Diagnosis of Wilson Disease in Young Children: Molecular Genetic Testing and a Paradigm Shift from the Laboratory Diagnosis / 대한소아소화기영양학회지

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism that results in accumulation of copper primarily in the liver, brain and cornea. Mutations in the WD gene, ATP7B, cause failure of copper excretion from hepatocyte into bile and a defective synthesis of ceruloplasmin. More than 500 mutations are now recognized, scattered throughout the ATP7B gene. Since WD has protean clinical presentations, awareness of WD in clinical practice is important for the early diagnosis and prevention of accumulated copper toxicity. Molecular genetic testing is playing an increasingly important role in the diagnosis of WD in uncertain cases and family screening. Siblings should be screened for WD once an index case has been diagnosed. Discrimination of heterozygotes from asymptomatic patients is essential to avoid inappropriate lifelong therapy for heterozygotes. Genetic testing, either by haplotype analysis or by mutation analysis, is the only definite solution for differentiating heterozygote carriers from affected asymptomatic patients. Routine genetic testing, because of the multitude of documented mutations, has been thought to be impractical until recently. However, genetic testing is now being more actively applied to the diagnosis of WD, particularly in young children in whom conventional biochemical diagnosis has much limitation and only genetic testing is able to confirm WD. Because advancement of modern biochemical technology now allows more rapid, easier, and less expensive mutation detection, direct DNA sequencing could be actively considered as the primary mode of diagnostic investigation rather than a supplementary test to the conventional biochemical tests. This review will focus on the recent advancement of molecular genetics and genetic diagnosis of WD in very young children on the basis of research data of the Seoul National University Children's Hospital and recent literature.

Novel CFTR Mutations in a Korean Infant with Cystic Fibrosis and Pancreatic Insufficiency

Cystic fibrosis (CF) is an autosomal recessive disease that is very rare in Asians: only a few cases have been reported in Korea. We treated a female infant with CF who had steatorrhea and failure to thrive. Her sweat chloride concentration was 102.0 mM/L. Genetic analysis identified two novel mutations including a splice site mutation (c.1766+2T>C) and a frameshift mutation (c.3908dupA; Asn1303LysfsX6). Pancreatic enzyme replacement and fat-soluble vitamin supplementation enabled the patient to get a catch-up growth. This is the first report of a Korean patient with CF demonstrating pancreatic insufficiency. CF should therefore be considered in the differential diagnosis of infants with steatorrhea and failure to thrive.

Development of a Nutrition Questionnaire and Guidelines for the Korea National Health Screening Program for Infants and Children / 대한소아소화기영양학회지

PURPOSE: A new health policy, referred to as the National Health Screening Program for Infants and Children, was launched in November 2007 by the Ministry of Health and Welfare and National Health Insurance Corporation in Korea. We have developed a nutrition-counseling program that was incorporated into this project. METHODS: We reviewed the nutritional guidelines published by The Korean Pediatric Society and internationally well-known screening programs such as Bright Future in the United States. We also reviewed the recent Korean national surveys on nutritional issues, including the Korea National Health and Nutrition Examination Survey (KNHANES) and the 2005 National Survey of Physical Body and Blood Pressure in Children and Adolescents. The development of questions, pamphlets, computer programs, and manuals for doctors was carried out after several meetings of researchers and governmental officers. RESULTS: We summarized the key nutritional issues according to age, including breastfeeding in infants, healthier complementary feeding, and prevention of iron deficiency anemia, establishment of healthier diets, as well as dietary prevention of overweight children with an emphasis on physical exercise. We have constructed a new Korean nutrition questionnaire and an anticipatory guidance program based on the primary care schedule of visits at 4, 9, 18, 30, and 60 months of age. Five to eight questions were asked at each visit and age-matched pamphlets for parents and guidelines for doctors were provided. CONCLUSION: We developed a nutrition-counseling program based on recent scientific evidence for Korean infants and children. Further research on this national program for screening the nutritional problems in detail and setting the therapeutic approaches may help identify areas of success as well as those that need further attention.

Trace Elements Deficiency and the Diagnostic Usefulness of Hair Mineral Analysis in Children with Chronic Gastrointestinal Disease / 대한소아소화기영양학회지

PURPOSE: Patients with chronic gastrointestinal disease are at risk for trace element deficiency due to impaired absorption and gastrointestinal loss. The aim of this study was to evaluate the trace element status of patients with gastrointestinal disease by blood and hair analysis, and to determine the usefulness of hair mineral analysis for diagnosing trace element deficiency not detected by a blood test. METHODS: An analysis of hair minerals was performed and compared with blood mineral analysis in 13 patients with chronic gastrointestinal disease. The concentration of each element in the hair and blood was compared in the subgroups based on parenteral nutritional support or clinical symptoms. RESULTS: Almost all patients had trace element deficiency. The trace elements deficient in the blood or hair analysis included zinc, selenium and copper. The hair zinc concentration was significantly lower in the group receiving parenteral nutritional support. The hair selenium concentration was statistically associated with the clinical symptoms of hair loss, brittle hair and loss of hair pigmentation. CONCLUSION: The results of this study suggest that patients with chronic gastrointestinal disease should receive adequate zinc and selenium replacement to avoid trace element deficiency especially when treated with long-term parenteral nutrition. Hair mineral analysis is useful as a complementary tool for the detection of a trace element deficiency.

A case of post-operative chylous ascites after a splenorenal shunt operation in a child with congenital hepatic fibrosis / 소아과

Chylous ascites is a rare condition caused by various diseases and conditions that interfere with the abdominal or retroperitoneal lymphatics, and uncommonly it can manifest as a post-operative complication after abdominal, retroperitoneal or mediastinal surgery. Chylous ascites can be diagnosed by a high triglyceride content in ascites. The authors experienced a 5-year-old girl with congenital hepatic fibrosis who presented with chylous ascites after a splenorenal shunt operation, who was successfully managed by fasting and total parenteral nutrition, followed by a lipid-free diet with medium chain triglyceride supplementation. Here, the authors report this case of post-operative chylous ascites after a splenorenal shunt (Warren shunt) operation with a review of the pertinent literature.

Motor Dysfunction of the Esophagus after Repair of Esophageal Atresia and Tracheoesophageal Fistula / 대한소화관운동학회지

BACKGROUND/AIMS: The aim of this study was to characterize the spectrum of esophageal motor dysfunction after repair of an esophageal atresia with a tracheoesophageal fistula (EATEF). METHODS: This study included 16 patients, aged 0.8 to 13.3 years, who were diagnosed with Gross Type C esophageal atresia and underwent a fistula repair and end to end anastomosis. Esophageal function was evaluated with manometry, 24 hour esophageal pH monitoring, a barium esophagogram, and an endoscopy. RESULTS: Symptoms were present in 8 patients (dysphagia for solid food in 2; frequent vomiting in 6; and poor weight gain in 4). Anastomotic stricture was present in 6 patients. An esophageal manometric study showed that the reflex relaxation of the lower esophageal sphincter (LES) was incomplete or absent in 9 patients (56%). The upper esophageal sphincter (UES) was completely relaxed in all 16 patients. In 14 patients (88%), a normal peristaltic wave was present in the proximal esophagus, but absent below the anastomotic site. Simultaneous contractions were observed in 2 patients (12%). Seven (64%) of 11 patients who underwent 24 hour esophageal pH monitoring presented gastroesophageal reflux. CONCLUSION: Most of the patients after the repair of an EATEF developed motor dysfunction of the esophagus. Poor transmission of the peristaltic waves beyond the anastomotic site and abnormal reflex relaxation of the LES were present.

Long-term Clinical Follow-up of Korean Children with Wilson Disease; Twenty Years' Experience

PURPOSE: To investigate the clinical features of long-term follow-up, and the treatment responses in Korean children with Wilson disease(WD). METHODS: The clinical data from ninety-two children with WD, diagnosed at Seoul National University Hospital from 1976 to 1999, were reviewed. Mean duration of follow-up was 5+/-4.5 years. We analysed the patient's records based on the clinical manifestations, laboratory findings, and responses to the treatment. RESULTS: Age of initial presentation was 9.6+/-2.6 years. Mean age of patients who developed neurologic symptoms was 11.6 years. Initial manifestations were characterized as hepatic(70.6%), neurologic(6.5%), and both hepatic and neurologic(10.9%). Kayser-Fleischer(KF) rings were observed in 59 patients(64.1%). All neurologic patients had KF rings. Level of serum ceruloplasmin was low in 91 patients(98.9%). Multiple nodules in the liver and high signal intensity lesions in basal ganglia of the brain were observed on magnetic resonance imaging. Seventy-six patients(82.6%) showed favorable responses to penicillamine(PNC) and the rest of the patients with poor responses were treated with zinc sulfate, trientine, or liver transplantation. Neurologic symptoms improved with PNC in ten out of sixteen patients. However, despite PNC treatment, six patients deteriorated neurologically. Factors affecting the poor response to PNC were associated with the presence of fulminant hepatitis, hemolysis, and KF ring. Ten patients expired due to fulminant hepatitis(9), and hepatocellular carcinoma(1). Most of them died within five months after initial presentations. Ten-year survival rate was 85.4%. CONCLUSION: WD in children begins with various manifestations. PNC is an effective and safe drug to treat WD in most cases. However, the supplementary modalities such as zinc sulfate, trientine and liver transplantation should be considered when the patients show poor responses or adverse reactions to PNC.

The Effect of a Left Stellate Ganglion Block on Left Ventricular Function / 대한마취과학회지

BACKGROUND: A Stellate ganglion block (SGB) is a sympathetic nerve block method which has been used most frequently in pain clinics due to its wide range of indications. However, SGB leads to regional sympathetic denervation of the heart and to changes in the hemodynamics. The aim of this study was to compare hemodynamic effects as well as echocardiographic changes after a left SGB (LSGB). METHODS: Fourteen healthy male volunteers were studied. The LSGB was performed with 1% mepicacaine 6 ml. Arterial blood pressure, electrocardiographic and echocardiographic variables were measured before the LSGB, 15 and 30 minutes after the LSGB. RESULTS: Arterial blood pressure, ejection fraction and transmitral inflow velocity variables showed no significant changes compared to pre-LSGB values. P-P interval increased significantly 15 minutes after the LSGB, and the Q-T interval increased significantly 30 minutes after the LSGB. The diastolic pulmonary venous flow velocity decreased significantly 15 minutes after the LSGB. CONCLUSIONS: These results showed that a LSGB decreased the heart rate without detrimental changes of left ventricular relaxation in healthy male volunteers.

Renal Problems in Wilson Disease

PURPOSE: Wilson disease is a hereditary metabolic disorder characterized by an accumulation of copper in tissues which sometimes results in renal problems. This study was performed to evaluate the prevalences of the renal problems in Wilson disease and related risk factors. METHODS: In 31 patients with Wilson disease, we looked for renal problems by history taking, physical examination and laboratory tests such as urinalysis, BUN, serum creatinine, creatinine clearance, 24-hour urine total protein, serum and urine electrolytes, serum and 24-hour urine calcium, phosphorus, uric acid, beta2-microglobulin(beta2-MG) levels and 24-hour urine N-acetyl-beta-glucosaminidase(NAG) excretion. RESULTS: All of the patients were on penicillamine therapy for 4.3+/-3.4 years. None of them had any renal symptoms or signs at the time of this study except one patient who had a history of intermittent puffy face for 6 months. In the laboratory studies, 21 cases(68%) had one or more renal problems. Sixteen cases(52%) had one or more tubular dysfunctions; individually, hypercalciuria, increased excretion of beta2-MG, decreased TRP, increased excretion of NAG were detected in 29%, 19%, 16%, and 10%, respectively. Microscopic hematurias were detected in 8 cases(26%), creatinine clearances(Ccr) were decreased in 4 cases(13%). Two cases(6%) revealed proteinuria. Hematurias were more frequent within 3 years after beginning penicillamine treatment(P<0.05). Though not proven statistically, tubular dysfunctions and proteinurias showed the same trends. Prevalence of the decreased Ccr did not change with the treatment duration. CONCLUSION: In Wilson disease, covert renal problems are relatively common. Tubular dysfunctions are the most frequently observed abnormalities followed by microscopic hematuria, proteinuria, and decreased creatinine clearance in order. Hematuria is more common within 3 years after beginning penicillamine treatment, which is also probable for tubular dysfunctions and proteinuria.

Mutation Analysis of Wilson Disease Gene: Arg778Leu Mutation in Korean Children / 대한소아소화기영양학회지

BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of copper transport and characterized by degenerative changes in the brain, liver dysfunction, and Kayser-Fleischer rings due to toxic accumulation of copper. Since the identification of Wilson disease gene (ATP7B), more than 80 mutations have been detected among the different ethnic groups. METHODS: Twenty three children with Wilson disease were included in this study. They were all diagnosed by low serum ceruloplasmin and increased 24 hour urinary copper excretion with characteristic clinical findings. We analysed WD gene mutation by assessing the nucleotide sequence of exon 7, 8, 9 and 10 including intron-exon boundaries of ATP7B gene from genomic DNA. RESULTS: Arg778Leu mutation was identified in 16 WD patients; three were homozygous and 13 were heterozygous for this mutation. Of the 46 alleles, 19 alleles had a Arg778Leu mutation (19/46=41%). Homozygote patients had neurologic forms of WD. Arg778Leu mutation was not found among 50 normal healthy persons. CONCLUSION: Arg778Leu mutation is a common mutation in Korean WD gene. Arg778Leu mutation screening might be used as a useful supplementary diagnostic test in some patients to confirm Wilson disease in Korea.

Anorectal Manometry in Idiopathic Constipation in Children / 대한소아소화기영양학회지

PURPOSE: Anorectal manometry is a way of investigation for anti-rectal sphincters. In this paper we evaluated the usefulness of anorectal manometry in constipation patients and compared the anal spnincter function in control, constipation and encopresis patients. METHOD: We analysed the data of anorectal function studies in normal children (control, n=11), children with constipation (constipation group, n=20) and children with encopresis (encopresis group, n=16). RESULTS: The specific manometric parameters in normal children were like as follows; external anal sphinter pressure 21.0+/-8.00 mmHg, internal anal sphicter pressure 30.0+/- 14.57 mmHg, conscious rectal sensitivity threshold 11.4+/-4.52 mmHg. The above results were not different from that of previous studies except conscious rectal sensitivity threshold, which was slightly lower than that of others. Internal and external anal sphincter pressure were elevated significantly in constipation and encopresis groups than in control, which results was the same in conscious rectal sensitivity threshold. But the values of rectoanal inhibitory threshold and percent relaxation of rectoanal inhibitory reflex were not different among control group, constipation group and encopresis group. External sphincter activity was increased during the act of bearing down for defecation in none of the child in control group, in 6 of 17 children in constipation group and 5 of 12 children in encopresis group. CONCLUSION: With the results of above we could say that complete history taking and physical examination are important in diagnosis of constipation, and we could say also that the anorectal manometry was a valuable tool to understand the physiology of normal defecation and the pathophysiology of constipation and encopresis.

A Case of Achalasia Managed by Balloon Dilatation

An 8-year-old male was admitted because of dysphagia and substernal pain suffered while eating followed by postprandial vomiting for 2 years. He was always hungry due to postprandial vomiting and willing to eat again just after vomiting. After this meals, he used to jump up and down to shake off the substernal discomfort. A narrowing of the gastroesophageal junction was noted by esophagogram. Manometry revealed high Lower esophageal sphincter (LES) pressure (51.6mmHg), incomplete LES relaxation during swallowing, loss of esophageal peristalsis and a positive pressure of the esophageal body compared to intragastric pressure. After the 1st balloon dilatation, symptoms were much improved even though LES pressure still remained high (37.2mmHg). About 2 months after the 1st balloon dilatation, symptoms relapsed and we managed him with a 2nd balloon dilatation. Symptoms were more improved than after the 1st dilatation and LES pressure normalized as well. Since the 2nd dilatation, symptoms have not recurred for 3 years. We present an 8-year-old boy with achalasia successfully managed by the use balloon dilatation.

Clinico-Pathological Characteristics of Congenital Megacolon

This study is based on 155 patients of congenital me colon. For the diagnosis, 93 cases were histologically proven and the remaining 63 cases were diagnosed on clinical basis including barium enema or surgical gross findings. On histologic examination, 80 cases(86%) showed typical features of absence of ganglion cell in the myenteric plexus and the 13 cases(14%) had atypical features which were segmental absence Of ganglion cell in one case. There we 127 males(82%) and 28 females(18%). The age at diagnosis was younger than 30 days in 87 cases(56%), I month to 1 year in 39 cases(25%) and older than I year in 29 cases(18%). The levels of aganglionosis were variable: short segment (rectosigmoid) in 134 cases(86%), intermediate segment (more proximal colon) in 14 cases(100%). and 6 cases(4%) had total aganglionosis. Common clinical presentations were abdominal distention, delayed meconium passage or bilious vomiting in neonate, and chronic constipation in infancy or childhood. Following initial colostomy or ileostomy, a definitive procedure was performed in 151 cases(Duhamel type in 150 cases; Soave type in 2 cases; Swenson type in 3 cases). Frequently associated problems after definitive procedure were persistent constipation(ll%) due to septum formation, fecaloma, remnant aganglionic segment and rectal stenosis. Overall mortality rate was 4%, and increased mortality was associated with enterocolitis(14%) which was the most frequent cause of death. The follow-up study longer than 3 months was available in 138 patients who underwent a definitive procedure(mean 2 year 11 months). Seventy-three cases(53%) had normal bowel function, 38cases(27.5%) had occasionally used enema or stool softners, and 27 cases(19.5%) had severe constipation or soiling. The bowel habit improved with time, and were considered normal in 60% of patients after follow-up more than 3 years. The results of definitive procedures for congenital megacolon including Duhamel operation was satisfactory, and long-term follow-up appeared an important and critical component of patients'care.