Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

Objectives: The aim of this study was to delineate the clinical and laboratory features suggestive of intralabyrinthine schwannoma (ILS). Methods: We compared the clinical features of 16 patients with ILS, who had been diagnosed at the Seoul National University Bundang Hospital from 2003 to 2018, with those of 18 patients with symptomatic unilateral intracanalicular schwannoma and randomly selected 20 patients with definite or probable unilateral Meniere's disease (MD). Results: Patients with ILS presented with either recurrent spontaneous dizziness/vertigo combined with auditory symptoms (n = 8), isolated auditory symptoms without dizziness/vertigo (n = 7), or recurrent spontaneous dizziness/vertigo without auditory symptoms (n = 1). Most patients reported no improvement (n = 11) or worsening (n = 1) of the symptoms despite medical treatments including intratympanic (n = 5) or intravenous steroids (n = 2). Conventional brain MRIs failed to detect ILS in about a half of the patients (7/16, 44%). However, ILS showed a filling defect on 3-dimensional (3D) heavily T2-weighted MRIs (n = 12), and nodular enhancement on 3D contrast-enhanced T1 (n = 15) or FLAIR MRIs (n = 13) targeted for the inner ear. Compared to MD or intracanalicular schwannoma, ILS showed mostly abnormal head-impulse tests (HITs, p = 0.001). In contrast, the incidence of canal paresis did not differ among the groups (p = 0.513). Conclusion: ILS may mimic MD by presenting recurrent dizziness/vertigo and auditory symptoms. ILS should be suspected in patients with recurrent audiovestibulopathy especially when (1) the duration of the dizziness is not typical for MD, (2) the patients do not respond to medical treatments, or (3) HITs are abnormal.

Differential diagnosis of wide QRS tachycardia (WQRST) on the electrocardiogram remains a challenging exercise. Correct diagnosis is important for prescribing appropriate therapy and determining prognosis. Differential diagnosis of wide QRS tachycardia revolves around differentiation between supraventricular tachycardia with aberrant conduction and ventricular tachycardia. Observations such as clinical history, findings of physical examination during tachycardia, AV dissociation, QRS morphology in lead V1 and lead V6, precordial concordance, RS complexes in precordial leads, contralateral bundle branch block during wide QRS tachycardia, R wave morphologies in lead aVR, and ventricular initial/terminal velocity of conduction ratio can help arrive at the correct diagnosis with reasonable accuracy. The observations described here can help arrive at the correct diagnosis of WQRST with both reasonable accuracy and confidence.

Desmoplastic fibroblastoma (collagenous fibroma) is an uncommon benign soft-tissue tumor, rarely involving bone. It shares some overlapping features with other infiltrate tumors, such as desmoid-type fibromatosis, neurofibroma, and low-grade fibromyxoid sarcoma. The misdiagnosis may cause unnecessary surgical overtreatment, especially for those involving bone. In order to deepen the understanding of the diagnosis and differential diagnosis of desmoplastic fibroblastoma, we planned to analyze the clinical, radiological, and histopathological features and the outcome of desmoplastic fibroblastoma on the basis of case analysis and literature review.

Therapy with immune checkpoint inhibitors (ICIs) has improved overall survival and cancer-related morbidity of cancer treatment even in cancer entities with poor prognosis. Since the approval of the first ICI, ipilimumab, for treatment of advanced melanoma by the Food and Drug Administration (FDA) in 2011, the spectrum of indications and approved ICIs has grown, rapidly. Up to now, seven different ICIs for more than 20 indications are available. However, their mechanisms of action can lead to immune-related adverse events (irAEs). In particular, neurological irAEs are clinically relevant. Although they are rare, an early and accurate diagnosis is challenging and neurological disease course and sequelae are potentially fatal. Between 08/2017 and 03/2020, 31 patients received ICI treatment at Hannover Medical School and presented with neurological adverse events (N-irAEs). Treated malignancies were metastatic melanoma, bronchial carcinoma, and urothelial cell carcinoma. All patients received comprehensive neurological diagnostics including clinical examination and magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) analysis was obtained in 21 patients and electroneurography was performed in 22 patients. Although N-irAEs were suspected in all 31 patients, 11 patients had other conditions leading to neurological symptoms including tumor metastases in seven patients and hemorrhagic or ischemic stroke in four patients. In the following, these patients are referred to as the differential diagnosis (DD) group. Patients with N-irAEs suffered from immune mediated neuropathy (9/20), myositis and/or myasthenic syndrome (6/20), or encephalitis/cerebellitis (5/20). Except for cell count, CSF results did not differ between the N-irAEs and the DD group. Symptoms related to N-irAEs are rather unspecific potentially mimicking other tumor-related symptoms such as metastases. Patients with malignancy are predominantly not treated by neurologists. Because of the complexity of neurological symptoms, detailed neurological investigations in specialized institutions are necessary in patients with new neurological symptoms and need to be critically discussed with treating oncologists.

Tiredness is one of the most frequent complaints in primary care. Although often self-limiting and frequently associated with psychosocial stress, patients but also their physicians are often uncertain regarding a serious cause and appropriate diagnostic work-up. We conducted a systematic review and meta-analysis of studies reporting on differential diagnosis of fatigue in primary care.

No abstract available

Pulmonary manifestations of tularaemia are reported to be infrequent in previous publications. During 2016, we noticed an increase in the number of hospitalised patients with pulmonary tularaemia in Eastern Norway. We aimed to investigate primary pulmonary tularaemia in Eastern Norway in terms of symptoms, radiological and microbiological findings, incidence and risk exposure.

Cardiac outpouchings encounter a series of distinct congenital or acquired entities (i.e. aneurysms, pseudoaneurysms, diverticula, and herniations), whose knowledge is still poorly widespread in clinical practice. This review aims to provide a comprehensive overview focusing on definition, differential diagnosis, and prognostic outcomes of cardiac outpouchings, as well as further insights on therapeutic options, in order to assist physicians in the most appropriate decision-making.

The imaging features of chronic periaortitis resemble those of infected aneurysms. Two illustrative cases of chronic periaortitis, in which the etiologies were caused by IgG4-related disease, are presented. The first case involved a 68-year-old man who presented with vague discomfort in his lower abdomen. The second case was a 42-year-old man who presented with a fever of 38°C and persistent, vague chest discomfort. Both cases demonstrated an increased amount of connective tissue around the aorta in computed tomography images and low intensity in the T2-weighed sequence and high intensity in the diffusion-weighed sequence, suggesting the presence of inflammation, in the magnetic resonance imaging. Negative blood cultures, elevated IgG4 levels, and pathological findings confirmed the diagnosis as chronic periaortitis due to IgG4-related disease. This is a newly recognized syndrome of unknown etiology, characterized by a fibroinflammatory condition, tumefactive lesions, and a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells. Both cases were successfully treated with corticosteroids. Infected aneurysms need to be carefully differentiated from this syndrome in view of the similar imaging features.

Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non-inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late-onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr-caveolinopathy and of limb-girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.

Previous studies suggest vergence and saccade abnormalities in dyslexic adolescents. However, these studies are mainly clinically based and do not provide objective measurements of eye movements, but rather subjectively evaluate vergence using haplosopic conditions in which the two eyes are dissociated (via polarizers, prisms, or intermittent spectacles). Other studies have identified deficits with binocular coordination during reading in dyslexics. Yet, there are few studies that provide objective measurements of eye movements in the dyslexic population to help provide more information regarding if these deficits could be due to an intrinsic motor problem or if they are the consequence of poor reading. 47 dyslexic adolescents (18 female, 29 male; mean age 15.5) and 44 non-dyslexic adolescents (22 female, 22 male; mean age 14.8) wore a head-based eye tracker (PupilCore, Pupil Labs, Berlin) which recorded wide angle saccade and vergence eye movements at 200 Hz. Tests were run using the REMOBI device, which produced a saccade or vergence audiovisual target. Analysis of eye movements was performed with lab-developed software, AIDEAL. The results showed statistically significant abnormalities in vergence and saccades. In vergence, dyslexics displayed a reduced amplitude of the visually driven portion of convergence and a longer duration in the initial phase of divergence. In saccades, dyslexic adolescents demonstrated slower saccades in both directions. They also had an increased disconjugate drift in the first 80 or 160 ms following saccades to the right, suggesting poor binocular coordination. For both vergence and saccades, the peak velocity and time to peak velocity was higher and earlier, respectively, in non-dyslexics compared to dyslexics; yet the average velocity of both movements was lower in dyslexics. Thus, these results indicate peculiar velocity profiles in dyslexics, particularly a slow deceleration phase in both vergence and saccades. The study provides an objective method to diagnose vergence and saccade abnormalities while viewing targets in the real three-dimensional space in a dyslexic population. Vergence abnormalities are demonstrated to be a problem in dyslexics, occurring independently from reading. We hypothesize these disconjugate drifts following saccades are the result of slow vergence capacity. Rehabilitation programs, such as those using REMOBI, should aim to target these deficits in vergence velocity, as this has been shown to improve binocular control.

In this prospective study, duplex Doppler ultrasound was used in 95 consecutive patients with solid breast masses to evaluate the presence of neovascular flow. A positive Doppler signal, i.e., a Doppler shift frequency of more than 1 kHz using a 5 MHz insonating frequency, was found in 34 of 57 patients with a carcinoma, and also in three patients with a benign condition. These results indicate that negative findings with pulsed Doppler ultrasound cannot be used to exclude malignancy. However, a frequency shift of more than 1 kHz indicates a high probability for malignancy. In our study a high frequency shift was not related to tumor size. We also evaluated the correlation between a high frequency shift and axillary nodal metastasis. According to our results there is a very low chance of axillary metastasis when no high frequency shifts are found.

Different neurodegenerative diseases can cause memory disorders and other cognitive impairments. The early detection and the stratification of patients according to the underlying disease are essential for an efficient approach to this healthcare challenge. This emphasizes the importance of differential diagnostics. Most studies compare patients and controls, or Alzheimer's disease with one other type of dementia. Such a bilateral comparison does not resemble clinical practice, where a clinician is faced with a number of different possible types of dementia. Here we studied which features in structural magnetic resonance imaging (MRI) scans could best distinguish four types of dementia, Alzheimer's disease, frontotemporal dementia, vascular dementia, and dementia with Lewy bodies, and control subjects. We extracted an extensive set of features quantifying volumetric and morphometric characteristics from T1 images, and vascular characteristics from FLAIR images. Classification was performed using a multi-class classifier based on Disease State Index methodology. The classifier provided continuous probability indices for each disease to support clinical decision making. A dataset of 504 individuals was used for evaluation. The cross-validated classification accuracy was 70.6% and balanced accuracy was 69.1% for the five disease groups using only automatically determined MRI features. Vascular dementia patients could be detected with high sensitivity (96%) using features from FLAIR images. Controls (sensitivity 82%) and Alzheimer's disease patients (sensitivity 74%) could be accurately classified using T1-based features, whereas the most difficult group was the dementia with Lewy bodies (sensitivity 32%). These results were notable better than the classification accuracies obtained with visual MRI ratings (accuracy 44.6%, balanced accuracy 51.6%). Different quantification methods provided complementary information, and consequently, the best results were obtained by utilizing several quantification methods. The results prove that automatic quantification methods and computerized decision support methods are feasible for clinical practice and provide comprehensive information that may help clinicians in the diagnosis making.

We report detection of cases of monkeypox virus infection in Argentina in the context of a marked increase in confounding cases of atypical hand-foot-and-mouth syndrome caused by enterovirus coxsackie A6. We recommend performing an accurate differential virological diagnosis for exanthematous disease in suspected monkeypox cases.

The study aimed to ascertain the clinical manifestations of inflammatory arthritis accompanying tuberculosis (TB) for the differential diagnosis.

The common finding of hypokalemic alkalosis in several unrelated disorders may confound the early diagnosis of salt-losing tubulopathy (SLT). Antenatal Bartter syndrome (BS) must be considered in idiopathic early-onset polyhydramnios. Fetal megabladder in BS may allow its distinction from third-trimester polyhydramnios that occurs in congenital chloride diarrhea (CCD). Fetal megacolon occurs in CCD while fecal chloride >90 mEq/L in infants is diagnostic. Failure-to-thrive, polydipsia and polyuria in early childhood are the hallmarks of classic BS. Unlike BS, there is low urinary chloride in hypokalemic alkalosis of intractable emesis and cystic fibrosis. Rarely, renal salt wasting may result from cystinosis, Dent disease, disorders of paracellular claudin-10b and Kir4.1 potassium-channel deficiency. Acquired BS may result from calcimimetic up-regulation of a calcium-sensing receptor or autoantibody inactivation of sodium chloride co-transporters in Sjögren syndrome. A relatively common event of heterozygous gene mutations for Gitelman syndrome increases the likelihood of its random occurrence in certain diseases of adult onset. Finally, diuretic abuse is the most common differential diagnosis of SLT. Unlike the persistent elevation in BS, urinary chloride concentration losses waxes and wanes on day-to-day assessment in patients with diuretic misuse.

The status of blood supply was examined in twenty-nine patients with pulmonary masses with color doppler flow imaging. The results showed that there are no significant blood signals in 5 benign masses. One patient with pulmonary arterio-venous fistula can be diagnosed. Pulmonary inflammatory pseudotumor and 20 lung cancers have rich blood supply. The peak forward velocity and resistance index between them have obvious difference statistically (P < 0.05, P < 0.01). It is concluded that color doppler can be regarded as an useful and noninvasive method before operation in diagnosing some pulmonary masses.

The PAX5, a paired box transcription factor and B-cell activator protein (BSAP), activates B-cell commitment genes and represses non-B-cell lineage genes. About 14 transcript variants of PAX5 have been observed in human. Any alteration in its expression pattern leads to lymphogenesis or associated diseases and carcinogenesis in non-lymphoid tissues. Its mechanisms of function in pathophysiology of non-Hodgkin's lymphoma (NHL) are unclear. This study was intended to explore influence of PAX5 in cascade of NHL pathogenesis and diagnosis.

Lipid keratopathy is a disease in which fat deposits accumulate in the cornea, leading to opacification and decrease of visual acuity. This condition can be idiopathic without signs of previous corneal disease or secondary to ocular or systemic diseases. Lipid keratopathy is usually associated with abnormal vascularization of the cornea, and the lipid classically deposits adjacent to these vessels. Treatment of this condition usually aims to eliminate or prevent abnormal vessel formation, and several modalities have been described. In this review we summarize the etiology, pathophysiology, and clinical presentation of lipid keratopathy and describe current and emerging treatment regimens.