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Background: Little is known about the causes of unexpected death in minors (0-17 years). In young adults an important cause is cardiovascular disease, with primary arrhythmogenic disorders, atherosclerotic events, cardiomyopathies and myocarditis as main contributors. The aim of this autopsy study was to determine the contribution of cardiovascular disease to unexpected death in minors.Methods and results: In the Netherlands, systematic investigation of all cases of unexplained death in minors was compulsory in a nationwide governmental project during a 15-month period. Autopsies were performed according to a standardised protocol (autopsy rate 85%). A cardiovascular cause of death was found in 13/56 cases (23%). In the group <1 year, the main cardiovascular causes were various congenital defects (n = 3) and myocarditis (n = 2). In the 1-9 year group, no cardiovascular causes were found. In the 10-14 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ascending aortic aneurysm (n = 1) were among the observed cardiovascular causes. In 14/56 (25%) cases autopsy revealed no structural abnormalities that could explain the sudden death, mostly in the group <1 year.Conclusion: This national cohort with a high autopsy rate reveals a high incidence (23%) of cardiovascular diseases as the pathological substrate of sudden unexpected death in children. Another high percentage of minors (25%) showed no structural abnormalities, with the possibility of a genetic arrhythmia. These findings underline the importance of systematic autopsy in sudden death in minors, with implications for cardiogenetic screening of relatives. [ABSTRACT FROM AUTHOR]

Clinical post-mortem radiology is a relatively new field of expertise and not common practice in most hospitals yet. With the declining numbers of autopsies and increasing demand for quality control of clinical care, post-mortem radiology can offer a solution, or at least be complementary. A working group consisting of radiologists, pathologists and other clinical medical specialists reviewed and evaluated the literature on the diagnostic value of post-mortem conventional radiography (CR), ultrasonography, computed tomography (PMCT), magnetic resonance imaging (PMMRI), and minimally invasive autopsy (MIA). Evidence tables were built and subsequently a Dutch national evidence-based guideline for post-mortem radiology was developed. We present this evaluation of the radiological modalities in a clinical post-mortem setting, including MIA, as well as the recently published Dutch guidelines for post-mortem radiology in foetuses, neonates, and children. In general, for post-mortem radiology modalities, PMMRI is the modality of choice in foetuses, neonates, and infants, whereas PMCT is advised in older children. There is a limited role for post-mortem CR and ultrasonography. In most cases, conventional autopsy will remain the diagnostic method of choice.Conclusion: Based on a literature review and clinical expertise, an evidence-based guideline was developed for post-mortem radiology of foetal, neonatal, and paediatric patients. What is Known: • Post-mortem investigations serve as a quality check for the provided health care and are important for reliable epidemiological registration. • Post-mortem radiology, sometimes combined with minimally invasive techniques, is considered as an adjunct or alternative to autopsy. What is New: • We present the Dutch guidelines for post-mortem radiology in foetuses, neonates and children. • Autopsy remains the reference standard, however minimal invasive autopsy with a skeletal survey, post-mortem computed tomography, or post-mortem magnetic resonance imaging can be complementary thereof. [ABSTRACT FROM AUTHOR]

The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits. Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor. PET117 has not been identified as a mitochondrial disease gene before. Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients, and indicating a pivotal role of this protein in the proper functioning of complex IV. Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this. This case presentation thus implicates mutations in PET117 as a novel cause of mitochondrial disease. [ABSTRACT FROM AUTHOR]

Congenital hepatic fibrosis is a rare disorder of intrahepatic bile ducts with the persistence of embryological bile duct structures in ductal plate configuration. Three siblings aged 18, 17 and 14 years old were found to have congenital hepatic fibrosis associated with a deficiency of the enzyme phosphomannose isomerase. The clinical symptoms were recurrent attacks of persistent vomiting with diarrhea and mild hepatomegaly. The biochemical abnormalities included elevated serum transferases during attacks, clotting factor deficiencies and persistent hypoalbuminemia. In the youngest patient protein-losing enteropathy was present. Liver biopsies of the three patients taken when they were 1, 3 and 14 years old showed an excess of bile duct structures in ductal plate configuration with mild fibrosis in the portal triads. In one patient the liver biopsy was repeated after 18 years and showed only a mild progression of fibrosis in the portal triads. Duodenal biopsies taken in infancy in two of the three patients did not show any abnormalities. Recognition of phosphomannose isomerase deficiency in association with congenital hepatic fibrosis and protein-losing enteropathy is important, because some of the clinical symptoms are potentially treatable by oral mannose therapy. [ABSTRACT FROM AUTHOR]

Unlabelled: A 12-year-old boy with tuberous sclerosis complex (TSC) presented with a large retroperitoneal tumour. Exploratory surgery revealed an infiltrative tumour originating from the pancreas, with local metastases to the lymph nodes. The histologal diagnosis was a malignant islet cell tumour. Retrospectively measured pancreatic hormone levels, however, were normal. A connection between the malignancy and TSC was demonstrated by loss of heterozygosity of the TSC2 gene in the tumour. The primary mutation Q478X in this patient was identified in exon 13 of the TSC2 gene on chromosome 16.Conclusion: Pancreatic islet cell tumours have been mainly associated with multiple endocrine neoplasia syndrome type 1. In our case we demonstrate a direct relationship of this tumour to tuberous sclerosis complex, in the absence of further signs of multiple endocrine neoplasia syndrome type 1. [ABSTRACT FROM AUTHOR]

Unlabelled: Isolated congenital lymphoedema of the external genitalia in boys is extremely rare. It can have major physical and emotional consequences for the children. Three male patients with primary lymphoedema of the penis and scrotum are described. The first case presented with lymphoedema of the prepuce and the phallic skin that persisted after the age of 1 year. Circumcision and excision of the subcutaneous tissues of the phallic skin were successful in producing the appearance of a normal circumcised penis. The second case presented with oedema of both phallic and scrotal skin. At age 1 year only a pastous thickening of the prepuce remained, scrotal and phallic skin normalised spontaneously. Routine circumcision was successful with a 5-year follow up. The third case presented with persistent oedema of both the scrotum and the phallus. He suffered leakage of lymph requiring incontinence pads, with complicating skin infections recurring every 4-6 weeks at age 8 years. After complete peeling of the scrotal and phallic skin from subcutaneous tissue some leakage persisted, infections subsided. The cause of this disorder remains unknown, although hypoplasia of the lymphatic vessels is reported in most cases. In the literature, several congenital malformations have been associated with primary lymphoedema. These were not noted in our patients. Rarely, the lymphoedema regresses spontaneously. The treatment of persistent lymphoedema is surgical and consists of meticulous excision of all subcutaneous layers of the affected skin, combined with reconstruction of the penis and/or scrotum.Conclusion: Primary lymphoedema of the male external genitalia is an extremely rare malformation of the lymphatic vessels of unknown origin. If persistent, surgical treatment is necessary. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) regulate connective tissue architecture and cell migration through extracellular matrix (ECM) degradation and are associated with both physiological and pathological processes. Although they are known to play a role in skeletal development, little is known about the role of MMPs in intervertebral disc (IVD) development. Sixteen fetal human lumbar spine segments, obtained at autopsy, were compared with five normal, non-fetal L4–L5 IVDs. Intensity and/or localization of immunohistochemical staining for MMP-1, -2, -3 and -14 were evaluated by three independent observers. MMP-2 production and activation was quantified by gelatin zymography. MMP-1 and -14 were abundantly present in the nucleus pulposus (NP) and notochordal (NC) cells of the fetal IVDs. In non-fetal IVDs, MMP-1 and -14 staining was significantly less intense ( p = 0.001 and p < 0.001, respectively). MMP-3 was found in almost the entire IVD with no significant difference from non-fetal IVDs. MMP-2 staining in the NC and NP cells of the fetal IVD was moderate, but weak in the non-fetal IVD. Gelatin zymography showed a negative correlation of age with MMP-2 activity ( p < 0.001). MMP-14 immunostaining correlated positively with MMP-2 activity ( p = 0.001). For the first time, the presence of MMP-1, -2, -3 and -14 in the fetal human IVD is shown and the high levels of MMP-1, -2 and -14 suggest a role in the development of the IVD. In particular, the gradual decrease in MMP-2 activation during gestation pinpoints this enzyme as key player in fetal development, possibly through activation by MMP-1 and -14. [ABSTRACT FROM AUTHOR]

To our knowledge this is the first report of Schneckenbecken dysplasia with the development of hydrops early in the second trimester. The radiological findings showed the typical hypoplastic iliac bones with medial extension and very flattened, on lateral view, oval-shaped vertebral bodies and short long bones. The histology showed hypercellular and hypervascular cartilage with chondrocytes with centrally located nucleus. The absence of the lacunar space as described before was also observed in some chondrocytes in our case. This male fetus was the product of consanguineous parents of Mediterranean origin compatible with autosomal recessive inheritance. [ABSTRACT FROM AUTHOR]

We describe a neonate with a large tumour involving cranial, cervical and upper mediastinal regions, which presented clinically as hygroma colli. Radiological and pathological investigations showed characteristics of a mature teratoma and prominent cystic components within the tumour. These findings suggest that during early fetal development primary lymphatic sacs were obstructed by a teratoma leading to hygromatous dilatations of lymphatic vessels or that the abnormal proliferation of lymphatic vessels (hygroma) was part of the teratoma, developing from mesoderm as one of the three germinal layers from which teratomas originate. A third possibility is that the cystic part of the tumour originated from plexus chorioideus tissue, containing CSF. The last possibility is most probable in this patient. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a treatment modality with potential application for premalignant lesions and squamous cell carcinoma of the oral mucosa. PDT in principle has dual selectivity. This may result from a 'preferential' retention of the photosensitizer in target tissue. In addition, the photodynamic activity will be limited to the irradiated area because PDT will not affect tissues in the absence of excitation light. The specificity of PDT is limited by the fact that normal tissues also retain the photosensitizer to some degree, which makes these tissues susceptible to PDT damage. To optimize PDT for oral malignancies, a study was undertaken on normal tissue to investigate the responses in rat palatal mucosa and surrounding anatomical structures. Eighty male Wistar rats were used in the study. Photofrin was administered i.v. at four doses (0, 2.5, 5 or 10 mg kg body weight). Irradiation for PDT was performed 24 h later. An argon pumped dye laser system was used to produce light of two different treatment wavelengths (514.5 and 625 nm), and various energy density levels (0, 25, 50, 100 or 200 J cm). Early effects of PDT were studied at 2 days and late effects at 2 months after treatment. Twenty-four hours after i.v. administration of Photofrin, it was found that PDT affects normal tissues of the oral cavity both macroscopically and microscopically. Combinations of photosensitizer doses ≥5 mg kg and light doses≥100 J cm caused severe and permanent damage to the palatal mucosa and adjacent normal structures such as palatal bone and dentition. Light scattering and internal reflection usually raise the fluence rate in tissue above the irradiance of the incident beam. In an additional study using six male Wistar rats, the energy fluence rate at two treatment wavelengths (514.5 and 625 nm) was measured ex vivo in the palatal mucosa and adjacent anatomical structures. As expected, the energy fluence rates were wavelength, tissue and depth dependent. At the air-mucosa boundary, light of 625 nm was found to have a three-times higher fluence rate than the primary incident beam. Under similar conditions, the fluence rate of 514.5 nm was found to be less, but still twice as high as the primary incident beam. At deeper levels of the rat maxilla, fluence rates were still elevated compared with the incident beam. For 625 nm light, this phenomenon was observed up to the level of the nasal cavity. These increased fluence rates could largely explain the pattern of damage to normal mucosa and surrounding anatomical structures. [ABSTRACT FROM AUTHOR]

Correction to:Neth Heart J 201810.1007/s12471-018-1152-yIn the version of the article originally published online, there was an error in the 'Methods and results' section of the Abstract. It is stated that 'In the 10-14 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ... [ABSTRACT FROM AUTHOR]

Background: Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a heterogeneous condition. A number of children have focal lesions, and removal of these lesions is curative. However, these lesions are difficult to detect, even during surgery. A laparoscopic approach is beneficial.Methods: Two children with PHHI underwent laparoscopic pancreatic inspection at 32 and 29 days of age, respectively.Results: In both children, a lesion was easily found in the head of the pancreas. The lesions looked more lobular, had a more pronounced blood supply, and appeared to have a firmer texture than the remaining pancreas. Enucleation was curative.Conclusion: A laparoscopic approach seems to be ideal for patients with PHHI not only because of the magnification but also because of the delicate surgery it allows and the avoidance of major abdominal wall problems. [ABSTRACT FROM AUTHOR]