Severe congenital lipodystrophy and a progeroid appearance

Mutation in the penultimate exon of FBN1 causing a recognizable phenotype

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Recently, three marfanoid patients with congenital lipodystrophy and a neonatal progeroid appearance were reported. Although their phenotype was distinct from that of classic Marfan syndrome, they all had a truncating mutation in the penultimate exon, i.e., exon 64, of FBN1, the causative gene for Marfan syndrome. These patients might represent a new entity, but the exact phenotypic and genotypic spectrum remains unknown. Here, we report on a girl born prematurely who exhibited severe congenital lipodystrophy and a neonatal progeroid appearance. The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain. She had a characteristic facial appearance with craniosynostosis. A mutation analysis identified c.8175_8182del8bp, p.Arg2726Glufs*9 in exon 64 of the FBN1 gene. A review of similar, recently reported patients revealed that the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features. Lines of molecular evidence suggested that this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling, rather than representing the severe end of the hypomorphic phenotype of the FBN1-TGF beta disorder spectrum. We propose that this marfanoid entity comprised of congenital lipodystrophy, a neonatal progeroid appearance, and a peculiar growth profile and caused by rare mutations in the penultimate exon of FBN1, be newly referred to as marfanoid-progeroid syndrome.

Original languageEnglish
Pages (from-to)3057-3062
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume161
Issue number12
DOIs
Publication statusPublished - 2013 Dec

Fingerprint

Lipodystrophy
Exons
Phenotype
Mutation
Marfan Syndrome
Growth
Transforming Growth Factor beta
Weight Gain
Nonsense Mediated mRNA Decay
Craniosynostoses
Amino Acid Motifs
Premature Birth
Genes

Keywords

  • Congenital lipodystrophy
  • Marfan syndrome
  • Progeroid appearance

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

@article{494aa8da19034a06873abac98fd155a9,
title = "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype",
abstract = "Recently, three marfanoid patients with congenital lipodystrophy and a neonatal progeroid appearance were reported. Although their phenotype was distinct from that of classic Marfan syndrome, they all had a truncating mutation in the penultimate exon, i.e., exon 64, of FBN1, the causative gene for Marfan syndrome. These patients might represent a new entity, but the exact phenotypic and genotypic spectrum remains unknown. Here, we report on a girl born prematurely who exhibited severe congenital lipodystrophy and a neonatal progeroid appearance. The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain. She had a characteristic facial appearance with craniosynostosis. A mutation analysis identified c.8175_8182del8bp, p.Arg2726Glufs*9 in exon 64 of the FBN1 gene. A review of similar, recently reported patients revealed that the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features. Lines of molecular evidence suggested that this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling, rather than representing the severe end of the hypomorphic phenotype of the FBN1-TGF beta disorder spectrum. We propose that this marfanoid entity comprised of congenital lipodystrophy, a neonatal progeroid appearance, and a peculiar growth profile and caused by rare mutations in the penultimate exon of FBN1, be newly referred to as marfanoid-progeroid syndrome.",
keywords = "Congenital lipodystrophy, Marfan syndrome, Progeroid appearance",
author = "Toshiki Takenouchi and Mariko Hida and Yoshiaki Sakamoto and Chiharu Torii and Rika Kosaki and Takao Takahashi and Kenjiro Kosaki",
year = "2013",
month = "12",
doi = "10.1002/ajmg.a.36157",
language = "English",
volume = "161",
pages = "3057--3062",
journal = "American Journal of Medical Genetics",
issn = "1552-4868",
publisher = "Wiley-Liss Inc.",
number = "12",

}

TY - JOUR

T1 - Severe congenital lipodystrophy and a progeroid appearance

T2 - Mutation in the penultimate exon of FBN1 causing a recognizable phenotype

AU - Takenouchi, Toshiki

AU - Hida, Mariko

AU - Sakamoto, Yoshiaki

AU - Torii, Chiharu

AU - Kosaki, Rika

AU - Takahashi, Takao

AU - Kosaki, Kenjiro

PY - 2013/12

Y1 - 2013/12

N2 - Recently, three marfanoid patients with congenital lipodystrophy and a neonatal progeroid appearance were reported. Although their phenotype was distinct from that of classic Marfan syndrome, they all had a truncating mutation in the penultimate exon, i.e., exon 64, of FBN1, the causative gene for Marfan syndrome. These patients might represent a new entity, but the exact phenotypic and genotypic spectrum remains unknown. Here, we report on a girl born prematurely who exhibited severe congenital lipodystrophy and a neonatal progeroid appearance. The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain. She had a characteristic facial appearance with craniosynostosis. A mutation analysis identified c.8175_8182del8bp, p.Arg2726Glufs*9 in exon 64 of the FBN1 gene. A review of similar, recently reported patients revealed that the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features. Lines of molecular evidence suggested that this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling, rather than representing the severe end of the hypomorphic phenotype of the FBN1-TGF beta disorder spectrum. We propose that this marfanoid entity comprised of congenital lipodystrophy, a neonatal progeroid appearance, and a peculiar growth profile and caused by rare mutations in the penultimate exon of FBN1, be newly referred to as marfanoid-progeroid syndrome.

AB - Recently, three marfanoid patients with congenital lipodystrophy and a neonatal progeroid appearance were reported. Although their phenotype was distinct from that of classic Marfan syndrome, they all had a truncating mutation in the penultimate exon, i.e., exon 64, of FBN1, the causative gene for Marfan syndrome. These patients might represent a new entity, but the exact phenotypic and genotypic spectrum remains unknown. Here, we report on a girl born prematurely who exhibited severe congenital lipodystrophy and a neonatal progeroid appearance. The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain. She had a characteristic facial appearance with craniosynostosis. A mutation analysis identified c.8175_8182del8bp, p.Arg2726Glufs*9 in exon 64 of the FBN1 gene. A review of similar, recently reported patients revealed that the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features. Lines of molecular evidence suggested that this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling, rather than representing the severe end of the hypomorphic phenotype of the FBN1-TGF beta disorder spectrum. We propose that this marfanoid entity comprised of congenital lipodystrophy, a neonatal progeroid appearance, and a peculiar growth profile and caused by rare mutations in the penultimate exon of FBN1, be newly referred to as marfanoid-progeroid syndrome.

KW - Congenital lipodystrophy

KW - Marfan syndrome

KW - Progeroid appearance

UR - http://www.scopus.com/inward/record.url?scp=84888042274&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888042274&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.36157

DO - 10.1002/ajmg.a.36157

M3 - Article

VL - 161

SP - 3057

EP - 3062

JO - American Journal of Medical Genetics

JF - American Journal of Medical Genetics

SN - 1552-4868

IS - 12

ER -