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Department of Pediatrics, West China
Second Hospital, Sichuan University, Chengdu 610041, China.
OBJECTIVE: Using molecular techniques,
we typed 2 short tandem repeat (STR) loci on 21 chromosome
to establish the method for rapid and accurate diagnosis
of trisomy 21. METHODS: Genomic DNA samples from 50 individuals
diagnosed previously by karyotype as trisomy 21 and 40 children
with severe mental retardation (IQ < 50) suspected of
trisomy 21 were analyzed for 2 short tandem repeat loci
on 21 chromosome, D21S1435 and D21S2055. Typing was carried
out after polymerase chain reaction (PCR) and silver staining.
The trisomy was identified by the number of alleles: 3 alleles
bands whose density is same, two alleles bands with one
obvious higher density compared to the other and one allele
band whose density is three times than the normal control.
RESULTS: All of the complete trisomy 21 were detected by
this method; the parental source was easily determined.
CONCLUSION: This method for diagnosing trisomy 21 is rapid
and accurate.
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Office of Genetics and Disease Prevention,
Centers for Disease Control and Prevention, Atlanta, Georgia,
USA.
OBJECTIVE: To investigate the impact
of early diagnosis on pulmonary function in a large cohort
of children with cystic fibrosis (CF). STUDY DESIGN: CF
cases identified from the CF Foundation National Patient
Registry and diagnosed between 1982 and 1990 were categorized
as: early asymptomatic diagnosis (EAD; n = 157), early symptomatic
diagnosis (ESD; n = 227), later asymptomatic diagnosis (LAD;
n = 161), and later symptomatic diagnosis (LSD; n = 3080).
Early CF diagnosis was diagnosis before 6 weeks of age;
later diagnosis was diagnosis at 6 weeks to 36 months of
age, inclusive. Asymptomatic diagnosis included diagnosis
by either family history, genotype, prenatally, or neonatally.
Pulmonary function was measured as percentage of predicted
forced expiratory volume in one second (FEV(1)). RESULTS:
There were no overall differences in pulmonary function
among the 4 diagnostic groups. However, EAD cases born more
recently (1987 or later) had a higher mean FEV(1) throughout
the study, compared with the remaining diagnostic groups.
For this later birth cohort, Cox regression analysis for
those diagnosed later and/or symptomatically, demonstrated
a 2-fold increase in risk (P =.06) for having moderate-to-severe
pulmonary function (FEV(1) <70%) at ages 6 to 10 years,
compared with EAD cases. CONCLUSIONS: Children diagnosed
with CF early, asymptomatically and more recently may have
better pulmonary function throughout early childhood, probably
as a result of improved CF treatments in recent years.
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First Affiliated Hospital, Soochow
University, Jiangsu Institute of Hematology, Suzhou 215006,
China.
OBJECTIVE: To evaluate the four techniques
for clonal analysis in the early diagnosis of myelodysplastic
syndromes (MDS). METHODS: Four techniques for clonal analysis
were performed in bone marrow samples from fifty patients
with suspected MDS: (1) Conventional cytogenetics (CC) for
clonal chromosomal abnormalities; (2) BrdU-sister chromatid
differentiation (BrdU-SCD) for cell cycle analysis; (3)
Fluorescence in situ hybridization (FISH) for trisomy 8;
(4) PCR-SSCP for N-ras mutation. RESULTS: The diagnosis
of forty-five patients was compatible with FAB criteria
of MDS, the other five patients didn't fully meet the FAB
criteria. They had either only one lineage dyspoiesis or
no any obvious dysplastic features and two of them were
diagnosed as suspicious refractory anemia (RA), one as anemia
with hypercellular bone marrow and two as chronic aplastic
anemia. The results of the four techniques performed in
them showed that four patients had clonal karyotype abnormalities,
two had prolonged cell cycle, three had trisomy 8 of different
proportions, and one had N-ras mutation. Thus, they were
all diagnosed as RA. CONCLUSION: The untypical MDS patients
can be diagnosed early by examination with combining several
clonal analysis techniques.
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Department of Diagnostics and Rontgenology,
University of Pretoria, PO Box 1266, Pretoria 0001.
Gardner's syndrome (familial polyposis
coli) is a genetic condition characterised by colonic polyps
that carry a 100% risk of malignancy if untreated. Early
diagnosis, in which an astute and knowledgeable dentist
can play an essential role, is therefore of paramount importance.
The presence of multiple unerupted teeth provides the dentist
with a major pointer to the possible presence of this disease,
which may be provisionally diagnosed on the detection of
two other obvious features, namely osteomas and cutaneous
lesions. This fact is clearly illustrated by the accompanying
case report. Extracolonic manifestations increase the morbidity
and make treatment more difficult. The presence of large
desmoid tumours may be a serious complicating factor. Gardner's
syndrome may be accompanied by adenomas of the stomach and
duodenum and very rarely by malignant tumours of the central
nervous system. Regular surveillance by means of colonoscopies
must be carried out on all individuals suspected of having
the disease in order to implement timeous life-saving prophylaxis.
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University of Wisconsin Medical School,
Madison, Wisconsin, USA.
OBJECTIVE: Despite its relative frequency
among autosomal recessive diseases and the availability
of the sweat test, cystic fibrosis (CF) has been difficult
to diagnose in early childhood, and delays can lead to severe
malnutrition, lung disease, or even death. The Wisconsin
CF Neonatal Screening Project was designed as a randomized
clinical trial to assess the benefits and risks of early
diagnosis through screening. In addition, the incidence
of CF was determined, and the validity of our randomization
method assessed by comparing 16 demographic variables. METHODOLOGY:
Immunoreactive trypsinogen analysis was applied to dried
newborn blood specimens for recognition of CF risk from
1985 to 1991 and was coupled to DNA-based detection of the
DeltaF508 mutation from 1991 to 1994. Randomization of 650
341 newborns occurred when their blood specimens reached
the Wisconsin screening laboratory. This created 2 groups-an
early diagnosis, screened cohort and a standard diagnosis
or control group. To avoid selection bias, we devised a
unique unblinding method with a surveillance program to
completely identify the control subjects. Because sequential
analysis of nutritional outcome measures revealed significantly
better growth in screened patients during 1996, we accelerated
the unblinding and completely identified the control group
by April 1998. Having each member of this cohort enrolled
and evaluated for at least 1 year and having completed a
comprehensive surveillance program, we performed another
statistical analysis of anthropometric evaluated indices
that includes all CF patients without meconium ileus. RESULTS:
The incidence of classical CF, ie, patients diagnosed in
this trial with a sweat chloride of 60 mEq/L greater, was
1:4189. By incorporating other CF patients born during the
randomization period, including 2 autopsy diagnosed patients
and 8 probable patients, we calculate a maximum incidence
of 1:3938 (95% confidence interval: 3402-4611). Although
there were group differences in the proportion of patients
with DeltaF508 genotypes and with pancreatic insufficiency,
validity of the randomization plan was demonstrated by analyzing
16 demographic variables and finding no significant difference
after adjustment for multiple comparisons. Focusing on patients
without meconium ileus, we found a marked difference in
the mean +/- standard deviation age of diagnosis for screened
patients (13 +/- 37 weeks), compared with the standard diagnosis
group (100 +/- 117). Anthropometric indices of nutritional
status were significantly higher at diagnosis in the screened
group, including length/height, weight, and head circumference.
During 13 years of study, despite similar nutritional therapy
and the inherently better pancreatic status of the control
group, analysis of nutritional outcomes revealed significantly
greater growth associated with early diagnosis. Most impressively,
the screened group had a much lower proportion of patients
with weight and height data below the 10th percentile throughout
childhood. CONCLUSIONS: Although the screened group had
a higher proportion of patients with pancreatic insufficiency,
their growth indices were significantly better than those
of the control group during the 13-year follow-up evaluation
and, therefore, this randomized clinical trial of early
CF diagnosis must be interpreted as unequivocally positive.
Our conclusions did not change when the height and weight
data before 4 years of age for the controls detected by
unblinding were included in the analysis. Also, comparison
of growth outcomes after 4 years of age in all subjects
showed persistence of the significant differences. Therefore,
selection bias has been eliminated as a potential explanation.
In addition, the results show that severe malnutrition persists
after delayed diagnosis of CF and that catch-up may not
be possible. We conclude that early diagnosis of CF through
neonatal screening combined with aggressive nutritional
therapy can result.
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Department of Neurology, Umea University
Hospital, Sweden.
The frequency of familial amyotrophic
lateral sclerosis (ALS) is usually reported as 5-10% of
all ALS cases. This figure is probably an underestimate,
primarily due to inadequate recording of family history
in the patients' charts, and to the not infrequent occurrence
of reduced disease penetrance in pedigrees with familial
ALS. The true familial ALS frequency may be at least double
this. Familial ALS is heterogenetic. The only known ALS-causing
gene is the CuZn-superoxide dismutase gene (CuZn-SOD). Mutations
in this gene account for a fifth of all familial ALS cases
and a few percent of apparent sporadic ALS cases. Genetic
testing for CuZn-SOD mutations can help confirm a diagnosis
of ALS, especially in cases with atypical features that
have been reported in some cases with CuZn-SOD mutations.
Genetic testing should only be performed after thorough
clinical examination and in cases with a proven or uncertain
family history of ALS. It is not warranted in cases with
no proven family history for three generations, unless the
patient shows the characteristic phenotype associated with
recessive inheritance of the D90A CuZn-SOD mutation.
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Department of Cytogenetics, St Mary's
Hospital, Paddington, London, U.K.
Ten-ml samples of amniotic fluid
were taken from pregnancies being terminated at 8-14 weeks'
gestation. DNA was extracted from the amniotic cells by
sequential centrifugation and analysed using the polymerase
chain reaction (PCR). Fifteen samples were analysed for
evidence of maternal contamination using Mfd5 oligonucleotide
primers for repeat polymorphisms. Ten amniotic fluid samples
were tested for the Delta-F508 deletion characteristic of
cystic fibrosis to demonstrate a diagnostic application
for the technique. In each case, DNA extracted from fetal
tissue from the same pregnancy was included in the controls.
In 14 of the 15 cases tested with the Mfd5 primers, both
the amniotic fluid DNA and the fetal DNA showed no evidence
of contaminating DNA. In one case, neither the amniotic
fluid cells nor the fetal cells yielded results. In nine
of the ten cases tested with the Delta-F508 primers, the
amniotic fluid cell DNA provided accurate information about
the genetic status of the fetus; in the tenth, the fetal
DNA failed to amplify. The results indicate that adequate
DNA can be extracted from amniotic fluid from 8 weeks' gestation
onward and these samples are suitable for prenatal diagnosis
using PCR.
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Department of Obstetrics and Gynecology,
Hutzel Hospital/Wayne State University, Detroit, MI 48201.
At centers where chorionic villus
sampling (CVS) programs are operational, first-trimester
prenatal diagnosis has been shown to have many advantages,
both medical and psychologic. However, most medical centers
do not have CVS capability, nor are all patients candidates
for CVS. We investigated the feasibility of performing very
early genetic amniocentesis (9-13 weeks' gestational age).
The results from those amniocenteses were compared to our
own CVS data. In experienced hands, (1) CVS can be performed
safely at 8-13 weeks, with the most technical ease at 9-11
weeks; (2) CVS or amniocentesis can be performed on many
patients at 12-13 weeks or perhaps even earlier, although
no accurate loss rates are available yet; (3) when technically
feasible, CVS may be advantageous because of the much faster
time period for cytogenetic results from direct preparation
or short-term culture; and (4) in those patients on whom
CVS cannot be performed, early amniocentesis in selected
patients may offer the benefits of early diagnosis.
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