Young Sil Eom

Identification and characterization of C106R, a novel mutation in the DNA-binding domain of GCMB, in a family with autosomal-dominant hypoparathyroidism

Overview  Glial cells missing B (GCMB) is a transcription factor that is expressed in the parathyroid hormone (PTH)‐secreting cells of the parathyroid glands. Several mutations in GCMB have been reported to cause hypoparathyroidism (HP). We identified a family with two individuals in two generations (mother and son), who are affected by autosomal‐dominant hypoparathyroidism (AD‐HP). A novel heterozygous mutation in exon 2 of GCMB was identified in both affected individuals that changes cysteine at position 106 of the putative DNA‐binding domain of GCMB to arginine (C106R).

Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914

Activating mutations of the calcium‐sensing receptor (CASR) gene are associated with autosomal dominant hypocalcemia (ADH) characterized by benign hypocalcemia, inappropriately low (PTH) levels and mostly hypercalciuria. Herein, we report a novel activating mutation in the CASR gene in a Korean family with ADH.

Role of Unilateral Aderenalectomy in ACTH-Independent Macronodular Adrenal Hyperplasia

We read with interest an article published recently in the World Journal of Surgery regarding the role of unilateral adrenalectomy in ACTH-independent macronodular adrenal hyperplasia (AIMAH) [1]. In our institution, we have experience with a few cases of AIMAH including the familial type that were all treated by bilateral adrenalectomy [2–4]. Among them, we initially treated one case of AIMAH by unilateral adrenalectomy; however, successive completion adrenalectomy was required owing to the detection of hypersecretion of cortisol in the remaining adrenal gland during follow-up [3]. A 39-year-old Asian woman was admitted to our hospital for evaluation and treatment of AIMAH. She had typical cushingoid features and hypertension. The 24-hr urinary free cortisol was 646 lg (20–90 lg/day). ACTH was not detectable. The computed tomography scan showed 2and 3-cm ovoid masses in both adrenal glands. Stimulation with mixed meal, arginine-vasopressin, luteinizing hormone, b-adrenergic agonist, serotonin, and upright posture did not change her cortisol secretion. Selective adrenal venous sampling was performed according to current recommendations [5]. It revealed a localized hyperfunctioning tumor in the left adrenal gland (Fig. 1). After laparoscopic left adrenalectomy was performed, the hypertension and cushingoid features disappeared, and the 24-hr urinary free cortisol level returned to normal. Thereafter, we have checked serial blood pressure measurements, the 24-hr urinary free cortisol level, and the size of the remaining adrenal gland. Two years after the left adrenalectomy, the patient became hypertensive again with an elevated 24-hr urinary free cortisol level and evidence of enlargement of the right adrenal gland. Completion adrenalectomy was performed laparoscopically. The patient is currently on replacement therapy with physiologic doses of steroid hormones. Many studies are underway to help define the pathophysiology of AIMAH, especially with respect to the underlying mechanisms of adrenal autonomy, including ectopic and eutopic expression of several candidate receptor genes in the adrenal gland [6]. When the molecular pathophysiology of AIMAH is completely understood, medical treatment with specific antagonizing agents or

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Genetic and Clinical Characteristics of Korean Patients with Isolated Hypoparathyroidism: From the Korean Hypopara Registry Study

Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.

Evaluation of Stress in Korean Patients with Diabetes Mellitus Using the Problem Areas in Diabetes-Korea Questionnaire

Background It is known that diabetes and stress are directly or indirectly related, and that it is important to evaluate stress in patients with diabetes. The relationship between Korean diabetics and diabetes-related stress has never been reported. The objective of this study was to develop a stress questionnaire suitable for use with Korean diabetics and to evaluate its utility. Methods This study subjects were 307 Korean diabetics, aged 40 to 74 years old, who visited the Department of Endocrinology and Metabolism at Gachon University Gil Hospital, Yeungnam University Medical Center, and Inha University Hospital in Korea between March 2006 and February 2008. We developed a Korean version of Polonskys Problem Areas in Diabetes (PAID) stress questionnaire (PAID-K) and used it to assess degrees of stress in our sample of Korean patients. We evaluated the utility of the questionnaire and analyzed the relationships between clinical characteristics of the study subjects and degrees of stress. Results Cronbachs alpha for PAID-K was 0.95, and PAID-K scores were significantly correlated with Hypoglycemia Fear Survey scores (r=0.44, P<0.05) and State Trait Anxiety Inventory-6 scores (r=0.21, P<0.05). PAID-K scores were significantly higher in patients with longer durations of diabetes, patients using insulin, and female patients (P=0.02, P=0.038, and P=0.001, respectively). The score also tended to increase as HbA1c levels increased, except for very high HbA1c levels (above 11%) (P for trend<0.05). Conclusion We developed the PAID-K questionnaire and demonstrated its utility to evaluate levels of stress in diabetic patients in Korea.

A Rare Case of Bleeding Ectopic Lingual Thyroid Presenting as Hematemesis.

To the Editor: Lingual thyroid is a rare embryological anomaly caused by failure of the gland to descend from the foramen cecum to its normal site in the pre-laryngeal area. Its precise pathogenesis is unknown, and has been found to be more prevalent in females (female:male ratio, 7:1).1 Although bleeding from an ectopic lingual thyroid is rare, life-threatening massive hemorrhage is possible, since the lingual thyroid may have prominent large blood vessels on its surface.2,3,4 We present a rare case of bleeding from an ectopic lingual thyroid presenting as hematemesis. A 42-year-old woman visited the emergency room of our hospital complaining of hematemesis. Her blood pressure was 110/70 mm Hg and pulse rate was 80 beats per minute. Given a history of recent drinking and vomiting, the initial impression was Mallory-Weiss syndrome. Initial emergency gastroendoscopic examination revealed fresh blood in the stomach, without any evidence of mucosal abnormalities in the esophagus and stomach. Under supportive care, the hematemesis spontaneously stopped two days later, and a follow-up gastroendoscopic examination showed no blood in the stomach. Neck computed tomography (CT) examination revealed a 3-cm enhancing mass on the midline base of the tongue and no presence of thyroid tissue in the normal thyroid position. On laryngoscopic examination, the mass had a smooth surface with engorged vessels, and the lesion was more clearly visualized when the tongue was pulled forward, which are characteristic findings of an ectopic lingual thyroid (Fig. 1). Thyroid ultrasonography revealed absence of the thyroid gland. Technetium (Tc99m) thyroid scan was performed and demonstrated isotope uptake at the base of the tongue and no uptake in the normal thyroid location (not shown here). A thyroid function test showed subclinical hypothyroidism: free thyroxine (fT4), 1.52 ng/dL (normal range, 0.89-1.78 ng/dL); T3, 95 ng/dL (normal range, 60-180 ng/dL); and thyroid-stimulating hormone, 6.43 mIU/mL (normal range, 0.17-4.78 mIU/mL). Although surgical removal was recommended due to the risk of re-bleeding, the patient refused surgery and opted for a wait and see approach. Fig. 1 (A) CT image showing a 3.0×2.5 cm enhancing mass (arrows) at the midline base of the tongue, above the epiglottis. (B) CT image showing no thyroid tissue in the neck or pretracheal area of the second to fourth tracheal rings (normal thyroid position). ... Ectopic thyroid is a rare developmental anomaly and is caused by aberrant embryogenesis during the descent of the thyroid gland to the neck. Thyroid tissue may be found anywhere along the course of the thyroglossal duct (i.e., oropharynx, infrahyoid area, trachea, mediastinum, esophagus, and cervical lymph nodes).2,5 Among these, lingual thyroid, complete arrest of thyroid tissue at the base of tongue, is the most common form, with a reported prevalence of 1 in 100000 to 1 in 300000 (90% of all cases of ectopic thyroid).6 Many patients are asymptomatic and a diagnosis is made incidentally as a result of neck imaging for localization of an ectopic thyroid tissue and to confirm the absence of thyroid tissue in the normal position (the pretracheal region of the second to fourth tracheal rings). In symptomatic patients, the lingual mass may result in dysphagia, foreign body sensation in the neck, dyspnea, and oropharyngeal obstruction. Although bleeding from an ectopic lingual thyroid is rare, it can be life-threatening, as massive hemorrhage is possible, since the surface of a lingual thyroid may be covered by engorged and irregular blood vessels.2,3,4 Mean age at clinical presentation is 40 years, with two peaks at 12 and 50 years of age.2,3 In our case, neck CT helped demonstrate that the lingual thyroid was the only functioning thyroid tissue, and a thyroid function test indicated mild hypothyroidism. Accordingly, we recommended thyroxine suppression therapy to prevent subsequent enlargement of the lingual thyroid and to reduce the risk of malignancy.3 Treatment of a lingual thyroid depends on the size, the presence of symptoms, and the presence of complications, such as ulceration, hemorrhage, and malignancy. Treatment of an ectopic thyroid is not necessary when the mass is asymptomatic and thyroid function and cytology are normal. However, surgery is considered when a mass produces obstructive symptoms or bleeding, demonstrates a sudden increase in size, or if malignancy is suspected.2,3,6 In patients being considered for surgical excision, it is essential to establish if any normal thyroid tissue is present elsewhere, because removal of a lingual thyroid will in most cases render the patient profoundly hypothyroidal. After ruling out common causes of acute gastrointestinal bleeding by gastroendoscopic examination, bleeding ectopic lingual thyroid could be considered as a rare cause of hematemesis in emergency situations.

Genetic Analysis of Multiple Endocrine Neoplasia Type 1 (MEN1) Leads to Misdiagnosis of an Extremely Rare Presentation of Intrasellar Cavernous Hemangioma as MEN1

Background Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder characterized by the simultaneous occurrence of endocrine tumors in target tissues (mainly the pituitary, endocrine pancreas, and parathyroid glands). MEN1 is caused by mutations in the MEN1 gene, which functions as a tumor suppressor and consists of one untranslated exon and nine exons encoding the menin protein. This condition is usually suspected when we encounter patients diagnosed with tumors in multiple endocrine organs, as mentioned above. Methods A 65-year-old woman who underwent surgery for a pancreatic tumor (serous cystadenoma) 5 years previously was referred to our hospital due to neurologic symptoms of diplopia and left ptosis. Brain magnetic resonance imaging revealed a 3.4-cm lesion originating from the cavernous sinus wall and extending into the sellar region. It was thought to be a nonfunctioning tumor from the results of the combined pituitary function test. Incidentally, we found that she also had a pancreatic tumor, indicating the necessity of genetic analysis for MEN1. Results Genomic analysis using peripheral leukocytes revealed a heterozygous c.1621G>A mutation in the MEN1 gene that was previously reported to be either a pathogenic mutation or a simple polymorphism. We pursued a stereotactic approach to the pituitary lesion, and microscopic findings of the tumor revealed it to be an intrasellar cavernous hemangioma, a rare finding in the sellar region and even rarer in relation to oculomotor palsy. The patient recovered well from surgery, but refused further evaluation for the pancreatic lesion. Conclusion There is great emphasis placed on genetic testing in the diagnosis of MEN1, but herein we report a case where it did not assist in diagnosis, hence, further discussion on the role of genetic testing in this disease is needed. Also, in cases of pituitary tumor with cranial nerve palsy, despite its low prevalence, intrasellar cavernous hemangioma could be suspected.