-The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.

Hyperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder that occurs in ~1 of 50,000 live births. Histologically, pancreases from HI patients can be divided into 2 major groups. In the first, diffuse HI, ␤-cell distribution is similar to that seen in normal neonatal pancreas, whereas in the second, focal HI, there is a discrete region of ␤-cell adenomatous hyperplasia. In most patients, the clinical course of the disease suggests a slow progressive loss of ␤-cell function. Using double immunostaining, we examined the proportion of ␤-cells undergoing proliferation and apoptosis during the development of the normal human pancreas and in pancreases from diffuse and focal HI patients. In the control samples, our findings show a progressive decrease in ␤-cell proliferation from 3.2 ± 0.5% between 17 and 32 weeks of gestation to 0.13 ± 0.08% after 6 months of age. In contrast, frequency of apoptosis is low (0.6 ± 0.2%) in weeks 17-32 of gestation, elevated (1.3 ± 0.3%) during the perinatal period, and again low (0.08 ± 0.3%) after 6 months of age. HI ␤-cells showed an increased frequency of proliferation, with focal lesions showing particularly high levels. Similarly, the proportion of apoptotic cells was increased in HI, although this reached statistical significance only after 3 months of age. In conclusion, we demonstrated that islet remodeling normally seen in the neonatal period may be primarily due to a wave of ␤-cell apoptosis that occurs at that time. In HI, our findings of persistently increased ␤-cell proliferation and apoptosis provide a possible mechanism to explain the histologic picture seen in diffuse disease. The slow progressive decrease in insulin secretion seen clinically in these patients suggests that the net effect of these phenomena may be loss of ␤-cell mass. Diabetes 49: 1325-1333, 2000 H yperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder, the molecular basis of which was recently elucidated. Most cases are caused by mutations in either the sulfonylurea receptor (SUR1) or the inward rectifying potassium channel (Kir6.2), 2 subunits of the ␤-cell K ATP channel (1-5). A minority of patients have glucokinase or glutamate dehydrogenase mutations, whereas in 40-50% of the patients, the genetic cause of the disease is still not known (4-7).The histologic appearance of the pancreases from affected children can be subdivided into 2 major forms: diffuse HI and focal HI (8-10). The former is more common and bears some characteristics of nesidioblastosis, a phenomenon observed in the healthy fetus and newborn but which normally evolves during the first year of life into the adult-type architecture (9,11,12). In diffuse HI, the neonatal-type ␤-cell distribution persists (8,13).Focal HI is generally easily recognized as a discrete region of adenomatous hyperplasia (8), whereas the rest of the pancreas appears normal for its age. Focal HI is caused by the somatic l...

In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy. This study of five patients with neonatal epileptic encephalopathy suggests that the same is true in man. Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO). Sequencing of the PNPO gene identified homozygous missense, splice site and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity. Maintenance of optimal PLP levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).

Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood, but an uncommon paediatric cancer, with a constant incidence worldwide of 1:15,000-1:20,000 live births. Despite its rarity, Rb has served as a cornerstone in the field of oncology in many of the aspects that comprise cancer management, including classification schemes, treatment modalities, genetic testing and screening. Until just over half a century ago, the major treatment for Rb was eye removal, and prognosis was poor with outcome fatal for most children. The dramatic evolution, in a short period of time across all fields of Rb management, as well as the development of specialized centres, better infrastructure and introduction of awareness campaigns, has resulted in nearly 100% survival in developed countries and allowed eye salvage in many of the cases. External beam radiotherapy was used as the main treatment choice for four decades, but replaced by chemotherapy at the turn of the century. Initially, and still in many centres, chemotherapy is administered intravenously, but recently is targeted directly into the eye by means of intra-ophthalmic artery and intravitreal chemotherapy. To date, a range of treatments is available to the Rb expert, including enucleation, but there is lack of consensus in a number of scenarios as to what to use and when. In such a rare cancer, treatment outcomes are reported usually via retrospective analyses, with few prospective randomized controlled trials. Classification schemes have also evolved following the introduction of new treatment modalities, but discrepancies exist among centres with respect to the preferred schema and its interpretation. Retinoblastoma management is a remarkable success story, but the future will require a collaborative effort in the form of multicentre randomized controlled trials in order to further improve the quality of care for this subset of young children with ocular cancer.

A histological review of dura mater taken from a post-mortem series of 50 paediatric cases aged up to 5 months revealed fresh bleeding in the dura in 36/50, the bleeding ranging from small perivascular haemorrhages to extensive haemorrhage which had ruptured onto the surface of the dura. Severe hypoxia had been documented clinically in 27 of the 36 cases (75%). In a similar review of three infants presenting with classical 'shaken baby syndrome', intradural haemorrhage was also found, in addition to subdural bleeding, and we believe that our findings may have relevance to the pathogenesis of some infantile subdural haemorrhage. Recent work has shown that, in a proportion of infants with fatal head injury, there is little traumatic brain damage and that the significant finding is craniocervical injury, which causes respiratory abnormalities, severe global hypoxia and brain swelling, with raised intracranial pressure. We propose that, in such infants, a combination of severe hypoxia, brain swelling and raised central venous pressure causes blood to leak from intracranial veins into the subdural space, and that the cause of the subdural bleeding in some cases of infant head injury is therefore not traumatic rupture of bridging veins, but a phenomenon of immaturity. Hypoxia with brain swelling would also account for retinal haemorrhages, and so provide a unified hypothesis for the clinical and neuropathological findings in cases of infant head injury, without impact or considerable force being necessary.