JrMed Genet 1998;35:579-589 579 Syndrome of the month J Med Genet: first published as 10.1136/jmg.35.7.579 on 1 July 1998. Downloaded from The fragile X syndrome Bert B A de Vries, Dicky J J Halley, Ben A Oostra, Martinus F Niermeijer Abstract an X linked disorder. 30% of The Approximately fragile X syndrome is characterised the obligate carrier females were mildly or by mental retardation, behavioural fea- moderately retarded and a large portion tures, and physical features, such as a long (±50%) had no cytogenetic fragile X expres- face with large protruding ears and sion. Also, mentally normal grandfathers link- macro-orchidism. In 1991, after identifi- ing two family branches with the fragile X syn- cation of the fragile X mental retardation drome were observed. These "normal (FMRI) gene, the cytogenetic marker (a transmitting males" without any clinical or fragile site at Xq27.3) became replaced by cytogenetic features could apparently transmit molecular diagnosis. The fragile X syn- the fragile X syndrome. drome was one of the first examples of a The gene involved in the fragile X syndrome, "novel" class of disorders caused by a tri- the Fragile X Mental Retardation (FMRl) nucleotide repeat expansion. In the nor- gene, was identified in 1991 .9-l' The gene mal population, the CGG repeat varies defect was the first expansion of a trinucleotide from six to 54 units. Affected subjects have repeat to be discovered and a whole class of expanded CGG repeats (>200) in the first disorders is now known to be associated with exon ofthe FMR1 gene (the full mutation). this type of mutation.'2 Phenotypically normal carriers of the fragile X syndrome have a repeat in the 43 to 200 range (the premutation). Clinical studies The cloning ofthe FAlR1 gene led to the The original "Martin-Bell family" was restud- ied in characterisation of its protein product 198113 and the typical cytogenetic and http://jmg.bmj.com/ FMRP, encouraged further clinical stud- clinical features were found. The "Martin-Bell ies, and opened up the possibility of more phenotype" was proposed as an eponym for the accurate family studies and fragile X phenotype of affected males. Additional clini- screening programmes. cal features include high arched palate (52%), (JMed Genet 1998;35:579-589) strabismus (36%), hyperextensible metacar- pophalangeal joints (67%), hand calluses Keywords: fragile X syndrome; FMR1 gene; mental (29%), double jointed thumbs (53%), retardation single on September 26, 2021 by guest. Protected copyright. palmar creases (25%), pes planus (71%), and heart murmur or click (18%) (figs 1 and 2, History table 1).8 '4 The facial features are often less In 1943, Martin and Bell' described sex linked noticeable, particularly in affected females and mental retardation without dysmorphic fea- children (fig 3). The macro-orchidism often tures in a family in which both affected males develops during or after puberty and is and females were observed. Thirty-six years frequently absent in young patients.7 8 Seizures later, Lubs2 a reported marker X chromosome are observed in approximately 20% of young (later to be known as the fragile X chromo- affected males, with a lower prevalence in some) as an inconsistent finding in cytogenetic adults.8 15 16 studies in leucocytes of some mentally retarded Fragile X infants often have relative macro- males. The folic acid and thymidine depleted cephaly persisting into adult life.'7 However, cell culture medium was identified as the the adult height of affected males is below the essential factor for the induction of this norm.'7 18 A few patients present with either Department of Clinical heritable fragile site at Xq27.3 During the sev- Genetics, University overweight or general persisting overgrowth enties, the combination of X linked mental which can be confused with either Prader-Willi Hospital Dijkzigt and retardation and Erasmus P macro-orchidism was syndrome or Sotos syndrome.'9-24 Associations University, recognised.4-6 Later, other clinical 0 Box 1738, 3000 DR characteris- with other syndromes are reported; examples Rotterdam, The tics were established, for example, a long face are the Robin sequence (micrognathia, glos- Netherlands with large, protruding ears, and behavioural soptosis, and cleft soft the FG B B A de Vries features, palate),25 including avoidance of eye contact, syndrome (congenital hypotonia, macro- D J J Halley hyperactivity, hand flapping, and B A Oostra perseverative cephaly, distinctive face, and imperforate speech.7 8 M F Niermeijer anus),26 27 and the DiGeorge anomaly (defects The fragile X syndrome was diagnosed at of thymus, and that time parathyroids, great vessels).28 Correspondence to: by cytogenetic detection of the fragile However, there is no definite evidence for a Dr de Vries. site at Xq27.3. It some had special features for causal relationship between the FMR1 gene 580 De Vries, Halley, Oostra, et al Table 1 Clinical features and medical problems offragile Although several neuroimaging and a few X males * neuropathological studies have been done on the central nervous system in fragile X patients, knowledge on specific structural and cellular J Med Genet: first published as 10.1136/jmg.35.7.579 on 1 July 1998. Downloaded from Clinlicalfeaturest defects is still limited. Reduced size of the pos- Long face Prominent ears terior cerebellar vermis on MRI in male High arched palate patients and increased size of the caudate Hyperextensible finger joints nucleus, thalamus, and hippocampus have Double jointed thumbs Single palmar creases been reported.47 48 These findings have neither Hand calluses been confirmed nor refuted by others. Flat feet studies of three fragile X Heart murmur or click Neuropathological Macro-orchidism males' brains showed immature, thin, and long Medical problemsf dendritic spines in different regions, with a Vomiting but with Failure to thrive in infancy reduction in mean synaptic contact Strabismus preservation of neuronal density in the Myopia or hyperopia neocortex." 49 5() Similar abnormal dendritic Hernia Joint dislocation spines were observed in fragile X knockout Orthopaedic problems mice.' Interestingly, in normal mouse brain, Otitis media high FMRP expression is observed in the sy- Sinusitis Seizures naptoneurosomes which could be related to the Mitral valve prolapse high transcriptional activity necessary for func- Apnoea tion of neuronal spines.52 However, abnormally Autism ADHD long, thin dendritic spines are also seen in cases Motor tics with chromosomal abnormalities53 or unspeci- fied mental retardation.'4 Apparently, these are *Majority of items scored in 100-280 patients. tAdapted from Merenstein et al.'-' non-specific neuropathological changes, as is tAdapted from Hagerman.' the neuronal heterotopia observed in two affected males and linked to their epilepsy. In mutation and these phenotypes. Several obser- the testes, macro-orchidism seems to be vations of the co-occurrence of the fragile X associated with increased tubular length and syndrome and sex chromosomal abnormalities interstitial oedema.5 4 5 like 47,XXY or 45,XO/46,XX25 34 suggest an increased rate of non-disjunction related to the The FMRl gene fragile X chromosome. The identification of the FMR1 gene5' princi- Scales for facilitating diagnosis based on pally elucidated the special characteristics of physical and behavioural features have been the transmission of the defect in fragile X fami- developed and found to be effective.35 lies rather than explaining the mental retarda- Recognition of behavioural features also assists tion itself. The FMR1 gene has a size of 38 kb http://jmg.bmj.com/ in the diagnosis. In the younger child, hand with 17 exons57 and an untranslated polymor- flapping, hand biting, tactile defensiveness, phic CGG repeat in the first exon.58 In the nor- poor eye contact, hyperactivity, and persevera- mal population, this CGG repeat varies from tive speech are suggestive ofthe diagnosis.8 The six to 54 units58 (fig 4) with an average of 30 "autistic-like" behaviour of many fragile X units. The mutations in the FMR1 gene can be males initiated the debate about whether divided into a major and a minor class (table autism is associated with the fragile X 2). The major class of FMR1 gene mutations on September 26, 2021 by guest. Protected copyright. syndrome."4 42 affects the CGG repeat, whereas mutations in Although in female premutation carriers an the coding region are infrequently observed. increased incidence of premature menopause has been reported,43 45 a recent study indicated CGG REPEAT EXPANSIONS that the premutation does not seem to be a On the basis of the size of the CGG repeat and major risk for early menopause.4" its effect on protein and phenotypic expression, .-I '.07 11 :': x '.4" ,.--M,Pmi;115: Figure 1 Three affected males with characteristic facialfeatures of the fragile X syndrome. Note the long, narrow face with large, everted ears and the poor eye contact. Thefragile X syndrome 581 J Med Genet: first published as 10.1136/jmg.35.7.579 on 1 July 1998. Downloaded from .....p Figure 2 Some clinicalfeatures in fragile X subjects. (A) High arched palate, (B) dental crowding, (C) hyperextensible MPjoints, (D) hand calluses, and (E) pes planus. two types of mutations within the CGG repeat The CGG repeat is generally interspersed http://jmg.bmj.com/ can be distinguished: the premutation (size 43 with two AGG triplets6'-66 and their position at to 200 units) apparently without clinical effect the 3' end influences repeat instability, with an and the full mutation (size >200 units) which, instability threshold of 34-38 uninterrupted if fully methylated, is associated with mental CGG repeats.6' 65 The potential predictive retardation in all male and in 50-70% offemale value of the size of the uninterrupted CGG patients. At the protein level, FMR1 is absent repeat for risk prediction in the offspring of from cells in cases with a fully methylated female premutation carriers has not been on September 26, 2021 by guest.