Clinical reportNeonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene
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)
- et al.
Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases
Mol Genet Metab
(2012) - et al.
Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study
Am J Hum Genet
(2007) - et al.
A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance
Trends Biochem Sci
(1998) - et al.
Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies
Hum Mutat
(2005) - et al.
FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations
Clin Genet
(2008) - et al.
Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability
Clin Genet
(2013) - et al.
Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database
Hum Mutat
(2003) - et al.
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations
Hum Mutat Sept
(2007) - et al.
Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3’ end of the FBN1 gene
Am J Med Genet A
(2011) - et al.
Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3’ terminus of the FBN1-gene
Am J Med Genet A
(2010)
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
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These authors contributed equally.