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A wide range of 3-selenylindoles were synthesized via an eco-friendly approach that uses Oxone® as the oxidant in the presence of a catalytic amount of iodine. This mild and economical protocol showed broad functional group tolerance and operational simplicity. A series of novel selenylindoles bearing a benzenesulfonamide moiety were also synthesized and evaluated as carbonic anhydrase inhibitors of the human (h) isoforms hCa I, II, IX, and XII, which are involved in pathologies such as glaucoma and cancer. Several derivatives showed excellent inhibitory activity towards these isoforms in the nanomolar range, lower than that shown by acetazolamide.
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Bencenosulfonamidas , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Indoles , Yodo , Oxidación-Reducción , Sulfonamidas , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Humanos , Anhidrasas Carbónicas/metabolismo , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Yodo/química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
We report a case of a patient with a de novo germline heterozygous truncating variant of CTNNB1 gene (c.2172del, p.Tyr724Ter) causing neurodevelopmental disorder with spastic diplegia and visual defects syndrome (NEDSDV) associated with a new clinical feature - severe pediatric-onset osteoporosis and multiple fractures. A functional effect of the identified variant was demonstrated using adipose-tissue derived primary mesenchymal stem cells, where we detected the alteration of CTNNB1mRNA and ß-catenin protein levels using real-time PCR and Western blot analysis.
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Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome caused by inactivating mutations in the MEN1 tumor suppressor gene. The three main clinical manifestations of MEN1 are primary hyperparathyroidism (PHPT), duodenal-pancreatic neuroendocrine tumors (DP-NETs) and anterior pituitary tumors. Endocrine tumors in patients with MEN1 differ from sporadic tumors because of their younger age at onset, common multiple presentations and the different clinical course. MEN1 is characterized by a complex clinical phenotype; thus, patients should be followed by a multidisciplinary team of experts that includes an endocrinologist, a surgeon, a oncologist, a radiotherapist, and not least, a nutritionist. It is important to remember the fundamental role that diet plays as a primary prevention tool, together with a healthy and active lifestyle in preventing osteoporosis/osteopenia and reducing the risk of developing kidney stones due to hypercalciuria, two frequent clinical complications in MEN1 patients. Is very important for MEN1 patients to have an adequate intake of calcium, vitamin D, magnesium and phosphate to maintain good bone health. The intake of foods containing oxalates must also be kept under control because in combination with calcium they concur to form calcium oxalate crystals, increasing the risk of nephrolithiasis. Another aspect to consider is the management of patients with pancreatic neuroendocrine tumors undergoing major surgical resections of the pancreas that can lead to alterations in digestion and absorption mechanisms due to partial or total reduction in pancreatic enzymes such as amylase, lipase, and protease, resulting in malabsorption and malnutrition. Therefore, the nutritionist's aim should be to devise a dietary plan that takes into consideration each single patient, educating them about a healthy and active lifestyle, and accompanying them through various life stages by implementing strategies that can enhance their quality of life.
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Neoplasia Endocrina Múltiple Tipo 1 , Estado Nutricional , Humanos , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Neoplasia Endocrina Múltiple Tipo 1/terapiaRESUMEN
Few studies have evaluated the association between circulating levels of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and the endocrine disruptor bisphenol A (BPA), with risk of cardiovascular (CV) disease in elderly individuals. This was a cross-sectional study in a subgroup of elderly people from the InCHIANTI Biobank in Italy. We examined the association between circulating serum vitamin D metabolites, 1,25(OH)2D, 25(OH)D, and the endocrine disrupting agent BPA, with an arbitrary CV risk score and the European Society of Cardiology-based 10-year CV risk (SCORE2/SCORE2-OP) using univariate and multiple regression. In 299 individuals, blood samples were tested for serum values of 25(OH)D, 1,25(OH)2D and urinary BPA levels. One hundred eighty individuals (60.2%) were deficient (< 20 ng/ml) in 25(OH)D. Levels of 25(OH)D and 1,25(OH)2D were negatively correlated with CV risk score (p < 0.0001 for both) as well as SCORE2/SCORE2-OP (p < 0.0001 for both) while BPA levels were positively correlated with both CV risk scores (p < 0.0001 for both). In a logistic regression model, male gender (odds ratio; OR: 2.1, 95% CI:1.1-3.8, p = 0.022), obesity (OR:2.8, 95% CI:1.2-6.5, p = 0.016) and BPA levels ≥ 110 ng/dl (OR:20.9, 95% CI:9.4-46.8, p < 0.0001) were associated with deficient levels of 25(OH)D. 1,25(OH)2D levels < 41 ng/dl and 25(OH)D levels < 20 ng/ml were associated with CV risk score ≥ 3 (OR: 4.16, 95% CI: 2.32-7.4, p < 0.0001 and OR: 1.86, 95% CI: 1.02-3.39, p = 0.044) respectively and 1,25(OH)2D levels < 41 ng/dl were associated with SCORE2/SCORE2-OP of ≥ 20% (OR:2.98, 95% CI: 1.7-5.2, p = 0.0001). In this cross-sectional analysis, BPA exposure was associated with significantly reduced levels of vitamin D that in turn were significantly associated with increased CV risk.
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Insulinoma and glucagonoma are two rare functioning neoplasms of the neuroendocrine cells of the pancreas, respectively, characterized by an uncontrolled over-secretion of insulin or glucagon, responsible for the development of the hypoglycemic syndrome and the glucagonoma syndrome. They prevalently arise as sporadic tumors; only about 10% of cases develop in the context of rare inherited tumor syndromes, such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC), being the result of an autosomal-dominant germline heterozygous loss-of-function mutation in a tumor-suppressor gene. Here, we reviewed the main epidemiological and clinical aspects of insulinoma and glucagonoma in the context of genetic syndromes.
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Glucagonoma , Insulinoma , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Humanos , Insulinoma/genética , Insulinoma/patología , Glucagonoma/genética , Glucagonoma/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasia Endocrina Múltiple Tipo 1/genética , Páncreas/patologíaRESUMEN
Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.
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Hipofosfatasia , Adulto , Niño , Humanos , Adolescente , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Fosfatasa Alcalina/genética , Europa (Continente) , Prevalencia , MutaciónRESUMEN
Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.
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Hipofosfatasia , Lactante , Adulto , Recién Nacido , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiología , Hipofosfatasia/genética , Fosfatasa Alcalina/genética , Mutación , PrevalenciaRESUMEN
BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
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Hipofosfatasia , Adulto , Niño , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Mutación , Estudios Retrospectivos , Fosfatasa Alcalina/genética , Genotipo , FenotipoRESUMEN
Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium-phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported a 33-year-old male patient presenting a history of recurrent nephrolithiasis and early onset osteopenia in the lumbar spine and femur. He was tested, through next generation sequencing (NGS), by using a customized multigenic panel containing 33 genes, whose mutations are known to be responsible for the development of congenital parathyroid diseases. Two further genes, SLC34A1 and SLC34A3, encoding two sodium-phosphate cotransporters, were additionally tested. A novel germline heterozygous mutation was identified in the SLC34A1 gene, c.1627G>T (p.Gly543Cys), currently not reported in databases of human gene mutations and scientific literature. SLC34A1 germline heterozygous mutations have been associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1). Consistently, alongside the clinical features of NPHLOP1, our patient experienced recurrent nephrolithiasis and lumbar and femoral osteopenia at a young age. Genetic screening for the p.Gly453Cys variant and the clinical characterization of his first-degree relatives associated the presence of the variant in one younger brother, presenting renal colic and microlithiasis, suggesting p.Gly453Cys is possibly associated with renal altered function in the NPHLOP1 phenotype.
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Raquitismo Hipofosfatémico Familiar , Nefrolitiasis , Osteoporosis , Humanos , Masculino , Adulto , Nefrolitiasis/complicaciones , Nefrolitiasis/genética , Raquitismo Hipofosfatémico Familiar/genética , Mutación , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato/genética , Sodio , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIaRESUMEN
Pancreatic neuroendocrine neoplasms (PNENs) affect over 80% of patients with multiple endocrine neoplasia type 1 (MEN1). Surgery is usually the therapy of choice, but the real immediate and long-term therapeutic benefit of a partial extensive pancreatic resection remains controversial. We analyzed, in 43 PNEN MEN1 patients who underwent 19 pancreaticoduodenectomies (PD), 19 distal pancreatectomies (DP), and 5 minimal pancreatectomies, the prevalence of surgery-derived early complications and post-operative pancreatic sequelae, and the PNEN relapse-free survival time after surgery, comparing major (PD+DP) and minimal pancreatic surgeries. No post-operative mortality was observed. Metastatic cancers were found in 12 cases, prevalently from duodenal gastrinoma. Long-term cure of endocrine syndromes, by the 38 major pancreatic resections, was obtained in 78.9% of gastrinomas and 92.9% of insulinomas. In only one patient, hepatic metastases, due to gastrinoma, progressed to death. Out of the 38 major surgeries, only one patient was reoperated for the growth of a new PNEN in the remnant pancreas. No functioning PNEN persistence was reported in the five minimal pancreatic surgeries, PNEN relapse occurred in 60% of patients, and 40% of cases needed further pancreatic resection for tumor recurrence. No significant difference in PNEN relapse-free survival time after surgery was found between major and minimal pancreatic surgeries.
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Due to its essential role in calcium and phosphate homeostasis, the secosteroid hormone calcitriol has received growing attention over the last few years. Calcitriol, like other steroid hormones, may function through both genomic and non-genomic mechanisms. In the traditional function, the interaction between the biologically active form of vitamin D and the vitamin D receptor (VDR) affects the transcription of thousands of genes by binding to repeated sequences present in their promoter region, named vitamin D-responsive elements (VDREs). Non-transcriptional effects, on the other hand, occur quickly and are unaffected by inhibitors of transcription and protein synthesis. Recently, calcifediol, the immediate precursor metabolite of calcitriol, has also been shown to bind to the VDR with weaker affinity than calcitriol, thus exerting gene-regulatory properties. Moreover, calcifediol may also trigger rapid non-genomic responses through its interaction with specific membrane vitamin D receptors. Membrane-associated VDR (mVDR) and protein disulfide isomerase family A member 3 (Pdia3) are the best-studied candidates for mediating these rapid responses to vitamin D metabolites. This paper provides an overview of the calcifediol-related mechanisms of action, which may help to better understand the vitamin D endocrine system and to identify new therapeutic targets that could be important for treating diseases closely associated with vitamin D deficiency.
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Calcifediol , Calcitriol , Calcitriol/farmacología , Calcitriol/metabolismo , Receptores de Calcitriol/genética , Vitamina D , Regulación de la Expresión Génica , HomeostasisRESUMEN
Autosomal dominant hypocalcemia (ADH1) is a genetic disorder characterized by low serum calcium and low or inappropriately normal levels of parathyroid hormone. The disease is caused by a heterozygous activating mutation of the calcium-sensing receptor (CaSR) gene, encoding a G-Protein-coupled cell membrane sensor of extracellular calcium concentration mainly expressed by parathyroid glands, renal tubules, and the brain. ADH1 has been linked to 113 unique germline mutations, of which nearly 96% are missense mutations. There is often a lack of a clear genotype/phenotype correlation in the reported literature. Here, we described a case series of 6 unrelated ADH1 probands, each one bearing a gain-of-function CaSR mutation, and two children of one of these cases, matching our identified mutations to the same ones previously reported in the literature, and comparing the clinical and biochemical characteristics, as well as the complication profile. As a result of these genetic and clinical comparisons, we propose that a genotype/phenotype correlation may exist because our cases showed similar presentation, characteristics, and severity, with respect to published cases with the same or similar mutations. We also contend that the severity of the presentation is highly influenced by the specific CaSR variant. These findings, however, require further evaluation and assessment with a systematic review.
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Mutación con Ganancia de Función , Receptores Sensibles al Calcio , Receptores Sensibles al Calcio/genética , Calcio , Investigación , MutaciónRESUMEN
A new protocol for the synthesis of N-vinyl azoles using vinyl selenones and azoles in the presence of potassium hydroxide was developed. This reaction proceeded under mild and transition metal-free conditions through an addition/elimination cascade process. Both aromatic and aliphatic vinyl selenones and various mono-, bi- and tri-cyclic azoles can be tolerated and give terminal N-vinyl azoles in moderate to high yields. A plausible mechanism is also proposed.
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Food supplements should not contain substances considered unsafe or pose a health risk to consumers. In recent years illegal adulterants have been found in various functional foods without notification of their presence or amount in the labelling. In this study, a validated method was developed and applied as a screening method to detect 124 forbidden substances belonging to 13 classes of compounds in food supplements. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) and a simple and rapid extraction protocol was applied to 110 food supplements collected from the internet market or during official controls in Italy. The percentage of non-compliant samples was 4.5%, relatively high compared with the official control results for these substances usually obtained on other food matrices. The results suggested the need to strengthen controls in this field to detect food supplement adulteration, which represents a potential health risk for the consumer.
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Suplementos Dietéticos , Contaminación de Alimentos , Contaminación de Alimentos/análisis , Espectrometría de Masas/métodos , Cromatografía Liquida , Suplementos Dietéticos/análisis , Preparaciones Farmacéuticas , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Vitamin D deficiency is a constantly growing health problem worldwide. Adults affected with hypovitaminosis D could experience negative consequences on their musculoskeletal system and extra-skeletal health. In fact, an optimal vitamin D status is essential to ensure the correct bone, calcium, and phosphate homeostasis. To improve vitamin D status, it is important to not only increase the intake of food fortified with vitamin D, but also to administer vitamin D supplementation when required. Vitamin D3 (cholecalciferol) is the most widely used supplement. In recent years, the administration of calcifediol (25(OH)D3), the direct precursor of the biologically active form of vitamin D3, as oral vitamin D supplementation has progressively grown. Here, we report the potential medical benefits of some peculiar biological actions of calcifediol, discussing the possible specific clinical scenarios in which the oral intake of calcifediol could be most effective to restore the correct serum levels of 25(OH)D3. In summary, the aim of this review is to provide insights into calcifediol-related rapid non-genomic responses and the possible use of this vitamin D metabolite as a supplement for the treatment of people with a higher risk of hypovitaminosis D.
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Parathyroid carcinoma (PC) is an extremely rare malignant tumor of the parathyroid glands, accounting for less than 1% of primary hyperparathyroidism, commonly characterized by severe and unmanageable hypercalcemia, aggressive behavior, high metastatic potential, and poor prognosis. PC manifests prevalently as a sporadic tumor and only occasionally it is part of congenital syndromic and non-syndromic endocrine diseases. Molecular pathogenesis of this form of parathyroid tumor is not fully elucidated and it appears to be caused by multiple genetic and epigenetic drivers, differing among affected patients and not yet clearly stated in distinguishing PC from the benign parathyroid adenoma (PA). Congenital forms of PC have been prevalently associated with germline heterozygous loss-of-function mutations of the CDC73 tumor suppressor gene, both in the context of the hyperparathyroidism jaw-tumor syndrome (HPT-JT) and of the isolated familial hyperparathyroidism (FIPH). Currently, surgical en bloc resection of affected gland(s) and other involved structures is the elective therapy for both primary and recurrent PC. However, it usually results ineffective for advance and metastatic disease, and a high percentage of post-operative recurrence is reported. Targeted medical therapies for surgically untreatable PC, based on the molecular profile of PC samples, are, therefore, needed. The characterization of genetic and epigenetic alterations and deregulated pathways in PC samples will be of fundamental importance to tailor treatment for each patient. Here, we reviewed main findings on molecular pathogenetic aspects of PC, and the current state of the art of therapies.
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Hiperparatiroidismo Primario , Neoplasias Maxilomandibulares , Neoplasias de las Paratiroides , Humanos , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/terapia , Neoplasias de las Paratiroides/complicaciones , Proteínas Supresoras de Tumor/genética , Recurrencia Local de Neoplasia , Neoplasias Maxilomandibulares/genética , Neoplasias Maxilomandibulares/terapia , Hiperparatiroidismo Primario/complicacionesRESUMEN
Introduction: Position sense, which belongs to the sensory stream called proprioception, is pivotal for proper movement execution. Its comprehensive understanding is needed to fill existing knowledge gaps in human physiology, motor control, neurorehabilitation, and prosthetics. Although numerous studies have focused on different aspects of proprioception in humans, what has not been fully investigated so far are the neural correlates of proprioceptive acuity at the joints. Methods: Here, we implemented a robot-based position sense test to elucidate the correlation between patterns of neural activity and the degree of accuracy and precision exhibited by the subjects. Eighteen healthy participants performed the test, and their electroencephalographic (EEG) activity was analyzed in its µ band (8-12 Hz), as the frequency band related to voluntary movement and somatosensory stimulation. Results: We observed a significant positive correlation between the matching error, representing proprioceptive acuity, and the strength of the activation in contralateral hand motor and sensorimotor areas (left central and central-parietal areas). In absence of visual feedback, these same regions of interest (ROIs) presented a higher activation level compared to the association and visual areas. Remarkably, central and central-parietal activation was still observed when visual feedback was added, although a consistent activation in association and visual areas came up. Conclusion: Summing up, this study supports the existence of a specific link between the magnitude of activation of motor and sensorimotor areas related to upper limb proprioceptive processing and the proprioceptive acuity at the joints.
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Osteoporosis is characterized by the alteration of bone homeostasis due to an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Estrogen deficiency causes bone loss and postmenopausal osteoporosis, the pathogenesis of which also involves oxidative stress, inflammatory processes, and the dysregulation of the expression of microRNAs (miRNAs) that control gene expression at post-transcriptional levels. Oxidative stress, due to an increase in reactive oxygen species (ROS), proinflammatory mediators and altered levels of miRNAs enhance osteoclastogenesis and reduce osteoblastogenesis through mechanisms involving the activation of MAPK and transcription factors. The present review summarizes the principal molecular mechanisms involved in the role of ROS and proinflammatory cytokines on osteoporosis. Moreover, it highlights the interplay among altered miRNA levels, oxidative stress, and an inflammatory state. In fact, ROS, by activating the transcriptional factors, can affect miRNA expression, and miRNAs can regulate ROS production and inflammatory processes. Therefore, the present review should help in identifying targets for the development of new therapeutic approaches to osteoporotic treatment and improve the quality of life of patients.
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MicroARNs , Osteoporosis , Humanos , MicroARNs/genética , Especies Reactivas de Oxígeno , Calidad de Vida , Osteoporosis/metabolismo , Estrés Oxidativo/fisiología , Osteogénesis/genética , Factores de Transcripción/metabolismo , InflamaciónRESUMEN
OBJECTIVE: Atypical femur fractures (AFFs) are rare fragility fractures originating at the lateral cortex of the femur, affecting the subtrochanteric or diaphyseal area of thebone with a transverse morphology. Occurrence of AFF is specifically associated with a small number of rare monogenic congenital metabolic bone disorders, such as hypophosphatasia, and with long-term treatment with antiresorptiondrugs. The exact pathogenesis of these fractures remains poorly understood and, except for cases of diagnosed HPP or other AFF-causing bone diseases, it is not possible to assess which patients are at higher riskof developing AFFs as a consequence of anti-resorption therapy. DESIGN: We genetically screened 25 unrelated patients who had developed at least one AFF. INTERVENTION: Genetic screening was performed through a nextgeneration sequencing analysis with a customized panel containing 76 human genes involved in the regulation of the mineralization processWe genetically screened 25 unrelated patients who had developed at least one AFF. RESULTS: We found a relatively high frequency (32.0%) of heterozygous rare variants inthe SLC34A1 and SLC9A3R1 genes, two genes whose heterozygous inactivating mutations have been respectively associated with autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis types 1 and 2 (NPHLOP1and NPHLOP2). Other heterozygous rare variants were found in the BMPR1B, CYP27B1, FBN1, MEPE, PIGO, and PHOSPHO1 genes, each in a single AFF case (4.0%). CONCLUSIONS AND RELEVANCE: Our findings suggest that rarevariants of SLC34A1 and SLC9A3R1 could represent a possible genetic risk factor for the occurrence of AFFs. On the other hand, AFFs could represent an unsuspected clinical manifestation and/or an anti-resorption therapycorrelatedadverse event in patients with NPHLOP disorders.