Children With Marfan Syndrome and Aortic Root Dilation
Children With Marfan Syndrome and Aortic Root Dilation
We have successfully enrolled a very large cohort of pediatric and young adult patients with MFS from 21 international sites into this trial comparing cardiovascular outcomes in subjects randomized to receive atenolol or losartan. This cohort is different from most previously published large series of MFS patients because of the range of age (6 months-25 years) and aortic root diameter z-score requirement for enrollment. The high percentage of subjects <18 years of age in this large cohort is novel.
With a few exceptions, the prevalence rates of the major and minor Ghent criteria were similar in our cohort compared with previously published series. By study design, all subjects had aortic root dilation and, therefore, met major Ghent criteria for the cardiovascular system. Older studies reported a higher prevalence of ectopia lentis of 60% to 70%, probably as result of selection bias; the prevalence of ectopia lentis in our series (48%) was similar to recently published large series (47%-54%). Imaging for dural ectasia was available in only 95 subjects (16%), and the prevalence was lower in our cohort compared with previous reports (34% vs 63%-92%). The prevalence of striae was similar (44% vs 47%), but pulmonary involvement was lower compared with published reports (3% vs 4%-15%).
Older subjects in this trial were more likely to exhibit more major and minor manifestations than younger subjects, but the prevalence of ectopia lentis was not dependent on age, consistent with the concept that ectopia lentis is most commonly detected at a young age in MFS. Similarly, aortic root diameter z-score did not vary with age in our cohort of children and young adults selected for moderate to severe aortic dilation. Although a selection bias cannot be completely excluded, the absence of variation in aortic root diameter z-score with age in our cross-sectional sample is consistent with previous longitudinal studies that have shown that aortic root diameter z-score is stable (z-score change per year close to 0), at least in young individuals with MFS. It is important to emphasize that, in growing individuals, the aortic root continues to enlarge despite a stable z-score. Subjects with higher aortic root diameter z-scores were more likely to have additional cardiovascular involvement—MVP and/or dilation of the main pulmonary artery.
That 60% of our cohort is male is intriguing, given that MFS is an autosomal dominant disorder and a balanced gender ratio is expected. The male predominance was present throughout the screening process including the initial medical record review, suggesting that the gender ratio reflected the general Marfan population, but the reason for this is unclear. Several studies in children and adults have also shown a male predominance (54%-60%).
Mitral valve prolapse and measurable (mild or more) MR were more common in females in our cohort. In contrast, Detaint et al found no gender differences in MVP or MR among 965 probands with pathogenic FBN1 mutations, but their cohort had a median age at diagnosis of 22 years, leaving open the possibility of an increased risk for MVP/MR in younger females. Of note, Detaint et al also found that men presented earlier and with more severe aortic dilation and related complications compared with the women. Similar trends of earlier and more severe aortic disease are observed in male Fbn1-deficient mice (personal communication, Harry C. Dietz, MD, 2012). However, aortic root diameter z-score was not dependent on gender in our randomized cohort. Thus, more severe disease in males cannot completely account for the greater proportion of males in the overall MFS population.
Hofman et al evaluated the neurodevelopmental status and cognitive ability of 30 consecutive school-aged children with MFS (70% male) and found ≥1 neuropsychologic deficits—learning disability, attention deficit disorder with or without hyperactivity, neuromaturational immaturity, and verbal performance discrepancy—in half of them (33% of the girls and 62% of the boys). Neurodevelopmental issues were more common in males in our cohort, but our estimates of prevalence were based on medical history and not on the results of formal testing. Whether the male predilection is specific for MFS or reflective of general population trends is unclear; further investigation with formal neuropsychologic testing and long-term follow-up is warranted.
The study design only included individuals with at least moderate aortic root dilation and excluded patients at the extremes of the spectrum of aortic disease in MFS. Patients with aortic root diameter z-scores ≤3 and those with previous or impending aortic surgery were excluded. Although the randomized subjects were well characterized, the screening process did not include detailed data collection on all screened patients as this was beyond the scope of the study. Therefore, a robust comparison between the randomized subjects and the screened population was not feasible.
In summary, we have characterized the largest cohort of pediatric and young adult patients with MFS. We found that aortic root z-score did not vary with age and was not dependent on gender. Among those with a family history of MFS, a family history of aortic surgery was more common in females.
The very high consent rate among eligible subjects is notable. The clinical profile of the cohort is representative of patients in this population with moderate to severe aortic root dilation. As expected with randomization, baseline demographic, clinical, and anthropometric characteristics of the study cohort are not different between treatment groups. As such, our multicenter trial is in an excellent position to evaluate the efficacy and safety of atenolol and losartan in young patients with MFS and to determine if the benefit of losartan in the mouse model of MFS translates to humans. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy. We expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with MFS.
Discussion
We have successfully enrolled a very large cohort of pediatric and young adult patients with MFS from 21 international sites into this trial comparing cardiovascular outcomes in subjects randomized to receive atenolol or losartan. This cohort is different from most previously published large series of MFS patients because of the range of age (6 months-25 years) and aortic root diameter z-score requirement for enrollment. The high percentage of subjects <18 years of age in this large cohort is novel.
With a few exceptions, the prevalence rates of the major and minor Ghent criteria were similar in our cohort compared with previously published series. By study design, all subjects had aortic root dilation and, therefore, met major Ghent criteria for the cardiovascular system. Older studies reported a higher prevalence of ectopia lentis of 60% to 70%, probably as result of selection bias; the prevalence of ectopia lentis in our series (48%) was similar to recently published large series (47%-54%). Imaging for dural ectasia was available in only 95 subjects (16%), and the prevalence was lower in our cohort compared with previous reports (34% vs 63%-92%). The prevalence of striae was similar (44% vs 47%), but pulmonary involvement was lower compared with published reports (3% vs 4%-15%).
Older subjects in this trial were more likely to exhibit more major and minor manifestations than younger subjects, but the prevalence of ectopia lentis was not dependent on age, consistent with the concept that ectopia lentis is most commonly detected at a young age in MFS. Similarly, aortic root diameter z-score did not vary with age in our cohort of children and young adults selected for moderate to severe aortic dilation. Although a selection bias cannot be completely excluded, the absence of variation in aortic root diameter z-score with age in our cross-sectional sample is consistent with previous longitudinal studies that have shown that aortic root diameter z-score is stable (z-score change per year close to 0), at least in young individuals with MFS. It is important to emphasize that, in growing individuals, the aortic root continues to enlarge despite a stable z-score. Subjects with higher aortic root diameter z-scores were more likely to have additional cardiovascular involvement—MVP and/or dilation of the main pulmonary artery.
That 60% of our cohort is male is intriguing, given that MFS is an autosomal dominant disorder and a balanced gender ratio is expected. The male predominance was present throughout the screening process including the initial medical record review, suggesting that the gender ratio reflected the general Marfan population, but the reason for this is unclear. Several studies in children and adults have also shown a male predominance (54%-60%).
Mitral valve prolapse and measurable (mild or more) MR were more common in females in our cohort. In contrast, Detaint et al found no gender differences in MVP or MR among 965 probands with pathogenic FBN1 mutations, but their cohort had a median age at diagnosis of 22 years, leaving open the possibility of an increased risk for MVP/MR in younger females. Of note, Detaint et al also found that men presented earlier and with more severe aortic dilation and related complications compared with the women. Similar trends of earlier and more severe aortic disease are observed in male Fbn1-deficient mice (personal communication, Harry C. Dietz, MD, 2012). However, aortic root diameter z-score was not dependent on gender in our randomized cohort. Thus, more severe disease in males cannot completely account for the greater proportion of males in the overall MFS population.
Hofman et al evaluated the neurodevelopmental status and cognitive ability of 30 consecutive school-aged children with MFS (70% male) and found ≥1 neuropsychologic deficits—learning disability, attention deficit disorder with or without hyperactivity, neuromaturational immaturity, and verbal performance discrepancy—in half of them (33% of the girls and 62% of the boys). Neurodevelopmental issues were more common in males in our cohort, but our estimates of prevalence were based on medical history and not on the results of formal testing. Whether the male predilection is specific for MFS or reflective of general population trends is unclear; further investigation with formal neuropsychologic testing and long-term follow-up is warranted.
Limitations
The study design only included individuals with at least moderate aortic root dilation and excluded patients at the extremes of the spectrum of aortic disease in MFS. Patients with aortic root diameter z-scores ≤3 and those with previous or impending aortic surgery were excluded. Although the randomized subjects were well characterized, the screening process did not include detailed data collection on all screened patients as this was beyond the scope of the study. Therefore, a robust comparison between the randomized subjects and the screened population was not feasible.
In summary, we have characterized the largest cohort of pediatric and young adult patients with MFS. We found that aortic root z-score did not vary with age and was not dependent on gender. Among those with a family history of MFS, a family history of aortic surgery was more common in females.
The very high consent rate among eligible subjects is notable. The clinical profile of the cohort is representative of patients in this population with moderate to severe aortic root dilation. As expected with randomization, baseline demographic, clinical, and anthropometric characteristics of the study cohort are not different between treatment groups. As such, our multicenter trial is in an excellent position to evaluate the efficacy and safety of atenolol and losartan in young patients with MFS and to determine if the benefit of losartan in the mouse model of MFS translates to humans. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy. We expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with MFS.
