might explain differences in this yield include timing of the counseling (whether it was tied directly to the sweat test or offered at a return visit), whether the counseling was performed before or after the sweat test, the ease in availability of genetic testing to the family (on-site cheekbrush in our case), and whether counseling or testing had to be preapproved by insurers. In the study by Mischler et al.,9 CF carrier testing occurred at a second visit after the initial genetic counseling. Attrition is a likely side-effect of requiring a second visit for testing. In our institute, counseling was done before giving sweat test results primarily for the convenience of the family, because our laboratory typically would take more than an hour to obtain results. We believed, given the very low chance for the infant to have CF, that we could primarily discuss carrier risks and carrier testing for the parents. The description of CF was brief and more for the purpose of explaining why carrier testing was being offered to the parents rather then preparing the family for a possible diagnosis of CF. The reasons couples gave in our study for having carrier screening done included concern over whether both could be CF carriers, and if only one was a carrier, the desire to know if other family members were also at risk to be carriers. At our institute, an MD clinical geneticist provided all of the genetic counseling, primarily because that was who was available. The counseling could also have been done by a genetic counselor. If CF newborn screening as described here becomes more prevalent in the United States, there will be a great need for individuals who can explain the testing and the carrier risks. We believe that such explanations are best given by individuals trained in genetic counseling, whether they be clinical geneticists or genetic counselors.

Of interest in our 101 families were those in which both parents were found to be CF carriers either through DNA testing or by their newborn having an abnormal sweat chloride concentration. Of these five families, only one presented with affected children (the twins). Another presented with a newborn who was only a CF carrier, but this finding led to an older sibling unexpectedly being found to have CF. Fortunately, the other three families did not have any affected children, but these couples were all considering having further children. Without the newborn screening for CF, these couples would not have known of their risk to have a child with CF. The 25% risk of having a child with CF has caused them to seriously consider whether or not to have more children, although to date none of these couples have made a definitive decision.

The advantages of performing sweat tests in conjunction with genetic counseling to parents include identifying the minority of infants with elevated trypsinogen levels and one detected CFTR mutation who are affected with CF, finding couples at high risk for having a subsequent affected child, identifying a previously undiagnosed sibling with CF, and potential identification of CF carriers in the extended family. The disadvantage of this IRT/DNA screening algorithm is identification of some infants who are only CF carriers (and, thus, at least one parent is an obligatory carrier) whether or not these individuals wish (or will wish) to know their carrier status.

One concern with newborn screening programs that use DNA testing as part of the screening process is that many infants who present with a single mutation on initial screening have been found to be only carriers. The American Society of Human Genetics, the American College of Medical Genetics, and the American Academy of Pediatrics (AAP) have recommended that testing children for carrier status for autosomal recessive conditions or presymptomatic testing for late-onset autosomal dominant conditions be delayed until a child is of sufficient maturity to understand the testing and agree to have the test done.10,11 Obviously, a newborn's consent cannot be obtained, and in the case of newborn screening, the AAP recommends that "newborn screening tests be introduced in a carefully designed manner that facilitates evaluation of the risks and benefits of screening, including the efficacy of follow-up and treatment protocols."10 The main concern from an ethical standpoint is that we are preventing an individual's freedom of choice with regard to diagnosis of his or her carrier status. As more and more genetic conditions are being mapped, this dilemma will come up more frequently and needs to be taken into consideration as part of the cost benefit equation when newborn screening is being planned.

CF carrier testing in the general population has been somewhat controversial, even though a 1999 National Institutes of Health (NIH) consensus development conference statement on genetic testing for cystic fibrosis recommended that CF testing should be offered to adults with a positive family history of CF, to partners of people with CF, to couples currently planning a pregnancy, and to couples seeking prenatal care.12 The American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology are in the process of determining exactly how such carrier testing should be implemented.13 A recent statement from the ACMG recommends offering CF carrier testing to all couples of non-Jewish Caucasian descent and of Ashkenazi Jewish descent. CF carrier testing should also be discussed with individuals of other racial and ethnic groups with the caveat that CF is much rarer in these populations and detection rates of CF mutations is also low.14 Even within the Caucasian population, a 25 CFTR mutation panel will only ascertain 80% of individuals of Northern European ancestry with a CFTR mutation.14 The ascertainment level is lower in other ethnic groups, particularly Hispanics and African Americans. An individual of Northern European descent has an ∼1 in 25 risk to be a CF carrier prior to any testing. If this individual has a negative result after carrier testing for 25 CFTR mutations, then his or her risk to be a CF carrier decreases to 1 in 140, which means there is still a small risk that he or she may be a carrier.14 One of the most difficult aspects of genetic counseling is ensuring that individuals understand that this testing only reduces their risk to be a carrier. It does not eliminate the risk. Thus, we believe that it will be important to have adequate genetic counseling resources, including explanatory literature and, if necessary, a genetic counselor or clinical geneticist, available to explain to individuals and couples the results of their testing if nationwide CF carrier testing is instigated.

How does national CF carrier screening impact on newborn screening for CF? While it would be preferable to detect all couples at risk to have a child with CF before a pregnancy or delivery, this is unlikely to happen due to some individuals' reluctance to be tested, the limitations of the testing as described above, and the fact that a significant proportion of the population does not access any prenatal care, let alone specialized services. The goal of newborn screening for CF is to identify affected children as early in life as possible; thus, relying only on preconceptual or prenatal testing of parents is not sufficient. Ideally, newborn screening for CF would avoid detection of infants who are only CF carriers, which would obviate the ethical dilemma of lack of informed consent from the individual being tested. Such testing is not yet available, but hopefully, as we learn more about early indicators of CF disease, screening algorithms can be improved to lower the number of babies for whom DNA testing will be prompted. Alternatively, the ability to economically and rapidly sequence entire genes will help to distinguish with near 100% accuracy individuals who are likely to be affected with CF and those who are only carriers based just on the initial blood sample for the newborn screen.

In summary, we have presented our experience with the genetic counseling performed at one academic center that evaluates infants with an abnormal IRT/DNA cystic fibrosis newborn screen, who have a single CFTR mutation detected, and are directed to undergo both sweat testing and genetic counseling. As a result of this protocol, three additional children with CF were detected, five couples found out that they had a 25% risk of having an affected child, and extended family members were made aware of their risk to be CF carriers. The long-term implications of diagnosing carrier status for an autosomal recessive disease in a newborn requires further public policy discussion.

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