Clinical and Molecular Study of 320 Children With Marfan Syndrome and Related Type I Fibrillinopathies in a Series of 1009 Probands With Pathogenic FBN1 Mutations

Abstract

From a large series of 1009 probands with pathogenic FBN1 mutations, data for 320 patients <18 years of age at the last follow-up evaluation were analyzed (32%). At the time of diagnosis, the median age was 6.5 years. At the last examination, the population was classified as follows: neonatal Marfan syndrome, 14%; severe Marfan syndrome, 19%; classic Marfan syndrome, 32%; probable Marfan syndrome, 35%. Seventy-one percent had ascending aortic dilation, 55% ectopia lentis, and 28% major skeletal system involvement. Even when aortic complications existed in childhood, the rates of aortic surgery and aortic dissection remained low (5% and 1%, respectively). Some diagnostic features (major skeletal system involvement, striae, dural ectasia, and family history) were more frequent in the 10- to <18-year age group, whereas others (ascending aortic dilation and mitral abnormalities) were more frequent in the population with neonatal Marfan syndrome. Only 56% of children could be classified as having Marfan syndrome, according to international criteria, at their last follow-up evaluation when the presence of a FBN1 mutation was not considered as a major feature, with increasing frequency in the older age groups. Eighty-five percent of child probands fulfilled international criteria after molecular studies, which indicates that the discovery of a FBN1 mutation can be a valuable diagnostic aid in uncertain cases. The distributions of mutation types and locations in this pediatric series revealed large proportions of probands carrying mutations located in exons 24 to 32 (33%) and in-frame mutations (75%). Apart from lethal neonatal Marfan syndrome, we confirm that the majority of clinical manifestations of Marfan syndrome increase with age, which emphasizes the poor applicability of the international criteria to this diagnosis in childhood and the need for follow-up monitoring in cases of clinical suspicion of Marfan syndrome.

Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition

“…In the study by Maumenee et al, 21 dislocation of the lens was observed in 12.5% of MFS children before 3 years of age and in 45% of 4-to 5-year-old children. Faivre et al 17 found ectopia lentis in 57% of MFS children under 10 years.…”

“…A single study included a large number of children (320 patients), but all were probands, thus excluding milder cases. 17 We thus think that the population we studied provides a better overview of children affected by MFS. We chose to compare the MFS group with children consulting for suspicion of Marfan in whom MFS could be ruled out with confidence (absence of the familial FBN1 mutation or no features at the age of 18).…”

“…It was anticipated that probands would be more severely affected than relatives for two reasons: (i) because children with severe mutations tend to be more seriously affected and easily recognized, and (ii) severely affected patients may not reproduce as much as nonseverely affected patients. 17 This may also be related to the fact that children in visible good health are not seeking medical advice, in addition to the fact that specific skeletal features are not well known to general practitioners or pediatricians and thus are not recognized.…”

Health Supervision for Children With Marfan Syndrome

“…For those suspected to have Marfan syndrome based on clinical grounds after physical, cardiac, and ophthalmic evaluation but who may not meet full clinical criteria, one can consider FBN1 testing. 7 Approximately one-quarter of cases occur as a result of a new mutation, with the remainder inherited from an affected parent. Because of the broad phenotypic variability, some parents will not be readily recognized as having Marfan syndrome.…”

Non-cardiac manifestations of Marfan syndrome

“…Gene mutations have been reported in clusters, with those having mainly ocular manifestations occurring in exons 1 to 15 of this 65-exon gene; those causing cardiac problems often involving cysteine replacement in a calcium binding EGF-like sequence; the most severe mutations occurring in exons 25-32, causing neonatal MFS diagnosed at birth, and severe enough to cause death frequently before the age of 2 (5,6).…”