Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies
Fanny KortümM. ChyrekSigrid FuchsBeate AlbrechtGabriele Gillessen‐KaesbachUlrike MützeE SeemanováSigrid TinschertDagmar WieczorekGeorg RosenbergerKerstin Kutsche
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Abstract:
Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24, respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.Keywords:
LMNA
Progeria
Premature aging
Hypotrichosis
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
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The metazoan nucleus is equipped with a meshwork of intermediate filament proteins called the A- and B-type lamins. Lamins lie beneath the inner nuclear membrane and serve as a nexus to maintain the architectural integrity of the nucleus, chromatin organization, DNA repair and replication and to regulate nucleocytoplasmic transport. Perturbations or mutations in various components of the nuclear lamina result in a large spectrum of human diseases collectively called laminopathies. One of the most well-characterized laminopathies is Hutchinson-Gilford progeria (HGPS), a rare segmental premature aging syndrome that resembles many features of normal human aging. HGPS patients exhibit alopecia, skin abnormalities, osteoporosis and succumb to cardiovascular complications in their teens. HGPS is caused by a mutation in LMNA, resulting in a mutated form of lamin A, termed progerin. Progerin expression results in a myriad of cellular phenotypes including abnormal nuclear morphology, loss of peripheral heterochromatin, transcriptional changes, DNA replication defects, DNA damage and premature cellular senescence. A key challenge is to elucidate how these different phenotypes are causally and mechanistically linked. In this mini-review, we highlight some key findings and present a model on how progerin-induced phenotypes may be temporally and mechanistically linked.
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Lamins belong to type V intermediate filaments superfamily. They are the main structural constituencies of the nuclear lamina but they also influence on chromatin structure, regulation of gene expression, localization and probably protein degradation. Because lamins play many different roles within the cell, mutations in their genes can results in variety of pathological phenotypes. Mutations in LMNA gene are the cause of many different diseases, called laminopathies. Among laminopathies are muscle tissue diseases, adipose tissue diseases and also progerias, the premature aging syndromes. One of the progerias, which results from mutation in LMNA gene, is Hutchinson-Gilford progeria syndrome (HGPS). It seems that the same molecular mechanisms which are responsible for premature aging of cells of HGPS patients, are involved in physiological aging.
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Lamin A, a product of the LMNA gene, is an essential nuclear envelope component in most differentiated cells. Mutations in LMNA have been linked to premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by progerin, an aberrant form of lamin A that leads to premature death, typically from the complications of atherosclerotic disease. A key characteristic of HGPS is a severe loss of vascular smooth muscle cells (VSMCs) in the arteries. Various mouse models of HGPS have been created, but few of them feature VSMC depletion and none develops atherosclerosis, the death-causing symptom of the disease in humans. We recently generated a mouse model that recapitulates most features of HGPS, including VSMC loss and accelerated atherosclerosis. Furthermore, by generating cell-type–specific HGPS mouse models, we have demonstrated a central role of VSMC loss in progerin-induced atherosclerosis and premature death.
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Abstract Hutchinson‐Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition that arises from a single nucleotide alteration in the LMNA gene, leading to the production of a defective lamin A protein known as progerin. The accumulation of progerin accelerates the onset of a dramatic premature aging phenotype in children with HGPS, characterized by low body weight, lipodystrophy, metabolic dysfunction, skin, and musculoskeletal age‐related dysfunctions. In most cases, these children die of age‐related cardiovascular dysfunction by their early teenage years. The absence of effective treatments for HGPS underscores the critical need to explore novel safe therapeutic strategies. In this study, we show that treatment with the hormone ghrelin increases autophagy, decreases progerin levels, and alleviates other cellular hallmarks of premature aging in human HGPS fibroblasts. Additionally, using a HGPS mouse model ( Lmna G609G/G609G mice), we demonstrate that ghrelin administration effectively rescues molecular and histopathological progeroid features, prevents progressive weight loss in later stages, reverses the lipodystrophic phenotype, and extends lifespan of these short‐lived mice. Therefore, our findings uncover the potential of modulating ghrelin signaling offers new treatment targets and translational approaches that may improve outcomes and enhance the quality of life for patients with HGPS and other age‐related pathologies.
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Hutchinson–Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670 ) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC→GGT) mutation within exon 11 of LMNA , which elicits a deletion of 50 aa near the C terminus of prelamin A. In this article, we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-dependent manner. In human HGPS fibroblast cultures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformations and invaginations preventable by farnesyltransferase inhibition. Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.
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Sir, Hutchinson–Gilford progeria syndrome (HGPS) is a rare, fatal, genetic condition of childhood with striking features resembling premature aging and profound growth delays, resulting in short stature and low weight and systemic hyperlipidemia. Here, we report a rare case of Hutchinson–Gilford syndrome with diabetes and hyperlipidemia with a heterozygous gene mutation in the LMNA gene-ENST00000368300.9, with a variant of uncertain significance in the mutation (p.Asp47Tyr), but presenting with mandibuloacral dysplasia (MAD) and acrogeroid features suggesting overlap of premature aging syndromes. The classic congenital premature aging syndromes include Werner’s syndrome, progeria, and acrogeria. These are rare genetic diseases associated with accelerated aging of the skin and other tissues. They come under the group of laminopathies due to mutations in the gene coding for lamin A (LMNA). Progeroid syndromes are a group of fatal, severe, and rare genetic disorders characterized by various clinical features and phenotypes of physiological aging prematurely. Among the different forms of progeria, the classical and most extensively studied type is the HGPS.[1] Acrogeria or Gottron’s syndrome begins at birth or soon afterward characterized by mild, non progressive form of skin atrophy involving the distal parts of the extremities with characteristic facies.[2] There have been many reports indicating that there is a considerable overlap between the premature aging syndromes as there is a common mutation in the gene LMNA in all these disorders.[3] Here, we report a rare case of Hutchinson–Gilford syndrome with a heterozygous gene mutation in the LMNA gene-ENST00000368300.9, with a variant of uncertain significance in the mutation (p.Asp47Tyr), but presenting with MAD and acrogeroid features suggesting of overlap of premature aging syndromes. A 23-year-old male patient born out of non-consanguineous marriage, with young onset diabetes mellitus presented with complaints of progressive skin thinning from birth and recurrent non healing ulcers over foot since the age of 8 years. The mother remembers that the child had hair on the scalp after birth and the head was normal in shape. There was no history of delayed milestones or seizures during childhood. There was no history of similar illness in family and siblings were normal. General examination revealed short stature with characteristic facies of beaked nose, hollowed-out cheeks, owl-eye appearance with thin lips, and micrognathia [Figure 1a] suggestive of acrogeria. The eyes were normal. The teeth were crowded and malformed. Dermatological examination showed sclerosis of the skin over distal third of all four extremities with dry, atrophic skin and loss of subcutaneous fat with prominent dilated veins and mottled pigmentation [Figure 1b]. Joint contracture was present over both knees [Figure 2a]. The patient had normal intelligence and the gonads were normal.Figure 1: (a) Beaked nose, hollowed-out cheeks, “owl eye” appearance with thin lips, and micrognathia suggestive of acrogeroid facies. (b) Sclerosis of the hands with mottled pigmentationFigure 2: (a) Sclerosis of the lower limbs with dilated veins and knee joint contractures. (b) X-ray of the hands showing acral osteolysisOn investigations, patient had elevated triglyceride levels (1672 mg/dL) and increased blood sugar levels. X-ray of hands showed acral osteolysis [Figure 2b], while X-ray of the chest showed normal thorax and normal clavicles.Arterial Doppler of bilateral lower limbs showed diffuse atherosclerotic wall thickening. ECG and echo cardiography did not show any abnormalities. CT scan and ultrasound abdomen of the patient were normal. Skin biopsy revealed homogenization of collagen and mild perivascular lymphocytic infiltrate suggestive of sclerodermatous histopathology [Figure 3]. A clinical exome genetic study showed LMNA mutation (ENST00000368300.9) with a variant of uncertain significance in the mutation (p.Asp47Tyr), suggestive of Hutchinson–Gilford syndrome (Progeria) with MAD overlap [Table 1].Figure 3: Skin biopsy showing homogenization of collagen and mild perivascular lymphocytic infiltrate suggestive of sclerodermatous change, H and E ×100Table 1: Genetic study of the patient indicating Hutchinson-Gilford syndrome with mandibuloacral dysplasia overlapHGPS presents with macrocephaly and dilated scalp veins at birth or soon after birth. Scalp hair is absent or sparse. The patient has beaked nose and short stature, altogether giving a “plucked bird” appearance. The skin has sclerodermoid changes with mottled pigmentation and long bones have acro-osteolytic changes. MAD presents with typical facies of micro gnathism and mandibular hypoplasia along with diabetes. Acrogeria presents with beaked nose, hollowed-out cheeks, “owl eye” appearance with thin lips, and micrognathia along with atrophy of the skin and subcutaneous tissue and with poikiloderma and telangiectasia. Our patient had facies of beaked nose, hollowed-out cheeks, owl-eye appearance with thin lips, and micrognathia suggestive of acrogeria [Figure 1a].Our patient has short stature, the teeth showed crowding and malformation, the skin of abdomen, and the limbs showed sclerodermoid features with mottled pigmentation, loss of subcutaneous fat, dilated veins, and joint contractures [Figures 1b and 2a]. Systemically there was elevated serum triglycerides levels. X-ray of the hands showed acro-osteolysis [Figure 2b]. All these are features of HGPS. However, the features of macrocephaly and alopecia at birth were absent in our patient. In addition, the patient had micrognanthia and mandibular hypoplasia with diabetes which are features of MAD. Genetic study showed features of HGPS with MAD overlap [Table 1]. Therefore, we made a diagnosis of HGPS presenting with MAD and Acrogeroid features, indicating overlap of premature aging syndromes. However, MAD type A and HGPS are caused by the same gene and may represent a single disorder with varying degrees of severity. The primary mutation in this patient was on the Exon 1 and qualifying for HGSP with MAD. But the genetic study also showed a variation in the mutation (p.Asp47Tyr) and we believe that this variation was responsible for the patient presenting with acrogeroid features and lacking some features of classical HGPS. Classical HGPS is usually caused by a sporadic autosomal dominant mutation in LMNA gene and/or abnormal posttranslational processing of ZMPSTE24 gene, both of which ultimately result in abnormally formed lamin A called progerin. Lamin A is a key protein component of nuclear scaffolding that holds the nucleus together by forming the inner layer of the membrane. This defect caused the typical phenotype of HGPS and cardiovascular defects at a very young age resulting in premature death. MAD can also present with short stature, bird-like facies, and micro gnathism like HGSP, but in addition, there may be diabetes. Our patient was diabetic. There is considerable overlap between HGSP and MAD (MAD type A) as in both premature aging syndromes, the mutation is in the LMNA gene, even though it is in the Exon 8–10 region for MAD and Exon 1 for HGSP and this has been reported in literature.[45] However, targeted mutation analysis could not be done in our case due to lack of resources. There is no specific treatment for premature aging syndromes. HGSP patients must have frequent cardiovascular reviews. Imaging tests should be done at regular intervals as malignancy-like fibrosarcomas can occur.[6] Mutation in the LMNA gene forms a defective lamin A protein which causes accumulation of prelamin A in the nucleus which causes defective DNA synthesis. A class of anticancer drugs (Tipifarnib) which inhibits the enzyme farnesyltransferase in trials is known to reverse the aforementioned changes in the nucleus and could be a promising drug in the future.[7] We are reporting a very rare presentation of overlap of premature aging syndromes and overlap of HGPS and MAD with acrogeria has not been reported in literature to the best of our knowledge. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
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Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.
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Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition arising from a single nucleotide alteration in the LMNA gene, which leads to the production of a defective lamin A protein known as progerin. The buildup of progerin hastens the onset of premature and expedited aging. Patients with HGPS exhibit short stature, low body weight, lipodystrophy, metabolic dysfunction, and skin and musculoskeletal abnormalities and, in most cases, die of cardiovascular disease by their early teenage years. Currently, no effective cure or treatment for the disease highlights the importance of discovering new therapeutic strategies. Herein, we present evidence that the hormone ghrelin, besides promoting autophagy and progerin clearance, rescued several cellular hallmarks of premature aging of human HGPS fibroblasts. Using an HGPS mouse model, Lmna G609G/G609G mice, we also show that ghrelin administration rescued the short-lived mice molecular and histopathological progeroid features, prevented progressive weight loss at later stages, reverted the lipodystrophic phenotype, and extended lifespan. Thus, we disclose that modulation of ghrelin signaling may give rise to new treatment targets and translational approaches that may improve outcomes and the health quality of HGPS patients and natural aging pathologies.
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