Identification of the KCNJ2 Mutation in a Korean Family with Andersen-Tawil Syndrome and Developmental Delay.

Andersen-Tawil syndrome is a rare autosomal dominant disease characterized by the clinical triad of periodic paralysis, long QT with ventricular arrhythmias, and dysmorphic facial or skeletal features. However, the phenotypic heterogeneity and poor disease awareness of this syndrome can hinder an accurate and timely diagnosis. In this study, we describe a Korean family with Andersen-Tawil syndrome with a G215D mutation of the KCNJ2 gene revealed by diagnostic exome sequencing. Two sisters had severe growth restriction, characteristic facial anomalies, and developmental delay. The father carried the same mutation with similar characteristic facial features and short stature. This family lacked periodic paralysis. This report highlights the importance of an exome study for unusual clinical manifestations, such as preand postnatal growth restriction, developmental delay, and the lack of a critical diagnostic clue, such as periodic paralysis.

Thyroid dysfunction in very low birth weight preterm infants.

PURPOSE: Thyroid dysfunction is common in preterm infants. Congenital hypothyroidism causes neurodevelopmental impairment, which is preventable if properly treated. This study was conducted to describe the characteristics of thyroid dysfunction in very low birth weight infants (VLBWIs), evaluate risk factors of hypothyroidism, and suggest the reassessment of thyroid function with an initially normal thyroid-stimulating hormone (TSH) as part of a newborn screening test. METHODS: VLBWIs (January 2010 to December 2012) were divided into two groups according to dysfunction-specific thyroid hormone replacement therapy, and associated factors were evaluated. RESULTS: Of VLBWIs, 246 survivors were enrolled. Only 12.2% (30/246) of enrolled subjects exhibited thyroid dysfunction requiring thyroid hormone replacement. Moreover, only one out of 30 subjects who required thyroid hormone treatment had abnormal thyroid function in the newborn screening test with measured TSH. Most of the subjects in the treatment group (22/30) exhibited delayed TSH elevation. Gestational age, Apgar score, antenatal steroids therapy, respiratory distress syndrome, patent ductus arteriosus, sepsis, intraventricular hemorrhage, postnatal steroids therapy, and duration of mechanical ventilation did not differ between the two groups. Birth weight was smaller and infants with small for gestational age were more frequent in the treatment group. CONCLUSION: Physicians should not rule out suggested hypothyroidism, even when thyroid function of a newborn screening test is normal. We suggest retesting TSH and free thyroxine in high risk preterm infants with an initially normal TSH level using a newborn screening test.

Efficacy of surfactant-TA, calfactant and poractant alfa for preterm infants with respiratory distress syndrome: a retrospective study.

PURPOSE: To compare the efficacy of the new drug calfactant with the commonly used drugs surfactant-TA and poractant alfa. MATERIALS AND METHODS: A total of 332 preterm infants at 24-31 weeks' gestation with respiratory distress syndrome (RDS) were enrolled and allocated to three groups according to the surfactant instilled; Group 1 (n=146, surfactant-TA), Group 2 (n=96, calfactant), and Group 3 (n=90, poractant alfa). The diagnosis of RDS and the decision to replace the pulmonary surfactant were left to the attending physician and based on patient severity determined by chest radiography and blood gas analysis. Data were collected and reviewed retrospectively using patient medical records. RESULTS: Demographic factors including gestational age, birth weight, Apgar score, clinical risk index for babies II score, and maternal status before delivery were not different between the study groups. Instances of surfactant redosing and pulmonary air leaks, as well as duration of mechanical ventilation, were also not different. Rates of patent ductus arteriosus, intraventricular hemorrhage (≥grade III), periventricular leukomalacia, high stage retinopathy of prematurity, necrotizing enterocolitis (≥stage II), and mortality were also similar, as was duration of hospital stay. Cases of pulmonary hemorrhage and moderate to severe bronchopulmonary dysplasia were increased in Group 3. CONCLUSION: Calfactant is equally as effective as surfactant-TA and poractant alfa. This was the first study comparing the efficacy of surfactant-TA, calfactant, and poractant alfa in a large number of preterm infants in Korea. Further randomized prospective studies on these surfactants are needed.

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.

Successful caspofungin treatment of persistent candidemia in extreme prematurity at 23 and 24 weeks' gestation.

Systemic fungal infection continues to be a major cause of mortality in extremely low-birth-weight premature infants. Amphotericin B has been recommended as the primary treatment; however, its use is limited due to drug-induced nephrotoxicity and amphotericin B-resistant candidemia. Caspofungin therapy was initiated in seven extremely premature infants at 23 and 24 weeks' gestation with persistent systemic candidiasis despite liposomal amphotericin B treatment. The gestational age was 23(+1)-24(+6) weeks, and birth weight was 530-825 g. Of the seven patients, the peripheral blood cultures of six patients were positive for Candida parapsilosis and one had positive culture for Candida albicans. The dosage of caspofungin was 2 mg/kg/day, and the mean treatment duration was 14 days. All of the persistent candidemia resolved on caspofungin therapy. There was no recurrent candidemia after discontinuing caspofungin. There were no adverse effects, hepatotoxicity, nephrotoxicity, anemia, or thrombocytopenia. Caspofungin successfully treated persistent candidemia in extremely premature infants at 23 and 24 weeks' gestational age.

Clinical and genetic analysis of a Korean patient with X-linked chondrodysplasia punctata: identification of a novel splicing mutation in the ARSE gene.

X-linked recessive chondrodysplasia punctata (CDPX1) is a rare congenital disorder of bone and cartilage development, characterized by punctate calcification in areas of endochondral bone formation, leading to stippled epiphyses, severe nasal and midfacial hypoplasia, short stature, and brachytelephalangy. CDPX1 is caused by mutations in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most affected males have milder symptoms, some have significant medical problems including respiratory compromise and cervical spinal stenosis due to dysplastic vertebrae. Herein, we present the case of a male infant with the characteristic features of CDPX1 and severe spinal cord compression. Direct sequencing analysis revealed a novel variation (c.430G>A) in the ARSE gene that was thought to be a missense mutation (p.Gly144Arg), but proved to be a novel splicing mutation (r.[430g>a; 430_431ins430+1_430+21) adding seven amino acids between p.Ile143 and p.Gly144 (p.Ile143_Gly-144insSerMetTyrValPheLysSer). This report expands the spectrum of mutations of the ARSE gene and, to the best of our knowledge, is the first clinically and genetically confirmed case of CDPX1 with severe spinal cord compression in Korea.

Risk factors of transfusion in anemia of very low birth weight infants.

PURPOSE: Anemia of prematurity is frequent in preterm infants, for which red blood cell (RBC) transfusion remains the treatment of choice. In this study, we attempted to evaluate the characteristics and risk factors of anemia of prematurity, and suggest ways to reduce anemia and the need for multiple transfusions. MATERIALS AND METHODS: Preterm infants weighing less than 1500 g (May 2008-May 2009) were divided into two groups depending on whether they received RBC transfusions (transfusion group and non transfusion group). Hemoglobin (Hb) concentration, phlebotomy blood loss, and the amount of RBC transfusion were analyzed. Risk factors of anemia and RBC transfusions were analyzed. RESULTS: Fifty infants that survived were enrolled in the present study: 39 in the transfusion group and 11 in the non transfusion group. Hb concentrations gradually decreased by eight weeks. In the transfusion group, gestational age and birth weight were smaller, bronchopulmonary dysplasia and sepsis were more frequent, full feeding was delayed, parenteral nutrition and days spent in the hospital were prolonged, and phlebotomy blood loss was greater than that in the non transfusion group. CONCLUSION: Anemia of prematurity was correlated with increased laboratory blood loss, decreased birth weight, prolonged parenteral nutrition, and delayed body weight gain. Accordingly, reducing laboratory phlebotomy loss and parenteral nutrition, as well as improving body weight gain, may be beneficial to infants with anemia of prematurity.

Immunogenicity, reactogenicity and safety of a human rotavirus vaccine (RIX4414) in Korean infants: a randomized, double-blind, placebo-controlled, phase IV study.

Rotavirus (RV) infection is the primary cause for childhood gastroenteritis worldwide. In Korea, RV infection is most common among children less than 5 years of age. This post-licensure study was conducted to further evaluate the RV vaccine (RIX4414) to provide additional local clinical data to the Korean Food and Drug Association. Healthy infants aged 6-12 weeks were enrolled to receive two doses of either RIX4414 or placebo as per 0, 1-2 month schedule. Blood samples were collected before dose-1 and one month post-dose-2 of RIX4414/placebo to assess serum anti-RV IgA antibody concentrations using ELISA. Gastroenteritis stool samples were tested for the presence of RV using ELISA. RV positive samples were subjected to further analysis for G and P typing. Among 684 infants enrolled and vaccinated, 432 infants (RIX4414=318; placebo=114) were included in the according-to-protocol cohort for immunogenicity. The anti-RV IgA antibody seroconversion rates in the RIX4414 group following one month post-dose-2 were 88.1% (95% CI: 84.0-91.4) and the corresponding geometric mean concentration in the RIX4414 group was 208.5 U/ml (95% CI: 174.2-249.5). Occurrence of solicited and unsolicited adverse events were similar in both, RIX4414 and placebo groups. None of the gastroenteritis stool samples tested positive for RV and no fatal SAEs were reported in either groups. The two-dose regimen of RIX4414 was observed to be immunogenic with a similar safety profile as compared to the placebo group, when administered to healthy Korean infants.

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

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.

Granulocyte colony stimulating factor attenuates hyperoxia-induced lung injury by down-modulating inflammatory responses in neonatal rats.

PURPOSE: Granulocyte colony stimulating factor (G-CSF) has been known to increase neutrophil production and have anti-inflammatory properties, but the effect of G-CSF on pulmonary system is in controversy. We investigated whether G-CSF treatment could attenuate hyperoxia-induced lung injury, and whether this protective effect is mediated by the down-modulation of inflammatory responses in a neonatal rat model. MATERIALS AND METHODS: Newborn Sprague-Dawley rats (Orient Co., Seoul, Korea) were subjected to 14 days of hyperoxia (90% oxygen) beginning within 10 h after birth. G-CSF (20 µg/kg) was administered intraperitoneally on the fourth, fifth, and sixth postnatal days. RESULTS: This treatment significantly improved hyperoxia-induced reduction in body weight gain and lung pathology such as increased mean linear intercept, mean alveolar volume, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling positive cells. Hyperoxia- induced activation of nicotinamide adenine dinucleotide phosphate oxidase, which is responsible for superoxide anion production, as evidenced by upregulation and membrane translocation of p67(phox) was significantly attenuated after G-CSF treatment, as were inflammatory responses such as increased myeloperoxidase activity and mRNA expression of transforming growth factor-ß. However, the attenuation of other proinflammatory cytokines such as tumor necrosis factor-α and interleukin- 6 was not significant. CONCLUSION: In sum, G-CSF treatment significantly attenuated hyperoxia-induced lung injury by down-modulating the inflammatory responses in neonatal rats.

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

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.

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.