Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance.

BACKGROUND: Precision (Personalized) medicine has the potential to revolutionize patient health care especially for many cancers where the fundamental disease etiology remains either elusive or has no available therapy. Here we outline a study in alveolar rhabdomyosarcoma, in which we use gene expression profiling and a series of drug prediction algorithms combined with a matched patient-derived xenograft (PDX) model to test bioinformatically predicted therapies. PROCEDURE: A PDX model was developed from a patient biopsy and a number of drugs identified using gene expression analysis in combination with drug prediction algorithms. Drugs chosen from each of the predictive methodologies, along with the patient's standard-of-care therapy (ICE-T), were tested in vivo in the PDX tumor. A second study was initiated using the tumors that re-grew following the ICE-T treatment. Further expression analysis identified additional therapies with potential anti-tumor efficacy. RESULTS: A number of the predicted therapies were found to be active against the tumors in particular BGJ398 (FGFR2) and ICE-T. Re-transplanted ICE-T treated tumorgrafts demonstrated a decreased response to ICE-T recapitulating the patient's refractory disease. Gene expression profiling of the ICE-T treated tumorgrafts identified cytarabine (SLC29A1) as a potential therapy, which was shown, along with BGJ398, to be highly active in vivo. CONCLUSIONS: This study illustrates that PDX models are suitable surrogates for testing potential therapeutic strategies based on gene expression analysis, modeling clinical drug resistance and hold the potential to assist in guiding prospective patient care.

Pediatric thoracic spine injuries: a single-institution experience.

OBJECTIVE: The objective of our study was to determine the incidence of various fractures of the thoracic spine in pediatric patients. CONCLUSION: Simple compression and process-only fractures were the most common types of fractures and all other fracture types were infrequent. Distraction injury was unexpectedly more common in the nonjunctional thoracic spine than in the junctional thoracic spine.

Segmental Agenesis of the Corpus Callosum With Pituitary Hypoplasia.

We report a 3-year-old male with findings of segmental agenesis of the corpus callosum, pituitary hypoplasia, and Chiari I malformation. The patient was born at 33 weeks and spent five weeks in the NICU for hypoglycemia, hypotension, and dyspnea. In infancy, the patient passed an adrenocorticotropic hormone stimulation test, while cortisol, growth hormone, and insulin-like growth factor levels were within reference range. Following height and weight percentile regression the patient underwent arginine and clonidine stimulation testing at 3 years of age, prompting pituitary evaluation via MRI. The results provided exemplary neuroimaging of segmental callosal agenesis, in which the genu and splenium form despite the absence of the callosal body. This finding adds support to a newer theory of embryological callosal development where progression does not occur linearly in the rosto-caudal direction.

Pediatric craniocervical junction injuries.

OBJECTIVE: The purpose of this article is to review pediatric craniocervical junction injuries in the context of embryology, developmental anatomy, and biomechanics. CONCLUSION: The craniocervical junction is functionally and developmentally distinct from the rest of the spine, and mechanistic models often fail to explain these injuries. Various developmental features and complex anatomy likely contribute to injury in this region in children. Some of the injury patterns at the craniocervical junction in children are similar to adults, but many are unique.

Ossification patterns of the atlas vertebra.

OBJECTIVE: The objective of this study was to characterize ossification patterns of the C1 (atlas) vertebra in children, to better differentiate normal variants from traumatic injury. MATERIALS AND METHODS: A retrospective review of all sinus and temporal bone CT examinations was performed for the period of 2002-2009. Patients 96 months old or younger for whom C1 level was at least partially imaged were included. Patients with a history of trauma or genetic disorder-associated spinal abnormalities were excluded. RESULTS: A total of 1270 CT examinations were reviewed. The anterior arch of C1 was completely imaged in 841 patients (66%), and the posterior arch was completely imaged in 378 patients (30%). Multiple anterior arch ossification centers were observed in 179 of 841 patients (21%), and posterior arch variants were present in nine of 378 patients (2%). At least partial ossification of the anterior arch was seen in 113 of 147 children (77%) younger than 25 months, whereas only 14 of the remaining 694 children (2%) older than 24 months failed to show any ossification. Incomplete ossification of the anterior arch was noted in 47 of 103 patients (46%) in the 85-96-month-old category. The posterior arches were at least partially ossified in all children. Incomplete fusion of the posterior synchondrosis was seen in 17 of 108 patients (16%) older than 60 months. CONCLUSION: C1 ossification patterns and timing of synchondrosis fusion are variable. Knowledge of these patterns is important to better differentiate a normal variant from traumatic injury.

Pediatric lateral atlantodental interval: how much asymmetry is normal?

Imaging of the cervical spine is commonly performed in the pediatric patient population, typically after trauma, as well as for a variety of nontraumatic reasons. There are many challenges in the interpretation of these studies, particularly at the level of the atlantoaxial joint. We recognized a particular problem with assessing the lateral atlantodental interval in our emergency radiology department. Mild lateral atlantodental interval asymmetry in relatively asymptomatic patients was being interpreted as indicative of atlantoaxial rotatory fixation, which leads to the recommendation for dynamic computed tomographic examinations. The goal of this study was to define the reference range of the lateral atlantodental interval in pediatric patients to help avoid misinterpretation of radiographic findings and resultant excessive imaging.

Relationship between the clinical characteristics of osteomyelitis and the finding of extraosseous fat on MRI in pediatric patients.

BACKGROUND: MRI is frequently utilized to evaluate patients for osteomyelitis. The findings of intramedullary and extramedullary fat globules as well as extramedullary fat-fluid levels can help improve the specificity of MRI for this diagnosis. OBJECTIVE: To correlate these MRI findings with the clinical characteristics in children with osteomyelitis. MATERIALS AND METHODS: A retrospective electronic medical record search for pediatric patient charts from March 2004 to November 2009 that contained the word "osteomyelitis" in the "principal diagnosis" portion of the international classification of disease (ICD) billing code. Each electronic chart was reviewed. MRI examinations of selected children were reviewed by a pediatric radiologist, a general radiologist and a transitional year resident. RESULTS: A total of 10 patients/11 MRI studies were included. Five of the 11 had the MRI finding of extramedullary globular fat signal. There was a significantly increased likelihood of seeing this finding in children of pubertal or postpubertal age compared to those of prepubertal age (p < 0.05). CONCLUSION: This study provides evidence that the MRI finding of extramedullary fat globules in children with acute osteomyelitis is associated with the clinical characteristic of being within or above the age range for puberty.

Cervical spine injuries in pediatrics: are children small adults or not?

Diagnosis of cervical spine injuries is crucial whether in children or adults. It is necessary to understand the injuries unique to the developing spine. Equally important is an insight to similarities in injury patterns between adults and children.

Sonographic assessment of renal size and growth in premature infants.

BACKGROUND: Low birth-weight infants are at risk for renal disease when renal insults occur in the neonatal period. Renal growth as measured by sonography over time is utilized by many nephrologists as predictors of future renal disease. OBJECTIVE: To identify infants at risk by defining normal renal growth for the very premature infant. MATERIALS AND METHODS: Renal growth was evaluated in 30 infants whose birth weight was 1,500 g or less and gestational age was <31 weeks. During a 2-month time period, three US measurements were taken (first week of life, age 28 days, and age 56 days or earlier if discharged). Infants were divided according to birth weight: the extremely low birth-weight group (ELBW) was <1,000 g (n = 14), and the very low birth-weight group (VLBW) was 1,000-1,500 g (n = 16). RESULTS: In both groups, the right and left renal lengths were similar. In the ELBW group, the initial mean length was 3.25 cm and grew to 4.16 cm, while the mean volume was 4.85 cm and grew to 10.39 cm. In the VLBW group the initial mean length was 3.69 cm and grew to 4.35 cm while the mean volume was 7.25 cm and grew to 11.83 cm. CONCLUSION: These data establish normal expected growth for future studies.

Occult injury of the pediatric craniocervical junction.

The objective of this study is to review the occurrence of occult craniocervical junction injury in children. All patients <18 years of age with negative CT of the craniocervical junction and subsequent MRI between July 2003 and June 2008 were included. Age, gender, mechanism of injury, and presence of injuries below C2 were tabulated. Of the forty-five patients with negative CT of the craniocervical junction, 30 had positive MRI findings at the craniocervical junction. Seventeen of the 30 patients fulfilled criteria for significant craniocervical junction injury by MRI. Eleven of 17 patients with significant craniocervical junction injury were less than 8 years old and 13 of 17 were involved in motor vehicle accidents. Six of 12 patients with injury below C2 had significant craniocervical injury. Pediatric craniocervical injuries are often not evident on radiographic or CT imaging but present on MR imaging. Craniocervical injury is most common in younger age groups and is associated with motor vehicle accidents and injuries of the lower cervical spine.

Distribution of spinal fractures in children: does age, mechanism of injury, or gender play a significant role?

BACKGROUND: The distribution of fractures in the spine reported in the literature is quite variable. Application of such data to the pediatric population needs to take into account differences between children and adults, including overall decreased fracture frequency in children, developmental and physiological differences, and mechanism of injury. Knowledge of specific regions of injury may alter search patterns and protocols. OBJECTIVE: To determine if the distribution of spinal injuries in pediatric patients is related to age, mechanism of injury, or gender. PATIENTS AND METHODS: All pediatric patients (<18 years old) referred to our trauma service over a 5-year period were retrospectively reviewed. All patients with vertebral fracture and/or neurological injury were included. The levels of the spinal fractures were tabulated. Correlation was then made with age, gender, and mechanism of injury (motor vehicle accident versus non-motor vehicle accident). RESULTS: Of the 2614 pediatric patients, 84 sustained vertebral fracture and 50 had neurological injury without radiographic abnormality. A total of 164 fractures were identified. The thoracic region (T2-T10) was most commonly injured, accounting for 47 fractures (28.7%) followed by the lumbar region (L2-L5) with 38 fractures (23.2%), the mid-cervical region with 31 fractures (18.9%), the thoracolumbar junction with 24 fractures (14.6%), the cervicothoracic junction with 13 fractures (7.9%), and the cervicocranium with 11 fractures (6.7%). There was no relationship to gender or mechanism of injury. CONCLUSIONS: Regardless of gender or mechanism of injury, the thoracic spine (T2-T10) is the most common region of fracture in pediatric trauma patients.