Marfan syndrome with neonatal progeroid syndrome‐like lipodystrophy associated with a novel frameshift mutation at the 3′ terminus of the FBN1‐gene

Abstract

We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed a novel de novo heterozygous deletion, c.8155_8156del2 in exon 64. The severe generalized lipodystrophy in this patient with progeroid features has not previously been described in other patients with MFS and FBN1 mutations. We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C). Other progeria syndromes were considered unlikely because premature greying, hypogonadism, and scleroderma-like skin disease were not present. Our patient shows striking similarity to two patients who have been published in this journal by O'Neill et al. [O'Neill et al. (2007); Am J Med Genet Part A 143A:1421-1430] with the diagnosis of neonatal progeroid syndrome (NPS). This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features. The course is usually progressive with early lethality. However this entity seems heterogeneous. We suggest that our patient and the two similar cases described before represent a new entity, a subgroup of MFS with overlapping features to NPS syndrome.

C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

“…In addition, the intracellular retention caused by the single amino acid L2780P substitution (20), which affects a highly conserved leucine, suggests that the function of the propeptide is dependent on its native structure and/or interactions. Recently a correlation has been established between a subset of mutations affecting the fibrillin-1 C terminus and a neonatal, progeroid form of MFS (30)(31)(32)(33)(34). All of these mutations result in a frameshift with the introduction of a stop codon before the sequence encoding the C-terminal furin cleavage site (33).…”

Progeroide Erkrankungen und ihre Mechanismen

“…Primär ein Protein der extrazellulären Matrix, Fibrillin 1, ist beim progeroiden Marfan-Syndrom betroffen, bei dem der vorgealterte Aspekt v. a. auf eine starke Lipodystrophie zurückgeht [17]. Ebenso durch eine starke Beteiligung der extrazellulären Matrix gekennzeichnet sind die Cutis-laxa-Syndrome, von denen v. a. die autosomal-rezessive Cutis laxa (ARCL) progeroide Züge zeigt.…”

Marfanoid–progeroid–lipodystrophy syndrome: a newly recognized fibrillinopathy

“…6,7 Six recent reports describe seven patients with a newly recognized syndrome, the clinical features of which overlap with those of congenital MFS, progeroid syndromes, and lipodystrophy. [8][9][10][11][12][13] All seven individuals harbor a disease-causing mutation in exon 64, the penultimate exon of the FBN1 gene (Table 1).…”

“…8 Recognizable mutations in seven known lipodystrophy-associated genes (APGAT2, BSCL2, CAV1, LMNA, PPARG, LMNB2, and PTRF-CAVIN) and two progeroid-associated genes (LMNA/C and ZMPSTE24) were ruled out by extensive molecular analysis. Additional sequencing of the coding regions of the MFSassociated genes (FBN1, TGFBR1, and TGFBR2) revealed a de novo heterozygous 2-bp deletion c.8155_8156delAA in the coding exon 64 of the FBN1 gene.…”

“…Additional sequencing of the coding regions of the MFSassociated genes (FBN1, TGFBR1, and TGFBR2) revealed a de novo heterozygous 2-bp deletion c.8155_8156delAA in the coding exon 64 of the FBN1 gene. 8 (The annotation of this and all the following FBN1 variants is with respect to NM_000138.4.) This mutation was absent in both parents, the patient's unaffected sister, and in 150 unrelated controls.…”