BACKGROUND: Type II autosomal dominant osteopetrosis (ADO II) is a rare genetically heterogeneous disorder characterized by osteosclerosis and increased bone mass, predominantly involving spine, pelvis, and skull. It is closely related to functional defect of osteoclasts caused by chloride voltage-gated channel 7 (CLCN7) gene mutations. In this study, we aimed to identify the pathogenic mutation in a Korean patient with ADO II using whole exome sequencing. METHODS: We evaluated the clinical, biochemical, and radiographic analysis of a 68-year-old woman with ADO II. We also performed whole exome sequencing to identify pathogenic mutation of a rare genetic disorder of the skeleton. Moreover, a polymorphism phenotyping program, Polymorphism Phenotyping v2 (PolyPhen-2), was used to assess the effect of the identified mutation on protein function. RESULTS: Whole exome sequencing using peripheral leukocytes revealed a heterozygous c.296A>G missense mutation in the CLCN7 gene. The mutation was also confirmed using Sanger sequencing. The mutation c.296A>G was regarded to have a pathogenic effect by PolyPhen-2 software. CONCLUSION: We detect a heterozygous mutation in CLCN7 gene of a patient with ADO II, which is the first report in Korea. Our present findings suggest that symptoms and signs of ADO II patient having a c.296A>G mutation in CLCN7 may appear at a very late age. The present study would also enrich the database of CLCN7 mutations and improve our understanding of ADO II.
Aged ; Exome ; Female* ; Humans ; Korea ; Leukocytes ; Mutation, Missense ; Osteoclasts ; Osteopetrosis* ; Osteosclerosis ; Pelvis ; Skeleton ; Skull ; Spine

BACKGROUND: Cushing syndrome is characterized by glucose intolerance, cardiovascular disease, and an enhanced systemic inflammatory response caused by chronic exposure to excess cortisol. Eosinopenia is frequently observed in patients with adrenal Cushing syndrome, but the relationship between the eosinophil count in peripheral blood and indicators of glucose level in patients with adrenal Cushing syndrome has not been determined. METHODS: A retrospective study was undertaken of the clinical and laboratory findings of 40 patients diagnosed with adrenal Cushing syndrome at Chungnam National University Hospital from January 2006 to December 2016. Clinical characteristics, complete blood cell counts with white blood cell differential, measures of their endocrine function, description of imaging studies, and pathologic findings were obtained from their medical records. RESULTS: Eosinophil composition and count were restored by surgical treatment of all of the patients with adrenal Cushing disease. The eosinophil count was inversely correlated with serum and urine cortisol, glycated hemoglobin, and inflammatory markers in the patients with adrenal Cushing syndrome. CONCLUSION: Smaller eosinophil populations in patients with adrenal Cushing syndrome tend to be correlated with higher levels of blood sugar and glycated hemoglobin. This study suggests that peripheral blood eosinophil composition or count may be associated with serum glucose levels in patients with adrenal Cushing syndrome.
Blood Cell Count ; Blood Glucose* ; Cardiovascular Diseases ; Chungcheongnam-do ; Cushing Syndrome* ; Eosinophils* ; Glucose ; Glucose Intolerance ; Hemoglobin A, Glycosylated ; Humans ; Hydrocortisone ; Leukocytes ; Medical Records ; Pituitary ACTH Hypersecretion ; Retrospective Studies

Isolated hypogonadotropic hypogonadism (IHH) is known to decrease bone mineral density due to deficiency of sex steroid hormone. Graves' disease is also an important cause of secondary osteoporosis. However, IHH does not preclude the development of primary hyperthyroidism caused by Graves' disease, leading to more severe osteoporosis rapidly. Here, we describe the first case of 35-year-old Asian female patient with IHH accompanied by Graves' disease and osteoporosis-induced multiple fractures. Endocrine laboratory findings revealed preserved anterior pituitary functions except for secretion of gonadotropins and showed primary hyperthyroidism with positive autoantibodies. Sella magnetic resonance imaging showed slightly small sized pituitary gland without mass lesion. Dual energy X-ray absorptiometry revealed severe osteoporosis in lumbar spine and femur neck of the patient. Plain film radiography of the pelvis and shoulder revealed a displaced and nondisplaced fracture, respectively. After surgical fixation with screws for the femoral fracture, the patient was treated with antithyroid medication, calcium, and vitamin D until now and has been recovering fairly well. We report a patient of IHH with Graves' disease and multiple fractures that is a first case in Korea.
Absorptiometry, Photon ; Adult ; Asian Continental Ancestry Group ; Autoantibodies ; Bone Density ; Calcium ; Female ; Femoral Fractures ; Femur Neck ; Gonadotropins ; Graves Disease* ; Humans ; Hyperthyroidism ; Hypogonadism* ; Korea ; Magnetic Resonance Imaging ; Osteoporosis ; Pelvis ; Pituitary Gland ; Radiography ; Shoulder ; Spine ; Vitamin D

We investigated an association between serum Growth Differentiation Factor 15 (GDF15) level and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus (T2D). A total of 107 participants were screened for T2D and divided into a T2D group and a control group (without diabetes). We used the Framingham risk score (FRS) and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease. Serum GDF15 levels were measured using an enzyme-linked immunosorbent assay. Correlation analyses were performed to evaluate the associations between GDF15 level and cardiovascular risk scores. The mean serum GDF15 level was elevated in the T2D group compared to the control group (P < 0.001). A positive correlation was evident between serum GDF15 level and age (r = 0.418, P = 0.001), the FRS (r = 0.457, P < 0.001), and the Pooled Cohort Equation score (r = 0.539, P < 0.001). After adjusting for age, LDL-C level, and body mass index (BMI), the serum GDF15 level was positively correlated with the FRS and the New Pooled Cohort Equation score. The serum GDF15 level is independently associated with cardiovascular risk scores of newly diagnosed T2D patients. This suggests that the level of GDF15 may be a useful predictive biomarker of cardiovascular risk in newly diagnosed T2D patients.
Body Mass Index ; Cardiovascular Diseases ; Cohort Studies ; Diabetes Mellitus, Type 2* ; Enzyme-Linked Immunosorbent Assay ; Growth Differentiation Factor 15* ; Humans

BACKGROUND: Although both thyroid histology and serum concentrations of hormones are known to change with age, only a few reports exist on the relationship between the age-related structural and functional changes of the thyroid follicles in both mice and humans. Our objectives were to investigate age-related histological changes of the thyroid follicles and to determine whether these morphological changes were associated with the functional activity of the follicles. METHODS: The thyroid glands of mice at 18 weeks and at 6, 15, and 30 months of age were histologically examined, and the serum levels of thyroid hormones were measured in 11-week-old and 20-month-old mice. Samples of human thyroid tissue from 10 women over 70 years old and 10 women between 30 and 50 years of age were analyzed in conjunction with serum thyroid hormone level. RESULTS: The histological and functional changes observed in the thyroid follicles of aged mice and women were as follows: variable sizing and enlargement of the follicles; increased irregularity of follicles; Sanderson’s polsters in the wall of large follicles; a large thyroglobulin (Tg) globule or numerous small fragmented Tg globules in follicular lumens; oncocytic change in follicular cells; and markedly dilated follicles empty of colloid. Serum T3 levels in 20-month-old mice and humans were unremarkable. CONCLUSIONS: Thyroid follicles of aged mice and women show characteristic morphological changes, such as cystic atrophy, empty colloid, and Tg globules.
Aged ; Animals ; Atrophy ; Colloids ; Female ; Humans* ; Infant ; Mice ; Thyroglobulin ; Thyroid Gland* ; Thyroid Hormones

BACKGROUND: Growth differentiation factor-15 (GDF15) is a protein that belongs to the transforming growth factor beta superfamily. An elevated serum level of GDF15 was found to be associated with type 2 diabetes mellitus (T2DM). T2DM is an inflammatory disease that progresses from normal glucose tolerance (NGT) to impaired fasting glucose (IFG). Hence, we aimed to validate the relationship between GDF15 and IFG. METHODS: The participants were divided into the following three groups: NGT (n=137), IFG (n=29), and T2DM (n=75). The controls and T2DM outpatients visited the hospital for routine health check-ups. We used fasting blood glucose to detect IFG in nondiabetic patients. We checked the body mass index (BMI), C-reactive protein level, metabolic parameters, and fasting serum GDF15 level. RESULTS: Age, BMI, triglyceride, insulin, glucose, homeostatic model assessment-insulin resistance (HOMA-IR), and GDF15 levels were elevated in the IFG and T2DM groups compared to the NGT group. In the correlation analysis between metabolic parameters and GDF15, age and HOMA-IR had a significant positive correlation with GDF15 levels. GDF15 significantly discriminated between IFG and NGT, independent of age, BMI, and HOMA-IR. The serum levels of GDF15 were more elevated in men than in women. As a biomarker for IFG based on the receiver operating characteristic curve analysis, the cutoff value of GDF15 was 510 pg/mL in males and 400 pg/mL in females. CONCLUSION: GDF15 had a positive correlation with IR independent of age and BMI, and the serum level of GDF15 was increased in the IFG and T2DM groups. GDF15 may be a novel biomarker for detecting IFG in nondiabetic patients.
Biomarkers ; Blood Glucose ; Body Mass Index ; C-Reactive Protein ; Diabetes Mellitus, Type 2 ; Fasting* ; Female ; Glucose* ; Growth Differentiation Factor 15 ; Humans ; Insulin ; Male ; Outpatients ; Prediabetic State ; ROC Curve ; Transforming Growth Factor beta ; Triglycerides

The Academy of Medicine (AMS) and the Ministry of Health (MOH) have developed the clinical practice guidelines on Attention Deficit Hyperactivity Disorder (ADHD) to provide doctors and patients in Singapore with evidence-based treatment for ADHD. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on ADHD, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html.The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.
Attention Deficit Disorder with Hyperactivity ; diagnosis ; drug therapy ; therapy ; Caregivers ; Child ; Evidence-Based Medicine ; Humans ; Methylphenidate ; therapeutic use ; Parents ; Psychiatry ; methods ; standards ; Singapore ; Societies, Medical

PURPOSE: NAD(P)H:Quinone Oxidoreductase 1 (NQO1) C609T missense variant (NQO1*2) and 29 basepair (bp)-insertion/deletion (I29/D) polymorphism of the NRH:Quinone Oxidoreductase 2 (NQO2) gene promoter have been proposed as predictive and prognostic factors for cancer development and progression. The purpose of this study is to investigate the relationship between NQO1/NQO2 genotype and clinico-pathological features of papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS: Genomic DNA was isolated from 243 patients; and clinical data were retrospectively analyzed. NQO1*2 and tri-allelic polymorphism of NQO2 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: PTMC with NQO1*2 frequently exhibited extra-thyroidal extension as compared to PTMC with wild-type NQO1 (p=0.039). There was a significant relationship between I29/I29 homozygosity of NQO2 and lymph node metastasis (p=0.042). Multivariate analysis showed that the I29/I29 genotype was associated with an increased risk of lymph node metastasis (OR, 2.24; 95% CI, 1.10-4.56; p=0.026). CONCLUSION: NQO1*2 and I29 allele of the NQO2 are associated with aggressive clinical phenotypes of PTMC, and the I29 allele represents a putative prognostic marker for PTMC.
Adult ; Carcinoma, Papillary/*genetics/pathology ; DNA Mutational Analysis ; Female ; Genetic Predisposition to Disease ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Multivariate Analysis ; Mutagenesis, Insertional ; Mutation, Missense ; NAD(P)H Dehydrogenase (Quinone)/chemistry/*genetics ; Phenotype ; Polymorphism, Genetic ; Prognosis ; Promoter Regions, Genetic ; Retrospective Studies ; Sequence Analysis, Protein ; Sequence Deletion ; Thyroid Neoplasms/*genetics/pathology

BACKGROUND AND OBJECTIVES: Recent studies have reported that vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1alpha are up-regulated in BRAF(V600E)-positive papillary thyroid carcinoma (PTC). We investigated whether papillary thyroid microcarcinomas (PTMCs) also exhibited increased expression of VEGF and HIF-1alpha. In addition, we analyzed the relationship between BRAF(V600E) mutation and clinicopathological parameters, as well as HIF-1alpha expression in PTMC. MATERIALS AND METHODS: We retrospectively selected 225 patients with PTMC. Immunohistochemical staining for HIF-1alpha and VEGF was performed using paraffinembedded PTMC tissue microarrays. BRAF(V600E) mutation status was analyzed by dideoxy sequencing. RESULTS: PTMCs larger than 0.5 cm tend to be related to aggressive clinicopathological features such as thyroid capsular invasion (p=0.023) and bilaterality (p=0.047). Immunoreactivity to HIF-1alpha (20.7%) and VEGF (30.2%) was more prominent in PTMCs as compared to normal follicular cells. However, HIF-1alpha and VEGF expression was not correlated with clinicopathological features. BRAF(V600E) mutation was found in 70.7% (159/225) of the PTMC cases. PTMCs harboring the BRAF(V600E) mutation exhibited larger tumor sizes as compared to PTMCs without the BRAF(V600E) mutation (p=0.038). However, BRAF(V600E) mutation status did not correlate with the expression of HIF-1alpha (p=0.623) or VEGF (p=0.990). CONCLUSION: HIF-1alpha and VEGF were more frequently detected in PTMCs as compared to normal thyroid tissues. However, BRAF(V600E) mutation status was not correlated with the expression of HIF-1alpha or VEGF in PTMCs.
Carcinoma ; Carcinoma, Papillary ; Humans ; Hypoxia-Inducible Factor 1 ; Proto-Oncogene Proteins B-raf ; Retrospective Studies ; Thyroid Gland ; Thyroid Neoplasms ; Vascular Endothelial Growth Factor A

Myotonic dystrophies (DM) are genetic neuromuscular diseases that have autosomal dominant inheritance and are characterized by progressive muscular weakness. Myotonic dystrophy type 1 (DM1) is caused by the expansion of an unstable CTG repeat in the DMPK (myotonic dystrophy protein kinase) gene on chromosome 19q13.3. Endocrine disorders associated with DM1 include primary hypogonadism with testicular atrophy and insulin resistance. However, DM1 accompanying hypogonodotropic hypogonadism has not previously been reported in Korea. A 56-year-old man who suffered from progressive weakness and walking disturbance for many years was hospitalized due to pneumonia. During his treatment for pneumonia, he received oral hypoglycemic agents because of hyperglycemia. He was diagnosed with DM1, based on the results of an EMG and genetic analyses. He also displayed anosmia and gynecomastia and was diagnosed with hypogonodotropic hypogonadism, based on the results of hormone tests.
Atrophy ; Gynecomastia ; Humans ; Hyperglycemia ; Hypoglycemic Agents ; Hypogonadism ; Insulin Resistance ; Korea ; Male ; Middle Aged ; Muscle Weakness ; Myotonic Dystrophy ; Neuromuscular Diseases ; Olfaction Disorders ; Pneumonia ; Walking ; Wills