Report of 5 novel mutations of the α-L-iduronidase gene and comparison of Korean mutations in relation with those of Japan or China in patients with mucopolysaccharidosis I.

BACKGROUND: Mucopolysaccharidosis I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a lack of the lysosomal enzyme α-L-iduronidase (IDUA). To date, more than 200 IDUA mutations have been reported. However, only a few types of mutations are recurrent and the frequencies of mutations differ from country to country. METHODS: We performed the IDUA mutation analysis in seven patients who were biochemically diagnosed with MPS I in the Department of Pediatrics, Samsung Medical Center, from 2009 to 2014. Here, we describe the results of the IDUA mutation analysis in seven patients with MPS I and the IDUA mutational spectrum in Korean patients with MPS I, including previous data. RESULTS: The IDUA mutations were found in all 14 alleles of 7 patients, and 11 kinds of IDUA mutations were identified. The detected mutations were five missense mutations (p.A79V, p.L346R, p.T388K, p.P496R, and p.C577Y), two nonsense mutations (p.Y618* and p.R628*), two deletions (c.683delC and c.1591delC), one splice site mutation (c.972+1G>A), and one duplication (c.613_617dup). Among these, p.T388K, p.C577Y, c.683delC, c.1591delC, and c.972+1G>A were novel mutations that have not previously been reported. After taking everything into consideration, including IDUA mutation analysis of the previously reported 10 unrelated Korean patients with MPS I, p.L346R and c.704ins5 were most commonly found in Korean patients with MPS I. However, p.W402* and p.Q70*, which have mainly been found in Caucasian patients, were not found. CONCLUSION: As a result, p.L346R and c.704ins5, which were the most common in Korea, which is geographically situated midway between China and Japan, were some of the most common mutations in China and Japan, respectively. These results are especially worthy of notice.

Late-onset noninfectious interstitial lung disease following autologous haematopoietic stem cell transplantation in paediatric patients.

BACKGROUND AND OBJECTIVE: High-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT) is widely used in paediatric cancer patients, but few data about noninfectious interstitial lung disease (ILD) following this treatment are available. Therefore, we aimed to evaluate the incidence, clinical features and risk factors of noninfectious ILD after HDCT in paediatric patients. METHODS: This was a retrospective cohort study of paediatric solid tumour patients who underwent HDCT and autologous HSCT between 1997 and 2012. ILD was diagnosed using clinical symptoms and radiography after excluding cardiac, renal and infectious causes. Risk factors were analysed using a Cox proportional hazard regression model. RESULTS: Three hundred and forty patients were enrolled, and the median age was 3 years (interquartile range 1-7). Eight patients (2.4%) were diagnosed with noninfectious ILD. The median duration of symptom onset was 30 months (range 7-74). Six (75%) of eight ILD patients died during the study period, even though steroids were administered for treatment. High-dose cyclophosphamide use (hazard ratio = 11.37, 95% confidence interval = 1.38-93.32, P = 0.023) and sex (hazard ratio = 0.10, 95% confidence interval = 0.01-0.84, P = 0.034) were associated with late-onset, noninfectious ILD upon multivariate analysis. CONCLUSION: The incidence of noninfectious ILD after HDCT and autologous HSCT was not negligible, and the clinical features of ILD showed late onset and a poor prognosis. Female gender and high-dose cyclophosphamide treatment may be risk factors for noninfectious ILD, but further studies with a larger number of ILD patients are suggested.

Estrogen-mediated Height Control in Girls with Marfan Syndrome.

This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old.

Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.

Safety and efficacy of enzyme replacement therapy with idursulfase beta in children aged younger than 6 years with Hunter syndrome.

Idursulfase beta (Hunterase®) has been used for enzyme replacement therapy (ERT) of patients with mucopolysaccharidosis II (MPS II, Hunter syndrome) aged 6 years or older since 2012 in Korea. The objective of this study was to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome children younger than 6 years. This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). Idursulfase beta (0.5mg/kg/week) was administered intravenously for 52 weeks. The primary endpoint was safety assessed by adverse events (AEs). Secondary endpoints included vital signs, physical examination, ECG, laboratory tests, anti-idursulfase antibodies, and efficacy represented by changes in urinary glycosaminoglycan (GAG) at week 53 from baseline. In addition, growth indices and developmental milestones (Denver II test) were evaluated as exploratory variables. All six patients experienced at least one AE. A total of 109 AEs were reported. One patient experienced a serious AE (hospitalization due to gastroenteritis) that was considered not to be treatment related. One patient (16.7%) experienced infusion-related adverse drug reactions (ADRs), developing urticaria six times and a cough five times. There were no serious ADRs and no clinically significant changes in vital signs, physical exam, laboratory parameters, or ECG. Of the six patients, four (66.7%) showed anti-idursulfase antibodies and neutralizing antibodies on at least one occasion during the study. At week 53, urinary GAG was significantly reduced by -35.1±30.6mgGAG/g creatine from baseline (P=0.038). This study indicates that the safety and efficacy of idursulfase beta are similar to those reported in Hunter syndrome patients aged 6 years or older.

Disease-specific growth charts for Korean infants with Prader-Willi syndrome.

Patients with Prader-Willi syndrome (PWS) present with short stature and obesity. The growth pattern of children with PWS is different from that of the healthy population. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of children with PWS. We aimed to develop disease-specific growth charts for height and weight for nongrowth hormone-treated Korean infants with PWS aged between 0 and 36 months and to use these growth charts for the evaluation and management of infants with PWS. We conducted a retrospective review of the medical records of 122 infants with genetically confirmed PWS. Data on the patients' height and weight measurements before they underwent growth hormone treatment were recorded. Disease-specific growth charts were generated and the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th centiles were calculated using the LMS (refers to λ, µ, and σ, respectively) smoothing procedure for height and weight. The disease-specific growth charts for Korean infants with PWS can be used when examining infants with PWS and when evaluating their growth at later stages for comparison purposes. They are also useful for monitoring growth patterns, nutritional assessments, and recording responses to growth hormone treatment.

Pharmacokinetics, Pharmacodynamics, and Efficacy of a Novel Long-Acting Human Growth Hormone: Fc Fusion Protein.

The current recombinant human growth hormone (rhGH) therapy requires daily subcutaneous (sc) injections, which results in poor patient compliance, especially in young children. To reduce the dosing frequency, we generated a chimeric protein of rhGH and the Fc-domain of immunoglobulin G (IgG) (rhGH-Fc). The pharmacokinetics and pharmacodynamics of sc-injected rhGH-Fc were assessed in male Sprague-Dawley rats and hypophysectomized rats, respectively. A single sc injection of rhGH-Fc at a dose of 0.2 mg/kg slowly reached a Cmax of 16.80 ng/mL and remained for 7 days with a half-life of 51.1 h. Conversely, a single sc injection of rhGH 0.2 mg/kg rapidly reached a Cmax of 46.88 ng/mL and declined with a half-life of 0.55 h to baseline values in 4 h. In the efficacy study, the sc-injected rhGH-Fc induced rapid weight gain and tibial width growth at a dose of 240 µg/animal. The effect of two injections of rhGH-Fc separated by 1 week was comparable to that of the same dose of 14 daily injections of rhGH. The rhGH-Fc is a novel candidate for long-acting rhGH therapy with more convenient weekly administration, as it reduces glomerular filtration and receptor-mediated clearance while allowing for the rapid reversal of potential adverse events.

Impact of enzyme replacement therapy on linear growth in Korean patients with mucopolysaccharidosis type II (Hunter syndrome).

Hunter syndrome (or mucopolysaccharidosis type II [MPS II]) arises because of a deficiency in the lysosomal enzyme iduronate-2-sulfatase. Short stature is a prominent and consistent feature in MPS II. Enzyme replacement therapy (ERT) with idursulfase (Elaprase®) or idursulfase beta (Hunterase®) have been developed for these patients. The effect of ERT on the growth of Korean patients with Hunter syndrome was evaluated at a single center. This study comprised 32 patients, who had received ERT for at least 2 yr; they were divided into three groups according to their ages at the start of ERT: group 1 (<6 yr, n=14), group 2 (6-10 yr, n=11), and group 3 (10-20 yr, n=7). The patients showed marked growth retardation as they got older. ERT may have less effect on the growth of patients with the severe form of Hunter syndrome. The height z-scores in groups 2 and 3 revealed a significant change (the estimated slopes before and after the treatment were -0.047 and -0.007, respectively: difference in the slope, 0.04; P<0.001). Growth in response to ERT could be an important treatment outcome or an endpoint for future studies.

Prevalence of idiopathic scoliosis in girls with central precocious puberty: effect of a gonadotropin-releasing hormone agonist.

PURPOSE: Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis and occurs in children between 10 to 18 years old, during periods of growth spurts and puberty changes. In patients with central precocious puberty (CPP), due to early growth spurt, AIS is expected to develop before 10 years of age. Both AIS and CPP are more common in girls than in boys. The aim of this study was to determine the prevalence of AIS in girls with CPP and to evaluate the effect of treatment with gonadotropin-releasing hormone (GnRH) agonists on progression of scoliosis in these patients. METHODS: We retrospectively reviewed medical records of 553 girls, 338 with CPP and 215 without CPP. Scoliosis angle was measured on the standing frontal radiograph of each patient according to the Cobb method. Patients with a Cobb angle of 10° or more were diagnosed with scoliosis. For girls with CPP, followup spine radiographs were collected 1 year after treatment with GnRH agonists. Progression of scoliosis before and after treatment was compared in terms of Cobb angle changes. RESULTS: AIS was more prevalent in girls that were affected by CPP compared to controls without CPP (11.5% vs. 6.0%, CPP girls vs. non-CPP girls, respectively, P=0.031). The peak serum luteinizing hormone level positively correlated with Cobb angle (R2=0.015, P=0.023) in the CPP group. No progression of scoliosis was observed in CPP girls after one year of GnRH agonist treatment. Additionally, the prevalence of scoliosis decreased in CPP girls after 1 year of the treatment. CONCLUSION: We report that the prevalence of AIS is higher in girls with CPP than in non-CPP patients. A regular follow-up schedule for spine radiographs should be considered to reduce the risk of progression. Furthermore, GnRH agonist treatment for CPP may have a suppressive effect on progression of AIS.

First Korean Case of Infantile Hypophosphatasia with Novel Mutation in ALPL and Literature Review.

Hypophosphatasia is a rare hereditary disorder characterized by defective bone and tooth mineralization and deficiency of tissue non-specific alkaline phosphatase activity. The prognosis for the infantile form is poor, with approximately 50% of patients dying within the first year of life from respiratory failure. We describe the clinical and biochemical findings as well as the molecular analysis of a Korean boy with infantile hypophosphatasia and present a literature review. A 1-month-old boy visited the clinic because of poor feeding, frequent vomiting, hypotonia, and failure to thrive from birth. Laboratory tests revealed high total calcium, low phosphorous, low alkaline phosphatase, low parathyroid hormone, and normal 25-hydroxyvitamin D. Intravenous hydration with normal saline was started, and dietary calcium intake was restricted. Skeletal X-rays showed a markedly increased distance of the anterior fontanelle, impaired mineralization, and rachitic changes in the metaphyses. By Sanger sequencing of the ALPL gene, we identified two heterozygous variants, including a missense (c.334G>A; p.Gly112Ser) and a nonsense (c.1039C>T; p.Gln347*) variant. The c.334G>A (p.Gly112Ser) variant had previously been reported in a patient with lethal type hypophosphatasia, while the nonsense c.1039C>T (p.Gln347*) variant was novel. In the current case, the accurate diagnosis and prompt intervention-including dietary calcium intake restriction, tracheostomy to prevent progression to respiratory failure, and fundoplication with gastrostomy to ensure the administration of adequate calories-seemed to play an important role for avoiding preventable morbidity and premature mortality.

Letter to the Editor: A Novel Mutation in the CREBBP Gene of a Korean Girl with Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is a rare congenital disorder characterized by broad thumbs and halluces, dysmorphic facial features, mental retardation, and short stature. Mutations in the cAMP-response element binding protein-BP (CREBBP) gene (50-60% of cases) and E1A-binding protein (EP300, 3%) are known genetic causes in affected individuals. Here, we describe a genetically confirmed Korean RTS patient with atypical features, including Hirschsprung disease and growth hormone deficiency. Mutational analysis revealed a novel heterozygous frameshift mutation, c.2064_2077del14 (p.Gly689Cysfs*32) in the CREBBP gene.

Elevation of serum creatine kinase during methimazole treatment of Graves disease in a 13-year-old girl and a literature review of similar cases.

We report a 13-year-old girl with Graves disease, who showed an increased level of serum creatine kinase (CK) accompanied by myalgia after methimazole (MMI) treatment. This patient developed muscular pain two weeks after MMI administration, along with increased CK levels. The level of thyroid hormone was within the normal range when she showed increased CK levels. After the MMI dose was decreased and levo-thyroxine was added, serum CK levels decreased to normal and the myalgia improved. The pathophysiologic mechanism of this effect has not yet been elucidated. An acute relatively hypothyroid state occurs secondary to antithyroid drug (ATD) administration in chronic hyperthyroidism, which may cause changes in the CK levels. In this report, we present a rare pediatric case, along with a literature review of similar cases. In the initial state of MMI treatment, myalgia should be detected and when it occurs, CK levels should be measured. The clinical strategy of monitoring CK levels with the aim of normalizing thyroid hormones is helpful in case of the development of adverse reactions, such as myalgia, during ATD treatment for Graves disease in children.

A novel splice site mutation in the PAX6 gene in a Korean family with isolated aniridia.

Aniridia is a rare congenital ocular disorder of complete or partial iris hypoplasia. Frequently associated ocular changes include corneal abnormalities, cataract, glaucoma, and foveal hypoplasia. In most cases, aniridia is caused by decreased dosage of the paired box 6 (PAX6) gene, which is located in chromosome 11p13. We report the case of a Korean family with isolated aniridia inherited in an autosomal dominant manner. The proband was a one-month-old boy. He presented with bilateral complete aniridia and congenital glaucoma. His four-year-old sister had bilateral complete aniridia, glaucoma, and a corneal ulcer. His father had bilateral microcornea and cataract without aniridia. Using PAX6 sequencing analysis, we identified a deletion at the splice donor site of intron 8 in the proband (c.357+1delG). To our knowledge, this variant has not been previously described.

Birth seasonality in Korean Prader-Willi syndrome with chromosome 15 microdeletion.

PURPOSE: Prader-Willi syndrome (PWS) is a well-known genetic disorder, and microdeletion on chromosome 15 is the most common causal mechanism. Several previous studies have suggested that various environmental factors might be related to the pathogenesis of microdeletion in PWS. In this study, we investigated birth seasonality in Korean PWS. METHODS: A total of 211 PWS patients born from 1980 to 2014 were diagnosed by methylation polymerase chain reaction at Samsung Medical Center. Of the 211 patients, 138 were born from 2000-2013. Among them, the 74 patients of a deletion group and the 22 patients of a maternal uniparental disomy (UPD) group were compared with general populations born from 2000 using the Walter and Elwood method and cosinor analysis. RESULTS: There was no statistical significance in seasonal variation in births of the total 211 patients with PWS (χ(2)=7.2522, P=0.2982). However, a significant difference was found in the monthly variation between PWS with the deletion group and the at-risk general population (P<0.05). In the cosinor model, the peak month of birth for PWS patients in the deletion group was January, while the nadir occurred in July, with statistical significance (amplitude=0.23, phase=1.2, low point=7.2). The UPD group showed the peak birth month in spring; however, this result was not statistically significant (χ(2)=3.39, P=0.1836). CONCLUSION: Correlation with birth seasonality was identified in a deletion group of Korean PWS patients. Further studies are required to identify the mechanism related to seasonal effects of environmental factors on microdeletion on chromosome 15.

Hypoparathyroidism in a 3-year-old Korean boy with Sotos syndrome and a novel mutation in NSD1.

Sotos syndrome is a common genetic overgrowth syndrome caused by a mutation of the NSD1 gene, which is located at chromosome 5q35 and normally encodes a histone methyltransferase protein. The general characteristics of this syndrome include a characteristic facial appearance, developmental delay, and overgrowth, resulting in macrocephaly and tall stature. We describe rhabdomyolysis and hypocalcemia due to hypoparathyroidism in a 3-year-old Korean boy with Sotos syndrome. He was diagnosed with Sotos syndrome based on the typical phenotype and has a heterozygous nonsense mutation (c.4710C>A [p.Cys1570*]) of the NSD1 gene, which causes a premature stop codon and a truncating protein mutation. Hypoparathyroidism has never been described in Sotos syndrome. This report may therefore expand the phenotypic spectrum of this syndrome.