9p21.3 Microdeletion involving CDKN2A/2B in a young patient with multiple primary cancers and review of the literature.

Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A/CDKN2B genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A/CDKN2B deletion.

The pathology and aetiology of subcortical clefts in infants.

In infants, traumatic surface contusions of the brain are rare but subcortical clefts or cysts, variously labelled "contusional tears", "contusional clefts", "cortical tears" or "parenchymal lacerations" have been ascribed to trauma, and are even said to be characteristic of shaking and abuse. We describe the pathology of subcortical clefts or haemorrhages in seven infants. In none were the axonal swellings characteristic of traumatic axonal injury seen in relation to the clefts. Subpial bleeding was associated with clefts in all the cases of recent onset. We hypothesize that subcortical clefts are not due to direct mechanical forces of trauma but are part of a secondary cascade caused by impaired venous drainage which may or may not follow trauma. The finding of subcortical and subpial haemorrhages should prompt a search for CVT. We consider the term "contusion" is not accurate and is misleading.

A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.

An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/ß-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

Reduced cell number in the neocortical part of the human fetal brain in Down syndrome.

Mental retardation is seen in all individuals with Down syndrome (DS) and different brain abnormalities are reported. The aim of this study was to investigate if mental retardation at least in part is a result of a lower cell number in the neocortical part of the human fetal forebrain. We therefore compared brains of DS fetuses aged 19 weeks of gestation with normal control brains. The cell numbers were estimated using the optical fractionator method. The total cell number in the neocortical part of four DS human fetal forebrain was found to be substantially smaller in DS compared to the normal fetus. The average total cell number of 6.85 billion was equal to a reduction by 34% compared to the 10.4 billion cells in a normal fetal brain of that age. This study indicates that the mental retardation found in DS is based on a structural deficit in the human fetal brain already present in the second trimester.

Neocortical and hippocampal neuron and glial cell numbers in the rhesus monkey.

The rhesus monkey is widely used as an experimental animal model in the study of brain function and disease. While previous quantitative studies have provided knowledge of regional numbers, little is known of the total neocortical neuron and glial cell numbers in this species. The aim of this study is to establish quantitative norms. We use the optical fractionator and Cavalieri principle to examine the right hemisphere of eight young rhesus monkeys taken from the control group of an ongoing study. Applying these methods to agar-embedded and vibratome-sectioned tissue, we generate estimates of cell numbers and regional volumes of neocortical and hippocampal regions with coefficients of variance (CV) around 10%. The mean unilateral neocortical neuron number is 1.35 x 10(9) (CV +/- 0.10) and the mean unilateral neocortical glial cell number is 0.78 x 10(9) (CV +/- 0.17). Mean unilateral neocortical volume is found to be 8.5 (CV +/- 0.10) cm(3) after processing, or 19 cm(3) when correcting for shrinkage. The neuron/glia ratio is 1.77. The neurons are distributed with 18% in the frontal cortex, 57% in the temporal and parietal cortices, and 25% in the occipital cortex. In the hippocampal subregions, we found unilateral neuron number of 1.72 x 10(6) (CV +/- 0.13) and glial number of 2.25 x 10(6) (CV +/- 0.17) in CA1, and 0.80 x 10(6) (CV +/- 0.27) neurons and 1.05 x 10(6) (CV +/- 0.26) glial cells in CA2-3. Comparisons with related studies show quantitative variation, but also variations in methods and applications. The results are phylogenetically consistent, apart from the neuron/glia ratio, which is remarkably higher than what is found in other species.

The changing number of cells in the human fetal forebrain and its subdivisions: a stereological analysis.

The total number of cells--including both neurons and glial cells - was estimated in the neocortical part of the human fetal telencephalon in 22 normal brains within four major developmental zones: the cortical plate/marginal zone, the subplate, the intermediate zone and the ventricular/subventricular zone. The fetal ages ranged from 13 to 41 weeks of gestation. The cellular growth in the human fetal forebrain appears to be two-phased: one rapid, exponential phase from 13 to 20 weeks of gestation and a second and slower phase, which increases linearly, from approximately 22 weeks of gestation to term. From 13 to 20 weeks of gestation the total number of cells increases by a factor of 4.3 from 3 x 10(9) cells to 13 x 10(9) cells at 20 weeks of gestation. From mid-gestation to term, the total cell number increases by a factor of 2.9 to 38 x 10(9) cells in the newborn infant. Studying cellular growth in the normal human fetal brain is important since it may serve as a useful parameter for the assessment of cortical growth in non-invasive and histological studies, and thus improve the analysis of fetal brain disturbances.