Most craniosynostoses are sporadic, but may have an underlying genetic basis. Secondary and syndromic craniosynostosis accompanies various systemic diseases or associated anomalies. Early detection of an associated disease may facilitate the interdisciplinary management of patients and improve outcomes. For that reason, systematic evaluation of craniosynostosis is mandatory. The authors reviewed systematic evaluation of craniosynostosis with an emphasis on genetic analysis.
Craniosynostoses* ; Diagnosis ; Humans

Duchenne muscular dystrophy (DMD) is the most common and lethal dystrophy in childhood, caused by mutations in the dystrophin (DMD) gene. Multiplex ligation dependent probe amplification (MLPA) or array comparative genome hybridization (aCGH) is widely used as an initial molecular diagnostic tool. If no deletions or duplications are found in MLPA or aCGH, the samples must be subjected to a second test of direct sequencing. Direct sequencing of the DMD gene, however, is time-consuming, high-cost, and can be inconclusive. Here, we performed whole exome sequencing on a patient with progressive muscle weakness whose MLPA result was negative; the result revealed a rare frame shift mutation. Direct sequencing on the patient's mother showed the same mutation. Whole exome sequencing can be a new diagnostic routine for DMD patients with negative MLPA3.
Comparative Genomic Hybridization ; Dystrophin ; Exome* ; Frameshift Mutation ; Genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Mothers ; Multiplex Polymerase Chain Reaction ; Muscle Weakness ; Muscular Dystrophy, Duchenne* ; Pathology, Molecular

Early-onset epileptic encephalopathies are one of the most severe early onset epilepsies that can lead to progressive psychomotor impairment. These syndromes result from identifiable primary causes, such as structural, neurodegenerative, metabolic, or genetic defects, and an increasing number of novel genetic causes continue to be uncovered. A typical diagnostic approach includes documentation of anamnesis, determination of seizure semiology, electroencephalography, and neuroimaging. If primary biochemical investigations exclude precipitating conditions, a trial with the administration of a vitaminic compound (pyridoxine, pyridoxal-5-phosphate, or folinic acid) can then be initiated regardless of presumptive seizure causes. Patients with unclear etiologies should be considered for a further workup, which should include an evaluation for inherited metabolic defects and genetic analyses. Targeted next-generation sequencing panels showed a high diagnostic yield in patients with epileptic encephalopathy. Mutations associated with the emergence of epileptic encephalopathies can be identified in a targeted fashion by sequencing the most likely candidate genes. Next-generation sequencing technologies offer hope to a large number of patients with cryptogenic encephalopathies and will eventually lead to new therapeutic strategies and more favorable long-term outcomes.
Electroencephalography ; Epilepsy ; Genetics ; High-Throughput Nucleotide Sequencing ; Hope ; Humans ; Neuroimaging ; Psychomotor Disorders ; Seizures ; Vitamins

PURPOSE: This study aimed to evaluate the clinical features of children who have survived a water submersion incident, and to identify risk factors for prognosis. METHODS: We retrospectively reviewed the medical records of patients who experienced submersion between January 2005 and December 2014. The patients were classified into 2 groups, according to complications, and prognostic factors were evaluated. RESULTS: During the study period, 29 children experienced submersion (20 boys and 9 girls; mean age, 83.8±46.4 months). Submersion occurred most commonly in the summer, with the peak incidence in August. The most frequent Szpilman clinical score was grade 5 (13 patients; 44.8%), followed by grade 6 (7 patients; 24.1%), and grades 1 or 2 (3 patients; 10.3%). Five children (17.2%) in the poor prognosis group died or had hypoxic ischemic encephalopathy, and the overall mortality rate was 6.9%. Poor prognosis after submersion was associated with lower consciousness levels (P=0.003), higher Szpilman scores (P=0.007), greater need for intubation and mechanical ventilator support (P=0.001), and longer duration of oxygen therapy (P=0.015). Poor prognosis was also associated with lower bicarbonate levels (P=0.038), as well as higher sodium, aspartate transaminase (AST), and alanine transaminase (ALT) levels (P=0.034, P=0.006, and P=0.005, respectively). Szpilman clinical scores were positively correlated with consciousness levels (r=0.489, P=0.002) and serum liver enzyme levels (AST and ALT; r=0.521, P=0.004). CONCLUSION: We characterized the prognostic factors associated with submersion outcomes, using the Szpilman clinical score, which is comparable to consciousness level for predicting mortality.
Alanine Transaminase ; Aspartate Aminotransferases ; Child* ; Consciousness ; Drowning* ; Female ; Humans ; Hypoxia-Ischemia, Brain ; Immersion ; Incidence ; Intubation ; Liver ; Medical Records ; Mortality ; Oxygen ; Prognosis ; Retrospective Studies ; Risk Factors ; Sodium ; Ventilators, Mechanical ; Water

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome) is a neurometabolic disorder with highly variable clinical severity ranging from mild learning disability to severe encephalopathy. Diagnosis of HHH syndrome can easily be delayed or misdiagnosed due to insidious symptoms and incomplete biochemical findings, in that case, genetic testing should be considered to confirm the diagnosis. HHH syndrome is caused by biallelic mutations of SLC25A15, which is involved in the urea cycle and the ornithine transport into mitochondria. Here we report a boy with spastic paraplegia and asymptomatic younger sister who have compound heterozygous mutations of c.535C>T (p.R179*) and c.116C>A (p.T39K) in the SLC25A15 gene. We identified that p.T39K mutation is a novel pathogenic mutation causing HHH syndrome and that p.R179*, which is prevalent in Japanese and Middle Eastern heritage, is also found in the Korean population.
Asian Continental Ancestry Group ; Brain Diseases ; Diagnosis ; Genetic Testing ; Genetics ; Humans ; Learning Disorders ; Male ; Mitochondria ; Ornithine ; Paraplegia ; Siblings ; Urea ; Urea Cycle Disorders, Inborn

PURPOSE: Orthostatic proteinuria accounts for the majority of cases of proteinuria that present in childhood or adolescent. This study was conducted to see the prevalence of Nutcracker syndrome (NCS) in children with orthostatic proteinuria using venography. METHODS: Study patients consisted of 23 children with orthostatic proteinuria. The diagnosis of NCS was made by high pressure gradients (> or =4 mmHg) between left renal vein (LRV) and inferior vena cava (IVC) in left renal venography and pressure tracing. RESULTS: Of 23 study patients, the venography showed 12 cases (52%) of typical NCS. Their mean age was 11.5 years (9-14 years). Female predominance (Male:Female=2:10) was noted. In NCS group (n=12), venous pressures of IVC and LRV were 6.50+/-3.34 and 13.21+/-3.53 mmHg, respectively. This pressure gradient between two veins was 6.71+/-2.54 mmHg, which is significantly higher than that of non-NCS group (n=11), 2.17+/-0.94 mmHg (p < 0.05). No positive correlation was observed between urinary protein during 24 hour and pressure gradient (r=0.152, p=0.636). CONCLUSION: NCS may be an important cause of orthostatic proteinuria in children. The prevalence of NCS shown in this study was very similar to that in a doppler sonographic observation published previously. A larger-scale study is necessary to confirm the prevalence.
Adolescent ; Child ; Female ; Humans ; Phlebography ; Prevalence ; Proteinuria ; Renal Veins ; Veins ; Vena Cava, Inferior ; Venous Pressure

Vascular anomalies are congenital localized abnormalities that result from improper development and maintenance of the vasculature. The lesions of vascular anomalies vary in location, type, and clinical severity of the phenotype, and the current treatment options are often unsatisfactory. Most vascular anomalies are sporadic, but patterns of inheritance have been noted in some cases, making genetic analysis relevant. Developments in the field of genomics, including next-generation sequencing, have provided novel insights into the genetic and molecular pathophysiological mechanisms underlying vascular anomalies. These insights may pave the way for new approaches to molecular diagnosis and potential disease-specific therapies. This article provides an introduction to genetic testing for vascular anomalies and presents a brief summary of the etiology and genetics of vascular anomalies.

PURPOSE: To ascertain the factors associated with the proportion of death certificate only (DCO) cases contained in the Kwangju Cancer Registry (KCR) that are not as yet in the good range. MATERIALS AND METHODS: The distribution of DCO cases was analyzed by sex, age, cancer site, histological verification (HV) as well as the physician's death certificate status. RESULTS: All cases (n=4,243) in Kwangju diagnosed as having cancer between 1997 and 1998 were registered with the KCR. Death certificates (n=2,390) reporting cancer as the causes of death were collected from the National Statistics Office and reviewed with hospital data linkage and a total of 590 cases were registered as DCO. DCOs accounted for 12.2% (male 12.8%, female 11.5%) of all registrations in Kwangju, 1997~1998. The proportion of DCO cases was high in subjects under 15 (male13.5%,female 9.4%) as well as those 75 and over (male 20.3%, female 27.2%). For cancer sites, the proportion of DCO cases was high (over 10%) for liver, bronchus-lung, esophagus and pancreas and low (under 3%) for skin, bladder, uteri cervix and breast. The proportion of DCO cases was inversely associated with HV%. When the death certificate was issued by physician, the possibility of DCO decreased. CONCLUSION: The proportion of DCO is positively associated with increasing age and negatively associated with HV% and the issuance of a physician's death certificate. These findings suggest that further socio-cultural efforts are required to reduce the DCO proportion.
Breast ; Cause of Death ; Cervix Uteri ; Information Storage and Retrieval ; Death Certificates* ; Esophagus ; Female ; Gwangju* ; Humans ; Korea ; Liver ; Pancreas ; Skin ; Urinary Bladder ; Uterus

PURPOSE: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. METHODS: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. RESULTS: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. CONCLUSION: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.
Biliary Atresia ; Choledochal Cyst ; Cholestasis ; Cholestasis, Intrahepatic ; Diagnosis ; Early Diagnosis* ; Exome ; Genetic Counseling ; Hepatitis ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperbilirubinemia ; Jaundice ; Liver Transplantation ; Liver* ; Metabolic Diseases ; Parenteral Nutrition, Total ; Syphilis, Congenital

PURPOSE: This study was aimed to compare the effectiveness and tolerability of topiramate add-on therapy versus lidocaine add-on therapy in children with refractory status epilepticus. METHODS: We performed a retrospective analysis of children with refractory status epilepticus who were hospitalized at Kyungpook National University Hospital during the period 2005 to 2012. We divided them into two groups, Group A (midazolam, MDZ, and Topiramate, TPM:11 patients) and Group B (midazolam and lidocaine, LDC:7 patients). Furthermore, they were sub-categorized according to children's sex, age, seizure duration, and seizure type. To comepare the effectiveness and tolerability between the two groups, we evaluated seizure freedom, >50% seizure reduction, adverse events and mortality rates, respectively. RESULTS: In MDZ/TPM group, average dosage of midazolam infusion was 10.8+/-6.8 mcg/kg/min, seizure freedom was achieved in 1 out of 11 patients (9%) and >50% seizure reduction was in 2 out of 11 patients (18%). On the other hand, in MDC/LDC group, average dosage of midazolam infusion is 11.3+/-5.2 mcg/kg/min, seizure freedom was achieved in 2 out of 7 patients (29%) and >50% seizure reduction was 3 out of 7 patients (43%). Aside from the promising effects, there was no significant difference between the two groups. CONCLUSION: In children with refractory status epilepticus, topiramate or lidocaine add-on therapy seemed to be effective and fairly tolerated and showed no serious adverse effects. Therefore they can be an alternative treatment option. However, further studies are required.
Child* ; Freedom ; Gyeongsangbuk-do ; Hand ; Humans ; Lidocaine* ; Midazolam ; Mortality ; Retrospective Studies ; Seizures ; Status Epilepticus*