Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs.

BACKGROUND: Spinal muscular atrophy with lower extremity predominance (SMA-LED) is an autosomal dominant disorder. Since SMA-LED affects lower motor neurons, the disease is characterized by weakness and atrophy of lower limb muscles. We present a familial case series of SMA-LED with upper motor neuron signs associated with a rare variant in DYNC1H1. CASE: The index case was referred to Pediatric Neurology at the age of two and half years, due to delayed mobility. The child was diagnosed with congenital vertical talus at birth, which was managed with serial bilateral casting and surgery. The delayed mobility was initially attributed to lower limb weakness secondary to prolonged periods of immobilization from casting of his lower limbs. He had a striking waddling gait and proximal muscle weakness on neurological assessment. He had lower motor neuron signs predominantly in his lower limbs that were in keeping with SMA-LED. Surprisingly, he also demonstrated a brisk crossed adductor response that was not in keeping with an isolated primary neuro-muscular disorder and suggested a mixed upper and lower motor neuron pathology. The inherited neuropathy gene panel revealed a heterozygous sequence change in the DYNC1H1 gene which was present in all affected family members. CONCLUSIONS: We present the first report of a familial case series of SMA-LED with upper motor neuron signs associated with an extremely rare variant in DYNC1H1: c.1808A > T (p.Glu603Val). As per the American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, we would recommend that this variant be reclassified as `Likely Pathogenic` due to matching 1 moderate (PM1-PM6) and ≥4 supporting (PP1-PP5) criteria in the reported case series.

Recognising side effects of antipsychotics in children with intellectual disabilities.

Risperidone and aripiprazole are increasingly used for behavioural indications in children and adolescents with intellectual disabilities, including autism. Although there are some reports in literature, the side effect profile in this population remains poorly defined and there is a need to raise awareness among clinicians across specialties. We present two patients with significant intellectual disabilities who developed extrapyramidal side effects (EPSE) including oculogyric crisis following risperidone and aripiprazole use. The onset of these side effects can be insidious and the non-specific nature of the presentation, for example, poor mobility and increased drooling on a background of severe intellectual disability, can lend itself to delay in recognition and reporting by families. There is also reduced awareness among paediatricians, which can further delay the treatment of this reversible condition. There needs to be ongoing vigilance for EPSE as they can develop years after treatment has been initiated.

Autoimmune hepatitis and acquired partial lipodystrophy.

The lipodystrophies are an extremely rare group of metabolic conditions which are categorised based on their pathogenesis and phenotype. While primarily known for the striking loss of subcutaneous adipose tissue which they induce, they may also be associated with significant liver injury. In most cases, this results from the secondary deposition of lipid within hepatic parenchyma and is seen predominantly in generalised lipodystrophy. More rarely, patients may develop autoimmune hepatitis. We report a rare case of a 17-month-old boy who developed features of acquired partial lipodystrophy in association with anti-LKM1-positive autoimmune hepatitis following initial presentation with a Henoch-Schönlein purpura-like illness. We describe his challenging path to diagnosis and discuss his ongoing management in an effort to further our understanding of this rare but significant association. This report highlights the need for close clinical observation and a high index of suspicion for recognising early features of lipodystrophy.

Paroxysmal kinesigenic dyskinesia: a diagnostic challenge.

A 10-year-old girl presented with a month long history of episodic limb movements. She had a normal neurological examination and after thorough investigation, she was thought to have possible tics. Anxiety was reported as being a trigger. Unusually, these 'tics' were not directly witnessed during hospital visits. Eighteen months after the initial presentation, the clinician observed dystonic posturing after the child stood up from having been seated during a consultation. Paroxysmal kinesigenic dyskinesia (PKD) was then suspected and confirmed on genetic testing. She was successfully treated with carbamazepine. In hindsight, it became apparent that her anxiety was related to a fear of uncontrolled movements, rather than it being a trigger. The abnormal involuntary movements in PKD are precipitated by sudden voluntary movement. Lack of recognition of this typical feature, normal examination and/or features such as coexisting anxiety can lead to misdiagnosis or delayed diagnosis of this easily treatable condition.

Disability and visual outcomes following suspected abusive head trauma in children under 2 years.

AIM: To report disability and visual outcomes following suspected abusive head trauma (AHT) in children under 2 years. METHODS: We present a retrospective case series (1995-2017) of children with suspected AHT aged ≤24 months. King's Outcome Score of Childhood Head Injury (KOSCHI) was used to assess disability outcomes at hospital discharge and at follow-up. The study used a retinal haemorrhage score (RHS) to record findings at presentation and a visual outcome score at follow-up. RESULTS: We included 44 children (median age 16 weeks). At presentation, 98% had a subdural haemorrhage and 93% had a retinal haemorrhage. At discharge, 61% had moderate-to-severe disability, and 34% a good recovery. A higher RHS was observed in those with more disability (r=-0.54, p=0.0002). At follow-up, 14% had a worse KOSCHI score (p=0.055). 35% children had visual impairment, including 9% with no functional vision. Those with poorer visual function had a higher RHS (r=0.53, p=0.003). 28% attended mainstream school without support; 50% were in foster care or had been adopted, 32% lived with birth mother and 18% with extended family. CONCLUSION: It is known that injuries from suspected AHT result in high levels of morbidity; our cohort showed significant rates of disability and visual impairment. Those with higher disability at discharge and poorer visual function showed more significant retinal changes. The extent of disability was not always apparent at hospital discharge, impacting on provision of prognostic information and targeted follow-up.

Evolving Cognitive Dysfunction in Children with Neurologically Stable Opsoclonus-Myoclonus Syndrome.

Cognitive and acquired neurodevelopmental deficits have been reported in children with opsoclonus-myoclonus syndrome (OMS) and are known to be associated with more severe and relapsing disease course. However, there is a paucity of data regarding cognitive dysfunction in children with stable neurological disease. We report three children with OMS and evolving cognitive dysfunction in the context of a mild disease course. The children's ages at disease onset were between 17 and 35 months and they were followed up for 4-10 years. Neuroblastoma was identified in one child. OMS severity scores ranged between 8 and 12/15 at presentation. They underwent immunotherapy and all were in remission by 7 months (range 4-13 months), with treatment maintained for 1 year. One child remained relapse-free, while two others had one clinical relapse each and were immunotherapy-responsive again. In all cases, evolving cognitive dysfunction was reported despite being in remission and stable off treatment for a median of 20 months (range of 12-31 months; two OMS scores of 0/15 and one of 2/15). In children with OMS who have completed treatment and have made full or near full neurological recovery, concerns remain regarding long-term outcome in terms of future learning and cognitive development.

Trends in phenotype in the English paediatric neurofibromatosis type 2 cohort stratified by genetic severity.

Childhood onset neurofibromatosis type 2 can be severe and genotype dependent. We present a retrospective phenotypic analysis of all ascertained children in England 1.0). Focal cortical dysplasia occurred in 26% group 3 and 4% 2A. A total of 48% of group 3 underwent ≥1 major intervention (intracranial/spinal surgery/Bevacizumab/radiotherapy) compared to 35% of 2A; with 23% group 3 undergoing spinal surgery (schwannoma/ependymoma/meningioma resection) compared to 4% of 2A. Mean age starting Bevacizumab was 12.7 in group 3 and 14.9 years in 2A. In conclusion, group 3 phenotype manifests earlier with greater tumour load, poorer visual outcomes and more intervention.

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population.

OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.

Altered functional brain connectivity in children and young people with opsoclonus-myoclonus syndrome.

AIM: Opsoclonus-myoclonus syndrome (OMS) is a rare, poorly understood condition that can result in long-term cognitive, behavioural, and motor sequelae. Several studies have investigated structural brain changes associated with this condition, but little is known about changes in function. This study aimed to investigate changes in brain functional connectivity in patients with OMS. METHOD: Seven patients with OMS and 10 age-matched comparison participants underwent 3T magnetic resonance imaging (MRI) to acquire resting-state functional MRI data (whole-brain echo-planar images; 2mm isotropic voxels; multiband factor ×2) for a cross-sectional study. A seed-based analysis identified brain regions in which signal changes over time correlated with the cerebellum. Model-free analysis was used to determine brain networks showing altered connectivity. RESULTS: In patients with OMS, the motor cortex showed significantly reduced connectivity, and the occipito-parietal region significantly increased connectivity with the cerebellum relative to the comparison group. A model-free analysis also showed extensive connectivity within a visual network, including the cerebellum and basal ganglia, not present in the comparison group. No other networks showed any differences between groups. INTERPRETATION: Patients with OMS showed reduced connectivity between the cerebellum and motor cortex, but increased connectivity with occipito-parietal regions. This pattern of change supports widespread brain involvement in OMS.

Nonotogenic Skull Base Osteomyelitis in Children: Two Cases and a Review of the Literature.

Skull base osteomyelitis is a rare condition in childhood and can be described according to whether it is associated with spread of infection from the middle ear (otogenic) or not (nonotogenic). Early recognition of this serious disease and prompt treatment are key to preventing extension to adjacent vascular and nervous system structures. Diagnosis can be challenging due to the variable presentation of the disease and potentially subtle radiological appearances. We present 2 cases of nonotogenic skull base osteomyelitis in childhood both affecting the clivus and review the 6 cases previously described. Both children presented with fever, headache and neck stiffness and responded well to medical management alone; detailed imaging was key to making a diagnosis.

Carpal tunnel syndrome following an electrical injury in a child.

Carpal tunnel syndrome (CTS) is very rare in children and has been reported very infrequently in the literature. We present an unusual case of CTS in a 14-year-old girl who developed this following an accidental electrical shock. As far as we are aware, this is the first case report of CTS in a child following electrical injury. This rare complication of electrical injury can easily be disregarded or misdiagnosed as neuropraxia, and this can delay appropriate treatment, as evidenced by this case. We propose that CTS should be considered when instigating initial medical care after an electrical injury, and that a referral to a hand surgeon should not be delayed, as these children need urgent surgical intervention to preserve hand function.

Cerebellar and cortical abnormalities in paediatric opsoclonus-myoclonus syndrome.

AIM: Paediatric opsoclonus-myoclonus syndrome (OMS) is a poorly understood condition with long-term cognitive, behavioural, and motor sequelae. Neuroimaging has indicated cerebellar atrophy in the chronic phase, but this alone may not explain the cognitive sequelae seen in many children with OMS. This study aimed to determine the extent of structural change throughout the brain that may underpin the range of clinical outcomes. METHOD: Nine participants with OMS (one male, eight females; mean age [SD] 14y, [6y 5mo], range 12-30y) and 10 comparison individuals (three males, seven females; mean age 12y 6mo, [4y 9mo], range 10-23y) underwent magnetic resonance imaging to acquire T1-weighted structural images, diffusion-weighted images, and magnetic resonance spectroscopy scans. Neuroblastoma had been present in four participants with OMS. Voxel-based morphometry was used to determine changes in grey matter volume, tract-based spatial statistics to analyze white matter integrity, and Freesurfer to analyze cortical thickness across visual and motor cortices. RESULTS: Whole-brain analysis indicated that cerebellar grey matter was significantly reduced in the patients with OMS, particularly in the vermis and flocculonodular lobe. A region-of-interest analysis indicated significantly lower cerebellar grey matter volume, particularly in patients with the greatest OMS scores. Diffusion-weighted images did not show effects at a whole brain level, but all major cerebellar tracts showed increased mean diffusivity when analysis was restricted to the cerebellum. Cortical thickness was reduced across the motor and visual areas in the OMS group, indicating involvement beyond the cerebellum. INTERPRETATION: Across individuals with OMS, there is considerable cerebellar atrophy, particularly in the vermis and flocculonodular lobes with atrophy severity associated with persistent symptomatology. Differences in cerebral cortical thickness indicate disease effects beyond the cerebellum.

H1N1 triggered recurrent acute necrotizing encephalopathy in a family with a T653I mutation in the RANBP2 gene.

A 28-month-old infant presented with fever, vomiting and encephalopathy. Magnetic resonance imaging findings and family history confirmed a diagnosis of recurrent familial acute necrotizing encephalopathy (ANE1). We believe that this is the first description implicating the H1N1 viral strain as a trigger and the second report of a T653I mutation in the RANBP2 gene described in relation to ANE1.

Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations.

Mutations in the recently described RARS2 gene encoding for mitochondrial arginyl-transfer RNA synthetase give rise to a disorder characterised by early onset seizures, progressive microcephaly and developmental delay. The disorder was named pontocerebellar hypoplasia type 6 (PCH6) based on the corresponding radiological findings observed in the original cases. We report two siblings with the RARS2 mutation who displayed typical clinical features of PCH6, but who had distinct neuroimaging features. Early scans showed marked supratentorial, rather than infratentorial, atrophy, and the pons remained preserved throughout. One sibling also had bilateral subdural effusions at presentation. The deceleration in head growth pointed to an evolving genetic/metabolic process giving rise to cerebral atrophy and secondary subdural effusions. RARS2 mutations should be considered in infants presenting with seizures, subdural effusions, decelerating head growth and evidence of cerebral atrophy even in the absence of pontocerebellar hypoplasia on imaging.

Isolated paediatric neurosarcoidosis presenting as epilepsia partialis continua: a case report and review of literature.

Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants.