Adult height of children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND/PURPOSES: Congenital adrenal hyperplasia attributable to 21-hydroxylase deficiency (21-OHD) is a disorder of adrenal steroidogenesis. Achievement of optimal growth by such patients is challenging. We evaluated the adult height of Taiwanese children with 21-OHD and the effect of a gonadotropin-releasing hormone analogue (GnRHa) in patients with central precocious puberty (CPP) complicating 21-OHD. METHODS: Among 116 patients with 21-OHD in Taiwan, 90 who had attained adult height were subjected to an analysis of height outcomes. Nine with progressive CPP were treated with GnRHa and the effects of this therapy on adult height were further analyzed. RESULTS: In the pre-screening era, the percentage of boys with 21-OHD was lower than expected. Although neonatal screening can prevent mortality caused by adrenal crisis, some cases may be missed. The pooled mean adult height of the 78 patients treated with conventional therapy were -1.1 SD and -0.5 SD adjusting for the genetic potential. The disease features affecting height outcomes are the genetic height potential and in boys the simple virilizing type. Nine patients with CPP were treated with GnRHa in addition to conventional therapy; the mean adult height increased from the predicted -4.1 SD to -1.0 SD after 6.0 ± 2.5 years of treatment. CONCLUSION: Patients with 21-OHD had poorer mean adult height. A high caregiver's index of suspicion is required for the early diagnosis of patients with 21-OHD missed on neonatal screening. Adjuvant therapy with GnRHa can improve the adult height of patients with CPP complicating 21-OHD.

Serum neutrophil gelatinase-associated lipocalin as a potential biomarker of diabetic kidney disease in patients with childhood-onset type 1 diabetes.

BACKGROUND/PURPOSE: Diabetic kidney disease (DKD) is a major complication in patients with type 1 diabetes (T1D). The aim of this study was to evaluate the role of serum neutrophil gelatinase-associated lipocalin (sNGAL) in the early detection of DKD in childhood-onset T1D patients. METHODS: A total of 116 patients (mean age, 22.3 ± 6.9 years) with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 were enrolled in this prospective cross-sectional study. Persistent albuminuria (PA) was defined as a urine albumin-to-creatinine ratio ≥ 30 mg/g for at least two consecutive years; non-albuminuria (NA) was defined otherwise. The patients were divided into the adult (Ad) (≥18 years, n = 91) and pediatric (Ped) (<18 years, n = 25) groups and further into the Ad-PA (n = 8), Ad-NA (n = 83), Ped-PA (n = 2), and Ad-NA (n = 23) subgroups. In all groups, the sNGAL level was determined. RESULTS: The mean diabetes duration was 14.2 ± 6.1 years, and 8.6% patients had PA. There was no significant difference in sNGAL levels between the PA and NA groups; notably, in adults, the sNGAL level was significantly higher in the Ad-PA than Ad-NA subgroups (P = 0.039). The sNGAL level was negatively correlated with the eGFR in adults (rho -0.41, P < 0.001). Multiple linear regression models showed that higher sNGAL levels in the adult group were independent and significant determinants of a lower eGFR (P < 0.001). CONCLUSION: An elevated sNGAL was significantly correlated with a decreased eGFR even in the range of normal to mildly decreased renal function. Thus, it is a potential biomarker of early deterioration of DKD in childhood-onset T1D.

Clinical and molecular features of idiopathic hypogonadotropic hypogonadism in Taiwan: A single center experience.

BACKGROUND: Idiopathic (isolated) hypogonadotropic hypogonadism (IHH) is a rare disease that can be classified as Kallmann syndrome (KS) or normosmic IHH (nIHH). This study investigated the phenotype and genotype of IHH in Taiwanese patients. METHODS: Twenty-six unrelated IHH patients were included in this study and their clinical, hormonal, and radiological findings were analyzed retrospectively. Whole exome sequencing (WES) was performed to identify the etiology. RESULTS: The 26 patients (M:F = 19:7) were divided into a KS group (n = 11) and a nIHH group (n = 15). The diagnosis was earlier in boys than in girls. Fifteen patients were found to have pathogenic/likely pathogenic (P/LP) variants of IHH-associated genes, and the mutation detection rate was 58%. CHD7, FGFR1, and ANOS1 were the most common genetic etiologies identified in this group. Two patients with nIHH were found to have de novo SOX11 mutations and Coffin-Siris syndrome features. After treatment, the height outcomes and secondary sexual characteristics were significantly improved. There were no obvious differences between the genetically resolved (GR), variants of uncertain significance (VUS) and genetically unresolved groups (GUR). CONCLUSION: Whole exome sequencing is useful in patients with IHH, and we identified the SOX11 gene as a causal factor in this study. We described the clinical, hormonal, and molecular characteristics, and the treatment outcomes, of Taiwanese patients with IHH, which should aid therapeutic planning and further research.

Resistance to thyroid hormone due to a novel THRB p.Val349Ala mutation in a Taiwanese boy.

Resistance to thyroid hormone (RTH) is a rare congenital disorder characterized by impaired sensitivity of target tissues to thyroid hormone. The disease is mostly caused by heterozygous mutations of thyroid hormone receptor ß (THRB) gene. We present a ten-year-old Taiwanese boy with goiter, mood disturbances and attention deficit hyperactivity disorder (ADHD). Blood tests showed elevated serum thyroxine (T4) and triiodothyronine (T3) levels with nonsuppressed thyrotropin (TSH) levels. Sella MRI failed to detect any pituitary adenoma. Initial treatment with anti-thyroid drugs resulted in increased TSH levels and goiter size. His medication was discontinued after his visit to our hospital for a second opinion. A thyrotropin-releasing hormone (TRH) stimulation test showed a normal TSH response to TRH stimulation. Molecular analysis identified a novel heterozygous THRB p.Val349Ala mutation. The patient attained normal growth and a paucity of symptoms without any medication during the follow-up period. We hope that the presentation of this case can make the early diagnosis of RTH possible so that inappropriate management of these patients can be avoided in the future.

Thyroid disorders in Taiwanese children with Down syndrome: The experience of a single medical center.

BACKGROUND/PURPOSE: Thyroid disorders are common in children with Down syndrome (DS), however, such data have rarely been reported in Taiwanese children. This study presents our experience with the management of these children. METHODS: Between 2006 and 2016, 51 children (31 boys and 20 girls) with DS were enrolled. Thyroid function was evaluated and natural course of thyroid status were analyzed. RESULTS: Of 51 patients with DS, 2 had congenital hypothyroidism due to dyshormonogenesis. Of the remaining 49 patients, 30 (61%) had euthyroidism (EuT), and 19 (39%) had subclinical hypothyroidism (SH). Eighteen (37%) had detectable thyroid antibodies. It occurred at any age and the incidence was not affected by sex. The mean follow-up duration for 39 DS children was 3.8 ± 2.4 years. Of the 26 children who had EuT at enrollment and were followed up, 22 remained EuT, 2 developed SH, 1 developed overt hypothyroidism, and 1 developed overt hyperthyroidism. Of the 13 patients with SH who were followed up, 1 was treated for high thyroid-stimulating hormone levels, 8 became EuT, and 4 maintained SH status. Children with DS and persistent SH had significantly higher maximum thyroid-stimulating hormone levels during follow-up than did those with transient SH. Fluctuation in thyroid status during follow-up was not uncommon in children with DS. CONCLUSION: The prevalence of thyroid disorders is higher in Taiwanese children with DS than in the general population. Because symptoms of hypothyroidism overlap those inherent to DS, regular follow-up of thyroid function in children with DS is indicated.

Mosaic paternal haploidy in a patient with pancreatoblastoma and Beckwith-Wiedemann spectrum.

Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith-Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome-wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.

The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center.

BACKGROUND/PURPOSE: 45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. PATIENTS AND METHODS: We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. RESULTS: Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4 ± 1.1 to -1.4 ± 0.9 in adulthood (P < 0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. CONCLUSION: The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy.

Comprehensive human leukocyte antigen genotyping of patients with type 1 diabetes mellitus in Taiwan.

BACKGROUND: Type 1 diabetes (T1D) mellitus is an autoimmune disorder involving both complex genetic and environmental factors. The incidence rates are low in Asian countries, and the specific, explanatory genetic factors underlying this have been investigated. The aim of this study was to elucidate the association of human leukocyte antigen (HLA) alleles/haplotypes with T1D in Taiwan. METHODS: We performed direct comprehensive genotyping of 6 classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1) to 4-digit resolution in 104 unrelated T1D patients and 504 controls. Twenty-four of the 104 patients also exhibited thyroid autoimmunity. RESULTS: Three major susceptibility haplotypes were identified: DRB1*03:01-DQB1*02:01 (odds ratio [OR] = 5.39 under the dominant model, P = 2.3 × 10-13 ), DRB1*04:05-DQB1*04:01 (OR = 2.44, P = 5.0 × 10-4 ), and DRB1*09:01-DQB1*03:03 (OR = 2.02, P = 1.4 × 10-3 ); one protective haplotype was identified: DRB1*08:03-DQB1*06:01 (OR = 0.10, P = 1.6 × 10-3 ). DRB1*03:01-DQB1*02:01, the major T1D susceptibility haplotype, was found at a lower frequency in T1D patients with thyroid autoimmunity. The T1D protective allele DRB1*12:02 was shown to be protective against Graves' disease in our previous report. CONCLUSION: In addition to clarifying the roles of several known T1D HLA alleles and haplotypes, we discovered that the DRB1*08:03-DQB1*06:01 haplotype is protective against T1D. The DRB1*12:02 allele protected against both T1D and Graves' disease.

Nutritional rickets in Taiwanese children: Experiences at a single center.

BACKGROUND/PURPOSE: The number of children with nutritional rickets in Taiwan has increased over the last decade. The aim of this study was to present our experiences in the management of patients with this condition. PATIENTS AND METHODS: From 2011 to 2016, 10 children (3 boys and 7 girls) with nutritional rickets were enrolled in this study. Their clinical and biochemical data were analyzed. RESULTS: The median age of the 10 patients was 21 months (range, 12-25 months). The predisposing factors included exclusive breastfeeding, dietary restriction, and limited outdoor activities. The most common presentations were unsteady gait and bowlegs, and two patients had hypocalcemic seizures. All patients had elevated alkaline phosphatase levels (median, 1008 U/L; range, 484-2051 U/L), elevated serum intact parathyroid hormone levels (median, 333.8 pg/mL; range, 130-817 pg/mL), and hypophosphatemia (median, 3.0 mg/dL; range, 2.4-3.9 mg/dL). The median serum 25-hydroxyvitamin D level was 7.44 ng/mL (range, 1.44-9.82 ng/mL). After vitamin D supplementation was initiated, serum phosphorus levels normalized within 1 month, and serum intact parathyroid hormone levels returned to the normal range within 2 months. Six of the 10 patients had serum alkaline phosphatase levels close to the normal range within 3 months. All 10 patients exhibited complete bone healing within 6 months of vitamin D treatment. CONCLUSION: Nutritional rickets is not as rare in Taiwan as previously thought. When physicians encounter infants or toddlers with typical bone deformities or hypocalcemic seizures, a high index of suspicion and a detailed nutritional history are important for early diagnosis and treatment.

Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening.

BACKGROUND/PURPOSE: Neonatal screening for congenital adrenal hyperplasia (CAH) has been conducted in Taiwan since 2000. This study aimed to determine the clinical characteristics of Taiwanese children with CAH due to 21-hydroxylase deficiency (21-OHD) detected by neonatal screening. METHODS: From 2000 to 2015, 26 neonates (14 boys and 12 girls) with classic 21-OHD detected by neonatal screening and confirmed at National Taiwan University Hospital were enrolled. Among them, 22 were diagnosed as salt wasting (SW) type and four as simple virilizing (SV) type. Through a review of medical records, their clinical presentations, laboratory data, and molecular studies were analyzed. RESULTS: The most common manifestation was hyperpigmentation. All female neonates regardless of 21-OHD type had atypical genitalia, clitoromegaly, and posterior labial fusion. All of the patients had baseline serum 17-hydroxyprogesterone levels higher than normal. Of the 26 patients, 24 had elevated adrenocorticotropic hormone levels, but only four had low serum cortisol levels. The median baseline adrenocorticotropic hormone, 17-hydroxyprogesterone, and androstenedione levels were significantly higher in patients with SW than in those with SV 21-OHD. All patients with SW 21-OHD had elevated plasma renin activity. The most frequent SW 21-OHD mutations were c.293-13C>G and gene deletion, whereas Ile173Asn and c.293-13C>G were the most frequently detected in SV 21-OHD. CONCLUSION: In Taiwan, neonatal screening effectively leads to the early diagnosis of CAH and reduces fatal adrenal crisis in neonates. This study may provide physicians with a better understanding of the clinical findings among children with early-diagnosed CAH, allowing for better care in the future.

SHOX deficiency in short Taiwanese children: A single-center experience.

BACKGROUND: SHOX deficiency is a common cause of idiopathic short stature. The aim of this study was to describe the clinical characteristics and molecular findings of patients with SHOX deficiency in Taiwan. METHODS: A phenotype scoring system was used to evaluate several anthropometric measures in patients with idiopathic short stature. Twenty-three patients with a phenotype score >7 were enrolled for SHOX gene analysis by MLPA and sequencing. Another patient with a deletion/insertion of the short arm of the X chromosome containing the SHOX gene was enrolled for the assessment. RESULTS: SHOX deficiency was detected in 26% of short children with a phenotype score >7. The arm-span-to-height ratio was significantly lower in SHOX-D patients than in non-SHOX-D patients. In patients with SHOX deficiency, an arm-span-to-height ratio <96.5% and short forearm were the most common characteristics. Three patients also exhibited typical radiological findings. A molecular analysis of the SHOX gene revealed five patients with intragenic deletions, one with a deletion in the regulatory region, and one with a missense mutation at exon 5. CONCLUSION: The phenotype scoring system is useful to select children with SHOX deficiency in Taiwan. Family history and radiological image of the radius are also of value for the diagnosis. This study may aid physicians in the early diagnosis of children with SHOX deficiency.

Clinical characteristics of type 1 diabetes mellitus in Taiwanese children aged younger than 6 years: A single-center experience.

BACKGROUND/PURPOSE: Cases of type 1 diabetes mellitus in children aged younger than 6 years in Taiwan has increased in the past 10 years. This retrospective study aimed to review the management experience of such patients in a single center. METHODS: From January 2004 to June 2015, 52 newly diagnosed diabetic children younger than 6 years who had regular follow-up for > 1 year were enrolled, as well as 94 older diabetic children for comparison. Their medical records were thoroughly reviewed. RESULTS: The most common symptoms and signs were polyuria, polydipsia, dry lips, weight loss, and nocturia. Among the children younger than 6 years, 87% had ketoacidosis upon diagnosis-significantly higher than that of the older age group-and 88% had at least one islet cell autoantibody detected. Their serum C-peptide levels were significantly lower and the frequency of insulin autoantibodies detected was significantly higher compared with the older age group (37% vs. 10%). The remission rate of the young diabetic patients was significantly lower than that of the older age group (40% vs. 59%), but there was no difference in time of onset and duration of remission between the two groups. CONCLUSION: Autoimmune destruction of pancreatic ß-cells is an important cause of type 1 diabetes mellitus in Taiwanese children aged younger than 6 years. These patients usually have a low insulin reserve and severe ketoacidosis upon diagnosis. A high index of suspicion in the presence of classic symptoms of diabetes in young children is important to prevent complications.

Clinical characteristics and long-term outcome of Taiwanese children with congenital hyperinsulinism.

BACKGROUND/PURPOSE: Congenital hyperinsulinism (CHI) is a rare condition causing severe hypoglycemia in neonates and infants due to dysregulation of insulin secretion. This study aimed to review 20 years' experience in the management of Taiwanese children with CHI. METHODS: Between 1990 and 2010, children diagnosed with CHI and followed up at the Pediatric Endocrine Clinic of the National Taiwan University Hospital were enrolled. Their medical records were thoroughly reviewed. RESULTS: In total, 13 patients (8 boys and 5 girls) were enrolled, including six patients with onset of hypoglycemia within 1 month of age and seven patients at 4.0 ± 2.1 months of age. The birth weight standard deviation scores of these two age groups were 4.6 ± 1.8 and 1.4 ± 1.3 standard deviation score, respectively (p < 0.01). Initial intravenous glucose infusion at rates of 22.9 ± 5.3 mg/kg/min and 13.4 ± 5.6 mg/kg/min, respectively, were mandatory to maintain euglycemia in these two groups (p < 0.05). All received pancreatectomy after failure of initial medical treatment. Twelve patients were followed up for a period of 2.5-19.8 years. Eight of them remained euglycemic without any medication and three patients developed diabetes mellitus. Seven of the nine patients who underwent intelligence evaluation had normal mental outcomes. Mental retardation of two patients was too severe to be evaluated. All four patients with mental retardation had a delay in the maintenance of euglycemia, and three of them also had seizure disorder. CONCLUSION: The age at onset of hypoglycemia reflects the severity of CHI. Early diagnosis and appropriate treatment are important for favorable mental outcomes.

Effect of menarche onset on the clinical course in females with chronic hepatitis B virus infection.

OBJECTIVE: To investigate the impact of menarche on the natural course of chronic hepatitis B virus (HBV) infection in women. STUDY DESIGN: Young women who are positive for hepatitis B e antigen (HBeAg; n = 101) chronically infected with genotypes B and C HBV were recruited at a mean age of 4.57 ± 3.08 years, and a mean follow-up duration of 23.98 ± 3.77 years. Clinical data, including age at menarche, HBV genotypes, serum HBV viral loads, hepatitis B surface antigen (HBsAg) titers, and serial liver functional profiles were analyzed. RESULTS: Women with earlier onset of menarche had earlier spontaneous HBeAg seroconversion than others (hazard ratio, 2.0; P = .02) adjusting for HBV genotype and peak alanine aminotransferase levels before HBeAg seroconversion. The annual decrease in HBsAg titer from 15 to 20 years of age also was greater in the early menarche group compared with the late menarche group (0.11 ± 0.11 vs 0.05 ± 0.11 log10 IU/mL, P = .04). The baseline HBV viral load was also borderline low in female subjects with earlier menarche as compared with others (P = .06). Earlier menarche onset was associated with higher spontaneous HBeAg seroconversion, HBsAg seroclearance, and HBsAg seroconversion rate before 15 years of age in females with chronic HBV infection. CONCLUSIONS: Earlier puberty-onset, indicated by menarche-onset, was associated with earlier spontaneous HBeAg seroconversion and greater rate of HBV clearance before 15 years of age in female subjects with chronic HBV infection.

Endocrine dysfunction in Taiwanese children with human chorionic gonadotropin-secreting germ cell tumors.

BACKGROUND/PURPOSE: Human chorionic gonadotropin (HCG)-secreting germ cell tumors (GCTs) are rare childhood malignancies with unique clinical manifestations but delayed diagnosis is common. The purpose of this study is to investigate the clinical manifestations and endocrine dysfunction of Taiwanese children with HCG-secreting GCTs. METHODS: From 1991 to 2011, 24 children (19 boys and five girls) with HCG-secreting GCTs were evaluated for their clinical findings and endocrine functions. RESULTS: The mean age at diagnosis of the study patients was 10.8 ± 3.1 years. Of the 24 patients, 20 had central nervous system (CNS) GCTs and four had primary mediastinal GCTs (PMGCTs). The most common pathologic findings were germinomas and mixed type GCTs. The common initial symptoms and signs included polyuria, polydipsia, rapid growth, neurologic deficit,sexual precocity, and growth retardation. There was a delay in diagnosis in about 60% of patients. Diabetes insipidus and hypopituitarism were common endocrine dysfunctions in patients with CNSGCTs. Twelve boys had gonadotropin-independent puberty upon diagnosis, which were related to their high serum ß-hCG levels. None of the five girls had this disorder despite their high serum ß-hCG levels. Three of the four PMGCTs patients had the classic form of Klinefelter syndrome. CONCLUSION: Taiwanese children with HCG-secreting GCTs often have clinical manifestations related to endocrine dysfunction. High index of suspicion is important to avoid delayed diagnosis in these children.

Clinical characteristics of central diabetes insipidus in Taiwanese children.

BACKGROUND/PURPOSE: Data on the clinical features of children with central diabetes insipidus (CDI) are lacking in Taiwan. This study investigated the clinical manifestations and etiology of CDI in Taiwanese children. METHODS: From 1983 to 2012, 62 children with permanent diabetes insipidus were enrolled in the study. They were diagnosed at the Department of Pediatrics of National Taiwan University Hospital. Their medical records were thoroughly reviewed and their clinical symptoms and signs, laboratory data, and etiologies were analyzed. RESULTS: The patients' median age at diagnosis was 10 years and the median interval between initial manifestations and diagnosis was 0.5 years. The most common symptoms and signs were polyuria, polydipsia, nocturia, and growth retardation. Most patients had low urine osmolality and elevated plasma osmolality on diagnosis. Absence of a posterior pituitary hyperintense signal and thickening of the pituitary stalk were common findings on magnetic resonance imaging. Approximately 80% of the patients had anterior pituitary hormone deficiency and all patients had growth hormone deficiency. Approximately 60% of patients had intracranial lesions, the most common causes of which were germ cell tumor and Langerhans cell histiocytosis. Two patients were initially believed to have idiopathic CDI but intracranial lesions were detected during the follow-up period. CONCLUSION: Because a delayed diagnosis of CDI is common in Taiwanese children, a high index of suspicion is important. The underlying etiology of CDI in children may not initially be obvious. Long-term surveillance is therefore necessary, especially for the early detection of evolving treatable intracranial lesions.

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Microbial methane cycling in a terrestrial mud volcano in eastern Taiwan.

Microbial communities responsible for methane cycling in mud volcanoes onshore are poorly characterized. This study analysed bubbling fluids and cored sediments retrieved from a mud volcano in eastern Taiwan. The pore water profiles revealed that methane concentrations generally increased with depth and changed dramatically at different depth intervals at different sites. The methane concentrations were inversely correlated with Fe(2+)/Mn(2+) concentrations and δ(13)C values of methane, marking iron/manganese-methane transition zones in the sediment cores. Archaeal communities were dominated by ANME-2a members and methylotrophic methanogens, whereas bacterial communities consisted primarily of Proteobacteria, Firmicutes and Bacteroidetes. The 16S rRNA gene copy numbers of ANME-2a and Desulfuromonas/Pelobacter populations varied by two to three orders of magnitude along the profile and exhibited a pattern comparable with those of Fe(2+) and δ(13)C values of methane. These lines of evidence suggest a coupling between anaerobic methanotrophy and metal reduction in the metal-methane transition zones under sulfate-deficient conditions, a metabolic scheme contrasting with that observed in marine cold seeps. Anaerobic methanotrophs proliferate by removing methane produced from in situ methanogenesis and originating from the deep source. Methane finally emitted into the atmosphere is quantitatively and isotopically altered by various microbial processes compartmentalized at different depth intervals.

Endocrine and Growth Disorders in Taiwanese Children With 22q11.2 Deletion Syndrome.

Background: Endocrine disorders are common in patients with 22q11.2 deletion syndrome (22q11.2DS). This study aimed to elucidate the clinical manifestations of endocrine disorders, including parathyroid, thyroid and growth disorders, in Taiwanese patients with 22q11.2DS. Methods: From 1994 to 2020, the medical records of 138 patients with 22q11.2DS diagnosed at a tertiary referral medical center in Taiwan were thoroughly reviewed retrospectively. Results: Hypocalcemia was detected in 57 of 135 patients (42%); 33 of 104 patients (32%) had hypoparathyroidism, and in 87% of them, hypocalcemia was detected before the age of one. Most patients had precipitating stressors during symptomatic hypocalcemic episodes. Eighteen of 29 patients had overt hypoparathyroidism at the last visit: 11 had persistent hypoparathyroidism and the other seven had recurrent hypoparathyroidism. Four of 84 patients had thyroid disorders, including thyroid developmental anomalies in two, dyshormonogenesis in one and Graves' disease in one. Fifty of 126 patients (40%) had short stature. Age (odds ratio (OR) 0.91; 95% confidence interval (CI) 0.86-0.96; P<0.001) and airway anomalies (OR 2.75; 95% CI 1.04-7.31; P<0.05) were significant risk factors for short stature in multivariate logistic regression model. Twenty-eight of the 30 patients with airway anomalies were associated with severe congenital heart disease. Adult height standard deviation score (SDS) in 19 patients was significantly lower than target height SDS (-1.15 ± 0.90 vs -0.08 ± 0.65, P<0.001). Conclusions: Hypoparathyroidism is a common endocrine disorder in patients with 22q11.2DS. It is prudent to assess parathyroid function at diagnosis and during follow-up, especially in the presence of stress, to prevent symptomatic hypocalcemia. Although thyroid disorders are not so common as hypoparathyroidism, screening of thyroid dysfunction is justified in these patients. Patients with 22q11.2DS demonstrate a retarded growth pattern with a tendency of catch-up and regular monitoring of growth is indicated.