Associations of central precocious puberty with blood pressure trajectories: prospective cohort study.

BACKGROUND: Sex differences in blood pressure (BP) appear during childhood and adolescence, but the role of central precocious puberty (CPP) remains unclear. In this study, we aimed to examine the association of CPP with the risk of early hypertension and BP trajectories in girls and boys. METHODS: We analyzed trajectories of BP before and after puberty in girls aged 6-13 years (n = 305) and boys aged 10-15 years (n = 153) in the Taiwan Pubertal Longitudinal Study. The timing of puberty onset was defined as the month at which the children reached Tanner stage 2. We examined the association of CPP with the risk of early hypertension and BP trajectories before and after puberty onset. RESULTS: Among boys, CPP was found to be associated with early hypertension (odds ratio, 7.45 [95% CI, 1.15-48.06]), whereas no such association was observed among girls. Boys with CPP had higher systolic BP than did those with normal puberty onset before puberty onset (mean difference, 6.51 [95% CI, 0.58-12.43]) and after puberty onset (mean difference, 8.92 [95% CI, 8.58-15.26]). CONCLUSION: A large proportion of the higher systolic BP observed in boys with CPP compared with in those with normal puberty onset is accrued after puberty. IMPACT: We examined the sex-specific association of central precocious puberty with blood pressure trajectories to better understand whether central precocious puberty was associated with early hypertension. Central precocious puberty was associated with differences in systolic blood pressure trajectories, especially after puberty onset in boys. For boys only, central precocious puberty was associated with early hypertension. A large proportion of the higher systolic blood pressure observed in boys with central precocious puberty compared with in those with normal puberty onset was accrued after puberty. Interventions targeting central precocious puberty are likely to influence systolic blood pressure in early adulthood.

Effects of high di(2-ethylhexyl) phthalate (DEHP) exposure due to tainted food intake on pre-pubertal growth characteristics in a Taiwanese population.

On May 23, 2011, a major scandal involving the illegal use of phthalates as clouding agents in food products was reported. Specifically, di(2-ethylhexyl) phthalate (DEHP) was purposefully added to foods as a substitute emulsifier. The purpose of this study was to examine the effects of DEHP exposure on the growth characteristics of the child victims of this scandal. Eighty-eight victims, originating from northern, central, and southern Taiwan and ranging in age from 6.0 to 10.5 years, were invited to participate in this study during clinic visits. The participants underwent follow-up health examinations from August 2012 to February 2013. We collected information on each participant's history of exposure to tainted food products using a questionnaire, and we analyzed their urinary concentrations of DEHP metabolites using high-performance liquid chromatography/tandem mass spectrometry. These data were then used to estimate their daily DEHP intake (DIAll) during the scandal. We also measured physical development parameters (height, weight, and bone age) and hormone levels (thyroid, sex and growth hormones) to evaluate their overall growth characteristics. The average (SD) duration of DEHP intake from tainted nutrition supplements was 1.39 (1.01) years. The median DIAll values were 19.93 and 20.69µg/kg bw/day for boys and girls, respectively. Among the enrolled children, the DIAll values of 46.9% of boys and 51.3% of girls exceeded the reference dose (RfD) of 20µg/kg bw/day established by the US Environmental Protection Agency. Our results demonstrate that DIAll is negatively associated with the height percentile, weight percentile, bone age/chronological age, and insulin-like growth factor 1 (IGF-1) levels but not with IGF binding protein 3 (IGF-BP3) level, IGF-1/IGF-BP3, sex hormones, or thyroid hormone levels. The DEHP DIAll value exceeded the RfD at high rates among children of both genders. Our results suggest that high levels of DEHP exposure due to the consumption of tainted food products are negatively associated with body weight, height, bone age, and IGF-1 levels in children. The likelihood of delayed puberty among the affected children is therefore a reasonable concern, and further follow-up is required.

The difference in immune response and IL-12p35 methylation between newborns and adults.

BACKGROUND: The immune system of newborn is generally depressed by impaired production of Th1-cell associated cytokines, which results in increased susceptibility to intracellular pathogens and poor response to vaccinations. For avoiding abortion, the maternal and fetal immune systems tend to Th2-cell polarizing cytokines. Besides, IL-12p35 is a determining factor of the bioactivity of IL-12, which has an important role in the Th1 response. Recently methylated DNA is known to associate to inhibit transcription. Therefore, we explored the methylation status of CpG sites upstream of the coding sequence of the IL-12p35 gene to determine whether neonatal peripheral blood mononuclear cell (PBMC) synthesis lower level of IL-12 is related to methylated DNA. RESULTS: PBMCs from adults expressed higher levels of IL-12p40 (p = 0.303) and IL-12p70 (p = 0.045) and had a strong ability to produce IL-12p35 mRNA (p = 0.01). However, there was no difference in the methylation status of CpG sites in the promoter of IL-12p35 between adults and newborns. CONCLUSIONS: We found that PBMC synthesis of bioactive IL-12p70 was significantly impaired in the neonatal period, potentially though a reduction in IL-12p35 production. The reeducation in IL-12p35 production might not be due to methylation of the promoter gene. But, the impairment of IL-12p35 expression during the neonatal period might be caused by other epigenetic regulation occurs in the chromatin level.

Development and Validation of Clinical Diagnostic Model for Girls with Central Precocious Puberty: Machine-learning Approaches.

BACKGROUND: A brief gonadotropin-releasing hormone analogues (GnRHa) stimulation test which solely focused on LH 30-minute post-stimulation was considered to identify girls with central precocious puberty (CPP). However, it was tested using traditional statistical methods. With advanced computer science, we aimed to develop a machine learning-based diagnostic model that processed baseline CPP-related variables and a brief GnRHa stimulation test for CPP diagnosis. METHODS: We recruited girls suspected of precocious puberty and underwent a GnRHa stimulation test at Children Hospital 2, Vietnam, and Cathay General Hospital, Taiwan. Clinical data, bone age measurement, and 30-min post-stimulation blood test were used to build up the predictive model. The candidate model was developed by different machine learning algorithms that were mainly evaluated by sensitivity, specificity, the area under the receiver operator characteristic curve (AUC), and F1-score in internal and external validation data to classify girls as CPP and non-CPP at different time-points (0-min, 30-min, 60-min, and 120-min post-stimulation). RESULTS: Among the 614 girls diagnosed with PP, 524 (85.3%) had CPP. The random forest algorithm yielded the highest value of F1-score (0.976), specificity (0.893), positive predicted value (0.987), and relatively high value of AUC (0.972) that contributed to high probability to identify CPP. The performance metrics of the 30-min post-stimulation diagnostic model including sensitivity and specificity surpassed those of the 0-minute model (0-min) and were equivalent to those of the model obtained 60-min and 120-min post-stimulation. Hence, our machine learning-based model helps shorten the stimulation test to 30 minutes after GnRHa injection, in general, it requires 120 minutes for a completed GnRHa stimulation test. CONCLUSIONS: We developed a diagnostic model based on clinical features and a single sample 30-minute post-stimulation to identify CPP in girls that can reduce distress for children caused by multiple blood samplings.

Exposome of attention deficit hyperactivity disorder in Taiwanese children: exploring risks of endocrine-disrupting chemicals.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is diagnosed in ~7% of school-aged children. The role of endocrine-disrupting chemicals (EDC) and oxidative stress in ADHD etiology are not clear. OBJECTIVE: Assessment of the associations between simultaneous exposure to multiple compounds and ADHD in children. METHODS: The case-control study included 76 clinically diagnosed ADHD cases and 98 controls, aged 4-15 years old. Concentrations quartiles of urinary metabolites of acrylamide, acrolein, nonylphenol, phthalates, and organophosphate pesticides and biomarkers of oxidative stress were used to fit logistic regressions for each compound and weighted quantiles sum (WQS) regression for the mixture. RESULTS: Positive dose-response relationships with ADHD were observed for 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) (odds ratio(OR)Q4 = 3.73, 95%CI [1.32, 11.04], ptrend = 0.003), dimethyl phosphate (DMP) (ORQ4 = 4.04, 95%CI [1.34, 12.94], ptrend = 0.014) and diethyl phosphate (ORQ4 = 2.61, 95%CI = [0.93, 7.66], ptrend = 0.030), and for the mixture of compounds (ORWQS = 3.82, 95%CI = [1.78, 8.19]) with the main contributions from HNE-MA (28.9%) and DMP (18.4%). CONCLUSIONS: The dose-response relationship suggests enhanced susceptibility to EDC burden in children even at lower levels, whereas the main risk is likely from organophosphate pesticides. HNE-MA is recommended as a sensitive biomarker of lipid peroxidation in the further elucidation of the oxidative stress role in ADHD etiology.

The sex-specific association of prenatal phthalate exposure with low birth weight and small for gestational age: A nationwide survey by the Taiwan Maternal and Infant Cohort Study (TMICS).

The Taiwan Maternal and Infant Cohort Study (TMICS) was launched with the aim to assess the effects of prenatal exposure to phthalic acid esters (PAEs) on infant health. A total of 1102 pregnant women were enrolled in this study from 2012 to 2015. All participants completed a structured questionnaire, and provided urine specimens. The urinary concentrations of PAE metabolites in the third trimester were measured using liquid chromatography-electrospray ionization tandem mass spectrometry. Generalized additive model-penalized regression splines and logistic regression models were employed to determine the risk for low birth weight (LBW) or small for gestational age (SGA) among pregnant women exposed to PAEs. After adjustments for other covariates, each incremental unit of ln-transformed mono-n-butyl phthalate (MnBP) for pregnant women increased the odds of SGA in male neonates by 1.44 (95% CI: 0.92-2.23). An inverse association between SGA and maternal MnBP exposure level was observed in female neonates. An increase in one ln-transformed MnBP concentration unit decreased the risk of female SGA to 0.50 (95% CI: 0.24-0.97). In the penalized regression splines, increased risks of LBW/SGA in male neonates were presented while pregnant women exposed to increased MnBP levels. However, an association in the opposite direction was observed between maternal MnBP and LBW or SGA for male and female neonates. This study indicated that high maternal MnBP exposure in the third trimester was associated with LBW or SGA for male infants. Adverse effects on susceptible populations exposed to high levels of PAEs should be of concern.

Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.

The associations among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of paraoxonases in children with attention deficit/hyperactivity disorder.

This study will help to clarify the relationship between organophosphate pesticides (OPs) and attention deficit/hyperactivity disorder (ADHD) related to oxidative stress and paraoxonases (PON) polymorphisms to further characterize the gene-environment interaction. This case-control study enrolled 85 children with ADHD and 96 control subjects. Urinary OP levels were analyzed by using gas chromatography-mass spectrometry (GC-MS). Oxidative stress biomarkers, such as 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2-Gua), 8-iso-prostaglandin F2α (8-iso-PGF2α), and 4-hydroxy-2-nonenoic acid-mercapturic acid (HNE-MA), were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) were calculated to evaluate the additive interactions between OP exposure and PON genetic polymorphism on ADHD. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to OP exposure on ADHD. Children with ADHD had significantly higher DMP (238.95 nmol/g cre. vs. 164.83 nmol/g cre., p value = 0.01) and HNE-MA (30.75 µg/g cre. vs. 18.41 µg/g cre., p value<0.01) concentrations than control children. Children who carried the PON1 GG genotype (rs705379) had low urinary DMP levels, and the level increased with increasing numbers of allele variants. The risk for developing ADHD reached 2.06-fold (OR = 2.06, 95% CI:1.23-3.44) and 1.43-fold (OR = 1.45, 95% CI:1.04-2.03) when the DMP and HNE-MA levels increased by 1 natural log of the concentration, respectively. The estimated AP value was 0.66 (95% CI: 0.17-1.15), indicating that 66% of ADHD cases in DMP-exposed children with the PON1 CT/TT (rs705381) genotype were due to gene-environment interactions. No significant mediation of HNE-MA was observed between DMP exposure and the risk of ADHD. The estimated proportion mediated was only 7.0% (95% CI: -0.08-0.46). This research suggests the role of OP exposure in the occurrence of ADHD after adjusting for covariates.

Recurrent chemical reactivations of EBV promotes genome instability and enhances tumor progression of nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is an endemic malignancy prevalent in South East Asia. Epidemiological studies have associated this disease closely with Epstein-Barr virus (EBV) infection. Previous studies also showed that EBV reactivation is implicated in the progression of NPC. Thus, we proposed that recurrent reactivations of EBV may be important for its pathogenic role. In this study, NPC cell lines latently infected with EBV, NA and HA, and the corresponding EBV-negative NPC cell lines, NPC-TW01 (TW01) and HONE-1, were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium n-butyrate (SB) for lytic cycle induction. A single treatment with TPA/SB revealed that DNA double-strand breaks and formation of micronuclei (a marker for genome instability) were associated with EBV reactivation in NA and HA cells. Examination of EBV early genes had identified several lytic proteins, particularly EBV DNase, as potent activators that induced DNA double-strand breaks and contribute to genome instability. Recurrent reactivations of EBV in NA and HA cells resulted in a marked increase of genome instability. In addition, the degree of chromosomal aberrations, as shown by chromosome structural variants and DNA copy-number alterations, is proportional to the frequency of TPA/SB-induced EBV reactivation. Whereas these DNA abnormalities were limited in EBV-negative TW01 cells with mock or TPA/SB treatment, and were few in mock-treated NA cells. The invasiveness and tumorigenesis assays also revealed a profound increase in both characteristics of the repeatedly reactivated NA cells. These results suggest that recurrent EBV reactivations may result in accumulation of genome instability and promote the tumor progression of NPC.

Amelioration of hypophosphatemic rickets and osteoporosis with pamidronate and growth hormone in Lowe syndrome.

The oculocerebrorenal syndrome of Lowe, an X-linked multisystem disorder, was diagnosed in a male patient who presented with typical abnormalities of the eyes, kidneys and nervous system. Besides congenital cataracts, renal tubular dysfunction and psychomotor retardation, the patient had also suffered from profound failure to thrive, growth hormone deficiency, severe osteoporosis with hypophosphatemic rickets, and progressive renal dysfunction since early childhood, which were attributed to the metabolic derangements following Fanconi syndrome. Direct sequencing of the OCRL1 gene (responsible for the oculocerebrorenal syndrome of Lowe) revealed a de novo c.2282_2283insT in exon 20, which resulted in premature termination of translation (D762X). After monthly intravenous administration of pamidronate since the age of 17.8 years, his urine creatinine clearance and tubular resorption of phosphate increased slightly and bone mineral density was much improved (Z score increased from -7.3 to -3.3) without deterioration of renal function. Simultaneous growth hormone therapy enhanced the positive response. The beneficial osseous and renal effects of the bisphosphonate, along with growth hormone treatment in Lowe syndrome with hypophosphatemia, may be related to reduced renal calcium and phosphate excretion.

Restrictive dermopathy: report of one case and the metabolic and post-mortem findings.

Restrictive dermopathy is a rare and lethal autosomal recessive genodermatosis characterized by tight skin, typical dysmorphic face, generalized arthrogryposis and pulmonary hypoplasia. Infants with restrictive dermopathy have similar findings in skin biopsy, but other abnormalities are unremarkable. We report a male preterm infant with restrictive dermopathy. The post-mortem examination revealed hypoplasia of the thymus, and the metabolic study of the urine and blood disclosed generalized organic aciduria and low free carnitine level. These data imply that restrictive dermopathy is associated with certain degrees of metabolic disturbance. With increasing reports of restrictive dermopathy, the affected infants can be diagnosed earlier and accurately.

Evidence of high di(2-ethylhexyl) phthalate (DEHP) exposure due to tainted food intake in Taiwanese pregnant women and the health effects on birth outcomes.

The contamination of a clouding agent with di(2-ethylhexyl) phthalate (DEHP), a substitute emulsifier-containing compound used in a variety of foods was announced on May 23, 2011. The aims of this study were as follows (1) compare the urine phthalates (PAE) metabolites concentration and estimate the daily intake (DI) of PAEs in pregnant women before and after the tainted food scandal and (2) examine the effect of relatively high PAEs exposure on birth outcome. One-hundred twelve pregnant women in Northern Taiwan participated in this study from March to December 2010, i.e., before the tainted food scandal. After the tainted food scandal, we collected 69, 73, and 180 urine specimens (January 2013 to August 2014) from women whom were in their first, second, and third trimesters of pregnancy, respectively. We measure urinary DEHP metabolite concentrations to estimate the DI of DEHP and the hazard quotient (HQ) of subjects. This was the first study to assess the effects of DEHP-tainted food scandal exposure in pregnant women across the three trimesters of pregnancy. After the tainted food report, the concentrations of urine PAE metabolite were significantly decreased, especially those of DEHP metabolites. Based on different reference limit values, the percentages of pregnant women whose HQDEHP value exceeded the limit ranged from 0.53% to 8.93%. Despite this low frequency, the higher ΣPAE exposure during the second trimester may significantly increase the risk of relatively low birth height compared to the lower exposure group (ß=-0.63 (-1.20 to -0.06)). Our results support the hypothesis that exposure to relatively high concentrations of DEHP in pregnant Taiwanese women may have an adverse effect on birth outcomes. The percentage of subjects whose exposure level exceeded the exposure limit was low; however, high PAEs exposure appears to be significantly associated with birth outcomes. Therefore, we suggest that reference dose for PAEs should be revised.

Variable expressivity in Patau syndrome is not all related to trisomy 13 mosaicism.

Patau syndrome (trisomy 13) is very rare in live-born babies. Individuals with this chromosomal syndrome have a short lifespan and are rarely seen beyond infancy. This study is aimed at the clinical spectrum, natural history, and survival of patients with trisomy 13. We reviewed the detailed data of 13 Patau syndrome live-born babies. Among them two individuals were delivered from continuation of pregnancy even after prenatal diagnosis. The remaining 11 patients were born to younger mothers who did not undergo amniocentesis because no major anomalies except for cleft lip/palate were found on prenatal sonograms. The common features of Patau syndrome including the clinical triad (microphthalmia, cleft lip/palate, and polydactyly) and non-cyanotic heart defects were always found in our series. However, certain serious central defects (holoprosencephaly, omphalocele, and single umbilical artery), which are easily recognized from prenatal sonogram, occurred less frequently than those stated in the literature. The median survival time was 95 days and was longer than that previously reported. There were two infants with trisomic mosaicism with different outcomes in both clinical spectrum and survival. Otherwise, we also found the increased recurrence risks of aneuploidy in two individuals, and the longest survivor (84 months) of non-mosaic trisomy 13 in Taiwan. We thus suggest that long-term survival in our series is strongly correlated with different expressivity after prenatal selection, in addition to cytogenetic mosaicism. Less associated anomalies such as polyhydramnios, oligohydramnios, intrauterine growth retardation, single umbilical artery, eye defects, holoprosencephaly, omphalocele, and polycystic kidney may contribute to their clinical courses.

Detection of lower levels of SNAP25 using multiple microarray systems and its functional significance in medulloblastoma.

Medulloblastoma (MB) is the most common pediatric malignant brain tumor and patients with high-risk or recurrent MB respond poorly to current therapies, and have a higher related mortality. For this reason, potential molecules related to MB need be identified in order to develop targets for the development of novel therapeutics. In the present study, we compared MB microarray data obtained using different microarray systems and significant targets were selected by gene annotation and enrichment analysis. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function 'vesicle' were identified and one of these proteins, synaptosomal-associated protein 25 (SNAP25), was found to have significantly lower expression levels in MB. In addition, SNAP25 was detected in a very low number of MB cells as shown by western blot analysis and immunohistochemical analyses of archived and formalin-fixed/paraffin-embedded human MB specimens. We found that SNAP25 altered the morphology and the chemotherapeutic effects of arabinofuranosyl cytidine (Ara-C) on SNAP25-expressing MB cells. On the whole, our data indicate that the expression of SNAP25 is crucial for dendrite formation and is associated with the effects of targeted chemotherapy. The detection of SNAP25 expression in MB cells may thus be essential for the chemotherapeutic application of Ara-C.

Concurrent exposures to nonylphenol, bisphenol A, phthalates, and organophosphate pesticides on birth outcomes: A cohort study in Taipei, Taiwan.

Prenatal exposure to phenols, phthalates (PAEs), and organophosphate (OP) pesticides may increase the risk of abnormal birth outcomes. However, many previous studies have examined exposure to a limited number of chemical classes or exposure profiles limited to a specific stage of pregnancy. This study aims to characterize the concurrent exposure scenario throughout pregnancy by simultaneously monitoring internal doses of several endocrine-disrupting compounds (EDCs), including 2 phenols (nonylphenol (NP) and bisphenol A (BPA)), 9 PAEs, and 6 OP pesticide metabolites and to assess the relationships between concurrent exposure to EDCs and infant birth weight, length, and head and chest circumference. One hundred and sixty two women provided three spot urine samples at approximately 11 and 26weeks gestation and at delivery. We applied multivariable linear regression and ridge regression models to estimate the effects of separate and correlated exposures. Multivariable linear regression models revealed that women with short birth-length infants had significantly higher urinary second-trimester NP levels (50th percentile, 5.03µg/g creatinine) (ß=-0.47cm; 95% CI=-0.93 to -0.01). Similarly significant relationships were observed between second-trimester mono-methyl phthalate (MMP) exposure and short birth length, second-trimester ΣPAEs and short birth length, second-trimester ΣPAEs exposure and reduced head and chest circumference, second-trimester diethylphosphate (DEP) exposure and reduced birth weight and length, and second-trimester ΣDEPs exposure and short birth length. Women with urinary BPA above the 75th percentile or ΣPAEs levels above the 50th percentile in the third trimester had infants with significantly reduced head circumference. These observations suggest that the second trimester may be the critical stage of susceptibility for fetal development. In ridge regression models, for which women with fewer measures for exposure to NP, BPA, MMP, ΣPAEs, DEP and ΣDEPs simultaneously were available, no relationships were found with infant size at birth. Additional studies with larger sample sizes are warranted.

A retrospective epidemiological and etiological study of metabolic disorders in children with cardiomyopathies.

Cardiomyopathies may be idiopathic or secondary to an underlying definable systemic disorder, especially in a young population. A number of inherited metabolic disorders will lead to hypertrophic or dilated cardiomyopathy. Identifying the metabolic etiologies of cardiomyopathy is important for genetic counseling and identification of appropriate therapeutic interventions. Fifty-eight children aged from 1 to 18 years were diagnosed as suffering from cardiomyopathy over six years. Cardiomyopathies (dilated, hypertrophic or restrictive) were confirmed by echocardiography together with extensive clinical and metabolic investigations. The patients could be divided into two groups, etiology known (50.0%) and idiopathic (50.0%). Among the definable underlying diseases, 31.0% were diagnosed as inherited metabolic disorders, including mitochondrial disorders (n=4), primary systemic carnitine deficiency (n=1), Pompe disease (n=3) and mucopolysaccharidosis (MPS) I (n=1). In this study, there was a large component of idiopathic cardiomyopathies (50.0%), and it is likely that a proportion of these "unknowns" have a diagnosable disorder. Therefore, for cardiomyopathies in children, after exclusion of non-genetic causes, genetic studies and metabolic screening, such as tandem mass spectrometry, urine gas chromatography/mass spectrometry, carnitine level and mitochondrial DNA screening, are recommended.

Maple Syrup Urine Disease Complicated with Kyphoscoliosis and Myelopathy.

Maple syrup urine disease (MSUD) is an autosomal recessive aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids (BCAAs: leucine, isoleucine, and valine). Accumulation of their corresponding keto-acids leads to encephalopathy if not treated in time. A newborn male patient was suspected to have MSUD after tandem mass study when he presented symptoms and signs suggestive neonatal sepsis, anemia, and diarrhea. Food restriction of BCAAs was started; however, acrodermatitis enteropathica-like skin eruptions occurred at age 2 months. The skin rashes resolved after adding BCAAs and adjusting the infant formula. At age 7 months, he suffered from recurrent skin lesions, zinc deficiency, osteoporosis, and kyphosis of the thoracic spine with acute angulation over the T11-T12 level associated with spinal compression and myelopathy. After supplementation of zinc products and pamidronate, skin lesions and osteopenia improved gradually. Direct sequencing of the DBT gene showed a compound heterozygous mutation [4.7 kb deletion and c.650-651insT (L217F or L217fsX223)]. It is unusual that neurodegeneration still developed in this patient despite diet restriction. Additionally, brain and spinal magnetic resonance imaging, bone mineral density study, and monitoring of zinc status are suggested in MSUD patients.