bluuebunny/crossref_metadata_2025 huggingface dataset:
Unique karyotypes in two patients with Prader‐Willi syndrome
Authors: Narahara Kouji , Hiramoto Kei , Murakami Masae , Miyake Susumu , Tsuji Kazushiro , Yokoyama Yuji , Namba Hiroshi , Ninomiya Shinsuke , Murakami Ryuko , Seino Yoshiki
Published: June 2005

A physical disruption of the Prader‐Willi syndrome (PWS) chromosome region is thought to cause PWS. We describe 2 girls with PWS phenotype, who had unique chromosome 15 abnormalities. The first patient showed mosaicism: 45,XX,t(15;15)(qter→p11.1::q11.200→ qter)/46,XX,t(15;15)(qter → p11.1::q11.200→ qter), + mar. The band 15q11.2 apparently remained intact in the t(15;15) chromosome, and the mar chromosome was considered as r(15) (p11.1q11.1). The second patient had a karyo‐type of 47,XX,del(15)(q11.200→q11.207), + idic (15)(pter → q11.1::q11.1→pter). The complex breakage and reunion involving the 15q11.2 regions of the father's homologous chromosomes 15 at meiosis appeared to have resulted in the idic(15) and the del(15) chromosomes. These cytogenetic findings suggest that the PWS chromosome region may be localized on the very proximal portion of band 15q11.2.
Interstitial deletion 8p21.3 → p23.1 in a 6‐year‐old girl
Authors: Morrison Patrick J. , Jones June , Nevin Norman C.
Published: June 2005

We present a 6‐year‐old mentally retarded girl. Chromosome analysis showed an interstitial deletion of chromosome 8; 46,XX,del(8) (pter → p23.1::p21.3 → qter). The proposita had normal activities of glutathione synthetase reductase (GSR) and factor VII. Parental chromosomes were normal.
β‐glucuronidase deficiency as a cause of fetal hydrops
Authors: Kagie M. J. , Kleijer W. J. , Huijmans J. G. M. , Maaswinkel‐Mooy P. , Kanhai H. H. H.
Published: June 2005

Mucopolysaccharidosis type VII (MPS VII) was diagnosed in a case of severe fetal hydrops. β‐glucuronidase deficiency was demonstrated in the amniotic fluid, which was obtanined at 25 weeks of gestation, and in the fibroblasts of the child, which were cultured atter fetal death in the 26th week of gestation. In the amniotic fluid the two‐dimensional eletrophoresis pattern of glycosaminoglycans was in agreement with MPS VII. Based on these results, prenatal diagnosis could be offered to the couple for the next pregnancy.
Segregation of three reciprocal translocations in the same family: t(3;4), t(5;10), and t(15;21)
Authors: Telvi Louise , Folhen Martine , Raoul Odile , Feingold Josué , Ponsot Gérard , Pompidou Alain , Rethoré Marie O. , Lejeune Jérǒme
Published: June 2005

A male infant with static antenatal encephalopathy and epilepsy was found to have a duplication of 5p12→5pter and deficiency of 10p13→10pter. Each of his parents was a carrier of a balanced reciprocal translocation. A third translocation was found in the maternal grandfather. The pedigree of each translocation and the segregation of parental reciprocal translocations are discussed.
Dwarfism, rhizomelic limb shortness, and abnormal face: New short stature syndrome sharing some manifestations with Robinow syndrome
Authors: Turnpenny Peter D. , Thwaites Richard J.
Published: June 2005

We describe a child with short stature of prenatal onset, rhizomelic limb shortness affecting the upper limbs particularly, and an unusual face. She had frontal balding, mid‐face hypoplasia, a small nose, macrostomia with down‐turned corners of the mouth, gingival hypertrophy, and hypoplasia or absence of the clitoris. There was no gross modelling defect of the skeleton and the vertebral column was normal. Some of these manifestations overlap with those of Robinow syndrome.
Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis
Authors: Semmekrot Ben A. , Haraldsson Asgeir , Weemaes Corry M. R. , Smeets Dominique F. C. M. , Geven Wil B. , Brunner Han G.
Published: June 2005

A patient is described who presented with severe congenital anemia, hydrops fetalis, immune disorder, and absent thumbs. No toxic, infectious, or metabolic cause was found to explain these symptoms. Immunologic and cytogenetic studies excluded several syndromes that combine radial ray anomalies with hematological involvement. After careful study of the literature, it is concluded that the disorder described here represents a new syndrome that can be added to a growing list of hematological‐radial syndromes.
Prenatal diagnosis of the Pallister‐Killian mosaic aneuploidy syndrome by CVS
Authors: Bernert Jürgen , Bartels Iris , Gatz Gudrun , Hansmann Ingo , Heyat Martina , Niedmann Paul D. , Rehder Helga , Waldenmaier Claus , Zoll Barbara
Published: June 2005

Prenatal cytogenetic analysis at 11 weeks of gestation revealed an abnormal karyotype 47, XX, + mar in all metaphases obtained from a chorionic villi sample after 24 h culture. Karyotyping of amniotic fluid cells in the second trimester showed mosaicism 47, XX, + i(12p)/46,XX with 10% aneuploid cells. The pregnancy was terminated at 20 weeks of gestation on the patient's request. The aborted fetus showed typical manifestations of the Pallister‐Killian mosaic aneuploidy syndrome. The identity of the supernumerary isochromosome 12p was proven by LDH isozyme electrophoresis using cultured fibro‐blasts and by nonradioactive in situ hybridization using a biotinylated set of chromosome 12‐specific DNA probes.
Cytogenetic and molecular investigation of a balanced Xq13q translocation in a patient with retinoblastoma
Authors: Stambolian Dwight , Sellinger Beatrice , Derrington Dennis , Sargent Robert , Emanuel Beverly S.
Published: June 2005

We report on a 4‐year‐old girl with retinoblastoma and de novo balanced translocation [46,X,t (X;13) (q23;q13)]. Unilateral retinoblastoma was discovered at age 9 months along with developmental delay and several manifestations of Turner syndrome. Chromosome studies showed an X/13 translocation and an X inactivation pattern showing the translocated X chromosome active in all 50 cells examined. Standard Southern blot analysis and pulsed field gel electrophoresis using a 3.8 kb EcoR1 fragment of the cDNA probe to the 3′ end of the RB1 locus demonstrated a normal genomic pattern. The results of the cytogenetic and molecular analysis suggests that the RB1 locus has not been disrupted by the chromosome rearrangement. This case is the fifth report of an X/13 translocation associated with a retinoblastoma.
The second report of Knobloch syndrome
Authors: Czeizel A. E. , Göblyös P. , Kustos G. , Mester E. , Paraicz E.
Published: June 2005

Two sibs affected with Knobloch syndrome comprising severe visual handicap (high myopia and retinal detachment with other defects), atypical occipital cephalocele, and unusual plantar creases are described.
Autosomal dominant congenital laryngomalacia
Authors: Shohat Mordechai , Sivan Yakov , Taub Ellen , Davidson Shmuel
Published: June 2005

A family is presented in which congenital stridor due to laryngomalacia was evident in 9 individuals through 3 generations. This report confirms the autosomal dominant transmission of at least one type of laryngomalacia.
Tissue specificity and stability of mosaicism in Pallister–Killian +i(12p) syndrome: Relevance for prenatal diagnosis
Authors: Priest Jean H. , Rust Jean M. , Fernhoff Paul M.
Published: June 2005

We ascertained +i(12p) mosaicism during third trimester in a case of polyhydramnios and diaphragmatic hernia. Primary cultures of amniocytes had colonies with +i(12p), colonies without +i(12p), and mixed colonies with 46/47, +i(12p). The likely explanation was instability and loss of i(12p) during somatic divisions of amniocytes. Fetal blood in third trimester retained +i(12p) in 13% of cells. A review of mosaicism in published cases indicates that factors influencing the presence of +i(12p) include tissue type and in vitro and in vivo age. In blood, amniocyte, and probably bone marrow cultures, +i(12p) is less stable than in fibroblast‐like cultures derived from skin and other tissues. Young cultures at early passage are more likely to have +i(12p) than old cultures. Cultures from young (especially fetal) donors are more likely to retain +i(12p) than cultures from adult donors. These rules will be important in determining appropriate tissues for diagnosis and interpretation of mosaicism in this disorder.
Survival of fetuses with 45,X: An instructive case and an hypothesis
Authors: Kelly Thaddeus E. , Ferguson James E. , Golden Wendy
Published: June 2005

The high (> 95%) fetal loss rate of 45,X embryos and fetuses has led to the suggestion that fetal survival with this karyotype requires the presence of mosaicism. However, in many instances, even given a “mild Ullrich‐Turner syndrome” phenotype, mosaicism is not detected. In a pregnancy studied for advanced maternal age, CVS cultured cells showed 65% 45,X and 35% 46,X,r(X). After termination, 2 fetal tissues showed 95% 45,X cells. It is suggested that infants with the 45,X karyotype likely had mosaicism for a structurally abnormal X or Y chromosome during embryogenesis, but the abnormal cell line disappeared prior to birth.
Pentalogy of Cantrell and ectopia cordis, a familial developmental field complex
Authors: Martin Rick A. , Cunniff Christopher , Erickson Lars , Jones Kenneth Lyons
Published: June 2005

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.
Longitudinal changes in IQ among fragile X males: Clinical evidence of more than one mutation?
Authors: Fisch G. S. , Shapiro L. R. , Simensen R. , Schwartz C. E. , Fryns J. P. , Borghgraef M. , Curfs L. M. , Howard‐Peebles P. N. , Arinami T. , Mavrou A.
Published: June 2005

Longitudinal changes in IQ among mentally retarded (MR) fragile X [fra(x)] males have been reported previously. While age is associated with decline in IQ, not all males are so affected. This suggests that there may be more than one subtype of affected fra(X) male. Therefore, we examined the distribution of standardized difference scores (Zdiff) in IQ to determine if subjects were from an admixture of at least 2 populations. Cluster analysis of Zdiff scores was used to partition subjects into 2 groups. Goodness‐of‐fit tests indicated that scores were more likely to come from an admixture. Discriminant functions (DF) were calculated to determine predictive validity of Zdiff scores. To eliminate the effect of skewing, a power transform was applied to Zdiff scores and DFs recomputed. Zdiff and transformed scores provided similar results. The mean and variance for one group showed no differences in test‐retest scores as would be expected from examining any population while the mean for the second group indicated significant decline in IQ nearly 4 standard errors below the first test score. These results suggest that there may be clinical evidence for 2 types of fra(X) mutation: One which causes MR but is static, and a second mutation which causes MR but is dynamic and contributes to an apparent longitudinal decline in cognitive function.
Brief screening questionnaire for determining affected state in fragile X Syndrome: A consensus recommendation
Authors: Reiss Allan L. , Cianchetti Carlo , Cohen Ira L. , Devries Bert , Hagerman Randi , Hinton Veronica , Froster Ursula , Lachiewicz Ave , Mazzocco Michele , Sobesky William , Sudhalter Vicki
Published: June 2005

New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene (s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.
Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome
Authors: Hinton V. J. , Dobkin C. S. , Halperin J. M. , Jenkins E. C. , Brown W. T. , Ding X. H. , Cohen I. L. , Rousseau F. , Miezejeski C. M.
Published: June 2005

The effect of mode of inheritance on expression of fragile X syndrome [fra(X)] was investigated in nonretarded female carriers. Examination included cognitive and molecular measures. A priori predictions about cognitive impairment and size of an unstable region of DNA containing a CGG repeat on the X chromosome were tested in age and education matched heterozygotes grouped according to parental inheritance.

Nine carriers with a maternal fra(X) chromosome, 11 carriers with a paternal fra(X) chromosome and 15 control mothers of children with non X‐linked developmental disabilities were tested. Inheritance was established through DNA linkage analysis. Cognitive skills were assessed using the Wechsler Adult Intelligence Scale‐Revised and the Benton Visual Retention Test. Molecular status was assessed by Southern blot analysis of genomic DNA digested with Eco RI and Eag I, and probed with StB 12.3.

Results supported the inheritance models' predictions. Heterozygotes who inherited the fra(X) from their fathers appeared to be a homogeneous group. They were indistinguishable from controls on cognitive measures and all had genomic insertions of <500 base pairs. In contrast, heterozygotes who inherited the fra(X) chromosome from their mothers appeared to be made up of 2 subpopulations. They were as a group deficient in measures of attention and visual memory, but not other measures, with scores of some women consistently below the other subjects. Further, they had some members with >500 base pair inserts.

Thus, parental origin of the chromosome appears to influence fra(X) expression on both a behavioral and molecular level.
Cognitive profile in adult, normal intelligent female fragile X carriers
Authors: Steyaert J. , Borghgraef M. , Gaulthier C. , Fryns J. P. , Van Den Berghe H.
Published: June 2005

Here we present the results of the study of the cognitive profile of 11 adult, normally intelligent female fragile X [fra(X)] carriers. In all individuals 3 types of testing were performed: full scale Wechsler Adult Intelligence Scale, a set of neuropsychological tests and an arithmetic achievement test.

All 11 subjects showed an average to above‐average intelligence but 10 of 11 performed better on the performance than on the verbal subscale. Neuropsychological tests suggest a dysfunction of the reticulo‐thalamic axis with deficiency on tests requiring visual memory and a pronounced deficiency of attention skills combined with an impulsive way of completing tests.
Mortality in the fragile X syndrome: Preliminary data
Authors: Partington M. W. , Robinson H. , Laing S. , Turner G.
Published: June 2005

Mortality was studied among 348 males and 433 females who had or who carried the gene for the fragile X syndrome. The average age of death was about 12 years lower than in the general population for both men and women but this was likely a bias of ascertainment. The commonest causes of death were cardiovascular, cerebrovascular and malignant disease similar to those in the general population. No evidence for any specific disease subsceptibility was found in this preliminary study.
Sleep apnea in fragile X syndrome
Authors: Tirosh Emanuel , Borochowitz Zvi
Published: June 2005

Seven subjects (age 6 to 21 years) with fragile X [fra(X)] were investigated for obstructive sleep apnea (OSA). After a structured interview, 4 of them underwent an overnight polygraphic study. The results indicate an increased risk for OSA among subjects with fra(X) (4/7). In 2 of the subjects polygraphic study indicated a severe OSA syndrome, whereas only mild and moderate severity was evident in the other two. Apnea in all 4 was associated with significant O2desaturation. Episodes of prolonged expiratory apnea were reported in 2 of the subjects and confirmed by the polygraphic study in one. A continuous positive airway pressure (C‐PAP) trial was successful in one of the two patients. It is suggested that subjects with fra(X) are at increased risk for OSA, and physicians should orientate their evaluation with this in mind.
Fra(X)(q27.2), the common fragile site, observed in only one of 760 cases studied for the fragile X syndrome
Authors: Jenkins Edmund C. , Genovese Marilyn J. , Duncan Charlotte J. , Gu Hong , Stark‐Houck Sandra L. , Lele Kusum , Li Shu‐Yun , Krawczun Michael S.
Published: June 2005

Cell cultures from 760 whole blood, amniotic fluid, chorionic villus sample, and peripheral umbilical blood sample specimens were exposed to multiple fra(X)(q27.3) induction systems (none had aphidicolin). Fifty‐three exhibited the rare fragile site, fra(X)(q27.3) or FRAXA, none of which demonstrated the common fragile site or FRAXD at band Xq27.2. Only one cell in one of the negative whole blood FUdR‐treated cultures from a mentally retarded male showed FRAXD. Therefore, it appears that FRAXD occurs very rarely in cultures treated to induce FRAXA since only one positive cell was observed in over 88,000 analyzed. It appears that very low frequencies of fra(X)(q27) can be accounted for only in part by the presence of the common fragile site, since only one of 9 cases, each with one fra(X)(q27) positive cell, exhibited FRAXD and the others were FRAXA. After confirmation of FRAXA with direct DNA testing in a large number of low frequency cases, it should be possible to rely on the detection of very low frequencies of fra(X)(q27.3), e.g., 1% with at least 2 positive cells.
Factors which contribute to cytogenetic frequency of expression in families of fragile X females
Authors: Fisch Gene S. , Fryns Jean‐Pierre
Published: June 2005

Frequency of expression in mentally retarded (MR) fragile X (fra[X]) males has been shown to be affected by genetic factors and laboratory procedures. Among MR females, factors that contribute to cytogenetic expression have been more problematic in part due to lower frequency of expression and X‐inactivation. We examined fra(X) sisters to determine whether genetic factors affecting frequency of expression in sisters were comparable to those in brothers. Evaluations obtained from 2 data sets for a total of 66 families in which at least 2 affected brothers and/or 2 affected sisters were found cytogenetically positive were selected. Of 166 subjects chosen, 118 were male and 48 were female. Sibs were evaluated using an analysis of covariance (ANCOVA) with 2 factors (family, sex) adjusted for the covariate, age. Results indicated that interactive effects (family‐by‐sex) and main effects (family, sex, age) were significant but the interactive effect of age‐by‐sex was not. Consequently, one‐way analyses of variance (ANOVA) of the effect of family were calculated separately for brothers and sisters. Correlation coefficients between family and cytogenetic frequency was r=.84 for brothers and r=.79 for sisters. Analysis of these coefficients indicated that they were not significantly different from one another (Z=0.85, p>.40). While other factors may affect cytogenetic expression, whatever familial factors control frequency of expression among brothers appear to affect frequency of expression among sisters as well.
Dialyzed fetal Bovine serum increases cytogenetic fragile X expression
Authors: Jenkins Edmund C. , Duncan Charlotte J. , Gu Hong , Genovese Marilyn , Krawczun Michael S.
Published: June 2005

Short‐term whole blood cultures from 9 unrelated male individuals with the fragile X [fra(X)] syndrome were exposed to 5‐fluorodeoxyuridine (FUdR). The fra(X) frequency was higher in 8 of 9 cases where the complete medium contained dialyzed fetal bovine serum (DFBS). In 3 of the cases, the fra(X) frequency nearly tripled (e.g., 12/100 to 33/100) while in 2 others, it nearly doubled (e.g., 15/100 to 29/100). When DFBS cultures from 2 other fra(X) individuals were exposed to increasing folic acid concentrations ranging from 2 to 4,000 × 10−6 M, there was virtually no change in fra(X) expression.

In 6 of 9 DFBS cultures, the mitotic index decreased, and it increased in 3. Therefore, although the fra(X) frequency increased, in most DFBS cultures the mitotic index decreased. Whether the reduction in mitotic index indicates an inverse correlation between reduced mitotic index and increased fra(X) expression, at least in cultures from some individuals, will be determined by additional studies.

In conclusion: (1) medium supplementation with dialyzed fetal bovine serum should be considered when using FUdR for fra(X) identification in order to avoid potentially false negative results; (2) there appears to be no direct correlation between increased mitotic index and increased fra(X) expression in whole blood cultures; (3) increased folic acid concentrations do not affect fra(X) expression when FUdR fra(X) induction is employed; therefore requesting people to refrain from taking vitamins, including folic acid, before fra(X) testing (a practice that still persists in some places) appears unnecessary.
Prenatal cytogenetic diagnosis of the fragile X chromosome: Feasibility and speed of in situ clonal method in amniotic fluid cell tissue culture
Authors: Shapiro Lawrence R. , Wilmot Patrick L. , Andree Lynn E.
Published: June 2005

We have had experience with over 300 amniotic fluid specimens for prenatal diagnosis for the fragile X chromosome [fra(X)], and the flask method of tissue culture has been routinely utilized requiring extended tissue culture periods of 3–4 weeks. The use of the in situ clonal method of tissue culture for routine prenatal cytogenetic diagnosis of amniotic fluid cells has shortened tissue culture time and resulted in more rapid reporting; however, it has not been widely employed for fra(X) prenatal diagnosis.

The simultaneous use of both methods of tissue culture has resulted in the detection of 2 cytogenetically fra(X) positive cases in amniotic fluid, with more rapid reporting and satisfactory expression of the fra(X) with the in situ clonal method.

Thus, the use of the in situ clonal method of tissue culture for fra(X) prenatal diagnosis in amniotic fluid cells is feasible, faster and can serve as a more rapid cytogenetic adjunct to the newer DNA testing methods.
Prenatal cytogenetic diagnosis of the fragile X syndrome in amniotic fluid: Calculation of accuracy
Authors: Shapiro Lawrence R. , Wilmot Patrick L. , Fisch Gene S.
Published: June 2005

We have completed over 350 prenatal diagnoses for the fragile X [fra (X)] syndrome using amniotic fluid, chorion villus specimen (CVS), fetal blood sampling and molecular methods. A total of 300 amniotic fluid specimens have been received for prenatal diagnosis of the fra(X) syndrome. There was a documented family history of fra(X) in 170/300 amniotic fluid cases, and 23/170 were correctly identified as cytogenetically fra(X) positive (16 male; 7 female). Three males were false‐negative, and one female was fra(X) negative but identified as a probable carrier by RFLPs. No fra(X) positive or false‐negative results were found in the absence of a fra(X) family history.

Because the a priori risk for the fra(X) syndrome for each pregnancy was different and widely variable, the determination of the accuracy of the prenatal diagnosis results requires a consideration of these variables. On this basis, the calculated accuracy of prenatal cytogenetic diagnosis for the fra(X) syndrome is approximately 97%. This accuracy can be improved further with the simultaneous use of molecular methods, especially in view of recent developments.
Prenatal diagnosis of fragile X syndrome: Results from parallel molecular and cytogenetic studies
Authors: Murphy Patricia D. , Wilmot Patrick L. , Shapiro Lawrence R.
Published: June 2005

Since 1985, we have provided coordinated DNA‐based and cytogenetic prenatal analysis for couples at risk for offspring afflicted with the fragile X [fra(X)] syndrome. To date, 40 pregnancies have been studied (22 males, 18 females). There were 5 males and 3 females identified to be at high risk by DNA but only 2 males and one female were demonstrated to be cytogenetically expressing the fra(X) prenatally. Of the other 3 males, one was a cytogenetic false negative (i.e. confirmed fra(X)+ at termination of pregnancy). The other 2 remain fra(X)‐ and are developing normally (undetected recombinants or non‐penetrat male carriers). All fetuses at low risk were carried to term and are reported to be normal.
Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development
Authors: Devys D. , Biancalana V. , Rousseau F. , Boué J. , Mandel J. L. , Oberlé I.
Published: June 2005

The fragile X syndrome, the most common cause of inherited mental retardation, is characterized by unique genetic mechanisms, which include amplification of a CGG repeat and abnormal DNA methylation. We have proposed that 2 main types of mutations exist. Premutations do not cause mental retardation, and are characterized by an elongation of 70 to 500 bp, with little or no somatic heterogeneity and without abnormal methylation. Full mutations are associated with high risk of mental retardation, and consist of an amplification of 600 bp or more, with often extensive somatic heterogeneity, and with abnormal DNA methylation. To analyze whether the latter pattern is already established during fetal life, we have studied chorionic villi from 10 fetuses with a full mutation. In some cases we have compared them to corresponding fetal tissues. Our results indicate that somatic heterogeneity of the full mutation is established during (and possibly limited to) the very early stages of embryogenesis. This is supported by the extraordinary concordance in mutation patterns found in 2 sets of monozygotic twins (9 and 30 years old). While the methylation pattern specific of the inactive X chromosome appears rarely present on chorionic villi of normal females, the abnormal methylation characteristic of the full mutation was present in 8 of 9 male or female chorionic villi analyzed. This suggests that the methylation mechanisms responsible for establishing the inactive X chromosome pattern and the full mutation pattern are, at least in part, distinct. Our results validate the analysis of chorionic villi for direct prenatal diagnosis of the fragile X syndrome.
Molecular studies of the fragile X syndrome
Authors: Knight Samantha J. L. , Hirst Mark C. , Roche Anya , Christodoulou Zoe , Huson Susan M. , Winter Robin , Fitchett Margaret , McKinley Mark J. , Lindenbaum Richard H. , Nakahori Yutaka , Davies Kay E.
Published: June 2005

We have studied families segregating for the fragile X syndrome for the presence of amplification of the CGG repeat sequence adjacent to the HpaII Tiny Fragment (HTF) island in the FMR‐1 gene. We demonstrate that 138/143 fragile X positive, mentally retarded males show a characteristic smear of fragments corresponding to somatic variation in the amplification of the CGG sequence. In 7/8 normal transmitting males (NTM's), we show that there is a small amplification of sequence but no evidence for somatic variation. Defined mutated fragments in the size range found in NTM's are seen in daughters of NTM's. The daughters of these female carriers show either a defined fragment in the NTM size range, a defined larger fragment or a heterogeneous pattern of fragments. In the latter 2 cases the clinical phenotype of the females cannot easily be predicted, presumably because of variable X inactivation. In some families, the observed DNA genotype does not correlate with the phenotype; in others we demonstrate the occurrence of individuals with a mosaic DNA genotype. The implications of these data for diagnosis of the disease are discussed.
Three families with high expression of a fragile site at Xq27.3, lack of anomalies at the FMR‐1 CpG Island, and no clear phenotypic association
Authors: Oberlé I. , Boué J. , Croquette M. F. , Voelckel M. A. , Mattei M. G. , Mandel J. L.
Published: June 2005

We report on 3 families where the presence and segregation at high frequency of a fragile Xq27.3 site is not associated with the mutations and methylation anomalies typically seen in the fragile X [Fra(X)] syndrome. In one family, a folate insensitive fragile site was associated with Robin sequence in the propositus. In a second family a fra(X) negative mother has two fra(X) positive sons (one mentally retarded and the other newborn). The third family presents very high expression of a folate sensitive site, unlinked to mental retardation, and was described previously by Voelckel et al. [1989]. The fragile sites in these or similar families recently described must be different from the one associated with the fra(X) syndrome. Their association with a clinical phenotype or with mental retardation is certainly not consistent, and may represent an ascertainment bias. However, the relatively high frequency with which they have been found among previously diagnosed fra(X) families suggests that, at least in some cases, the association with mental impairment may be significant. In two families reported up to now, a male with high expression of such variant fra(X) site failed to transmit it to his daughter, which may reflect an imprinting effect. Previously diagnosed families should be reinvestigated before direct DNA analysis is used for prenatal or carrier diagnosis of the fra(X) syndrome.
Analysis of mutations at the fragile X locus using the DNA probe Ox1.9
Authors: Snow Karen , Doud Laurie , Hagerman Randi , Hull Claire , Hirst Mark C. , Davies Kay E. , Thibodeau Stephen L.
Published: June 2005

In this study, 40 families segregating for fragile X [fra (X)] syndrome were examined for the presence of a mutation within the FMR‐1 gene. Using the DNA probe Ox1.9, both carriers and affected individuals were found to contain an insertion/amplification‐type of mutation with somatic instability. Variability in the size of the mutation, which ranged from less than 0.2 kb to approximately 13 kb, was observed both between individuals (even from the same family) and within individuals, who showed a smear rather than a discrete band(s) on Southern blot analysis. Transmission of the mutation by males resulted in little change of its size, while transmission by females usually resulted in an increase in size. Correlations were observed between the size of inserted/amplified DNA and the level of chromosome fragility and the presence or absence of mental impairment. Overall, a mutation was detected in 66 of 67 (99%) clinically affected males, in 12 of 13 (92%) transmitting males and in 95 of 112 (85%) carrier females. Equivocal results were obtained in 12 (11%) of the carrier females. No mutation was detected in 58 females and 33 males predicted to be normal by linkage, or in one female and 36 normal control males. These results strongly suggest that the mutation detected by Ox1.9 is closely associated with the cytogenetic and clinical expression of fra(X) syndrome. Additionally, the use of this probe along with other probe/enzyme combinations should provide a sensitive clinical assay for the detection of carriers of fra(X) syndrome.
Concerning the role of X‐inactivation and DNA methylation in fragile X syndrome
Authors: Migeon Barbara R.
Published: June 2005

Elucidation of the role of DNA methylation in X chromosome inactivation along with recent studies of the fragile X mutation suggests that DNA methylation is likely to be a late event in the pathogenesis of the fragile X syndrome. Thus far, the evidence does not support suggestions that an impediment to X reactivation and failure to demethylate the inactive X in oocytes is responsible for silencing the fragile X. The role of DNA methylation is probably secondary to amplification of the CGG repeat to a critical size whether on active or inactive X. Further studies are needed to determine if late replication of the inactive X predisposes the locus on that chromosome to more extensive amplification.
Carrier detection of the fragile X syndrome with flanking RFLP markers and linkage analysis
Authors: Väisänen Marja‐Leena , Kähkönen Marketta , Leisti Jaakko
Published: June 2005

Linkage analysis was performed in 34 fragile X (fra[X]) families in order to study the efficiency of carrier detection using the restriction fragment length polymorphisms (RFLPs) closely linked to fra(X) locus (FRAXA).

The marker loci used were F9, DXS105, DXS98, DXS369, DXS297 and DXS477 proximally and DXS465, DXS296, DXS304, DXS52 and F8C distally to FRAXA. Flanking heterozygosity was achieved in 60% of the females with a combination of 3 restriction enzymes and 6 closest RFLP markers. When adding more distant markers and other restriction enzymes to the analysis, the proportion of females heterozygous for flanking polymorphisms increased to 96%. With RFLP‐analysis most (85/91) females at high risk of being a carrier could be separated clearly into 2 groups: those with a very low and those with a very high risk. The 6 cases with a recombination between flanking markers did not benefit from RFLP‐analysis.
Validation of linkage‐based DNA‐diagnosis of fragile X gene carriers with the CGG repeat probe
Authors: Van Oost Bernard A. , Smits Arie P. T. , Dreesen Jos C. F. M. , van den Ouweland Ans M. W. , Oostra Ben A.
Published: June 2005

We have evaluated our carrier testing for the fragile X [fra(X)] syndrome, which was based on linked DNA markers, with the direct analysis of the CGG repeat sequence in the fra(X) gene. PstI and EcoRI blots were hybridized with a probe derived from the region just 3′ of the CGG repeat in Xq27.3. We found the mutation analysis to be very sensitive as all 71 obligate gene carriers as well as 135 fra(X) patients tested showed evidence for an increased restriction fragment length encompassing the CGG repeat sequence with or without dispersion of the hybridization signal (mosaicism). Based on linked DNA markers, 6 out of 50 cytogenetic negative and mentally normal males at risk and 15 of 72 females at risk had inherited the allele at risk. All of these diagnoses could be confirmed by analysis of the CGG repeat length.
New York State screening program for fragile X syndrome: A progress report
Authors: Nolin Sarah L. , Snider Donald A. , Jenkins Edmund C. , Dobkin Carl S. , Patchell Kathleen , Krawczun Michael , Strong Gloria , Colwell Maryanne , Victor Arnold , Payyapilli Thomas , Turczyn Marianne , Little Anne , Nagaraja U. , Doyle Nancy , Kenefick Barbara , Sullivan Connie
Published: June 2005

New York State has established a program to screen post‐pubertal mentally retarded males for the fragile X [fra(X)] syndrome. The goal of the program is to identify affected males and inform their families of the diagnosis. Females in these families who are at risk for inheriting the mutation will then be able to determine their carrier status and consider that information in making reproductive decisions.

Males were evaluated for 10 features of the syndrome by physicians and nurses throughout the state; cytogenetic analysis was carried out on a subset of this population. A total of 1332 males has been screened and chromosome studies have been completed for 489. Forty‐three (9%) were positive for fra(X), and an additional 11 other chromosome abnormalities were identified. The 43 patients belonged to 38 families. Of the 24 families who were informed of the diagnosis, 12 consulted genetic counseling centers for follow‐up studies and 12 did not.
Notes on the population genetics of fragile X syndrome
Authors: Vianna‐Morgante Angela M. , Otto P. A.
Published: June 2005

Our analysis of fragile X‐inactivation in normal and mentally retarded heterozygotes led us to conclude that a fraction of female carriers of the imprinted (fully mutated) allele is phenotypically normal as a consequence of X‐inactivation. Taking this into accout, we derived equilibrium equations for the fragile X [fra(X)] genotype frequencies. We also showed that small variations in the value of s (selection coefficient of affected heterozygotes) and r (imprinting rate during oogenesis) affect genotype ratios significantly.
High prevalence of the Fra(X) syndrome cannot be explained by a high mutation rate
Authors: Smits Arie , Smeets Dominique , Hamel Ben , Dreesen Jos , van Oost Bernard
Published: June 2005

The overall prevalence of the fragile X [fra(X)] mutation, as determined by population studies, is approximately 1 in 850 [Gustavson et al., 1986; Webb et al., 1986]. This prevalence suggests a very high mutation rate which, in turn, suggests that many patients have to represent sporadic cases. In order to obtain an accurate estimate of the proportion of sporadic cases, we performed genealogic, cytogenetic and DNA linkage studies as well as direct analysis of the CGG repeat in relatives of 84 fra(X) probands. We did not find any evidence for the presence of sporadic cases. In 11 probands consanguinity could be proven by the detection of common ancestors, in 5 related families up to 9 generations ago. In the other 6 related families the mutation could be traced back 4‐6 generations. In 3 or more generation families we were able to demonstrate that half of the probands carried the grandpaternal fra(X) gene. These results imply that rather than a high mutation rate, both Normal Transmitting Males (NTM's) and mentally normal female carriers contribute considerably to the high prevalence of the fra(X) syndrome.
Penetrance estimate of the Fra(X) gene using pointer versus direct estimate
Authors: de Haan A. F. J. , Smits A. P. T. , Smeets D. F. C. M. , van Oost B. A.
Published: June 2005

Direct estimate of the penetrance of the fra(X) gene was compared with the estimate using the Pointer computer program. Direct estimate gave overall penetrances of 85% for male and 64% for female carriers. The estimates calculated by the Pointer program were 82% for males and 38% for females. It is argued that the use of the Pointer program gives incorrect estimates of the penetrance of the fra(X) gene.
Simpson‐golabi‐behmel syndrome associated with renal dysplasia and embryonal tumor: Localization of the gene to Xqcen‐q21
Authors: Hughes‐Benzie Rhiannon M. , Hunter Alasdair G. W. , Allanson Judith E. , Mackenzie Alex E.
Published: June 2005

We report 6 affected males in a 5‐generation family with X‐linked Simpson‐Golabi‐Behmel (SGB) syndrome. All had pre‐ and postnatal overgrowth with 2 adult males attaining heights over 195 cm. Other features included “coarse” face with hypertelorism, broad nasal root, cleft palate, full lips with a midline groove of the lower lip, grooved tongue with tongue tie, prominent mandible, congenital heart defects, arrhythmias, supernumerary nipples, splenomegaly, large dysplastic kidneys, cryptorchidism, hypospadias, skeletal abnormalities and postaxial hexadactyly. All affected individuals were of normal intelligence. One boy died at age 19 months of a neuroblastoma.

The putative origin of the gene in this family was the maternal great grandmother of the propositus. Eight carrier females, who showed varying manifestations of the gene, have been identified.

Anthropometric analysis has identified preliminary characteristic craniofacial dimensions in this syndrome. Molecular studies have shown a maximal lod score of 2.81 with no recombinants observed for the SGB‐DXYS68 pairing, mapping the disorder to Xqcen‐Xq21.3.
MRX8: An X‐linked mental retardation condition with linkage to Xq21
Authors: Schwartz Charles E. , May Melanie , Huang Tim , Ledbetter David , Anderson Gail , Barker David F. , Lubs Hebert A. , Arena Fernando , Stevenson Roger E.
Published: June 2005

A family in which 6 males have X‐linked mental retardation has been studied with polymorphic DNA probes. The males differ from unaffected males only in impaired intellect and in smaller head size. The gene that causes mental retardation in the family appears to be located in band Xq21 on the basis of linkage with 3 markers: DXS250, DXS345 and DXS3 (θmax = 0.00; Zmax = 1.6). A multipoint lod score of 2.36 was obtain with no recombination relative to DXS326 in Xq21. This family is considered to have nonspecific X‐linked mental retardation and has been given the designation MRX8.
Neuropsychological studies in families with fragile‐X negative X‐linked mental retardation
Authors: Cianchetti Carlo , Sannio‐Fancello Giuseppina , Fratta Anna‐Lisa , Pischedda Maria‐Paola , Spinicci Gabriella , Marrosu Maria‐Giovanna , Filippi Giorgio
Published: June 2005

Neuropsychological studies were performed in 82 subjects of 12 families with X‐linked, fragile X negative, mental retardation (MR). Subjects were examined with Wechsler tests (WPPSI, WISC‐R or WAIS, according to their capabilities), Progressive Matrices, Bender or Santucci and memory tests.

Physical findings in 5 families were characterised by micro‐orchidism (MiO), microcephaly (MiC), short stature (SS) and non‐specific facial features (XMR±MiO±MiC±SS). The 11 males with MR had a very low IQ, ranging from 13 to 37 (mean 21.2±8.8); this did not constitute a profile definition. Among the females of their families, 4 had subnormal or borderline IQ, respectively 74, 66, 38 and 37.

A second group (2 families) had MiO but with normal stature and occipito‐frontal circumference (XMR±MiO). The 7 males with MR had an IQ ranging from 24 to 43 (mean 35.1±5.8) and showed frequently better results in performance than in verbal subtests. In these 2 families, 5 females had subnormal or borderline IQ, respectively 77, 72, 71, 70 and 20.

In the 5 families of the third group, XMR±MaO(fraX‐), several affected males had macro‐orchidism (MaO) and facial changes similar to those of fragile X syndrome. IQ variability, also in the same family (e.g.: the 3 brothers of family 3 had, respectively, an IQ of 26, 28 and 68; the 2 brothers of family 1 had an IQ of 13 and 63) and different profiles. Two females were severely affected (IQ 16 and 24), while another 4 had an IQ, respectively, of 63, 69, 71 and 72.
Hypothalamic‐pituitary‐gonadal function in two infants with Smith‐Lemli‐Opitz syndrome
Authors: Pankau Rainer , Partsch Carl‐Joachim , Funda Johannes , Sippell Wolfgang Günther
Published: June 2005

We report on the hypothalamic‐pituitary‐gonadal function in 2 male infants with the Smith‐Lemli‐Opitz (SLO or RSH) syndrome. Both infants had abnormal external genitalia. Basal and LHRH stimulated plasma gonadotropins were normal for age (1 month). Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate were normal for age and sex. Some forms of congenital adrenal hyperplasia (17,20‐desmolase deficiency, 17α‐hydroxylase deficiency, and 3β‐hydroxysteroid dehydrogenase deficiency) were ruled out by hormonal studies. The endocrinological findings indicate a normal hypothalamic‐pituitary‐gonadal function and a normal adrenal steroid biosynthesis in these 2 patients. A partial androgen receptor defect causing the genital malformations seems possible in one patient. Whether 5α‐reductase deficiency is the cause of the male pseudohermaphroditism in SLO syndrome remains the subject of future studies. © 1992 Wiley‐Liss, Inc.
Skeletal dysplasia, intracerebral calcifications, optic atrophy, hearing impairment, and mental retardation: Nosology of dysosteosclerosis
Authors: Chitayat David , Silver Keneth , Azouz E. Michel
Published: June 2005

A girl who presented at 3 months of life with severe developmental delay, blindness, and hearing impairment was found to have intracerebral calcifications. Skeletal films showed craniotubular bone modeling consistent with dysosteosclerosis. The nosology of this disorder is discussed. © 1992 Wiley‐Liss, Inc.
Restrictive dermopathy, a lethal form of arthrogryposis multiplex with skin and bone dysplasias: Three new cases and review of the literature
Authors: Verloes Alain , Mulliez Nicole , Gonzales Marie , Laloux Françoise , Hermanns‐Lě Trinh , Piérard Gérald E. , Koulischer Lucien
Published: June 2005

Restrictive dermopathy is a rare, lethal autosomal recessive syndrome. We report on 3 unrelated affected stillborn infants of consanguineous parents. Clinical findings include a tight, thin, translucent, taut skin, which tears spontaneously in flexion creases, arthrogryposis multiplex congenita (including the temporomandibular joint), enlarged fontanelles, typical face and dysplasia of clavicles and long bones. Histologic abnormalities include hyperplastic, abnormally keratinized epidermis, reduced tonofilaments, thin, compact dermis with hypoplasia of the elastic fibres, and abnormal subcutaneous fat. Fifteen previous cases are reviewed. © 1992 Wiley‐Liss, Inc.
Autosomal dominant polycystic kidney disease: New information for genetic counselling
Authors: Bear John C. , Parfrey Patrick S. , Morgan Janet M. , Martin Christopher J. , Cramer Benvon C.
Published: June 2005

We evaluated the accuracy of ultrasonographic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) and factors influencing its prognosis in members of 17 Newfoundland families originally described in 1984. In 10 families showing genetic linkage between ADPKD and markers for the PKD1 locus, rates of false negative ultrasonographic diagnosis are estimated as 36% below the age of 10 years and 8% or less thereafter, comparable with findings of genetic linkage studies of a subset of family members. At ages above 30 years, false negative ultrasonographic diagnosis of PKD1 disease is unlikely. In 2 families in which PKD1 disease is unlikely. In 2 families in which ADPKD is not coinherited with PKD1 markers, only 11% of members aged less than 30 years had kidney cysts. The mean (SE) age of onset of ESRD is 56.3 (1.8) years for persons with the PKD1 form of ADPKD, and 68.7 (1.7) years for affected members of families in which ADPKD is not co‐inherited with PKD1 markers (P = 0.01). In the PKD1 families, age of onset of end stage renal disease (ESRD) was unrelated to the sex of the affected individual but was earlier in persons inheriting the disease from their mothers than from their fathers (50.5 vs. 64.8 years, P = 0.004), consistent with an influence of genetic imprinting on disease progresion. In females with a PKD1 mutation, onset of ESRD was not influenced by parity. In PKD1 families, resemblance in age of onset of ESRD was apparent; variation was less within than between families (F = 13.0, P < 0.0001), and risk of false negative ultrasonographic diagnosis appears largely restricted to families in which ESRD occurs relatively late. © 1992 Wiley‐Liss, Inc.