bluuebunny/crossref_metadata_2025 huggingface dataset:
Follow‐up study of patients with Wiedemann‐Beckwith syndrome with emphasis on the change in facial appearance over time
Authors: Hunter Alasdair G. W. , Allanson Judith E.
Published: June 2005

We have carried out a follow‐up study of 13 children with Wiedemann‐Beckwith syndrome (WBS) using a standard protocol which included facial anthropometric measurements. We confirm that most patients with WBS do well and that their clinical abnormalities become less apparent with age. We suggest that there is a characteristic neonatal appearance in WBS and that the expected pattern of facial growth generally results in a normal appearance by mid‐ to late childhood. We tentatively propose that there is a distinct facial anthropometric pattern profile in WBS. © 1994 Wiley‐Liss, Inc.
Jackson‐Weiss syndrome: Clinical and radiological findings in a large kindred and exclusion of the gene from 7p21 and 5qter
Authors: Adès L. C. , Mulley J. C. , Senga I. P. , Morris L. L. , David D. J. , Haan E. A.
Published: June 2005

We describe the clinical and radiological manifestations of the Jackson‐Weiss syndrome (JWS) in a large South Australian kindred. Radiological abnormalities not previously described in the hands include coned epiphyses, distal and middle phalangeal hypoplasia, and carpal bone malsegmentation. New radiological findings in the feet include coned epiphyses, hallux valgus, phalangeal, tarso‐navicular and calcaneo‐navicular fusions, and uniform absence of metatarsal fusions.

Absence of linkage to eight markers along the short arm of chromosome 7 excluded allelism between JWS and Saethre‐Chotzen syndrome at 7p21. No linkage was detected to D5S211, excluding allelism to another recently described cephalosyndactyly syndrome mapping to 5qter. © 1994 Wiley‐Liss, Inc.
Deletion (2) (q37)
Authors: Stratton Robert F. , Tolworthy Janet A. , Young Robert S.
Published: June 2005

We report on a 5‐month‐old girl with widely spaced nipples, redundant nuchal skin, coarctation of the aorta, anal atresia with distal fistula, postnatal growth retardation, hypotonia, and sparse scalp hair. Initial clinical assessment suggested the diagnosis of Ullrich‐Turner syndrome. Chromosome analysis showed a 46,XX,del(2)(q37) karyotype in peripheral lymphocytes. We compare her findings to those of other reported patients with terminal deletions of 2q. © 1994 Wiley‐Liss, Inc.
Spondyloepimetaphyseal dysplasia (SEMD) Shohat type
Authors: Figuera L. E. , Ramírez‐Dueñas M. L. , Gallegos‐Arreola M. P. , Cantú J. M.
Published: June 2005

Recently a distinct spondyloepimetaphyseal dysplasia (SEMD) was reported in three members of a Jewish family. We present a 3.5‐year‐old Mexican boy with disproportionate short stature, peculiar face, short neck, small chest, abdominal distension, lumbar lordosis, short limbs, marked genuavara, and joint laxity. Roentgenologic findings include short long bones, wide and flared metaphyses with irregularities, delayed epiphyseal ossification, platyspondyly and morphological changes of vertebral bodies and fibular overgrowth. The striking resemblance of this patient to those previously reported confirms this form of SEMD as a distinct entity. Autosomal recessive inheritance is supported and the designation SEMD Shohat type is proposed. © 1994 Wiley‐Liss, Inc.
Two Prader‐Willi/Angelman syndrome loci present in an isodicentric marker chromosome
Authors: Luke Sunny , Verma Ram S. , Giridharan Radha , Conte Robert A. , Macera Michael J.
Published: June 2005

We found an abnormal 47,XX,+mar karyotype in a patient with developmental delay, hypotonia, microcephaly, failure to thrive, and cognitive delay. When metaphases were hybridized with Prader‐Willi and Angelman loci‐specific probes by the FISH technique, two sites were noted at opposite positions on the marker chromosome. The alphoid satellite DNA probe documented the isodicentric nature while retention of the p arms on both sides of the marker chromosome was demonstrated by beta satellite probe. The patient does not exhibit manifestations of either syndrome despite the presence of these loci in tetrasomic dose. The present investigation suggests that other marker chromosomes be reevaluated, as their clinical manifestations are quite variable. © 1994 Wiley‐Liss, Inc.
Six cases of 7p deletion: Clinical, cytogenetic, and molecular studies
Authors: Chotai Kokila A. , Brueton Louise A. , van Herwerden Lyn , Garrett Christine , Hinkel Georg K. , Schinzel Albert , Mueller Robert F. , Speleman Frank , Winter Robin M.
Published: June 2005

To date, 32 cases of partial 7p monosomy have been described, 14 of which have been associated with craniosynostosis (CRS). There is considerable variation in the size and location of the deleted segment. However, CRS appears to be consistently associated with either a deletion or partial deletion 7p21→7p22 or more rarely a deletion of 7p13→7p14.

Analysis of a panel of six 7p deletion cases (three with CRS) was undertaken using informative DNA probes, in order to characterize and define the extent of the deletions at the molecular level. There were five de novo deletions and one resulting from the unbalanced product of a paternal balanced insertion.

The putative proximal CRS locus at 7p13→7p14 does not appear to be allelic with Greig cephalopolysyndactyly syndrome. Three probe positions have been refined: pJ5.11 (D7S10) previously mapped to 7p14→pter does not appear to map proximal to p15; TM102L (D7S135) does not map distal to p22; CRI‐P137 (D7S65) maps distal to 7p13. © 1994 Wiley‐Liss, Inc.
Is fragile X syndrome a pervasive developmental disability? Cognitive ability and adaptive behavior in males with the full mutation
Authors: Fisch Gene S. , Holden Jeanette J. A. , Simensen Richard , Carpenter Nancy , Howard‐Peebles Patricia N. , Maddalena Anne , Sandgrund Alice , Jacques Jean‐Robert , McGann Barbara
Published: June 2005

In addition to mental retardation (MR), fragile X [fra(X)] syndrome has been associated with various psychopathologies, although it appears that the link is secondary to MR. It has been proposed that individuals with the full mutation be classified as a subcategory of pervasive developmental disorders (PDD). If fra(X) males are to be categorized as PDD, how do they compare with other types of developmental disabilities? We examined 27 fra(X) males aged 3–14 years, from 4 sites in North America. Measures of cognitive abilities were obtained from the Stanford‐Binet Fourth Edition (SBFE), while levels of adaptive behavior were evaluated using the Vineland Adaptive Behavior Scales (VABS). Control subjects were sex‐, age‐, and IQ matched children and adolescents ascertained from the Developmental Evaluation Clinic (DEC) at Kings County Hospital. At the DEC, control subjects were diagnosed as either MR (n=43) or autistic disorder (AD; n=22). To compare subjects' adaptive behavior (SQ) with their cognitive abilities (IQ), a ratio of {(SQ/IQ)x100} was computed. Results graphed as cumulative distribution functions (cdf) revealed that the cdf for AD males, who by definition are socially impaired, was positioned to the left of the cdf for MR controls, as expected. Mean ratio for AD males (70) was lower than for MR males (84). On the other hand, the cdf for fra(X) males was positioned far to the right of either AD or MR controls (mean ratio = 125). Statistical tests showed that SQ of fra(X) males was significantly higher than controls. Moreover, in 23/26 (88%) of the fra(X) males tested, SQ was greater than IQ, indicating that adaptive behavior was not as impaired as cognitive abilities. Our results have consequences for the clinical evaluation of fra(X). In particular, fra(X) individuals may appear to function at higher cognitive levels than may be the case. We suggest that, while fra(X) may produce mild to profound developmental delay, it should not be included as a separate subtype of developmental disorder. © 1994 Wiley‐Liss, Inc.
Longitudinal changes in IQ among fragile X females: A preliminary multicenter analysis
Authors: Fisch Gene S. , Simensen Richard , Arinami Tadao , Borghgraef Martine , Fryns Jean‐Pierre
Published: June 2005

Longitudinal declines in IQ among fragile X [fra(X)] males have been reported previously by several investigators. Remarkably little is known about longitudinal changes in IQ scores among fra(X) females. Previously, one cross‐sectional study showed a significant negative correlation between age and IQ scores. However, a recent investigation of girls with fra(X) syndrome noted longitudinal increases in IQ scores in 8 of 11 individuals. Therefore, the purpose of this preliminary multicenter study was to determine: (1) the characteristics of longitudinal changes in IQ among fra(X) females; and (2) whether these changes were comparable to those which have been observed among fra(X) males. IQ test and retest scores for 11 fra(X) females were obtained from 3 centers: Greenwood, South Carolina; Ibaraki, Japan; and Leuven, Belgium. To ensure high reliability, only test‐retest scores from the Wechsler and Stanford‐Binet tests were used. Age of subjects at initial testing ranged from 5 to 35 years. Mean intertest interval was 4.5 years. In contrast to a report of longitudinal increases, we found 9/11 (82%) subjects demonstrated decreases in IQ scores. Mean decline was 9 points. Females over 18 years of age showed little or no change in IQ scores. Decreases in scores appeared to be related to initial IQ score. Females in the earlier longitudinal report were higher functioning than those in our study, which may account for the observed difference in direction of change; or, change in IQ score may be related to size of the fra(X) mutation. These preliminary findings are consistent with our earlier multicenter study of fra(X) males and suggest that while cognitive deficits are greater initially among males than females, longitudinal changes in IQ scores are comparable. © 1994 Wiley‐Liss, Inc.
Personality profile in adult female fragile X carriers: Assessed with the Minnesota Multiphasic Personality Profile (MMPI)
Authors: Steyaert Jean , Decruyenaere Marleen , Borghgraef Martine , Fryns Jean‐Pierre
Published: June 2005

To assess if the higher incidence of psychiatric morbidity in fragile X carriers is related to a particular pathological personality profile, we obtained a Minnesota Multiphasic Personality Profile from 11 normally intelligent (female) fragile X carriers. The sample mean for the clinical and validity scales all fell within the normal range. Although no pathological profile was found, some unexpected results emerged: low scores for the scales “schizophrenia” and “social introversion” and a so‐called faking‐good profile on the validity scales. This combination suggests that the subjects might not be aware of some personality characteristics in these areas. Implications for further research are discussed. © 1994 Wiley‐Liss, Inc.
Behavioural and emotional disturbance in fragile X syndrome
Authors: Einfeld Stewart L. , Tonge Bruce J. , Florio Tony
Published: June 2005

A range of behaviours has been postulated as specific manifestations of the Fragile X (fra(X)) syndrome. This study examines a broad range of behaviours in subjects with fra(X) syndrome and in control individuals. It was designed to take account for differing findings in previous studies. Subjects were 48 children, adolescents, and young adults with fra(X) syndrome. They were compared with a large community epidemiological sample (N = 454) of persons with mental retardation (M.R.), matched for age, sex, and IQ. Behavioural problems were studied using the Developmental Behaviour Checklist, an instrument of established reliability and validity in the evaluation of behavioural and emotional disturbance in children and adolescents with mental retardation. Fragile X subjects had more shyness and avoidance of eye contact and less antisocial behaviour. Further methodological issues pertaining to studies of behaviour phenotype in general are discussed. © 1994 Wiley‐Liss, Inc.
Population genetics of fragile X: A multiple allele model with variable risk of CGG repeat expansion
Authors: Kolehmainen Karen
Published: June 2005

A model of the population genetics of fragile X that incorporates an arbitrarily large number of alleles based on CGG repeat number is presented. The probability of transition from a premutation to a full mutation upon maternal transmission depends on maternal allele size, as suggested by molecular data. Transitions among various sizes of premutation alleles upon both maternal and paternal transmission are also included using empirically determined transition probabilities. Multiple paths to the final full mutation allele are allowed. Algebraic results for equilibrium allele frequencies are presented for an arbitrary number of alleles, and numerical results are presented for the case of 9 alleles. The model predicts large frequencies for alleles near the normal premutation borderline and high mutation probabilities for the first few mutational steps. The model also predicts that the approach to equilibrium allele frequencies is quite slow, and that a premutation allele typically persists for many generations in a given family before the final transition to a full mutation allele. These nonequilibrium effects are sensitive to the transition probability from large normal alleles to small premutation alleles. © 1994 Wiley‐Liss, Inc.
Fragile X induction systems in CVS cultures: Effect on cytogenetic, PCR, and genomic southern blot DNA analyses of the FMR‐1 gene
Authors: Jenkins Edmund C. , Morys Iwana , Henderson Jeanine , Genovese Marilyn , Carter Mary , Li Shu‐Yun , Houck George E. , Ding Xiaohua , Stark‐Houck Sandra L. , Dobkin Carl S. , Brown W. Ted
Published: June 2005

Low fragile X frequencies have been commonly observed in chorionic villus sample (CVS) cultures, compared to subsequent analysis in whole blood or products of conception (POC). To investigate possible mechanisms for this effect, CVS cultures from a previously identified fragile X positive male, were restudied and compared to subsequent POC cultures from lung, muscle, skin, and thymus. Cultures were exposed, for the last 24 hours before harvesting, to FUdR, excess thymidine, and a combination of both. For CVS, only those cultures that were exposed to a combination of FUdR and excess thymidine showed positive cytogenetic findings (1/90 or 1.1%), agreeing with our original positive cytogenetic results (2/86 or 2.3%) for cultures exposed to excess thymidine. Fragile X frequencies in the POC tissues from this fetus increased to an average of 14%. PCR analyses showed full mutations (>200 CGG repeats) in uninduced CVS cultures but induced cultures exhibited apparently smaller sizes in the range of 120–180 repeats. The results showed variability. In one instance, the banding pattern from one of the uninduced cultures was similar to the results where cultures were exposed to a double induction system. When PCR analyses were conducted on induced POC cultures, full mutations were observed in virtually all samples. Southern blot genomic analysis using probe StB12.3 showed an unmethylated full mutation in CVS cultures. Southern blot patterns from cultures of muscle revealed size variations of DNA bands in the premutation range representing unmethylated DNA as well as methylated full mutations. Finally, variations were also observed in lung and skin cultures, compared to CVS and muscle. The multiple banding patterns that occurred as a function of methylation appeared to be histiotypic.

These results suggest that fragile X induction in CVS cultures causes a decrease in apparent CGG repeat size, an effect not seen or less apparent in most cultured POC tissues. Alternatively, apparent histiotypic variations in banding patterns observed in PCR and StB12.3 genomic Southern blot analyses may reflect differences in tissue type mosaicism, methylation, and/or stage of development. Our findings may help explain the relatively low cytogenetic frequencies commonly seen in CVS cultures. © 1994 Wiley‐Liss, Inc.
Male with typical fragile X phenotype is deleted for part of the FMR1 gene and for about 100 kb of upstream region
Authors: Trottier Yvon , Imbert Georges , Poustka Annemarie , Fryns Jean‐Pierre , Mandel Jean‐Louis
Published: June 2005

We report on a patient with moderate mental retardation and a typical fragile X phenotype, with no family history and no fragile X site on cytogenetic analysis. The patient was found to have a deletion encompassing part of the FMR1 gene and a 70–100 kb region upstream of the FMR1 promotor region. This deletion is smaller than those previously reported and confirms that FMR1 is the major and probably the only gene implicated in the phenotype of the fragile X syndrome. © 1994 Wiley‐Liss, Inc.
Fragile‐X syndrome in east Finland: Molecular approach to genetic and prenatal diagnosis
Authors: Ryynänen Markku , Pulkkinen Leena , Kirkinen Pertti , Saarikoski Seppo
Published: June 2005

Fragile X is the most common inherited form of mental retardation, having an incidence of one in 1,250 males. The fragile X syndrome results from amplification of the CGG repeat found in the fragile X mental retardation‐1‐gene (FMR‐1). This CGG repeat shows length variation in normal individuals and is increased significantly in both carriers and patients.

Non‐retarded carriers of both sexes can be detected reliably only by direct DNA analysis of the fra(X) mutation. Here we investigate fragile X families using the intragenic probes St.B 12.3 and St.B 12.3 XX (J‐L Man‐del). Fragile X syndrome could be verified in 51 families of the population of 900,000 in East‐Finland during 1989–92. The index cases of the syndrome were found by the help of health care personnel, 463 relatives of these families consented to be tested for the mutation of the FMR‐1 gene. Ninety‐three relatives with the full mutation and 127 healthy carriers with the premutation of the fragile X syndrome were diagnosed. In addition, 28 deceased males were obligate carriers. During the year 1992 prenatal diagnosis for fragile X was carried out in nine pregnancies.

For understanding of the occurrence of fragile X syndrome and for better prevention of this syndrome in next generations, systematic genetic counseling and carrier screening in these families is essential. © 1994 Wiley‐Liss, Inc.
Strategy for reliable prenatal detection of normal male carriers of the fragile X syndrome
Authors: Halley Dicky , Van Den Ouweland Ans , Deelen Wout , Verma Ishwar , Oostra Ben
Published: June 2005

Prenatal diagnosis of fragile X syndrome identifying full mutations has been described. Here we report on a case of a prenatal test concerning a normal male carrier of the fragile X syndrome. Southern blot analysis of the fragile X gene resulted in the identification of a premutation in DNA isolated from the chorionic villus sample. Using a polymerase chain reaction (PCR)based assay the CGG repeat length was determined to be 82 CGG repeat units. Confirmation of this premutation in the chorionic villus sample was based on the cytogenetic analysis of the expression of the fragile site at Xq27 applied on a cordocentesis‐derived blood sample. © 1994 Wiley‐Liss, Inc.
Evaluation of school children at high risk for fragile X syndrome utilizing buccal cell FMR‐1 testing
Authors: Hagerman Randi J. , Wilson Philip , Staley Louise W. , Lang Kirsten A. , Fan Tammi , Uhlhorn Cynthia , Jewell‐Smart Sabrina , Hull Claire , Drisko Jodi , Flom Kerry , Taylor Annette K.
Published: June 2005

We describe a pilot project utilizing saliva to identify the FMR‐1 mutation in high‐risk special education students from four public school districts in Colorado. The program included presentations to special education teachers regarding fragile X syndrome, parental consent for testing, completion of a behavior checklist by the teachers, identification of special education students at high risk for fragile X syndrome, subsequent brief examination of face and hands, collection of a saliva sample by either Gatorade swish or brushing of the inside of the cheek, and analysis for the FMR‐1 mutation by PCR. Equivocal samples were studied by direct DNA testing using Southern blot analysis, and abnormal results were confirmed by a blood analysis for the FMR‐1 mutation. Mutant individuals received genetic counseling and medical and educational assessments to optimize treatment and intervention.

This pilot project was met with enthusiasm by the schools. Of the first 439 students evaluated, 68% were male with an average age of 7.75 years; 13% were mentally retarded or autistic. Most students referred for the evaluation were learning disabled (51%) and/or had an Attention Deficit Hyperactivity Disorder (ADHD) (35%). The overall prevalence of the FMR‐1 mutation was 5 of 439 or 1.1%. This relatively low yield is probably due to the high number of non‐retarded but learning disabled students tested. Of the mentally retarded patients tested, 3.5% were positive for the FMR‐1 mutation; however, of the non‐retarded or learning disabled patients, only 0.79% were FMR‐1 positive. The high‐risk criteria have been strengthened with a focus on mentally retarded individuals in an effort to increase our yield of affected individuals in the future. © 1994 Wiley‐Liss, Inc.
Prediction of mental status in carriers of the fragile X mutation using CGG repeat length
Authors: Smits Arie , Smeets Dominique , Hamel Ben , Dreesen Jos , de Haan Anton , van Oost Bernard
Published: June 2005

For genetic counseling in fragile X (fra(X)) families, it is important to know the diagnostic impact of the CGG repeat length in carriers of the fragile X mutation. We have analyzed the CGG repeat length in 106 males and 73 females who had inherited the maternal fra(X) mutation. The sensitivity, specificity, and predictive value of the CGG repeat analyses, as measured on Southern blots of PstI/EcoRI digests, were calculated. In males the sensitivity, specificity and negative predictive value were 99%, 100% and 94%; respectively. In females the specificity (60%) and, consequently, the positive predictive value (82%) was reduced. Therefore, it remains impossible to predict accurately whether a female fetus demonstrating a full mutation will be affected. On the other hand, the negative predictive value of the CGG test in females was 100%. We have no evidence, as yet, that for female carriers with the full mutation, cytogenetic analysis is of additional value to predict the mental status. However, we have observed one mentally retarded fra(X) case with extreme mosaicism in which a typical premutation fragment was the predominant DNA species. Therefore, until more data and better DNA tests are available, we would like to advocate additional cytogenetic investigation if in a fetus a CGG repeat length in the premutation range is found. © 1994 Wiley‐Liss, Inc.
Direct mutation analysis of 495 patients for fragile X carrier status/proband diagnosis
Authors: Kaplan Gail , Kung Melissa , McClure Melody , Cronister Amy
Published: June 2005

With the cloning of the FMR‐1 gene, direct mutation analysis is possible for fragile X syndrome. We have analyzed 495 patients using the StB12.3 probe/EcoRI/EagI system of Rousseau et al. [N Engl J Med 325:1673–1681, 1991] and 167 of these also with PCR analysis according to Brown et al. [JAMA 270:1569–1575, 1993]. For 28 patients requesting carrier status due to a family history of fragile X, 10 were shown to have either premutations or full mutations; for the remainder with varied backgrounds, 1 in 182 was shown to carry a premutation. For proband diagnosis, 7 of 14 with a fragile X family history carried a full mutation; 11 of 271 with other family histories carried the full mutation. © 1994 Wiley‐Liss, Inc.
Characteristics of the transmission of the FMR1 gene from carrier females in a prospective sample of conceptuses
Authors: Sherman S. L. , Maddalena A. , Howard‐Peebles P. N. , Brown W. T. , Nolin S. , Jenkins E. , Schwartz C. , Tarrelton J. , Shapiro L. R. , Smits A. P. T. , van Oost B. A. , Youings S. , Jacobs P. A. , Martinez F. , Barnicoat A. , Hockey A. , Staley L. , Hagerman R. , Kennerknecht I. , Steinbach P. , Barbi G. , Filippi G. , Grasso M. , Taylor S. A. M. , Robinson H. , Webb T. , Broome D. , Dixon J. , Ferreira P. , Gustavson K.‐H. , Meyer J. L. , Pai G. S.
Published: June 2005

The Prospective Study of the Fragile X Syndrome is a large collaborative effort designed to collect prospective data on the pregnancy outcomes of individuals who carry the fragile X mutation. The goal of this 5‐year study is to obtain empiric recurrence risks and population parameters for the fragile X syndrome in order to characterize the underlying mechanism of the mutation and the factors that influence its expression. This report presents the DNA results on the first 152 cases of female carriers and their pregnancy outcomes. It was found that the sex ratio of conceptuses was not significantly different from 1.0 and was not associated with mutation status. Thus, there was no evidence for selection against zygotes with full mutations. There was a significant association between the form of the mutation in carrier mothers and the frequency of its transmission. Examination of the segregation ratios from premutation mothers showed that there was a deficit of conceptuses that received the fragile X mutation. The segregation ratio from full mutation carrier mothers did not differ from expected. Several explanations for this observation are discussed. Numbers of cases are too small to estimate recurrence risks; however, the general trend of the data confirm the association of recurrence risks and the repeat number carried by the mother. © 1994 Wiley‐Liss, Inc.
Asymmetry of methylation with FMR‐1 full mutation in two 45,X/46,XX mosaic females associated with normal intellect
Authors: Shapiro Lawrence R. , Simensen Richard J. , Wilmot Patrick L. , Fisch Gene S. , Vibert Betsy K. , Fenwick Raymond G. , Tarleton Jack , Phelan Mary Catherine
Published: June 2005

The full FMR‐1 mutation is known to cause the fragile X syndrome [Fra(X)], but variable expression in females, including normal to deficient intellect, may be related to random X‐inactivation (lyonization).

We have evaluated 2 mosaic 45,X/46,XX females who are cytogenetically fra(X) positive, have an FMR‐1 full mutation, and are of normal intellect. There were 50% fra(X) chromosomes in the 45,X cells of one of the females; this has not been reported previously. In both patients, there was a strong asymmetry of FMR‐1 methylation with the normal allele being totally or 90% unmethylated and the mutant allele being similarly methylated. Thus, the apparent selective inactivation of the full mutant FMR‐1 allele appears to have resulted in limited expression with normal intellect.

The presence of the fra(X) chromosome in 45,X cells is unique; however, there may be no relationship to the asymmetric inactivation of the mutant allele which could be due to chance or a mechanism yet to be delineated. © 1994 Wiley‐Liss, Inc.
Unstable triplets and their mutational mechanism: Size reduction of the CGG repeat vs. germline mosaicism in the fragile X syndrome
Authors: Chiurazzi Pietro , Kozak Libor , Neri Giovanni
Published: June 2005

The mechanism responsible for the characteristic expansion of the trinucleotide repeat involved in the pathogenesis of the fragile X syndrome is still largely unclear. Slipped strand mispairing (SSM) and similar DNA replication errors could determine both increases and decreases of the unit number in simple repetitive sequences. Actually, there have been a few reports of size reduction of the (CGG)n in parent‐to‐child transmission of the fragile X syndrome, which may help in understanding the mutational mechanism and may have practical implications for genetic counseling. We describe here 5 such cases from our series of fragile X patients and emphasize the possible role of SSM‐like events in causing (CGG)n expansions and reductions.

The possibility that some of these reductions are only apparent, resulting from parental germinal mosaicism is also considered. © 1994 Wiley‐Liss, Inc.
Robust amplification and ethidium‐visible detection of the fragile X syndrome CGG repeat using Pfu polymerase
Authors: Chong Samuel S. , Eichler Evan E. , Nelson David L. , Hughes Mark R.
Published: June 2005

We report on a method for ethidium bromide detection of FMR1 normal and premutation‐size CGG triplet repeats. A set of PCR conditions has been optimized for the polymerase of the hyperthermophilic bacterium, Pyrococcus furiosus. Using this protocol, normal‐size alleles ranging from 5 to 50 repeats, as well as most of premutation‐size alleles, varying from >50 to approximately 200 repeats, could be detected by ethidium bromide staining of agarose gels. Since the protocol requires neither autoradiography nor polyacrylamide gel electrophoresis, it promises to provide a rapid means for the exclusion of fragile X syndrome in males with mental retardation.
Improved sizing of fragile X CCG repeats by nested polymerase chain reaction
Authors: Levinson Gene , Maddalena Anne , Palmer Frances T. , Harton Gary L. , Bick David P. , Howard‐Peebles Patricia N. , Black Susan H. , Schulman Joseph D.
Published: June 2005

We have developed an improved method for polymerase chain reaction (PCR)‐based sizing of the CCG repeat region at the fragile X locus, FMR‐1. This method is designed to optimize denaturation and replication of long repeats with high G + C content, which are otherwise refractory to amplification. The method utilizes nested PCR primers to increase sensitivity and specificity. Alkaline denaturation of the genomic template DNA, combined with addition of glycerol and deaza‐dGTP, facilitates strand separation. Labeled PCR products are sized on denaturing polyacrylamide gels. For alleles in the normal‐to‐premutation size range, strong reproducible signals are routinely obtained from small amounts of rapidly prepared DNA. This allows precise determination of the CCG repeat number, providing data related to the expansion potential of the repetitive segment. Detection of large premutations and some full mutations is also enhanced by the improved procedure. © 1994 Wiley‐Liss, Inc.
X‐linked mental retardation with dystonic movements of the hands (PRTS): Revisited
Authors: Gedeon Agi , Partington Michael , Mulley John
Published: June 2005

A family with a syndrome of mental retardation, dystonic movements of the hands, and dysarthria (MIM no. 309510) was described and mapped to Xp22 by Partington et al. (Am J Med Genet 1988; 30:251–262). The original localization encompassed the distal half of the short arm of the X chromosome, with a peak lod score of 2.1 at the DXS41 locus. The gene localization for this disorder (PRTS) has now been refined using recently characterized dinucleotide repeat markers. The PRTS gene maps between DXS365 and DXS28, an interval estimated to be less than 15 cM. A peak lod score of 3.01 at a recombination fraction of zero was generated by 2‐point linkage analysis with the marker DXS989. Dystonic movements may be progressive and could be overlooked in children. Clinical assessments of affected men who are mentally retarded should be critically evaluated for this manifestation, where they belong to families in which the gene localization overlaps with PRTS. © 1994 Wiley‐Liss, Inc.
Regional localisation of a non‐specific X‐linked mental retardation gene (MRX19) to Xp22
Authors: Donnelly Andrew J. , Choo K. H. Andy , Kozman Helen M. , Gedeon Agi K. , Danks David M. , Mulley John C.
Published: June 2005

A gene responsible for a non‐specific form of X‐linked mental retardation (MRX19) was localised by linkage analysis. Exclusions and regional localisation were made using 21 highly informative PCR‐based markers along the X chromosome. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS207, DXS987 (Zmax = 3.58) and DXS999 (Zmax = 3.28) indicating that this gene is localised to the proximal portion of Xp22. Recombination between MRX19 and the flanking loci KAL and DXS989 was observed. The multipoint CEPH background map, with map distances in cM, DXS996‐1.8‐KAL‐19.0‐DXS207‐0.9‐[DXS987, DXS443]‐4.3‐DXS999‐3.5‐DXS365‐14.0‐DXS989. Two other MRX disorders and two syndromal mental retardations, Coffin‐Lowry syndromal and Partington syndrome, have been mapped to this region. There is a possibility that the 3 MRX disorders are the same entity. Most MRX disorders remain clustered around the pericentromeric region. © 1994 Wiley‐Liss, Inc.
New X‐linked mental retardation (XLMR) syndrome with distinct facial appearance and growth retardation
Authors: Brooks Susan Sklower , Wisniewski Krystyna , Brown W. Ted
Published: June 2005

We report on 2 brothers and their nephew with an apparently new X‐linked mental retardation (XLMR) syndrome characterized by a distinct facial appearance, growth retardation, and severe mental retardation. The facial traits included triangular shape; bifrontal narrowness; malar flatness; blepharophimosis; very deeply set eyes; epicanthus inversus; bulbous nose; low hairline; low‐set, deeply cupped, and protruding ears; short ill‐defined philtrum; and thin tented upper lip. These facial anomalies are particularly striking and recognizable even at birth. The boys were small for gestational age and remained below −2 SD in growth parameters. With age, large joint contractures developed. Pectus excavatum was apparent at birth but became more obvious with age. Global developmental delay was evident in infancy. The brothers were nonverbal while their nephew spoke simple words. Optic atrophy, esotropia, nystagmus, and spastic diplegia were evident. They were self‐abusive, hyperactive, and poorly coordinated. CT scans demonstrated atrophic hydrocephalus. No EEG abnormalities were detected. Karyotypes were 46,XY and fragile X negative. Routine chemistries; amino, organic, and uronic acids; oligosaccharides; lysosomal enzymes; and very long chain fatty acids were normal. Remarkable phenotypic similarity between these brothers and their nephew and lack of manifestations in their mothers makes X‐linked recessive inheritance likely. This syndrome, which does not appear to have been reported previously, adds to the delineation of XLMR. © 1994 Wiley‐Liss, Inc.
Is Rett syndrome a chromosome breakage syndrome?
Authors: Telvi Louise , Leboyer Marion , Chiron Catherine , Feingold Josué , Ponsot Gérard
Published: June 2005

Lymphocytes from venous blood from 15 girls with Rett syndrome (RTS), 7 girls with RTS “forme fruste,” and 46 unrelated control females were examined. All subjects had a normal karyotype using RHG and RTBG technique. The frequency of gaps and breaks was determined for each group. A significantly higher (P < 0.01) frequency of chromosome breakage was observed in RTS subjects compared to controls. This work suggests that an increased tendency to chromosome breakage may be part of a genetically determined disorder in RTS patients. © 1994 Wiley‐Liss, Inc.
Epidemiology of congenital hydrocephalus in Utah, 1940–1979: Report of an iatrogenically related “epidemic”
Authors: Blackburn Brent L. , Fineman Robert M.
Published: June 2005

As part of an epidemiological study of congenital hydrocephalus in Utah, we focused on the effect of ascertainment sources and temporal variability to further delineate the causes of this relatively common, handicapping birth defect. The incidence and distribution of 934 reported cases diagnosed prior to age 6 months, and born to Utah residents from 1940 to 1979, were analyzed. Data were ascertained by examination of multiple sources, e.g., 982,066 birth, 11,161 fetal death, and 248,208 death certificates, and selected hospital and clinic records. Of the 934 reported cases, 700 met our selection criteria for congenital hydrocephalus, which results in a crude incidence of 0.70 per 1,000 live and stillbirths. Seventy‐one cases (10.1%) had additional, multiple congenital anomalies. The male/female sex ratios of the 619 cases of isolated congenital hydrocephalus (occurring as a single entity or in the absence of other reported or known birth defects) and those with multiple congenital anomalies (71 cases) were virtually identical, being 1.45 and 1.48, respectively. A significant 85% increase in the rate of reported cases was observed for the period 1966 to 1970. However, examination of patients' records from 1966 to 1975 in the hospital responsible for almost all of this increase suggests that this was an iatrogenically related “epidemic” caused by several factors: the introduction and possible misinterpretation of pneumoencephalograms (PEG) in the diagnosis of hydrocephalus (PEG was replaced by CAT scanning in the early 1970s), inappropriate diagnosis, and incorrect recording of age at time of diagnosis. © 1994 Wiley‐Liss, Inc.
Preimplantation genetics: A case for prospective action
Authors: Pergament Eugene , Bonnicksen Andrea
Published: June 2005

Preimplantation genetics describes a newly‐emerging field in medical genetics, the consequence of the implementation of clinical preimplantation diagnosis and the likely future development of germ‐line gene therapy. Given the existing clinical and laboratory difficulties already demonstrated in preimplantation diagnosis and the sensitive ethical issues surrounding genetic manipulation of human embryos, there is a need for 1) critical and objective evaluation of developments in this field by human and medical geneticists and 2) development of guidelines for research and clinical practice in the years ahead. We propose a course of prospective action for preimplantation genetics implemented through the newly‐formed American College of Medical Genetics in order to address the ethics, safety, accuracy, cost, and overall merit of preimplantation genetics. © 1994 Wiley‐Liss, Inc.
Duplication 10q confirmed by DNA in situ hybridization
Authors: Johnson Virginia P. , Sutliff Willis C.
Published: June 2005

Partial duplication of 10q is a recognizable clinical entity. In most of the reported cases, the trisomic segment is identified by a balanced translocation state in a parent. Verification remains a problem in de novo cases. However, the recent availability of whole chromosome probes allows for confirmatory diagnosis of suspected cases. We describe a case of de novo duplication (10q) wiht verification using DNA in situ hybridization. © 1994 Wiley‐Liss, Inc.
Monozygotic twins discordant for gastroschisis: Case report and review of the literature of twins and familial occurrence of gastroschisis
Authors: Bugge Merete , Petersen Michael B. , Christensen M. Fjord
Published: June 2005

We describe a pair of monozygotic (MZ) female twins discordant for gastroschisis. To our knowledge, this is the first such case reported. The zygosity was verified by DNA analysis using highly polymorphic microsatellites. There was no family history of gastroschisis. During pregnancy there was no suspicion of any exposure responsible for the malformation. The number of twin cases described so far does not allow any conclusion as to hereditary factors in the cause of gastroschisis, but the number of families reported with familial gastroschisis suggests that the recurrence risk is higher than previously thought. © 1994 Wiley‐Liss, Inc.
Intermittent hair loss in a child with PIBI(D)S syndrome and trichothiodystrophy with defective DNA repair‐xeroderma pigmentosum group D
Authors: Kleijer Wim J. , Beemer Frits A. , Boom Bart W.
Published: June 2005

We describe a girl with photosensitivity (P), ichthyosis (I), brittle hair (B), impaired intelligence (I), possibly decreased fertility (D), and short stature (S). The clinical findings fit into the PIBI(D)S syndrome and trichothiodystrophy. A remarkable and probably unique observation for this disorder was the intermittent character of the scalp hair loss during infectious periods in this patient.

Easy suntanning suggested photosensitivity and prompted DNA repair studies which demonstrated reduced UV‐induced DNA repair synthesis. Subsequent studies have assigned this patient to xeroderma pigmentosum group D and suggested a specific deficiency of 6–4 photoproduct repair. An unaffected child was diagnosed in the next pregnancy of the mother. © 1994 Wiley‐Liss, Inc.
Historical study: Cornelia C. de Lange (1871–1950)—a pioneer in clinical genetics
Authors: de Knecht‐van Eekelen Annemarie , Hennekam Raoul C. M.
Published: June 2005

The life and work in the field of clinical genetics of one of the most outstanding Dutch pediatricians of the first half of the twentieth century, Cornelia C. de Lange (1871–1950), is described against the background of the development of pediatrics, anthropogenetics, and clinical genetics in the Netherlands.

Cornelia de Lange specialized in and worked on all aspects of the broad field of pediatrics. During her 50 years of practice she collected an immense series of observations on pediatric disorders. As theories on human genetics developed during the 1920s and 1930s, her interest in congenital disorders and heredity increased as she saw the implications for the pediatric clinic. She benefitted from her vast experience and her knowledge of the national and international literature when she recognised and described new entities, one of which is named after her: the Brachmann‐De Lange syndrome. © 1994 Wiley‐Liss, Inc.
Comparative study of fanconi anemia in children of different ethnic origin in South Africa
Authors: Macdougall Lorna G. , Rosendorff Jennifer , Poole Janet E. , Cohn Richard J. , McElligott Susan E.
Published: June 2005

A comparative study of clinical, hematologic, and cytogenetic findings was made in 40 black and 35 white children with Fanconi anemia. The black children were Bantu‐speaking Negroid stock of diverse tribal origin. The white children were predominantly Afrikaans stock of Dutch/German/French Huguenot origin. All of the patients had IFAR scores of 2 to 4+ and over 80% in each group had increased spontaneous and/or mutagen‐induced chromosomal breakage (CB‐positive). There were no significant clinical differences between black and white patients or between CB‐pos and CB‐neg patients, with the exception of white children in whom significantly more CB‐pos patients had thumb and radial anomalies than the CB‐neg patients. The age‐at‐onset of hematologic manifestations was the same for all groups, but more black than white CB‐pos patients were severely anemic at the time of diagnosis.

Response to androgen and steroid therapy occurred in only 33% of black children compared with 86–90% of white children; 81% of black patients died during the 18 year study period compared with 30% of white children, but the age at death was similar. More sophisticated studies are required to determine whether these differences are genetically determined or related to cultural, educational, and socio‐economic differences between the two ethnic groups. © 1994 Wiley‐Liss, Inc.
Three decades of follow‐up of aortic and pulmonary vascular lesions in the Williams‐Beuren syndrome
Authors: Wessel A. , Pankau R. , Kececioglu D. , Ruschewski W. , Bürsch J. H.
Published: June 2005

The diagnostic criteria of the Williams‐Beuren syndrome (WBS) were established almost 3 decades ago. Until now there has been little knowledge about the natural and post‐surgical history of vascular lesions in this syndrome. In order to evaluate the long term follow‐up of aortic and pulmonary vascular lesions, we have analysed the catheterization data, angiocardiograms, and Doppler‐echo measurements in 59 patients who were seen at least twice in our institution between 1961 and 1993. Their follow‐up periods ranged from 2.1 to 28.2 years. Of 45 patients with supravalvular aortic stenosis (SVAS) with a mean follow‐up period of 12.9 years, it became evident that pressure gradients of less than 20 mm Hg in infancy generally remained unchanged during the first two decades of life. Pressure gradients exceeding 20 mm Hg increased from an average of 35.5 mm Hg to 52.7 mm Hg in 13 patients. Of these, 8 required surgical relief of the narrowing. In 7 patients aortic hypoplasia was documented. In 5 of them the caliber of the aorta showed a tendency towards normalisation within a period of 11.9 to 23.9 years. Of 6 individuals with aortic hypoplasia and surgical relief of SVAS, 4 patients developed restenosis at the distal end of the aortoplasty patch. In contrast, 9 patients with operated SVAS—but without aortic hypoplasia—remained free of restenosis over a period of 11 years (mean). Coarctation occurred in 4/59 patients; restenosis was seen in 2 after 5 and 16 years. Peripheral pulmonary stenosis was followed in 23 patients over 14.4 years (mean). During this period the systolic pressure gradients fell from 23 to 9.3 mm Hg (mean). In adolescence and adulthood the gradients were below 20 mm Hg in 22/23 individuals.

In WBS there is a good long‐term prognosis for SVAS if gradients during infancy are low. SVAS with gradients above 20 mm Hg tend to increase; 60% of them require surgical relief with good long‐term results. But aortic hypoplasia impairs the prognosis of operated SVAS, because restenosis may occur. Peripheral pulmonary stenosis generally shows a good long‐term prognosis. © 1994 Wiley‐Liss, Inc.
Diploid/triploid mosaicism: Further delineation of the phenotype
Authors: Carakushansky Gerson , Teich Evelyn , Ribeiro Marcia G. , Horowitz Dafne D. G. , Pellegrini Sandra
Published: June 2005

Here we report on a girl with diploid/triploid mosaicism followed up to age 5 years. The clinical manifestations are compared to those of other reported cases. In contrast to most cases, our patient was not growth retarded despite severe delays in psychomotor development. We also discuss 2 manifestations that have not received sufficieent attention in previous reports: pigmentary dysplasia and truncal obesity. © 1994 Wiley‐Liss, Inc.
Pulmonary hyperplasia in the Fraser cryptophthalmos syndrome
Authors: Stevens Cathy A. , McClanahan Carolyn , Steck Audrey , Shiel Fergus O'M. , Carey John C.
Published: June 2005

We report on 2 sibs with the Fraser cryptophthalmos syndrome who had pulmonary hyperplasia and laryngeal stenosis. A third unrelated patient with Fraser syndrome had laryngeal stenosis, renal agenesis, and normal lung development, rather than the expected pulmonary hypoplasia. Three additional cases of pulmonary hyperplasia in the Fraser syndrome were ascertained from a review. In all of these cases the likely mechanism for pulmonary hyperplasia is retention of fetal lung fluid by laryngeal or tracheal obstruction. © 1994 Wiley‐Liss, Inc.
Familial total anomalous pulmonary venous return: A large Utah‐Idaho family
Authors: Bleyl Steven , Ruttenberg Herbert D. , Carey John C. , Ward Kenneth
Published: June 2005

Total anomalous pulmonary venous return (TAPVR) is a rare form of cyanotic congenital heart disease which, without surgical correction, has a high mortality rate in the first year of life. It usually occurs without a family history, and is generally thought to have a low recurrence risk. However, 15 instances of familial TAPVR have been reported previously, suggesting a genetic cause in some cases. We report on a large family in which TAPVR appears to be determined multifactorially or as an autosomal dominant trait with variable expressivity and reduced penetrance. © 1994 Wiley‐Liss, Inc.
Congenital hypotrichosis and milia: Report of a large family suggesting X‐linked dominant inheritance
Authors: Rapelanoro Rabenja , Taïeb Alain , Lacombe Didier
Published: June 2005

We report on a large family of four generations in which individuals have congenital hypotrichosis and multiple milia disappearing by adolescence. The propositus a 30‐month‐old boy, has coarse, sparse hair and multiple milia on face, chest, axillae and pubic region. At 16 years, his sister has apparently normal hair and few milia persisting on the forehead. The same symptoms were present in the mother from birth and disappeared at 40 years. There are no abnormalities of teeth and nails. Polarizing light microscopy shows an increased diameter of the hair shaft. The pedigree is compatible with an autosomal or an X‐linked dominant mode of inheritance. © 1994 Wiley‐Liss, Inc.