Hereditary syndromes with signs of premature aging

Aging is a multi-factor biological process that inevitably affects everyone. Degenerative processes, starting at the cellular and molecular levels, gradually influence the change in the functional capabilities of all organs and systems. Progeroid syndromes (from Greek. progērōs prematurely old), or premature aging syndromes, represent clinically and genetically heterogeneous group of rare hereditary diseases characterized by accelerated aging of the body. Progeria and segmental progeroid syndromes include more than a dozen diseases, but the most clear signs of premature aging are evident in Hutchinson-Guilford Progeria Syndrome and Werner Syndrome. This review summarizes the latest scientific data reflecting the etiology and clinical picture of progeria and segmental progeroid syndromes in humans. Molecular mechanisms of aging are considered, using the example of progeroid syndromes. Modern possibilities and potential ways of influencing the mechanisms of the development of age-related changes are discussed. Further study of genetic causes, as well as the development of treatment for progeria and segmental progeroid syndromes, may be a promising direction for correcting age-related changes and increasing life expectancy

Osteogenesis imperfecta as a cause of death

Osteogenesis imperfecta (OI) is a rare heterozygous connective tissue disordercaused by mutations in genes that affect collagen components (in most cases mutations in COL1A1 и COL1A2 genes). The current classification system includes 15 types of OI, one of which (type II) is characterized by 100% intrauterine or perinatal mortality. The structure of mortality in other OI types is poorly understood because of the heterogeneity of clinical symptoms and the severity of connective tissue damage. W present a clinical case of type III osteogenesis imperfecta, complicated by generalized osteoporosis with multiple fractures of vertebrae and tubular bones and progressive kyphoscoliosis. Late-initiated treatment led to progression of the disease and led to cardiopulmonary insufficiency and death of the patient. Our clinical case highlights the importance of timely diagnosis, treatment and regular observation in patients with OI

Evaluation of diagnostic potential of the collagen osteogenesis marker (P1NP) compared with osteocalcin in Cushing’s disease

Background: Secondary osteoporosis is a significant problem, especially in patients with endocrine pathology, which is not accompanied constantly by distinct clinical symptoms. Markers of bone origin are needed, which could be used in osteoporosis diagnosis to clarify its genesis, especially in young people who have secondary osteoporosis more often than older patients. In Cushings disease (CD), such a marker, in addition to osteocalcin, could be another bone formation marker, procollagen type 1 N-terminal propeptide (P1NP). Aims: To study the diagnostic potential of P1NP as an additional marker of endogenous hypercortisolism (Cushings disease) compared to osteocalcin. Materials and methods: The study involved patients with Cushings disease and healthy volunteers, matched by gender, age, and body mass index. The levels of osteocalcin and P1NP were assessed in both groups, the electrochemiluminescence method for P1NP (Cobas e411 (Roche, Switzerland)) and for osteocalcin (Cobas 6000 Module e601 (Roche, Switzerland)) was used. ROC analysis was performed with the calculation of sensitivity and specificity of the method to determine the cut-off point for P1NP in CD diagnosis. Results: 29 patients with Cushings disease and 27 healthy individuals from the control group were included in the study. There were no differences in age, sex and body mass index (p = 0.488, 0.426 and 0.531, respectively). Both studied bone formation markers (osteocalcin and P1NP) were reduced in patients with CD: 8.53 ng/ml (Q25%;Q75% 5.40; 12.41) versus 22.45 ng/ml (Q25%;Q75% 17.36; 26.31) (p 0.001) and 28.50 ng/ml (Q25%;Q75% 18.00; 44.00) versus 56.50 ng/ml (Q25%;Q75% 39.50; 65.50) (p 0.001), respectively. The area under the receiver operating characteristic curve (AUC) was 0.808 (95% CI 0.6930.924) for P1NP and 0.925 (95% CI 0.8570.992) for osteocalcin, that indicates the greater diagnostic value of osteocalcin for CD verification in healthy controls. Optimal cut-off points were obtained: 53.4 ng/ml (values below are more typical for patients with CD; sensitivity of the method is 96.55%, specificity 57.69%) for P1NP and 15.285 ng/ml (below for patients with CD; sensitivity was 92.59%, specificity 77.78 %) for osteocalcin. Conclusions: The diagnostic potential of osteocalcin to detect Cushings disease in the population is higher compared to P1NP. However, applying of P1NP can be useful because, unlike osteocalcin, it is a direct indicator of the formation of bone matrix collagen structures, that is important for assessing the degree of inhibition of collagen type 1 synthesis in CD and deterioration of bone tissue due to glucocorticoid-induced osteoporosis

Sclerostin antibodies as novel anabolic therapy for osteoporosis

Osteoporosis medications are dividedinto two groups: those inhibiting bone resorption and formation (bisphosphonates and denosumab), and those stimulating bone formation i.e. having an anabolic effect. The latter include teriparatide, parathyroid hormone 1-84 and abaloparatide, all of which stimulate bone resorption as well as bone formation, which limits their anabolic effect. The discovery of sclerostin the key inhibitor of bone formation has led to development of the concept that inhibition of this protein could stimulate bone formation. Romosozumab is a human monoclonal antibody to sclerostin that binds to sclerostin and enables Wnt-signaling pathway ligands and their co-receptors to interact with each other, which, in turn, leads to increased bone formation and bone mineral density. Unlike classical anabolic drugs in osteoporosis treatment, romosozumab stimulates bone formation and inhibits bone resorption. In clinical trials, romosozumab showed marked increase in lumbar spine and hip bone mineral density. Presented article contains information about pre-clinical and clinical studies of romosozumab

Treatment of severe idiopathic hypoparathyroidism: a case report

Hypoparathyroidism is a rare disorder characterized by parathyroid hormone (PTH) insufficiency, the development of hypocalcemia and alteration of bone tissue remodeling. The goal of treatment is to normalize the indicators of calcium-phosphorus metabolism and leveling of clinical manifestations. Standard treatment of hypoparathyroidism consists of oral calcium and active forms of vitamin D, in doses necessary to maintain calcium levels at the lower limit of the reference interval. Nevertheless, treatment of the disease exerts certain difficulties in clinical practice. At the same time, compensation of the hypoparathyroidism is necessary to prevent ectopic calcification. Daily subcutaneous delivery of PTH (184) and PTH (134) has emerged as a promising therapeutic tool. However, its use should be restricted to patients insufficiently controlled with the standard treatment with active vitamin D and calcium. We present a clinical case of idiopathic hypoparathyroidism with severe clinical presentation of hypocalcaemia and ectopic calcification. Idiopathic hypoparathyroidism is a consequence of autoimmune destruction of the parathyroid glands and is exhibited by excluding all known causes of hypoparathyroidism. PTH (134) treatment allowed reducing the dose of calcium and vitamin D and achieving compensation of the disease

Case report of Sagliker syndrome in a young patient with secondary hyperparathyroidism and chronic renal failure

Sagliker syndrome is a rare complication of renal osteodystrophy, characterized by severe skeletal and cranium deformities, neurologic and soft tissue abnormalities in patients with chronic renal failure (CRF) and untreated secondary hyperparathyroidism. This article reports a 29-year-old female patient with end-stage CRF after 9 years of hemodialysis. She had severe secondary hyperparathyroidism, hyperplasia of three parathyroid glands and cranium and skeletal bone structure deformation. The first changes appeared after 4 years of therapy with peritoneal dialysis. They included uglifying face appearances, short stature, severe maxillary changes, chest deformity. During the examination we revealed severe tomographical and X-ray changes: maxillary and mandibular hyperplasia, temporomandibular articulation changes, affected cheekbones, sphenoid bone and bones of the cranial vault, fingertip changes, vertebral body compression. Although surgical parathyroidectomy was effective at biochemical abnormalities, severe bone deformities were not regressed. This case highlights the importance of clinicians attention for early monitoring and appropriate treatment of secondary hyperparathyroidism in patients with end-stage CRF

Dynamics of NT-proBNP and ST2 levels as markers of heart failure in patients with endogenous Cushing syndrome (hypercortisolism)

Aim. To evaluate frequency of heart failure syndrome in patients with endogenous hypercortisolism and to establish relationship between effective treatment for hypercortisolism and regression of heart failure with particular emphasis on the observation of NT-proBNP and ST2 levels. Materials and methods. 56 patients with endogenous hypercortisolism (45 female, mean age 47 years [36; 55] hospitalized with endogenous hypercortisolism to National Medical Research Center for Endocrinology were enrolled in the study. All patients underwent comprehensive clinical investigation including expert echocardiography with speckle tracking and evaluation of NT-proBNP and ST2 cardiac biomarkers at baseline and 6 months after surgical treatment. Results. According to clinical data and elevated biomarkers of cardiac stress 28 out of 56 patients (50%) at baseline met the criteria for heart failure. 20 patients were included in the final analysis. Follow-up investigation with focus on changes in NT-proBNP and ST2 levels demonstrated that surgical correction of endogenous hypercortisolism resulted in resolution of heart failure syndrome in 11 patients (55%). Conclusion. These preliminary data suggest that signs and symptoms of heart failure are observed in patients with endogenous hypercortisolism in about half the cases. Surgical correction results in resolution of heart failure in approximately two thirds of the cases. Prospective evaluation NT-proBNP and ST2 levels may provide important diagnostic and prognostic information in patients with endogenous hypercortisolism

Rare genetic diseases of the bone tissue: the case of a family with osteogenesis imperfecta and X-linked hypophosphataemia

Osteogenesis imperfecta (OI) and X-linked hypophosphataemia (XLH) are rare genetic diseases, which lead to childhood-onset bone fragility, low-trauma fractures and limb deformities. OI occurs as a result of impaired type 1 collagen synthesis at different stages, depending on the type of a genetic mutation, which leads to bone strength impairment. In most cases OI is a disorder with an autosomal dominant inheritance. However, there are also cases of autosomal recessive inheritance. To date, 16 types of OI are distinguished, with type 2 being the most severe due to 100% mortality rate in neonatal and perinatal periods. XLH is characterized by altered bone mineralization due to impaired phosphorus absorption and reabsorption, as a result of mutations in the PHEX gene. The bone tissue softens, and this process is accompanied by deformities in long tubular bones. In this article we describe the family, in which both diseases are presented, despite their rarity. The case is investigated from points of view: the clinicians and the patients perspective

First description of a type v osteogenesis imperfecta clinical case with severe skeletal deformities caused by a mutation p.119C> T in IFITM5 gene in Russia

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder. Main clinical manifestations include recurring pathological fractures and progressive skeletal deformation. Five types of OI are distinguished based on clinical symptoms. In most cases, the disease is caused by mutations in the COL1A1 and COL1A2 genes, leading to a defect of type 1 collagen synthesis, which is the main component of the bone matrix. Up to 5% of patients with OI have a mutation in IFITM5 gene, which leads to the development of OI type V. Approximately 150 cases of the OI type V are described in the literature, and mutation c.-14C T in IFITM5 gene is found in most of the cases. Only 5 patients have a c.119C T: p.S40L.mutation. Pathogenesis of OI type V is not fully understood. It is assumed that mutations in the IFITM5 gene cause impaired osteoblastogenesis, decreased bone mineral density and multiple low-traumatic fractures. There is probably a phenotype-genotypic correlation in cases with different mutations of the IFITM5. However, it is currently difficult to assess the relationship in view of the variability of the characters and the low prevalence of the OI type V. We present the first description in Russia of the clinical case of an adult patient with OI type V due to a rare mutation p.119C T: p.S40L in the IFITM5 gene

The changes of standard DXA measurements and TBS depending on outcomes of neurosurgical treatment in patients with Cushing's disease

BACKGROUND:Patients with endogenous hypercortisolism have reduced bone mineral density (BMD) and trabecular bone score (TBS) that are the causes of secondary osteoporosis and low-traumatic fractures. It is well known that radical treatment (neurosurgery or radiosurgery) of Cushings disease leads to a decline of cortisol levels in all body fluids to normal values. However, it is still uncertain whether bone tissue structure, and particularly its microarchitecture, does recover in remission of the disease. AIMS:To evaluate an influence of hormone activity (presence or absence of remission) in patients with Cushing's disease on changes of bone structure measurements in accordance with DXA values (TBS, BMD, T- and Z-scores), as well as significance of such changes in 12 and 24 months after neurosurgical treatment. MATERIALS AND METHODS:In patients with confirmed active Cushing's disease (ACTH-producing pituitary adenoma) (n = 44) and in control group of healthy volunteers (n = 40), BMD in lumbar spine (L1-L4) and simultaneously TBS, in cut-off points before neurosurgical treatment (in both groups) and in 12 and 24 months after it (only in patients), were assessed. We diagnosed presence or absence of disease remission at cut-offs. All measurements were performed using a GE iDXA device (GE Healthcare Lunar, Madison, Wisconsin, USA). The TBS was calculated simultaneously from taken BMD scans, blinded to clinical outcome using TBS iNsight software v2.1 (Medimaps, Merignac, France). The activity of Cushings disease was evaluated using late-night salivary cortisol (LNSC, at 23:00). To determine the differences in DXA and TBS values before and after neurosurgical intervention depending on remission occurrence, covariate analysis (ANCOVA) was applied. RESULTS:There were found significant changes in TBS, BMD and T-score values in 12 months after neurosurgical treatment associated with presence or absence of disease remission (p = 0.039, 0.046 and 0.048, respectively). No differences in Z-score as well as in all measurements in 24 months, that might be associated with remission occurrence, were revealed. The gain in all DXA measurements (including TBS) during 24 months of observation period was statistically significant when analyzing data using Students paired t-test. However, the values corresponding to the age references had not been achieved for the specified time interval. CONCLUSIONS:Patients with Cushings disease have lower TBS values. In remission conditions TBS is getting significantly higher. The increase in BMD and TBS occurs during 24 months after achieving remission of Cushings disease but doesnt lead to a full restoration of normal bone mass and microstructure throughout observation period of 24 months