DNA testing for fragile X syndrome in schools for learning difficulties.

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

Screening for fragile X syndrome: results from a school for mentally retarded children

Fragile X syndrome is the most common inherited form of familial mental retardation. The purpose of this study was to identify yet unrecognized fragile X individuals and to estimate the frequency of both the FRAXA and FRAXE forms of the disease in a population of mentally retarded children attending a special school in Croatia. The results are reported of molecular screening of 114 children with mild to severe mental retardation. Three individuals (2.6%) with the FRAXA form of the fragile X syndrome and one boy (0.9%) with FRAXE mental retardation were detected; a total of four newly diagnosed fragile X families were identified. Closer clinical examination revealed that behavioural and speech disturbances were clearly present among all fragile X cases (both FRAXA and FRAXE), indicating that these features could be additional diagnostic criteria for the preselection of individuals at risk.

Conclusion: Fragile X screening among mentally retarded children attending a special school should be highly encouraged to reveal the cause of mental retardation and to detect yet unrecognized fragile X individuals. The frequency of fragile X syndrome in a such population in Croatia was found to correlate with similar results from previous studies. However, since at the time of diagnosis all affected families had a second or even a third child born, earlier diagnosis should be considered to provide greater benefit to fragile X families.     

Use of a molecular genetic approach to diagnosing the fragile X genotype.

We report the direct molecular detection of the fragile X genotype in 111 individuals from 17 families with a total of 31 cases of fragile X syndrome. Comparison of our molecular data with our previous cytogenetic and linkage data from these same families indicates the effectiveness of the direct molecular analysis. We have been able to assign a genotype unambiguously in 100% of the persons tested, and in all cases the molecular data correlated with the cytogenetic or linkage findings or both. Two of the three families presented in this study represent inheritance of this gene through normal transmitting males, and the third is strongly suggestive of this mode of inheritance. Our data show that the direct molecular approach will be of great utility for confirmation of the diagnosis and for the detection of female carriers and normal transmitting males who are at high risk for having affected children or grandchildren.     

Health supervision for children with fragile X syndrome

Fragile X syndrome (an FMR1-related disorder) is the most commonly inherited form of mental retardation. Early physical recognition is difficult, so boys with developmental delay should be strongly considered for molecular testing. The characteristic adult phenotype usually does not develop until the second decade of life. Girls can also be affected with developmental delay. Because multiple family members can be affected with mental retardation and other conditions (premature ovarian failure and tremor/ataxia), family history information is of critical importance for the diagnosis and management of affected patients and their families. This report summarizes issues for fragile X syndrome regarding clinical diagnosis, laboratory diagnosis, genetic counseling, related health problems, behavior management, and age-related health supervision guidelines. The diagnosis of fragile X syndrome not only involves the affected children but also potentially has significant health consequences for multiple generations in each family.     

Ethical, legal, and social concerns about expanded newborn screening: fragile X syndrome as a prototype for emerging issues

Technology will make it possible to screen for fragile X syndrome and other conditions that do not meet current guidelines for routine newborn screening. This possibility evokes at least 8 broad ethical, legal, and social concerns: (1) early identification of fragile X syndrome, an "untreatable" condition, could lead to heightened anxiety about parenting, oversensitivity to development, alterations in parenting, or disrupted bonding; (2) because fragile X syndrome screening should be voluntary, informed consent could overwhelm parents with information, significantly burden hospitals, and reduce participation in the core screening program; (3) screening will identify some children who are or appear to be phenotypically normal; (4) screening might identify children with other conditions not originally targeted for screening; (5) screening could overwhelm an already limited capacity for genetic counseling and comprehensive care; (6) screening for fragile X syndrome, especially if carrier status is disclosed, increases the likelihood of negative self-concept, societal stigmatization, and insurance or employment discrimination; (7) screening will suggest risk in extended family members, raising ethical and legal issues (because they never consented to screening) and creating a communication burden for parents or expanding the scope of physician responsibility; and (8) screening for fragile X syndrome could heighten discrepancies in how men and women experience genetic risk or decide about testing. To address these concerns we recommend a national newborn screening research network; the development of models for informed decision-making; materials and approaches for helping families understand genetic information and communicating it to others; a national forum to address carrier testing and the disclosure of secondary or incidental findings; and public engagement of scientists, policy makers, ethicists, practitioners, and other citizens to discuss the desired aims of newborn screening and the characteristics of a system needed to achieve those aims.     

Learning disabilities and attentional problems in boys with the fragile X syndrome

The fragile X syndrome is a relatively common form of mental retardation that tends to affect boys more severely than girls. The syndrome is associated with a fragile site at q27 on the X chromosome and with physical features including large or prominent ears and macro-orchidism. Four boys had physical and cytogenetic features of the fragile X syndrome. However, the IQ scores of these patients extended into the normal range. All four patients demonstrated similar learning difficulties that included hyperactivity, visuomotor incoordination, language deficits, and academic delays in mathematics. The fragile X syndrome should be considered in the differential diagnosis of learning disabled children.     

Discovering fragile X syndrome: family experiences and perceptions

We used surveys from 274 families who had at least 1 child with fragile X syndrome (FXS) to determine their experiences in discovering FXS, factors associated with the timeliness of discovery, and the perceived consequences of obtaining this information. For families of male children who were born in the last decade, someone first became concerned about the child's development at an average age of 13 months. Professional confirmation of a developmental delay did not occur until an average age of 21 months, and a FXS diagnosis occurred at an average age of nearly 32 months. Families reported several barriers to discovering FXS and frustration with the process. Many families had additional children with FXS without knowing reproductive risk. A range of perceived benefits and challenges associated with the discovery were reported. We conclude that selected pediatric practices could promote earlier identification but in only a limited way and predict that disorders such as FXS will continue to challenge current criteria for determining viable candidate disorders for newborn screening.     

Fragile X syndrome: current knowledge]

Fragile X syndromes is a disease characterized by the association of mental retardation and dysmorphic features to a fragile site on Xq27-3. It is a frequent genetic disorder (1 in 1,500 males) recognized only 20 years ago but remaining difficult to understand, because its transmission among generations does not correspond to the classical model of recessivity linked to chromosome X. In fact, carrier females can express the disease and transmitting males can be normal. With DNA probes, molecular biology has contributed to genetic counselling and prenatal diagnosis. Restriction polymorphisms have long been used to study the inheritance of fragile X syndrome and DNA markers' analysis improved risk estimates for carriers. From a clinical viewpoint, there was a need for more closely linked probes to help in prenatal diagnosis and to assess carrier status and hence reduce risk of recombination. In 1991, new probes allowed direct diagnosis of the Fra (X) mutation and a gene was sequenced. Nevertheless the understanding of the mechanism involved in the underlying mutation is still unknown. Geneticists, cytogeneticists and biologists must collaborate further to elucidate the fragile site mystery.     

The fragile X syndrome (Martin-Bell syndrome). Clinical and cytogenetic findings in 16 prepubertal boys and in 4 of their 5 families

Clinical and cytogenetic findings from 16 prepubertal males with the fragile X syndrome (X-linked mental retardation with postpubertal macro-orchidism and fragile site at Xq27/8, or Martin-Bell syndrome) and from their families are reported. During the first postnatal years, protruding, large ears, full periorbital tissue, and thick septum and alae nasi were the most characteristic phenotypic findings, while after approximately 6 years of age a longish face with full lips and prominent maxilla and mandible became more distinct. It was estimated that a clinical suspicion of the fragile X syndrome could be made in most of the 16 boys from phenotypic findings in combination with the characteristic developmental profile described in our previous paper. The marker X chromosome was demonstrated in each of the 16 patients; the incidence of fra(X)-positive cells did not correlate with either age or the degree of mental retardation. 13 boys stemmed from 2 families, the other 3 were sporadic cases. In one family with 11 affected boys, the gene was transmitted by 4 brothers, grandfathers to the probands, who were intellectually normal; three of them did not show the clinical picture of the fragile X syndrome and did not express the marker. All mentally subnormal heterozygote females and one half of daughters of heterozygotes revealed the marker, but this was present only in a minority of non-retarded adult heterozygotes. In contrast to the overall incidence of about 1/4 to 1/3 mentally retarded heterozygotes, all 15 daughters of the four normal obligatory hemizygous brothers were of normal intelligence.     

Fragile X syndrome

Fragile X syndrome is the most common familial form of mental retardation. This X-linked disorder affects one in every 1000 males and one in every 2000 females. The female carrier rate in the general population is estimated to be 1/600. A fragile site at the distal long arm of the X chromosome (Xq 27.3) is the hallmark cytogenetic feature of the syndrome. Clinical features include physical as well as cognitive and neuropsychological deficits. Although fragile X syndrome follows an X-linked pattern of inherltance (which explains the predominance of affected males), females can also beaffected,Many inconsistencies exist between the genetic inheritance pattern of fragile X and traditional Mendelian inheritance tenets of most X-linked diseases. Due to recent molecular advances, our understanding of the perplexing genetic issues surrounding fragile X syndrome has grown and diagnostic techniques have become both reliable and readily available.     

Gastrointestinal Polyposis in Childhood: Clinicopathologic and Genetic Features

Gastrointestinal polyps and certain extraintestinal lesions in children may herald a hereditary polyposis syndrome, with an increased risk of neoplasia and other health problems for both children and their relatives. The availability of molecular/genetic screening tests has increased early diagnosis of younger members of known polyposis families. This article reviews the gross and microscopic features of polyposis syndromes of childhood and summarizes the molecular/genetic advances in this field. Clinical management is also briefly discussed.     

Fragile X syndrome: recognition in young children

In recent years, a number of articles have appeared in the literature concerning the fragile X syndrome; however, in few cases was the diagnosis of the syndrome in young children discussed. A review of 20 children younger than 7 1/2 years of age who had the fragile X syndrome seen at the Cincinnati Center of Developmental Disorders was undertaken in an attempt to establish guidelines that would aid the practicing physician in determining which children should have a chromosomal analysis. All children were developmentally delayed; 95% had speech delays. Short attention span with hyperactivity, temper tantrums, mouthing of objects persisting at an age beyond when it would be expected, autistic behaviors, and poor gross motor coordination were seen in 50% or more of the children. Mental retardation was present in the family history of 65%, and 90% had a family history of at least one of the following: mental retardation, learning disabilities, or hyperactivity. The most common physical findings were long and/or wide and/or protruding ears, prominent jaw and/or long face, high arched palate, and a flattened nasal bridge. The fragile X syndrome can be recognized by noting key aspects of the behavioral and family histories as well as the physical findings.     

Diagnostic yield of genetic testing in children diagnosed with autism spectrum disorders at a regional referral center

The aim was to systematically review genetic testing guidelines in the evaluation of children with autism spectrum disorders (ASDs). The Clinical Report published by the American Academy of Pediatrics (AAP)(1) recommended individualizing the workup, including karyotype and specific DNA testing for fragile X syndrome. A recent publication reported higher rates of abnormalities on CGH microarray (CMA) testing on children with ASD.(2) The medical records of 507 children seen through the Kirch Developmental Services Center were abstracted for genetic testing and factors associated with this testing. Abnormalities were found on karyotype in 2.3% and in DNA for fragile X in 0.04%. The author concludes that the diagnostic yield of the genetic testing was low in this population. Furthermore, their findings support the theory that CMA can be considered as part of the initial genetic screening in children with ASD in most situations. Future studies will need to be done prospectively to evaluate children in a standard fashion.     

Family experiences and factors associated with the diagnosis of fragile X syndrome

The authors interviewed 41 mothers of young boys with fragile X syndrome to determine the process by which they learned their child had fragile X syndrome. The average family had concerns about the child's development at 9 months of age. Developmental delay was determined at an average age of 24 months, and fragile X syndrome was diagnosed at a mean age of 35 months. Considerable variability was found in age of first concern, determination of delay, and diagnosis of fragile X syndrome. Three child variables (severity of delay, autistic behavior, temperament style) and four family variables (mother's age, mother's education, sibling status, social support) did not account for this variability, although birth year did (children born more recently were somewhat more likely to be identified earlier). Families often encountered physicians who initially discounted concerns or said that it was too early to determine whether a problem did indeed exist. Given current knowledge and practice, improving the early identification (under 3 years of age) of children with fragile X syndrome is likely to remain difficult if based solely on behavioral and clinical observations.     

Fragile X syndrome

The fragile X syndrome is the most common inherited form of mental retardation known. Its phenotype includes large or prominent ears, macroorchidism, and characteristic behavioral problems. It has attracted the interest of cytogeneticists and molecular biologists because of its characteristic fragile site on the X chromosome. It has puzzled geneticists because of its unusual inheritance pattern involving nonpenetrant males. This syndrome has also spearheaded an appreciation of cytogenetic abnormalities in the etiology of all degrees of developmental delay.     

Language use in females with fragile X or Turner syndrome during brief initial social interactions

Fragile X and Turner syndromes are associated with risk of atypical social function. We examined language use, including normal and atypical speech, during initial social interactions among participants engaged in a brief social role play with an unfamiliar adult. There were 27 participants with Turner syndrome, 20 with fragile X syndrome and 28 in an age-matched comparison group. Females with fragile X did not exhibit more abnormal language, but exhibited less of what is typical during initial interactions. Overall rates of dysfluencies did not differ, although females with fragile X made more phrase repetitions. Females with Turner syndrome had no language use abnormalities. Our findings suggest that language use may influence social function in females with fragile X syndrome and that such language characteristics may be observed in the context of brief encounters with an unfamiliar adult.     

Developmental screening and detection of developmental delays in infants and toddlers with fragile X syndrome

Three developmental screening tests (the Denver-II, Battelle Developmental Inventory Screening Test, and Early Language Milestone Scale-2) were administered to 18 infants and toddlers (13 boys and 5 girls) with confirmed diagnoses of fragile X syndrome as part of a comprehensive developmental assessment at 9, 12, and 18 months of age. The Denver-II identified delays for 10 of 11 boys at 9 months of age and the Denver-II and the Early Language Milestone Scale-2 identified delays in 100% of the boys at 12 and 18 months. The Battelle Developmental Inventory Screening Test identified delays in 75% of the children at 12 and 18 months. When compared with more comprehensive developmental tests (Mullen Scales of Early Learning and Receptive-Expressive Emergent Language Scale-2), the screening tests concurred at least 76% of the time at the 12- and 18-month assessments. These results indicate that developmental delays could be detected in most children with fragile X syndrome through routine developmental screening by the age of 9 to 12 months.     

Ethical aspects of neonatal screening for sickle cell disease in Western European countries

Sickle cell disease raises some important ethical questions regarding neonatal screening in Western European countries such as France, England or Belgium, which have already introduced either universal or selective screening. Such screening is aimed at benefiting children affected with major sickle cell syndrome. It also detects heterozygous babies and, in doing so, heterozygous parents. The latter information, which is ignored most of the time, risks making parents feel guilty and can raise fears of stigmatization. Whether it would change their future reproductive decisions requires further studies, for cultural and religious reasons may have a strong negative influence on the request for prenatal diagnosis. Disclosure of the child's illness may oblige the family to remain in the country they have emigrated to because it offers the best chance of treatment. As a result, links between the family and its original community are modified. Parents must more or less sever links with their family in Africa and try to trust and adapt to the public health services in Europe.

Conclusion: Neonatal screening of sickle cell disease is highly ethical in facilitating the prevention of the early death of affected children. It also detects heterozygous parents and offers at-risk couples the possibility to perform a prenatal diagnosis during the next pregnancy. Adequate counselling must consider the risk of stigmatization that carrier status represents, especially for women in many cultural beliefs, and the numerous cultural and religious reasons which limit parental uptake for prenatal diagnosis. Disclosure of their child's illness may oblige immigrant families to stay in Europe, where free and adapted healthcare is available.     

Fragile X syndrome among children with mental retardation

Prospective screening for fragile X syndrome was carried out among 1,111 patients with mental retardation who attended the Genetic clinic. Using defined clinical criteria, 55 patients were selected for cytogenetic studies to detect folate sensitive fragile sites. Twenty patients were diagnosed to have the fragile X syndrome. The prevalence of fragile X (A) syndrome was 18 per 1,000 patients of both sexes with mental retardation, 2.8% among male patients with mental retardation, and 5.8% among subjects with nonspecific mental retardation.     

Fragile X syndrome and very early onset schizophrenia: a female case study.]

Genotype-phenotype relationship studies for psychiatric disorders in females carrying fragile X syndrome full mutation and premutation underline association with schizo-affective disorders. In female children with X fragile full mutation, only behavioural symptoms and no standardised psychiatric disorders have been systematically explored. Therefore, we report the case of a nine-year-old girl carrying the fragile X syndrome full mutation with a comorbid childhood onset schizophrenia (COS), and of her mother carrying the fragile X syndrome premutation and a comorbid schizotypal personality disorder. The impact of these associations is discussed regarding the recent literature in chromosome anomalies in COS.