Ts unrestricted use, distribution, and reproduction in any medium, provided the
Ts unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Donadille et al. Orphanet Journal of Rare Diseases 2013, 8:106 http://www.ojrd.com/content/8/1/Page 2 ofBackground The studies of clinical and cellular consequences of LMNA mutations in humans have provided several indications of a close physiopathological relationship between premature aging and lipodystrophic syndromes. Indeed, human naturally-occuring LMNA mutations, among other phenotypes of laminopathies, have been shown to be responsible for premature ageing syndromes (HutchinsonGilford progeria, HGPS, and mandibuloacral dysplasia, MAD) [1-4], lipodystrophic syndromes (familial partial lipodystrophy of the Dunnigan type, FPLD2) [5,6], and mixed PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28607003 phenotypes [7-10]. At the cellular level, a Oxaliplatin biological activity highly similar disorganization of the nuclear lamina is observed in fibroblasts from patients with FPLD2, MAD and HGPS [3,11,12], including cellular replicative senescence and prelamin A accumulation [13-15]. Although the pathophysiological mechanisms leading to LMNA-linked premature aging are not fully understood, a major hypothesis is that alterations in maturation and farnesylation of lamin A induce genomic instability, abnormal epigenetic control of heterochromatin and DNA damage responses, and mesenchymal stem cell defects [16-18]. Werner syndrome (WS) is an autosomal recessive premature aging syndrome due to biallelic inactivating mutations in WRN, encoding a RecQ DNA helicase/exonuclease involved in DNA replication and repair [19]. Its prominent features, occurring after adolescence, associate “bird-like” facies, scleroderma-like skin changes with tight and atrophic skin, bilateral cataracts, short stature and premature greying of scalp hair [20]. An initial clinical presentation as a lipodystrophic syndrome has not been previously described. In women with familial partial lipodystrophies, decreased fertility and obstetrical complications have been reported to be mainly linked to insulin resistance and metabolic disturbances, with an increased prevalence of polycystic ovary syndrome, gestational diabetes and eclampsia [21,22]. The mechanisms leading to decreased fertility in Werner syndrome have not been deciphered. Only rare cases of pregnancies have been reported in women with probable, but not genetically-confirmed Werner syndrome [23-26]. Here we report the cases of two women investigated for lipodystrophy and severe insulin resistance, which revealed Werner syndrome due to homozygous or compound heterozygous, non-sense or frameshift mutations in the WRN gene. The two patients became pregnant after initiation of metformin therapy. Both pregnancies were complicated by cervical incompetence, leading to a second-trimester abortion in one case and to a preterm delivery in the other patient. Cultured fibroblasts obtained from one patient showed cellular senescence, nuclear dysmorphies, and lamin staining abnormalities similar to those found in laminopathies, but did not overexpress immature prelamin A.Our study points out that primary defects in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes with extreme insulin resistance. In addition, we show that cell nuclear dysmorphies with alterations in lamin staining can be secondary to cellular senescence of different origin.Patients and methodsPatientsTwo women of 32 and 36 years old were referred to us for partial lipodystrophic syndrome.