Maternal age in Down syndrome

A patient with partial trisomy 9 (47,XX,+9pter→q22.1) had bilateral cleft lip and cleft palate, enophthalmos, severe micrognathia, small, apparently low-set ears, and dislocatable knees. The phenotypic findings are compared with those of other documented cases of total trisomy 9.     

Olfactory impairment increases as a function of age in persons with Down syndrome.

Neuropathology similar to that found in the brains of patients with Alzheimer's disease (AD) has consistently been observed in older individuals with Down syndrome (DS) and this neuropathology is particularly prevalent in areas involved in olfaction. The present study investigated the effects of age on the expression of olfactory impairment in Down syndrome to address the hypothesis that older adults with DS show greater deficits in olfactory function compared with younger persons with DS and compared with age and IQ matched control groups. Between group differences showed that persons with DS had significant deficits in olfactory functioning compared to the two control groups. Further, within the DS group, older adults performed more poorly than the young adults or children. Results support the hypothesis that in a group of persons at risk for AD because of DS, olfactory impairment is greater in older individuals, suggesting progressive impairment over time. Deficits in olfactory function may be useful in signalling incipient dementia in DS.     

Down syndrome and maternal age in South Glamorgan

Seventy cases of Down syndrome have been ascertained in South Glamorgan during the period 1968 to 1976. This gives an overall incidence of 1 in 658 live births. Analysis of the data on the basis of single years of maternal age gives an incidence of 1 in 200 by 36 years, 1 in 100 by 40 years, and 1 in 50 by 44 years. All incidence figures are for live births at age of delivery.     

AFP and age screening for Down syndrome

The availability of maternal serum alpha-fetoprotein (AFP) values from neural tube defect screening programmes offers the opportunity to improve the effectiveness of screening for Down syndrome. By appropriately combining information on maternal serum AFP and maternal age fewer women would need an amniocentesis to detect a given number of Down syndrome pregnancies or, for a given number of women having amniocentesis, more cases of Down syndrome would be detected than if age alone were used. For example to detect 40% of pregnancies with Down syndrome using AFP and age, 7% of women would need an amniocentesis compared with 11% using age alone. If an amniocentesis and a chromosome analysis together cost $1,000 this is equivalent to a saving of $37,000 per 1000 women screened. The use of AFP as well as age in Down syndrome screening allows patients to be better informed of their risk of having an affected pregnancy. For example, a 35-year-old woman has a risk of a Down syndrome term pregnancy of about 1:380, the risk is 1:120 if the AFP level is 0.40 multiples of the normal median (MoM) and 1:1800 if it is 2.50 MoM. Software providing computer assisted test interpretation has been produced to facilitate the estimation of risk and to identify women with positive screening results.     

Chromosome 7 abnormalities in acute megakaryoblastic leukemia associated with Down syndrome

Deletions of the 5′ ABL region adjacent to the t(9;22)(q34;q11) have recently been reported in 8–32.7% of patients with chronic myeloid leukemia (CML). The deletions were visualized with fluorescence in situ hybridization using, in the majority of the cases, the Vysis LSI BCR/ABL ES (extra signal) probe. In our series, 10 of 99 CML patients (10.1%) were characterized by a 5′ ABL deletion. We show that 3′ BCR losses are observed in nearly all the cases with 5′ ABL deletions. Moreover, the different genetic events (Philadelphia chromosome formation; 5′ ABL and 3′ BCR deletions) occur simultaneously in a one-step process without any evidence for genetic instability in the target bone marrow cells.     

Down syndrome, paternal age, maternal age and birth order

Recent cytogenetic evidence has shown that trisomy 21 can arise, perphaps even in substantial proportion, from paternal nondisjunction. The statistical association between Down syndrome incidence and maternal age, paternal age and birth order has been studied in a sample of over 4000 cases. The size of this sample made it possible to control for the effect of maternal age by single years of age during the search for a paternal age effect and vice versa, and the importance of such stringent control is emphasized. The maternal age association was confirmed with an extremely high degree of statistical significance while no independent effect of paternal age was found; indeed, the rates at paternal ages over 45 years appear to be nearly constant. After adjusting for the effects of parental age, a significant inverse association of birth order with incidence was noted. It also appears that the incidence among very young mothers may be high: for maternal ages 15 years and less the rates seem to be equivalent to those found at 30 or 35 years. In order to help answer the question of whether the maternal age association is the result of increasing rates of nondisjunction or of some other mechanism (for example, an age related defect in a spontaneous abortion screening mechanism), the proportion of cases due to maternal and paternal nondisjunction at different parental ages must be determined.     

Down syndrome associated with a retroperitoneal teratoma and Morgagni hernia

Down syndrome may be associated with many complications. Among the malignancies associated with Down syndrome, leukaemia is the most common. This is a case report of a patient with Down syndrome associated with both a retroperitoneal teratoma and a Morgagni hernia.     

The mortality of adults with Down syndrome as a function of age

This study sought to test the hypothesis that adults with Down Syndrome may age faster than the general population by comparing the rate of increase in their mortality with age with that of the general population by the method originally described by Gompertz. The differences were not statistically significant. There is a striking difference in morbidity, the Down's adults being highly vulnerable. Alzheimer populations do not lend themselves readily to this type of analysis.     

Paternal age as a risk factor for Down syndrome

Although the effect of maternal age as a risk factor for Down syndrome (DS) is well known, the role of paternal age in the cause of DS has not been clearly established. To investigate this phenomenon we conducted a case-control study between July 1989 and February 1990. The cases were 318 children and teenagers with DS studied at the Specialized Educational Institutions of Lima City, Perú. They were paired with 1,196 control individuals that were selected from the birth records of 2 general hospitals of the city. For each case we tried to obtain 4 controls, paired by their date of birth, sex, and maternal age. The means of paternal age in the 2 groups were compared, first globally and then by groups of maternal age (<21 years, 21–29 years, 30–34 years, 35–39 years and >39 years). None of the comparisons gave a statistically significant difference between the 2 groups, using either the Student t-test or the Mann-Whitney U-test. The results obtained in this study give no evidence that paternal age can be considered a risk factor for the conception of a child with DS. © 1993 Wiley-Liss, Inc.     

The incidence of Down syndrome in northern Finland with special reference to maternal age

The incidence of live-born children with Down syndrome was found to be 1.73/1000 (1:578) in northern Finland over the years 1965 to 1979. Despite a marked reduction in the proportion of older mothers, no significant change in the incidence was observed. Instead, an age-specific rise in the incidence for mothers aged 25 to 29 years could be shown during the last five-year period in years 1975 to 1979.     

Survival of children with Down syndrome in Italy.

A cohort of 917 Down syndrome (DS) children born in Italy between 1978 and 1984 was studied for survival through the age of 8 years. The highest mortality occurred in the first month of life (7.9%); survival was about 80% at 1 year, 78% at 2 years, and 76% at 5 years, with small decreases thereafter. At the univariate analysis, survival was lower for subjects with congenital heart disease (CHD), birth weight less than 2,500 g, parity of 3 or plus, maternal age greater than or equal to 35 years, and for those born in Southern Italy compared with Northern Italy. No differences in survival were observed by sex and by socioeconomic status. The Cox proportional hazard model was used to evaluate the effect of each variable adjusted for all the others present in the model. Presence of CHD (odds ratio = 3.27; 95% confidence interval (C.I.) 2.31-4.63), birth in the South (odds ratio = 2.69; 95% C.I. 1.91-3.79), and low birth weight (odds ratio = 1.87; 95% C.I. 1.29-2.72) were independently associated with survival. None of the other variables emerged as a statistically significant prognostic factor. Various hypotheses were considered to interpret the unexpected effect of place of birth on survival. Quality of medical care provided in the South of Italy is the most likely determinant of the high mortality observed among children with DS born in that area of Italy. Such differences in survival within the same country could occur in other developed nations as well.     

Maternal age and Down syndrome: age-specific incidence rates by single-year intervals.

Maternal age-specific risks of giving birth to a child with the Down syndrome (DS) are given by single-year age intervals. Such data are of value for more precise genetic counseling and in cost-benefit analyses of prenatal diagnosis programs. The data were obtained by linking records of children with DS at the British Columbia Health Surveillance Registry ( BCHSR ) to the appropriate birth registrations to derive maternal ages. The data related to 519 affected children out of a total of 354,880 live births in British Columbia between 1961 and 1970. The results, which are based on a high level of ascertainment, are compared to those reported in the only other published study relating to risks by single-year maternal age groupings, where completeness of ascertainment was estimated to be only 38%.     

Parental age and unbalanced Robertsonian translocations associated with Down syndrome and Patau syndrome: comparison with maternal and paternal age effects for 47, + 21 and 47, + 13

Data are analysed on livebirths with trisomic syndromes associated with unbalanced Robertsonian translocations born from 1968 to 1981 and reported to the New York State Chromosome Registry. The maternal ages of reported cases were compared with those of the livebirths in the general population who were born in the same year. The number of translocations studied, the mean case-control differences in years in maternal age (and the standard errors of the mean) were respectively, as follows: D/21 mutants, n= 36. – 0·1 (±0·9); G/21 mutants, n= 46, + 1·5 (±0·8); D/13 mutants, n= 16, + 0·6 (± 1·5); D/21 inherited, n= 12, – 1·0 (± 1·4); G/21 inherited, n= 3, – 0·3 (± 4·4); and D/13 inherited, n= 6, + 2·1 (± 2·4). There was little change in any category if the few cases diagnosed prenatally were included. Only the value for the G/21 mutants is significantly different from zero at the 0·05 level. (The results on G/21 mutants in maternal age are consistent with an earlier Japanese report of an increase of about 2 years over the control values.) The distribution of maternal ages suggests that G/21 mutants may be produced both by maternal age-independent, and maternal age-dependent components. The data on D/21 mutants, however, do not indicate the negative association with maternal age reported in Japan. Differences between this study and the Japanese study in analyses of controls may explain this slight variation. But in any event both studies reveal no evidence for an increase in maternal age for unbalanced D/21 mutant or D/21 inherited translocations associated with Down syndrome. This is evidence against the hypothesis that relaxed selection during gestation, after recognition of pregnancy, accounts for the maternal age effects of 47, + 21. In comparison with the results on Robertsonian translocations, the case-control differences in maternal age in years (and the standard errors of the mean) for 47. + 21 for 2148 livebirths was + 4·6 (± 0·2), and for 2354 cases including those diagnosed prenatally was + 5·3 (± 0·2). The most likely value for an estimated total of 2292 cases of 47, + 21 livebirths that would have been reported in the absence of prenatal diagnosis was + 5·1 (± 0·2). For 47, + 13, for 98 livebirths the mean case-control difference in maternal age in years was + 1·5 (± 0·7) and for 116 cases including those diagnosed prenatally was + 3·2 (± 0·7). The most likely value for an estimated 108 cases of 47, + 13 in the absence of prenatal diagnosis was + 1·7 (± 0·6). The data on 47, + 13 livebirths confirm suggestive trends from earlier studies at prenatal diagnosis that the maternal age association of this trisomy is weaker than for 47, + 21 or 47, + 18. With regard to paternal age effects, there was no evidence for case-control differences in paternal age (after controlling on maternal age as well as year of birth) for any category of defect analysed.     

Down syndrome in association with features of the androgen insensitivity syndrome.

Three cases of Down syndrome (DS) are reported in association with features of the androgen insensitivity syndrome (AIS). All were 47, XY, +21 and reared as females. One case had a normal female phenotype, and two cases showed minimal clitoromegaly and labial fusion. Minor genital underdevelopment has been reported as common in males with DS; however, AIS has not previously been associated with DS. Androgen binding studies in genital skin fibroblasts were normal in two cases and in the 46,XY brother of the third who has perineal hypospadias. Mutation screening of the androgen receptor (AR) gene by PCR-SSCP was normal in all cases. Normal androgen binding and the absence of an identified mutation in the coding region of the AR gene is very unusual in AIS, particularly in the complete form. This finding suggests the operation of hitherto unrecognised genes on chromosome 21 with a role in androgen response and sex differentiation.     

Influence of advanced age of maternal grandmothers on Down syndrome

Background  

Down syndrome (DS) is the most common chromosomal anomaly associated with mental retardation. This is due to the occurrence of free trisomy 21 (92–95%), mosaic trisomy 21 (2–4%) and translocation (3–4%). Advanced maternal age is a well documented risk factor for maternal meiotic nondisjunction. In India three children with DS are born every hour and more DS children are given birth to by young age mothers than by advanced age mothers. Therefore, detailed analysis of the families with DS is needed to find out other possible causative factors for nondisjunction.