Recombinant growth hormone therapy in children with Turner Syndrome in Korea: a phase III Randomized Trial.

BACKGROUND: Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. METHODS: This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450-0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450-0.050 mg] /kg/day). RESULTS: The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (- 1.02) satisfied the non-inferiority margin (- 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups. CONCLUSIONS: This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).

Identification of a novel mutation in EXT2 in a fourth-generation Korean family with multiple osteochondromas and overview of mutation spectrum.

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal-dominant disease characterized by growths of MOs, which are benign cartilage-capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype-phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four-generation Korean family with 11 MO-affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate-to-severe phenotypes (clinical classes II-III), including bony deformities and limb misalignment with pain requiring surgical correction. The x-rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic-genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient.

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report.

BACKGROUND: Hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic heterogeneity caused by haploinsufficiency of the GATA3 gene on chromosome 10p14-p15. For these reasons, the diagnosis of HDR syndrome is challenging and requires a high index of suspicion as well as genetic analysis. CASE PRESENTATION: A 14-month-old boy, with sensorineural hearing loss in both ears, showed typical radiological features of X-linked stapes gusher on preoperative temporal bone computed tomography (CT) for cochlear implantations. Then after his discharge from hospital, he suffered a hypocalcemic seizure and we discovered a renal cyst during investigation of hypocalcemia. He was finally diagnosed with HDR syndrome by clinical findings, which were confirmed by molecular genetic testing. Direct sequencing of the GATA3 gene showed a heterozygous 2-bp deletion (c.1201_1202delAT), which is predicted to cause a frameshift of the reading frame (p.Met401Valfs*106). CONCLUSIONS: To our knowledge, this is the first case of HDR syndrome with a novel de novo variant mimicking a congenital X-linked stapes gusher syndrome. Novel mutations and the diversity of clinical manifestations expand the genotypic and phenotypic spectrum of HDR syndrome. Diagnosis of HDR syndrome is still challenging, but clinicians should consider it in their differential diagnosis for children with a wide range of clinical manifestations including hypocalcemia induced seizures and deafness. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations.

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.

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.

2022 Clinical practice guidelines for central precocious puberty of Korean children and adolescents.

The Committee of Central Precocious Puberty of Korean Pediatrics and Adolescents of the Korean Society of Pediatric Endocrinology has newly developed evidence-based 2022 clinical practice guidelines for central precocious puberty in Korean children and adolescents. These guidelines provide the grade of recommendations, which includes both the strength of recommendations and the level of evidence. In the absence of sufficient evidence, recommendations are based on expert opinion. These guidelines have been revised and supplement the previous guidelines "Clinical Guidelines for Precocious Puberty 2011," and are drawn from a comprehensive review of the latest domestic and international research and the grade of recommendation appropriate to the domestic situation. This review summarizes the newly revised guidelines into 8 key questions and 27 recommendations and consists of 4 sections: screening, diagnosis, treatment, and long-term outcome of central precocious puberty.

Preclinical trial of noncontact anthropometric measurement using IR-UWB radar.

Anthropometric profiles are important indices for assessing medical conditions, including malnutrition, obesity, and growth disorders. Noncontact methods for estimating those parameters could have considerable value in many practical situations, such as the assessment of young, uncooperative infants or children and the prevention of infectious disease transmission. The purpose of this study was to investigate the feasibility of obtaining noncontact anthropometric measurements using the impulse-radio ultrawideband (IR-UWB) radar sensor technique. A total of 45 healthy adults were enrolled, and a convolutional neural network (CNN) algorithm was implemented to analyze data extracted from IR-UWB radar. The differences (root-mean-square error, RMSE) between values from the radar and bioelectrical impedance analysis (BIA) as a reference in the measurement of height, weight, and body mass index (BMI) were 2.78, 5.31, and 2.25, respectively; predicted data from the radar highly agreed with those from the BIA. The intraclass correlation coefficients (ICCs) were 0.93, 0.94, and 0.83. In conclusion, IR-UWB radar can provide accurate estimates of anthropometric parameters in a noncontact manner; this study is the first to support the radar sensor as an applicable method in clinical situations.

Abnormal thalamocortical connectivity of preterm infants with elevated thyroid stimulating hormone identified with diffusion tensor imaging.

While thyroid disturbances during perinatal and postnatal periods in preterm infants with congenital hypothyroidism reportedly disrupt neuronal development, no study has considered the effect of thyroid disturbances in premature infants with subclinical hypothyroidism with elevations of thyroid stimulating hormone. We aimed to identify altered fiber integrity from the thalamus to cortices in preterm infants with subclinical hypothyroidism. All preterm infants born were categorized according to thyroid stimulating hormone levels through serial thyroid function tests (36 preterm controls and 29 preterm infants with subclinical hypothyroidism). Diffusion tensor images were acquired to determine differences in thalamocortical fiber lengths between the groups, and cerebral asymmetries were investigated to observe neurodevelopmental changes. Thalamocortical fiber lengths in the subclinical hypothyroidism group were significantly reduced in the bilateral superior temporal gyrus, heschl's gyrus, lingual gyrus, and calcarine cortex (all p < 0.05). According to the asymmetric value in the orbitofrontal regions, there is a left dominance in the subclinical hypothyroidism group contrary to the controls (p = 0.012), and that of the cuneus areas showed significant decreases in the subclinical hypothyroidism group (p = 0.035). These findings could reflect altered neurodevelopment, which could help treatment plans using biomarkers for subclinical hypothyroidism.

Different maturation of gut microbiome in Korean children.

Introduction: Gut microbiome plays a crucial role in maintaining human health and is influenced by food intake, age, and other factors. Methods: In this study based in Korea, we examined the bacterial taxonomic composition of the gut microbiota in infants (≤ 1 year), toddlers (1-<4 years), and school-aged children (4-13 years) and compared them with those of healthy adults to investigate the microbiota changes in early life and their association with the resistome. We used whole metagenome sequences obtained by Illumina HiSeq sequencing and clinical information of 53 healthy children, and sequence data of 61 adults from our previous study. Results: Our results indicate that the bacterial proportion of the gut in the population ranging from infants to adults forms three clusters: the Ruminococcus-Eubacterium (G1), Bifidobacterium-Escherichia (G2), and Bacteroides-Faecalibacterium (G3) groups. The gut microbiota of infants and toddlers (100% of infants and 85% of toddlers) constituted mostly of G2 and G3 groups, whereas 90% of adults showed G1-type gut microbiota. School-aged children showed a transitional gut microbiota composition of both infants and adults (31%, 38%, and 31% in G1, G2, and G3, respectively). Notably, the three clusters of microbiota showed significantly different patterns of bacterial diversity (p < 0.001): G2 showed the lowest Shannon index, followed by G3 and G1 (1.41, 2.08, and 2.48, respectively; median Shannon index). When combined with the adult group, alpha diversity showed a positive correlation with age (R2 = 0.3). Furthermore, clustering the composition of antibiotic resistance genes (ARG) identified two clusters (A1 and A2), and most of G1 (95%) and G3 (80%) belonged to A1. However, G2 showed the least diversity and the highest abundance of ARGs. Nine ARG families showed a significant difference among age groups; three tetracycline resistance genes, tet32, tetO, and tetW, showed a positive correlation, and six other genes, ampC, TEM, ileS, bacA, pmr transferase, and cepA, showed a negative correlation with age. Discussion: In conclusion, our results highlighted that a delayed persistence of the Bifidobacterium-dominant enterotype with a lower bacterial diversity was observed in Korean children up to 13 years of age, which suggests a different maturation process with a delayed maturation time.

Identification of a novel KAT6A variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review.

BACKGROUND: Arboleda-Tham syndrome (ARTHS), caused by a pathogenic variant of KAT6A, is an autosomal dominant inherited genetic disorder characterized by various degrees of developmental delay, dysmorphic facial appearance, cardiac anomalies, and gastrointestinal problems. CASE PRESENTATION: A baby presented multiple facial deformities including a high arched and cleft palate, with philtral ridge and vermilion indentation, a prominent nasal bridge, a thin upper lip, low-set ears, an epicanthal fold, and cardiac malformations. Whole exome sequencing (WES) revealed a heterozygous nonsense mutation in exon 8 of the KAT6A gene (c.1312C>T, p.[Arg438*]) at 2 months of age. After a diagnosis of ARTHS, an expressive language delay was observed during serial assessments of developmental milestones. CONCLUSIONS: In this study, we describe a case with a novel KAT6A variant first identified in Korea. This case broadens the scope of clinical features of ARTHS and emphasizes that WES is necessary for early diagnosis in patients with dysmorphic facial appearances, developmental delay, and other congenital abnormalities.

Brain White Matter Maturation and Early Developmental Outcomes in Preterm Infants With Retinopathy of Prematurity.

Purpose: To investigate brain white matter pathways using magnetic resonance diffusion tensor imaging (DTI) and correlate the findings with developmental outcomes at 18 months of corrected age in preterm infants with and without retinopathy of prematurity (ROP). Methods: In this prospective cohort study, probabilistic maps of the 26 white matter pathways associated with motor, cognitive, visual, and limbic/language functions were generated in 84 preterm infants using DTI obtained at term-equivalent age. The mean fractional anisotropy (FA) and mean diffusivity (MD) values were compared between those with and without ROP. Developmental outcomes were assessed using the third edition of Bayley Scales of Infant and Toddler Development (BSID-III) at 18 months of corrected age. Multiple regression analyses were performed to confirm the association among developmental outcomes, white matter pathways, and ROP or severe ROP after adjusting for potential confounders. Results: The white matter pathways were insignificantly associated with ROP or severe ROP. There were no significant differences in the FA and MD values of the pathways between ROP infants treated with and without bevacizumab therapy. Furthermore, there were no significant differences in BSID-III scores between infants with and without ROP or severe ROP. The BSID-III scores at 18 months of age showed a significant association with FA or MD values in several pathways. Conclusions: ROP or severe ROP was insignificantly associated with maturation delay of the white matter pathways. Developmental outcomes were similar between preterm infants with and without ROP or severe ROP or between ROP infants with and without intravitreal bevacizumab therapy.

Altered structural brain networks at term-equivalent age in preterm infants with grade 1 intraventricular hemorrhage.

BACKGROUND: Preterm infants are at risk for structural disruption of brain connectivity due to perinatal complications encountered during the fetal and neonatal periods. This study aimed to investigate the development of connectivity using diffusion tensor imaging at near-term age and the effect of grade 1 intraventricular hemorrhage on it. METHODS: A total of 86 infants (55 preterm infants, 24 full-term infants) without apparent brain injury underwent diffusion magnetic resonance imaging (MRI) between 36 and 41 weeks post-menstrual age. The diffusion-MRI based connectomics were constructed from 64-segmented regions by using the Johns Hopkins University neonate atlas and were weighted with fractional anisotropy. The connectomes were quantified in the structural networks and investigated using network metrics, such as the clustering coefficient, local efficiency, characteristic path length, global efficiency, and small-worldness. We compared the differences in the brain networks of preterm infants with or without grade 1 intraventricular hemorrhage in binary and fractional anisotropy-weighted (wFA) connectomes. RESULTS: The 55 preterm infants had a mean gestational age at birth of 29.3 ± 4.1 weeks and the 24 term-born infants, 38.1 ± 1.1 weeks. A total of 13 of the 55 preterm infants (23.6%) were diagnosed with grade 1 intraventricular hemorrhage. The development of connectivity of the brain network in preterm infants without intraventricular hemorrhage was comparable at near-term age to that in term infants. The preterm infants with germinal matrix hemorrhage exhibited higher clustering (0.093 ± 0.015 vs. 0.088 ± 0.007, p = 0.027) and local efficiency (0.151 ± 0.022 vs. 0.141 ± 0.010, p = 0.025), implying the potential for segregation. However, the preterm infants with intraventricular hemorrhage revealed a longer path length (0.291 ± 0.035 vs. 0.275 ± 0.019, p = 0.020) and lower global efficiency (3.998 ± 0.473 vs. 4.212 ± 0.281, p = 0.048), indicating a decreased integration in the wFA connectivity matrix than those without germinal matrix hemorrhage, after correcting for gestational age, sex, bronchopulmonary dysplasia, and age at scan. CONCLUSION: Grade 1 intraventricular hemorrhage in preterm infants may enhance the capacity for local information transfer and the relative reinforcement of the segregation of networks at the expense of global integration capacity.

A case of de novo 18p deletion syndrome with panhypopituitarism.

Deletion on the short arm of chromosome 18 is a rare disorder characterized by intellectual disability, growth retardation, and craniofacial malformations (such as prominent ears, microcephaly, ptosis, and a round face). The phenotypic spectrum is wide, encompassing a range of abnormalities from minor congenital malformations to holoprosencephaly. We present a case of a 2-year-old girl with ptosis, a round face, broad neck with low posterior hairline, short stature, and panhypopituitarism. She underwent ventilation tube insertion for recurrent otitis media with effusion. Brain magnetic resonance imaging showed an ectopic posterior pituitary gland and a shallow, small sella turcica with poor visualization of the pituitary stalk. Cytogenetic and chromosomal microarray analysis revealed a de novo deletion on the short arm of chromosome 18 (arr 18p11.32p11.21[136,227-15,099,116]x1). She has been treated with recombinant human growth hormone (GH) therapy since the age of 6 months after diagnosis of GH deficiency. Her growth rate has improved without any side effects from the GH treatment. This case expands the phenotypic spectrum of 18p deletion syndrome and emphasizes the positive impact of GH therapy on linear growth in this syndrome characterized by growth deficiency. Further studies are required to define the genotype-phenotype correlation according to size and loci of the deletion in 18p deletion syndrome and to predict prognosis.

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center.

PURPOSE: Pompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alphaglucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center. METHODS: The medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT. RESULTS: Common initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT. CONCLUSION: As ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

Etiological trends in male central precocious puberty.

PURPOSE: In the present study, the etiological trends in male central precocious puberty (CPP) were examined, and annual distribution was evaluated. METHODS: Seventy-one male CPP subjects who started puberty before 9 years of age were included in this study. All individuals were diagnosed as having CPP at Samsung Medical Center between 2001 and 2016. Chronological age at puberty onset, diagnosis of CPP, bone age, weight (kg), height (cm), puberty stage, brain magnetic resonance imaging findings, testosterone level, basal gonadotropin level, and gonadotropin level after gonadotropin releasing hormone stimulation were analyzed. RESULTS: The 71 patients were divided into 2 groups: idiopathic (group I) and organic (group II) when the lesion was identified as associated with the central nervous system (CNS) or when the patient received chemotherapy for non-CNS tumors before CPP diagnosis, respectively. Forty-four cases (62%) were idiopathic, and 27 (38%) were organic. The proportion of idiopathic CPP was higher than that of organic CPP during the study period. In 51.9% of organic cases, puberty started before 8 years of age, whereas it started after that age in 93.2% of the idiopathic cases. CONCLUSION: In the present study, among all male CPP cases, 62% were idiopathic. The probability of idiopathic CPP prevalence was higher in males when the puberty onset was after 8 years of age with no history of cranial radiotherapy or chemotherapy.

De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism.

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.

A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets.

X-linked hypophosphatemic rickets is caused by loss-of-function mutations in PHEX, which encodes a phosphate-regulating endopeptidase homolog. We report a 26-year-old man with X-linked hypophosphatemic rickets who showed decreased serum phosphate accompanied by bilateral genu valgum and short stature. He had received medical treatment with vitamin D (alfacalcidol) and phosphate from the age of 3 to 20 years. He underwent surgery due to valgus deformity at the age of 14 and 15. Targeted gene panel sequencing for Mendelian genes identified a nonsense mutation in PHEX (c.589C>T; p.Gln197Ter) and a mosaic pattern where only 38% of sequence reads showed the variant allele. This mutation was not found in his mother, who had a normal phenotype. This is a case of a sporadic nonsense mutation in PHEX and up to date, this is the first case of a mosaic mutation in PHEX in Korea.

First Korean Case of Renpenning Syndrome with Novel Mutation in PQBP1 Diagnosed by Targeted Exome Sequencing, and Literature Review.

Renpenning syndrome is a rare X-linked disorder characterized by mental retardation, leanness, microcephaly, facial dysmorphism, short stature, and small testes. This disease is caused by PQBP1 mutations. Herein, we present a literature review and describe the clinical and molecular findings in a Korean boy with Renpenning syndrome. A 23-month-old boy presented with mental retardation, narrow face, bulbous nose, and cardiac anomaly. Interestingly, targeted exome sequencing identified a novel mutation c.559delT (p.Tyr187llefs*8) in the PQBP1 gene, and he was diagnosed as having Renpenning syndrome. In line with previously reported studies, our case suggests that men with mental retardation, short stature, and microcephaly should include Renpenning syndrome as a differential diagnosis.

Oculodentodigital Dysplasia with a Novel Mutation in GJA1 Diagnosed by Targeted Gene Panel Sequencing: A Case Report and Literature Review.

Oculodentodigital dysplasia (ODDD; MIM #164200), a rare genetic disorder characterized by abnormal craniofacial, dental, ocular, and digital features, is caused by mutations in the gap junction alpha-1 (GJA1) gene. We report a case of a 6-year-old male who presented with dysmorphic facial features (short palpebral fissure, thin nose with hypoplastic alae nasi, and flat face), bilateral syndactyly, abnormal dentition, and proportionate short stature with growth hormone deficiency. A novel de novo heterozygous missense mutation (c.221A>C, p.H74P) in GJA1 was identified by targeted gene panel sequencing. This is the first case report of a novel ODDD-causing mutation in GJA1 confirmed by genetic analysis in Korea.

Prevalence and risk factors for type 2 diabetes mellitus with Prader-Willi syndrome: a single center experience.

BACKGROUND: Prader-Willi syndrome (PWS) is often related to severe obesity and type-2 diabetes mellitus (T2DM). However, few studies, and none in Korea, have examined prevalence of T2DM and other variables in PWS. The aim of this study was to identify the prevalence and associated risk factors for T2DM in Korean patients with PWS. METHODS: We performed a retrospective cohort study of the 84 PWS patients aged 10 or over (10.3-35.8 years of age) diagnosed with PWS at Samsung Medical Center from 1994 to 2016. We estimated occurrence of T2DM according to age (10-18 years versus >18 years), body mass index (BMI), genotype, history of growth hormone therapy, homeostasis model of assessment-insulin resistance (HOMA-IR), and the presence of dyslipidemia, hypogonadism, or central precocious puberty. Additionally, we investigated cutoff values of risk factors for development of T2DM. RESULTS: Twenty-nine of a total 211 patients, diagnosed with PWS over the study period, were diagnosed as having T2DM (13.7%, mean age 15.9 ± 3.6 years). In the >18 years group, obesity, HOMA-IR, and presence of dyslipidemia, hypogonadism, or central precocious puberty were associated with the occurrence of T2DM in univariate analysis. In multivariate logistic regression analysis, only obesity (p = 0.001) and HOMA-IR (p < 0.001) were significant predictive factors for T2DM. Based on the receiver operating a characteristic curve analysis, the cutoff values of HOMA-IR and BMI for predicting T2DM were >2.7 and >28.49 kg/m2, respectively. Of the 29 patients, seven had ≥1 microvascular complication, with non-proliferative diabetic retinopathy in 6 of 7 cases. Advanced age and HOMA-IR were positively correlated with diabetic microvascular complications (p < 0.05, Spearman correlation coefficient 0.393 and 0.434, respectively). CONCLUSIONS: The prevalence of diabetes in Korean PWS was similar to that in previous results. BMI and HOMA-IR were strong predictive factors for the development of T2DM in PWS. We specifically suggest the regular monitoring of glucose homeostasis parameters through a detailed settlement of ethnically specific cutoff values for BMI and HOMA-IR in PWS to prevent progression of T2DM and diabetic microvascular complications.