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.
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.
Faivre
Laurence
L
Genetic Center, Centre Hospitalier Universitaire Dijon, Dijon, France. laurence.faivre@chu-dijon.fr
Masurel-Paulet
Alice
A
Collod-Béroud
Gwenaëlle
G
Callewaert
Bert L
BL
Child
Anne H
AH
Stheneur
Chantal
C
Binquet
Christine
C
Gautier
Elodie
E
Chevallier
Bertrand
B
Huet
Frédéric
F
Loeys
Bart L
BL
Arbustini
Eloisa
E
Mayer
Karin
K
Arslan-Kirchner
Mine
M
Kiotsekoglou
Anatoli
A
Comeglio
Paolo
P
Grasso
Maurizia
M
Halliday
Dorothy J
DJ
Béroud
Christophe
C
Bonithon-Kopp
Claire
C
Claustres
Mireille
M
Robinson
Peter N
PN
Adès
Lesley
L
De Backer
Julie
J
Coucke
Paul
P
Francke
Uta
U
De Paepe
Anne
A
Boileau
Catherine
C
Jondeau
Guillaume
G
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005500:Follow-Up Studies; D005820:Genetic Testing / Q000379:methods / Q000639:trends; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines