bluuebunny/crossref_metadata_2025 huggingface dataset:
C syndrome with apparently normal development
Authors: Stratton Robert F. , Sykes Norman J. , Hassler Terence W.
Published: June 2005

C syndrome is an autosomal recessive craniosynostosis syndrome with characteristic cranial, facial, palate, and joint abnormalities. All but 2 of the reported patients have had severe mental retardation. We report on an 8‐month‐old girl with C syndrome and apparently normal development except for tasks hindered by her lower body abnormalities. We also offer a possible explanation for the palatal configuration.
Deletion of 16q with prolonged survival and unusual radiographic manifestations
Authors: Casamassima Anthony C. , Klein Robert M. , Wilmot Patrick L. , Brenholz Pauline , Shapiro Lawrence R.
Published: June 2005

Deletion of 16q is characterized by mental retardation, microcephaly, a characteristic combination of minor facial anomalies, and broad halluces. Various break points have been described. This patient's phenotype is typical of this syndrome, but in addition, unusual radiographic findings were present. This chromosome abnormality is compatible with survival into adulthood. Expression of this phenotype does not appear to be correlated with specific break points.
Conjoined twins discordant for cleft lip and palate
Authors: Seller Mary J.
Published: June 2005

Female thoraco‐omphalopagus twins were of equal size and had similar abnormalities related to the twinning site. However, one twin was more severely affected and also had cleft lip and palate which the co‐twin did not have. The implications of this are discussed.
Application of a flowchart for the detection of lysosomal storage diseases in 105 high‐risk Brazilian patients
Authors: Barth Maria Luiza , Giugliani Roberto , Goldenfum Sandra L. , Munarski Roberta , Folberg Adriana , Lekhwani Chandra , Slade Christina , Fensom Anthony H.
Published: June 2005

Lysosomal storage diseases (LSD) are a group of more than 40 disorders, many of them with overlapping phenotype, in which clinical diagnosis is often difficult. Definitive diagnosis is based on enzyme assays, a large number of such assays usually being necessary during the investigation of each patient. In addition, there will frequently be a need for tissue culture in order to provide enough material for analysis. Taking into account these difficulties, we designed a flowchart for the detection of LSD that is based on 2 sets of tests requiring only random urine and heparinized blood. Here we describe this routine and report the results of its application to 105 Brazilian patients in whom a LSD was suspected. We think that the application of this rationale represents a saving of work and costs, and should be of special interest to genetic centers in developing countries.
New study on the relationship between oral clefts and fetal loss
Authors: Menegotto Beatriz G. , Salzano Francisco M.
Published: June 2005

The sibships of 741 non‐syndromic individuals with cleft lip with or without cleft palate (CL ± P), those of 115 subjects with isolated cleft palate (CP), plus 2 series of controls of the same size were studied in a variety of ways. The 2 most significant findings were (a) a higher fetal loss in the sibships of probands of the most frequently affected sex (CL ± P: male; CP: female) and (b) increased fetal mortality in the sibships with sporadic cases of CL ± P when compared to that found in sibships with more than one affected. In general the result do not support the hypothesis of a causal relationship between fetal death and non‐syndromic CL ± P or CP.
Euchromatic 16p + heteromorphism: First report in North America
Authors: Jalal S. M. , Schneider Nancy R. , Kukolich Mary K. , Wilson Golder N.
Published: June 2005

A heteromorphism of the short arm of 16 (16p+) was discovered in 2 unrelated infants. By G banding, the euchromatic variant appears as a light and a medium dark band just distal to the centromere. This results in an increase of the short arm by about 1/3. The same variant was present in the normal father and the normal paternal grandmother in one family and mildly retarded mother in the 2nd family. The anomalies of the 2 infants are not similar and are apparently unrelated to the 16p + variant. Though the discovery of such euchromatic variants is highly significant for clinical diagnosis, their genetic significance and mode of origin remain to be elucidated.
Monochorionic diamniotic minimally conjoined twins: A case report
Authors: Weston P. J. , Ives E. J. , Honore R. L. H. , Lees G. M. , Sinclair D. B. , Schiff D.
Published: June 2005

We present the second case of monochorionic diamniotic (MC/DA) conjoined twins. There was minimal conjunction, which was predominantly extrafetal and confined to the periumbilical ventral region. The omphalopagus twins, attached to a single forked umbilical cord, were connected by a shared umbilical hernia containing the ileum of twin B. The only visceral conjunction, located just within the belly of twin A, was midileal with the 2 separate ileums converging toward a short segment of shared muscularis propria and of side‐to‐side fistulization. Gastrointestinal and musculoskeletal anomalies were present in both twins with severe amyoplasia and arthrogryposis multiplex in twin A. Possible mechanisms underlying this unusual form of MZ twinning are discussed.
Combined deficiency of β‐galactosidase and neuraminidase: Natural history of the disease in the first 18 years of an American patient with late infantile onset form
Authors: Strisciuglio Pietro , Sly William S. , Dodson W. Edwin , McAlister William H. , Martin Thomas C.
Published: June 2005

We describe the clinical findings over the first 18 years of a patient with a novel phenotype for galactosialidosis, the storage disease produced by the combined deficiency fo β‐galactosidase and neuraminidase. Clinical findings in the first few months included somewhat unusual appearance and hepatosplenomegaly. Dysostosis multiplex was evident by age 2 1/2 years. Mitral and aortic valvular disease appeared over the next few years and cardiac disease has become the most important clinical problem. Foam cells were present in the bone marrow, and vacuolated lymphocytes were present in the peripheral blood smear. The patient had no neurological symptoms, cherry red spots, or intellectual deterioration during the first 18 years. Evidence presented elsewhere indicates that the basic defect in this late infantile form of galactosialidosis (as is thought to be true for the other forms of galactosialidosis) is a reduced amount of the 32 kDa phosphoglycoprotein which associates with β‐galactosidase and α‐neuraminidase in lysosomes.
Alveolar synechia, ankyloblepharon, and ectodermal disorders: An autosomal recessive disorder?
Authors: Ohishi Masamichi , Kai Sadako , Ozeki Satoru , Tashiro Hideo
Published: June 2005

A male patient with alveolar synechia and ankyloblepharon filiforme adnatum is reported. He also had bilateral commissural lip pits, inferiorly attached frenulum, generalized hypo‐plastic nails, and wooly scalp hair. He was a product of consanguineous parents. The disease seemed to be an autosomal recessive syndrome with heterozygote expression.
Roberts syndrome with normal cell division
Authors: Keppen Laura Davis , Gollin Susanne M. , Seibert Joanna J. , Sisken Jesse E.
Published: June 2005

Roberts‐SC phocomelia syndrome (RS) is an autosomal recessive disorder of symmetric limb defects, craniofacial abnormalities, pre‐and postnatal growth retardation, and mental retardation. Patients with RS have been reported to have premature separation of heterochromatin of many chromosomes and abnormalities in the cell‐division cycle. We report an infant whose clinical and radiologic findings resemble those of RS but who lacks the cytogenetic and cell division abnormalities reported in RS. This patient may represent a variant of RS or a new syndrome.
Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs
Authors: Rosenak D. , Ariel I. , Arnon J. , Diamant Y. Z. , Chetrit A. Ben , Nadjari M. , Zilberman R. , Yaffe H. , Cohen T. , Ornoy A.
Published: June 2005

A term amelic female infant was born to an apparently nonconsanguineous Arab Moslem couple. This was followed by the birth of 4 normal children. Afterwards, in 2 subsequent pregnancies, 2 amelic fetuses were diagnosed by transabdominal ultrasonography in the 18th and 12th week of gestation. Pregnancies were terminated and on autopsy both amelic fetuses had severe lung hypoplasia and aplasia of the peripheral pulmonary vessels. The first fetus also had apparently low‐set ears and micrognathia, whereas the last had hydrocephaly and left cleft lip beside the lung hypoplasia and aberrant pulmonary artery. This appears to be a new autosomal recessive malformation syndrome.
Diagnosis of Angelman syndrome in infants
Authors: Fryburg Julie Shapiro , Breg W. Royxs , Lindgren Valerie
Published: June 2005

The diagnosis of Angelman syndrome (AS) has seldom been made in infants because the previously described characteristic manifestations usually are not apparent until after age 2 years. We describe 4 AS patients, one of whom has oculocutaneous albinism, who were < 2 years old when first evaluated. All 4 have deletions of the region q11.2‐q13 of chromosome 15. In the 3 cases in which parents were available for study the deleted chromosome 15 was maternally derived, as determined by cytological markers.

All of the patients presented with severe to profound global developmental delay and postnatal‐onset microcephaly; they had seizures, hypotonia, hyperreflexia, and hyperkinesis. All were hypopigmented as compared to their relatives. Each had eye abnormalities; all had choroidal pigment hypoplasia. None were initially described as having an abnormal appearance.

We believe that AS is far more common than previously thought and present these 4 children to emphasize the manifestations that may be helpful in making the diagnosis in the young patient. We also emphasize the hypopigmentation that patients with AS frequently have, including what we think is the first reported case of albinism and AS.
Aicardi syndrome: Early neuroradiological manifestations and results of DNA studies in one patient
Authors: Nielsen Karen Bröndum , Anvret Maria , Flodmark Olof , Furuskog Peter , Bohman‐Valis Kjersti
Published: June 2005

A patient with Aicardi syndrome is presented. We report results of DNA analysis from the patient and her parents with probes mapped to Xp21.3–22.3 in an attempt to localize a deletion in this region. No signs of a microdeletion could be detected, using 5 different DNA markers. Further, it is suggested that a specific combination of cerebral abnormalities may be characteristic of the syndrome and that antenatal ultrasonographic diagnosis may be feasible.
An infant with deletion of the distal long arm of chromosome 15 (q26.1→qter) and loss of insulin‐like growth factor 1 receptor gene
Authors: Roback Ellen W. , Barakat Amin J. , Dev V. G. , Mbikay Majambu , Chrétien Michel , Butler Merlin G.
Published: June 2005

We report on an infant with a previously undescribed chromosome 15 deletion (q26.1→qter) and compare the clinical findings with those of 7 reported patients with deletions of distal 15q, as well as ring chromosome 15 syndrome patients. Most of the patients with deletions of distal 15q, including our patient, have intrauterine growth retardation (IUGR), microcephaly, abnormal face and ears, micrognathia, highly arched palate, renal abnormalities, lung hypoplasia, failure to thrive, and developmental delay/mental retardation. Several genes have been assigned to the 15q25→qter region, including insulin‐like growth factor 1 receptor (IGF1R). DNA analysis from our patient documented the loss of one IGF1R gene copy. Our study further localizes the IGF1R gene distal to the 15q26.1 band. It is interesting to speculate that the severe IUGR and postnatal growth deficiency of our patient and other patients with similar chromosome 15 deletions are related to the loss of an IGF1R gene copy which may lead to an abnormal number and/or structure of the receptors.
Familial occurrence of Duchenne dystrophy through paternal lines in four families
Authors: Zatz Mayana , Passos‐Bueno Maria Rita , Rapaport Debora , Vainzof Mariz
Published: June 2005

In a survey of 454 families with patients affected with Duchenne muscular dystrophy (DMD) we have found 4 genealogies with 2 or more affected patients who were related through paternal lines. In 1 of these families, 2 affected cousins showed different DNA deletions suggesting 2 independent mutations; in the other 2, in which only the propositus could be studied, DNA deletions were also detected in the dystrophin gene. In the last one, with 3 affected patients, no DNA deletions were detected but immunohistochemical study of muscle biopsies showed a negative dystrophin pattern typical of DMD.

Although one of these families might have occurred by chance, the probability of finding the other 3 in our sample of families with DMD patients constitutes a rare event. It is suggested that other mechanisms, such as the presence of transposable elements in other sites of the genome, could be responsible in some families, for a greater predisposition for the occurrence of pathogenic deletions, duplications or mutations.
Retrospective survey of urea cycle disorders: Part 1. Clinical and laboratory observations of thirty‐two Japanese male patients with ornithine transcarbamylase deficiency
Authors: Matsuda I. , Nagata N. , Matsuura T. , Oyanagi K. , Tada K. , Narisawa K. , Kitagawa T. , Sakiyama T. , Yamashita F. , Yoshino M.
Published: June 2005

In a retrospective survey done from 1978–1988 in Japan, 32 male patients with ornithine transcarbamylase (OTC) deficiency were identified. We classified a neonatal and 2 late‐onset groups, depending on clinical manifestations and the age at onset; group 1 (0–28 days; N = 10), group 2 (29 days–5 years; N = 13), and group 3 (<5 years; N = 9). Compared to findings in the group 2 patients, there was a higher rate of mortality and a higher incidence of mental retardation in association with a great decrease in enzyme activity in group 1. In group 3, the mortality rate and enzyme activities were similar to those in group 1. However, patients in this group were asymptomatic prior to the first episode. Enzyme activities were measured mostly in autopsy samples. The serum citrulline levels (enzyme product) were highest in this group. Thus, the mutant enzymes were apparently labile with greater activities in vivo than in vitro. Treatments, including a protein‐restricted diet, arginine supplementation, and sodium benzoate administration, resulted in a favorable prognosis for survivors with partial enzyme deficiency. We wish to emphasize that the incidence of late onset of this disease is higher than heretofore considered.
Mental retardation, acromegalic face, and megalotestes in two half‐brothers: A specific form of X‐linked mental retardation without fra(X) (q)?
Authors: Tariverdian G. , Froster‐Iskenius U. , Deuschl G. , Wolff G.
Published: June 2005

We describe a family with two half‐brothers affected with severe mental retardation. The phenotype in the affected individuals is characterized by apparent acromegaly, profound mental retardation, and hyperactivity. The mother has analogous but less severe facial anomalies and mild mental impairment. Screening for fra(X) (q) was negative in peripheral lymphocytes using methotrexate for fra(X) enhancement. The clinical findings in our patients are similar to those described by Fryns et al. [1986] in two patients with acquired lesions of the central nervous system. CT investigations in one of our patients showed areas of hyperdensity in the pontine region and a small subarachnoid cyst. The pedigree suggests X‐linked inheritance. The association of apparent acromegaly, CNS anomalies, megalotestes, and mental retardation in this family supports the hypothesis that a distinct syndrome may exist with phenotype anomalies more severe than those characteristic for the Martin‐Bell syndrome but without fragile X.
Unique X‐linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31
Authors: Miles Judith H. , Carpenter Nancy J.
Published: June 2005

We studied 10 members of a 4 generation Missouri kindred with a dominant mental retardation syndrome with increasing severity in males. The 21 year‐old propositus presented with severe mental retardation, microcephaly, asymmetric face, exotropia, hypogonadism, joint hypermobility, rocker bottom feet, and 10 low digital arches. Two brothers and a male cousin had similar features. The mother, sister, niece, maternal aunt, female cousin, and grandmother were examined and each had 8 to 10 low digital arches. Five of the women had exotropia and one had pes cavus feet. Chromosome analysis for fragile X in multiple relatives was normal.

To determine the likelihood that this was an X‐linked syndrome, DNA from relatives was hybridized to probes which detect 13 different loci spanning the X‐chromosome. A peak LOD score of 2.78 at θ equal to 0.0 was calculated for the syndrome locus and DXYS1 (pDP34). The more distal Xq loci showed increasing recombination with the syndrome locus. These results are consistent with location for this syndrome near Xq21.31, the chromosomal locus for DXYSI.
Gene localization in a family with X‐linked syndromal mental retardation (Prieto syndrome)
Authors: Watty Anke , Prieto Félix , Beneyto Magdalena , Neugebauer Meinhard , Gal Andreas
Published: June 2005

A mapping study was performed on a 3‐generation Spanish family with X‐linked syndromal mental retardation. Affected males have a typical facial appearance, ear malformations, abnormal growth of teeth, clinodactyly, dimpled skin at the lower back, and patellar luxation. In pneumoencephalography a marked subcortical cerebral atrophy was evident. In the linkage studies with polymorphic DNA markers, no recombination was found between the disease locus and the loci OTC and DXS148, both assigned to Xp21.1. One or more recombinants were observed between the disease locus and loci from the distal part of Xp and the pericentromeric region. Close linkage to loci of Xq has also been excluded. The analysis of multiple informative meioses suggests that the disease locus maps between DXS255 (Xp11.22) and DXS84 (Xp21.1) on Xp.
Heterozygous fragile X female: Historical, physical, cognitive, and cytogenetic features
Authors: Cronister Amy , Schreiner Rebecca , Wittenberger Michael , Amiri Khaled , Harris Keri , Hagerman Randi J.
Published: June 2005

Historical, physical, cognitive, and cytogenetic data were documented in 105 heterozygous fragile X [fra(X)] females and 90 controls in a prospective fashion. For comparisons, we divided heterozygotes and controls into those with cognitive impairment (IQ <85) and normal IQ (IQ ≥ 85). The only finding that was significantly more frequent in impaired heterozygotes compared with impaired controls χ2 analysis was shyness. Features that were more frequent in normal IQ heterozygotes compared with normal controls were voluntary thumb dislocation and hyperextensible metacarpal‐phalangeal (MP) joints. Comparisons among heterozygotes demonstrated more math problems, hand biting, strabismus, higharched palate, hyperextensible finger joints, and flat feet in impaired heterozygotes than in normal heterozygotes. Premature menopause was present in 8 of 61 normal heterozygotes and in none of the impaired heterozygotes. A multiple regression analysis demonstrated a significant inverse correlation between the percent fragility and IQ for the heterozygotes as a group. However, no correlation existed between IQ and fragility when the percent fragility was 2% or greater. However, a higher percentage of fragility was positively correlated with the total number of physical findings present.
DNA linkage analysis of 26 families with fragile X syndrome
Authors: Carpenter Nancy J.
Published: June 2005

Linkage data using the markers F9 (factor IX), DXS105 (cX55.7), DXS98 (4D‐8), DXS52 (St14), DXS15 (DX13), and DXS134 (cpX67) are presented from 26 pedigrees segregating with fragile X (fra[X]) syndrome. Cytogenetic and DNA data were combined in 2‐point linkage analysis for the estimation of lod scores and carrier probabilities in potential carriers. Recombination fractions (θ) corresponding to the maximum lod scores (Ẑ) were obtained for F9 (Ẑ = 2.78, θ = 0.15), DXS105 (Ẑ = 1.72, θ = 14), DXS98 (Ẑ = 3.74, θ = 0.00), DXS52 (Ẑ = 3.53, θ = 0.17), DXS15 (Ẑ = 4.03, θ = 0.11), and DXS134 (Ẑ = 2.12, θ = 0.16) and for the fragile X locus (FRAXA). Recombination fractions between marker loci in the families are also presented. Discordance between the results of cytogenetic and DNA analyses in 2 potential carrier females was investigated by reexamination of the fragile site expression and was concluded to be due to the expression of the common fragile site at Xq27.2.
Linkage analysis of the fragile X syndrome using a new DNA marker U6.2 defining locus DXS304
Authors: Goonewardena Ponmani , Brown W. Ted , Gross Anne C. , Ferrando Charles , Dobkin Carl , Romano Valentino , Bosco Paolo , Ceratto Nadia , Pettersson Ulf , Dahl Niklas
Published: June 2005

A new RFLP marker U6.2 defining the locus DXS304 was recently mapped to the distal long arm of the X chromosome. In the present study we report the results of genetic linkage analysis of 13 fragile X [fra(X)] families that were informative for the new marker. Analysis of the recombinants for F9‐FRAXA, DXS105‐FRAXA, DXS98‐FRAXA, DXS52‐FRAXA, DXS15‐FRAXA, and F8C‐FRAXA, places DXS304 distal and near to the FRAXA locus. Combined with results from previous studies, our results support the order Xcen.‐F9‐DXS105‐DXS98‐FRAXA‐DXS304‐DXS52‐DXS15‐F8C‐Xqter. Close linkage was observed between DXS304 and the disease locus with a peak lod score of 5.12 at Θ = 0.04 from the present study and, with a peak lod score of 17.45 at Θ = 0.035 when our data are combined with published data from 2 other studies. The present study confirms that U6.2 is useful for prenatal diagnosis and carrier testing in families affected by fra(X) syndrome.
Mapping of a cerebellar degeneration related protein and DXS304 around the fragile site
Authors: Hirst M. C. , Bell M. V. , MacKinnon R. N. , Watson J. E. V. , Callen D. , Sutherland G. , Dahl N. , Patterson M. N. , Schwartz C. , Ledbetter D. , Ledbetter S. , Davies K. E.
Published: June 2005

We have localized the gene encoding a cerebellar degeneration related (CDR) protein to a region proximal to the fragile site close to DXS98 and DXS105. This gene is polymorphic with the enzyme RsaI and therefore also provides a new genetic marker in this region. We have refined the localization of the locus DXS304 distal to the breakpoint in a patient suffering from Hunter disease. This confirms the localization of DXS304 distal to the fragile site previously suggested by linkage studies and localizes the fragile X mutation to a relatively small region between the Hunter breakpoint and the breakpoint in another hybrid B17.
Cytogenetically negative, linkage positive “fragile X” syndrome
Authors: Brooks Susan Sklower , Cohen Ira , Ferrando Charles , Jenkins Edmund C. , Brown W. Ted , Dobkin Carl
Published: June 2005

We investigated the family of a 3‐year‐old boy with manifestations of the Martin‐Bell syndrome (MBS). His 17‐year‐old cousin had classic manifestations of MBS and was fragile X [fra(X)] positive. The 3‐year‐old boy was fra(X) negative. Linkage analysis with probes flanking the fra(X) region indicated that these cousins had the same X chromosome inherited from a normal grandfather. The DNA and cytogenetic analyses suggest that limitations in the ability to detect the fra(X) mutation cytogenetically may be responsible for fra(X) negative MBS; or, alternatively, that a crossover occurred between a locus determining the MBS phenotype and one determining fra(X) expression.
Cloning the ends of size selected Sfi I fragments
Authors: Nolin Sarah L. , Dobkin Carl S.
Published: June 2005

As an initial step in the physical mapping of the fragile X region a library of Sfi I ends was constructed from the size class of human Sfi I DNA fragments, which includes the fragment with the locus DXS105. Since Sfi I recognizes the sequence GGCCNNNNNGGCC and leaves a 3 base indeterminate “sticky” end, we used a mixture of 64 synthetic deoxynucleotide oligomers to modify these ends for cloning. The oligomers were of the general form AATTNNN. Ligation of these heptamers to the indeterminate Sfi I ends converted them to the EcoR I sticky end. A suppressor tRNA gene was ligated onto this end as a selectable marker and the DNA was cloned in the lambda phage vector Charon 21A. Analysis showed that clones selected for the presence of the tRNA gene contained Sfi I ends. Because this library was constructed from a specific size class of fragments, it was very reduced in complexity. This will simplify the process of identifying the clone which contains the end of the DXS105 fragment. The use of this strategy for chromosome “jumping” is discussed.
New somatic cell hybrids for physical mapping in distal Xq and the fragile X region
Authors: Ledbetter Susan A. , Schwartz Charles E. , Davies Kay E. , Ledbetter David H.
Published: June 2005

Somatic cell hybrids were constructed from 3 patients carrying X chromosome abnormalities with breakpoints in distal Xq: (1) 94‐3, from a patient with 46, XX, t(X;15)(q25 or q26;q25), (2) 8121‐A1, from a patient with 46, X, del(X)(q26), and (3) 2384‐A2, from a patient with 46, X, del(X)(q27). The breakpoint of patient 94 is proximal to HPRT in q26, a significant distance from the fragile X locus. The breakpoint of patient 8121 is distal to F9, but proximal to DXS98, and is thus proximal to the fragile site region. The breakpoint of 2384 is distal to DXS98 but proximal to DXS52, placing it within the region of the fragile site. Use of these physical mapping reference points will aid in the rapid localization of new DNA markers to distal Xq and the fragile X region.
Effect of X inactivation on fragile X frequency and mental retardation
Authors: Rosenberg Carla , Vianna‐Morgante Angela M. , Otto Paulo A. , Navajas Leda
Published: June 2005

The probability of a heterozygote being affected was estimated from the distribution of frequencies of early‐replicating fragile X [fra(X)] chromosome in normal and mentally retarded heterozygotes, taking into account the prior probabilities of 0.35 for mental retardation and 0.65 for normality. The estimated probability of a heterozygote with 100% early‐replicating fra(X) being mentally retarded was 78%, which coincides with the value of penetrance in males. Therefore, the manifestation of retardation in females seems to differ from that in males due solely to X inactivation. The frequencies of early‐replicating fra(X) were significantly increased among the heterozygotes with the highest frequencies of fra(X) both in the normal group and in the mentally retarded. The mean frequencies of early‐replicating fra(X) were 0.42 and 0.68 for normal and mentally retarded heterozygotes, respectively. Considering the overall frequency of retarded heterozygotes as 0.35, the mean frequency of early‐replicating fra(X) obtained for all heterozygotes was 0.51, which is in accordance with the hypothesis of random X inactivation. Thus the fragile site appears to have equal chances of being detected when located either on the early‐ or on the late‐replicating X. This leads to the conclusion that the frequency of the fragile site is a consequence of the proportion of cells with the active Martin‐Bell syndrome (MBS) gene and not the result of a better visualization of the site on the early‐replicating X.
Fragile Xq27 in somatic cells derived from different tissues
Authors: Webb T.
Published: June 2005

Prenatal diagnosis for the Martin‐Bell syndrome resulted in the detection of 4 fragile X‐positive male fetuses and 2 female fetuses. Studies carried out on monolayer cultures derived from various tissues from these show that fra‐Xq27 can be ascertained in cells from testis, lung, kidney, skin, ovary, and muscle. This suggests that the fragility of the X chromosome may be present in all somatic cells. There appears to be no strong correlation between the level of marker detected and the involvement of the tissue from which the cells were derived in the manifestation of the syndrome. The level of fra‐X is dependent rather more on culture conditions than on cell type except for lymphocytes, in which detection is easier.
Distribution of diploidy, polyploidy, and endoreduplication in fra(X) positive and negative lymphocytes, amniocytes, and chorionic Villi
Authors: Jenkins Edmund C. , Sanz Maureen M. , Ray James H. , Stark‐Houck Sandra L. , Brown W. Ted
Published: June 2005

Expression of fragile X [fra(X)] (q27.3) and en‐doreduplicated metaphases have been reported in methotrexate‐treated (MTX) fra(X) cultures (Kerem B, Biotein R, Schaap T [1988]: Chromosoma 97: 6–10). Further, new data (Kimchi‐Sarfaty C, Goitein R, Kerem B, Werner M, Medan B, Schaap T [1991]: Am J Med Genet, this issue) indicate that MTX may specifically induce polyploidy and endo‐reduplication in cells with the fra(X) mutation. To confirm and extend these results, we have studied short‐term lymphocyte cultures incubated in M199, a folate deficient system, and RPMI‐1640 in the presence and absence of 5‐fluorodeoxyuridine (FUdR) exposure during the last day of a 4 day culture. No endo‐reduplicated cells were seen under these conditions and there was no change in the level of polyploidy. We also studied the distribution of polyploid and endoreduplicated cells in amniotic fluid and chorionic villus sample cultures from one fra(X) positive and 4 at‐risk specimens. No increase in the incidence of polyploidy or endoreduplication was observed in cultures exposed to MTX for both 24 and 48 hours from a fra(X) positive amniotic fluid case. Cytogenetic results were fra(X) negative for the remaining 4 cases tested. There was significant discordance between our findings and those expected based on MTX‐induced increased frequencies of polyploidy and endoreduplication. Thus, our studies do not confirm the reported correlation between the presence of FRAXA and increased frequencies of polyploidy and endoreduplication in MTX‐exposed amniocyte cultures and there was no evidence for increased levels of polyploidy and endoreduplication in short‐term fra(X) lymphocyte cultures exposed to non‐MTX fra(X) induction.
Distribution of autosomal fragile sites in specimens cultured for prenatal fragile X diagnosis
Authors: Krawczun Michael S. , Jenkins Edmund C. , Duncan Charlotte J. , Stark‐Houck Sandra L. , Kunaporn Suphat , Schwartz‐Richstein Carol , Gu Hong , Brown W. Ted
Published: June 2005

We reviewed the distribution of autosomal fragile sites (FS) and spontaneous chromosome breaks or gaps (CB) at chromosome locations other than those recognized as FS from 100 amniotic fluid samples (AF), 19 chorionic villus samples (CVS), and 5 percutaneous umbilical blood samples (PUBS) referred for fragile X [fra(X)] analysis. We present data on the degree of expression of autosomal fragility in AF, CVS, and PUBS samples, and the relationship between degree of expression and induction system. The most common observed FS were: 3p14, 9p32, and 6q26 in AF; 9q32, 3q27, and 8q22 in CVS; and 3p14, Xq22, and 16q23 in PUBS cases. Distribution of FS and CB, when compared by induction system, was not found to be identical. Our data also indicate that the presence of any particular FS cannot be used as an indicator for the effectiveness of the fra(X) induction system in prenatal samples.
SV40‐transformed fragile (X) amniocytes
Authors: Jenkins Edmund C. , Brooks Steven E. , Stark‐Houck Sandra L. , Duncan Charlotte J. , Brooks Susan L. Sklower , Brown W. Ted
Published: June 2005

We report SV‐40 transformation of female and male fragile X [fra(X)] amniocytes. In the transformants, fra(X) (q27.3) was detected in the 7th passage (9 cell generations) in fra(X) female amniocytes. It was conserved until at least the 20th passage (42 cell generations) although the frequency was reduced or became difficult to detect due to karyotypic evolution in the later generations. Similarly, for the male fra(X) amniocyte line, fra(X) was demonstrated at the 2nd passage (3 cell generations) and persisted until at least the 13th passage (29 cell generations). The prolonged period of reproductive potential of these transformed lines ranging from at least 29–42 generations suggests that the cryopreservation of significant quantities of early passage fra(X) transformed amniocytes will assure a reliable and continuous supply of positive control cells. These lines may be used for fra(X) prenatal diagnostic studies thereby improving the ability to quality control the particular fra(X) induction system being used.
Syntactic delay and pragmatic deviance in the language of fragile X males
Authors: Sudhalter Vicki , Scarborough Hollis S. , Cohen Ira L.
Published: June 2005

The expressive language of 19 fragile X [fra(X)] males with chronological ages between 5 and 36 years and Vineland Adaptive Behavior Scores between 21 and 79 was examined for syntactic as well as pragmatic proficiency. The production of deviant repetitive language was observed with this group, corroborating the results of an earlier study with a smaller sample of fra(X) males. In contrast, when 2 syntax scores, mean length of utterance (MLU), and Index of Productive Syntax (IPSyn) were derived from naturalistic language observations, the relation of complexity to length was observed to be very similar to the known relationship of these 2 facets of syntactic ability in normal preschoolers. These results, and the absence of correlations between syntactic scores and proportions of deviant repetitive language are consistent with the notion that the syntactic development of fra(X) males is typically delayed rather than deviant. For effective assessment and remediation of communicative problems associated with the syndrome to be developed, it is argued, language must be considered as a combination of competencies rather than as a unitary skill.
Epilepsy and fragile X syndrome: A follow‐up study
Authors: Musumeci S. A. , Ferri R. , Elia M. , Colognola R. M. , Bergonzi P. , Tassinari C. A.
Published: June 2005

This paper describes EEG and clinical findings resulting from a follow‐up investigation in a group of 18 males with fragile X syndrome, in whom a characteristic paroxysmal EEG pattern was previously described. The following types of evolution were observed: (1) disappearance of the pattern (with a gradual lowering of the amplitude of spikes and in some cases with asynchrony between the two hemispheres); (2) disappearance of the quasirhythmic centrotemporal spikes and persistence of bisynchronous polyspike and wave complexes in the temporo‐parieto‐frontal regions; and (3) persistence of the previously observed pattern. These results confirm the already observed similarity between this condition and the benign childhood epilepsy with centrotemporal spikes, also from the maturational point of view; on the other hand, they also indicate some difference (i.e., mental retardation, slow background EEG activity, brain atrophy). Moreover, these findings are encouraging for the possible development of research in the field of molecular genetics in epilepsy, because they provide a precise site of investigation on the X chromosome.
New multiple congenital anomalies syndrome in a stillborn infant of consanguinous parents and a prediabetic pregnancy
Authors: Van Allen Margot I. , Myhre Selma
Published: June 2005

We report on a term stillborn female infant with multiple congenital anomalies (MCA) which have not previously been reported as occurring together. The malformations include a first and second branchial arch sequence, ectopia cordis with congenital heart defect, caudal “regression” sequence with absent sacrum and hypoplastic right femur, ectrodactly, left radial abnormality, islet cell hyperplasia, and skin lesions. The pregnancy was complicated by abdominal cramping with exercise, heavy vaginal bleeding, maternal obesity, and a normal screening glucose tolerance test at 6 months gestation. The infant was born to 20‐year‐old G3P1SAB2 Mexican‐American parents who are first cousins. There was strong maternal family history of adult‐onset diabetes.

The malformations have some findings in common with those seen in infants of diabetic mothers. Structural defects similar to, but not inclusive of, those in our infant have been reported in 2 sibs born to a prediabetic mother with a first cousin marriage as well as in focal dermal hypoplasia. Parental consanguinity is suggestive of an autosomal recessive disorder. Alternatively, it may represent a combined multifactorial effect making the conceptus more sensitive to metabolic teratogens and thus placing it at increased risk for disruption of normal development.
Ectrodactyly, cleft lip/palate syndrome
Authors: Rodini Elaine S. O. , Freitas J. A. S. , Richieri‐Costa A.
Published: June 2005

We report on a Brazilian boy with ectrodactyly, cleft lip/palate, and abnormal pinnae. The clinical aspects involving this patient strongly suggest those reported by Lewis and Pashayan in 1981. Clinical and genetic aspects are discussed.
Floating‐Harbor syndrome and celiac disease
Authors: Chudley Albert E. , Moroz Stanley P.
Published: June 2005

We report on a 17‐year‐old young woman with a speech impediment, developmental delay, short stature, and facial anomalies consistent with the Floating‐Harbor syndrome (FHS). In addition, she has clinical and histological evidence of celiac disease, which was observed in 1 of the 6 previously reported cases of FHS, suggesting a possible association between the 2 conditions or pleiotropism of a presumed autosomal recessive disorder.
Balanced translocation 12/13 and situs abnormalities: Homology of early pattern formation in man and lower organisms?
Authors: Wilson Golder N. , Stout J. Patrick , Schneider Nancy R. , Zneimer Susan M. , Gilstrap Larry C.
Published: June 2005

Studies in “lower” organisms have identified a set of homologous sequences expressed in oocytes and early embryos that is critical for pattern formation. Mutations in such genes may exhibit maternal effect—they cause abnormalities in the fetus only when present in the mother. We report on a mother and child with identical, apparently balanced translocations having the breakpoints 12q13.1 and 13p13. The fetus had multiple anomalies including bilateral trilobar lungs, complex heart defect, malrotation of the gut, and asplenia, while the mother was entirely normal. Several hypotheses are advanced to explain this variable expression including transection of a gene with maternal effect—lateral asymmetry in the fetus is influenced by the maternal genotype. This explanation would account for the higher transmission of congenital heart disease to offspring by affected females noted in several studies. The human counterparts of 2 loci (int‐1 and HOX 3) involved in Drosophila early pattern formation are located near the translocation breakpoint 12q13.1. If one of these genes is responsible for situs abnormality, then universality of positional code (but not of embryologic mechanism) is suggested for higher metazoans.
Rubinstein‐Taybi syndrome with de novo reciprocal translocation t(2;16) (p13.3; p13.3)
Authors: Imaizumi Kiyoshi , Kuroki Yoshikazu
Published: June 2005

We describe a girl with typical Rubinstein‐Taybi syndrome with apparently balanced reciprocal translocation between chromosome 2 and 16. The patient has a condition characterized by mental retardation, typical facial manifestations, broad thumbs and first toes. Cytogenetic studies of the patient showed a reciprocal translocation without visible deletion, karyotype: 46, XX, t(2;16) (p13.3; p13.3). Her parents had normal chromosomes. These results suggest that the locus of the gene for the Rubinstein‐Taybi syndrome may be situated at 2p13.3 or 16p13.3.
45,X/47,XYY mosaicism: Clinical discrepancy between prenatally and postnatally diagnosed cases
Authors: Pettenati M. J. , Wheeler M. , Bartlett D. J. , Subrt I. , Rao N. , Kroovand R. L. , Burton B. K. , Kahler S. , Park H. K. , Cosper P. , Kelly D. R. , Ranells J. D.
Published: June 2005

45,X/47,XYY mosaicism is a rare chromosomal disorder with clinical information limited to 11 postnatal cases in the literature and with uncertainty regarding prenatal prediction of phenotype and prognosis. We report on 7 new cases of 45,X/47,XYY mosaicism, three detected prenatally and 4 diagnosed postnatally. A clinical comparison of the cases of 45,X/47,XYY mosaicism is presented together with a literature review.
Deletion of 20p 11.23→pter with normal growth hormone‐releasing hormone genes
Authors: Shohat M. , Herman V. , Melmed S. , Neufeld N. , Schreck R. , Pulst S. , Graham J. M. , Rimoin D. L. , Korenberg J. R.
Published: June 2005

Using a molecular analysis of the DNA from a patient with a deletion of chromosome 20 [46,XX,del(20)(p11.23)], we have excluded the growth hormone‐releasing hormone (GHRH) gene from the region 20p11.23→pter. The patient had minor facial anomalies, Rieger eye anomaly, a congenital heart defect, severe failure to thrive, and a neurosecretory problem in growth hormone (GH) secretion. Since the GHRH gene was previously mapped to chromosome 20, we used molecular genetic methods to determine whether the growth abnormalities were due to the deletion of this gene. DNAs of the patient and 2 normal control subjects were analyzed by quantitative Southern blotting using a DNA probe for the GHRH gene and 2 reference DNA probes mapping to chromosome 21. The GHRH gene was found to be present in 2 copies in the patient. This indicates that the gene for GHRH maps to the region outside the patient's deletion, in 20p11.23→qter. Furthermore, our results suggest that genes other than GHRH on 20p are important for developmental steps leading to normal neurosecretory function of GH and may also be involved in generating Rieger eye anomaly. Finally, GH deficiency and Rieger eye anomaly should be sought in other patients with deletions of 20p.
“Pseudomosaicism” for 4p – in amniotic fluid cell culture proven to be true mosaicism after birth
Authors: Vockley Jerry , Inserra JoAnn , Breg W. Roy , Yang‐Feng Teresa L.
Published: June 2005

Pseudomosaicism is noted in approximately 1% of amniotic fluid cell studies. Some represent numerical abnormalities, but pseudomosaicism for structural chromosomal abnormalities is also seen. Pseudomosaicism is not usually considered clinically significant. Recently, we evaluated a 13‐month‐old girl with developmental delay and minor anomalies suggestive of 4p – syndrome. In 5 of 100 peripheral lymphocytes, she had a deletion 46,XX,del(4)(p15). Review of a prenatal amniocentesis study performed on the mother of our patient disclosed that one colony of 18 examined from 2 in situ cultures had the same abnormality, whereas none of the 27 cells from a flask culture showed the abnormality. Results of this study had originally been reported as showing pseudomosaicism. To our knowledge, amniotic fluid pseudomosaicism of a structural abnormality has not previously been shown to reflect true mosaicism in fetal tissue or liveborn children. The actual incidence of this phenomenon is unknown, but it may be present in unexamined children with minimal clinical findings. Apparently only one previous case of mosaic 4p – in a liveborn individual has been reported.
Biochemical and genetic analysis of a child with cystic fibrosis and cystinosis
Authors: Smith Margaret L. , Pellett Ocean L. , Cahill Timothy C. , David Denise N. , Kaskel Frederick J. , Smolin Lori A. , Greene Alice A. , Weissbecker Karen , Dean Michael , Schneider Jerry A.
Published: June 2005

We have studied a child with cystic fibrosis (CF), nephropathic cystinosis, and manifestations of Bartter syndrome, a finding reported previously in both of these diseases (CF and cystinosis). The chance of an individual inheriting a mutant allele for both CF and cystinosis from each of his parents by independent segregation is very small. Therefore, other mechanisms of inheritance were investigated, including whether his diseases were caused by a chromosome deletion or rearrangement that caused defects in both genes, whether his phenotype was caused by a new mutation or variant of either disease, or whether both diseases were inherited together due to inheritance of 2 copies of the same chromosome from one of the parents (uniparental disomy). An investigation was made of whether having mutations for both CF and cystinosis resulted in a different phenotype for either disease and whether the child was a heterozygote rather than a homozygote for one of the mutations. The results suggest that neither disease influenced the expression of the defect in the other and that this child inherited a mutant allele for both diseases independently from each parent.
Unique phenotype associated with a pericentric inversion of chromosome 6 in three generations
Authors: Wenstrom Katharine D. , Muilenburg Ann C. , Patil Shivanand R. , Hanson James W.
Published: June 2005

We observed a pericentric inversion of chromosome 6 in three generations of one family. Carriers had several phenotypic alterations including congenital cataracts, hearing loss, dental anomalies, ear anomalies, premature graying, unilateral strabismus, coloboma, and mild mental retardation. These manifestations may all be explained by a failure or delay in development of tissues derived from neural crest cells and are similar to these seen in the Rieger syndrome. The description of this family extends the known phenotypic abnormalities associated with alterations of chromosome 6.
Prenatal lesions in an ovine fetus with GM1 gangliosidosis
Authors: Murnane Robert D. , Wright Raymond W. , Ahern‐Rindell Amelia J. , Prieur David J.
Published: June 2005

Sheep affected with ovine GM1 gangliosidosis are normal at birth and develop clinical signs, initially ataxia, commencing at approximately 5 months of age, which progresses rapidly to recumbency. Superovulation and embryo transfer techniques were applied to a flock of carrier sheep of ovine GM1 gangliosidosis to increase the numbers of carrier and affected animals. A recipient ewe with 3 at‐risk fetuses died at 4 months of gestation (normal ovine gestation is 5 months), and spectrofluorimetric assay of cerebral lysosomal β‐galactosidase of the fetuses showed that 2 were carriers and one was an affected fetus. The affected fetus had marked cytoplasmic enlargement and vacuolization of central and peripheral nervous system neuronal soma and of hepatocytes and renal epithelial cells. Lectin histochemistry indicated abnormal storage of complex carbohydrates, with terminal saccharide moieties consisting of β‐galactose, N‐acetylneuraminic acid, and N‐acetylgalactosamine. This case underlines the need for prenatal initiation of therapy and also demonstrates that vacuolization alone is not the cause of clinical signs in this lysosomal storage disease in that clinical signs do not commence until at least 5 months after vacuolization is histologically apparent.
X‐linked syndrome: Mental retardation, hip luxation, and G6PD variant [Gd(+) Butantan]
Authors: dos Santos R. C. Stocco , Barretto O. C. O. , Nonoyama K. , Castro N. H. C. , Ferraz O. P. , Walter‐Moura J. , Vescio C. C. S. , Beçak W.
Published: June 2005

An apparently new X‐linked syndrome is presented. It occurred in four male first cousins. The main manifestations of this syndrome are severe mental retardation, bilateral congenital hip luxation, and short stature. Three of the affected males showed a new glucose‐6‐phosphate dehydrogenase variant.