PUF60-related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants.

PUF60-related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of PUF60, is associated with multiple congenital anomalies affecting a wide range of body systems. These anomalies include ophthalmic coloboma, and congenital anomalies of the heart, kidney, and musculoskeletal system. Behavioral and intellectual difficulties are also observed. While less common than other features associated with PUF60-related developmental disorder, for instance hearing impairment and short stature, identification of specific anomalies such as ophthalmic coloboma can aid with diagnostic identification given the limited spectrum of genes linked with this feature. We describe 10 patients with PUF60 gene variants, bringing the total number reported in the literature, to varying levels of details, to 56 patients. Patients were recruited both via locally based exome sequencing from international sites and from the DDD study in the United Kingdom. Eight of the variants reported were novel PUF60 variants. The addition of a further patient with a reported c449-457del variant to the existing literature highlights this as a recurrent variant. One variant was inherited from an affected parent. This is the first example in the literature of an inherited variant resulting in PUF60-related developmental disorder. Two patients (20%) were reported to have a renal anomaly consistent with 22% of cases in previously reported literature. Two patients received specialist endocrine treatment. More commonly observed were clinical features such as: cardiac anomalies (40%), ocular abnormalities (70%), intellectual disability (60%), and skeletal abnormalities (80%). Facial features did not demonstrate a recognizable gestalt. Of note, but remaining of unclear causality, we describe a single pediatric patient with pineoblastoma. We recommend that stature and pubertal progress should be monitored in PUF60-related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with PUF60-related developmental disorder which has important genetic counseling implications for families.

The significance of internal calcifications on perinatal post-mortem radiographs.

AIM: To determine whether the presence of internal calcifications on perinatal post-mortem skeletal surveys (PMSS) are associated with certain diagnoses of fetal loss. METHODS AND MATERIALS: A 6-month retrospective, single-centre, cohort study was conducted on PMSS performed for perinatal death assessment. One reader re-reviewed all PMSS images for the presence and location of internal calcifications, and noted whether these were included within the original radiology report. Findings at autopsy were then reviewed independently by a second researcher and cause of fetal loss or main diagnosis recorded. Chi-squared tests were conducted to identify differences between those with and without internal calcifications at PMSS. RESULTS: Two hundred and thirty perinatal deaths (mean gestational age 18 weeks; average 12-35 weeks) were included in the study, of which 42 (18.3%) demonstrated intra-abdominal calcifications, and 16/42 (38.1%) were mentioned in the radiology reports. Most calcifications were found to be within the lumen of the gastrointestinal tract, and in the left upper quadrant of the abdomen. There was no statistical difference between identifiable causes for fetal loss at autopsy in cases with and without calcification at PMSS (59.5% versus 58.5% respectively, p=0.904). Nevertheless, where calcification and a cause for fetal loss were found, the aetiology was more likely to be due a fetal rather than placental issue. CONCLUSION: The presence of internal calcifications on PMSS was not associated with an increased likelihood of explainable fetal loss or particular diagnosis at autopsy.

Quantitative bowel apparent diffusion coefficient measurements in children with inflammatory bowel disease are not reproducible.

AIM: To investigate the intra-observer and interobserver variability of quantitative apparent diffusion coefficient (ADC) measurements in children with inflammatory bowel disease. MATERIALS AND METHODS: Nine readers were recruited. Six magnetic resonance imaging (MRI) enterography cases with known active disease in the jejunum, terminal ileum, or colon were analysed. Readers measured repeat ADC values from the known diseased site and an unaffected site, at two sittings. RESULTS: Seven readers completed the study. The Lin concordance coefficient for intra-observer agreement was poor (0.844, 95% confidence interval [CI]: 0.77, 0.896). Bland-Altman limits of agreement for intra-observer agreement were 0.66×10-3 mm2/s (95% CI: 0.46, 0.86), and -0.56×10-3 mm2/s (95% CI: -0.36, -0.76). Therefore, a single measured value would be compatible with no disease, superficial ulceration, or deep ulceration according to published thresholds. Interobserver variability was poor to moderate across all observers (intraclass correlation coefficient [ICC]: 0.51, 95% CI: 0.27, 0.77). Between the two best-agreeing observers, agreement was good using the ICC (ICC 0.85, 95% CI: 0.43, 1.0), but poor using the Lin correlation coefficient (Lin 0.83, 95% CI: 0.65, 0.93), and Bland-Altman. CONCLUSION: The intra-observer and interobserver agreement is inadequate to allow accurate characterisation of disease activity using previously published thresholds. Qualitative ADC assessment may be preferable.

Abnormalities of the craniovertebral junction in the paediatric population: a novel biomechanical approach.

The craniovertebral junction (CVJ) is the bony transition between the cranium and cervical spine. It is a biomechanically complex articulation comprising the occipital condyles (Oc) the atlas (C1) and axis (C2). Pathologies affecting the CVJ in children are myriad with clinical features resulting from biomechanical instability, deformity, or neuraxial compression. Establishing the natural history and clinical burden of a condition is challenging in infants and young children, often complicated by co-existing neuromuscular and cognitive impairment. This makes investigation and treatment planning difficult. Each disease entity has a predilection for a particular biomechanical abnormality. Investigation using dynamic imaging is most appropriate in instability, computed tomography examination in abnormalities of deformity and magnetic resonance imaging examination in neuraxial compression. Treatment comprises reduction and immobilisation of instability, re-alignment of deformity, or decompression of the neuraxis. We present a review of disease entities affecting the CVJ in children categorised according to a simple mechanistic approach to aid investigation and treatment planning.

Current and future approaches to large airways imaging in adults and children.

"Large airways disease" is a catch-all phrase encompassing a wide variety of pathology affecting the trachea, main, lobar, segmental, and proximal sub-segmental bronchi. Relevant pathologies can be divided into focal or diffuse processes and many conditions have classic appearances on computed tomography (CT). We provide a review of the imaging specifics of a wide range of large airway pathologies in adult, childhood, and fetal life with examples of common and rare pathologies ranging from well-known entities such as cystic fibrosis and allergic bronchopulmonary aspergillosis to rarities such as Williams-Campbell, primary ciliary dyskinesia, and congenital high-airway obstruction syndrome (CHAOS). Although the spatial and temporal resolution of modern multidetector CT lends itself well to the depiction of small structures such as the peripheral airways, concerns regarding radiation exposure and increasing interest in the role of functional and quantitative imaging have led to a surge in research into dose reduction in CT and both structural and functional airway imaging via magnetic resonance imaging. We discuss the current literature on these emerging techniques along with some exiting near future directions for large airways imaging.

The end for the 'Roman Sandal': an observational study of methods of securing chest drains in a deployed military setting.

INTRODUCTION: There is ongoing debate regarding the optimal method of securing chest drains in trauma patients. Various courses describe methods for chest drain insertion, but little has been published to identify the best method to secure the drain. AIM: This article aims to examine differences in approach to securing chest drains and the security of the methods used. METHOD: Whilst in a deployed medical treatment facility, 26 clinicians from various specialties and nationalities were asked to secure a pre-placed drain. A 32F drain was placed in a manikin and the clinicians were given a chance to prepare their equipment. They were given a choice of suture and their attempts were observed by one of the researchers. The attempts were timed and photographed. A second researcher, who had not observed the technique, then assessed the security of the drain. RESULTS: 15/26 clinicians used a 'Roman Sandal' technique with 5/26 proving to be insecure. Other techniques used showed no failure. The rate of consultant-secured failure was 12.5% compared to 40% for registrars and 33% for General Duties Medical Officers. CONCLUSIONS: The type of suture used made no difference, but the traditional 'Roman Sandal' method was insecure. Knots tied close to the skin and those that bit into the drain were shown to be most effective.

'Reading the Mind in the Eyes': an fMRI study of adolescents with autism and their siblings.

BACKGROUND: Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the 'Reading the Mind in the Eyes' task (the Eyes task) have been identified in individuals with ASC in previous studies. METHOD: Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC-control and sibling-control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC-control and sibling-control differences across multiple thresholds. RESULTS: Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups. CONCLUSIONS: Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.

The management of the acutely swollen ankle.

Patients presenting with an acutely swollen ankle are common in both the military and civilian settings. Accurate diagnosis is vital, as there are various potentially serious causes. This article aims to review the common causes of an acutely swollen ankle, as well as the rarer causes, with their significant consequences.

It is all in the face: carotenoid skin coloration loses attractiveness outside the face.

Recently, the importance of skin colour for facial attractiveness has been recognized. In particular, dietary carotenoid-induced skin colour has been proposed as a signal of health and therefore attractiveness. While perceptual results are highly consistent, it is currently not clear whether carotenoid skin colour is preferred because it poses a cue to current health condition in humans or whether it is simply seen as a more aesthetically pleasing colour, independently of skin-specific signalling properties. Here, we tested this question by comparing attractiveness ratings of faces to corresponding ratings of meaningless scrambled face images matching the colours and contrasts found in the face. We produced sets of face and non-face stimuli with either healthy (high-carotenoid coloration) or unhealthy (low-carotenoid coloration) colour and asked participants for attractiveness ratings. Results showed that, while for faces increased carotenoid coloration significantly improved attractiveness, there was no equivalent effect on perception of scrambled images. These findings are consistent with a specific signalling system of current condition through skin coloration in humans and indicate that preferences are not caused by sensory biases in observers.

Computed tomography scanning of implanted hypoglossal nerve stimulators and approach to device malfunction: case series.

OBJECTIVE: Serious device-related complications for hypoglossal nerve stimulators are rare, but surgeons should implement a prompt and systematic approach to quickly troubleshoot a non-functioning device. METHOD: Records were queried at a single academic tertiary referral centre between January 2019 and June 2021. RESULTS: The authors present four cases of non-functioning hypoglossal nerve stimulator devices: one case in which migration of the stimulation lead required a revision implantation, one in which the implantable pulse generator was found to be non-functional intra-operatively, one case of an intramuscular sensory lead tract causing pain and one case of implantable pulse generator failure that was probably triggered by implantable cardiac device discharge. In this study, computed tomography imaging was critical to the diagnosis for the first and third cases. CONCLUSION: Given the limited complication reporting available for hypoglossal nerve stimulators, these cases highlight management and unique imaging findings. The authors present an algorithm to work-up non-functioning hypoglossal nerve stimulator devices.

Effects of methyl-deficient diets on methionine and homocysteine metabolism in the pregnant rat.

Although the importance of methyl metabolism in fetal development is well recognized, there is limited information on the dynamics of methionine flow through maternal and fetal tissues and on how this is related to circulating total homocysteine concentrations. Rates of homocysteine remethylation in maternal and fetal tissues on days 11, 19, and 21 of gestation were measured in pregnant rats fed diets with limiting or surplus amounts of folic acid and choline at two levels of methionine and then infused with L-[1-(13)C,(2)H(3)-methyl]methionine. The rate of homocysteine remethylation was highest in maternal liver and declined as gestation progressed. Diets deficient in folic acid and choline reduced the production of methionine from homocysteine in maternal liver only in the animals fed a methionine-limited diet. Throughout gestation, the pancreas exported homocysteine for methylation within other tissues. Little or no methionine cycle activity was detected in the placenta at days 19 and 21 of gestation, but, during this period, fetal tissues, especially the liver, synthesized methionine from homocysteine. Greater enrichment of homocysteine in maternal plasma than placenta, even in animals fed the most-deficient diets, shows that the placenta did not contribute homocysteine to maternal plasma. Methionine synthesis from homocysteine in fetal tissues was maintained or increased when the dams were fed folate- and choline-deficient methionine-restricted diets. This study shows that methyl-deficient diets decrease the remethylation of homocysteine within maternal tissues but that these rates are protected to some extent within fetal tissues.

Is D-methionine bioavailable to the dairy cow?

Rumen-protected forms of Met contain an equimolar mixture of the D- and L-isomers. Only L-Met can be directly used for protein synthesis, but it is unclear how much of the D-isomer can be transformed into L-Met in ruminants. Four lactating dairy cows, with an average milk yield of 32.4 kg/d, received a basal diet (12.5% crude protein, supplying 1,718 g/d of metabolizable protein) in 12 equal meals per day plus an abomasal infusion of amino acids (590 g/d, casein profile without Met). They were used in 3 consecutive studies to determine utilization of D-Met. First, the cows each received portal vein infusions for d of 5, 10, or 15 g/d of DL-Met in a Youden square. On the last day of each period, 6 arterial samples were collected at 45-min intervals. Concentrations of L- and D-Met were determined on a chiral column by gas chromatography-mass spectrometry. Portal infusion of 5, 10, and 15 g/d of DL-Met increased plasma total Met concentrations (19.7, 25.0, and 34.4±0.6 µM) and the proportion of Met as D (19.4, 30.5, and 37.3±0.7%). The fractional removal of D-Met was 6 to 7 times lower than the fractional removal of L-Met, with mean half-lives of 52 versus 8 min, respectively. Second, the same cows were infused for 8 h with L[methyl-(2)H(3)]Met at 1.3 mmol/h; at 2 h, cows received a bolus injection i.v. of D-[1-(13)C]Met (6.8 mmol), and arterial samples were collected after 10, 20, 30, 40, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min. Expressed relative to L-[(12)C]Met; that is, as tracer:tracee ratios, enrichments of plasma D-[1-(13)C]Met and L-[1-(13)C]Met averaged 1.77±0.14 and 0.144±0.026, respectively, 10 min after the bolus injection and declined exponentially thereafter. A minimum of 75±3% of the D-[1-(13)C]Met was transformed into L-[1-(13)C]Met. Third, the cows received, in a crossover design, an abomasal infusion for D of either DL-Met or L-Met (1g/d) and, on the last day of each experimental period, blood samples were collected simultaneously from arterial, portal, hepatic, and mammary vessels. Arterial total Met concentrations were higher with DL- versus L-Met infusions (37.4 vs. 25.4±0.5 µM), with 37.1±5.0% as D-Met. The mammary gland did not extract any D-Met. Hepatic removal of D-Met was observed, but was numerically lower than the fractional extraction of L-Met. In conclusion, much of the D-Met is transformed into L-Met by the dairy cow but at a slow rate. No uptake of D-Met occurs across the mammary gland but L-Met synthesized from the D-isomer elsewhere in the body can be utilized for milk protein synthesis.

Accuracy and self-validation of automated bone age determination.

The BoneXpert method for automated determination of bone age from hand X-rays was introduced in 2009 and is currently running in over 200 hospitals. The aim of this work is to present version 3 of the method and validate its accuracy and self-validation mechanism that automatically rejects an image if it is at risk of being analysed incorrectly. The training set included 14,036 images from the 2017 Radiological Society of North America (RSNA) Bone Age Challenge, 1642 images of normal Dutch and Californian children, and 8250 images from Tübingen from patients with Short Stature, Congenital Adrenal Hyperplasia and Precocious Puberty. The study resulted in a cross-validated root mean square (RMS) error in the Tübingen images of 0.62 y, compared to 0.72 y in the previous version. The RMS error on the RSNA test set of 200 images was 0.45 y relative to the average of six manual ratings. The self-validation mechanism rejected 0.4% of the RSNA images. 121 outliers among the self-validated images of the Tübingen study were rerated, resulting in 6 cases where BoneXpert deviated more than 1.5 years from the average of the three re-ratings, compared to 72 such cases for the original manual ratings. The accuracy of BoneXpert is clearly better than the accuracy of a single manual rating. The self-validation mechanism rejected very few images, typically with abnormal anatomy, and among the accepted images, there were 12 times fewer severe bone age errors than in manual ratings, suggesting that BoneXpert could be safer than manual rating.

Monitoring Skull Base Abnormalities in Children with Osteogenesis Imperfecta - Review of Current Practice and a Suggested Clinical Pathway.

OBJECTIVES: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI. METHODS: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging. RESULTS: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients. CONCLUSION: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI.

Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF.

RATIONALE: High resolution computed tomography (HRCT) is a more sensitive tool for detecting early cystic fibrosis (CF) lung disease than either spirometry or plain radiography, but its relationship to other measures of lung function has not been established in young children. OBJECTIVES: (1) To assess whether the lung clearance index (LCI) derived from multiple breath inert-gas washout (MBW) is as effective as HRCT in identifying pulmonary abnormalities; and (2) explore the relationships between abnormalities detected by HRCT and by spirometry, plethysmography and MBW (collectively, LFTs) in young children with CF. METHODS: Children with CF underwent LFTs and volumetric HRCT on the same day. Healthy age-matched controls underwent identical LFTs without HRCT. Scans were anonymised, and scored using the Brody-II CT scoring system, to assess for presence and extent of bronchiectasis, airway wall thickening, mucus plugging, and parenchymal opacities. RESULTS: Assessments were undertaken in 60 children with CF (mean (SD) 7.8 (1.3 years) and 54 healthy controls (7.9 (1.2) y). Among children with CF, 84% (47/56) had abnormal LCI, 58% (27/47) abnormal plethysmographic lung volumes (FRC(pleth) or RV), 35% (21/60) abnormal sRaw and 47% (28/60) abnormal spirometry (FEV1 or FEF(25-75)); whereas HRCT scans were abnormal in 85% (51/60): median total Brody-II score: 9.5% (range 0-51%). Total CT score correlated more strongly with LCI (Spearman correlation = 0.77) than with spirometry (R = -0.43) or any other marker of lung function. Of the nine children with normal LCI, five had abnormalities on HRCT, whereas five children with normal HRCT had raised LCI. CONCLUSIONS: These results suggest that while LCI and HRCT have similar sensitivity to detect CF lung disease, complimentary information may be gained in individual patients.

Thoracic situs as an indicator of atrial appendage morphology: a postmortem study of 306 specimens with situs solitus in 250 and heterotaxy in 56 cases.

Symmetry of bronchi, lung lobation, and atrial appendages is frequently found in patients with heterotaxy syndromes. To evaluate the reliability of thoracic situs as an indicator of atrial appendage morphology, thoracic situs was assessed in 306 postmortem cases: 250 with atrial situs solitus and 56 with heterotaxy syndromes. Five features that indicate thoracic situs were assessed: (1) lung lobation, (2) lengths of main bronchi, (3) ratio of left to right (L/R) bronchial lengths, (4) relationship of bronchi to ipsilateral pulmonary artery, and (5) number of cartilage rings in each main bronchus. In the group with heterotaxy, the expected symmetrical lung lobation, lengths of bronchi, number of cartilage rings, and relations to pulmonary arteries were found in 77, 77, 77, and 95% of cases, respectively. The ratios of L/R bronchial lengths were ≤ 1.5 in 90% of cases. The relations of the bronchi to the pulmonary arteries were the best predictors of symmetrical atrial appendages or splenic syndromes. Bronchial-atrial discordance occurred in ten cases: in situs solitus in one case and in heterotaxy in nine cases. Detection of heterotaxy syndromes is important because of the associated severe congenital cardiac defects. No single feature of thoracic situs is completely reliable. All available data should be used to make the diagnosis.

Deficits in facial, body movement and vocal emotional processing in autism spectrum disorders.

BACKGROUND: Previous behavioural and neuroimaging studies of emotion processing in autistic spectrum disorder (ASD) have focused on the use of facial stimuli. To date, however, no studies have examined emotion processing in autism across a broad range of social signals. METHOD: This study addressed this issue by investigating emotion processing in a group of 23 adults with ASD and 23 age- and gender-matched controls. Recognition of basic emotions ('happiness', 'sadness', 'anger', disgust' and 'fear') was assessed from facial, body movement and vocal stimuli. The ability to make social judgements (such as approachability) from facial stimuli was also investigated. RESULTS: Significant deficits in emotion recognition were found in the ASD group relative to the control group across all stimulus domains (faces, body movements and voices). These deficits were seen across a range of emotions. The ASD group were also impaired in making social judgements compared to the control group and this correlated with impairments in basic emotion recognition. CONCLUSIONS: This study demonstrates that there are significant and broad-ranging deficits in emotion processing in ASD present across a range of stimulus domains and in the auditory and visual modality; they cannot therefore be accounted for simply in terms of impairments in face processing or in the visual modality alone. These results identify a core deficit affecting the processing of a wide range of emotional information in ASD, which contributes to the impairments in social function seen in people with this condition.