Haddad Syndrome with a Germ-Line Mutation in the PHOX2B Gene in a Korean Neonate

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disease that primarily manifests as sleep-associated respiratory insufficiency and a markedly impaired ventilatory response to hypercarbia and hypoxemia. Paired-like homeobox 2b (PHOX2B) gene mutations are known to cause CCHS. Almost all patients with CCHS are heterozygous for a poly-alanine expansion in PHOX2B. However, some patients have other germ-line abnormalities, including missense, nonsense and frame shift mutations. CCHS combined with Hirschsprung disease (Haddad syndrome) is extremely rare. Here, we report the case of a 1-day-old male neonate with recurrent apnea and bowel distension. Genetic analysis showed that he was heterozygous for a germ-line mutation in the PHOX2B gene. Only three cases of CCHS including two with Haddad syndrome confirmed by PHOX2B gene mutations have been reported in Korea. All of these cases have been heterozygous for a poly-alanine expansion mutation. This is the first report describing Haddad syndrome with a germ-line mutation in the PHOX2B gene in a Korean neonate.

Erratum: Impact of Meconium Obstruction-Related Risk Factors on Surgical Intervention in Very Low Birth Weight Infants

We found an error in this article.

Impact of Meconium Obstruction-Related Risk Factors on Surgical Intervention in Very Low Birth Weight Infants

PURPOSE: This study investigated the risks of development and surgical complications of meconium obstruction (MO) in very low birth weight (VLBW) infants. METHODS: We performed a retrospective medical record review of VLBW infants admitted to the neonatal intensive care unit of Haeundae Paik hospital and diagnosed with MO of prematurity (MOP) between March 2010 and August 2013. RESULTS: Of 267 VLBW infants admitted to the neonatal intensive care unit, 28 were diagnosed with MOP. Perinatal factors including maternal pregnancy-induced hypertension and small for gestational age were associated with MOP development (P<0.05). Over two-thirds of VLBW infants with MOP were successfully treated with a gastrografin enema. The remaining eight VLBW infants required surgery. Although small for gestational age was more frequent in the medical treatment group, specific risk factors associated with MOP development did not affect the need for surgical intervention. CONCLUSION: MOP is common in VLBW infants, as most VLBW infants have risk factors for MOP. Identifying risk factors permits early diagnosis and initiation of appropriate medical treatment, reducing the necessity for surgery. However, the presence of specific risk factors does not increase risk of surgical complications.

Identification of a De Novo Heterozygous Missense FLNB Mutation in Lethal Atelosteogenesis Type I by Exome Sequencing

BACKGROUND: Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows. AO-I is caused by mutations in the filamin B (FLNB) gene; however, several other genes can cause AO-like lethal skeletal dysplasias. METHODS: In order to screen all possible genes associated with AO-like lethal skeletal dysplasias simultaneously, we performed whole-exome sequencing in a female newborn having clinical features of AO-I. RESULTS: Exome sequencing identified a novel missense variant (c.517G>A; p.Ala173Thr) in exon 2 of the FLNB gene in the patient. Sanger sequencing validated this variant, and genetic analysis of the patient's parents suggested a de novo occurrence of the variant. CONCLUSIONS: This study shows that exome sequencing can be a useful tool for the identification of causative mutations in lethal skeletal dysplasia patients.

A novel PRF1 gene mutation in a fatal neonate case with type 2 familial hemophagocytic lymphohistiocytosis / 소아과

Hemophagocytic lymphohistiocytosis (HLH) occurs in the primary form (genetic or familial) or secondary form (acquired). The familial form of HLH (FHL) is a potentially fatal autosomal recessive disorder that occurs because of constitutional defects in cell-mediated cytotoxicity. Here, we report a fatal neonatal case of type 2 FHL (FHL2) that involved a novel frameshift mutation. Clinically, the newborn presented with severe sepsis-like features and required mechanical ventilation and continuous venovenous hemodiafiltration. Flow cytometry analysis showed marked HLH and complete absence of intracytoplasmic perforin expression in cytotoxic cells; therefore, we performed molecular genetic analyses for PRF1 mutations, which showed that the patient had a compound heterozygous mutation in PRF1, that is, c.65delC (p.Pro22Argfs*2) and c.1090_1091delCT (p.Leu364Glufs*93). Clinical and genetic assessments for FHL are required for neonates with refractory fever and progressive multiple organ failure, particularly when there is no evidence of microbiological or metabolic cause.

Retropharyngeal abscess coinfected with Staphylococcus aureus and Mycobacterium tuberculosis after rhinoviral infection in a 1-month-old infant / 소아과

A retropharyngeal abscess is a rare disease entity in young infants but can develop after nasopharyngeal viral infection. Group B Streptococcus and Staphylococcus aureus are the most common pathogens in young infants, however, Mycobacterium tuberculosis is very rare. We report the case of retropharyngeal abscess and coinfection with S. aureus and M. tuberculosis in a very young infant presenting with respiratory symptoms due to upper airway obstruction. Usually tuberculous retropharyngeal abscesses are caused by the direct invasion of the bacteria from the spine via anterior longitudinal ligament of the spine. However, in this case, no associated spinal disease was observed.

Evaluation of Cardiovascular Anomalies in Patients with Asymptomatic Turner Syndrome Using Multidetector Computed Tomography

Turner syndrome is well known to be associated with significant cardiovascular abnormalities. This paper studied the incidence of cardiovascular abnormalities in asymptomatic adolescent patients with Turner syndrome using multidetector computed tomography (MDCT) instead of echocardiography. Twenty subjects diagnosed with Turner syndrome who had no cardiac symptoms were included. Blood pressure and electrocardiography (ECG) was checked. Cardiovascular abnormalities were checked by MDCT. According to the ECG results, 11 had a prolonged QTc interval, 5 had a posterior fascicular block, 3 had a ventricular conduction disorder. MDCT revealed vascular abnormalities in 13 patients (65%). Three patients had an aberrant right subclavian artery, 2 had dilatation of left subclavian artery, and others had an aortic root dilatation, aortic diverticulum, and abnormal left vertebral artery. As for venous abnormalities, 3 patients had partial anomalous pulmonary venous return and 2 had a persistent left superior vena cava. This study found cardiovascular abnormalities in 65% of asymptomatic Turner syndrome patients using MDCT. Even though, there are no cardiac symptoms in Turner syndrome patients, a complete evaluation of the heart with echocardiography or MDCT at transition period to adults must be performed.

Effect of Umbilical Cord Milking in Extremely Low Birth Weight Infants

PURPOSE: To investigate the effects of umbilical cord milking on the level of the hemoglobin, frequency of transfusion, initial adaptation after birth and morbidities in the extremely low birth weight infants (ELBWI). METHODS: Medical records of ELBWI admitted to the Samsung Medical Center Neonatal Intensive Care Unit from November 2007 to October 2010 were reviewed retrospectively. Before June 2009, infants' umbilical cords were clamped immediately (control group, n=39). After that time, umbilical cords were clamped after repeated (two or three times) milking of the cord toward the neonate under the radiant warmer (milking group, n=37). RESULTS: ELBWI with a gestational age of > or =26 weeks presented higher level of hemoglobin at the age of 3 days (16.9+/-2.6 vs. 14.3+/-2.3 g/dL, P=0.008) and 7 days (14.6+/-1.7 vs. 12.6+/-1.8 g/dL, P=0.005), lower frequency of transfusion during the hospital days (2.5+/-0.7 vs. 4.0+/-3.0) and smaller number of neonate undergoing transfusion within the first three weeks of life in the milking group than the control group (30% vs. 70%). There was no significant difference between the two groups in blood pressure and the urine output changes. There was no significant difference in mortality and morbidity, including respiratory distress syndrome, patent ductus arteriosus, bronchopulmonary dysplasia and intraventricular hemorrhage. CONCLUSION: Umbilical cord milking in ELBWI may be a useful method to reduce transfusion in neonates, especially in those of longer than 26 weeks gestation.

Sequential magnetic resonance spectroscopic changes in a patient with nonketotic hyperglycinemia / 소아과

Nonketotic hyperglycinemia (NKH) is a rare inborn error of amino acid metabolism. A defect in the glycine cleavage enzyme system results in highly elevated concentrations of glycine in the plasma, urine, cerebrospinal fluid, and brain, resulting in glycine-induced encephalopathy and neuropathy. The prevalence of NKH in Korea is very low, and no reports of surviving patients are available, given the scarcity and poor prognosis of this disease. In the current study, we present a patient with NKH diagnosed on the basis of clinical features, biochemical profiles, and genetic analysis. Magnetic resonance spectroscopy (MRS) allowed the measurement of absolute glycine concentrations in different parts of the brain that showed a significantly increased glycine peak, consolidating the diagnosis of NKH. In additional, serial MRS follow-up showed changes in the glycine/creatinine ratios in different parts of the brain. In conclusion, MRS is an effective, noninvasive diagnostic tool for NKH that can be used to distinguish this disease from other glycine metabolism disorders. It may also be useful for monitoring NKH treatment.

Permissive Hypotension in Extremely Low Birth Weight Infants (< or =1000 gm)

PURPOSE: We performed this study to evaluate the safety of permissive hypotension management in extremely low birth weight infants (ELBWIs). MATERIALS AND METHODS: Medical records of all inborn ELBWIs admitted to Samsung Medical Center from January 2004 to December 2008 were reviewed retrospectively. Of a total of 261 ELBWIs, 47 (18%) required treatment for hypotension (group T), 110 (42%) remained normotensive (group N), and 104 (40%) experienced more than one episode of hypotension without treatment (group P) during the first 72 hours of life. Treatment of hypotension included inotropic support and/or fluid loading. RESULTS: Birth weight and Apgar scores were significantly lower in the T group than the other two groups. In the N group, the rate of pathologically confirmed maternal chorioamnionitis was significantly higher than other two groups, and the rate was higher in the P group than the T group. After adjusting for covariate factors, no significant differences in mortality and major morbidities were found between the N and P groups. However, the mortality rate and the incidence of intraventricular hemorrhage (> or =stage 3) and bronchopulmonary dysplasia (> or =moderate) were significantly higher in the T group than the other two groups. Long term neurodevelopmental outcomes were not significantly different between the N and P groups. CONCLUSION: Close observation of hypotensive ELBWIs who showed good clinical perfusion signs without intervention allowed to avoid unnecessary medications and resulted in good neurological outcomes.

Effects of Early Parenteral Nutrition for Extremely Low Birth Weight Infants

PURPOSE: The object of this study was to evaluate the efficacy of early total parenteral nutrition with early amino acid in extremely low birth weight infant (ELBWI). METHODS: We retrospectively analyzed the medical records of all ELBWIs who were born and admitted to Samsung Medical Center from January 2003 to December 2003 and January 2009 to December 2009 and alive at the time of discharge. Data for nutritional status and morbidities were compared between period 1 (2003, n=22), in which parenteral nutritional support was started gradually over several days and period 2 (2009, n=38), in which parenteral nutrition with amino acid was started as soon as possible after birth. RESULTS: Compared to period 1, birth weight and Apgar score were lower in period 2. The intake amount of glucose, amino acid and total calorie was higher and the level of blood urea nitrogen was increased more from 7th day to 14th day after birth in period 2 when compared than period 1. The weight gain velocity was faster at 7th and 14th postnatal day in period 2. There were no differences in the incidence of necrotizing enterocolitis, moderate to severe bronchopulmonary dysplasia, and severe intraventricular hemorrhage (> or = Gr III) between two periods but, the incidence of periventricular leukomalacia(PVL) was significantly lower in period 2. CONCLUSION: Early initiation of total parenteral nutrition with early amino acid in ELBWIs was beneficial at weight gain with lowering catabolism and increasing anabolism. And it could be related with reducing the incidence of PVL.

The Clinical Effects of Early Trophic Feeding in Extremely Low Birth Weight Infants / 대한주산의학회잡지

PURPOSE: This study investigated the effects of early enteral feeding on the morbidities of extremely low birth weight infants (ELBWI) weighing less than 1,000 g. METHODS: We conducted a retrospective review of the medical records of sixty one ELBWI who were admitted to the neonatal intensive care unit of Inje University Busan Paik Hospital from January 2007 to October 2009. ELBWI were divided into two groups; the control group included ELBWI from January 2007 to March 2008, for whom enteral feeding was started beyond 3 days and the early feeding group included ELBWI from April 2008 to October 2009, for whom enteral feeding was started within 3 days. RESULTS: Gestational age and birth weight did not differ between the two groups. In the early feeding group, start day of enteral feeding (control group vs. early feeding group; 7+/-2days vs. 2+/-1days), time to achieve full enteral feeding (68+/-6 days vs. 22+/-2 days), and the duration of parenteral nutrition (58+/-6 days vs. 22+/-2 days) were significantly shorter, and weight gain at postnatal day 28 was significantly higher than that of the control group (P<0.001). No differences were observed in the incidence of sepsis and necrotizing enterocolitis and duration of hospitalization; however, the incidence of total parenteral nutrition induced cholestasis (44% vs. 7%) and bronchopulmonary dysplsia (78% vs. 24%) was significantly lower in the early feeding group. CONCLUSION: Early enteral feeding in ELBWI shortened the time to achieve full enteral feeding, improved weight gain, and decreased the incidence of brochopulmonay dysplasia and cholestasis.

Prognosis of Extremely Low Birth Weight infants (1,000 g) Associated with Antenatal Magnesium Sulfate (MgSO4) Exposure / 대한주산의학회잡지

OBJECTIVE: To determine whether magnesium sulfate exposure is associated with a reduced risk of perinatal complications in extremely low birth weight infants (ELBWIs). METHODS: Total 351 inborn extremely low birth weight infants admitted between January 2000 and December 2008 to Samsung Medical Center were divided into the prenatal MgSO4-exposed group (n=76), and control group (n=275), and were retrospectively analyzed. Multiple demographic, clinical characteristics and neonatal complications were compared. RESULTS: Prenatally MgSO4-exposed ELBWIs had significantly higher gestational age, birth weight, and incidence of small for gestational age. In neonatal complications, retinopathy of premature (ROP) treated with laser was less common in MgSO4-exposed group. There were no differences between two groups in the incidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), PDA ligation, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), and mortality. CONCLUSION: Perinatal exposure to magnesium sulfate was associated with decreased incidence of ROP treated with laser.

A case of de novo duplication of 15q24-q26.3 / 소아과

Distal duplication, or trisomy 15q, is an extremely rare chromosomal disorder characterized by prenatal and postnatal overgrowth, mental retardation, and craniofacial malformations. Additional abnormalities typically include an unusually short neck, malformations of the fingers and toes, scoliosis and skeletal malformations, genital abnormalities, particularly in affected males, and, in some cases, cardiac defects. The range and severity of symptoms and physical findings may vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15q. Most reported cases of duplication of the long arm of chromosome 15 frequently have more than one segmental imbalance resulting from unbalanced translocations involving chromosome 15 and deletions in another chromosome, as well as other structural chromosomal abnormalities. We report a female newborn with a de novo duplication, 15q24-q26.3, showing intrauterine overgrowth, a narrow asymmetric face with down-slanting palpebral fissures, a large, prominent nose, and micrognathia, arachnodactyly, camptodactyly, congenital heart disease, hydronephrosis, and hydroureter. Chromosomal analysis showed a 46,XX,inv(9)(p12q13),dup(15)(q24q26.3). Array comparative genomic hybridization analysis revealed a gain of 42 clones on 15q24-q26.3. This case represents the only reported patient with a de novo 15q24-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component in Korea.

The First Korean Case of Cutaneous Lung Tissue Heterotopia

Cutaneous lung tissue heterotopia is a very rare disorder where mature lung tissues develop in the skin. This is only the second known report of cutaneous lung tissue heterotopia, with the first by Singer et al. in 1998. A newborn infant had a hemangioma-like, freely movable mass connected to the anterior aspect of the sternal manubrium. Pathologic findings showed mature lung tissues with bronchi, bronchioles, and alveoli through the dermis and subcutis, and it was diagnosed as cutaneous lung tissue heterotopia. Cutaneous lung tissue heterotopia is hypervascular, so grossly it looks like a hemangioma. It can be differentiated from pulmonary sequestration, teratoma, bronchogenic cyst, and branchial cleft cyst by histology and the location of the mass. We describe the clinical, radiologic, and pathologic findings of a cutaneous lung tissue heterotopia, the first reported in Korea.

A case of Pfeiffer syndrome with c833_834GC>TG (Cys278Leu) mutation in the FGFR2 gene / 소아과

Pfeiffer syndrome is a rare autosomal dominant disorder characterized by coronal craniosynostosis, brachycephaly, mid-facial hypoplasia, and broad and deviated thumbs and great toes. Pfeiffer syndrome occurs in approximately 1:100,000 live births. Clinical manifestations and molecular genetic testing are important to confirm the diagnosis. Mutations of the fibroblast growth factor receptor 1 (FGFR1) gene or FGFR2 gene can cause Pfeiffer syndrome. Here, we describe a case of Pfeiffer syndrome with a novel c833_834GC>TG mutation (encoding Cys278Leu) in the FGFR2 gene associated with a coccygeal anomaly, which is rare in Pfeiffer syndrome.

Recent Outcomes of Very Low Birth Weight Infants of the Three University Hospital in the Busan Area / 대한주산의학회잡지

OBJECTIVE: The survival rate of very low birth weight infants (VLBWI) has increased markedly in Korea. The purpose of this study was to investigate the outcome of VLBWI in Busan area. METHODS: We retrospectively reviewed 273 VLBWI less than 1,500 g who were admitted to the neonatal intensive care units of three university hospitals in Busan between January, 2007, to December, 2008. The survival rate, distribution of infants by birth weight and gestational age, and complications were compared with previous reports in Busan. RESULTS: We enrolled 273 VLBWI, including 31.1% extremely low birth weight infants, and the overall survival rate of VLBWI was 77.3%. Mean gestational age was 29.2+/-2.9 weeks and birth weight was 1,115+/-249 g. Infants weighing or =29 weeks had survival rates of 25.0%, 57.5%, 75.0%, and 91.0%, respectively. Survival rates by birth weight ( or =stage III) (6.2%) and intraventricular hemorrhage (> or =Gr III) (5.1%). CONCLUSIONS: The survival rate of VLBWI born in Busan was 77.3% over the past 2 years. Survival rates of extreme prematurity weighing less than 1,000g and gestational age of < or =26 weeks were significantly increased.

A Comparative Study of Two Different Heel Lancet Devices for Blood Collection in Preterm Infants

PURPOSE: To evaluate two different heel lancet device in terms of pain response and success of the procedure in the preterm infants undergoing heel puncture. METHODS: 100 preterm infants undergoing capillary blood gas analysis or capillary bilirubin monitoring underwent heel puncture, were randomly allocated to blood sampling from the heel with either a conventional manual lancet or an automatic incision device. Primary outcome measures included the Premature Infants Pain Profile (PIPP) score, total duration of procedure, number of heel puncture and number of bruise. The pain response was evaluated using PIPP score and the effectiveness was evaluated using three criteria: total duration of blood sampling, number of puncture, bruising of the heel or ankle. Statistical analysis was performed using the SPSS ver. 13.0 program. Difference between the groups were analysed with t test (continuous variables) and the Chi square test or Fisher test (categorical variables). RESULTS: The mean PIPP score was 4.91 for the automatic lancet group compared with 5.84 for the conventional manual lancet group (P=0.0255).The number of pain scores above 7 during blood collection did not differ between two groups (P=0.2167). The procedure took less time to perform in the automatic lancet group (mean, 30.69 seconds) than in the conventional lancet group (mean, 48.92 seconds) (P<0.0001). CONCLUSION: This study demonstrated that the automatic lancet device causes less pain and a shorter procedure time than the conventional manual lancet in preterm infants undergoing heel puncture. On the basis of these results the automatic lancet device is very useful method for blood collection in preterm infants by heel puncture.

A Comparative Study of Two Different Heel Lancet Devices for Blood Collection in Preterm Infants

PURPOSE: To evaluate two different heel lancet device in terms of pain response and success of the procedure in the preterm infants undergoing heel puncture. METHODS: 100 preterm infants undergoing capillary blood gas analysis or capillary bilirubin monitoring underwent heel puncture, were randomly allocated to blood sampling from the heel with either a conventional manual lancet or an automatic incision device. Primary outcome measures included the Premature Infants Pain Profile (PIPP) score, total duration of procedure, number of heel puncture and number of bruise. The pain response was evaluated using PIPP score and the effectiveness was evaluated using three criteria: total duration of blood sampling, number of puncture, bruising of the heel or ankle. Statistical analysis was performed using the SPSS ver. 13.0 program. Difference between the groups were analysed with t test (continuous variables) and the Chi square test or Fisher test (categorical variables). RESULTS: The mean PIPP score was 4.91 for the automatic lancet group compared with 5.84 for the conventional manual lancet group (P=0.0255).The number of pain scores above 7 during blood collection did not differ between two groups (P=0.2167). The procedure took less time to perform in the automatic lancet group (mean, 30.69 seconds) than in the conventional lancet group (mean, 48.92 seconds) (P<0.0001). CONCLUSION: This study demonstrated that the automatic lancet device causes less pain and a shorter procedure time than the conventional manual lancet in preterm infants undergoing heel puncture. On the basis of these results the automatic lancet device is very useful method for blood collection in preterm infants by heel puncture.

Associated Malformations and Chromosomal Defects in Antenatally Diagnosed Hydronephrosis / 대한주산의학회잡지

PURPOSE: With the increasing use of antenatal sonography, fetal hydronephrosis has been reported more frequently. But, despite extensive clinical and scientific research much controversy still exists about the assessment and management of hydronephrosis. We performed a retrospective study to determine the frequency of associated malformations and chromosomal defects in prenatally diagnosed hydronephrosis. METHODS: The records of 297 neonates who were diagnosed with hydronephrosis through antenatal ultrasonographic screening, were retrospectively analyzed. They were confirmed at 3 days to 1 month after birth with postnatal ultrasonography in Busan Paik Hospital, between January 2000 and December 2008. We karyotyped 297 neonates after ultrasonographic examination revealed hydronephrosis and malformations. RESULTS: Chromosomal abnormalities were detected in 31 (11%) cases of 297 cases and more common in female than male. The commonest chromosomal abnormality was trisomy 21, followed by Turner syndrome, deletion of autosome, unbalanced translocation. 127 cases in 109 infants had associated malformations such as urogenital and cardiovascular and gastrointestinal anomalies. The associated malformations were more common in moderate to severe hydronephrosis than mild and the number of additional abnormalities increased with the chromosomal defects. CONCLUSION: Particular attention should be paid for the cases in congenital hydronephrosis with any associated malformation such as urogenital and cardiac malformation, to investigate chromosomal abnormalities. This will enable clinicians to establish appropriate management and postnatal care.