Clinical use of whole exome sequencing in children with developmental delay/intellectual disability.

BACKGROUND: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. METHODS: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. RESULTS: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. CONCLUSION: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Clinical application of prospective whole-exome sequencing in the diagnosis of genetic disease: Experience of a regional disease center in South Korea.

INTRODUCTION: Next-generation sequencing helps clinicians diagnose patients with suspected genetic disorders. The current study aimed to investigate the diagnostic yield and clinical utility of prospective whole-exome sequencing (WES) in rare diseases. METHODS: WES was performed in 92 patients who presented with clinical symptoms suggestive of genetic disorders. The WES data were analyzed using an in-house developed software. The patients' phenotypic characteristics were classified according to the human phenotype ontology. RESULTS: WES detected 64 variants, 13 were classified as pathogenic, 26 as likely pathogenic, and 25 as variants of uncertain significance. In 57 patients with these variants, 30 were identified as causal variants. The diagnostic yield was higher in patients with abnormalities in joint mobility and skin morphology than in those with cerebellar hypoplasia/atrophy, epilepsy, global developmental delay, dysmorphic features/facial dysmorphisms, and chronic kidney disease/abnormal renal morphology. CONCLUSION: In this study, a WES-based variant interpretation system was employed to provide a definitive diagnosis for 28.3% of the patients suspected of having genetic disorders. WES is particularly useful for diagnosing rare diseases with symptoms that affect more than one system, when targeted genetic panels are difficult to employ.

Pontocerebellar Hypoplasia 7 with Novel Compound Heterozygous Variants of TOE1 in a Boy with Micropenis, Developmental Delay, and Ataxia: The First Korean Case Report.

Pontocerebellar hypoplasia (PCH) is a rare neurodegenerative disorder characterized by hypoplasia of the pons and cerebellum and global developmental delay. Among several PCH types, PCH7 is a characteristic type that manifests with not only brain lesions but also sexual developmental disorders. The causative gene, TOE1, encodes a protein involved in small ribonucleic acid maturation and processing. TOE1 mutation is associated with neuronal survival that causes hypoplasia of the cerebellum and pons. We report the case of a male patient with PCH7, developmental delay, ataxia, micropenis, and undescended testis. Genetic analysis revealed compound heterozygous missense variants (c.955C>T and c.533T>G) in the TOE1 gene.

Efficacy of single dose of phenytoin/fosphenytoin in benign convulsions with mild gastroenteritis.

BACKGROUND: This study evaluated the efficacy of a single dose of phenytoin/fosphenytoin (PHT) to control repetitive seizures in children with benign convulsions with mild gastroenteritis (CwG). METHODS: Children aged between 3 months and 5 years with CwG were retrospectively enrolled. Convulsions with mild gastroenteritis were defined as (a) seizures with acute gastroenteritis without fever or dehydration; (b) normal blood laboratory results; and (c) normal electroencephalography and brain imaging findings. Patients were divided into two groups according to whether or not intravenous PHT (10 mg/kg of phenytoin or phenytoin equivalents) was administered. Clinical manifestations and treatment efficacy were evaluated and compared. RESULTS: Ten of 41 children eligible for inclusion received PHT. Compared to children in the non-PHT group, those in the PHT group had a higher number of seizures (5.2 ± 2.3 vs. 1.6 ± 1.0, P < 0.001) and a lower serum sodium level (133.5 ± 3.2 mmol/L vs. 137.2 ± 2.6 mmol/L, P = 0.001). Initial serum sodium levels were negatively correlated with seizure frequency (r = -0.438, P = 0.004). In all patients, seizures were completely resolved with a single dose of PHT. There were no significant adverse effects from PHT. CONCLUSIONS: A single dose of PHT can effectively treat CwG with repetitive seizures. The serum sodium channel may play a role in seizure severity.

Multiple ectopic germinomas presenting as focal dystonia of fingers: a case report and literature review.

BACKGROUND: Intracranial primary germinomas predominantly develop on or near the midline structure in children and young adults and are diagnosed by brain imaging and biopsy. However, if brain imaging and pathology show unusual findings, it becomes difficult to make an accurate diagnosis. CASE REPORT: Herein, we report the case of a 14-year-old boy who presented with focal dystonia of the fingers as an initial symptom. Magnetic resonance imaging of the brain showed multifocal heterogeneous lesions with solid and cystic components involving the right frontal lobe, corpus callosum, left basal ganglia, and left corona radiata. A stereotactic biopsy of the right frontal lesion revealed several granulomatous areas with abundant inflammatory cells. After immunohistochemical staining, the patient was diagnosed with germinoma and treated with chemoradiotherapy according to the Korean Society for Pediatric Neuro-Oncology protocol. The patient has been in complete remission for five years. CONCLUSION: Germinomas can develop in intracranial off-midline structures, with unusual clinical, radiological, and pathological presentations. It is important to include intracranial germinomas in the differential diagnosis of infiltrative parenchymal tumors, especially in children.

Coffin-Siris Syndrome: Case Series of Three Patients and a Novel ARID2 Variant.

Coffin-Siris syndrome (CSS) is a rare congenital disorder characterized by coarse facial features, intellectual disability or developmental delay, and aplasia or hypoplasia of the tips of the fifth finger and/or toes. Mutations in genes affecting the switch/sucrose non-fermenting ATP-dependent chromatin remodeling complex are reported to cause CSS. Here, we describe three CSS patients. Two girls aged 3 and 2 years old presented with global developmental delay, poor growth, and a dysmorphic face. Whole-exome sequencing (WES) was performed and they were diagnosed with CSS due to heterozygous frameshift variants (c.3443_3444del, p.Lys1148ArgfsTer9 and c.2869_2890del, p.Pro957CysfsTer20) in ARID1B A 2-year-old girl presented with gross motor delay and dysmorphic face. She was diagnosed with CSS due to a novel heterozygous frameshift variant (c.4942_4943del: p.Gln1648GlyfsTer8) in ARID2.

A Novel Frameshift CASK Variant in a 6-Month-Old Korean Female Infant with Global Developmental Delay, Progressive Microcephaly, and Pontocerebellar Hypoplasia: A Case Report.

Pontocerebellar hypoplasia is a heterogeneous group of rare genetic neurodevelopmental disorders marked by early degeneration of the cerebellum and brainstem. Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; MIM#300749) is a disorder caused by pathogenic loss-of-function variants in CASK CASK gene plays a critical role in brain development by controlling neuronal development and synapse formation. This report describes a 6-month-old Korean female infant with global developmental delay, sensorineural hearing loss, axial hypotonia with hypertonia of extremities, progressive microcephaly, and pontocerebellar hypoplasia. On whole exome sequencing, the patient had a novel heterozygous frameshift CASK variant, NM_003688.3:c.535del (NP_003679.2:p. Arg179Valfs*22). This report highlights the importance of considering CASK pathogenic variants in patients with global developmental delay, progressive microcephaly, and pontocerebellar hypoplasia and the genotype-phenotype relationships.

Long-term cognitive outcomes in term newborns with watershed injury caused by neonatal encephalopathy.

BACKGROUND: We previously reported that increasing severity of watershed (WS) injury in neonatal magnetic resonance imaging (MRI) is associated with worse language outcomes in early childhood. In the present study, we investigated the relationship between neonatal injury patterns and cognitive profile in adolescents with neonatal encephalopathy. METHODS: Term neonates with encephalopathy were prospectively enrolled and imaged using brain MRI from 1999 to 2008. Neonatal brain injury was scored according to the degree of injury in WS and basal ganglia/thalamus (BG/T) areas. The children underwent a neurocognitive assessment and follow-up brain MRI at the age of 10-16 years. The relationship between neonatal brain injury patterns and adolescent cognitive outcomes was assessed. RESULTS: In a cohort of 16 children, neonatal MRI showed WS injury in 7, BG/T injury in 2, and normal imaging in 7. Children with WS injury had lower estimated overall cognitive ability than those with normal imaging. Increasing WS injury score was associated with decreasing estimated overall cognitive ability, Perceptual Reasoning Index, and digit span score. CONCLUSIONS: Children with the WS injury are at an increased risk of having problems in long-term intellectual ability. These cognitive outcomes may underlie early language difficulties seen in children with neonatal WS injury. IMPACT: Adolescents with a history of neonatal encephalopathy and watershed pattern of injury on neonatal brain magnetic resonance imaging (MRI) had lower overall cognitive ability, perceptual reasoning skills, and auditory working memory than those with normal neonatal imaging. Children with post-neonatal epilepsy and cerebral palsy had the worst cognitive outcomes. Watershed pattern of injury confers high long-term differences in intellectual ability.

Compound Heterozygous PIGT Mutations in Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome: First Case in Korea and Characterization by Persistent Hypophosphatasia.

Mutations of phosphatidylinositol glycan biosynthesis class T (PIGT), which encodes a subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, can lead to multiple anomalies, including seizures, intellectual disabilities, facial dysmorphism, and various congenital malformations. We performed whole-exome sequencing in a patient with seizures, intellectual disabilities, truncal ataxia, facial dysmorphism, and persistent hypophosphatasia without rickets or bone mineralization defects, and identified two heterozygous mutations in PIGT, c.250G>T (p.Glu84*) and c.1582G>A (p.Val528Met). GPI-linked protein analyses found no abnormalities. Although the patient's hypophosphatasia persists, no skeletal, urological, or dental abnormalities were found. The seizures disappeared after administering antiepileptic drugs. PIGT mutations should be considered in patients with multiple congenital symptoms and persistent hypophosphatasia.

Cognitive outcomes in late childhood and adolescence of neonatal hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy with a global incidence of approximately 1 to 8 per 1,000 live births. Neonatal encephalopathy can cause neurodevelopmental and cognitive impairments in survivors of hypoxic-ischemic insults with and without functional motor deficits. Normal neurodevelopmental outcomes in early childhood do not preclude cognitive and behavioral difficulties in late childhood and adolescence because cognitive functions are not yet fully developed at this early age. Therapeutic hypothermia has been shown to significantly reduced death and severe disabilities in term newborns with HIE. However, children treated with hypothermia therapy remain at risk for cognitive impairments and follow-up is necessary throughout late childhood and adolescence. Novel adjunctive neuroprotective therapies combined with therapeutic hypothermia may enhance the survival and neurodevelopmental outcomes of infants with HIE. The extent and severity of brain injury on magnetic resonance imaging might predict neurodevelopmental outcomes and lead to targeted interven tions in children with a history of neonatal encephalopathy. We provide a summary of the long-term cognitive outcomes in late childhood and adolescence in children with a history of HIE and the association between pattern of brain injury and neurodevelopmental outcomes.

First Korean Case of Coffin-Siris Syndrome with a Novel Frameshift ARID1B Mutation.

Coffin-Siris Syndrome (CSS) is a rare neurodevelopmental disorder characterized by intellectual disability, coarse facial features, hypoplastic digits/nails, and hypertrichosis. The genes causative of CSS mainly encode the SWI/SNF complex, which contributes to chromatin remodeling and regulates the access of transcriptional factors to specific gene sites. While ARID1B mutations account for a third of all CSS cases, the condition's phenotypic features vary widely. We document the case of a girl with CSS who presented with a variant facial appearance, global developmental delay with speech impairment, agenesis of the corpus callosum, funnel chest, and bilateral renal stones without hypertrichosis or hypoplasia of the fifth fingernail. Genetic analysis revealed that the patient had a novel heterozygous frameshift mutation c.2201dupG (p.Ser736Ilefs*27) on the ARID1B gene.

Epilepsy caused by an unrecognized pencil lead misdiagnosed as intracerebral cavernous malformation.

Transorbital penetrating injury is relatively uncommon following head trauma, and delayed onset of neurological complications due to retained intracerebral foreign bodies has rarely been reported. We describe the first child case of late-onset epilepsy caused by an accidental transorbital penetrating injury, resulting in a retained pencil lead fragment that was mistaken for cavernous malformation. A 14-year-old girl presented with abrupt onset of nocturnal bilateral tonic seizures. The patient was previously healthy and denied any head trauma. The seizures were not well controlled by antiepileptic drugs. Right frontal lobe epilepsy due to a cavernous malformation was suspected on the basis of brain magnetic resonance imaging and electroencephalography findings. A planned operation unexpectedly revealed the intracerebral pencil lead. This foreign body had gone undetected for 11 years following a minor transorbital penetrating injury. The patient remained seizure-free during the 1-year post-operative follow-up period. Head trauma by a pencil can cause transorbital penetrating injury in children. It is difficult to detect retained small foreign body fragments and the clinical presentation can be delayed. It may be mistakenly diagnosed as other pathologies, especially when patients deny any history of head trauma.

Acute Encephalopathy With Biphasic Seizures and Late Reduced Diffusion Associated With Adenoviral Pneumonia.

Acute encephalopathy with biphasic seizures and late reduced diffusion is a subtype of acute encephalopathy described in a cohort of Japanese children. Few cases have been reported in countries other than Japan. It is characterized clinically by biphasic seizures and late reduced subcortical diffusion on magnetic resonance imaging (MRI). We report the case of a 3-year-old Korean girl with acute encephalopathy with biphasic seizures and late reduced diffusion who presented with status epilepticus associated with fever and pneumonia. Human adenovirus was detected from a respiratory specimen using multiplex real-time reverse transcriptase polymerase chain reaction. After 5 days, she developed a second cluster of seizures followed by altered consciousness, aphasia, stereotypic movement, and developmental regression. Her brain MRI showed symmetrical and extensive restricted diffusion in the subcortical white matter, which finally resulted in global brain atrophy, consistent with acute encephalopathy with biphasic seizures and late reduced diffusion. Here, we report a case of acute encephalopathy with biphasic seizures and late reduced diffusion associated with preceding adenoviral pneumonia.

The first Korean case report with scaphocephaly as the initial sign of X-linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemic rickets (XLH) can occasionally cause premature fusion of cranial sutures through an increased level of fibroblast growth factor 23 (FGF-23), which leads to the dysregulation of phosphate and vitamin D metabolism. Secondary craniosynostosis has long been considered to present late after XLH has already been diagnosed either clinically or genetically. CASE PRESENTATION: We present observations of a male infant showing sagittal synostosis as the first sign of XLH. Our patient did not show any other skeletal deformities except macrocephaly with a long head shape. There is a family history of genetically unconfirmed hypophosphatemic rickets in his mother. Direct sequencing by genomic polymerase chain reaction revealed that the patient has a large deletion comprising exons 1-3 of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. CONCLUSION: Our observations suggest that craniosynostosis secondary to rickets can develop in early infancy. Careful monitoring of head shape and growth is therefore critical for early detection of craniosynostosis in XLH.

Clinical Findings and Neurologic Outcome in Neonatal Encephalopathy With White Matter Injury Accompanied by Rotavirus.

Our objective was to elucidate the clinical characteristics and neurodevelopmental outcomes in neonatal encephalopathy with characteristic white matter injury as compared with other injury patterns on magnetic resonance diffusion-weighted imaging. We conducted a retrospective study comparing clinical and laboratory findings, and neurologic outcomes between 17 newborns with diffuse lesions in the periventricular white matter and white matter tract (group I) and 22 newborns with other patterns (group II). Stool samples indicated that 16 neonates (94.1%) in group I were rotavirus-positive, whereas none in group II had rotavirus infection. Significantly lower calcium levels were found in group I than in group II ( P < .001). Moreover, a more favorable neurodevelopmental outcome was observed in group I than in group II. This study suggests that characteristic white matter injury in neonatal encephalopathy may be related to decreased calcium levels induced by rotavirus, and may have a better neurodevelopmental prognosis than other causes.

Paroxysmal nonepileptic events in pediatric patients.

OBJECTIVES: Paroxysmal nonepileptic events (PNEs) are frequently encountered phenomena in children. Although frequencies and types of PNEs have been extensively studied in adult populations, the data available for children and adolescents are limited, especially in patients without underlying neurologic disorders. In this study, we evaluated and compared the characteristics of PNEs between age groups and according to the presence of neurologic deficits to improve early detection and diagnosis of PNEs. METHODS: We retrospectively reviewed 887 pediatric patients who were admitted to the epilepsy monitoring unit at the Samsung Medical Center between December 2001 and July 2014. One hundred and forty-one patients (15.9%) were diagnosed as having PNEs on the basis of their clinical history and long-term video-electroencephalography (EEG) monitoring (VEM). RESULTS: Children with PNEs were divided into three groups by age: 1) the infant, toddler, and preschool group (<6 years, N=50, 35.5%); 2) the school-age group (6-<12 years, N=30, 21.3%); and 3) the adolescent group (12-<18 years, N=61, 43.3%). Physiologic disorders, such as normal infant behavior, sleep movement, and staring, were more common in patients younger than 6 years of age, whereas psychogenic nonepileptic seizures were predominant in patients older than 6 years. Vasogenic syncope was also frequently observed in the adolescent group and was confirmed by the head-up tilt test. There was no significant difference in specific PNE types between the groups of patients with or without neurologic deficits. CONCLUSIONS: Physiologic symptoms were predominant in the younger age group, whereas psychogenic nonepileptic seizures were observed in older age groups more often. Clinical pattern recognition by age plays an important role in clinical practice, because pediatric patients present various types of PNEs with age-specific patterns. Considering various and inconsistent presentations and the importance of correct diagnosis, long-term VEM can be helpful in diagnosing normal infant behavior and psychogenic nonepileptic seizures.

Genetic analysis of dystrophin gene for affected male and female carriers with Duchenne/Becker muscular dystrophy in Korea.

Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked recessive disorders caused by mutation in dystrophin gene. We analyzed the results of a genetic test in 29 DMD/BMD patients, their six female relatives, and two myopathic female patients in Korea. As the methods developed, we applied different procedures for dystrophin gene analysis; initially, multiplex polymerase chain reaction was used, followed by multiplex ligation-dependent probe amplification (MLPA). Additionally, we used direct DNA sequencing for some patients who had negative results using the above methods. The overall mutation detection rate was 72.4% (21/29) in DMD/BMD patients, identifying deletions in 58.6% (17/29). Most of the deletions were confined to the central hot spot region between exons 44 and 55 (52.9%, 7/19). The percentage of deletions and duplications revealed by MLPA was 45.5% (5/11) and 27.2% (3/11), respectively. Using the MLPA method, we detected mutations confirming their carrier status in all female relatives and symptomatic female patients. In one patient in whom MLPA revealed a single exon deletion of the dystrophin gene, subsequent DNA sequencing analysis identified a novel nonsense mutation (c.4558G > T; Gln1520X). The MLPA assay is a useful quantitative method for detecting mutation in asymptomatic or symptomatic carriers as well as DMD/BMD patients.

The role of ketogenic diet in the treatment of refractory status epilepticus.

Ketogenic diet (KD) is known to be effective in intractable epilepsy. However, the role of KD in refractory status epilepticus (RSE) has not been well described. The aim of this study is to explore the role of KD in patients with RSE. We retrospectively reviewed the medical records of four children and one adult with RSE between October 2006 and August 2010. All presented with status epilepticus (SE) that was presumed to be associated with viral encephalitis. After we failed to control the seizures with standard measures for SE, we tried KD. The overall seizure frequency decreased to <50% of baseline in median eight (1-19) days. At one month of KD, two patients were seizure-free, one patient showed >90% seizure reduction, and the others had >75% decrease without generalized seizures. With improvement in the RSE, we were able to taper the antiepileptic drugs (AEDs) and wean patients from prolonged mechanical ventilation. The adverse events of KD in RSE included aspiration pneumonia, gastroesophageal reflux, constipation, and hypertriglyceridemia. Those results demonstrate that KD can be a valuable therapeutic option for patients with RSE.