Genetic Analysis of CLCN7 in an Old Female Patient with Type II Autosomal Dominant Osteopetrosis

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.

Oncogenes, mitochondrial metabolism, and quality control in differentiated thyroid cancer

Thyroid cancer is one of the most common malignancies of endocrine organs, and its incidence rate has increased steadily over the past several decades. Most differentiated thyroid tumors derived from thyroid epithelial cells exhibit slow-growing cancers, and patients with these tumors can achieve a good prognosis with surgical removal and radioiodine treatment. However, a small proportion of patients present with advanced thyroid cancer and are unusually resistant to current drug treatment modalities. Thyroid tumorigenesis is a complex process that is regulated by the activation of oncogenes, inactivation of tumor suppressors, and alterations in programmed cell death. Mitochondria play an essential role during tumor formation, progression, and metastasis of thyroid cancer. Recent studies have successfully observed the mitochondrial etiology of thyroid carcinogenesis. This review focuses on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism.

The Eosinophil Count Tends to Be Negatively Associated with Levels of Serum Glucose in Patients with Adrenal Cushing Syndrome

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.

Association between Growth Differentiation Factor 15 (GDF15) and Cardiovascular Risk in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

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.

Morphological and Functional Changes in the Thyroid Follicles of the Aged Murine and 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.

Multiple Fractures in Patient with Graves' Disease Accompanied by Isolated Hypogonadotropic Hypogonadism

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.

A Case of Low Bone Mineral Density with Vitamin D Deficiency Due to Prolonged Lactation and Severe Malnutrition

Malnutrition associated vitamin D deficiency contributes to the calcium loss from bone and results in osteoporosis and osteomalacia at final stage. Osteomalacia is characterized with softening of bone secondary to defective bone mineralization. Here, we report a case of possible osteomalacia caused by prolonged lactation and severe malnutrition in 35-year-old female. She was a housewife and her body mass index was 11.8 kg/m2. She was diagnosed with severe osteoporosis in regular health check-up 2 years ago, but did not take any medication. Nine months ago, she had been treated with anti-tuberculosis medications for 6 month due to active pulmonary tuberculosis. After complete remission of pulmonary tuberculosis, she had lost her appetite severely. Furthermore, she felt gait difficulty and suffered from generalized bone pain. On serologic examination, hypocalcemia, hypophosphatemia, high alkaline phosphatase, low vitamin D3 and high parathyroid hormone level were seen. In the bone mineral density, Z-score from her lumbar spine was -6.5. She was treated with oral calcium and vitamin D3 intramuscularly. After 1 year treatment, she felt significant improvement in bone pain and could walk alone. Also her serum calcium, phosphate and vitamin D3 level are all normalized.

GDF15 Is a Novel Biomarker for Impaired Fasting Glucose

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.

A Novel PHEX Gene Mutation in a Patient with Sporadic Hypophosphatemic Rickets

Phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) is a common cause of X-linked hypophosphatemic (XLH) rickets. Diverse PHEX gene mutations have been reported; however, gene mutations in sporadic rickets are less common than in XLH rickets. Herein, we describe a 50-year-old female patient with sporadic hypophosphatemic rickets harboring a novel splicing-site mutation in the PHEX gene (c.663+1G>A) at the exon 5-intron 5 boundary. The patient had recently suffered from right thigh pain and an aggravated waddling gait. She also presented with very short stature, generalized bone pain, and muscle weakness. Despite low serum phosphate levels, her phosphate reabsorption rate was lower than normal. Additionally, her 1,25-dihydroxyvitamin D3 concentration was lower than normal, although FGF23 level was normal. After treatment with alfacalcidol and elemental phosphate, her rachitic symptoms subsided, and callus formation was observed in the fracture site on the right femur.

NAD(P)H: Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 Polymorphisms in Papillary Thyroid Microcarcinoma: Correlation with Phenotype

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.

Aberrant L1 Cell Adhesion Molecule Expression in Cancer: In View of Proliferation, Migration and Invasion / 대한갑상선학회지

L1 cell adhesion molecule (L1CAM) is a 220-kDa type I membrane glycoprotein and is normally expressed in neuronal cells, endothelial cells, and renal epithelial cells. Recent clinical studies demonstrated aberrant L1CAM expression in various cancers, especially at the invasive area of cancers. L1CAM has a key role in tumorigenesis, tumor invasion, and it is associated with a poor prognosis of cancer. Anaplastic thyroid carcinoma (ATC) has a highly poor outcome and it is resistant to conventional treatment. In this review, I discuss the biological role of L1CAM in proliferation, migration, and invasion in the ATC.

Effects of Diabetic Camp in Type 2 Diabetic Patients / 대한내과학회지

BACKGROUND/AIMS: When a patient is diagnosed with diabetes mellitus, it is important to help both the patient and their family members gain knowledge and confidence with regard to self-management. A diabetes camp is an excellent way to recognize the benefits of education. This study was conducted to evaluate the effects of diabetes camp on patients with type 2 diabetes. METHODS: This study comprised 30 patients with diabetes who had participated in a diabetes camp from August 2005 through August 2011. The effectiveness of the diabetes camp was examined retrospectively via clinical parameters, compliance behavior, and a self-esteem questionnaire. RESULTS: Glycated hemoglobin (HbA1c; p = 0.004) was significantly decreased, while measures of self-esteem (p = 0.000) and compliance (p = 0.001) were significantly increased after attending the camp. No significant differences were observed in other clinical parameters, such as weight, body mass index (BMI), and lipid profiles, before and after camp attendance. CONCLUSIONS: Diabetes camp may be an effective way to control diabetes mellitus.

Case of Myotonic Dystrophy with Hypogonadotropic Hypogonadism / 대한내과학회지

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.

HIF-1alpha Expression in BRAF(V600E)-Positive Papillary Thyroid Microcarcinoma / 대한갑상선학회지

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.

A Case of Gastrointestinal Stromal Tumor with Recurrent Hypoglycemia

Non-islet cell tumor induced hypoglycemia (NICTH) is attributable to overproduction of insulin-like growth factor-II (IGF-II) by solid tumors, and these tumors usually originate from mesenchymal or epithelial cells. Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor and most commonly find in the gastrointestinal tract. It is usually expresses the CD117 (stem cell factor receptor, c-kit) detected by immunohistochemistry. Hypoglycemia associated with GIST is very rare and this has not yet been reported in Korea. A 72-year-old man was hospitalized due to frequent episodes of confusion. It was observed that non-hyperinsulinemic hypoglycemia, an elevated serum IGF-II level and a huge liver mass. The histology of liver mass showed c-kit (CD117) positivity, which was consistent with GIST, but it was surgically unresectable. He was treated with imatinib mesylate. Although he recieved palliative treatment, he still experienced intermittent fasting hypoglycemia. After 2 months, the serum IGF-II level was even higher than before. We changed imatinib mesylate to sunitinib malate and performed radiotherapy on the liver mass. Although the change of the liver mass was not significant, he did not suffer from hypoglycemia for three months afterwards.

The Relationship between the BRAF Mutations in Thyroid Papillary Carcinomas and the Prognostic Factors / 대한내분비학회지

BACKGROUND: Thyroid cancers account for about 1% of all human malignancies, with papillary thyroid carcinomas being the most common istotype. Several investigators have recently identified the most common BRAF mutation, the T1796A transversion mutation, in 29~69% of papillary thyroid cancers. The BRAF mutation has been demonstrated as a novel prognostic biomarker for the prediction of poor clinicopathological outcomes, such as increased incidence of extrathyroid invasion and distant metastasis of the tumor. In this study, we investigated the prevalence of the BRAF mutation of thyroid tissues obtained by a thyroidectomy, and its correlation with the clinicopathological outcomes. METHODS: We studied 36 thyroid tissues obtained from 24 women and 12 men by thyroidectomies, including 30 papillary carcinomas, 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia. The mutation was sought in all specimens using DNA sequencing. RESULTS: We studied the BRAF exon 15 T1796A in these 36 thyroid tissues. The mean age at surgery was 46.6, ranging from 18 to 72 years, with a median tumor size of 2.79, ranging from 1.5 to 4.5cm. At the time of diagnosis, 27 of the 34 patients presented with some kind of extrathyroidal invasion of the tumor, and 16 had lymph node metastases. 16, 2 and 16 patients were in stages I, II and III, respectively. There was no distant metastasis. A missense mutation was found at T1796A in exon 15 in 21 of the 30 papillary carcinomas(70%). The other thyroid diseases, including the 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia show no exon 15 T1759A transversion mutation. No statistically significant association was found between the BRAF mutations and clinicopathological characteristics of papillary carcinomas. CONCLUSION: The BRAF mutation is a important genetic alteration, with a high prevalence in papillary thyroid carcinomas. However, there was no significant association between the BRAF mutation and any of the clinicopathological factors. Further, large scale studies will be needed to evaluate the correlation between the BRAF mutation and the clinicopathological factors

The Relationship between the BRAF Mutations in Thyroid Papillary Carcinomas and the Prognostic Factors / 대한내분비학회지

BACKGROUND: Thyroid cancers account for about 1% of all human malignancies, with papillary thyroid carcinomas being the most common istotype. Several investigators have recently identified the most common BRAF mutation, the T1796A transversion mutation, in 29~69% of papillary thyroid cancers. The BRAF mutation has been demonstrated as a novel prognostic biomarker for the prediction of poor clinicopathological outcomes, such as increased incidence of extrathyroid invasion and distant metastasis of the tumor. In this study, we investigated the prevalence of the BRAF mutation of thyroid tissues obtained by a thyroidectomy, and its correlation with the clinicopathological outcomes. METHODS: We studied 36 thyroid tissues obtained from 24 women and 12 men by thyroidectomies, including 30 papillary carcinomas, 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia. The mutation was sought in all specimens using DNA sequencing. RESULTS: We studied the BRAF exon 15 T1796A in these 36 thyroid tissues. The mean age at surgery was 46.6, ranging from 18 to 72 years, with a median tumor size of 2.79, ranging from 1.5 to 4.5cm. At the time of diagnosis, 27 of the 34 patients presented with some kind of extrathyroidal invasion of the tumor, and 16 had lymph node metastases. 16, 2 and 16 patients were in stages I, II and III, respectively. There was no distant metastasis. A missense mutation was found at T1796A in exon 15 in 21 of the 30 papillary carcinomas(70%). The other thyroid diseases, including the 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia show no exon 15 T1759A transversion mutation. No statistically significant association was found between the BRAF mutations and clinicopathological characteristics of papillary carcinomas. CONCLUSION: The BRAF mutation is a important genetic alteration, with a high prevalence in papillary thyroid carcinomas. However, there was no significant association between the BRAF mutation and any of the clinicopathological factors. Further, large scale studies will be needed to evaluate the correlation between the BRAF mutation and the clinicopathological factors

The Adequacy of Ultrasound-Guided Fine Needle Aspiration in Thyroid Nodules / 대한내분비학회지

BACKGROUND: Fine needle aspiration(FNA) is an accurate and safe method for the diagnosis of thyroid nodules. One of the limitations of FNA is the variable rate of unsatisfactory specimens, especially in small sized, deep seated or complex cystic nodules. To overcome this problem, ultrasound-guided FNA(US-FNA) has been widely used. In this study, the adequacy of cytologic specimens by US-FNA was compared with that of conventional palpation-guided FNA(P-FNA). METHODS: The medical records of all patients who were engaged in FNA due to thyroid nodules at Chungnam National University Hospital from January 2003 to July 2004 were retrospectively examined. The US-FNA and P-FNA were performed in 114 and 185 patients, respectively. RESULTS: Comparison of the adequacy of the two techniques in providing sufficient material for the cytologic diagnosis showed that specimens in 24(13.0%) and 6(5.3%) patients collected by P-FNA and US-FNA, respectively, were unsatisfactory(P=0.031). A total of 23 patients underwent thyroid surgery due to strong suspicion of malignancy at cytologic finding and/or on clinical judgement. Seventeen patients belonged to the P-FNA group and 6 patients to the US-FNA group. In the P-FNA group, a histologic diagnosis revealed two false-negative cytologic findings, but no false-negative findings were found in the US-FNA group. CONCLUSION: Compared with P-FNA, US-FNA may reduce the possibility of unsatisfactory cytologic specimens and the rate of false-negative diagnosis, and may improve the diagnostic accuracy in investigating thyroid nodules

The STAT3 in Glucose Homeostasis / 대한내분비학회지

No abstract avaiable.