Trisomy 21 Down syndrome

Summary The lymphocyte chromosomes of trisomy 21 Down syndrome patients and their parents in a random series of 374 families were analyzed, the objective being the identification of parental mosaicism. The numbers of parents in whom at least two trisomy 21 cells were detected were seven mothers and three fathers, a frequency of 2.7% of families. Confirmation of mosaicism was by identification of parental transmission of the extra chromosome to the progeny, by repeat chromosome analysis, and/or by the presence of more than one affected child. If to these are added six others in whom only one trisomic cell was detected, but with no other supporting evidence, the frequency could be as high as 4.3%. Differences in parental age at the birth of Down syndrome progeny may be accounted for by differences in frequencies of mosaicism in germ cells and somatic tissue. Mosaicism was found more frequently in the mothers than in the fathers, but more data are required for confirmation of a real difference.     

Case-control study of congenital anomalies in children of cancer patients.

OBJECTIVES--To determine whether the offspring of cancer survivors are at an increased risk of congenital anomalies and whether cancer therapy before conception is associated with such an increase. DESIGN--Case-control study using computerised record linkage. SETTING--Ontario, Canada. SUBJECTS--Parents of children born during April 1979 to December 1986 who had a congenital anomaly diagnosed within the first year of life (45,200 mothers and 41,158 fathers) and a matched sample of parents whose children did not have a congenital anomaly (45,200 mothers and 41,158 fathers). MAIN OUTCOME MEASURES--Cancer diagnosed in either parent before conception and radiotherapy to the pelvis or abdomen or chemotherapy with an alkylating agent. RESULTS--Among the mothers, 54 cases and 52 controls were identified as having had cancer diagnosed in Ontario (relative risk = 1.04, 95% confidence interval 0.7 to 1.5) and among the fathers, 61 cases and 65 controls were identified (0.9, 0.7 to 1.4). No significant associations were found between congenital anomalies in the offspring and any type of cancer treatment in either the mothers or the fathers. CONCLUSIONS--The risk of congenital anomalies among liveborn offspring whose parents have had cancer or been treated for cancer is not higher than that in the general population.     

Grandmaternal age at birth of parents of children with trisomy 21

Summary The authors investigated the age of the parents and grandmothers of 262 children with simple trisomy 21. In cases in which the mother was under 30, the mean grandmaternal age was higher than that of the controls. This might mean that some of these cases, being the children of old mothers, began their lives as trisomic zygotes.The authors assume that not only maternal but also paternal mosaicism might be significant. They evaluate their results in light of genetic counseling and in consideration of practical conclusions that can be used in prenatal genetic diagnosis.     

Cytochemical and biochemical studies on neutrophil alkaline phosphatase in parents of trisomy 21 children

Summary A study of karyotypes and neutrophil alkaline phosphatase (NAP) was carried out for 66 parents (33 couples) of trisomy 21 children and for 60 control parents (30 couples). Enzyme activity was determined simultaneously by biochemical and cytochemical techniques. In the mothers of trisomy 21 children we found: (a) by biochemical techniques, a significant increase of NAP activity in polymorphonuclear leukocyte (PMN) homogenates (P<0.01) and a lower supernatant/pellet ratio (P<0.01); (b) by cytochemical techniques (with or without thermal and urea treatments) NAP activity was significantly higher (P<0.001) than in control mothers; in the fathers, the two techniques gave normal NAP activity results.     

Down's syndrome: chromosome analysis of 362 cases in Hungary.

A survey is given of the karyotypes observed in 362 children clinically diagnosed as cases of Down's syndrome from whom material was sent to 8 collaborating cytogenic laboratories in Hungary during the period 1965-1974. The sample studied cytogenetically constitutes about 20% of all children born in Hungary in this decade with Down's syndrome. The ways in which patients were selected for cytogenetic examinations could not be specified. In the sample, standard trisomy 21 was found in 91.7%, translocations in 3.9% and mosaicism in 4.4%. The mean age of the mothers of the children investigated was 29.05 years, a relatively low figure which may be explained by the decrease of the mean maternal age over the last decades.     

Chromosomal mosaicism in amniotic fluid cell cultures.

Over the past 6 years, using in situ processing methods, we have identified 32 cases of mosaicism in amniotic fluid cell cultures prepared from 1,100 samples. Two of these (45,X/46,XX and 46,XX/47,XX, + 21) were called true mosaics because multiple colonies demonstrated the same abnormal chromosome complement, and on subsequent evaluation of the newborn blood or fetal tissues, mosaicism was confirmed. Of the remaining cases, 29 were designated as pseudomosaics because only single or partial colonies exhibited an aberrant chromosome complement, 12 having a trisomy 2 line. In the final case, a double trisomy was demonstrated in only one of eight colonies in the first culture, but in the culture from a repeat sample an additional two colonies showed the same double trisomy. Since no abnormal cells were observed in infant blood, it was postulated that the mosaicism may only have been present in the extraembryonic tissues. It is our conviction that the use of these cloning methods should diminish the danger of misdiagnosis in genetic amniocentesis.     

Increased methotrexate-induced chromosome breakage in patients with free trisomy 21 and their parents

Summary Increased susceptibility of chromosomes from peripheral blood lymphocytes to the antimetabolite methotrexate (2×10^-6 M) has been found in patients with free trisomy 21 and their parents (N=14). The level of induced chromatid and chromosome breaks is lowest in normal controls intermediate in patients' mothers and fathers, and highest in trisomy 21 patients. The findings are viewed as a special type of cytogenetic polymorphism or as a defective chromosomal infrastructure, also in the parents of trisomic children.Dedicated to Professor Dr. H.A. Freye, Halle/Saale, in honor of his 65th birthday     

Karyological characteristics of Down's syndrome: clinical and theoretical aspects

These data have been collected from St. Petersburg Down Syndrome Register that comprises information on 1778 liveborn children with the Down syndrome, including three twin sets, ascertained within 1970-1996. Karyotypes were obtained in 1223 cases, of which 1119 (90.7%) displayed regular trisomy. Mosaicism was found in 44 cases (3.6%), including 21 males and 24 females, and among these one familial case of mosaicism in a daughter and in a healthy mother. Of 70 cases of translocations, 41(5.7%) were Robertsonian D ones. 21 (17 inherited, 16 de novo and 8 of unknown origin), 28 translocations of isochromosomes 21q; 21q (1 inherited translocation 21; 22, 22 de novo and 5 of unknown origin). One child received the anomaly from his 46XX/45XX, t(D;G) mother-carrier. In 6 cases, free trisomy 21 was associated with structural or numerical anomalies: 46XY,t(13;14)mat + 21 in twins, 47XY,t(C;C) + 21, 47XY,t(10;15)pat + 21, 47XY,inv(19)mat + 21, 47XX + 21/48XX + 21 + ring, 48XXX + 21. In 12 families parental mosaicism was shown or suspected. In 6 families one parent had chromosome anomaly, in three cases it was not inherited: t(15;22) and t(6;21) in mothers and an additional small marker in a father. In cases confirmed cytogenetically an increased sex ratio was shown (679 males and 551 females, SR = 1.23), but it was not shown in patients not tested cytogenetically (264 males and 275 females, SR = 0.96, different from the expected 297 males and 242 females, P < 0.01).     

Parental trisomy 21 mosaicism.

A family with three children with trisomy 21 in which the mother is a phenotypically normal, trisomy 21/normal mosaic was studied. Chromosome 21 fluorescent heteromorphisms were used to document that two of the three number 21's in two of the Down syndrome offspring were of maternal origin. Five cytogenetic surveys in which both parents of a child with trisomy 21 were studied have been reviewed. From these data, it is estimated that 3% of couples producing a child with trisomy 21 can be explained by parental mosaicism. From 17 informative sibships, with one parent mosaic, the segregation ratio was estimated to be 0.43 +/- 0.11.     

Multiple recurrence of trisomy 21 Down syndrome

Summary A young family with four chromosomally documented cases of trisomy 21, at least two, further cases of Down syndrome diagnosed only clinically, and no healthy children among their offspring is reported. No sign of mosaicism was found in studies of lymphocytes and skin fibroblasts from the parents. In a biopsy from the mother's ovary a trisomic cell line was found, thus giving some, but not a complete explanation for this extraordinary family. Additional explanations are suggested.     

Parent-offspring resemblance of palmar and plantar dermatoglyphic patterns in Down syndrome

With the aim of investigating the influence of trisomy 21 on the expression of heritable morphological features, we recorded the palmar and plantar dermatoglyphic patterns in 48 children with Down syndrome (DS), in both their parents, and, as a control, in 57 of their siblings. Using the Kendall tau rank correlation test, a considerable parental influence on the frequency of true patterns in the interdigital areas (IDA) III and IV of the palms (P = 0.3%) and soles (P = 1.0% and 3.8%, respectively) is demonstrated for the control siblings. In the children with DS, this influence is discernible as well, although with no statistical significance. A greater number of families may be required to settle the question.     

Sociodemographic and motivational characteristics of parents who volunteer their children for clinical research: a controlled study.

OBJECTIVE--To determine the sociodemographic and motivational characteristics of parents who volunteer their children for clinical research. DESIGN--A questionnaire was administered to parents who volunteered their children for a randomised, double blind, placebo controlled trial of a drug to treat asthma and to a control group of parents whose children were eligible for the trial but had refused the invitation. SETTING--A children''s hospital in Australia. SUBJECTS--68 Parents who had volunteered their children and 42 who had not; a response rate of 94% and 70%, respectively. MAIN OUTCOME MEASURES--Responses of parents to questionnaire designed to assess their perceptions, attitudes, and health seeking behaviour as well as sociodemographic data. RESULTS--Volunteering parents were less well educated with only 15% (10/68) of mothers and 16% (11/68) and of fathers having had a tertiary or university education compared with 26% (11/42) of mothers and 45% (19/42) in the non-volunteering group. Fewer volunteering parents had professional or administrative jobs than did non-volunteering parents (mothers 6% (4/68); fathers 9% (6/68) v mothers 14% (6/42); fathers 31% (13/42)). Volunteering parents had less social support, and they displayed greater health seeking behaviour and consumed more habit forming substances. They were motivated by a desire to help others and to contribute to medical research, but they were also searching for more information and better ways to help their own children. CONCLUSION--Parents who volunteer their children for medical research are significantly more socially disadvantaged and emotionally vulnerable.     

Correlations between individual and familial variables in Turner's syndrome]

In 20 cases of Turner's syndrome (10 with complete X monosomy, 10 with partial X monosomy or mosaicism) aged 3.47 to 15.5 years, the stature of the individual cases and their parents were evaluated. A significant frequency of short stature in mothers (25% below--2.0 S.D.S) has been observed, with a significant difference compared to the mean female stature of the general population. No significant difference has been observed on the stature of fathers. There was a closer correlation with mother's height (r = 0.65, p = 0.001) than with father's height (p = 0.07).     

Associations between parental and child overweight and obesity

Results of the analysis showed that parents and children overweight/obesity were significantly correlated. The sample includes 318 pairs of mothers and children, and 336 pairs of fathers and children at the age 11.3 +/- 0.4 years in Trogir, Croatia. Child overweight and obesity were defined according to body mass index (BMI) 25 and 30 equivalents (kg/m2). The prevalence of total overweight in girls was 25.6% and among boys was 20.5%. Mother's weight (p = 0.003) and BMI (p = 0.006) were greater in obese than in other groups of children. Overweight/obese children were more often found among overweight/obese mothers (p = 0.009) and fathers (p = 0.039). Correlation between overweight/obese children and their father (odds ratio 3.2, 95% CI 1.5-6.8) was stronger than between overweight/obese children and their mothers (odds ratio 2.2, 95% CI 1.2-3.9). Associations with mothers' and daughters' overweight/obesity were stronger (p = 0.017) than mothers' and sons'(p = 0.12). Correlations between children's BMI and fathers' BMI (r = 0.265, p < 0.0001) and between children's BMI and mothers' BMI (r = 0.173, p = 0.002) were significant. Children whose parents are overweight/obese look for greater attention in future preventive programme.     

Detection of gonadal mosaicism in parents of offspring with down syndrome

A review of data of a standard clinical karyological analysis and study of QFQ chromosomal polymorphism in 151 families of children with Down syndrome is performed. A total of eight families with proved and predicted trisomy 21 gonadal mosaicism were identified; in all the cases the mothers were younger than 35 years of age. The prevalence of carriers of mosaicism in young families amounted to 6.5% (8/123). In a standard analysis, if the capabilities of the QFQ method had not been employed, this prevalence would have amounted to only 1%. A comparison of the results of a retrospective analysis of the data obtained by the QFQ method with the expected results of molecular testing of the same families leads to the conclusion that both methods should be used.     

MTHFR Gene variants C677T, A1298C and association with Down syndrome: A Case-control study from South India

BACKGROUND:

The 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and low folate levels are associated with inhibition of DNA methyltransferase and consequently DNA hypomethylation. The expanding spectrum of common conditions linked with MTHFR polymorphisms includes certain adverse birth outcome, pregnancy complications, cancers, adult cardiovascular diseases and psychiatric disorders, with several of these associations remaining still controversial. Trisomy 21 or Down syndrome (DS) is the most common genetic cause of mental retardation. It stems predominantly from the failure of chromosome 21 to segregate normally during meiosis. Despite substantial research, the molecular mechanisms underlying non-disjunction leading to trisomy 21 are poorly understood.

MATERIALS AND METHODS:

Two common variants C677T and A1298C of the MTHFR gene were screened in 36 parents with DS children and 60 healthy couples from Tamil Nadu and Karnataka. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products and confirmed by sequencing.

RESULTS:

The CT genotype was seen in three each (8.3%) of case mothers and fathers. One case father showed TT genotype. All the control individuals exhibited the wild type CC genotype. A similar frequency for the uncommon allele C of the second polymorphism was recorded in case mothers (0.35) and fathers (0.37) in comparison with the control mothers (0.39) and fathers (0.37).

CONCLUSION:

This first report on MTHFR C677T and A1298C polymorphisms in trisomy 21 parents from south Indian population revealed that MTHFR 677CT polymorphism was associated with a risk for Down syndrome.     

Paternal age and Down's syndrome data from prenatal diagnoses (DFG)

Summary From prenatal diagnosis data obtained on mothers aged 35 years and above in the Federal Republic of Germany (DFG data), older fathers are demonstrated to have an increased risk of having trisomy 21 offspring. For paternal ages of 41 years upward, the age effect is quite strong. The risk for a fetus to have any de novo chromosomal aberration increases more with advancing paternal age for older mothers than for younger ones. Thus the ages of both parents have to be taken into account as an indication for prenatal diagnosis. Risk figures for trisomy 21 and for any de novo chromosomal aberration are given, together with preliminary recommendations for prenatal diagnosis for different combinations of parental ages.     

The frequency of fingerprint type in parents of children with Trisomy 21 in Japan

Analysis of the frequency data of each fingerprint type (arch, ulnar loop, radial loop, and whorl) of the parents of children with Trisomy 21 (Fathers: 71; Mothers: 128) born between 1965 and 1970 obtained from the Tokyo Medical and Dental University Hospital was carried out. Japanese controls were taken from dermatoglyphics data in Japan. We conducted the Friedman test on each type of fingerprint between Japanese controls and parents of Trisomy 21 children.Results from a statistical analysis based on the above data showed significant differences, more arches (p < 0.0001) and fewer whorls (p < 0.05) in mothers of children with Trisomy 21. Among fathers of Trisomy 21 children, a significant difference was found in there being fewer whorls (p < 0.05) and ulnar loops (p = 0.06). Considering the mothers' fingerprints, we suspected that females with a higher frequency of arches and a lower frequency of whorls had a stronger possibility of bearing Trisomy 21 babies. On the other hand, in fathers of Trisomy 21 children, we considered that there would be a possibility of significant differences if cases in the sample were increased.     

A family with three sibs carrying trisomy 21.

A family with three sibs, including a pair of dizygotic twins, all affected by Down's syndrome with regular trisomy 21, is described. The chromosome counts carried out on prolonged fibroblasts cultures of the mother, revealed the presence of the trisomy 21 in 6 out of 688 scored mitoses. The cytological findings give support to the hypothesis of a chromosome mosaicism in one of the normal parents, as a cause of the recurrence of the trisomy 21.     

Self-reported reading problems in parents of twins with reading difficulties.

Parents of 323 twin pairs with reading disability (RD) reported significantly more problems learning to read (16% of mothers and 33% of fathers) than parents of 309 twin pairs without reading difficulties (6% of mothers and 9% of fathers). These rates of self-reported reading problems in parents of twins are highly similar to those previously obtained in parents of non-twin children with RD and controls, suggesting that the etiology of reading deficits in twin and non-twin children may also be highly similar. Moreover, within both the RD and control samples, twins whose parents self-reported a positive history of reading problems had lower reading performance test scores, on average, than those whose parents reported no reading problems. Therefore, results of the present twin study support those of previous studies with non-twin children in which parental self-reports have been found to provide a valid index of family history status for reading difficulties.