Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta-analysis.

OBJECTIVES: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. METHODS: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. RESULTS: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. CONCLUSIONS: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.

Cranial Vault Distraction in Nonsyndromic Sagittal Synostosis.

ABSTRACT: A multitude of operations exists for the treatment of patients with sagittal craniosynostosis presenting after 6 months of age, of which total cranial vault remodeling now provides the most reliable aesthetic outcome. As our national craniofacial center evolved and began to develop a comprehensive multi-disciplinary team to manage complex surgical cases, we offered cranial vault distraction as an alternative to more invasive surgery for late presentation nonsyndromic scaphocephaly. The authors conducted a retrospective review of all patients undergoing this procedure.An average distraction distance of 39.4 mm was achieved in 15 patients aged 1 to 9 years. As a result, the cephalic index changed an average of 4%. The mean transfusion volume in the perioperative period was 32.47% of estimated blood volume. There were 2 complications requiring further operative intervention and distraction was stopped early in 1 patient.The authors propose that internal calvarial distraction is a viable alternative to total cranial vault remodeling for the management of late presentations of sagittal craniosynostosis.

Randomised trial of estimating oral endotracheal tube insertion depth in newborns using weight or vocal cord guide.

BACKGROUND: When intubating newborns, clinicians aim to position the endotracheal tube (ETT) tip in the midtrachea. The depth to which ETTs should be inserted is often estimated using the infant's weight. ETTs are frequently incorrectly positioned in newborns, most often inserted too far. Using the vocal cord guide (a mark at the distal end of the ETT) to guide insertion depth has been recommended. OBJECTIVE: To determine whether estimating ETT insertion depth using the vocal cord guide rather than weight results in more correctly positioned ETT tips. DESIGN: Single-centre randomised controlled trial. SETTING: Level III neonatal intensive care unit (NICU) at a university maternity hospital (National Maternity Hospital, Dublin, Ireland). PATIENTS: Newborn infants without congenital anomalies intubated in the NICU. INTERVENTIONS: Participants were randomised to have ETT insertion depth estimated using weight [insertion depth (cm) = weight (kg) +6] or vocal cord guide. MAIN OUTCOME MEASURE: Correct ETT position, that is, tip between the upper border of the first thoracic vertebra (T1) and the lower border of the second thoracic vertebra (T2) on a chest X-ray as determined by one paediatric radiologist masked to group assignment. RESULTS: 136 participants were randomised. The proportion of correctly positioned ETTs was similar in both groups (weight 30/69 (44%) vs vocal cord guide 27/67 (40%), p=0.731). Most incorrectly positioned ETT (69/79, 87%) were too low. CONCLUSION: Estimating ETT insertion depth using the vocal cord guide did not result in more correctly positioned ETT tips. TRIAL REGISTRATION NUMBER: ISRCTN39654846.

Oculo-facio-cardio-dental syndrome with craniosynostosis, temporal hypertrichosis, and deafness.

We report the case of a 7-month-old girl with atypical oculo-facio-cardio-dental syndrome (OFCD). A novel de novo pathogenic mutation in the BCL6 interacting co-repressor gene (BCOR) (c.4540C>T; p.Arg1514*), was identified on the X chromosome. This case expands the phenotype of OFCD as it is the first report of a case presenting with craniosynostois, temporal hypertrichosis, supraorbital grooving, and underdevelopment of the midface.

Possible toxicity following embolization of congenital giant vertex hemangioma: case report.

The authors describe the case of a 3-year-old boy with a giant congenital vertex hemangioma who underwent presurgical embolization with Onyx (ethylene-vinyl alcohol copolymer dissolved in dimethyl sulfoxide) and Glubran ( N-butyl-2-cyanoacrylate). This vascular tumor had no intracranial vascular communication as assessed by pre-embolization MRI and catheter angiography. All embolizations were performed by direct percutaneous injection. One week following the last embolization procedure the child presented with a 24-hour history of ataxia and extrapyramidal tremor. He was diagnosed with a possible immune-mediated reaction to Onyx or Glubran, which was treated with an urgent surgical excision of the hemangioma followed by intravenous administration of immunoglobulin and steroids. To the authors' knowledge, this is the first case of possible immune-mediated toxicity secondary to either Onyx or Glubran administration. This case highlights the need for awareness of potential toxic reactions to these embolic agents in the treatment of hemangiomas in the pediatric patient.

Positioning newborns on their back or right side for umbilical venous catheter insertion.

AIM: Newborns are placed supine for umbilical venous catheter insertion, and catheter tip position is confirmed with X-ray. Umbilical venous catheters are considered correctly positioned when the tip is in the inferior vena cava; however, frequently, the catheter tip enters the portal venous circulation. We wished to determine whether placing infants on their right side, rather than on the back, for umbilical venous catheter insertion results in more correctly placed catheters. METHODS: Newborns were randomised to be placed on their back, or turned onto their right side for catheter insertion. Primary outcome was correct catheter tip position on X-ray (visible in the midline at diaphragm level). RESULTS: Umbilical venous catheter insertion was successful in all infants enrolled. There was no difference in the proportion of correctly positioned catheters between the groups [back 23/44 (52%) versus right side 27/44 (61%), p = 0.389]. More infants randomised to back had the catheter tip in the portal circulation [back 13/44 (30%) versus right side 5/44 (11%), p = 0.034]. CONCLUSION: Positioning newborn infants on their right side did not result in more correctly placed umbilical venous catheters. The procedure was well tolerated and reduced the rate of tip insertion into the portal venous circulation.

Estimating umbilical catheter insertion depth in newborns using weight or body measurement: a randomised trial.

OBJECTIVE: Incorrectly positioned umbilical venous and arterial catheters (UVC and UAC) are associated with increased rates of complications in newborns. Catheter insertion depth is often estimated using body surface measurement. We wished to determine whether estimating insertion depth of umbilical catheters using birth weight (BW), rather than surface measurements, results in more correctly positioned catheters. INTERVENTIONS/OUTCOME: Newborns were randomised to have UVC and UAC insertion depth estimated using formulae based on BW or using graphs based on shoulder-umbilicus length. The primary outcome was correct catheter tip position on X-ray determined by one radiologist masked to group assignment. RESULTS: UVC insertion was successful in 97/101 (96%) infants but the catheter was not advanced to the estimated depth in 22. There was no difference in the proportion of correctly positioned UVCs between groups (weight 16/51 (31%) vs measurement 13/46 (28%), p=0.826). The tips of 52 (54%) UVCs were in the portal venous system or too low on X-ray. Attempted UAC insertion was successful in 62/87 (71%) infants. More infants in the weight group had a correctly positioned UAC tip (weight 29/32 (91%) vs measurement 15/30 (50%), p=0.001). CONCLUSIONS: UVCs were often not inserted to the estimated depth, and their tips were in the portal venous system or too low on X-ray. Using BW to estimate insertion depth did not result in more correctly positioned UVCs. UAC insertion attempts were often unsuccessful, but when successful, using BW to estimate insertion depth resulted in more correctly positioned catheters. TRIAL REGISTRATION NUMBER: (ISRCTN17864069).

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS.

BACKGROUND: Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management. METHODS: We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed. RESULTS: Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell. CONCLUSIONS: We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis.

Estimating the endotracheal tube insertion depth in newborns using weight or gestation: a randomised trial.

BACKGROUND: When intubating newborns, clinicians aim to place the tip of the endotracheal tube (ETT) in the mid-trachea. Clinicians usually estimate the ETT insertion depth based on weight. ETT tips are often incorrectly positioned in newborns. Estimating the insertion depth based on gestation may be more accurate. OBJECTIVE: To determine whether estimating the ETT insertion depth using gestation, compared to weight, results in more correctly placed ETTs. METHODS: Newborn infants without congenital anomalies who were intubated orally were randomised to having their ETT insertion depth estimated using weight [insertion depth (cm) = weight (kg) + 6] or gestation [value determined from a table]. The primary outcome was correct ETT position, defined as an ETT tip between the upper border of the first thoracic vertebra (T1) and the lower border of the second thoracic vertebra (T2) on a chest X-ray. The primary outcome was determined by one paediatric radiologist who was masked to group assignment. RESULTS: Ninety infants were enrolled and the groups were well matched. The proportion of correctly placed ETTs was not significantly different between the groups [weight, 25/49 (51%), vs. gestation, 16/41 (39%), p = 0.293]. We found no significant differences in the secondary outcomes measured. CONCLUSION: Estimating the ETT insertion depth in newborns using gestation compared to weight did not result in more correctly placed ETTs.

Isolated acute non-cystic white matter injury in term infants presenting with neonatal encephalopathy.

We discuss possible aetiological factors, MRI evolution of injury and neuro-developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%) were identified with injury predominantly in the deep white matter on MRI who were significantly of younger gestation, lower birthweight with higher Apgars at one and five minutes compared to controls. Placental high grade villitis of unknown aetiology (VUA) was identified in all four of these infants. Our hypothesis states VUA may induce white matter injury by causing a local inflammatory response and/or oxidative stress during the perinatal period. We underline the importance of continued close and systematic evaluation of all cases of NE, including examination of the placenta, in order to come to a better understanding of the clinical presentation, the patterns of brain injury and the underlying pathophysiological processes.

Congenital Growth Hormone Deficiency - A Review with a Focus on Neuroimaging.

Growth hormone deficiency is an important cause of short stature in childhood. It is characterised by low growth velocity in childhood and is diagnosed by stimulation testing. Individuals with growth hormone deficiency may have other pituitary hormone deficits in addition to growth hormone deficiency. When multiple pituitary hormone deficiencies are present, abnormal pituitary anatomy, as visualised on magnetic resonance imaging (MRI), is a frequent finding. The classic triad (ectopic posterior pituitary, hypoplastic or aplastic anterior pituitary and absent/thin pituitary stalk) or variants of the classic triad are commonly seen in these patients. Volumetric sequencing allows all three planes of visualisation to be reconstructed in post-processing, allowing the radiologist to more fully evaluate pituitary anatomy. The normal dimensions of the pituitary gland vary by age and precise definitions of what constitutes a hypoplastic gland are not clearly defined in the medical literature. Having an experienced neuroradiologist interpret the MRI in patients with pituitary dysfunction is very important.

A retrospective review of pituitary MRI findings in children on growth hormone therapy.

BACKGROUND: Patients with congenital hypopituitarism might have the classic triad of pituitary stalk interruption syndrome, which consists of: (1) an interrupted or thin pituitarys talk, (2) an absent or ectopic posterior pituitary (EPP), and (3) anterior pituitary hypoplasia or aplasia. OBJECTIVE: To examine the relationship between pituitary anatomy and the degree of hormonal dysfunction. MATERIALS AND METHODS: This study involved a retrospective review of MRI findings in all children diagnosed with congenital growth hormone deficiency from 1988 to 2010 at a tertiary-level pediatric hospital. RESULTS: Of the 52 MRIs reviewed in 52 children, 26 children had normal pituitary anatomy and 26 had one or more elements of the classic triad. Fourteen of fifteen children with multiple pituitary hormone deficiencies had structural anomalies on MRI. Twelve of 37 children with isolated growth hormone deficiency had an abnormal MRI. CONCLUSION: Children with multiple pituitary hormone deficiencies were more likely to have the classic triad than children with isolated growth hormone deficiency. A normal MRI was the most common finding in children with isolated growth hormone deficiency.

Review of interventional procedures in the very low birth-weight infant (<1.5 kg): complications, lessons learned and current practice.

BACKGROUND: Interventional radiology (IR) procedures in very low birth-weight (VLBW) infants (<1.5 kg) are challenging due to size, immaturity, comorbidities and lack of devices of suitable size. Infants are moved from the neonatal intensive care unit to the IR suite, further exposing them to risk. Our purpose was to review our experience of interventional procedures in VLBW infants, specifically complications and potential risks. MATERIALS AND METHODS: VLBW infants referred for image-guided therapy between 1998 and 2005 were identified and medical records reviewed. "Complications" were divided into: major or minor, periprocedural or postprocedural, and intervention-/device-related, patient-related or equipment-related. Transport risk index of physiological stability (TRIPS) scores were calculated. RESULTS: A total of 116 infants (68 male, 48 female) underwent 176 procedures (159 vascular access-related and 17 nonvascular). Of 158 complications identified, 116 were major and 42 were minor. Major complications included hypothermia (n=33), line manipulations/removals (n=25), bleeding (n=12), thrombosis (n=4), cardiac arrest (n=3), tamponade (n=2), and multiorgan failure (n=1). Of the complications, 119 were categorized as intervention-/device-related, 32 patient-related and 7 equipment-related. There were no significant differences between pre- and postprocedural TRIPS scores. CONCLUSION: Successful completion of IR procedures in the VLBW infant is possible, but complications still occur in these fragile infants.

Colour Doppler ultrasound assessment of the normal neonatal hip.

OBJECTIVE: To determine the morphology and hemodynamic characteristics of the arterial vessels of the proximal femur according to specific anatomic regions in asymptomatic neonates in 2 pediatric-based health care institutions. METHODS: Forty-three neonates (29 female, 14 male; age range, 2 d-3 mo; median age, 3 d) were enrolled in the study. Thirty-two (37%) of 86 hips were classified as Graf type IIA joints (mean alpha angle, 56.0 degrees +/- 2.7 degrees ), and 54 (63%) were classified as type I joints (mean alpha angle, 65.0 degrees +/- 4.6 degrees ). RESULTS: Colour and spectral Doppler imaging identified vessels running along the acetabular labrum, epiphyseal vessels, and femoral neck. We showed 4 different patterns of vascularity of the hips: radial, parallel, mixed radial-parallel, and indeterminate, however, they were not related to the hip maturity (P = .3, coronal plane; P = .62, transverse plane) or to the amount of colour pixels identified in each region (P = .35). The mean number of pixels in the ligamentum teres region was significantly higher than that in other regions of interest (P = .03). Except for the acetabular labrum arteries, Doppler spectrum waveforms of proximal femur arteries presented with low resistivity. There was a tendency towards females' acetabular arteries presenting with lower peak systolic velocities than males' acetabular arteries (P = .06). CONCLUSIONS: Colour Doppler spectrum waveforms and intensity of vascularity in normal neonatal hips differ according to the anatomic region under evaluation. This observation deserves further investigation on its role on the physiopathogenesis of neonatal hip disorders.

Pediatric soft-tissue tumors and pseudotumors: MR imaging features with pathologic correlation: part 2. Tumors of fibroblastic/myofibroblastic, so-called fibrohistiocytic, muscular, lymphomatous, neurogenic, hair matrix, and uncertain origin.

In the final part of this two-part review article on soft-tissue masses in children, the magnetic resonance (MR) imaging features, clinical findings, and pathologic findings in a wide variety of tumors, including those of fibroblastic/myofibroblastic origin, so-called fibrohistiocytic tumors, smooth-muscle tumors, skeletal-muscle tumors, tumors of uncertain differentiation, and lymphoma, are described. Other neoplasms that are not included in the World Health Organization classification of soft-tissue tumors but may be seen clinically as soft-tissue masses, specifically dermatofibrosarcoma protuberans, neurogenic tumors and pilomatricoma, are also included. In contrast to the tumors reviewed in Part 1 of this review, the MR imaging features and clinical findings of the tumors included here are largely nonspecific. However, MR imaging is useful in determining site of tumor origin, extent of disease, and relation of tumor to adjacent anatomic structures, and for follow-up after therapy. In some of these entities, the combination of findings may aid in narrowing the differential diagnosis, such as persistent low signal intensity on T1- and T2-weighted images in some fibroblastic lesions, identification of hemosiderin and a synovial origin in pigmented villonodular synovitis, or the presence of multiple target signs on T2-weighted images in deep plexiform neurofibroma. In a large number of cases, however, tissue biopsy is required for final diagnosis.

Pediatric soft-tissue tumors and pseudo-tumors: MR imaging features with pathologic correlation: part 1. Imaging approach, pseudotumors, vascular lesions, and adipocytic tumors.

A wide spectrum of entities may give rise to soft-tissue masses in children, including benign and malignant tumors, pseudotumors, and both neoplastic and nonneoplastic vascular lesions. Because of its excellent tissue contrast, multiplanar capability, and lack of ionizing radiation, magnetic resonance (MR) imaging has become the modality of choice in the evaluation of deep and large soft-tissue masses in children. In the vast majority of cases, however, accurate interpretation of the MR imaging findings requires correlation with the clinical findings. For example, in most posttraumatic and inflammatory pseudotumors, the clinical history is fundamental to establishing the diagnosis. In the evaluation of periarticular cysts, the location of the mass and its relationship to a joint are crucial for diagnosis, whereas in the evaluation of vascular lesions, including hemangiomas and vascular malformations, clinical findings combined with MR imaging findings are needed for accurate diagnosis in most cases. The identification of fat within adipocytic tumors is useful, but tissue biopsy may be required for final diagnosis. Nevertheless, MR imaging is useful in determining the origin and character of pediatric soft-tissue masses, defining their extent and their relationship to adjacent structures, and performing posttherapy follow-up.

Homozygous contiguous gene deletion of 13q12 causing LGMD2C and ARSACS in the same patient.

We describe a 10-year-old girl with limb-girdle muscular dystrophy type 2C (LGMD2C, gamma-sarcoglycan deficiency) with additional features that include progressive lower limb spasticity, peripheral neuropathy, and ataxia. The gene for LGMD2C lies in close approximation to the gene for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) on chromosome 13q12. The clinical presentation was suspicious for a genomic rearrangement affecting the expression of both genes. Using chromosomal microarray analysis, a homozygous deletion that encompassed the genes for both disorders was identified. This is the first report of a patient with both neurological diseases, and this case illustrates the clinical utility of microarray technology in the investigation of patients with unusual presentations.

Tracheoesophageal fistula without esophageal atresia: are pull-back tube esophagograms needed for diagnosis?

BACKGROUND: A pull-back tube esophagogram (PBTE) is widely accepted in the literature as the radiological investigation of choice for the diagnosis of tracheoesophageal fistula without esophageal atresia. However, PBTE is rarely performed in our institution, as we have been successful in confirming the presence of such fistulae with a contrast material swallow (CS). We hypothesized that PBTE is not the radiological investigation of choice for the diagnosis of the fistula in this condition. OBJECTIVE: We sought to determine what proportion of patients with tracheoesophageal fistula without esophageal atresia can be diagnosed promptly by a CS and what the indications are for a PBTE. MATERIALS AND METHODS: We retrospectively analyzed the clinical and radiological findings in patients with tracheoesophageal fistula without esophageal atresia to determine whether the fistula was diagnosed with a CS or PBTE. RESULTS: We identified 20 children (13 female and 7 male) with tracheoesophageal fistula without esophageal atresia. Their age at diagnosis ranged from 3 days to 168 months with a median of 9 days. The diagnosis was documented by CS in 12, PBTE in 7 and CT in 1. In three of the seven who had the fistula documented by PBTE, a previous CS had shown contrast material in the trachea, but no fistulous tract or aspiration was identified. CONCLUSION: We believe that CS should be the examination of choice in most patients suspected of having a tracheoesophageal fistula without esophageal atresia. A PBTE is indicated in patients who are intubated or are at significant risk of aspiration. Furthermore, a PBTE is also indicated where contrast material is seen in the airway on CS and there is uncertainty whether this is due to aspiration or a fistula.

Serial diffusion-weighted MRI correlates with clinical course and treatment response in children with intracranial pus collections.

BACKGROUND: Accurate assessment of treatment response in children with intracranial pus collections is vital to guide appropriate therapy and reduce morbidity and mortality. OBJECTIVE: To correlate serial MR-measurable changes in diffusion-weighted imaging (DWI) with clinical response to treatment. MATERIALS AND METHODS: We retrospectively reviewed clinical notes, conventional MR sequences and DWI in eight children with intracranial pus collections. Trace DWI signal intensity and apparent diffusion coefficient (ADC) values were compared at three time points: at initial diagnosis (eight children, 13 collections), at follow-up during continued clinical infection (three children, sp collections), and at follow-up when clinical infection had resolved (seven children, 12 collections). RESULTS: At initial diagnosis all patients were septic and collections showed restricted diffusion (mean ADC 0.61+/-0.15 x 10(-3) mm(2)/s). Patients with persistent clinical sepsis at follow-up DWI had collections with persistent low ADC values (0.66+/-0.21 x 10(-3) mm(2)/s), significantly (P<0.001) below normal cortical gray matter values. Successful resolution of the infection was associated with a significant rise in ADC values (1.57+/-0.57 x 10(-3) mm(2)/s, P<0.01) compared both to patients with signs of continued sepsis and to normal gray matter values. CONCLUSION: Persistent restricted diffusion in pus collections correlates with continued sepsis. Treatment response is associated with clinical resolution of sepsis and ADC value elevation significantly above normal gray matter values.