Alternative titles; symbols
ORPHA: 300382;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.1 | Marfan lipodystrophy syndrome | 616914 | Autosomal dominant | 3 | FBN1 | 134797 |
A number sign (#) is used with this entry because of evidence that the marfanoid-progeroid-lipodystrophy syndrome (MFLS) is caused by heterozygous mutation occurring in or affecting exon 64 of the FBN1 gene (134797) on chromosome 15q21.
The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development (Takenouchi et al., 2013).
Takenouchi et al. (2013) noted phenotypic overlap with Marfan syndrome (154700) and Shprintzen-Goldberg craniosynostosis syndrome (182212).
Verloes et al. (1998) described a 1-year-old girl with an 'unclassifiable' form of connective tissue disorder. She had severe intrauterine growth retardation, and she was born with long narrow hands, long thin feet and toes, mild arthrogryposis of the large joints, extreme hyperlaxity of the small joints, and facial dysmorphism consisting of relative macrocephaly with widely open anterior fontanel, hypoplasia of facial bones, upward-slanting palpebral fissures that remained gaping in sleep, and entropion of the upper eyelid. Heart and large vessels were normal. During her first year of life, she showed persistent growth retardation and marked thinness, with atrophic, loose skin and prominent scalp veins, and fontanels remained widely open. Skin biopsy in the neonatal period showed dermal atropy, anarchic and hyperplastic elastin network, hypoplastic collagen bundles, and fibroblasts filled with granulous vesicles. Jacquinet et al. (2014) provided follow-up on the patient originally reported by Verloes et al. (1998). Ocular examination at age 2 years was normal. Severe gastroesophageal reflux required operative repair at age 3 years. Echocardiography at age 12 years was normal; however, at age 16, cardiac ultrasound showed aortic root dilation. Ophthalmologic examination revealed severe myopia without ectopia lentis.
Graul-Neumann et al. (2010) studied a 27-year-old German woman who fulfilled the clinical Ghent criteria for Marfan syndrome (MFS; 154700) with 3 major features, including ectopia lentis, aortic dilatation, and dural ectasia, who also showed an extreme reduction in the amount of subcutaneous fat tissue since birth and had prominent facial lipodystrophy. Graul-Neumann et al. (2010) noted a 'striking resemblance' between this patient and the 2 girls with neonatal progeroid syndrome (264090) described by O'Neill et al. (2007).
Goldblatt et al. (2011) reported a 20-year-old Irish man with marfanoid features, including arachnodactyly with generalized mild digital hyperextensibility and bilateral lens subluxations, who also had decreased subcutaneous fat of neonatal onset with a progeroid facial appearance.
Horn and Robinson (2011) reported a 3.5-year-old girl with tall stature, arachnodactyly, decreased subcutaneous fat, and a progeroid facial appearance resembling that of the patient reported by Graul-Neumann et al. (2010). She also had a large head with arrested hydrocephalus, and mild mitral valve prolapse on echocardiography.
Takenouchi et al. (2013) described a 10-year-old Japanese girl who had a progeroid appearance at birth with a wide open anterior fontanel, long arms and legs, arachnodactyly, and arthrogryposis, especially in the lower extremities. During childhood she had consistently poor weight gain with disproportionately accelerated height growth. On examination at age 10 years, she was extremely thin with little palpable subcutaneous adipose tissue. She had arachnodactyly, a progeroid appearance, and scaphocephaly with a prominent forehead, proptosis, and pectus excavatum. She reported a recent decline in visual acuity, and ophthalmologic examination showed bilateral severe myopia, proptosis, and enlarged optic discs, but no subluxation of the lenses. Imaging studies of the entire neuroaxis revealed craniosynostosis of the posterior sagittal suture, mild enlargement of the ventricles consistent with arrested hydrocephalus, and lumbosacral dural ectasia. Echocardiography showed no evidence of annuloaortic ectasia.
The transmission pattern of MFLS in the patient reported by Graul-Neumann et al. (2010) was consistent with autosomal dominant inheritance.
In a German woman with Marfan lipodystrophy syndrome, Graul-Neumann et al. (2010) identified identified heterozygosity for a 2-bp deletion in exon 64 of the FBN1 gene (134797.0064), and excluded mutations in the TGFBR1 (190181) and TGFBR2 (190182) genes.
In a man with MFLS, Goldblatt et al. (2011) identified a heterozygous 20-bp deletion in exon 64 of the FBN1 gene (134797.0065) resulting in a frameshift and stop codon at the same relative location in the mRNA as that found by Graul-Neumann et al. (2010).
In a 3.5-year-old girl with MFLS, Horn and Robinson (2011) identified heterozygosity for a de novo splice site transversion in intron 64 of the FBN1 gene (c.8226+1G-T; 134797.0066).
In a 10-year-old Japanese girl with Marfan lipodystrophy syndrome, Takenouchi et al. (2013) identified heterozygosity for an 8-bp deletion in exon 64 of the FBN1 gene (134797.0069).
In a 16-year-old girl with Marfan lipodystrophy syndrome, originally described by Verloes et al. (1998), Jacquinet et al. (2014) identified heterozygosity for a de novo splice site transition in intron 64 of FBN1 (c.8226+1G-A; 134797.0070). Jacquinet et al. (2014) noted that all 5 reported mutations in MFLS result in a truncated mRNA predicted to encode a shorter protein with an altered protein sequence at the C terminus. In addition, the authors tabulated clinical features of the 5 MFLS patients; metabolic characteristics were available for 3 of the patients, including normal fasting glucose, insulin, and lipids in 2 and a normal glucose tolerance test in 1.
In 2 female patients with congenital partial lipodystrophy and a progeroid appearance, Romere et al. (2016) identified heterozygosity for truncating mutations in exon 64 of the FBN1 gene (see, e.g., 134797.0066). Both patients exhibited overnight-fasted plasma insulin levels that were 2-fold lower than unaffected individuals, while maintaining euglycemia. No additional clinical information on these patients was provided. Romere et al. (2016) also studied the C-terminal cleavage product of profibrillin, which they designated 'asprosin' after the Greek word for white, because of the reduction in subcutaneous white adipose tissue displayed by asprosin-deficient patients. Both of their patients showed lower levels of asprosin than would be expected with a heterozygous genotype, suggesting a dominant-negative effect.
Reviews
Passarge et al. (2016) reviewed 6 reports between 2000 and 2014 of 7 unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in or affected exon 64 of the FBN1 gene (2 were splice site mutations in intron 64 that resulted in skipping of exon 64; 134797.0066 and 134797.0070). A distinctive phenotype consisting of partial manifestions of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy were present in all individuals. Passarge et al. (2016) suggested that this genotype-phenotype relationship constituted a novel fibrillinopathy for which they considered the name marfanoid-progeroid-lipodystrophy syndrome to be appropriate.
Duerrschmid et al. (2017) demonstrated that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway, causing inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then results in appetite stimulation and a drive to accumulate adiposity and body weight. Noting that Romere et al. (2016) had found pathologically elevated concentrations of circulating asprosin in obese humans and mice, Duerrschmid et al. (2017) showed that neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. The authors concluded that asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
Duerrschmid et al. (2017) generated mice that were heterozygous for a mutation that results in skipping of Fbn1 exon 65, analogous to a mutation (134797.0066) found in patients with Marfan lipodystrophy syndrome, and observed a phenocopy of the human disorder. The mutant mice displayed extreme leanness compared to sex-matched littermates, and DEXA scan revealed reductions in both fat mass and lean mass, with no significant change in body length. When exposed to severe diabetogenic and obesogenic stress, the mutant mice were completely protected from both obesity and diabetes. Similar to the human disorder, the mutant mice exhibited hypophagia as well as a reduction in energy expenditure.
Duerrschmid, C., He, Y., Wang, C., Li, C., Bournat, J. C., Romere, C., Saha, P. K., Lee, M. E., Phillips, K. J., Jain, M., Jia, P., Zhao, Z., and 9 others. Asprosin is a centrally acting orexigenic hormone. Nature Med. 23: 1444-1453, 2017. [PubMed: 29106398] [Full Text: https://doi.org/10.1038/nm.4432]
Goldblatt, J., Hyatt, J., Edwards, C., Walpole, I. Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3-prime end of the FBN1 gene. Am. J. Med. Genet. 155A: 717-720, 2011. [PubMed: 21594992] [Full Text: https://doi.org/10.1002/ajmg.a.33906]
Graul-Neumann, L. M., Kienitz, T., Robinson, P. N., Baasanjav, S., Karow, B., Gillessen-Kaesbach, G., Fahsold, R., Schmidt, H., Hoffmann, K., Passarge, E. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3-prime terminus of the FBN1-gene. Am. J. Med. Genet. 152A: 2749-2755, 2010. [PubMed: 20979188] [Full Text: https://doi.org/10.1002/ajmg.a.33690]
Horn, D., Robinson, P. N. Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene. Am. J. Med. Genet. 155A: 721-724, 2011. [PubMed: 21594993] [Full Text: https://doi.org/10.1002/ajmg.a.33905]
Jacquinet, A., Verloes, A., Callewaert, B., Coremans, C., Coucke, P., de Paepe, A., Kornak, U., Lebrun, F., Lombet, J., Pierard, G. E., Robinson, P. N., Symoens, S., Van Maldergem, L., Debray, F.-G. Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3-prime end of FBN1 gene. Europ. J. Med. Genet. 57: 230-234, 2014. [PubMed: 24613577] [Full Text: https://doi.org/10.1016/j.ejmg.2014.02.012]
O'Neill, B., Simha, V., Kotha, V., Garg, A. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am. J. Med. Genet. 143A: 1421-1430, 2007. [PubMed: 17523150] [Full Text: https://doi.org/10.1002/ajmg.a.31840]
Passarge, E., Robinson, P. N., Graul-Neumann, L. M. Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy. Europ. J. Hum. Genet. 24: 1244-1247, 2016. [PubMed: 26860060] [Full Text: https://doi.org/10.1038/ejhg.2016.6]
Romere, C., Duerrschmid, C., Bournat, J. Constable, P., Jain, M., Xia, F., Saha, P. K., Del Solar, M., Zhu, B., York, B., Sarkar, P., Rendon, D. A., Gaber, M. W., LeMaire, S. A., Coselli, J. S., Milewicz, D. M., Sutton, V. R., Butte, N. F., Moore, D. D., Chopra, A. R. Asprosin, a fasting-induced glucogenic protein hormone. Cell 165: 566-579, 2016. [PubMed: 27087445] [Full Text: https://doi.org/10.1016/j.cell.2016.02.063]
Takenouchi, T., Hida, M., Sakamoto, Y., Torii, C., Kosaki, R., Takahashi, T., Kosaki, K. Severe congenital lipodystrophy and a progeroid appearance: mutation in the penultimate exon of FBN1 causing a recognizable phenotype. Am. J. Med. Genet. 161A: 3057-3062, 2013. [PubMed: 24039054] [Full Text: https://doi.org/10.1002/ajmg.a.36157]
Verloes, A., Pierard, G., Lombet, J., De Paepe, A. Congenital progeroid-marfanoid syndrome: variant of Wiedemann-Rautenstrauch or new syndrome? (Abstract) Proc. Greenwood Genet. Center 17: 103-104, 1998.