Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...

Health Technology Assessment 1997; Vol. 1: No. 4Chapter 7Screening and diagnosisAims of screeningThe ultimate public health purpose of geneticscreening is prevention. With fragile X syndromethere are two possibilities, namely, primary orsecondary prevention aimed at reducing the birthprevalence of the disorder, and tertiary preventionaimed at improving prognosis by appropriate managementwhen the diagnosis is brought forwardthrough screening. Closely allied to this is theprovision of information for its own sake which,in general, also appears to be of value (Mooney& Lange, 1993). The two aims are not mutuallyexclusive in that, for example, the early diagnosisof one affected child in a family may lead to theavoidance of further affected children. Similarly,as a consequence of an affected pregnancy beingdetected and terminated, family studies may beinitiated which bring forward the diagnosis ofsome affected relative.Reducing affected birthsThe ability to reduce the number of affected birthsis contingent on the identification of young womenwith a PM or an FM, and therefore at high risk ofan affected pregnancy. Once these have been identified,there are several preventive options. Thefirst is prenatal diagnosis and selective abortionof foetuses with an FM. Other options are to avoidpregnancy, have in-vitro fertilisation of a donatedova and, in the near future, pre-implantationdiagnosis and selected implantation of anunaffected zygote.Earlier diagnosisAlthough there is a general awareness of fragile Xsyndrome amongst health professionals, the clinicalfeatures which separate this disorder from othernon-specific forms of learning disability are notwell known. This is compounded by the lack ofobvious clinical features which accompany developmentaldelay early in life. Thus, as the prevalencestudies show, many cases go unrecognised or thereis a considerable delay in diagnosis.Improving prognosisAlthough fragile X syndrome is not curable thereare a number of interventions that can improve theprognosis (see page 6). Nonetheless, there is nospecific evidence that intervening at an early stagewill achieve a better long-term outcome thandoing so at the usual time of presentation, butquality of life for the affected individual and familymay be improved by early intervention. A morepalpable advantage of early diagnosis is theprovision of an explanation to the family forthe child’s behavioural and intellectual problems.Subsequent genetic counselling may also removesome of the burden of responsibility and guiltassociated with bearing affected children (Royet al, 1995). On the negative side, a specificdiagnosis may lead to stigmatisation of theaffected individual and even the family.When all these factors are taken into consideration,many would agree that preventing affected birthsis a more achievable aim of screening thanattempting to improve prognosis.Screening strategiesThere are three possible strategies aimed atidentifying females at high risk of an affectedpregnancy. These are:• antenatal testing of apparently low riskpregnancies• pre-conceptual testing of young women• systematic testing within the families of affectedindividuals (cascade screening).Two strategies aimed at improving prognosis are:• an active search for paediatric cases amonghigh risk children• routine testing of neonates.Antenatal testingThe testing of pregnant women for a PM or FMcould be incorporated into existing screeningprogrammes for neural tube defects, Down’ssyndrome and ultrasound detectable structuralabnormalities (Palomaki, 1994). Those who arefound to have a mutation would then be offeredprenatal diagnosis. Antenatal screening could beoffered either routinely to all women or selectivelyto those at relatively higher prior risk. The lattergroup would be principally those with a familyhistory of fragile X syndrome, but could be25