Illuminating the Genetic Basis of Congenital Heart Disease in Patients with Kabuki Syndrome.

Congenital heart defects (CHDs) affect a substantial proportion of patients with Kabuki syndrome. However, the prevalence and type of CHD and the genotype-phenotype correlations in Asian populations are not fully elucidated. This study performed a retrospective analysis of 23 Taiwanese patients with molecularly confirmed Kabuki syndrome. Twenty-two patients presented with pathogenic variants in the KMT2D gene. Comprehensive clinical assessments were performed. A literature review was conducted to summarize the spectrum of CHDs in patients with Kabuki syndrome. In total, 16 (73.9%) of 22 patients with pathogenic KMT2D variants had CHDs. The most common types of CHD were atrial septal defects (37.5%), ventricular septal defects (18.8%), coarctation of the aorta (18.8%), bicuspid aortic valve (12.5%), persistent left superior vena cava (12.5%), mitral valve prolapse (12.5%), mitral regurgitation (12.5%), and patent ductus arteriosus (12.5%). Other cardiac abnormalities were less common. Further, there were no clear genotype-phenotype correlations found. A literature review revealed similar patterns of CHDs, with a predominance of left-sided obstructive lesions and septal defects. In conclusion, the most common types of CHDs in Taiwanese patients with Kabuki syndrome who presented with KMT2D mutations are left-sided obstructive lesions and septal defects.

Mature neurons from iPSCs unveil neurodegeneration-related pathways in mucopolysaccharidosis type II: GSK-3ß inhibition for therapeutic potential.

Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/ß-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3ß inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.

Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

22q11.2 Deletion Syndrome in Taiwan: Clinical Presentation and Immune System Status of Patients.

Background: 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome exhibiting significant clinical phenotype variability. This study aimed to investigate the clinical features, immune profiles, and cognitive abilities of 22q11.2DS patients receiving treatment at MacKay Memorial Hospital in Taipei, Taiwan. Methods: This is a cross-sectional analysis between January 2001 and December 2022. We recruited 27 patients with 22q11.2DS using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). Our evaluation included patient history, physical examination, laboratory analysis, and cardiac and cognitive assessment. Results: We included 27 patients with 22q11.2DS, 7 (25.9%) of whom were female. The median age of the patients was 17.9 yr. Ninety-three percent of the patients exhibited the characteristic facial features associated with the syndrome. A family history of 22q11.2DS was found in 11.1% of the patients. Furthermore, 74.1% of the patients had a congenital heart defect, the most common of which was tetralogy of Fallot (40.7%). Hypocalcemia was observed in 40.7% of the patients. A low T-cell count was observed in 66.7% of the patients, whereas 18.5% had low immunoglobulin levels. Cognitive assessments revealed that four out of six evaluated patients (66.7%) had an intellectual disability, as evidenced by intellectual quotient scores less than 70. The remaining two patients (33.3%) had a borderline intellectual function. Conclusion: Tetralogy of Fallot, hypocalcemia, immunologic defects, and cognitive impairment were common among our patients. To address the potential multisystem involvement, we recommend that all affected individuals undergo a comprehensive evaluation by a multidisciplinary care team.

Endoscopic and Image Analysis of the Airway in Patients with Mucopolysaccharidosis Type IVA.

Mucopolysaccharidosis (MPS) is a hereditary disorder arising from lysosomal enzymes deficiency, with glycosaminoglycans (GAGs) storage in connective tissues and bones, which may compromise the airway. This retrospective study evaluated patients with MPS type IVA with airway obstruction detected via endoscopy and imaging modalities and the effects of surgical interventions based on symptoms. The data of 15 MPS type IVA patients (10 males, 5 females, mean age 17.8 years) were reviewed in detail. Fiberoptic bronchoscopy (FB) was used to distinguish adenotonsillar hypertrophy, prolapsed soft palate, secondary laryngomalacia, vocal cord granulation, cricoid thickness, tracheal stenosis, shape of tracheal lumen, nodular deposition, tracheal kinking, tracheomalacia with rigid tracheal wall, and bronchial collapse. Computed tomography (CT) helped to measure the deformed sternal angle, the cross-sectional area of the trachea, and its narrowest/widest ratio (NW ratio), while angiography with 3D reconstruction delineated tracheal torsion, kinking, or framework damage and external vascular compression of the trachea. The NW ratio correlated negatively with age (p < 0.01), showing that airway obstruction progressed gradually. Various types of airway surgery were performed to correct the respiratory dysfunction. MPS type IVA challenges the management of multifactorial airway obstruction. Preoperative airway evaluation with both FB and CT is strongly suggested to assess both intraluminal and extraluminal factors causing airway obstruction.

Maternal and neonatal risk factors of asthma in children: Nationwide population based study.

BACKGROUND: Small population group-based cohorts have found that perinatal factors may contribute to the development of asthma in children. We aimed to investigate maternal and neonatal risk factors for the asthma phenotypes using two databases from the Taiwan's Maternal and Child Health Database (TMCHD) and the National Health Insurance Research Database (NHIRD). METHODS: Perinatal data was obtained from 2004 to 2008 in the TMCHD and linked the NHIRD to obtain relevant medical information regarding maternal and neonatal risk factors of three asthma phenotypes which were identified as transient early asthma, persistent asthma, and late-onset asthma. A multivariate logistic regression analysis was conducted to adjust for covariates. RESULTS: The percentage of non-asthmatic patients was 77.02% and asthmatic (transient early asthma, late onset asthma, and persistent asthma) patients were 8.96%, 11.64%, and 2.42%, respectively. Maternal risk factors-including Cesarean section, maternal asthma, maternal allergic rhinitis (AR), and premature rupture of membranes-and neonatal risk factors, such as male gender, gestational age 29-37 weeks, ventilator use, antibiotics use, AR, and atopic dermatitis, were associated with the development of these three asthma phenotypes. Twins and a gestational age of 28 weeks or less premature were associated with the development of transient early asthma and persistent asthma, but not late onset asthma. Triplets and above were associated with the development of transient early asthma, but not late onset or persistent asthma. CONCLUSION: Various asthma phenotypes have different risk factors; therefore, their distinct risk factors should be identified in order to early diagnosis and treatment.

Discovery of small-molecule protein stabilizers toward exogenous alpha-l-iduronidase to reduce the accumulated heparan sulfate in mucopolysaccharidosis type I cells.

Synthesis of a series of l-iduronic acid (IdoA)- and imino-IdoA-typed C-glycosides for modulating α-l-iduronidase (IDUA) activity is described. In an enzyme inhibition study, IdoA-typed C-glycosides were more potent than imino-IdoA analogs, with the most potent IdoA-typed C-glycoside 27c showing an IC50 value of 1 µM. On the other hand, co-treatment of 12 with rh-α-IDUA in mucopolysaccharidosis type I (MPS I) fibroblasts exhibited a nearly 3-fold increase of the IDUA activity, resulting in a clear reduction of the accumulated heparan sulfate (HS) compared to the exogenous enzyme treatment alone. This is the first report of small molecules facilitating IDUA stabilization, enhancing enzyme activity, and reducing accumulated HS in MPS I cell-based assays, which reveals that small molecules as rh-α-IDUA stabilizers to improve enzyme replacement therapy (ERT) efficacy toward MPS I is feasible and promising.

Adjuvant probiotic Bifidobacterium animalis subsp. lactis CP-9 improve phototherapeutic treatment outcomes in neonatal jaundice among full-term newborns: A randomized double-blind clinical study.

BACKGROUND: Probiotics had been used to decreased bilirubin level in neonatal jaundice (NJ) without being further studied mechanism and stratification. The intestinal pathogen Escherichia coli produced ß-glucuronidase would increase enterohepatic circulation and elevate serum bilirubin levels (SBLs) which might worsen the disease process of NJ. STUDY OBJECTIVE: We hypothesized that some probiotics could decrease bilirubin level through inhibiting the growth of E. coli. It's assumed that adjuvant probiotic intervention might accelerate the phototherapy for NJ and alleviate the severity of the NJ. Besides, it's further study the efficacy of the probiotic intervention in NJ among the full-term and preterm newborns. MATERIALS AND METHODS: Firstly, the Bifidobacterium animalis subsp. lactis CP-9 was screened for its anti-E. coli activity. Then, it was orally administered to newborns with NJ in combination with conventional phototherapy (wavelength 425-457 nm) to determine its efficacy. 83 neonatal patients whose serum bilirubinemia was at a concentration of ≥ 15 mg/dL were participated the double-blind randomized trial and conducted in the neonatal ward of China Medical University Children's Hospital (CMUCH, Taichung, Taiwan). The test was conducted in 2 groups: experimental group: phototherapy + B. animalis subsp. lactis CP-9 (n = 43; 5 × 109 CFU/capsule) and control group: phototherapy + placebo (n = 40). The SBL and total phototherapy duration were measured. RESULTS: The experimental group showed improved serum bilirubin decline rate (-0.16 ±â€…0.02 mg/dL/h; P = .009, 95% CI -0.12 to -0.2), particularly in the first 24 hour of in-hospital care, and reduced total phototherapy duration (44.82 ±â€…3.23 h; P = .011, 95% CI: 51.3-38.2) compared with the control group. Especially, probiotics had a significant therapeutic effect (serum bilirubin decline rate: -0.18 ±â€…0.02 mg/dL/h, 95% CI -0.12 to -0.23, P = .014; phototherapy duration: 43.17 ±â€…22.72 h, 95% CI 51.9-34.3, P = .019) in the low-risk subgroup (full-term newborns). CONCLUSIONS: In conclusion, B. animalis subsp. lactis CP-9 synergistically improves treatment outcomes of NJ during in-hospital phototherapy including reduced total phototherapy duration and improved serum bilirubin decline rate, particularly in full-term newborns.

De Novo Mosaic 6p23-p25.3 Tetrasomy Caused by a Small Supernumerary Marker Chromosome Presenting Trisomy Distal 6p Phenotype: A Case Report and Literature Review.

Small supernumerary marker chromosomes (sSMCs) derived from the chromosome 6 short arm are rare and their clinical significance remains unknown. No case with sSMC(6) without centromeric DNA has been reported. Partial trisomy and tetrasomy of distal 6p is a rare but clinically distinct syndrome. We report on a de novo mosaic sSMC causing partial tetrasomy for 6p23-p25.3 in a male infant with symptoms of being small for gestational age, microcephaly, facial dysmorphism, congenital eye defects, and multi-system malformation. Conventional cytogenetic analysis revealed a karyotype of 47,XY,+mar [25]/46,XY [22]. Array comparative genomic hybridization (aCGH) revealed mosaic tetrasomy of distal 6p. This is the first case of mosaic tetrasomy 6p23-p25.3 caused by an inverted duplicated neocentric sSMC with characteristic features of trisomy distal 6p. Comparison of phenotypes in cases with trisomy and tetrasomy of 6p23-p25.3 could facilitate a genotype-phenotype correlation and identification of candidate genes contributing to their presentation. The presentation of anterior segment dysgenesis and anomaly of the renal system suggest triplosensitivity of the FOXC1 gene. In patients with microcephaly growth retardation, and malformation of the cardiac and renal systems, presentation of anterior segment dysgenesis might be indicative of chromosome 6p duplication, and aCGH evaluation should be performed for associated syndromic disease.

Updated Confirmatory Diagnosis for Mucopolysaccharidoses in Taiwanese Infants and the Application of Gene Variants.

Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by genetic defects that result in deficiency of one specific enzyme activity, consequently impairing the stepwise degradation of glycosaminoglycans (GAGs). Except for MPS II, the other types of MPS have autosomal recessive inheritance in which two copies of an abnormal allele must be present in order for the disease to develop. In this study, we present the status of variant alleles and biochemistry results found in infants suspected of having MPS I, II, IVA, and VI. A total of 324 suspected infants, including 12 for MPS I, 223 for MPS II, 72 for MPS IVA, and 17 for MPS VI, who were referred for MPS confirmation from newborn screening centers in Taiwan, were enrolled. In all of these infants, one specific enzyme activity in dried blood spot filter paper was lower than the cut-off value in the first blood sample, as well asin a second follow-up sample. The confirmatory methods used in this study included Sanger sequencing, next-generation sequencing, leukocyte enzyme fluorometric assay, and GAG-derived disaccharides in urine using tandem mass spectrometry assays. The results showed that five, nine, and six infants had MPS I, II, and IVA, respectively, and all of them were asymptomatic. Thus, a laboratory diagnosis is extremely important to confirm the diagnosis of MPS. The other infants with identified nucleotide variations and reductions in leukocyte enzyme activities were categorized as being highly suspected cases requiring long-term and intensive follow-up examinations. In summary, the final confirmation of MPS depends on the most powerful biomarkers found in urine, i.e., the quantification of GAG-derived disaccharides including dermatan sulfate, heparan sulfate, and keratan sulfate, and analysis of genetic variants can help predict outcomes and guide treatment.

Efficacy of Intravenous Elosulfase Alfa for Mucopolysaccharidosis Type IVA: A Systematic Review and Meta-Analysis.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were -0.260, -0.102, -0.182, -0.360, -0.408, -0.587, -0.293, -0.311, and -0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.

The Anesthetic Strategy for Patients with Mucopolysaccharidoses: A Retrospective Cohort Study.

Anesthesia for patients with mucopolysaccharidoses (MPS) is quite challenging due to vital systemic dysfunction following progressive accumulation of lysosomal glycosaminoglycans. Previous studies focused on perioperative difficult airway management under general anesthesia but rarely depicted the concern of choosing the size of the endotracheal tube (ETT) as well as neuraxial anesthesia. This study aimed to analyze the overall anesthetic management and related complications for a thorough anesthetic strategy. Within the study period from 2002 to 2021, each record of the anesthetic and perioperative quality assurance/improvement system for patients with a diagnosis of MPS at MacKay Memorial Hospital was retrospectively reviewed. A total of 51 individuals with 151 anesthesia for 163 interventions were cohort studied, and there were 136 general anesthesia and 15 neuraxial anesthesia. We found that the most common interventions for MPS patients were otolaryngological surgeries (49.6%). Additionally, a secured airway played a marked preference for the most general anesthesia (87.1%). The incidence of difficult intubation was 12.5%. In view of ETT size, a smaller than estimated size was used in MPS type II, III, IV, and VI patients and also in patients who received intubation with multiple attempts. However, a larger than estimated size of ETT was adopted whilst choosing cuffed ones. For neuraxial anesthesia, two failed spinal anesthesia procedures were converted to general anesthesia and 73 percent of the patients received perioperative sedation. In conclusion, through the individualized anesthetic strategy and build-up of an experienced team for airway management, high-quality anesthesia can be ensured in each patient.

Quantification of Idua Enzymatic Activity Combined with Observation of Phenotypic Change in Zebrafish Embryos Provide a Preliminary Assessment of Mutated idua Correlated with Mucopolysaccharidosis Type I.

Mucopolysaccharidosis type I (MPS I) is an inherited autosomal recessive disease resulting from mutation of the α-l-Iduronidase (IDUA) gene. New unknown mutated nucleotides of idua have increasingly been discovered in newborn screening, and remain to be elucidated. In this study, we found that the z-Idua enzymatic activity of zebrafish idua-knockdown embryos was reduced, resulting in the accumulation of undegradable metabolite of heparin sulfate, as well as increased mortality and defective phenotypes similar to some symptoms of human MPS I. After microinjecting mutated z-idua-L346R, -T364M, -E398-deleted, and -E540-frameshifted mRNAs, corresponding to mutated human IDUA associated with MPS I, into zebrafish embryos, no increase in z-Idua enzymatic activity, except of z-idua-E540-frameshift-injected embryos, was noted compared with endogenous z-Idua of untreated embryos. Defective phenotypes were observed in the z-idua-L346R-injected embryos, suggesting that failed enzymatic activity of mutated z-Idua-L346R might have a dominant negative effect on endogenous z-Idua function. However, defective phenotypes were not observed in the z-idua-E540-frameshifted-mRNA-injected embryos, which provided partial enzymatic activity. Based on these results, we suggest that the z-Idua enzyme activity assay combined with phenotypic observation of mutated-idua-injected zebrafish embryos could serve as an alternative platform for a preliminary assessment of mutated idua not yet characterized for their role in MPS I.

Functional Independence of Taiwanese Children with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a group of rare genetic disorders that affect bone formation. Patients with OI present mainly with increased bone fragility and bone deformities. Twenty-seven Taiwanese children between 2 and 21 years of age with OI and their parents were recruited at MacKay Memorial Hospital from January 2013 to December 2019. We used the Functional Independence Measure for Children (WeeFIM) questionnaire to assess the functional independence of the children and describe any functional limitations or additional burden of daily care. Out of a potential score of 126, the mean total WeeFIM score was 113.7. There was a statistically significant difference between the scores of type I, type III and type IV OI (121.88 [SD 7.01] vs. 80.8 [SD 26.25] vs. 119.17 [SD 10.89]; p < 0.001). There were no statistically significant differences between the scores in different age groups, the male and female participants, and patients with pathogenic variants in COL1A1 and COL1A2. The mean scores for the self-care, mobility, and cognition domains were 48.78 (maximum 56, mean quotient 91.14%), 30.44 (maximum 35, mean quotient 87.12%), and 34.44 (maximum 35, mean quotient 99.05%), respectively. The best performance was in the cognition domain (mean quotient 99.05%), and the worst was in the mobility domain (mean quotient 87.12%). There were no statistically significant correlations between WeeFIM scores and age, or age when symptoms began. The total WeeFIM score and 13 subscores for the self-care and mobility domains were all positively correlated with body height (p < 0.01). The correlation was lowest for bowel and walking/wheelchair tasks, and the highest for bathing and dressing-upper tasks. For tasks in bathing, over 40% of the patients needed help. For tasks in the cognition domain, most patients required no help. For the Taiwanese children with OI, some support and supervision were required for self-care and mobility tasks, and the functional independence in these two domains was correlated with body height and disease types. The WeeFIM questionnaire may be a useful tool to assess the functional strengths and weaknesses of children with OI.

Newborn Screening Program for Mucopolysaccharidosis Type II and Long-Term Follow-Up of the Screen-Positive Subjects in Taiwan.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is an X-linked disorder resulting from a deficiency in lysosomal enzyme iduronate-2-sulfatase (IDS), which causes the accumulation of glycosaminoglycans (GAGs) in the lysosomes of many tissues and organs, leading to progressive cellular dysfunction. An MPS II newborn screening program has been available in Taiwan since 2015. The aim of the current study was to collect and analyze the long-term follow-up data of the screen-positive subjects in this program. METHODS: From August 2015 to April 2022, 548,624 newborns were screened for MPS II by dried blood spots using tandem mass spectrometry, of which 202 suspected infants were referred to our hospital for confirmation. The diagnosis of MPS II was confirmed by IDS enzyme activity assay in leukocytes, quantitative determination of urinary GAGs by mass spectrometry, and identification of the IDS gene variant. RESULTS: Among the 202 referred infants, 10 (5%) with seven IDS gene variants were diagnosed with confirmed MPS II (Group 1), 151 (75%) with nine IDS gene variants were classified as having suspected MPS II or pseudodeficiency (Group 2), and 41 (20%) with five IDS gene variants were classified as not having MPS II (Group 3). Long-term follow-up every 6 months was arranged for the infants in Group 1 and Group 2. Intravenous enzyme replacement therapy (ERT) was started in four patients at 1, 0.5, 0.4, and 0.5 years of age, respectively. Three patients also received hematopoietic stem cell transplantation (HSCT) at 1.5, 0.9, and 0.6 years of age, respectively. After ERT and/or HSCT, IDS enzyme activity and the quantity of urinary GAGs significantly improved in all of these patients compared with the baseline data. CONCLUSIONS: Because of the progressive nature of MPS II, early diagnosis via a newborn screening program and timely initiation of ERT and/or HSCT before the occurrence of irreversible organ damage may lead to better clinical outcomes. The findings of the current study could serve as baseline data for the analysis of the long-term effects of ERT and HSCT in these patients.

Surgical Strategy to Decrease the Revision Rate of Fassier-Duval Nailing in the Lower Limbs of Osteogenesis Imperfecta.

(1) Background: The Fassier−Duval (FD) nail was developed for the treatment of osteogenesis imperfecta (OI). The aim of this study was to review the results of OI patients treated with the FD nail at our institution and discuss a surgical strategy to decrease the FD nail revision rate; (2) Methods: We retrospectively reviewed OI patients treated at our institution between 2015 and 2020. OI patients treated with FD nail insertion in the long bones of the lower extremities were included, and those with a follow-up duration <1 year or incomplete radiographs were excluded. Data on the type of OI, age, sex, use of bisphosphonate treatment, and nail failure were recorded; (3) Results: The final cohort consisted of seven patients (three females and four males) with ten femurs and ten tibiae involved. Six of the patients had type III OI, and one had type IV OI. An exchange of implant was required in 11 limbs. The average interval between previous FD nail insertion and revision surgery was 2.4 years; (4) Discussion: The main reasons for revision surgery were migration of the male/female component, refracture/nail bending, and delayed union. In the femur, migration of the female component or nail bending were common reasons for failure, while migration of the male component and delayed union were common in the tibia; (5) Conclusions: Surgery for OI patients is challenging, and physicians should aim to minimize complications and the need for revision. Sufficient depth of purchase, center−center nail position, and adequate osteotomy to correct bowing are the key factors when using the FD nail.

Rapid Weight Loss and Severe Failure to Thrive Mimicking Lipodystrophy Syndrome in a 1-Year-Old Taiwanese Girl with Costello Syndrome.

Costello syndrome (CS) is a type of RASopathy caused mainly by de-novo heterozygous pathogenic variants in the HRAS gene located on chromosome 11p15.5. The phenotype of CS is characterized by prenatal overgrowth, postnatal failure to thrive, curly or sparse fine hair, coarse facial features, and multisystem involvement, including cardiovascular, endocrine, and gastroenterological disorders. We present a one-year-old girl with rapid weight loss and severe failure to thrive. She had gastroesophageal reflux at the age of four months with subsequent rapid weight loss. The loss of fat tissue over the whole body, refractory to a hypercaloric diet, mimicked the presentation of progressive lipodystrophy and masked the dysmorphic features of CS. The final diagnosis of CS was made by whole exome sequencing, which demonstrated a hot-spot, heterozygouspathogenic variant in the HRAS gene (c.34G > A, rs104894229). Our patient illustrates that the excessive energy needs in CS patients may lead to severe failure to thrive and cause challenges in diagnosing CS. This case also highlights the importance of recognizing CS in patients with a history of prenatal overgrowth, polyhydramnios presenting with severe failure to thrive refractory to pharmacotherapy and tube feeding.

Long-Term Cardiovascular Findings in Williams Syndrome: A Single Medical Center Experience in Taiwan.

Williams syndrome (WS) is a rare genetic disorder caused by the microdeletion of chromosome 7q11.23. Cardiovascular defects (CVDs) are the leading causes of morbidity and mortality in patients with WS. The most common CVD in patients with WS is supravalvular aortic stenosis (SVAS), which recovers spontaneously similar to branch pulmonary stenosis (PS). Recently, conventional beliefs, such as SVAS improving rather than worsening in WS, have been challenged. This study thoroughly reviews the medical records of 30 patients with a molecular diagnosis of WS. We followed up these patients at Taipei MacKay Memorial Hospital from January 1999 to December 2021. The long-term outcomes of cardiovascular lesions as well as the change in peak pressure gradient in obstructive cardiovascular lesions over time were studied. Among these 30 patients, the most common cardiovascular lesion was SVAS (50.0%), followed by branch PS (36.7%). During the follow-up period, severe SVAS was aggravated (p = 0.021). The peak pressure gradient decreased from 38.4 to 25.3 mmHg (p = 0.001) in patients with branch PS. Among patients with WS, those with severe SVAS deteriorated over time, whereas those with branch PS improved on their own. In patients with WS who presented with branch PS, no disease-specific intervention was needed.

Epidemiological evolution of early-onset neonatal sepsis over 12 years: A single center, population-based study in central Taiwan.

BACKGROUND: We aimed to explore the epidemiology and evolution of pathogens, antibiotic susceptibility, and mortality rate in cases of neonatal early-onset sepsis (EOS) reported over a period of 12 years in a level III neonatal center in Central Taiwan. METHODS: Patients' medical records in a neonatal center from 2007 to 2018 were reviewed to obtain information on infants with culture-proven EOS, which included pathogens found in the blood or cerebrospinal fluid cultures. RESULTS: The incidence of neonatal EOS during this period was 2.11 cases/1,000 admissions. Group B streptococcal (GBS) and Escherichia coli were the most common pathogens. The overall rates of GBS and E. coli infections were 0.68/1,000 and 0.77/1,000 live births, respectively. The incidence of EOS in infants with a birth weight ≥1,500 g decreased significantly with decreasing incidence of GBS-related sepsis. The incidence of EOS remained high in very-low-birth-weight (VLBW) infants and increased over time. There was an increasing trend in of E. coli infection and emergence of drug-resistant strains. In addition, E. coli sepsis had high mortality in VLBW infants. CONCLUSION: Novel screening and prevention strategies against E. coli and reserving broad-spectrum antibiotics for the most critically ill or VLBW patients with maternal chorioamnionitis might help in early diagnosis and further improve the outcomes of EOS.

Clinical Utility of Elosulfase Alfa in the Treatment of Morquio A Syndrome.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive disorder and is one of the lysosomal storage diseases. Patients with MPS IVA have a striking skeletal phenotype but normal intellect. The phenotypic continuum of MPS IVA ranges from severe and rapid progress to mild and slow progress. The diagnosis of MPS IVA is usually suspected based on abnormal bone findings and dysplasia on physical examination and radiographic investigation in the preschool years. In the past, only supportive care was available. Due to the early and severe skeletal abnormalities, the orthopedic specialist was usually the main care provider. However, patients need aggressive monitoring and management of their systemic disease. Therefore, they need an interdisciplinary team for their care, comprising medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. After the US Food and Drug Administration approved elosulfase alfa in 2014, patients older than 5 years could benefit from this treatment. Clinical trials showed clinically meaningful improvements with once-a-week intravenous dosing (2.0 mg/kg per week), significantly improving the 6min walk test, the 3min stair climb test, and respiratory function when compared with placebo. Elosulfase alfa is well-tolerated, and there is a good response indicated by decreasing urine glycosaminoglycans.