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

Health Technology Assessment 1997; Vol. 1: No. 4Chapter 3Natural historyThe fragile X syndrome phenotype is characterisedby a complex mixture of physical, cognitiveand behavioural features. Although males andfemales display similar features, most of the publishedstudies on the phenotype refer to males.Physical characteristicsThere are several physical features that distinguishaffected individuals. These include facial atypia,orthopaedic abnormalities, skin manifestations,unusual growth patterns, cardiac anomalies, andendocrine dysfunction. Despite so many systemsbeing affected, there is no evidence for a substantialimpairment of physical health. In one study,life expectancy was reduced by 12 years on averagebut the authors concluded that this was probablydue to biased ascertainment of cases (Partingtonet al, 1992).Facial features can include prominent ears(increased length and breadth), reduced bizygomaticdiameter, prognathism, high arched palate,dental overcrowding and increased head circumference(Simko et al, 1989; Hagerman, 1991;Partington, 1984; Sutherland & Hecht, 1985; Butleret al, 1991a; Meryash et al, 1984). Ocular abnormalitiessuch as strabismus are associated with a varietyof chromosomal abnormalities (Elston, 1989;Catalono, 1990) and, in fragile X syndrome, theyare present in about one-third to a half of cases(Schinzel & Largo, 1985; Storm et al, 1987; Mainoet al, 1991; King et al, 1995). Macro-orchidismis present in over three-quarters of adult males,although it is not specific to fragile X syndromeand is a common secondary feature to otherforms of X-linked mental retardation (BrondumNielson et al, 1981; 1982; Sutherland & Hecht,1985). Common musculo-skeletal findings includepes planus, scoliosis and excessive joint laxity(Davids et al, 1990). In one study, about threequartersof boys under the age of 10 years displayedhyper-extension of the metacarpophalangealjoints (Davids et al, 1990). Although recurrentear infection is a common complaint in clinicallynormal children, it is found more frequently inboys with fragile X syndrome – about two-thirds ofcases in one study (Hagerman, 1987). There maybe characteristic markings on the skin, usuallyincluding either simian or Sydney palmar creases(Simpson, 1986), and calluses are often presenton the hand as a result of hand-biting. Generalovergrowth (de Vries et al, 1995a) as well as abnormalgrowth patterns have also been reported inboth males and females, with a premature growthspurt resulting in a higher than average height inchildhood but a reduced final height in adulthood(Loesch et al, 1995; Loesch et al, 1988; Meryashet al, 1984).Mitral valve prolapse is present in about onequarterto one-half of affected individuals and,although this finding is generally benign, it canpredispose to cardiac arrhythmias (Loehr et al,1986; Sreeram et al, 1989). Epilepsy has also beenlinked with fragile X syndrome (Brøndum Nielsonet al, 1983; Partington, 1984; Musumeci et al, 1988;Wisniewski et al, 1991), although it is not clearwhether the association is primary to the syndromeor whether it is non-specific or familial (Vieregge& Froster-Iskenius, 1989).Cognitive profileApproximately 80% of affected males are moderatelyto profoundly mentally-impaired, with anIQ of less than 50 (Maes et al, 1994). Females withfragile X syndrome usually display a milder phenotype,the majority having a borderline low IQ ofbetween 70 and 85 (Rousseau et al, 1994; Tayloret al, 1994). A substantial decline in IQ with increasingage has been observed in a proportionof affected individuals (Fisch et al, 1991a; Dykenset al, 1989; Hagerman et al, 1989; Lachiewicz et al,1987) and is suggested as being a consequence ofprogressive neurological dysfunction (Fisch et al,1991a; Sutherland & Hecht, 1985). However, IQstudies must be interpreted with caution as theyare complicated by the use of different measuresof intelligence and the presence of cognitive andbehavioural problems (Hay, 1994).Some of the cognitive deficits observed in affectedmales and females are not specific to fragile Xsyndrome and are consistent with other forms ofmental retardation (Fisch, 1993; Einfield & Hall,1992). However, published studies also suggest thatspecific cognitive impairments are present. Most5