Clinical report
Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene

https://doi.org/10.1016/j.ejmg.2014.02.012Get rights and content

Abstract

We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann–Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid–progeroid–lipodystrophy syndrome) and frameshift mutations at the 3′ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.

Introduction

Progeroid syndromes belong to a large group of heterogeneous conditions that display, as in the prototypic Hutchinson–Gilford progeria, progeroid changes in several organ systems. A progeroid appearance, often stemming from altered cutaneous or subcutaneous structures, may be present at birth in several of these syndromes, including Wiedemann–Rautenstrauch syndrome, cutis laxa syndromes, and congenital lipodystrophies. Although pathophysiological mechanisms are still largely unknown, a number of involved pathways recently came to attention. An important group of progeroid disorders are due to defective genomic maintenance leading to loss of cells, cellular senescence and impaired replacement of damaged cells [Kudlow et al., 2007]. A second group of these diseases are associated with altered TGF-β signaling, which might play an important role in the pathogenesis since it is known to be involved in the induction of cellular senescence [Passos et al., 2010]. This group comprises cutis laxa syndromes and a progeroid variant of Marfan syndrome.

This singular marfanoid–progeroid phenotype was initially briefly reported by one of us [Verloes et al., 1998]. Its genetic cause has recently been solved in four patients [Goldblatt et al., 2011, Graul-Neumann et al., 2010, Horn and Robinson, 2011, Takenouchi et al., 2013]. It associates intrauterine growth retardation and/or preterm birth, senile facial appearance and decreased subcutaneous fat at birth, and progressive marfanoid features (Table 1). Aortic root dilation, ectopia lentis and dural ectasia can appear with time. Developmental milestones and intelligence appear to be normal. All four patients harbored mutations at the 3′ end of the FBN1 gene [Goldblatt et al., 2011, Graul-Neumann et al., 2010, Horn and Robinson, 2011, Takenouchi et al., 2013] (Table 1).

FBN1 is a 230 kb gene with 65 coding exons that encode the structural glycoprotein fibrillin-1, a major component of the microfibrils in elastic and non-elastic extracellular matrix. Microfibrils have a structural function, can associate with elastin to form elastic fibers and regulate, among others, the biodisponibility of growth factors including TGF-β [Piha-Gossack et al., 2012]. Fibrillin-1 is synthetized as a propeptide, profibrillin-1, which is processed by proteolysis before incorporation into the extracellular matrix [Wallis et al., 2003]. FBN1 mutations have been associated with a variety of conditions : type I fibrillinopathies, including Marfan syndrome, MASS syndrome, isolated ectopia lentis syndrome, thoracic aortic aneurysms, Weill–Marchesani syndrome, geleophysic and acromicric dysplasia, and stiff skin syndrome [Davis and Summers, 2012]. The most common is the autosomal dominant Marfan syndrome comprising ocular, cardiovascular and skeletal manifestations [Loeys et al., 2010].

Mutations in classical Marfan syndrome are scattered throughout the FBN1 gene. Two thirds are missense mutations that often involve a cysteine residue in calcium binding epidermal growth factor-like (cbEGF) domains [Faivre et al., 2007]. Genotype–phenotype relationship are limited [Faivre et al., 2007].

We report the clinical follow up of the patient originally reported by Verloes et al. (1998) as Marfanoid-Progeroid Syndrome and discuss genotype-phenotype relationship for mutations at the 3′ end of the FBN1 gene.

The patient was born at 39 weeks of gestation to non-consanguineous Caucasian parents. Family history was unremarkable. Father and mother's heights were respectively 186 cm and 171 cm. During the third trimester, pregnancy was complicated by intrauterine growth retardation and oligohydramnios. Birth weight, height and cranial circumference were 1720 g (−4 SD), 45 cm (−2.5 SD) and 32 cm (−1.75 SD), respectively. Clinical examination showed long narrow hands with arachnodactyly, long, thin feet and toes, mild arthrogryposis of the large joints, and severe hyperlaxity of the small joints. She presented a relative macrocephaly with widely opened anterior fontanel, hypoplasia of facial bones, upward slant of palpebral fissures and entropion of the upper eyelids. Subcutaneous fat was nearly absent and there was moderate muscle waste. Heart and large vessels were normal. There were no neonatal teeth. During the first year, persistent growth retardation and impressive thinness were noted. Skin became more atrophic and loose, and scalp veins more prominent. At one year, she underwent surgery to correct entropion and lacrimal ducts stenosis. At 19 months, height was 86.5 cm (+2.25 SD) and weight was 8.2 kg (−2.25 SD). Arm span was 88 cm. Her head was disproportionately large compared to her small face with a high and bulging forehead. Generalized lack of subcutaneous fat was observed, except over genitalia and iliac wings. The skin was thin with particularly apparent veins. Psychomotor development was normal. Ocular examination was normal at the age of two. In early childhood, she presented feeding problems, with severe gastroesophageal reflux. At age three, Nissen fundoplicature was performed and gastrostomy was required during the first year of life. During childhood, she underwent two cosmetic maxillofacial surgeries. She presented frequent upper airway and bronchopulmonary infections and bronchial asthma. At twelve years, her weight was 29.7 kg (−1.25 SD) and height was 166 cm (+3.5 SD). Heart ultrasonography was normal. At age 16, weight was 41.8 kg (−2 SD) and height was 177 cm (+3 SD). Dolichostenomelia and arachnodactyly persisted. Cardiac ultrasound scan indicated an aortic root dilatation at 3.3 DS. Ophthalmologic examination showed severe myopia without ectopia lentis. Clinical pictures of the patient at different ages are shown in Fig. 1.

Section snippets

Molecular investigations

A de novo c.8226+1G>A heterozygous mutation was found in FBN1 by Sanger sequencing. This mutation is predicted to alter the donor splice site of intron 64 (reference sequence NM_000138.4 and ENST00000316623; exon numbering starting from exon 2 according to the localization of the ATG start codon). FBN1 analysis was normal in both unaffected parents. In order to investigate the causal effect of the identified mutation, RT-PCR was performed on mRNA from a skin fibroblast culture of the patient.

Discussion

Our patient reinforces the genotype–phenotype relationship between Marfanoid–Progeroid–Lipodystrophy (MPL) phenotype and mutations in exon 64 of FBN1. Fig. 2 summarizes the five mutations identified in patients with MPL syndrome, and their consequences on the FBN1 RNA and predicted protein products. In three previously reported patients, the identified mutations (c.8155_8156del; c8156_8175del; c.8175_8182del) are small frameshift deletions leading to a PTC less than 55 nucleotides upstream the

References (22)

  • D. Horn et al.

    Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene

    Am J Med Genet A

    (2011)
  • Cited by (35)

    • Fibrillin-1 regulates white adipose tissue development, homeostasis, and function

      2022, Matrix Biology
      Citation Excerpt :

      Fibrillin-1 also directly interacts with several bone morphogenetic proteins (BMP) including BMP-2, -4, -7 and -10 [30,31], and osteoclastogenic cytokine receptor activator of nuclear factor κβ ligand (RANKL) in various cellular microenvironments [32]. Marfan syndrome (MFS) and Marfanoid progeroid lipodystrophy syndrome are caused by mutations in fibrillin-1 and are often characterized by lipodystrophic phenotypes of various severities [4,25,33-37]. A significant subset of MFS patients (36%), however, is typified as overweight or even obese with elevated body mass indices of >30 kg/m2 [38].

    • Transforming growth factor β1 signaling links extracellular matrix remodeling to intracellular lipogenesis upon physiological feeding events

      2022, Journal of Biological Chemistry
      Citation Excerpt :

      In accordance with the results, previous studies have shown that defects in lipogenesis-related factors, including ACC, SCD, ACLY, DGAT1/2, and BSCL2 (Berardinell–Seip congenital lipodystrophy 2), lead to loss of adipose tissue and are associated with systemic metabolic abnormalities (44–51). Similar phenotypes were found with defects of the ECM and related signaling molecules, including collagen, FBN, integrin, and FAK (52–57). Since the discovery of TGF-β in the 1970s (58), it has long been studied in a wide range of research areas.

    View all citing articles on Scopus
    §

    These authors contributed equally.

    View full text