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.

Pertussis carries a high risk of mortality in very young infants. The mechanism of refractory cardio-respiratory failure is complex and not clearly delineated. We aimed to examine the clinico-pathological features and suggest how they may be related to outcome, by multi-center review of clinical records and post-mortem findings of 10 patients with fulminant pertussis (FP). All cases were less than 8 weeks of age, and required ventilation for worsening respiratory symptoms and inotropic support for severe hemodynamic compromise. All died or underwent extra corporeal membrane oxygenation (ECMO) within 1 week. All had increased leukocyte counts (from 54 to 132 x 10(9)/L) with prominent neutrophilia in 9/10. The post-mortem demonstrated necrotizing bronchitis and bronchiolitis with extensive areas of necrosis of the alveolar epithelium. Hyaline membranes were present in those cases with viral co-infection. Pulmonary blood vessels were filled with leukocytes without well-organized thrombi. Immunodepletion of the thymus, spleen, and lymph nodes was a common feature. Other organisms were isolated as follows; 2/10 cases Para influenza type 3, 2/10 Moraxella catarrhalis, 1/10 each with respiratory syncytial virus (RSV), a coliform organism, methicillin-resistant Staphylococcus aureus (MRSA), Haemophilus influenzae, Stenotrophomonas maltophilia, methicillin-sensitive Staphylococcus aureus (MSSA), and candida tropicalis. We postulate that severe hypoxemia and intractable cardiac failure may be due to the effects of pertussis toxin, necrotizing bronchiolitis, extensive damage to the alveolar epithelium, tenacious airway secretions, and possibly leukostasis with activation of the immunological cascade, all contributing to increased pulmonary vascular resistance. Cellular apoptosis appeared to underlay much of these changes. The secondary immuno-compromise may facilitate co-infection.

The clinicopathologic features of three examples of mesenchymal hamartoma of the chest wall are described. The entity has been recorded under a number of names including osteochondroma, osteochondrosarcoma, benign chondroblastoma, mesenchymoma, and chondromatous hamartoma. The condition is manifest at birth or shortly thereafter with deformity of the chest wall and respiratory distress. Radiographic examination reveals a well-defined, partly calcified mass involving one or more ribs. The tumor is composed predominantly of chondroid tissue with large endothelium-lined blood spaces and immature mesenchyme with osteoclastic giant cells and osteoid. We review the literature and suggest that the lesion should be distinguished from aneurysmal bone cyst, chondroma, and other mesenchymal neoplasms. In order to avoid local recurrence the recommended treatment is complete surgical resection.

The occurrence of subdural hemorrhage (SDH) on the convexities of the cerebral hemispheres is not an unusual finding in the setting of intrauterine, perinatal, or neonatal deaths, the hemorrhage usually presenting either as a thin film over the occipital poles or as a small infratentorial bleed. Working in 2 referral centers with over 30,000 deliveries per year, we routinely examine the dura macroscopically and histologically in nonmacerated fetuses over 24 weeks in gestation and in neonates. This paper describes our experience of intradural hemorrhage (IDH) and SDH associated with hypoxia. Our series comprises 25 fetuses and 30 neonates with obvious macroscopic intradural hemorrhage and hypoxia of varying degrees of severity diagnosed by systematic examination of the brain. Fetal gestational age ranged from 26-41/40 weeks (all no more than 24 hours from intrauterine death), while the 30 neonates lived for between 1 hour and 19 days. Simultaneously with IDH, frank SDH was seen in 2 of 3 of all cases (16 fetuses and 20 neonates). Intradural hemorrhage was more prominent in the posterior falx and tentorium, most likely because of the existence of 2 venous plexus at these sites. Our findings demonstrate that SDH and cerebral hypoxia are common associations of IDH and that SDH (often seen as a thin film ofhemorrhage) almost always occurs in association with diffuse falcine IDH. Diffuse IDH with SDH are more frequently associated with severe or moderate hypoxic ischemic encephalopathy (HIE), while mild or early HIE is more common with focal IDH without SDH.

De Barsy syndrome is a rare, autosomal recessive syndrome characterised by a progeria-like appearance with distinctive facial features and cutis laxa. Ophthalmological, orthopaedic and neurological abnormalities are also typically present. The syndrome was first described by de Barsy et al. in 1967 and since that time approximately 27 further cases have been reported worldwide. We present a case that demonstrates the typical clinical and histological features of de Barsy syndrome. A female infant, the second child of first-cousin parents from a multiply consanguineous family of Pakistani origin, presented at birth with growth retardation, cutis laxa and a progeria-like appearance. She had thin, overlapping fingers and adducted thumbs, blue sclerae, cloudy corneas and myopia. She has failed to thrive and has marked developmental delay and abnormal athetoid movements. During the first year of life she developed pectus excavatum and her facial appearance became more aged. To our knowledge there are no previous reports of de Barsy syndrome in individuals of Pakistani origin.