Advanced Parental Age Research Articles

Does late childbearing increase the risk for behavioural problems in children? A longitudinal cohort study.

This study aimed to examine the relationship between advanced parental age and behavioural outcomes in offspring in a longitudinal cohort of children in Western Australia. The Western Australian Pregnancy Cohort (Raine) is a prospective study of 2900 pregnancies. Offspring were followed up at ages 2, 5, 8, 10, 14, and 17 years, and 1754 adolescents were available for follow-up at 17 years. The Child Behaviour Checklist was used to measure child behaviour, including internalising (e.g. anxious/withdrawn) and externalising (e.g. aggressive/destructive) behaviours. There was a significant linear relationship between maternal age and total internalising and externalising behaviour outcomes, but not paternal age. Increasing maternal age was associated with decreasing risk for problem behaviours in offspring. In the categorical models, young maternal age (20-24 years) was associated with significantly increased risk for problem behaviours in offspring relative to offspring of parents in the reference group (25-29 years), and a paternal age of 35-39 years was associated with decreased risk for total behaviour morbidity in offspring. This study showed no evidence that late fatherhood is associated with adverse behavioural outcomes in offspring. Increasing maternal age was found to be a protective factor for child behaviour morbidity.

Abstract 2165: Parents' ages at birth and risk of hormone-related cancer among women in the California Teachers Study

Abstract Childbearing age has increased in Western countries over the last several decades. The immediate effects of advanced parental age on the health of offspring have been extensively studied. However, few studies have examined the effect of parental age at birth on the risk of adult-onset cancer. We explored the association between parental age at birth and the risk of adult-onset hormone-related cancers (i.e., breast cancer, ovarian cancer and endometrial cancer) in the prospective California Teachers Study cohort of 133,479 female teachers and administrators. Between 1995 and 2010, 5359 women were diagnosed with breast cancer, 515 women were diagnosed with ovarian cancer, and 1110 women were diagnosed with endometrial cancer. Multivariate adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated by fitting Cox proportional hazards models. After mutual adjustment for paternal age/maternal age at birth, no association was observed for maternal age at birth for any of the three types of cancer. However, compared to those born to a father whose age at his daughter's birth was 25-29 years, women born to a father under age 20 years had 35% greater risk of breast cancer (RR=1.35, 95% CI=1.03-1.76) and more than 2 times greater risk of ovarian cancer (RR=2.26, 95% CI=1.14-4.50); women born to a father whose age at childbirth was 30-34 years had 25% greater risk of endometrial cancer (RR=1.25, 95% CI=1.05-1.48) than women whose father was 25-29 years. In an interaction model, relative to daughters born to a mother younger than 25 year and a father between 25-29 years, relative risk was elevated for those born to a mother younger than 25 and a father younger than 20 years (RR=1.37, 95% CI=1.07-1.76), or to a father older than 34 years old regardless of mother's age (mother <25 or ≥25 years old; RR=1.31 and 1.12 respectively). Lower ovarian cancer risk was observed among women born to a mother ≥25 years and a father between 25-29 years (RR=0.66, 95% CI=0.48-0.90); no association was observed for endometrial cancer. These findings indicate that parental age at birth, especially paternal age at birth, may affect the adult-onset cancer risk of daughters, especially breast cancer. Citation Format: Yani Lu, Jianning Luo, Sophia Wang, Huiyan Ma, Jane Sullivan-Halley, Peggy Reynolds, Leslie Bernstein. Parents' ages at birth and risk of hormone-related cancer among women in the California Teachers Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2165. doi:10.1158/1538-7445.AM2014-2165

Do First Generation Immigrant Adolescents Face Higher Rates of Bullying, Violence and Suicidal Behaviours Than Do Third Generation and Native Born?

We conducted a systematic review to examine first generation immigrant adolescents’ likelihood of experiencing bullying, violence, and suicidal behaviours compared to their later-generation and native born counterparts, and to identify factors that may underlie these risks. Eighteen studies met full inclusion criteria. First generation immigrant adolescents experience higher rate of bullying and peer aggression compared to third generation and native counterparts. Refugee status and advanced parental age were associated with increased parent to child aggression among South East Asians. Family cohesion was associated with lower rates of violence. Suicidal ideation was lower across most immigrant adolescents’ ethnicities, with the exception of Turkish and South Asian Surinamese female adolescents in the Netherlands. Bullying and peer aggression of immigrant children and adolescents and potential mitigating factors such as family cohesion warrant research and program attention by policymakers, teachers and parents.

Young maternal age and old paternal age induce similar risk of mental disorders in offspring

There is robust evidence of an increased risk for autism, schizophrenia and learning disabilities in children born to older fathers, and an increased risk for Down's syndrome in children born...

Multi-factorial influences on sex ratio: a spatio-temporal investigation of endocrine disruptor pollution and neighborhood stress.

Background:It is suggested the declining male birth proportion in some industrialized countries is linked to ubiquitous endocrine disruptor exposure. Stress and advanced parental age are determinants which frequently present positive findings. Multi-factorial influences on population sex ratio are rarely explored or tested in research.Objectives:To test the hypothesis that dual factors of pollution and population stress affects sex proportion at birth through geographical analysis of Central Scotland.Methods:The study incorporates the use of Geographical Information Systems (GIS) tools to overlay modeled point source endocrine disruptor air emissions with “small-area” data on multiple deprivation (a proxy measurement of stress) and birth sex. Historical review of regional sex ratio trends presents additional data on sex ratio in Scotland to consider.Results:There was no overall concentration in Central Scotland of low sex ratio neighborhoods with areas where endocrine disruptor air pollution and deprivation or economic stress were high. Historical regional trends in Scotland (from 1973), however, do show significantly lower sex ratio values for populations where industrial air pollution is highest (i.e. Eastern Central Scotland).Conclusions:Use of small area data sets and pollution inventories is a potential new method of inquiry for reproductive environmental and health protection monitoring and has produced interesting findings.

The association between advanced maternal and paternal ages and increased adult mortality is explained by early parental loss

The association between advanced maternal and paternal ages at birth and increased mortality among adult offspring is often attributed to parental reproductive aging, e.g., declining oocyte or sperm quality. Less attention has been paid to alternative mechanisms, including parental socio-demographic characteristics or the timing of parental death. Moreover, it is not known if the parental age-adult mortality association is mediated by socioeconomic attainment of the children, or if it varies over the lifecourse of the adult children. We used register-based data drawn from the Finnish 1950 census (sample size 89,737; mortality follow-up 1971–2008) and discrete-time survival regression with logit link to analyze these alternative mechanisms in the parental age–offspring mortality association when the children were aged 35–49 and 50–72. Consistent with prior literature, we found that adult children of older parents had increased mortality relative to adults whose parents were aged 25–29 at the time of birth. For example, maternal and paternal ages 40–49 were associated with mortality odds ratios (ORs) of 1.31 (p < .001) and 1.22 (p < .01), respectively, for offspring mortality at ages 35–49. At ages 50–72 advanced parental age also predicted higher mortality, though not as strongly. Adjustment for parental socio-demographic characteristics (education, occupation, family size, household crowding, language) weakened the associations only slightly. Adjustment for parental survival, measured by whether the parents were alive when the child reached age 35, reduced the advanced parental age coefficients substantially and to statistically insignificant levels. These results indicate that the mechanism behind the advanced parental age–adult offspring mortality association is mainly social, reflecting early parental loss and parental characteristics, rather than physiological mechanisms reflecting reproductive aging.

Expanding upon the ‘extreme male brain’ theory of autism as a common link between other major risk factors: A hypothesis

On average, males have a stronger preference for physical systems and machines over interpersonal interactions; they have lower average levels of cognitive empathy or social cognition than females; and they have higher rates of ‘extreme’ intelligence when it comes to abstract concepts such as those found in mathematics and sciences. All three traits are also commonly associated with individuals with an autism spectrum disorder or ASD; clearly, it is not coincidental that incidence rates of autism are reportedly four times higher in males than in females.The common link between the majority of risk factors assessed in this review (including technological advancements, advanced parental age, socioeconomic status, and genetic predispositions towards ASDs in families of scientists and engineers) can be traced to a specific hormone, testosterone. It was established that traits which are typically associated with males are also typically associated with ASDs as well as individuals with antisocial personality disorder, or APD. The key distinction between individuals who are considered to be ‘autistic’ as opposed to those who are considered ‘sociopathic’ lies in the difference between their empathy deficits: whereas those who are ‘autistic’ are said to lack cognitive empathy (the ability to identify and understand the thoughts and feelings of others and to respond to these with appropriate emotions), those who are ‘sociopathic’ are said to lack emotional empathy (which is responsible for inhibiting acts of physical aggression or violence). This would explain why autistic individuals can have elevated testosterone levels without becoming physically aggressive.

EMAS position statement: Late parenthood

IntroductionDuring the last decades, couples in Europe have been delaying parenthood, mainly due to socio-demographic factors that include increased rates of university education and employment in women and poorer financial status. AimsThe aim of this position statement is to provide and critically appraise evidence on the impact of late parenthood, focusing on the pathophysiology and management of male and female infertility, pregnancy complications and long-term offspring health. Materials and methodsLiterature review and consensus of expert opinion. Results and conclusionsAdvanced parental age is associated with infertility and pregnancy complications and may have an impact on long-term offspring health. All adults of reproductive age should receive counseling on the risks of advanced parental age, so they can make informed decisions about the timing of childbearing. All parents-to-be of advanced age should receive advice on the potential pregnancy, neonatal and long-term offspring health-related issues. These tasks require an interdisciplinary approach that could lead to patient-centered, informed decision-making strategies.

De novo dup p/del q or dup q/del p Rearranged Chromosomes: Review of 104 Cases of a Distinct Chromosomal Mutation

We compiled 104 constitutional de novo or sporadic rearranged chromosomes mimicking recombinants from a parental pericentric inversion in order to comment on their occurrence and parental derivation, meiotic or postzygotic origin, mean parental ages, and underlying pathways. Chromosomes involved were 1-9, 13-18, 20-22, and X (64 autosomes and 40 X chromosomes). In the whole series, mean paternal and maternal ages in cases of paternal (proved or possible; n = 29) or maternal (proved or possible; n = 36) descent were 31.14 and 28.31 years, respectively. Rearranged X chromosomes appeared to be of paternal descent and to arise through intrachromosomal non-allelic homologous recombination (NAHR), whereas rec-like autosomes were of either maternal or paternal origin and resulted from mechanisms proper of non-recurrent rearrangements. Except for some mosaic cases, most rearranged chromosomes apparently had a meiotic origin. Except for 8 rearranged X chromosomes transmitted maternally, all other cases compiled here were sporadic. Hence, the recurrence risk for sibs of propositi born to euploid parents is virtually zero, regardless of the imbalance's size. In brief, recombinant-like or rea chromosomes are not related to advanced parental age, may (chromosome X) or may not (autosomes) have a parent-of-origin bias, arise in meiosis or postzygotically, and appear to be mediated by NAHR, nonhomologous end joining, and telomere transposition. Because rearranged chromosomes 10, 11, and Y are also on record, albeit just in abstracts or listed in large series, we remark that all chromosomes can undergo this distinct rearrangement, even if it is still to be described for pairs 12 and 19.

Impact of Prenatal Risk Factors on Congenital Heart Disease in the Current Era

BackgroundThe healthcare burden related to congenital heart disease (CHD) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort.Methods and ResultsCHD patients <18 years old (n=2339) and controls without structural heart disease (n=199) were prospectively enrolled in an Ontario province‐wide biobank registry from 2008–2011. Family history, frequency of extra‐cardiac anomalies (ECAs), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECAs was higher in cases versus controls (P<0.001). Despite an increase in genetic testing in the recent era, only 9.5% of cases with CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990–2011. Later year of birth, family history of CHD, presence of major ECAs, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD (P<0.05 for all). Advanced parental age was associated with increased odds of CHD caused by genetic abnormalities.ConclusionsThe increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene‐environment interactions that contribute to CHD.

Age as a criterion for parenting competence

Several criteria are being used to restrict access to medically assisted reproduction. In many countries, parental characteristics such as age and sexual orientation are used for this purpose. Valid use of such criteria is hampered by two elements: first, there is no consensus on which features good parents should possess, and second, there is a dearth of empirical data about the effect of parental characteristics on the wellbeing of the child. The Italian Court goes even a step further: they use such criteria, in this case parental age, not only to determine eligibility for assisted reproduction but also to terminate parental rights. However, termination of parental rights can only be justified when the child is abused or when there is a high risk of serious harm. Advanced parental age does not create such a situation.

Parental Age and Risk of Autism Spectrum Disorders in a Finnish National Birth Cohort

Aim of the study was to examine the associations between parental age and autism spectrum disorders (ASD). Data were based on the FIPS-A (Finnish Prenatal Study of Autism and Autism Spectrum Disorders), a case-control study with a total of 4,713 cases with childhood autism (n=1,132), Asperger's syndrome (n=1,785) or other pervasive developmental disorder (PDD) (n=1,796), which were ascertained from the Finnish Hospital Discharge Register. Controls were selected from the Finnish Medical Birth Register. Conditional logistic regression models were used for statistical analyses. Advanced paternal age (35-49years) was associated with childhood autism in offspring, whereas advanced maternal age was associated with both Asperger's syndrome and PDD in offspring (35years or more and 40years or more, respectively). Teenage motherhood (19years or less) was associated with PDD in offspring. The main finding was that maternal and paternal ages were differentially associated with ASD subtypes. In addition to advanced parental age, teenage pregnancy seems to incur a risk for PDD in offspring.

Is Later Better or Worse? Association of Advanced Parental Age With Offspring Cognitive Ability Among Half a Million Young Swedish Men

Parental ages are increasing in the developed world, and postponed parenthood may have a negative association with the cognitive ability of offspring. There is, however, inconclusive evidence regarding the impact of both maternal and paternal ages. We have been able to reduce or eliminate unobserved confounding by using methods that account for fixed parental characteristics shared by brothers. Associations between parental age and intelligence quotient (IQ) among 565,433 Swedish males (birth cohorts 1951 to 1976) were analyzed, with IQ measured at conscription examinations (given between ages 17 and 20 years). When we accounted for the IQ time trend by adjusting for birth year, advanced paternal age showed no association with offspring IQ; however, maternal ages above 30 years were inversely associated with offspring IQ. For example, maternal ages 40-44 years were associated with an offspring IQ that was 0.07 standard deviations lower than that for maternal ages 25-29 years (P < 0.001). However, the IQ trend more than offset the impact of age, as without birth year adjustment, advanced maternal age was positively associated with IQ. Although the results confirmed that maternal age was negatively associated with offspring IQ, the association was small enough that delaying parenthood resulted in higher offspring IQ scores because of the positive IQ test score trend.

Potential Explanation of the Reported Association between Maternal Smoking and Autism

Kalkbrenner et al. (2012) reported a positive association between maternal smoking and higher functioning autism syndrome disorder (ASD) subtypes. Other studies had previously reported associations between maternal smoking and ASD (St. Pourcain et al. 2011) and between maternal smoking and attention deficit hyperactivity disorder (Langley et al. 2012). Kalkbrenner et al. (2012) concluded that the association warrants further research. No explanation for an association between autism and maternal smoking has been established, so I would like to suggest one. Baron-Cohen (2002) proposed that one cause of autism is exposure to high levels of intrauterine testosterone; I recently noted that if the mother is the source of the testosterone, many of the established risk factors for autism may be interpreted as confirmation for this hypothesis (James 2012). Stress causes women to secrete adrenal androgens including testosterone; thus, any maternal-stress–related risk factor for autism may be interpreted as supporting Baron-Cohen’s hypothesis (Baron-Cohen 2002). Some of the many risk factors are well established, having been identified by Gardener et al. (2009) in a comprehensive meta-analysis, for example, advanced parental age at birth, maternal use of prenatal medications, maternal bleeding, gestational diabetes, being firstborn, and having a mother who was born abroad. I have identified other risk factors using a less rigorous criterion, namely, risk factors that had been reported as statistically significant more than once (James 2012). These included low birth weight, short duration of gestation, maternal obesity, mother in a technical occupation, lack of breastfeeding, race, and increasing time trend. No previous explanation had been offered for all of these risk factors collectively. Evidence suggests that the risk factor reported by Kalkbrenner et al. (2012)—maternal smoking—may increase maternal testosterone levels. For example, androgen levels are reportedly high in women who smoke (Kaergaard et al. 2000; Polkki and Rantala 2009; Sowers et al. 2001), and this has been specifically reported in pregnant women (Toriola et al. 2011). One may infer that maternal smoking (like the other risk factors for autism cited above) is positively associated with increased levels of intrauterine testosterone and thus—invoking the hypothesis of Baron-Cohen (2002)—with autism. Beaudet (2012) has recently proposed a category of autism that he designated as a milder, more homogeneous form in which the mean IQ is higher. This category is more subject to the recent reported increase in autism and to environmental, as contrasted with genetic, factors. The data of Kalkbrenner et al. (2012) suggest that the association of autism with maternal smoking is confined to higher-functioning autism subtypes. Thus, I suggest that their data could be explained by the high levels of testosterone associated with maternal smoking.

Environmental Contributions to Autism: Explaining the Rise in Incidence of Autistic Spectrum Disorders

The incidence of autism spectrum disorders, a heterogenous group of neurodevelopmental disorders is increasing. In response, there has been a concerted effort by researchers to identify environmental risk factors that explain the epidemiological changes seen with autism. Advanced parental age, maternal migrant status, maternal gestational stress, pregnancy and birth complications, maternal obesity and gestational diabetes, maternal vitamin D deficiency, use of antidepressants during gestation and exposure to organochlorine pesticides during pregnancy are all associated with an increased risk of autism. Folic acid use prior to pregnancy may reduce the risk of autism. Exposure to antenatal ultrasonography, maternal gestational cigarette and alcohol use do not appear to influence the risk of autism in offspring. There is little evidence that exposure to environmental toxins such as thimerosal, polybrominated diphenyl ethers and di-(2-ethylhexyl) phthalate in early childhood increases the risk of autism. Apart from birth complications, the current evidence suggests that the majority of environmental factors increasing the risk of autism occur in the antenatal period. Consistent with the rise in incidence in autism, some of these environmental factors are now more common in developed nations. Further research is required to determine how these environmental exposures translate to an increased risk of autism. Understanding how these exposures alter neurodevelopment in autistic children may inform both the aetiopathogenesis and the strategies for prevention of autism.

A systematic analysis of small supernumerary marker chromosomes using array CGH exposes unexpected complexity

A small supernumerary marker chromosome is often seen in patients with developmental disorders. Prior to array-based comparative genomic hybridization markers were rarely genotyped end to end. In this study, a valid genotype-to-phenotype correlation was possible because the supernumerary marker chromosomes were fully characterized by array-based comparative genomic hybridization in a genome-wide analysis. Ten consecutive de novo small supernumerary marker chromosome cases were systematically genotyped using G-banding, C-banding, AgNOR staining, whole-genome array-based comparative genomic hybridization, and fluorescence in situ hybridization. Among 10 small supernumerary marker chromosome cases studied, 4 (40%) were not identified by array-based comparative genomic hybridization because of low-level mosaicism or because they lacked euchromatin. One case (10%) was a simple pericentromeric marker extending from 5p13.3 to 5q11.2. Five (50%) markers showed unexpected complexity. Two cases had markers that were derivative acrocentric (AgNOR+) chromosomes with the euchromatin from chromosomes 18p or 19p. Each of the other three cases with complex markers had unusual characteristics including a marker from noncontiguous segments of chromosome 19q, a highly complex rearrangement involving a chromosome 20 homolog as well as the small supernumerary marker chromosome, and a mosaic duplication of a proximal 8p marker. Small supernumerary marker chromosomes are frequently complex on the basis of our small sample. Whole-genome array-based comparative genomic hybridization characterization of the small supernumerary marker chromosome provided informed genetic counseling.

Parental Age, Family Size, and Offspring's Risk of Childhood and Adult Acute Leukemia

An association between childhood acute leukemia and advanced parental age was observed more than 50 years ago, and the association has been repeated in several, but not all, subsequent studies. In contrast to the many studies addressing childhood leukemia, few have included adult patients. In this register-based case-control study, we examined the association between parental age and incidence of acute leukemia in 2,660 childhood cases and 4,412 adult cases of acute leukemia, compared with 28,288 age-matched controls selected from a population-based register. Relative risks were estimated with conditional logistic regression. We found a small increased risk of childhood acute lymphoblastic leukemia with increasing paternal age (adjusted OR, 1.05 per 5-year increase in age). Risk estimates were similar for childhood acute myeloid leukemia (AML), whereas no association was found with adult leukemia. Meanwhile, we observed a decreased risk of adult AML with increasing number of siblings, both older and younger. The results support the idea of a prenatal etiology of leukemia but indicate that parental age effects are limited to childhood cases. This is the first large study on parental age and leukemia risk, which includes adult cases. The finding on family size and risk of adult AML needs to be validated in future studies.

Developmental, familial and educational characteristics of a sample of children with Autism Spectrum Disorders in Greece

The aim of this study is to describe the developmental, familial and educational characteristics of 91 children with a clinical diagnosis of autism spectrum disorders (ASDs), from one educational district of Athens, Greece. Records of the 91 children, aged 4–14 years old, were examined with respect to sex, age of diagnosis, type of ASDs, school placement, co-existing disorders, parental ages, type of conception, prematurity and birth order. The results indicated that the boy:girl ratio was 4.3:1 while the average age of diagnosis was 6 years which implies a delay in the early detection of ASDs. Children with typical autism constituted 80% of the sample, while the Asperger group constituted 20%. The majority of pupils were served in general education, and only a small percentage attended special schools. The preferable type of support was one-to-one support in the classroom (47%). Among the most common disorders that coexist with the ASDs was ADHD, epilepsy, dyslexia and learning difficulties. Interesting findings were obtained for the advanced parental age, birth order and the relationship of assisted conception and premature birth with the presence of autism. The present study offers some useful insights about the characteristics of ASDs in a Greek school-based sample.

Dystonia in Costello syndrome

BackgroundCostello Syndrome is a rare multiple congenital anomaly disorder caused by de novo heterozygous mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) gene. Recent studies seem to support apparent autosomal dominant inheritance and somatic mosaicism and an association with advanced parental age. Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear. MethodsWe evaluated and described posture and movement in six consecutive subjects with genetically proven Costello Syndrome, in order to better characterize the phenomenology of the associated postural abnormalities and any related motor abnormalities. We also evaluated motor cortex plasticity by applying Paired Associative Stimulation. ResultsAll the patients presented the typical postural abnormalities reported in Costello Syndrome, in particular the ulnar deviation of fingers. The latter was reducible and not fixed. In addition, patients exhibited more explicit dystonic features of the face, limbs and trunk and altered sensorimotor plasticity consistent with generalized dystonia. ConclusionsThese findings suggest that dystonia may underlie the abnormal postures described in Costello Syndrome patients.

The importance of advanced parental age in the origin of neurofibromatosis type 1

Von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder with a prevalence about 1/3,000 (1/2,000-1/5,000 in various population-based studies). About 30-50% of cases are sporadic, resulting from a new mutation. NF1 is fully penetrant by mid-childhood, stigmata, and medical problems (neurological, dermatological, endocrine, ophthalmological, oncological) are highly variable. Advanced paternal age (APA) has been known to increase the risk of new germline mutations that contribute to the presence of a variety of genetic diseases in the human population. The trend in developed countries has been toward higher parental age due to various reasons. In a cross-sectional study, in two university hospital centers, data on parental age of 103 children (41 female) born between 1976 and 2005 with sporadic NF1 were analyzed. Parental age at birth was compared with the Czech general population matched to birth year. The mean NF1 sporadic case paternal age at birth was 32.0 years (95% CI 30.7-33.3 years) compared with 28.8 years (95% CI 28.6-29.1 years) in the general population (P < 0.001). The mean maternal age at birth was 27.4 years (95% CI 26.3-28.5 years) compared with 25.8 years (95% CI 25.5-26.0 years) in the general population (P < 0.05). The case-control difference in the father's age was higher than it was for the mother's age. Sporadic NF1 cases accounted for 35.6% of our entire NF1 cohort. We confirmed an association of advanced parental and particularly paternal age with the occurrence of sporadic NF1.