First-line Diagnostic Approach Research Articles

AI-Driven Colon Cleansing Evaluation in Capsule Endoscopy: A Deep Learning Approach

Gastroenterology is increasingly moving towards minimally invasive diagnostic modalities. The diagnostic exploration of the colon via capsule endoscopy, both in specific protocols for colon capsule endoscopy and during panendoscopic evaluations, is increasingly regarded as an appropriate first-line diagnostic approach. Adequate colonic preparation is essential for conclusive examinations as, contrary to a conventional colonoscopy, the capsule moves passively in the colon and does not have the capacity to clean debris. Several scales have been developed for the classification of bowel preparation for colon capsule endoscopy. Nevertheless, their applications are limited by suboptimal interobserver agreement. Our group developed a deep learning algorithm for the automatic classification of colonic bowel preparation, according to an easily applicable classification. Our neural network achieved high performance levels, with a sensitivity of 91%, a specificity of 97% and an overall accuracy of 95%. The algorithm achieved a good discriminating capacity, with areas under the curve ranging between 0.92 and 0.97. The development of these algorithms is essential for the widespread adoption of capsule endoscopy for the exploration of the colon, as well as for the adoption of minimally invasive panendoscopy.

Real-World Diagnostic Accuracy of the On-Site Cytopathology Advance Report (OSCAR) Procedure Performed in a Multidisciplinary One-Stop Breast Clinic.

Fine-needle aspiration (FNA) cytology has been widely used for the diagnosis of breast cancer lesions with the objective of differentiating benign from malignant masses. However, the occurrence of unsatisfactory samples and false-negative rates remains a matter of concern. Major improvements have been made thanks to the implementation of rapid on-site evaluation (ROSE) in multidisciplinary and integrated medical settings such as one-stop clinics (OSCs). In these settings, clinical and radiological examinations are combined with a morphological study performed by interventional pathologists. The aim of our study was to assess the diagnostic accuracy of the on-site cytopathology advance report (OSCAR) procedure on breast FNA cytologic samples in our breast OSC during the first three years (April 2004 till March 2007) of its implementation. To this goal, we retrospectively analyzed a series of 1820 breast masses (1740 patients) radiologically classified according to the American College of Radiology (ACR) BI-RADS lexicon (67.6% being either BI-RADS 4 or 5), sampled by FNA and immediately diagnosed by cytomorphology. The clinicoradiological, cytomorphological, and histological characteristics of all consecutive patients were retrieved from the hospital computerized medical records prospectively registered in the central information system. Histopathological analysis and ultrasound (US) follow-up (FU) were the reference diagnostic tests of the study design. In brief, we carried out either a histopathological verification or an 18-month US evaluation when a benign cytology was concordant with the components of the triple test. Overall, histology was available for 1138 masses, whereas 491 masses were analyzed at the 18-month US-FU. FNA specimens were morphologically nondiagnostic in 3.1%, false negatives were observed in 1.5%, and there was only one false positive (0.06%). The breast cancer prevalence was 62%. Diagnostic accuracy measures of the OSCAR procedure with their 95% confidence intervals (95% CI) were the following: sensitivity (Se) = 97.4% (96.19-98.31); specificity (Sp) = 94.98% (92.94-96.56); positive predictive value (PPV) = 96.80% (95.48-97.81); negative predictive value (NPV) = 95.91% (94.02-97.33); positive likelihood ratio (LR+) = 19.39 (13.75-27.32); negative predictive ratio (LR-) = 0.03 (0.02-0.04), and; accuracy = 96.45% (95.42-97.31). The respective positive likelihood ratio (LR+) for each of the four categories of cytopathological diagnoses (with their 95% CI) which are malignant, suspicious, benign, and nondiagnostic were 540 (76-3827); 2.69 (1.8-3.96); 0.03 (0.02-0.04); and 0.37 (0.2-0.66), respectively. In conclusion, our study demonstrates that the OSCAR procedure is a highly reliable diagnostic approach and a perfect test to select patients requiring core-needle biopsy (CNB) when performed by interventional cytopathologists in a multidisciplinary and integrated OSC setting. Besides drastically limiting the rate of nondiagnostic specimens and diagnostic turn-around time, OSCAR is an efficient and powerful first-line diagnostic approach for patient-centered care.

Is Infectious Endocarditis Evolving into a Time-Dependent Diagnosis in the Contemporary Epidemiological Era? Emphasis on the Role of Echocardiography as a First-Line Diagnostic Approach

Is Infectious Endocarditis Evolving into a Time-Dependent Diagnosis in the Contemporary Epidemiological Era? Emphasis on the Role of Echocardiography as a First-Line Diagnostic Approach

Teaching Tip: Design and Implementation of a Safe Equine Radiation-Free Radiographic Simulator for Veterinary Skills Training in the Pre-clinical Curriculum

The ninth standard of accreditation as outlined by the American Veterinary Medical Association (AVMA) Council on Education (COE) mandates that all accredited colleges of veterinary medicine must provide instruction in medicine and surgery, including principles of practice, hands-on experiences with diagnostic methods, and interpretation of clinical findings. In equine practice, diagnostic imaging is used as a first-line diagnostic approach and is an integral part of pre-purchase and lameness examinations. Accuracy and consistency of radiographic interpretation relies heavily upon procedural techniques to acquire diagnostic images and overcome both motion artifacts and obliquity. Because the sizes and temperaments of equine patients potentiate hazardous working conditions for the veterinary team, learners might benefit from simulations that allow them to practice holding the x-ray generator and the imaging plate for diagnostic image acquisition in the absence of live horses. This teaching tip describes the development of a novel equine radiographic simulator for skills training in the veterinary curriculum. The model allows learners to handle imaging equipment safely and without radiation exposure as they develop proficiency positioning radiographic plates and placing directional markers. Learners can also test their understanding of radiographic positioning in reverse: if given a radiograph, they can be asked to describe how the x-ray generator was positioned to obtain the diagnostic image. Future iterations will investigate the simulator's efficacy with respect to learning outcomes when the model is paired with an assessment rubric as part of an objective standardized clinical examination.

Editors' Note: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.

Investigators at the Mitochondrial Disease Clinic at Royal North Shore Hospital (Sydney, Australia) prospectively recruited 242 patients who satisfied the Nijmegen criteria for possible, probable, or definite mitochondrial disease (MD). The investigators tested the variant detection rate for a variety of mitochondrial disorders using whole-genome sequencing (WGS) of peripheral blood. Disease-causing variants were found in 53.7% of tested individuals. With more widespread availability and the decreasing cost of WGS, it may become more frequently used as a first-line diagnostic approach in patients with suspected MD. Dr. Schon acknowledged one rare MD, alpha-methylacyl-CoA racemase deficiency, which has been reported in slightly more than a dozen cases to date. Although it may be rare, Dr. Schon maintains that the condition is likely underdiagnosed. The authors agreed and emphasized that dietary restriction of pristanic acid may lessen the risk of severe neurologic disease and manifestations such as seizures and stroke-like episodes. The growing use of technologies such as WGS may facilitate earlier identification and effective treatment of patients with this and other MDs, especially with enriched populations. Investigators at the Mitochondrial Disease Clinic at Royal North Shore Hospital (Sydney, Australia) prospectively recruited 242 patients who satisfied the Nijmegen criteria for possible, probable, or definite mitochondrial disease (MD). The investigators tested the variant detection rate for a variety of mitochondrial disorders using whole-genome sequencing (WGS) of peripheral blood. Disease-causing variants were found in 53.7% of tested individuals. With more widespread availability and the decreasing cost of WGS, it may become more frequently used as a first-line diagnostic approach in patients with suspected MD. Dr. Schon acknowledged one rare MD, alpha-methylacyl-CoA racemase deficiency, which has been reported in slightly more than a dozen cases to date. Although it may be rare, Dr. Schon maintains that the condition is likely underdiagnosed. The authors agreed and emphasized that dietary restriction of pristanic acid may lessen the risk of severe neurologic disease and manifestations such as seizures and stroke-like episodes. The growing use of technologies such as WGS may facilitate earlier identification and effective treatment of patients with this and other MDs, especially with enriched populations.

Incorporation of ultrasound-guided core biopsy with flow cytometry to assist the diagnosis of cervical lymphoma.

The main purpose of surgery for cervical lymphoma is only for tissue sampling. To establish a patient-friendly diagnostic approach, we investigated the feasibility of ultrasound-guided core biopsy with flow cytometry in the patients with suspected cervical lymphoma. We prospectively recruited patients with suspected cervical lymphoma from Nov 2017 till Jan 2021 in a referral medical center and performed retrospective interpretation of the prospectively acquired data. Ultrasound-guided core biopsy as the tissue sampling approach for the targeted lesions was performed in all patients. The ultrasound-guided core biopsy samples were analyzed by immunohistochemical stains and flow cytometry. The sample quality and therate of definite and decisive diagnosis obtainedby ultrasound-guided core biopsy alone and ultrasound-guided core biopsy with flow cytometry were evaluated. Total 81 consecutive patients were recruited for analysis. All ultrasound-guided core biopsy samples were qualified for analysis of pathology and flow cytometry. Pathologically, the diagnoses were definite and compatible with their flow cytometry results in 70 patients (86.42%). Either newly-diagnosed or recurrent cervical lymphoma/lymphoproliferative disorders with histologic transformation could be diagnosed by ultrasound-guided core biopsy with flow cytometry. Nine of the 11 patients with pathologically indefinite diagnosis became clinically decisive when flow cytometry was incorporated into the process, which improved the rate of decisive diagnosis to 98.77% (Odds ratio [95% CI]: 6.21 [1.28, 58.96]). Ultrasound-guided core biopsy combined with flow cytometry is suggested to serve as the first-line and patient-friendly diagnostic approach for the patients with suspected cervical lymphoma.

A roadmap for a comprehensive diagnostic approach to fine needle cytology of lymph node metastases.

Fine needle cytology (FNC) is widely used as a first-line procedure in the diagnostic algorithm of lymphadenopathies. In a metastatic setting, a first-line diagnostic approach identifies non-haematopoietic malignancy; however, cytopathologists could also provide a second diagnostic level, identifying the origin of the primary tumour. This paper outlines a comprehensive and practical approach to the cytological diagnosis of lymph node metastases. Cytological diagnoses of lymph node metastases performed over a 10-year period were selected and divided into two groups. The first group, labelled "oncological," comprised patients with a previous history of malignancy; the second group, labelled "naïve," included patients with no relevant history. Pathology records were retrieved to record microscopic findings, namely, background appearance, group architecture, and specific cell features; data from cell block (CB) preparations were also collected. Overall, 982 cases were selected: 497 cases (50.61%) in the naïve group, and 485 (49.39%) in the oncological group. Overall, a second diagnostic level was achieved in 834/982 cases (84.92%); cases diagnosed as carcinoma not otherwise specified were more frequent in the naïve group than in the oncological group (17.51% vs. 8.04%, P < 0.01). Notably, although CB material was available in only 44.87% of the naïve cases, we were able to achieve a second diagnostic level thanks to the integration of clinical and cytomorphological findings, plus lymph node topography, in 82.49% of the cases. Our results confirmed that in a metastatic setting, FNC can reliably lead to the identification of the origin of the primary tumour.

Urologists' knowledge base and practice patterns in Peyronie's disease. A national survey of members of the italian andrology society.

Aim of our study was to explore the basic knowledge base and diagnostic and therapeutic practice patterns in Peyronie's disease (PD) of a large number of physicians belonging to the Italian Andrology Society (SIA). Our survey is based on two questionnaires which were e-mailed to the members of the SIA. The first questionnaire explored diagnostic and therapeutic practice patterns of SIA physicians, while the second questionnaire focused on their knowledge of the disease, as well as their training and level of experience in the specific field. We then planned to compare our outcomes with similar PD surveys from other countries. The first questionnaire was answered by 142 SIA physicians. The second questionnaire was answered by 83 SIA physicians. Most respondents (74.6%) chose penile ultrasonography as first-line diagnostic approach and 47.1% prefer to perform a color Doppler ultrasound after pharmaco-induced erection. Concerning the therapeutic practice patterns in active stage of the disease, most respondents (99.29%) prefer conservative medical therapy. Additionally, most respondents (64.78%), when failure of conservative treatment had been established, considered surgical treatment necessary, specifically corporoplasty, which may be associated with other techniques. The results of our survey show that, in comparison to their foreign counterparts, Italian SIA uro-andrologists have a more proactive diagnostic approach right from when patients first present. When PD is still in its active stage, SIA uro-andrologists mostly opt for medical therapy. In advanced disease or if conservative treatment fails, our survey indicates a greater preference for surgical treatment. Answers to the theoretical knowledge questions showed that SIA physicians have a good understanding of the disease's etiology, epidemiology, and clinical picture, and of the appropriate indications for treatment.

Image-guided core needle biopsy as the first-line diagnostic approach in lymphoproliferative disorders-A review of the current literature.

The World Health Organization (WHO) and numerous expert guidelines for lymphoma diagnosis and subclassification advocate the use of histology from surgical nodal excision biopsy (SEB) over core needle biopsy (CNB) due to perceived higher diagnostic yield. CNB is associated with lower morbidity and is more cost-effective compared to SEB. Furthermore, current practice increasingly demonstrates material obtained from CNB can rapidly diagnose individuals with a clinical suspicion of lymphoma and allow initiation of treatment in the majority of patients. We performed a literature review to assess the suitability of CNB in lymphoma diagnosis given recent advances in radiological and histopathological techniques in obtaining and processing tissue. Additionally, expert international guidelines in lymphoma diagnosis were compared. We found that CNB demonstrated a diagnostic efficacy between 79% and 97% (median 91%) where the diagnostic outcome was conclusive with full lymphoma subclassification. Studies demonstrate that there is a high diagnostic reproducibility amongst haematopathologists (87%-93%) in lymphoma diagnoses with full subtyping from material obtained via CNB. Furthermore, CNB is a safe, rapid and reliable method of obtaining tissue from lymph nodes for histopathological analysis. These procedures are minimally invasive, well-tolerated and should be considered the first-line diagnostic approach in clinical practice in patients with suspected lymphoproliferative disorders.

The Role of Nuclear Medicine in the Clinical Management of Benign Thyroid Disorders, Part 1: Hyperthyroidism.

Benign thyroid disorders, especially hyper- and hypothyroidism, are the most prevalent endocrine disorders. The most common etiologies of hyperthyroidism are autoimmune hyperthyroidism (Graves disease, GD), toxic multinodular goiter (TMNG), and toxic thyroid adenoma (TA). Less common etiologies include destructive thyroiditis (e.g., amiodarone-induced thyroid dysfunction) and factitious hyperthyroidism. GD is caused by autoantibodies against the thyroid-stimulating hormone (TSH) receptor. TMNG and TA are caused by a somatic activating gain-of-function mutation. Typical laboratory findings in patients with hyperthyroidism are low TSH, elevated free-thyroxine and free-triiodothyronine levels, and TSH-receptor autoantibodies in patients with GD. Ultrasound imaging is used to determine the size and vascularity of the thyroid gland and the location, size, number, and characteristics of thyroid nodules. Combined with lab tests, these features constitute the first-line diagnostic approach to distinguishing different forms of hyperthyroidism. Thyroid scintigraphy with either radioiodine or 99mTc-pertechnetate is useful to characterize different forms of hyperthyroidism and provides information for planning radioiodine therapy. There are specific scintigraphic patterns for GD, TMNG, TA, and destructive thyroiditis. Scintigraphy with 99mTc-sestamibi allows differentiation of type 1 from type 2 amiodarone-induced hyperthyroidism. The radioiodine uptake test provides information for planning radioiodine therapy of hyperthyroidism. Hyperthyroidism can be treated with oral antithyroid drugs, surgical thyroidectomy, or 131I-iodide. Radioiodine therapy is generally considered after failure of treatment with antithyroid drugs, or when surgery is contraindicated or refused by the patient. In patients with TA or TMNG, the goal of radioiodine therapy is to achieve euthyroid status. In GD, the goal of radioiodine therapy is to induce hypothyroidism, a status that is readily treatable with oral thyroid hormone replacement therapy. Dosimetric estimates based on the thyroid volume to be treated and on radioiodine uptake should guide selection of the 131I-activity to be administered. Early side effects of radioiodine therapy (typically mild pain in the thyroid) can be handled by nonsteroidal antiinflammatory drugs. Delayed side effects after radioiodine therapy for hyperthyroidism are hypothyroidism and a minimal risk of radiation-induced malignancies.

Novel PET Tracers in the Management of Cardiac Sarcoidosis.

Sarcoidosis is a systemic inflammatory disease of unknown etiology, pathologically characterized by non-caseating granulomas involving several organs and tissues. This pathological process can eventually affect the heart during his course leading to fibrosis associated with systolic dysfunction, conduction disturbance, and even sudden cardiac death. Due to this prognostic impact, diagnosis is crucial to optimize clinical management. The low sensitivity of endomyocardial biopsy and its invasive nature prevents its application as a first-line diagnostic approach. Thus, several efforts have been dedicated to the identification of advanced imaging tools for the diagnosis and monitoring of cardiac involvement in systemic sarcoidosis, including Positron Emission Tomography (PET). Starting from strengths and disadvantages of 18F-Fluorodeoxyglucose (18F-FDG) PET imaging, the present narrative review will summarize state of the art and future perspectives about radiotracers other than 18F-FDG of potential interest in the field of CS, including somatostatin receptor- ligands, proliferation markers and hypoxia displaying agents.

The recurrent SETBP1 c.2608G\u2009>\u2009A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate

BackgroundSchinzel-Giedion syndrome (SGS) is a multiple malformation syndrome mainly characterized by severe intellectual disability, distinctive facial features, and multiple congenital anomalies, including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as an increased pediatric cancer risk. Recently, SGS has been associated with de novo heterozygous deleterious variants in the SETBP1 gene; to date, nine different variants, clustering in exon 4 of SETBP1, have been identified in 25 patients.Case presentationIn this study, by using Whole Exome Sequencing (WES), we identified a patient with a recurrent missense mutation in SETBP1, the c.2608G > A, p.(Gly870Ser) variant, previously reported as likely pathogenic. This finding allowed us to confirm the suspected clinical diagnosis of SGS. Clinical features of patients carrying the same variant, including our patient, were evaluated by a review of medical records.ConclusionsOur study confirms SGS as a severe disorder potentially presenting at birth as a critically ill neonate and demonstrates the causal role of the c.2608G > A, p.(Gly870Ser) variant in the etiology of the syndrome. Moreover, although the cohort of SETBP1-patients reported in the literature is still small, our study reports for the first time the prevalence of the variant (about 27%, 7/26). Finally, given the heterogeneity of clinical presentations of affected patients hospitalized in Neonatal Intensive Care Units (NICU) and/or Pediatric Intensive Care Units (PICU), in agreement with emerging data from the literature, we suggest that WES should be used in the diagnosis of unexplained syndromic conditions, and even as part of a standard first-line diagnostic approach, as it would allow a better diagnosis, counseling and management of affected patients and their families.

Ultrasound-Guided Treatment of Extrusive Medial Meniscopathy: A 3-Step Protocol.

Medial knee pain is commonplace in clinical practice and can be related to several pathologic conditions: ie, medial plica syndrome, saphenous nerve entrapment, pes anserine syndrome, medial collateral ligament injury, and medial meniscus disorders. Ultrasound (US) imaging represents a valuable first-line diagnostic approach to adequately visualize the superficial structures in the medial compartment of the knee to easily plan for prompt treatment. Currently, the management of chronic degenerative diseases involving the menisci, and causing their extrusion, consists of surgery (arthroscopic partial meniscectomy). This procedure often allows only a partial resolution of pain and functional impairment. In the pertinent literature, US-guided interventions for the medial meniscus are proposed, mainly to decrease pain and inflammation or to induce regeneration. Likewise, this Technical Innovation describes in detail the US findings of medial extrusive meniscopathy and also illustrates a novel US-guided technique to treat the bursa of the medial collateral ligament, the extruded fragment of the medial meniscus, and the synovial parameniscal recesses simultaneously.

Mitochondrial disease genetics update: recent insights into the molecular diagnosis and expanding phenotype of primary mitochondrial disease.

Primary mitochondrial disease (PMD) is a genetically and phenotypically diverse group of inherited energy deficiency disorders caused by impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity. Mutations in more than 350 genes in both mitochondrial and nuclear genomes are now recognized to cause primary mitochondrial disease following every inheritance pattern. Next-generation sequencing technologies have dramatically accelerated mitochondrial disease gene discovery and diagnostic yield. Here, we provide an up-to-date review of recently identified, novel mitochondrial disease genes and/or pathogenic variants that directly impair mitochondrial structure, dynamics, and/or function. A review of PubMed publications was performed from the past 12 months that identified 16 new PMD genes and/or pathogenic variants, and recognition of expanded phenotypes for a wide variety of mitochondrial disease genes. Broad-based exome sequencing has become the standard first-line diagnostic approach for PMD. This has facilitated more rapid and accurate disease identification, and greatly expanded understanding of the wide spectrum of potential clinical phenotypes. A comprehensive dual-genome sequencing approach to PMD diagnosis continues to improve diagnostic yield, advance understanding of mitochondrial physiology, and provide strong potential to develop precision therapeutics targeted to diverse aspects of mitochondrial disease pathophysiology.

Imaging Evaluation of Pediatric Parotid Gland Abnormalities.

Parotid gland lesions in children can be divided into benign or malignant. The age of the patient helps narrow the differential diagnosis, with vascular and congenital lesions being more frequent in the 1st year of life, while solid tumors are more frequent in older children. Inflammatory disease usually has rapid onset in comparison with that of neoplastic or congenital processes, which have more gradual clinical evolution. Currently, multiple imaging techniques are available to study the parotid region, such as US, CT, and MRI. However, it is still a challenge to distinguish nonmalignant lesions from malignant ones. US is the first-line diagnostic approach in children to characterize the morphology and vascularity of these lesions. CT in children may be indicated for evaluation of abscesses or sialolithiasis. MRI is the imaging modality of choice for investigating the nature of the lesion and its extent. In addition to complete and detailed clinical information, knowledge of parotid gland anatomy and characteristic radiologic features of parotid disorders is essential for optimal radiologic evaluation and avoiding unnecessary interventional diagnostic procedures or treatment. This article illustrates a variety of entities (congenital, inflammatory, vascular, neoplastic) that can occur in the parotid gland, highlighting the most frequent radiologic patterns of manifestation and correlating them with clinical, surgical, and pathologic findings. ©RSNA, 2018.

The Accuracy of ACR TI-RADS Classification of Neck Ultrasound as a First-Line Diagnostic Approach for Thyroid Neoplasms in Pediatric Patients: A Retrospective Study

Background.Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the gold standard in diagnosing the pathological nature of undetermined thyroid nodules. However, in some instances limitations and shortcomings arise, making it insufficient for determining a specific diagnosis.Objective.Our aim was to evaluate the effectiveness of ACR TI-RADS classification of neck ultrasound as a first-line diagnostic approach for thyroid neoplasms in pediatric patients.Methods.A retrospective analysis was made of FNA and US protocols in 70 patients who underwent the examination and treatment at Dmitry Rogachev National Research Center between January 2012 and August 2017. In the retrospective series 70% (49/70) of patients undergone FNA and 43% (30/70) of them undergone repeated FNA. All US protocols were interpreted according to ACR TI-RADS system by the two independent experts. The clinical judgment was assessed using the concordance test and the reliability of preoperative diagnostic methods was analized.Results.According to histologic examination protocols, benign nodules reported greater multimorbidity 29% (20/70), compared with thyroid cancer 17% (12/70), complicating FNA procedure. A statistically significant predictor of thyroid cancer with a tumor size ACR TI-RADS showed a significant advantage of ACR TI-RADS due to higher sensitivity (97.6 vs 60%), specificity (78.6 vs 53.8%), positive predictive value (87.2 vs 71.4%), and negative predictive value (95.7 vs 41.2%). Concordance on the interpreted US protocols according to ACR TI-RADS classification between two experts was high, excluding accidental coincidence.Conclusion.The data support the feasibility of US corresponding to the ACR TI-RADS classification as a first-line diagnostic approach for thyroid neoplasm reducing the number of unnecessary biopsies for thyroid nodules.

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience

OBJECTIVE:The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients.METHODS:We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays.RESULTS:Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes.CONCLUSION:The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis.

Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation.

Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs.

Chapter 8 - Approach to the male patient with sexual dysfunction

The management of the male patient with sexual dysfunction (SD) requires special knowledge and abilities. Generally, SD is best approached from the physiologic perspective, keeping in mind that sexual functioning has important psychosocial dimensions. The history obtained from the patient and, if possible, from his partner should seek information not only on the SD, but also on coexisting neurologic or medical disorders. A list of drugs should be obtained, as many prescription drugs, even in low doses, can influence sexual function. The clinical examination, including sensory, motor, and reflex testing of the lumbosacral segments, may reveal pertinent somatic abnormalities, which in the case of a suspected peripheral nervous system lesion may be supported by clinical neurophysiologic testing. The first-line diagnostic approach includes defining the type of sexual dysfunction to allow the most appropriate therapy. Metabolic and other systemic diseases need to be ruled out. Patients suspected of having psychologic, structural, urologic, endocrinologic, or vascular etiology of SD should be referred to the appropriate specialist.