Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging.

Progeroid syndromes are rare genetic diseases with most of autosomal dominant transmission, the prevalence of which is less than 1/10,000,000. These syndromes caused by mutations in the <i>LMNA</i> gene encoding A-type lamins belong to a group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated aging of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. To identify pathways altered in progeroid patients' MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford progeria syndrome (HGPS, c.1824C&gt;T-p.G608G), HGPS-like syndrome (HGPS-L; c.1868C&gt;G-p.T623S) associated with farnesylated prelamin A accumulation, or atypical progeroid syndromes (APS; homozygous c.1583C&gt; T-p.T528M; heterozygous c.1762T&gt;C-p.C588R; compound heterozygous c.1583C&gt;T and c.1619T&gt;C-p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient's MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of <i>LMNA</i> variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern; an increased response to double-strand DNA damage; and telomere erosion in HGPS, HGPS-L, and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared with APS cells.

Case Report: Identification of Novel Variants in ERCC4 and DDB2 Genes in Two Tunisian Patients With Atypical Xeroderma Pigmentosum Phenotype.

Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair system (NER). It is characterized by an extreme sensitivity to sunlight that induces cutaneous disorders such as severe sunburn, freckling and cancers. In Tunisia, six complementation groups have been already identified. However, the genetic etiology remains unknown for several patients. In this study, we investigated clinical characteristics and genetic defects in two families with atypical phenotypes originating from the central region in Tunisia. Clinical investigation revealed mild cutaneous features in two patients who develop multiple skin cancers at later ages, with no neurological disorders. Targeted gene sequencing revealed that they carried novel variants. A homozygous variation in the ERCC4 gene c.1762G>T, p.V588F, detected in patient XP21. As for patient XP134, he carried two homozygous mutations in the DDB2 gene c.613T>C, p.C205R and c.618C>A, p.S206R. Structural modeling of the protein predicted the identified ERCC4 variant to mildly affect protein stability without affecting its functional domains. As for the case of DDB2 double mutant, the second variation seems to cause a mild effect on the protein structure unlike the first variation which does not seem to have an effect on it. This study contributes to further characterize the mutation spectrum of XP in Tunisian families. Targeted gene sequencing accelerated the identification of rare unexpected genetic defects for diagnostic testing and genetic counseling.

Author Correction: Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to a defect in the nucleotide excision repair (NER) DNA repair pathway, characterized by severe sunburn development of freckles, premature skin aging, and susceptibility to develop cancers at an average age of eight. XP is an example of accelerated photo-aging. It is a genetically and clinically heterogeneous disease. Eight complementation groups have been described worldwide. In Tunisia, five groups have been already identified. In this work, we investigated the genetic etiology in a family with an atypically mild XP phenotype. Two Tunisian siblings born from first-degree consanguineous parents underwent clinical examination in the dermatology department of the Charles Nicolle Hospital on the basis of acute sunburn reaction and mild neurological disorders. Blood samples were collected from two affected siblings after written informed consent. As all mutations reported in Tunisia have been excluded using Sanger sequencing, we carried out mutational analysis through a targeted panel of gene sequencing using the Agilent HaloPlex target enrichment system. Our clinical study shows, in both patients, the presence of achromic macula in sun exposed area with dermatological feature suggestive of Xeroderma pigmentosum disease. No developmental and neurological disorders were observed except mild intellectual disability. Genetic investigation shows that both patients were carriers of an homozygous T to C transition at the nucleotide position c.2333, causing the leucine to proline amino acid change at the position 778 (p.Leu778Pro) of the ERCC5 gene, and resulting in an XP-G phenotype. The same variation was previously reported at the heterozygous state in a patient cell line in Europe, for which no clinical data were available and was suggested to confer an XP/CS phenotype based on functional tests. This study contributes to further characterization of the mutation spectrum of XP in consanguineous Tunisian families and is potentially helpful for early diagnosis. It also indicates that the genotype-phenotype correlation is not always coherent for patients with mild clinical features. These data therefore suggest that targeted NGS is a highly informative diagnostic strategy, which can be used for XP molecular etiology determination.

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of several genes belonging to the RAS Mitogen Activated Protein Kinase (MAPK) signaling pathway. Incontinentia Pigmenti (IP) is an X-linked, dominantly inherited multisystem disorder. CASE PRESENTATION: This study is the first report of the coexistence of Noonan (NS) and Incontinentia Pigmenti (IP) syndromes in the same patient. We report on the clinical phenotype and molecular characterization of this patient. The patient was examined by a pluridisciplinary staff of clinicians and geneticist. The clinical diagnosis of NS and IP was confirmed by molecular investigations. The newborn girl came to our clinics due to flagrant dysmorphia and dermatological manifestations. The clinical observations led to characterize the Incontinentia Pigmenti traits and a suspicion of a Noonan syndrome association. Molecular diagnosis was performed by Haloplex resequencing of 29 genes associated with RASopathies and confirmed the NS diagnosis. The common recurrent intragenic deletion mutation in IKBKG gene causing the IP was detected with an improved PCR protocol. CONCLUSION: This is the first report in the literature of comorbidity of NS and IP, two rare multisystem syndromes.

Low lamin A expression in lung adenocarcinoma cells from pleural effusions is a pejorative factor associated with high number of metastatic sites and poor Performance status.

The type V intermediate filament lamins are the principal components of the nuclear matrix, including the nuclear lamina. Lamins are divided into A-type and B-type, which are encoded by three genes, LMNA, LMNB1, and LMNB2. The alternative splicing of LMNA produces two major A-type lamins, lamin A and lamin C. Previous studies have suggested that lamins are involved in cancer development and progression. A-type lamins have been proposed as biomarkers for cancer diagnosis, prognosis, and/or follow-up. The aim of the present study was to investigate lamins in cancer cells from metastatic pleural effusions using immunofluorescence, western blotting, and flow cytometry. In a sub-group of lung adenocarcinomas, we found reduced expression of lamin A but not of lamin C. The reduction in lamin A expression was correlated with the loss of epithelial membrane antigen (EMA)/MUC-1, an epithelial marker that is involved in the epithelial to mesenchymal transition (EMT). Finally, the lamin A expression was inversely correlated with the number of metastatic sites and the WHO Performance status, and association of pleural, bone and lung metastatic localizations was more frequent when lamin A expression was reduced. In conclusion, low lamin A but not lamin C expression in pleural metastatic cells could represent a major actor in the development of metastasis, associated with EMT and could account for a pejorative factor correlated with a poor Performance status.

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition. PATIENTS AND METHODS: We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents. RESULTS: Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del). CONCLUSION: Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features.

A High Throughput Phenotypic Screening reveals compounds that counteract premature osteogenic differentiation of HGPS iPS-derived mesenchymal stem cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation. Results revealed seven compounds that normalized the osteogenic differentiation process and, among these, all-trans retinoic acid and 13-cis-retinoic acid, that also decreased progerin expression. This study highlights the potential of high-throughput drug screening using HGPS iPS-derived cells, in order to find therapeutic compounds for HGPS and, potentially, for other aging-related disorders.

Antisense-Based Progerin Downregulation in HGPS-Like Patients' Cells.

Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named "HGPS-like" patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90) at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A Δ35, Prelamin A Δ90) in HGPS-like patients' cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A), was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.

Novel LMNA mutations cause an aggressive atypical neonatal progeria without progerin accumulation.

BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations in LMNA leading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause. METHODS AND RESULTS: Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia. However, pathological signs appear earlier, are more aggressive and present distinctive features including episodes of severe upper airway obstruction. Exome and Sanger sequencing allowed the identification of heterozygous de novo c.163G>A, p.E55K and c.164A>G, p.E55G mutations in LMNA as the alterations responsible for this disorder. Functional analyses demonstrated that fibroblasts from these patients suffer important dysfunctions in nuclear lamina, which generate profound nuclear envelope abnormalities but without progerin accumulation. These nuclear alterations found in patients' dermal fibroblasts were also induced by ectopic expression of the corresponding site-specific LMNA mutants in control human fibroblasts. CONCLUSIONS: Our results demonstrate the causal role of p.E55K and p.E55G lamin A mutations in a disorder which manifests novel phenotypic features of the progeria spectrum characterised by neonatal presentation and aggressive clinical evolution, despite being caused by lamin A/C missense mutations with effective prelamin A processing.

Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome.

BACKGROUND: SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance. CASE PRESENTATION: In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene. CONCLUSIONS: We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective.

Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.

Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

Acro-osteolysis, keloid like-lesions, distinctive facial features, and overgrowth: two newly recognized patients with premature aging syndrome, Penttinen type.

We report on two unrelated patients with a rare progeroid syndrome first described by Penttinen. Patients presented with prematurely aged appearance, delayed dental development, acro-osteolysis, diffuse keloid-like lesions, and ocular pterygia. Facial features are progressive but recognizable at birth. Premaxillary and maxillary retraction with pseudo-prognathism and palpebral malocclusion are characteristic. Thumbs and halluces are broad and spatulated. Linear growth is increased and intellectual functions are preserved. Skin retractions and joint contractures progressively developed during adolescence. Death occurred in the second decade in one of the patient due to restrictive respiratory insufficiency and cachexia. LMNA and ZMPSTE24 sequencing were normal. The molecular basis of the disorder remains unknown.

An inherited LMNA gene mutation in atypical Progeria syndrome.

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation.

Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T>C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general.

Restrictive dermopathy in a Turkish newborn.

A 4-day-old boy presented with tight, translucent skin, prominent vessels, skin erosions, and dysmorphic findings, including hypertelorism, antimongoloid axis, sparse eyelashes and eyebrows, pinched nose, natal teeth, microretrognathia, and an "o-shaped" mouth. Multiple joint contractures, dysplastic clavicles, and thin ribs were also observed. He died at 2 weeks of age of respiratory distress. The patient was diagnosed as being affected with restrictive dermopathy, which is a rare, lethal genodermatosis caused by recessive mutations of the zinc metalloproteinase ZMPSTE24 gene or less frequently, by dominant lamin A/C gene mutations. Direct sequencing of the ZMPSTE24 gene was performed, and the most common, homozygous, inactivating mutation in exon 9 was identified in the patient (c.1085_1086insT; p.Leu362PhefsX19). Autosomal recessive transmission was confirmed by parental DNA analysis. After genetic counseling, a prenatal diagnosis could be performed during the subsequent pregnancy. ZMPSTE24 screening was performed by direct sequencing and fluorescent fragment analysis on DNA derived from a chorionic villus sample after exclusion of maternal contamination. The fetus had inherited both normal parental alleles, avoiding the recurrence of the disease.

An association of Hutchinson-Gilford progeria and malignancy.

Mutations in the LMNA gene encoding lamins A/C are responsible for a variety of disorders, commonly referred to as "laminopathies," including the segmental premature aging syndrome Hutchinson-Gilford progeria. We describe in this report the rare association of osteosarcoma and slowly progressing progeria in an 11-year-old girl carrying a truncating heterozygous c.1868C > G (p.T623S) prelamin A mutation. These findings are discussed in light of recent data on the pathophysiological mechanisms underlying progeria and "physiological" aging in human, as well as previous data on other well-known segmental aging syndromes.