BackgroundSudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.ObjectivesThis study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.MethodsWe evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.ResultsA clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.ConclusionsMolecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Molar ultrasonographic appearances associated with increased maternal serum alpha-fetoprotein but normal, or slightly elevated, levels of ss human Chorionic Gonadotrophin should raise the clinical suspicion of PMD. The diagnosis of this condition should not be disregarded when an abnormal fetus and/or an abnormal karyotype are demonstrated.

Primary pulmonary tumors are infrequent in childhood, therefore an accurate diagnosis and treatment is often delayed. We review the English language literature and report the clinical and pathological features of eight tumors arising in the lungs of pre-adolescent children, accessioned between 1960 and 1991 in the pathology department of a children's hospital in South Africa. The ratio of pulmonary primary tumors to secondary neoplasms and to non-neoplastic lesions of the lung examined during this period was 1:5:60. Over the last 31 years we received three plasma cell granulomas, two pleuro-pulmonary blastomas, a mucoepidermoid carcinoma, an endobronchial fibrosarcoma, and a hemangioma. All patients presented with cough unresponsive to medical treatment. The incidence and spread of primary lung tumors in children was similar to that reported from other centers. Plasma cell granuloma is the most common primary tumor in the lungs of children. Aggressive behavior is most frequently encountered with pleuro-pulmonary blastoma and rhabdomyosarcoma, and because of their association with cystic lesions careful examination of lungs is required in such cases. Most other malignant neoplasms, such as muco-epidermoid carcinoma and primary fibrosarcoma, are usually of a low grade of malignancy. A decreasing incidence of bronchogenic carcinoma seems to be reported during the first two decades of life.

Solitary and multiple myofibromas are benign tumours that predominantly occur in infancy and childhood. Myofibromas occur especially in the head and neck region, and are characterized by SMA and, to a lesser extent, MSA expression. The clinical course is self-limiting, and local excision appears to be sufficient.