Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype–phenotype correlation, this cannot yet be confirmed. © The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

A genetic register for von Hippel-Lindau disease was set up in the north west of England in 1990.

We analyzed transiliac bone biopsy specimens from 30 end-stage renal failure patients, taken at the time of admission for CAPD training. Results were compared with values of iPTH, bone alkaline phosphatase, 1,25-dihydroxyvitamin D3, skeletal survey, quantitative computed tomography (QCT) and single photon absorptiometry (SPA) bone density measurements. Osteitis fibrosa was the most common histological diagnosis, present in 15 of the 30 patients (50%), with eight classified as "severe" and seven as "mild." Eight patients (27%) had adynamic bone lesion, four mixed renal osteodystrophy (13%), and two (7%) osteomalacia. The mean age of the adynamic group was higher than the osteitis fibrosa group (41 +/- 12.1 vs. 56 +/- 10.2 years; P < 0.01), and than the mixed group (39 +/- 7.5 vs. 56 +/- 10.2 years; P < 0.02). Levels of iPTH enabled discrimination between groups, but not between individual patients, and values correlated with bone alkaline phosphatase (r = 0.62; P < 0.001). Erosion of the terminal phalanges was seen on the plain X-rays of 7 of 15 patients with mild or severe OF, and in three patients with another diagnosis. The majority of patients (> 90%) had bone density measurements within the normal range. No significant correlation existed between QCT or SPA scores and any of the histomorphometric parameters, or iPTH. We conclude that iPTH is the most helpful non-invasive investigation in this group of patients. Plain X-ray of the hands is the most useful radiological investigation, but single measurements of bone density are not diagnostic.

In 11 patients with blow out fracture of the orbit, measurement of orbital volume using computed tomography (CT) more than 20 days after injury correlated weli with enophthalmos measured from the same scans (r=0.87, p<0-001, SEE 0-63 mm), with a 1 cm3 increase in orbital volume causing 0*8 mm of enophthalmos. This confirms the cause of enophthalmos after blow out fracture to be increase in orbital volume rather than fat atrophy or fibrosis. In a further 25 patients scanned within 20 days of injury the degree of enophthalmos was less marked than would be predicted from the orbital volume measurement. This was probably because of the presence of oedema, haemorrhage, or both behind the globe which would prevent immediate development of enophthalmos. CT

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A recent neurophysical model of brain electrical activity is outlined and applied to EEG phenomena. It incorporates single-neuron physiology and the large-scale anatomy of corticocortical and corticothalamic pathways, including synaptic strengths, dendritic propagation, nonlinear firing responses, and axonal conduction. Small perturbations from steady states account for observed EEGs as functions of arousal. Evoked response potentials (ERPs), correlation, and coherence functions are also reproduced. Feedback via thalamic nuclei is critical in determining the forms of these quantities, the transition between sleep and waking, and stability against seizures. Many disorders correspond to significant changes in EEGs, which can potentially be quantified in terms of the underlying physiology using this theory. In the nonlinear regime, limit cycles are often seen, including a regime in which they have the characteristic petit mal 3 Hz spikeand-wave form.

The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2–27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5–49.9%) and seven controls (15.9, 95% CI 6.7–30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-017-9965-1) contains supplementary material, which is available to authorized users.