Chronic recurrent multifocal osteomyelitis with a comprehensive approach to differential diagnosis of paediatric skull pain.

A girl in middle childhood was referred to rheumatology with a 1-month history of progressive skull pain, preceded by fleeting musculoskeletal symptoms. Apart from a scaly rash on her scalp, she was well, with moderately elevated inflammatory markers. Skull imaging (radiographs, CT and MRI) revealed osteolytic lesions, soft tissue swelling and pachymeningeal enhancement at frontal and temporal convexities. Langerhans cell histiocytosis, bone infection/inflammation or malignancy was considered. Skin and bone biopsies eventually ruled out mimicking diseases and confirmed the diagnosis of chronic recurrent multifocal osteomyelitis (CRMO). She was treated with intravenous pamidronate (IVPAM) for 9 months, with rapid resolution of pain and gradual resolution of bony abnormalities. She remains in remission at 15-month follow-up. While CRMO can affect any bone, skull involvement is extremely rare, with a broad differential diagnosis. We recommend bone biopsy to confirm skull CRMO. The patient achieved excellent clinical and radiological response to IVPAM.

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.

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates.

The development of the cerebral cortex requires balanced expansion and differentiation of neural stem/progenitor cells (NPCs), which rely on precise regulation of gene expression. Because NPCs often exhibit transcriptional priming of cell-fate-determination genes, the ultimate output of these genes for fate decisions must be carefully controlled in a timely fashion at the post-transcriptional level, but how that is achieved is poorly understood. Here, we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb NPC fate decisions in mice by disrupting CELF2 nucleocytoplasmic transport. In self-renewing NPCs, CELF2 resides in the cytoplasm, where it represses mRNAs encoding cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNA for translation and thereby triggers NPC differentiation. Our results reveal that CELF2 translocation between subcellular compartments orchestrates mRNA at the translational level to instruct cell fates in cortical development.

Diffuse Intracerebral Hemorrhage in an Infant With a Novel Homozygous Variant Leading to Severe Protein C Deficiency.

Protein C is a circulating anticoagulant that inhibits factor Va and VIIIa and promotes fibrinolysis. Compound heterozygous or homozygous variants in the Protein C gene (PROC) lead to severe deficiency of protein C and affected neonates typically present shortly after birth with purpura fulminans. We describe an infant who suffered a diffuse intracranial hemorrhage as a neonate and presented with purpura fulminans as an older infant which led to investigations that were consistent with severe protein C deficiency. We demonstrate subacute findings on neuroimaging and suggest this condition should be considered with neonatal presentations of bilateral intraparenchymal hemorrhage.

MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease.

Mitochondrial diseases, due to nuclear or mitochondrial genome mutations causing mitochondrial dysfunction, have a wide range of clinical features involving neurologic, muscular, cardiac, hepatic, visual, and auditory symptoms. Making a diagnosis of a mitochondrial disease is often challenging since there is no gold standard and traditional testing methods have required tissue biopsy which presents technical challenges and most patients prefer a non-invasive approach. Since a diagnosis invariably involves finding a disease-causing DNA variant, new approaches such as next generation sequencing (NGS) have the potential to make it easier to make a diagnosis. We evaluated the ability of our traditional diagnostic pathway (metabolite analysis, tissue neuropathology and respiratory chain enzyme activity) in 390 patients. The traditional diagnostic pathway provided a diagnosis of mitochondrial disease in 115 patients (29.50%). Analysis of mtDNA, tissue neuropathology, skin electron microscopy, respiratory chain enzyme analysis using inhibitor assays, blue native polyacrylamide gel electrophoresis were all statistically significant in distinguishing patients between a mitochondrial and non-mitochondrial diagnosis. From these 390 patients who underwent traditional analysis, we recruited 116 patients for the NGS part of the study (36 patients who had a mitochondrial diagnosis (MITO) and 80 patients who had no diagnosis (No-Dx)). In the group of 36 MITO patients, nuclear whole exome sequencing (nWES) provided a second diagnosis in 2 cases who already had a pathogenic variant in mtDNA, and a revised diagnosis (GLUL) in one case that had abnormal pathology but no pathogenic mtDNA variant. In the 80 NO-Dx patients, nWES found non-mitochondrial diagnosis in 26 patients and a mitochondrial diagnosis in 1 patient. A genetic diagnosis was obtained in 53/116 (45.70%) cases that were recruited for NGS, but not in 11/116 (9.48%) of cases with abnormal mitochondrial neuropathology. Our results show that a non-invasive, bigenomic sequencing (BGS) approach (using both a nWES and optimized mtDNA analysis to include large deletions) should be the first step in investigating for mitochondrial diseases. There may still be a role for tissue biopsy in unsolved cases or when the diagnosis is still not clear after NGS studies.

Transiently elevated plasma methionine, S-adenosylmethionine and S-adenosylhomocysteine: Unreported laboratory findings in a patient with NGLY1 deficiency, a congenital disorder of deglycosylation.

We report on a 5-year-old female born to consanguineous parents, ascertained at the age of 23 months for an elevated plasma methionine level, a mildly abnormal total plasma homocysteine (tHcy), and elevated aminotransferases. She had global developmental delay, microcephaly, dysmorphic facial features, hypotonia, nystagmus and tremor in her upper extremities. Metabolic investigations demonstrated elevations in plasma methionine, plasma S-adenosylmethionine (SAM) and plasma S-adenosylhomocysteine (SAH), with normal urine adenosine levels. Some of the elevations persisted for over 1 year. Sequencing of the ADK and AHCY genes was negative for causative variants. Plasma methionine normalized 1 year after ascertainment, but SAM and SAH continued to be elevated for six more months before normalization, and aminotransferases remained mildly elevated. Whole exome sequencing demonstrated a homozygous pathogenic variant; NM_018297.3(NGLY1):c.1405C>T (p.Arg469*) in exon 9 of the NGLY1 gene, for which both parents were heterozygous. To our knowledge, this is the first report of NGLY1 deficiency with elevations in plasma methionine, SAM and SAH and a slight elevation of tHcy. Less than 20 patients have been reported with NGLY1 deficiency worldwide and this case expands on the biochemical phenotype of this newly discovered inborn error of metabolism.

Single-center experience with Beta-propeller protein-associated neurodegeneration (BPAN); expanding the phenotypic spectrum.

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) that presents with childhood developmental delay (especially speech delay), occasionally associated with epileptic encephalopathy, autism, or Rett-like syndrome. The majority of children described to date have been severely affected, with little to no expressive speech function, severe developmental delay, and cognitive impairment. Herein, five additional patients with BPAN identified in the same center in Canada are described, four with the typical severe phenotype and one with a milder phenotype. Our findings provide further evidence that a spectrum of severity exists for this rare and newly described condition. Challenges in identifying iron accumulation on brain MRI are also addressed. Additionally, the importance of including the WDR45 gene on epilepsy and Rett-like syndrome genetic panels is highlighted.

Diffusion Imaging of Cerebral Diaschisis in Neonatal Arterial Ischemic Stroke.

BACKGROUND: Neonatal arterial ischemic stroke is a leading cause of cerebral palsy and lifelong disability. Diffusion-weighted imaging has revolutionized diagnosis and facilitated outcome prognostication in acute neonatal arterial ischemic stroke. Diaschisis refers to changes in brain areas functionally connected but structurally remote from primary injury. We hypothesized that acute diffusion-weighted imaging can quantify cerebral diaschisis and is associated with outcome from neonatal arterial ischemic stroke. METHODS: Subjects were identified from a prospective, population-based research cohort (Alberta Perinatal Stroke Project). Inclusion criteria were unilateral middle cerebral artery neonatal arterial ischemic stroke, diffusion-weighted magnetic resonance imaging within 10 days of birth, and more than 12-months follow-up (pediatric stroke outcome measure). Diaschisis was characterized and quantified using a validated software method (ImageJ). Volumetric analysis assessed atrophy of affected structures. Diaschisis scores were corrected for infarct size and compared with outcomes (Mann-Whitney). RESULTS: From 20 eligible neonatal arterial ischemic strokes, two were excluded for poor image quality. Of 18 remaining (61% male, median age 3.2 days), 16 (89%) demonstrated diaschisis. Thalamus (88%) was the most common location in addition to corpus callosum (50%). Age at imaging was not associated with diaschisis. Affected structures demonstrated atrophy on imaging. Long-term outcomes available in 81% (median age 7.5 years) were not associated with diaschisis scores. CONCLUSIONS: Cerebral diaschisis occurs in neonatal arterial ischemic stroke and can be quantified with diffusion-weighted imaging. Occurrence is common and should not be mistaken for additional infarction. Determining clinical significance will require larger samples with well-characterized long-term outcomes.

AIMP1 Mutation Long-Term Follow-Up, With Decreased Brain N-Acetylaspartic Acid and Secondary Mitochondrial Abnormalities.

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N-acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N-acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

Aphonogelia After Recovery From Severe Traumatic Brain Injury: A Case Report.

During rehabilitation from a severe traumatic brain injury, a 16-year-old girl became aware that she had lost the ability to laugh out loud. This rare phenomenon previously has been described as "aphonogelia." A discussion of therapeutic avenues that were explored with this patient is presented in the first case, to our knowledge, of aphonogelia after a traumatic brain injury. LEVEL OF EVIDENCE: V.

Crossed Cerebellar Atrophy in Perinatal Stroke.

Background and Purpose- Perinatal stroke causes most hemiparetic cerebral palsy and lifelong disability. Crossed cerebellar atrophy (CCA) is chronic cerebellar volume loss following contralateral motor pathway injury. We hypothesized that CCA is quantifiable in perinatal stroke and associated with poor motor outcome. Methods- Term-born children with perinatal stroke, magnetic resonance imaging beyond 6 months of age, and no additional neurological disorders were recruited. Blinded scorers measured cerebellar volumes expressed as ratios (contralesional/ipsilesional), with values <1 suggesting CCA. Motor outcomes including perinatal stroke outcome measure (PSOM) motor and cognitive scores (good/poor), Assisting Hand Assessment, and Melbourne Assessment were compared with cerebellar volume measures. Results- Seventy-three children met criteria (53% male). Mean cerebellar ratios were <1.0 (0.975±0.04; range, 0.885-1.079; P<0.001) suggesting occurrence of CCA. Cerebellar ratios did not differ between stroke types or across PSOM motor outcomes. Larger ipsilesional cerebellar volume was associated with poor PSOM cognitive outcome (P=0.042), possibly with poor PSOM motor outcome (P=0.063), and overall PSOM score (P=0.034). Conclusions- CCA occurs in perinatal stroke but is not strongly associated with motor outcome. However, ipsilesional cerebellar volume is associated with poor cognitive and overall outcomes.

Stroke in Pediatric Bacterial Meningitis: Population-Based Epidemiology.

BACKGROUND: Bacterial meningitis is a severe infection of the nervous system with a high complication rate including stroke. The purpose of this study is to assess the incidence, risk factors, patterns, and outcomes in pediatric meningitis complicated by stroke. METHODS: The study design was a population-based, 10-year retrospective (2002 to 2012) cohort study set in Southern Alberta, Canada. The inclusion criteria were: (1) age from newborn to 18 years, (2) brain magnetic resonance imaging (MRI) including diffusion-weighted imaging during admission, and (3) laboratory confirmed acute bacterial meningitis. The main outcomes were demographics, clinical presentations, risk factors, laboratory findings, radiographic findings, and neurological outcomes. FINDINGS: Forty-three patients had confirmed bacterial meningitis and diffusion MRI (9 neonates (21%), 89% male; 22 infants aged one month to one year (51%), 50% male; and 12 children older than one year (28%), 58% male, median age four years (interquartile range 7.9 years). Ischemic stroke was confirmed in 16/43 (37%), often multifocal (94%). Patients with stroke were significantly more likely to have seizures (P = 0.025), otitis media (P = 0.029), and multiple presentations to hospital (P = 0.013). Mortality was 25% in children with stroke compared with 4% in those without (P = 0.067). Survivors with stroke were more likely to have neurological deficits at follow-up (69% versus 26%, P = 0.019). CONCLUSIONS: More than one-third of children with acute bacterial meningitis and clinically indicated MRI had ischemic stroke. Stroke was associated with clinical factors including duration of illness, seizures, and causative organisms. Stroke was associated with higher mortality and morbidity, warranting consideration of increased MRI screening and new approaches to treatment.

Metallic intraocular foreign body as detected by magnetic resonance imaging without complications- A case report.

PURPOSE: To describe a case and present unique images of a metallic intraocular foreign body that was identified in a 12-year-old male patient who underwent routine magnetic resonance imaging (MRI) to assess neurodevelopmental delay. OBSERVATIONS: We present MRI and diagnostic imaging of a metallic intraocular foreign body in a young patient with no known history of trauma or reason for the existence of metal in the eye area. Computed tomography scan was performed to confirm the presence of the intraocular foreign body, followed by optical coherence tomography and electroretinogram to assess visual status. It was determined that no surgical intervention was currently required as no visual impairment or ocular toxicity was identified. The patient continues to be monitored. CONCLUSIONS AND IMPORTANCE: This case presentation highlights the novel imaging features of a metallic intraocular foreign body, unexpectedly detected with MRI.

ALG9-CDG: New clinical case and review of the literature.

Congenital disorders of glycosylation (CDG) are a group of metabolic diseases resulting from defects in glycan synthesis or processing. The number of subgroups and their phenotypic spectrums continue to expand with most related to deficiencies of N-glycosylation. ALG9-CDG (previously CDG-IL) is the result of a mutation in ALG9. This gene encodes the enzyme alpha-1,2-mannosyltransferase. To date, a total of 10 patients from 6 different families have been reported with one of four ALG9 mutations. Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia. This report describes an additional patient with ALG9-CDG who has a milder phenotype. This patient is a term female born to Caucasian, Canadian, non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. The metabolic work-up included analysis of a transferrin isoelectric focusing, which showed a type 1 pattern. This was confirmed by glycan profiling, which identified ahomozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) (NM_1234567890). This had been previously published as a pathogenic mutation in two Canadian patients. Our goal is to contribute to the growing body of knowledge for this disorder by describing the phenotypic spectrum and providing further insight on prognosis.

Systematic review of MRI findings in children with developmental delay or cognitive impairment.

AIM: To summarize the reported rates of magnetic resonance imaging (MRI) abnormalities in children with isolated global developmental delay (GDD) or intellectual disability (ID). METHOD: A literature search was conducted using electronic databases for studies reporting the rate of MRI abnormalities in children with clinically diagnosed ID or GDD and no other neurological signs, symptoms, or previously determined aetiology. All investigations with participants from birth to 18years were considered. Study quality was evaluated using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) critical appraisal checklist items. RESULTS: Eighteen cross sectional, and 11 case-controlled studies adhered to inclusion criteria. Reported rates of abnormalities ranged from 0% to 98%. When all subjects with developmental delay from all papers were considered (n=2299) the total percentage found to have abnormalities was 38%. Abnormalities led to an etiological diagnosis for delay in 7.9% of cases. INTERPRETATION: Definitions of abnormalities varied widely between studies, and drastically different rates of abnormalities are reported. Currently available evidence is not of sufficient quality to make firm recommendations on the use of neuroimaging in ID or GDD but MRI should be considered for children that do not have a diagnosis after thorough clinical evaluation.

Segmental Diffusion Properties of the Corticospinal Tract and Motor Outcome in Hemiparetic Children With Perinatal Stroke.

Perinatal stroke injures developing motor systems, resulting in hemiparetic cerebral palsy. Diffusion tensor imaging can explore structural connectivity. We used diffusion tensor imaging to assess corticospinal tract diffusion in hemiparetic children with perinatal stroke. Twenty-eight children (6-18 years) with unilateral stroke underwent diffusion tensor imaging. Four corticospinal tract assessments included full tract, partial tract, minitract and region of interest. Diffusion characteristics (fractional anisotropy, mean, axial, and radial diffusivity) were calculated. Ratios (lesioned/nonlesioned) were compared across segments and to validated long-term motor outcomes (Pediatric Stroke Outcome Measure, Assisting Hand Assessment, Melbourne Assessment). Fractional anisotropy and radial diffusivity ratios decreased as tract size decreased, while mean diffusivity showed consistent symmetry. Poor motor outcomes were associated with lower fractional anisotropy in all segments and radial diffusivity correlated with both Assisting Hand Assessment and Melbourne Assessment. Diffusion imaging of segmented corticospinal tracts is feasible in hemiparetic children with perinatal stroke. Correlations with disability support clinical relevance and utility in model development for personalized rehabilitation.

Olfactory Development, Part 1: Function, From Fetal Perception to Adult Wine-Tasting.

Discrimination of odorous molecules in amniotic fluid occur after 30 weeks' gestation; fetuses exhibit differential responses to maternal diet. Olfactory reflexes enable reliable neonatal testing. Olfactory bulbs can be demonstrated reliably by MRI after 30 weeks' gestation, and their hypoplasia or aplasia also documented by late prenatal and postnatal MRI. Olfactory axons project from nasal epithelium to telencephalon before olfactory bulbs form. Fetal olfactory maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the transitory fetal ventricular recess. Immaturity does not signify nonfunction. Olfaction is the only sensory system without thalamic projection because of its own intrinsic thalamic equivalent. Diverse malformations of the olfactory bulb can be diagnosed by clinical examination, imaging, and neuropathology. Some epileptic auras might be primarily generated in the olfactory bulb. Cranial nerve 1 should be tested in all neonates and especially in patients with brain malformations, endocrinopathies, chromosomopathies, and genetic/metabolic diseases.

Two De Novo Mutations in an Autistic Child Who Had Previously Undergone Transplantation for Dilated Cardiomyopathy: The Importance of Keeping an Open Mind.

We report the finding of 2 de novo mutations in an 8-year-old boy with developmental delay and autism who underwent heart transplantation at 1 year of age for idiopathic dilated cardiomyopathy. We identified a de novo microdeletion at chromosome 2p16.3 involving the neurexin-1 (NRXN1) gene and a de novo pathologic variant (Pro838Leu) in the myosin heavy chain 7 (MYH7) gene. This case emphasizes the importance of comprehensive genetic evaluation in patients with cardiomyopathy, particularly if they have extracardiac abnormalities, and the necessity of interpreting variants with attention to the phenotype. A complete genetic diagnosis may require multiple testing modalities.