Features of chinese patients with sitosterolemia.

BACKGROUND: Sitosterolemia is a lipid disorder characterized by the accumulation of phytosterols in plasma and organs, caused by mutations in the ABCG5 and/or ABCG8 genes. The disease is frequently misdiagnosed and mistreated as familial hypercholesterolemia (FH). To gain a better understanding of the disease, the current status of diagnosis and treatment of Chinese patients with sitosterolemia was reviewed and summarized. METHOD: Literature search was performed. The clinical features and molecular characteristics of Chinese patients with sitosterolemia were analysed. Four children with sitosterolemia and the treatment experience were described. RESULTS: Fifty-five patients with sitosterolemia have been reported in China. These patients were aged from 3 months to 67 years at diagnosis, and the median was 8 years of age. Several complications, such as xanthomas in 47 patients (85%), thrombocytopenia in 17 patients (31%), anemia in 14 patients (25%), and cardiovascular damage in 12 patients (22%), were observed. Thirty-nine patients (71%) exhibited mutations in the ABCG5 gene, 15 patients (27%) showed mutations in ABCG8, and variations in both genes occurred in one patient (2%). A patient with two clinically rare diseases, namely, sitosterolemia and glycogen storage disease type VI (GSD VI)), is reported here for the first time. The four reported patients were treated with low cholesterol and phytosterol-limited diet alone or combined with cholestyramine. Even though decreases were observed for total plasma cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C), and these levels were as low as normal in some patients, the levels of plant sterols remained above the normal range. However, TC, LDL-C and plant sterol levels remained at high levels in patients treated with a control diet control only. CONCLUSIONS: The analysis reveals that different from Caucasians carrying mainly variations in ABCG8, most Chinese patients have mutations in the ABCG5 gene, and Arg446Ter, Gln251Ter, anArg389His might be hot-spot mutations in Chinese patients. The current survey provides clinical data to enable the development of a standardized protocol for the diagnosis and treatment of sitosterolemia in China.

Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children.

OBJECTIVE: The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China. METHODS: Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES. RESULTS: Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels. CONCLUSIONS: Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations.

Early transition from insulin to sulfonylureas in neonatal diabetes and follow-up: Experience from China.

BACKGROUND: Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation. OBJECTIVE: This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available. METHODS: The medical records of NDM patients with their follow-up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient. RESULTS: There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14-120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3-0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2-0.4 mg/kg/d). No serious adverse events were reported. CONCLUSIONS: Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM.

Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY).

BACKGROUND: There is scarcity of information on the clinical features and genetics of glucokinase-maturity-onset diabetes of the young (GCK-MODY) in China. The aim of the study was to investigate the clinical and molecular characteristics of Chinese children with GCK-MODY. METHODS: Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China. Clinical data were obtained from medical records. Blood was collected from the patients and their parents for glucokinase (GCK) gene analysis. Parents without diabetes were tested for fasting glucose and HbA1c. Clinical information and blood for GCK gene analysis were obtained from grandparents with diabetes. GCK gene mutational analysis was performed by polymerase chain reaction and direct sequencing. Patients without a GCK gene mutation were screened by targeted next-generation sequencing (NGS) technology for other MODY genes. RESULTS: Nine children tested positive for GCK gene mutations while two were negative. The nine GCK-MODY patients were from unrelated families, aged 1 month to 9 years and 1 month at first detection of hyperglycaemia. Fasting glucose was elevated (6.1-8.5 mmol/L), HbA1c 5.2-6.7% (33.3-49.7 mmol/mol), both remained stable on follow-up over 9 months to 5 years. Five detected mutations had been previously reported: p.Val182Met, c.679 + 1G > A, p.Gly295Ser, p.Arg191Gln and p.Met41Thr. Four mutations were novel: c.483 + 2 T > A, p.Ser151del, p.Met57GlyfsX29 and p.Val374_Ala377del. No mutations were identified in the other two patients, who were also tested by NGS. CONCLUSIONS: GCK gene mutations are detected in Chinese children and their family members with typical clinical features of GCK-MODY. Four novel mutations are detected.

Identification of a Novel IGSF1 Variant in Two Malaysian Male Siblings with Central Hypothyroidism and Macroorchidism.

IGSF1 mutation is the commonest cause of mild to moderate isolated central congenital hypothyroidism and has an X-linked recessive inheritance, primarily affecting males. Other notable clinical features are macroorchidism with delayed pubertal testosterone rise, large birth weight, increased body mass index, low prolactin, transient growth hormone deficiency and low prolactin. Two male siblings with central hypothyroidism were found to have a novel IGSF1 c.3467T>A variant that was likely pathogenic based on the family segregation study. The proband, aged 3 years presented at 18 days old with prolonged jaundice while his 16-year-old brother was only detected to have central hypothyroidism after the proband's genetic analysis result was known. Both siblings were obese, had large birth weights, macroorchidism and low prolactin. The proband's brother had intellectual disability while the proband had normal development. This case study highlights the importance of evaluation for the IGSF1 variant in patients with unexplained central hypothyroidism, especially when accompanied by X-linked inheritance and macroorchidism. Family segregation analysis allows detection of other affected family members or carriers who may also benefit from thyroxine treatment.

Diagnosis of an intermediate case of maple syrup urine disease: A case report.

BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive genetic disorder caused by defects in the catabolism of the branched-chain amino acids (BCAAs). However, the clinical and metabolic screening is limited in identifying all MSUD patients, especially those patients with mild phenotypes or are asymptomatic. This study aims to share the diagnostic experience of an intermediate MSUD case who was missed by metabolic profiling but identified by genetic analysis. CASE SUMMARY: This study reports the diagnostic process of a boy with intermediate MSUD. The proband presented with psychomotor retardation and cerebral lesions on magnetic resonance imaging scans at 8 mo of age. Preliminary clinical and metabolic profiling did not support a specific disease. However, whole exome sequencing and subsequent Sanger sequencing at 1 year and 7 mo of age identified bi-allelic pathogenic variants of the BCKDHB gene, confirming the proband as having MSUD with non-classic mild phenotypes. His clinical and laboratory data were retrospectively analyzed. According to his disease course, he was classified into an intermediate form of MSUD. His management was then changed to BCAAs restriction and metabolic monitoring conforming to MSUD. In addition, genetic counseling and prenatal diagnosis were provided to his parents. CONCLUSION: Our work provides diagnostic experience of an intermediate MSUD case, suggesting that a genetic analysis is important for ambiguous cases, and alerts clinicians to avoid missing patients with non-classic mild phenotypes of MSUD.

Novel PAX4 variant in a child and family with diabetes mellitus - case report and review of the literature.

OBJECTIVES: PAX4 (Paired box 4), a transcription factor crucial in pancreatic beta cell development and function, is a rare cause of maturity-onset diabetes of the young (MODY). What is new? A novel PAX4 variant is verified by family segregation study to be likely pathogenic. A child below 10 years of age diagnosed to have PAX4-MODY, differing from previously reported paediatric cases diagnosed in adolescence. CASE PRESENTATION: A child with diabetes diagnosed at age 8 years, harbored a PAX4 variant, c.890G>A (p.Gly297Asp), initially classified as variant of uncertain significance. Eleven family members (7 adults and 4 children) with and without diabetes across 3 generations were genotyped. The variant co-segregated with diabetes or prediabetes across 3 generations of the family. The variant is reclassified as likely pathogenic according to standard guidelines. CONCLUSIONS: Genetic testing is essential to confirm PAX4-MODY as the presentation is variable even within the same family. PAX4 mutation needs to be considered in MODY genetic testing in Asian patients.

Features of BSCL2 related congenital generalized lipodystrophy in China: long-term follow-up of three patients and literature review.

OBJECTIVES: Congenital generalized lipodystrophy (CGL) is a group of rare autosomal inherited diseases characterized by a widespread loss of adipose tissue. The main purpose of this study was to evaluate the features of Chinese patients with CGL2. METHODS: Three patients diagnosed with CGL2 from our center were reviewed. Data on clinical features, results of laboratory analyses, and previous treatments were retrospectively collected. This study also reviewed studies that reported patients diagnosed with CGL2 in the last 30 years. RESULTS: All patients presented a lack of subcutaneous fat, hypertriglyceridemia, reversed triangular faces, acanthosis nigricans, and hepatomegaly within the first six months of life. All three patients developed splenomegaly, and mental retardation in later life. Dietary control dramatically lowered triglyceride levels in all patients. One patient presented with diabetes mellitus at 1 year-old. Although combined therapy with low fat diet and metformin maintained normal levels of blood lipid and glucose, this patient developed hypertrophic cardiomyopathy at the age of three. By a literature review on all Chinese cases with CGL2, it is known that classic manifestations such as hypertriglyceridemia, hepatomegaly and diabetes mellitus can occur shortly after birth, and early diagnosis and treatment can improve quality of life. In this cohort, the most frequent variations are c.782dupG and c.974dup in the BSCL2 gene. However, the same genotype may have different clinical phenotypes in patients with CGL2. CONCLUSIONS: This study not only described the clinical and genetic features of three patients with CGL2 in China, but also reviewed literature about CGL2 around the world.

Whole exome sequencing identifies two novel variants in PHEX and DMP1 in Malaysian children with hypophosphatemic rickets.

BACKGROUND: Hypophosphatemic rickets (HR) is a genetic disease of phosphate wasting that is characterized by defective bone mineralization. The most common cause of the disease is mutations in the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. The aims of this study were to identify the gene variants responsible for HR in three cases of Malaysian origin from three independent families and to describe their clinical, biochemical, and radiological features. METHODS: Whole exome sequencing (WES) was performed on all patients and their parents, followed by Sanger sequencing validation. Bioinformatics tools were used to provide supporting evidence for pathogenicity of variants. To confirm that a mutation is de novo, paternity test was carried out. High resolution melting curve analysis was performed to assess the allele frequency in normal controls for mutations that were found in the patients. RESULTS: The patients showed typical characteristics of HR including lower limb deformity, hypophosphatemia, and elevated alkaline phosphatase. WES revealed two variants in the PHEX gene and one variant in the dentin matrix protein 1 (DMP1) gene. Two of the three variants were novel, including c.1946_1954del (p.Gly649_Arg651del) in PHEX and c.54 + 1G > A in DMP1. Our data suggests that the novel p.Gly649_Arg651del variant is likely pathogenic for HR disease. CONCLUSIONS: This study extends the variant spectrum of the PHEX and DMP1 genes. Our findings indicate that WES is an advantageous approach for diagnosis of genetic diseases which are heterogeneous.

Genetic basis of hereditary hypophosphataemic rickets and phenotype presentation in children and adults.

Hypophosphataemic rickets (HR) is a genetic disorder causing defects in the renal handling of phosphorus, resulting in rickets. HR can be classified into two groups. First- those with excess fibroblast growth factor 23(FGF23) levels, which are due to gene mutations in extrarenal factors and include X-linked dominant hypophosphataemic rickets (XLHR), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR), and hypophosphataemic rickets with hyperparathyroidism. Second- those with normal or low FGF23, which are caused by gene mutations in renal tubular phosphate transporters and include hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and X-linked recessive hypophosphataemic rickets. The radiographical changes and clinical features of rickets in various types of HR are similar but not identical. Short stature, bone deformities mainly in the lower limbs, and dental problems are typical characteristics of HR. Although the initial diagnosis of HR is usually based on physical, radiological, and biochemical features, molecular genetic analysis is important to confirm the diagnosis and differentiate the type of HR. In this review, we describe clinical and biochemical features as well as genetic causes of different types of HR. The clinical and biochemical characteristics presented in this review can help in the diagnosis of different types of HR and, therefore, direct genetic analysis to look for the specific gene mutation.

Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age.

INTRODUCTION: A specific molecular diagnosis of monogenic diabetes mellitus (MDM) will help to predict the clinical course and guide management. This study aims to identify the causative genes implicated in Chinese patients with MDM with onset before 3 years of age. RESEARCH DESIGN AND METHODS: 71 children with diabetes mellitus (43 diagnosed before 6 months of age, and 28 diagnosed between 6 months and 3 years of age who were negative for diabetes-associated autoantibodies) underwent genetic testing with a combination strategy of Sanger sequencing, chromosome microarray analysis and whole exome sequencing. They were categorized into four groups according to the age of onset of diabetes (at or less than 6 months, 6 to 12 months, 1 to 2 years, 2 to 3 years) to investigate the correlation between genotype and phenotype. RESULTS: Genetic abnormalities were identified in 39 of 71 patients (54.93%), namely KCNJ11 (22), ABCC8 (3), GCK (3), INS (3), BSCL2 (1) and chromosome abnormalities (7). The majority (81.40%, 35/43) of neonatal diabetes diagnosed less than 6 months of age and 33.33% (3/9) of infantile cases diagnosed between 6 and 12 months of age had a genetic cause identified. Only 11.11% (1/9) of cases diagnosed between 2 and 3 years of age were found to have a genetic cause, and none of the 10 patients diagnosed between 1 and 2 years had a positive result in the genetic analysis. Vast majority or 90.48% (19/21) of patients with KCNJ11 (19) or ABCC8 (2) variants had successful switch trial from insulin to oral sulfonylurea. CONCLUSIONS: This study suggests that genetic testing should be given priority in diabetes cases diagnosed before 6 months of age, as well as those diagnosed between 6 and 12 months of age who were negative for diabetes-associated autoantibodies. This study also indicates significant impact on therapy with genetic cause confirmation.

Clinical and Mutational Features of Three Chinese Children with Congenital Generalized Lipodystrophy.

OBJECTIVE: To investigate the clinical and molecular features of congenital generalized lipodystrophy (CGL) in three Chinese patients with various typical manifestations. METHODS: Data on clinical symptoms, results of laboratory analyses, and previous treatments in three Chinese patients were collected by a retrospective review of medical records. All coding regions and adjacent exon-intron junction regions of AGPAT2 and BSCL2 genes were amplified by polymerase chain reaction and sequenced. RESULTS: Generalized lipodystrophy, acanthosis nigricans, muscular hypertrophy, severe hypertriglyceridemia, and hepatomegaly were features in all three patients. Patient 1 developed diabetes mellitus at the early age of 2 months and he was the youngest CGL patient reported with overt diabetes. Patient 2 was found to have cardiomyopathy when she was aged 6 months. All of the patients were found to have mutations in the BSCL2 gene, but none of these was a novel mutation. We did not find any AGPAT2 mutation in our patients. CONCLUSION: All of our patients exhibited characteristic features of CGL due to mutations in the BSCL2 gene.

Chinese translation of strengths and difficulties questionnaire requires urgent review before field trials for validity and reliability.

UNLABELLED: Strengths and Difficulties Questionnaire (SDQ) is a brief behavioural screening questionnaire for children and teenagers aged 3 to 16 years. It is available in 66 languages, and gaining more popularity world wide. Chinese translation of SDQ is available and has been used in clinical practice and research. We undertook the exercise to back-translate the current Chinese translation and it showed a number of differences compared to the original English SDQ. The differences and concerns include: (1) the flow and grammar of Chinese translation as well as wrongly written Chinese characters; (2) translated words that have deviated from the original meaning; (3) significant numbers of wording that are somewhat different from the original English version; (4) addition of auxiliary verbs that do not exist in original English version; and (5) the current Chinese SDQ is a general questionnaire for all age groups that does not observe the differences of wording that exist in the English versions. CONCLUSION: An accurate translated Chinese version is important for researchers, clinicians and educators who work in the Chinese communities. There is an urgent need to review the translation of the Chinese SDQ version before more studies use it in the field.