bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term outcomes in paediatric asthma
Authors: Pedersen S.
Published: March 2003

Over the years the aims of asthma management have changed markedly from effective prednisolone treatment of symptoms and exacerbations towards more use of continuous prophylactic treatment. With our new understanding of the disease and its management definition of the aims of treatment and assessment of optimal asthma control have become much more complex. Even in times of evidence‐based medicine our asthma management is based upon findings of effects on various outcomes in somewhat short‐term (<1 year) controlled studies. However, assumptions about long‐term effects upon the basis of findings in such studies should be made with great caution. Good examples of this are studies which assess the risk of systemic effects and clinical adverse effects of inhaled corticosteroids. From such studies it has become clear that systemic effects detected in short‐term trials may have no predictive value of long‐term adverse effects. Thus steroid‐induced changes in lower leg growth rates assessed by knemometry do not predict long‐term statural growth. Moreover, steroid‐induced changes in statural growth over 1 year are not predictive of effects upon attained adult height. In contrast, reduced growth caused by uncontrolled asthma disease also seems to affect attained adult height adversely. These findings suggest that long‐term outcomes should play a larger role when future asthma management strategies are decided. Some important long‐term outcomes of asthma management in children include cure or remission of the disease, prevention of complications of the disease (airway remodelling, adverse effects upon growth/adult height, peak bone mineral density, physical impairment and psychosocial development) or its pharmacological management (adverse effects upon adult height, peak bone mineral density). More controlled long‐term studies (several years) are needed to provide a better understanding of how these outcomes are best achieved.
Efficacy of steroid treatments in the asthmatic preschool child
Authors: Bisgaard H.
Published: March 2003

Asthma represents the most common chronic disease in preschool children. Hospital admission for wheezy disorders is the most common paediatric chronic disease causing hospital admission and more common in young children than later in life.
Effectiveness of pharmacotherapy in asthmatic preschool children
Authors: De Jongste J. C. , Janssens H. M. , Van der Wouden J.
Published: March 2003

The term “effectiveness” relates to the question of whether or not a certain treatment works in practice. Usually, such a treatment was first evaluated under tightly controlled conditions in selected patient populations, and the potential benefits were shown. There is, however, a great difference between the efficacy of a given treatment, indicating its optimal therapeutic action in controlled trials, and its effectiveness when applied to a less well‐defined population of patients in daily practice. This is especially relevant for asthma in young children, where many factors are responsible for the difference. Among these are, first of all, the heterogeneity of the wheezing phenotype. Other factors include the compliance with prescribed treatments, as determined by the attitude of doctors and parents towards such treatment, the ease of administration and the perceived effects and side effects. Also, the performance of different inhaler devices may be insufficient for a good, reliable dose deposition in young children in daily life. As a result, the current treatment guidelines for preschool children with recurrent wheeze are probably too optimistic in assuming that inhaled treatment is most effective and feasible at all ages. We propose careful re‐evaluation of such recommendations in a first‐line setting resembling daily life as closely as possible, and consideration of oral treatments as well. Also, we need methods to separate the different phenotypes within the group of recurrently wheezing preschool children to optimize targeting of asthma treatment to those who have ongoing airway inflammation.
The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies
Authors: Brock David JH , Gilfillan Annette , Holloway Susan
Published: March 2003

The incidence of cystic fibrosis (CF) has previously been calculated from epidemiological surveys and from neonatal screening. With the cloning of the CF gene it has become possible to derive incidence figures from heterozygote frequencies, provided that the distribution of mutant alleles among healthy carriers is the same as among affected people. We have estimated the allele frequencies for four CF mutations, AF508, G551D, G542X and R117H, in 14360 unselected women undergoing antenatal heterozygote screening. The proportion of R117H, an allele of known mild effect, was much greater for het‐erozygotes than for homozygotes. The incidence of CF was therefore calculated from the heterozygote frequencies of AF508, G551D and G542X in a larger cohort of 27 161 successively screened women. The point estimate for the incidence of CF in the Scottish population was 1 in 1984, with 95% confidence intervals of 1 in 1692 to 1 in 2336.
X‐inactivation and marker studies in three families with incontinentia pigmenti: implications for counselling and gene localisation
Authors: Woffendin Hayley , Jakins Tracy , Jouet Monique , Stewart Helen , Landy Sarah , Haan Eric , Harris Ann , Donnai Dian , Read Andrew , Kenwrick Sue
Published: March 2003

Familial incontinentia pigmenti (IP) is an X‐linked dominant disorder with an extremely variable clinical presentation. Ambiguous diagnosis can complicate genetic counselling and attempts to refine the gene location in Xq28. Marked skewing of X‐inactivation patterns is a hallmark of IP and provides a means for investigating uncertain cases. We have conducted X‐inactivation studies in three families where Xq28 marker studies were at odds with the original clinical assessment. The results indicate that no recombination between the disease locus and Xq28 loci has occurred and suggest that mosaicism is responsible for the discrepancy in one family.
Centromere–telomere (12;8p) fusion, telomeric 12q translocation, and i(12p) trisomy 1
Authors: Rivera Horacio , Vásquez Ana Isabel , Perea Francisco J
Published: March 2003

The concurrence of a short arm isochromosome and a translocation of the entire long arm of the same chromosome to a telomere of another chromosome, implying trisomy for 4p, 5p, 7p, 9p, 10p or 12p, has been described in 13 patients. We have now used fluorescence in situ hybrization (FISH) to better characterize one of these rearrangements in which 12q was translocated to 8pter, whereas 12p was converted into an isochromosome. An alphoid centromere‐12 repeat gave a strong signal on the i(12p) and a weak but distinct signal at the breakpoint junction of the der(8), whereas the pantelomeric probe revealed three clear hybridization sites on the der(8): one at each end and another at the breakpoint junction. These findings suggest that the prime event was a post‐fertilization centric fission of chromosome 12 leading to the 12q translocation via a real centromere–telomere fusion and the i(12p). Alternatively, the crucial event may have been a centromere–telomere recombination. An interstitial telomere has been documented by means of FISH at the breakpoint junction of the sole derivative usually present in 20 constitutional translocations including eight with a jumping behavior. In addition, six other telomeric translocations defined by banding methods, including another case of 12q translocation/i(12p), have also been jumping ones. These telomeric translocations have been de novo events and their proneness to exhibit a jumping behavior appears to be independent of the involved chromosomes, size of the translocated segments, and concomitant abnormalities.
An unbalanced half‐cryptic translocation involving the 6q subtelomeric region and 2p25.3 in a child with mental retardation: uses and limitations of fluorescence insitu hybridization
Authors: Batanian JR , Hussain MI
Published: March 2003

We report on a 5‐year‐old boy with minor anomalies, growth retardation, and developmental delay carrying an extra chromatin material on the terminal band of the long arm of chromosome 6. To determine the origin of this extra material, whole chromosome fluorescence in situ hybridization (FISH) was used initially. Results showed fully painted 6qs, excluding the possibility of a derivative. However, maternal cytogenetic investigation suggested the presence of a possible half‐cryptic balanced translocation that was further assessed using specific subtelomeric FISH probes of chromosome 6. Results showed that the 6q subtelomeric region was translocated on an A‐group chromosome that was ultimately characterized, using FISH, as chromosome 2. This illustrates the use of specific subtelomeric regions and the limitations of whole chromosome FISH to identify the origin of a subtle chromosomal abnormality.
Allele distribution at the FMR1 locus in the general Chinese population
Authors: Chiang Shu‐Chuan , Lee Yu‐May , Wang Tso‐Ren , Hwu Wuh‐Liang
Published: March 2003

Fragile X syndrome is an important disease of hereditary mental retardation. Its prevalence in the Chinese population is not clear. We amplified FMR1 CGG repeats from male newborns’ blood spots. Approximately 45% of the males had 28 CGG repeats and another 19% had 29 repeats. Besides this major peak, there was a second peak at 34 and 35 repeats. From the 1000 males studied, 3 were found to have repeat numbers in the high borderline range (each with 50, 52 and 53 repeats). This result provides a low but significant risk of fragile X syndrome in the Chinese population.
Psychological and social determinants of women's decisions to undergo genetic counseling and testing for breast cancer
Authors: Cappelli M , Surh L , Humphreys L , Verma S , Logan D , Hunter A , Allanson J
Published: March 2003

This study examined the demand for breast cancer genetic testing and counseling among Canadian women diagnosed with breast cancer under the age of 50, together with some of the factors predicting both their intentions to be tested and the degree to which they act on their intentions. Participants were 110 women under the age of 50 and comprised of two groups: 1) women diagnosed with breast cancer (BC, n=60); and 2) an index group of unaffected women from the general population (GP, n=50). All participants completed a survey that addressed family history of breast and other cancers, demographic variables, knowledge and attitudes about breast cancer, and genetic testing. Members of the BC group were offered genetic counseling and testing for BRCA1 and BRCA2 free of charge. Overall, 60% of participants indicated they would like the test, and 40% either did not want it or were uncertain. Seventy‐two percent of women in the BC group wanted to be tested. Of these, only 49% had actually contacted the genetic counselor about testing at follow‐up 3–15 months later. Intention to be tested was associated with presence of breast cancer, greater perceived benefits of testing, fewer perceived ‘costs’ of testing, and higher levels of concern about the risk of relatives developing breast cancer. Actual arranging to meet with the genetic counselor among women in the BC group was associated with fewer perceived costs of having the test. Results suggest a moderate level of interest in gene testing, though intention to be tested may not translate into actual uptake. Women who do choose to have the test may believe the potential ‘costs’ of using this new genetic technology to be relatively few. This has implications for genetic counselors in terms of providing balanced and complete information to women considering genetic testing for breast cancer susceptibility.
Association between AGT codon 235 polymorphism and variation in serum concentrations of creatinine and urea in Canadian Oji‐Cree
Authors: Hegele Ra , Harris Sb , Hanley Ajg , Zinman B
Published: March 2003

Finding the genetic determinants of intermediate quantitative traits, such as serum creatinine and urea, might aid in finding the determinants of disease phenotypes, such as renal failure, that are, in part, defined according to threshold values imposed upon such traits. We evaluated the association between common variation in the gene encoding angiotensinogen, AGT, and the serum concentrations of creatinine and urea in non‐diabetic Canadian Oji‐Cree. We determined genotypes of the AGT codon 235 polymorphism among 502 non‐diabetic Oji‐Cree. We used multivariate analysis of variance to identify significant determinants of variation in serum concentrations of creatinine and urea and of systolic and diastolic blood pressure. We found significant associations between the AGT codon 235 genotype and serum concentrations of creatinine and urea (p=0.017 and 0.049, respectively) and systolic blood pressure (p=0.041). Compared with subjects with the other two genotypes, homozygotes for AGT T235/T235 had significantly lower serum concentrations of creatinine and urea and significantly higher mean systolic blood pressure. The findings suggest that the AGT T235 allele is a determinant of intermediate traits related to renal function in these aboriginal Canadians.
Assessment of RS1 in X‐linked juvenile retinoschisis and sporadic senile retinoschisis
Authors: Gehrig Andrea , White Karen , Lorenz Birgit , Andrassi Monika , Clemens Stefan , Weber Bernhard Hf
Published: March 2003

The RS1 gene is the causative gene in X‐linked juvenile retinoschisis (RS). We have screened this gene for mutations in 13 patients with RS and in 7 probands with senile retinoschisis, a sporadic, later‐onset form of retinoschisis. Mutations were detected in all RS patients. Of the 11 different mutations identified, six have been reported previously and five are novel. We did not find mutations in any of the senile retinoschisis patients and conclude that senile retinoschisis is not the result of germline mutations in the RS1 gene.
Cohen syndrome: evaluation of its cardiac, endocrine and radiological features
Authors: Kivitie‐Kallio Satu , Eronen Marianne , Lipsanen‐Nyman Marita , Marttinen Eino , Norio Reijo
Published: March 2003

Cohen syndrome (MIM no. 216550) is an autosomal recessive disorder with a typical clinical picture. Since the first report, most publications have represented single case reports. In this study, our aim was to describe cardiac, endocrine and radiological abnormalities in 22 Cohen patients of Finnish descent. Detailed investigations of the heart revealed the anatomy of the heart to be normal with no evidence for clinically significant mitral prolapse. However, a decreased left ventricular function with advancing age was identified. No significant endocrine abnormalities were found at the examination of pituitary, adrenal and thyroid function. The height was either normal or patients were moderately short (mean height standard deviation score (SDS) −2) at all ages, associated, however, often with the marked kyphosis. Truncal obesity was seen in 4/22 patients. X‐rays of the chest, lumbar and thoracic spine, long bones, ankles and metacarpophalangeal pattern profiles revealed kyphosis, scoliosis and calcaneo planovalgus as common features. Fingers of these patients were slender but short with a characteristic metacarpophalangeal pattern profile.
Physical activity modulates the effect of a lipoprotein lipase mutation (D9N) on plasma lipids and lipoproteins
Authors: Boer Jolanda MA , Kuivenhoven Jan Albert , Feskens Edith JM , Schouten Evert G , Havekes Louis M , Seidell Jacob C , Kastelein John JP , Kromhout Daan
Published: March 2003

We investigated interactions between a mutation (D9N) in the lipoprotein lipase (LPL) gene and physical activity, as well as other lifestyle factors, on lipid traits in a population‐based sample of Dutch men and women (n=379). We used questionnaire information to classify physical activity, alcohol consumption, and smoking habits, while overweight was defined as a body mass index (BMI)> 25 kg/m2. Non‐fasting blood samples were used for the determination of lipid traits and the D9N genotype. Fifteen subjects (4%) carried the mutation. They presented with higher levels of total cholesterol, apolipoprotein (apo) B and triglycerides compared to non‐carriers. While no interactions with overweight, alcohol consumption, and smoking were found, a strong interaction between the D9N mutation and physical activity became apparent. Physically inactive D9N carriers (n=5) had considerably higher total cholesterol (+2 mmol/l, p≤0.0001) and apo B levels (+63 mg/dl, p≤0.0001) compared to non‐carriers of this mutation, whereas their high‐density lipoprotein (HDL)‐cholesterol concentrations were lower (−0.22 mmol/l, p<0.05). This was not the case for physically active D9N carriers (n=10).

In conclusion, a common variant of the LPL gene (D9N) adversely affects plasma lipid and lipoprotein profiles. However, the unfavorable consequences may be counteracted by physical activity.
Polyvariant mutant CFTR genes in patients with chronic pancreatitis
Authors: Arduino C , Gallo M , Brusco A , Garnerone S , Piana Mr , Di Maggio S , Gerbino Promis G , Ferrone M , Angeli A , Gaia E
Published: March 2003

Several authors have reported an association between mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and chronic pancreatitis. CFTR gene transcription and protein efficiency are influenced by two polymorphic loci, (TG)m and M470V, other than the T5 allele, whose role is already well‐established. The TG11/T5 haplotype is commonly found in healthy subjects, while the TG12/T5/V470 and TG13/T5/V470 haplotypes are present in congenital bilateral absence of the vas deferens (CBAVD) patients. While the T5 allele is a mutation that is over‐represented in patients with chronic pancreatitis, no data are available concerning the possible allelic preference at the other two polymorphic loci, (TG)m and M470V, in these patients. For this reason, we screened 39 patients with chronic pancreatitis for the most common CFTR mutations found so far in the Italian population; in addition, we examined the length of the polypyrimidine (poly‐T) tract in intron 8, the (TG)m length and the M or V codon at position 470. CFTR mutations were found in 3 patients. Poly‐T variant typing identified genotype T5/T7 in 5 patients and T5/T9 in 1 patient. Direct sequencing of intron 8 in patients with the T5 variant revealed the TG12/T5/V470∥TG11/T7/V470 genotype in 5 patients and TG10/T9∥TG11/T5 genotype in 1 patient. In patients with chronic pancreatitis, the T5 allele is frequently associated with TG12 and V470, a haplotype already reported in CBAVD cases and quite uncommon in healthy subjects.
Molecular genetics of Turner syndrome: correlation with clinical phenotype and response to growth hormone therapy
Authors: Tsezou A , Hadjiathanasiou Ch , Gourgiotis D , Galla A , Kavazarakis Em , Pasparaki A , Kapsetaki M , Sismani C , Theodoridis Ch , Patsalis Pc , Moschonas N , Kitsiou S
Published: March 2003

To correlate the origin of the retained X in Turner syndrome with phenotype, pre‐treatment height and response to recombinant human growth hormone (rhGH) therapy, systematic clinical assessment and molecular studies were carried out in 33 Greek children with Turner syndrome and their parents including 18 children with 45,X and 15 with X‐mosaicism. Microsatellite markers on X chromosomes (DXS101 and DXS337) revealed that the intact X was paternal (Xp) in 15/30 and maternal (Xm) in 15/30 children, while 3/33 families were non‐informative. No significant relationship was found between parental origin of the retained X and birth weight/length/gestational age, blepharoptosis, pterygium colli, webbed neck, low hairline, abnormal ears, lymphoedema, short 4th metacarpal, shield chest, widely spaced nipples, cubitus valgus, pigmented naevi, streak gonads, and cardiovascular/renal anomalies. With regard to the children's pre‐treatment height, there was a significant correlation with maternal height and target height in both Xm and Xp groups. No differences were found between Xm and Xp groups and the improvement of growth velocity (GV) during the first and second year of rhGH administration, while for both groups GV significantly improved with rhGH by the end of the first and the second year. To our knowledge, this is the first attempt to correlate the parental origin of Turner syndrome with the response to rhGH therapy.
Assessment of education and counselling offered by a familial colorectal cancer clinic
Authors: Collins Veronica , Halliday Jane , Warren Rosemary , Williamson Robert
Published: March 2003

We have evaluated whether or not client expectations, in terms of education and information needs, have been met by a multi‐disciplinary familial colorectal cancer clinic. The study used a pre‐ and post‐clinic questionnaire design and 126 (84 women, 42 men) clients of the clinic participated. The most common reason for coming to the clinic is to ‘find out whether there is a gene for colorectal cancer in the family’, followed by ‘to reduce risk for bowel cancer’ and ‘concern for children's risk’. Clients would have preferred to receive more information before attendance at the clinic to help with preparation. Information given during the clinic increased knowledge of bowel cancer genetics and had a positive effect on the accuracy of some clients’ perceptions of their risk of developing cancer. In multivariate analysis, higher risk perceptions, higher education level and greater baseline knowledge predicted post‐clinic knowledge of bowel cancer genetics and an increase in knowledge. Client reports of the presence of a genetic counsellor or medical geneticist in the session also predicted post‐clinic knowledge and an increase in knowledge. Most participants felt they received enough information during the clinic session on various aspects of familial colorectal cancer, but the desire for more written information on prevention, including lifestyle actions, was expressed by many.
Pseudodominance of lipoprotein lipase (LPL) deficiency due to a nonsense mutation (Tyr302>Term) in exon 6 of LPL gene in an Italian family from Sardinia (LPLOlbia)
Authors: Bertolini S , Simone Ml , Pes Gm , Ghisellini M , Rolleri M , Bellocchio A , Elicio N , Masturzo P , Calandra S
Published: March 2003

We analyzed the molecular defect in the lipoprotein lipase (LPL) gene of a young boy from Sardinia who had primary hyperchylomicronemia, pancreatitis, and a complete LPL deficiency in post‐heparin plasma. Analysis of LPL gene was performed by using single strand conformation polymorphism (SSCP) and direct sequencing of SSCP‐positive region. The proband was homozygous for a C>A transversion in exon 6, which converts the codon for tyrosine at position 302 into a termination codon and eliminates an RsaI restriction site; this allowed the rapid screening of the proband's family members, among whom nine heterozygotes and one additional homozygote were identified. The homozygote was the proband's paternal grandmother who had shown the first clinical manifestation (recurrent pancreatitis) of LPL deficiency at the age of 54 years. LPL mutation carriers showed a mild dyslipidemic phenotype characterized by a reduction of high density lipoprotein‐cholesterol (HDL‐C) levels, HDL‐C/total cholesterol ratio, and low density lipoprotein (LDL) size, associated with a variable increase of triglyceride levels. Five of these carriers were also heterozygotes for β°‐thalassemia (Q39X mutation). In these double mutation carriers, plasma HDL‐C levels were higher and plasma triglycerides tended to be lower than in carriers of LPL mutation alone. The Tyr302>Term mutation encodes a truncated protein of 301 amino acids that is probably not secreted by the LPL producing cells. This is the first mutation of LPL gene found in Sardinians.
Hypogonadotrophic hypogonadism in Roifman syndrome
Authors: Robertson Stephen P , Rodda Christine , Bankier Agnes
Published: March 2003

The combination of spondyloepiphyseal dysplasia, humoral immune deficiency, growth retardation, intellectual deficit and characteristic facial dysmorphism has recently been delineated as a discrete disorder thus far only reported in males. This report describes a fifth individual with co‐existent hypogonadotrophic hypogonadism, thereby expanding the phenotype and possibly offering insight into the genetic aetiology of this condition.
Hereditary colorectal cancer: risk assessment and management
Authors: Hampel Heather , Peltomaki Paivi
Published: March 2003

There are at least nine major cancer susceptibility syndromes that infer an increased risk for colorectal cancer and/or colorectal polyposis; hereditary nonpolyposis colorectal cancer syndrome, Muir–Torre syndrome, Turcot syndrome, the I1307K polymorphism of the APC gene, attenuated familial adenomatous polyposis, Peutz–Jeghers syndrome, juvenile polyposis, and the PTEN hamartoma tumor syndrome. As a result, the differential diagnosis of hereditary colorectal cancer can be complex. In addition, there has been a dramatic increase in the knowledge available regarding risk assessment and management of hereditary colorectal cancer syndromes. The literature was reviewed to develop this concise review of the hereditary colorectal cancer syndromes to facilitate the accurate diagnosis of each syndrome and the appropriate medical care for individuals with these diagnoses. Referral to a qualified Clinical Cancer Genetics program is appropriate if any of these syndromes is suspected and they will ensure the most up‐to‐date information is available to the patient, their family, and their health care professionals.
Prenatal diagnosis of fragile X syndrome and the risk of expansion of a premutation
Authors: Kallinen Juuso , Heinonen Seppo , Mannermaa Arto , Ryynänen Markku
Published: March 2003

The aim of the present study was to evaluate prospectively the dynamics of the FMR1 gene. The risk of full mutation among pregnant women and the carriers, and the risk of expansion of a premutation allele to a full mutation were estimated. We identified 89 pregnant women with an expanded FMR1 gene seeking prenatal diagnosis. Amniocentesis or chorion villus sampling (CVS) was offered and a DNA test of the FMR1 gene was carried out in such pregnancies.  The overall risk of full mutation among women (N=21) with a repeat size between 60 and 80 was 4.8% (one fetus with mosaicism), and the risk of expansion of the premutation allele to a full mutation was 14% in those offspring to whom the premutation allele was transmitted. The risk of full mutation among the carriers (N=13) with a repeat size between 81 and 100 was 61.5% (8/13), and the risk of expansion of a premutation allele to a full mutation was 89%. Only one case fell into the category of 101–200 repeats, and expansion to a full mutation was recorded. Fetuses of full mutation mothers inherited the larger allele in 64% (14/22) of the cases.  The range of 40–59 repeats was safe: there were no fetal full mutations. The risk of full mutation was also low among the subjects with a repeat size between 60 and 80, whereas the risk increased significantly after 80 repeats. Maternal premutation size was positively correlated with the risk of having a full mutation offspring.
Intrachromosomal triplications: molecular cytogenetic and clinical studies
Authors: Reddy Kavita S , Logan James J
Published: March 2003

A newborn boy had meconium aspiration syndrome, hypospadias, a supernumerary digit on the left hand, hyperbilirubinemia, a fractured right clavicle, osteopenia, liver calcification, and mild pulmonary hyperplasia. Cytogenetic studies showed a chromosome 13 with additional material in 33% of the metaphases. The add(13) was considered to be a probable duplication of 13q12q22. The 13 paint probe hybridized to the add(13) from end to end. Fluorescence in situ hybridization (FISH) studies using retinoblastoma probe (RB)‐1 that maps to 13q14 and D13S585 that maps to 13q32‐q33 gave one signal for RB and three signals for D13S585. The pattern of the three signals from the 13q32q33 region and the G‐banding pattern was best explained as a triplication of 13q22q33, with an inverted middle repeat resulting in tetrasomy for this segment. Mosaicism was confirmed by FISH using a D13S585 probe on a buccal smear. Three triplications detected in our laboratory were compared – 13q22q33, 15q11q13, and 2q11.2q21. FISH was critical in identifying triplications 13q22q33 and 15q11q13. The hybridization pattern also indicated an inverted middle repeat. We conclude that intrachromosomal triplications may be more prevalent than previously assumed and they probably share a common mechanism in their formation. When the G‐bands do not correspond exactly to a duplication or to a tandem triplication, an important consideration is that the majority of triplications have an inverted middle repeat. Triplications can be mistaken for duplications. Therefore, in assessing duplications, FISH confirmation is recommended.
Parental and meiotic origin of triploidy in the embryonic and fetal periods
Authors: McFadden DE , Langlois S
Published: March 2003

Triploidy is a common finding both in early spontaneous abortions and in the fetal period. Previous studies suggested that the majority of triploidy was the result of diandry, specifically dispermy. Molecular determination of parental origin in fetal triploids has shown that digyny accounts for the majority of triploids in the fetal period. The aim of this study was to determine the meiotic level at which the error leading to digynic triploidy occurs and to extend the molecular analysis of parental origin of triploidy into the embryonic period. Maternal age of digynic triploids was compared with that of the diandric cases. Using polymorphic pericentromeric markers, we have shown that the majority of digynic triploidy is the result of errors in the second meiotic division. Digyny accounted for the majority of triploids, even in the non‐fetal cases. Diandry predominated in a subset of the non‐fetal cases in which embryos were not present and in which the placental findings of partial hydatidiform mole (PHM) were encountered. Maternal age differed between the digynic and diandric groups only for the non‐fetal cases; this was attributed to differences in ascertainment.
Optimization of the fluorescence in situ hybridization (FISH) technique for high detection efficiency of very small proportions of target interphase nuclei
Authors: Yan J , Guilbault E , Massé J , Bronsard M , DeGrandpré P , Forest J‐C , Drouin R
Published: March 2003

Using commercially available fluorochrome‐labeled probes specific for chromosomes X, Y, 13, 18, and 21, we optimized the technical protocols for fluorescence in situ hybridization (FISH) so that the highest sensitivity and specificity were achieved. Also, we compared the optical properties of different types of fluorescent labels in an effort to develop the most efficient FISH protocol, including the determination of which types of labels are the easiest to count accurately. The lymphocytes were purified from blood of normal male and female newborns, normal male and female adults, and a trisomy 21 male adult. Male and female lymphocytes were mixed in five different combinations. For each combination, the male lymphocytes either from newborns or from adults were diluted with female lymphocytes in seven different proportions. For each of these 35 different cell mixtures, 100 000 nuclei were analyzed and scored in a blind fashion. Among the different fluorochrome‐labeled probes, the highest sensitivity and specificity were achieved when SpectrumAqua CEP‐Y/SpectrumOrange CEP X probe mixture, SpectrumAqua CEP‐18, SpectrumOrange LSI‐13, and SpectrumOrange LSI‐21 were hybridized. The hybridization sensitivity and specificity were higher than 99% for the identification of chromosomes X, Y, 13, and 18, and higher than 98% for the detection of trisomy 21. The proportion of false‐positive signals was under 0.005% for XY detection and lower than 0.14% for autosome detection. With these high hybridization sensitivities and specificities, the optimized FISH protocol developed in our laboratory has the potential to detect very rare events, e.g., when the proportion of cells being sought is lower than 0.01%. In other words, our protocol allows the specific detection of one male cell sunken among 10 000 female cells.
Two unbalanced translocations involving a common 6p25 region in two XY female patients
Authors: Batanian JR , Grange DK , Fleming R , Gadre B , Wetzel J
Published: March 2003

We report two 46,XY female patients with two differentde novounbalanced translocations, each involving the chromosomal region 6p25. The patient with a 46,XY,der(6)t(X;6)(p21.2;p25) karyotype had a sex reversal phenotype. The patient with a 46,XY,der(13)t(6;13)(p25;q33) karyotype had a male pseudohermaphrodite phenotype. Multi‐paint fluorescentin situhybridization was performed to determine the origin of the derivative material on 6p and 13q. The association of abnormalities of the 6p25 region with either an Xp duplication or a 13q deletion is reported here for the first time.
Identification of two de novo partial trisomies by comparative genomic hybridization
Authors: Rigola Ma , Carrera M , Ribas I , De La Iglesia C , Mendez B , Egozcue J , Fuster C
Published: March 2003

We report the use of comparative genomic hybridization (CGH) to define the extra chromosome region present in two de novo partial trisomies 15q25‐qter and Xp21‐pter, which could not be clarified by conventional G‐banding. Investigation with fluorescence in situ hybridization (FISH) revealed that the partial trisomy corresponded to an unbalanced translocation between Y and 15 chromosomes in 1 patient and an unbalanced X/X reorganization in the other patient. The combination of classical karyotyping, CGH, and FISH is useful for the identification and characterization of partial trisomies in clinical diagnostic laboratories, in order to delineate the chromosome regions implicated in specific clinical disorders.
Multicultural education and genetic counseling
Authors: Weil J
Published: March 2003

The responsibility to provide accessible, useful genetic counseling to individuals from many cultures and ethnicities arises from the increasing ethnocultural diversity of the populations served, coupled with the ethical goal of providing equal access and quality of services for all individuals. The multicultural education, training, and practice of genetic counseling involves three major components: knowledge of relevant ethnocultural groups, ethnocultural self‐awareness, and an understanding of institutional and social barriers to services. Despite the diversity of ethnocultural groups served and the critical role of direct experience and training for the genetic counselor, some general guidelines for multicultural genetic counseling can be identified. These include the importance of establishing and maintaining trust, the essential need to respect the counselee's healthcare beliefs and practices, and the necessity of understanding the impact of culture on the process of decision making and on counselee responses to nondirective counseling.
Novel molecular defects in the androgen receptor gene of Mexican patients with androgen insensitivity
Authors: Chávez B , Vilchis F , Zenteno Jc , Larrea F , Kofman‐Alfaro S
Published: March 2003

The androgen insensitivity syndrome (AIS) is an X‐linked form of male pseudohermaphroditism caused by mutations in the androgen receptor (AR) gene. In the present study, we analyzed the AR gene in 8 patients, 4 sporadic and 2 familial cases with the syndrome, using exon‐specific polymerase chain reaction, single‐stranded conformational polymorphism and sequencing analysis and identified six new single base mutations, including one nonsense mutation at the hinge region of the receptor. These molecular lesions occurred in the steroid‐binding domain (SBD) and all but one affected the first nucleotide of their respective codons. A nonsense mutation in exon 4, which converts a glutamine into a premature termination signal (Q657stop), a missense mutation changing arginine instead of glycine (G743R) and a conservative substitution of leucine with valine at amino acid 830 (L830V) were detected in patients with CAIS. Three other missense mutations located in exons 4 (L701I), 5 (A765S), and 6 (Q802R) were present in individuals bearing a partial form of AIS. These data allow us to reaffirm the view that nonsense mutations in the AR results almost invariably in a CAIS phenotype and underly the importance of the SBD for the AR functional activity.
Co‐occurrence and contribution of Fabry disease and Klippel–Trénaunay–Weber syndrome to a patient with atypical skin lesions
Authors: Germain DP
Published: March 2003

Fabry disease (FD) is an X‐linked recessive inborn error of glycosphingolipid metabolism. Among clinical symptoms, maculopapular skin lesions, known as angiokeratoma, most often appear on the lower abdomen, scrotum, and thighs, with a tendency toward bilateral symmetry. A 30‐year‐old male patient was referred to us for evaluation of a complex vascular and cutaneous malformation. Skin examination showed numerous angiokeratoma, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk. The diagnosis of FD was confirmed by demonstration of a decreased α‐galactosidase A activity, and the patient was shown to be hemizygote for a missense mutation (R342Q) in the α‐galactosidase A gene (GLA). This mutation was also demonstrated in DNA extracted from fibroblast cultures established from both affected and unaffected skin areas, thus excluding the hypothesis of somatic mosaicism or revertant mosaicism. Interestingly, the diagnosis of Klippel–Trénaunay–Weber syndrome (KTWS) was also made, through clinical and radiological investigations. This is the first report on the association between FD and KTWS. Karyotype analysis was normal. It is likely that the mixed vascular malformations of KTWS affecting capillary and venous systems have contributed to the unusual angiokeratoma distribution pattern observed in the patient.
Comparative genomic hybridisation in mentally retarded patients with dysmorphic features and a normal karyotype
Authors: Joly G , Lapierre J‐M , Ozilou C , Gosset P , Aurias A , De Blois M‐C , Prieur M , Raoul O , Colleaux L , Munnich A , Romana SP , Vekemans M , Turleau C
Published: March 2003

Segmental aneusomy for small chromosomal regions has been shown to be a common cause of mental retardation and multiple congenital anomalies. A screening method for such chromosome aberrations that are not detected using standard cytogenetic techniques is needed. Recent studies have focused on detection of subtle terminal chromosome aberrations using subtelomeric probes. This approach however excludes significant regions of the genome where submicroscopic rearrangements are also liable to occur. The aim of the present study was to evaluate the efficiency of comparative genomic hybridisation (CGH) for screening of submicroscopic chromosomal rearrangements. CGH was performed in a cohort of 17 patients (14 families) with mental retardation, dysmorphic features and a normal karyotype. Five subtle unbalanced rearrangements were identified in 7 patients. Subsequent FISH studies confirmed these results. Although no interstitial submicroscopic rearrangement was detected in this small series, the study emphasises the value of CGH as a screening approach to detect subtle chromosome rearrangements in mentally retarded patients with dysmorphic features and a normal karyotype.
Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome
Authors: Takahashi T , Takahashi I , Komatsu M , Sawaishi Y , Higashi K , Nishimura G , Saito H , Takada G
Published: March 2003

Proximal symphalangism is an autosomal‐dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype–phenotype correlations have not been recognized from the mutations in the NOG gene.
A logistic regression model for measuring gene–longevity associations
Authors: Tan Q , Yashin AI , De Benedictis G , Cintolesi F , Rose G , Bonafe M , Franceschi C , Vach W , Vaupel JW
Published: March 2003

The logistic regression model is a popular model for data analysis in epidemiological research. In this paper, we use this model to analyze genetic data collected from gene–longevity association studies. This new approach models the probability of observing one genotype as a function of the age of investigated individuals. Applying the model to genotype data on the TH and 3′ApoB‐VNTR loci collected from an Italian centenarian study, we show how it can be used to model the different ways that genes affect survival, including sex‐ and age‐specific influences. We highlight the advantages of this application over other available models. The application of the model to empirical data indicates that it is an efficient and easily applicable approach for determining the influences of genes on human longevity.
A familial cryptic subtelomeric deletion 12p with variable phenotypic effect
Authors: Baker E , Hinton L , Callen DF , Haan EA , Dobbie A , Sutherland GR
Published: March 2003

A 15‐year‐old‐boy and his mother, both carrying a cryptic deletion within 12p13.33, are described. The proband has a mild phenotype with moderate mental retardation and severe behavioural problems. The mother had some learning difficulties at school. Conventional GTL‐banded high‐resolution chromosome analysis showed normal karyotypes. Subsequent analysis by fluorescence in situ hybridization using a set of probes specific for the subtelomeric regions of all chromosomes, plus a series of probes at 12p13.33 extending from the 12p telomere, showed that both mother and son carry a 1.65 Mb terminal deletion in this region. There are 10 predicted genes within the deleted region. The unanticipated familial nature of the deletion emphasizes the value of family studies in all cases with subtelomeric abnormalities. It also demonstrates the difficulty in making a clinical diagnosis of individuals with this deletion. To the best of the present authors' knowledge, the proband and his mother are the first patients described with a submicroscopic deletion at 12p13.33.
Mutation in the FGFR2 gene in a Taiwanese patient with Beare–Stevenson cutis gyrata syndrome
Authors: Wang T‐J , Huang C‐B , Tsai F‐J , Wu J‐Y , Lai R‐B , Hsiao M
Published: March 2003

The present authors report the first case of Beare–Stevenson syndrome in Taiwan. The patient shares several clinical characteristics of Beare–Stevenson syndrome such as cutis gyrata, cloverleaf skull, prominent eyes, cleft palate, ear defects and a protruding umbilical stump. Molecular genetic analysis of the FGFR2 gene in this patient's DNA revealed a missense A → G mutation on nucleotide 1303 of the FGFR2 cDNA. This mutation leads to a Tyr → Cys substitution at residue 375 located at the N‐terminal end of the transmembrane domain of FGFR2. The present results are in accordance with other previously published reports and strengthen the importance of the FGFR2 gene in the pathogenesis of Beare–Stevenson syndrome.
Type III hyperlipoproteinema with apolipoprotein E2/2 genotype in Japan
Authors: Eto M , Saito M , Nakata H , Iwashima Y , Watanabe K , Ikoda A , Kaku K
Published: March 2003

Limited information is available concerning type III hyperlipoproteinemia (HLP) in the Asian population. Therefore, clinical and biochemical characteristics of type III HLP were examined in 16 Japanese patients. Mean plasma triglyceride (TG) and total cholesterol (chol) levels were 381 mg/dl and 253 mg/dl, respectively, and the mean very low density lipoprotein (VLDL)‐chol/plasma TG ratio was 0.27, which were lower than those reported in Western countries. Eighty percent of the patients had high plasma remnant‐like particles (RLP)‐chol levels above 50 mg/dl and a high RLP‐chol/plasma TG ratio above 0.1. Twelve patients (75.0%) were obese. Seven patients (43.8%) had type 2 diabetes mellitus and four patients (25.0%) had impaired glucose tolerance. Six patients (37.5%) had coronary heart disease (CHD), but none had peripheral vascular disease or xanthomas. TG‐rich lipoproteins from type III HLP patients with diabetes mellitus stimulated cholesteryl ester synthesis by human macrophages significantly (p < 0.001) more than those from type III HLP patients without diabetes mellitus. In conclusion, the Japanese type III HLP patients had lower plasma TG and total chol levels and a lower VLDL‐chol/plasma TG ratio, but CHD was more common. The patients were characterized by a high frequency of obesity and/or glucose intolerance. The TG‐rich lipoproteins from type III HLP patients with diabetes mellitus were more atherogenic.
Living with Marfan syndrome III. Quality of life and reproductive planning
Authors: Peters KF , Kong F , Hanslo M , Biesecker BB
Published: March 2003

As individuals with Marfan syndrome are increasingly diagnosed earlier in life and prior to life‐threatening cardiovascular events, there is opportunity to study factors that influence their reproductive planning and quality of life. In this study of 174 affected adults, the overall quality of life was reported to be adequate, although it was significantly decreased within the spiritual/psychological domain. Approximately 62% agreed that having Marfan syndrome significantly affected their reproductive decision‐making. This view was correlated with age of diagnosis, mitral valve prolapse, and the view that Marfan syndrome has adverse consequences on life. Sixty‐nine percent reported personal interest in prenatal testing for Marfan syndrome. Respondents most commonly cited increased worries about personal health and the recurrence risk as ways that Marfan syndrome affects their reproductive decisions. Age, striae, back pain, and low quality of life were each independently correlated with lack of sex drive. These results affirm the importance of both clinical and psychosocial issues on affected adults' reproductive decision‐making and sexual well‐being. Genetic professionals are ideally positioned to discuss concerns about quality of life and reproduction with patients with Marfan syndrome and refer those with significant concerns for further evaluation and management.
Haplotype analysis of a BRCA1: 185delAG mutation in a Chilean family supports its Ashkenazi origins
Authors: Ah Mew N , Hamel N , Galvez M , Al‐Saffar M , Foulkes WD
Published: March 2003

At least 25% of Ashkenazi Jewish families with two or more cases of premenopausal breast cancers are attributable to one of three founder mutations in BRCA1 or BRCA2. As these three founder mutations are common in the Ashkenazi Jewish population (∼ 2.5%) and can easily be tested for in a multiplex assay, establishing ethnicity can expedite genetic testing. It is not always possible, however, to conclusively establish ethnicity before offering testing. We report here the occurrence of a founder Ashkenazi Jewish BRCA1 mutation, 185delAG (also known as 187delAG), in a non‐Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. This case report not only illustrates the problem of the definition of ethnicity but also points to the possibility of further studies of the frequency of founder Ashkenazi Jewish mutations in populations not generally considered to be of Ashkenazi Jewish origin.