Young-Lim Shin

Endocrine Manifestations of Chromosome 22q11.2 Microdeletion Syndrome

Background: Endocrine abnormalities, including hypocalcemia, thyroid dysfunction, and short stature, are associated with chromosome 22q11.2 microdeletion syndrome. This study was undertaken to examine the frequencies and clinical features of endocrine abnormalities in patients with 22q11.2 microdeletion syndrome. Methods: We analyzed 61 patients with 22q11.2 microdeletion syndrome diagnosed based on the verification of microdeletion by fluorescent in situ hybridization (FISH) using a probe of the DiGeorge syndrome critical region (TUPLE1) at 22q11.2 and a control probe, ARSA at 22q13. Serum total calcium, phosphorus, and intact parathyroid hormone (PTH) levels were measured, thyroid function test was performed, and serum IGF-1 and IGFBP-3 levels were also estimated. Height and weight of patients were compared with individual chronological ages. Results: Hypocalcemia was found in 20 patients (32.8%), and overt hypoparathyroidism in 8 (13.1%). Two patients (3.3%) showed autoimmune thyroid diseases, 1 each with Graves’ disease and Hashimoto thyroiditis. Ten patients (16.4%) were below the third percentile in height, but the serum IGF-1 level was normal in 9 out of these 10 patients. Conclusion: Our findings show that patients with chromosome 22q11.2 microdeletion syndrome present with variable endocrine manifestations and variable clinical phenotypes. In addition to FISH analysis, careful endocrine evaluations are required in patients with this microdeletion syndrome, particularly for those with hypoparathyroidism or thyroid dysfunction.

Identification of a novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome presenting with neonatal diabetes mellitus and galactosaemia

We describe a patient with Fanconi-Bickel syndrome diagnosed by clinical manifestations and the identification of a novel mutation in the GLUT 2 gene. She was initially diagnosed with neonatal diabetes mellitus due to hyperglycaemia and glycosuria at 3 days of life. In addition, newborn screening for galactosaemia revealed hypergalactosaemia. Thereafter, she was managed with lactose-free milk and insulin therapy. However, she failed to grow and her liver became progressively enlarged. Her liver function deteriorated with increased prothrombin time. A liver biopsy done at age 9 months showed micronodular cirrhosis with marked fatty changes and she succumbed to hepatic failure with pneumonia at 10 months of age. DNA sequencing analysis of the GLUT 2 gene using her genomic DNA revealed a novel mutation in codon 5, lysine5 stop(K5X).

Identification of Novel Mutations of the DAX-1 Gene in Patients with X-Linked Adrenal Hypoplasia Congenita

Objective: X-linked adrenal hypoplasia congenita (AHC) is a condition clinically featuring adrenal insufficiency and hypogonadotropic hypogonadism caused by mutations of DAX-1. This study was undertaken to characterize the molecular defects of DAX-1 in 3 unrelated Korean patients with AHC. Patients and Methods: Patient 1 is a 6-year-old boy who presented with a salt-losing adrenal crisis in the neonatal period. Patient 2 is a 3-year-old boy who manifested aspiration pneumonia and adrenal insufficiency at the age of 1 month. Patient 3 is a 7-year-old boy who developed an adrenal crisis at the age of 3 days. In each of these patients, DAX-1 was analyzed by direct DNA sequencing after polymerase chain reaction amplification of the entire coding region. Results: Direct sequencing of DAX-1 revealed two novel mutations, 1156_1157delCT in patient 1 and another novel nonsense mutation W105X in patient 2. Patient 3 had complete deletion of DAX-1. In patient 3, serum transaminases and creatine kinase levels were elevated while the glycerol kinase activity of leukocytes was decreased. Markedly elevated glycerol excretion was detected by urine organic acid analysis. Patient 3 was diagnosed as Xp21 contiguous gene syndrome associated with deletions of the entire IL1RAPL, GK genes and the C-terminal region of DMD gene. Conclusions: Two novel mutations of DAX-1 were detected in 2 unrelated patients with AHC, and complete deletion of DAX-1 in a patient with Xp21 contiguous gene syndrome who also presented with glycerol kinase deficiency, Duchenne muscular dystrophy, and AHC.

Diverse genetic aetiologies and clinical outcomes of paediatric hypoparathyroidism

Hypoparathyroidism is characterized by hypocalcaemia, hyperphosphataemia, and low or inappropriately normal parathyroid hormone (PTH) levels. Idiopathic or genetic drivers are the predominant causes of hypoparathyroidism in paediatric‐age patients.

Comparison of clinical, radiological and molecular findings in Korean infants and children with achondroplasia and hypochondroplasia.

Achondroplasia (ACH) and hypochondroplasia (HCH) share clinical features characterized by disproportionate short stature with rhizomelic shortening of the limbs. In an attempt to clarify genotype-phenotype correlation in ACH and HCH, we investigated the presence of the previously identified mutations of FGFR3 in 26 patients with ACH- or HCH-mimicking features and compared clinical and radiographic findings between the two groups. Using genomic DNA sequencing and RFLP analysis, G380R, an ACH-specific mutation, and N540K, an HCH-specific mutation, were detected in 13 patients (50%) and five patients (19%), respectively. No mutations of FGFR3 were detected in eight patients (31%). No remarkable clinical or radiological differences were evident among the ACH infants and children with G380R, the HCH patients with N540K, and the patients without verified mutations. These results suggest that genotype-based diagnosis needs to precede proper genetic counseling for patients with ACH or HCH, which show very similar clinical and radiological features.

Frequency of Self-Monitoring of Blood Glucose during the School Day Is Associated with the Optimal Glycemic Control among Korean Adolescents with Type 1 Diabetes

Background This study aimed to evaluate the relationship between the frequency of self-monitoring of blood glucose (SMBG) and glycosylated hemoglobin (HbA1c) levels among Korean adolescents with type 1 diabetes mellitus (T1DM). Factors affecting the SMBG frequency were analyzed in order to improve their glycemic control. Methods Sixty-one adolescents aged 13 to 18 years with T1DM were included from one tertiary center. Clinical and biochemical variables were recorded. Factors associated with SMBG frequency were assessed using structured self-reported questionnaires. Results Average total daily SMBG frequency was 3.8±2.1 and frequency during the school day was 1.3±1.2. The mean HbA1c level was 8.6%±1.4%. As the daily SMBG frequency increased, HbA1c levels declined (P=0.001). The adjusted odds of achieving the target HbA1c in participants who performed daily SMBG ≥5 significantly increased 9.87 folds (95% confidence interval [CI], 1.58 to 61.70) compared with those performed SMBG four times a day. In the subjects whose SMBG frequency <1/day during the school day, an 80% reduction in the adjusted odds ratio 0.2 (95% CI, 0.05 to 0.86) showed compared to the group with performing two SMBG measurements in the school setting. The number of SMBG testing performed at school was significantly high for individuals assisted by their friends (P=0.031) and for those who did SMBG in the classrooms (P=0.039). Conclusion Higher SMBG frequency was significantly associated with lower HbA1c in Korean adolescents with T1DM. It would be necessary to establish the school environments that can facilitate adequate glycemic control, including frequent SMBG.

Two sporadic patients of Perrault syndrome with ovarian dysgenesis and sensorineural deafness

Perrault syndrome is an autosomal recessive disorder characterized by sensorineural deafness and ovarian dysgenesis. Some patients also have neurologic abnormalities, including cerebellar ataxia, nystagmus, polyneuropathy and mild mental retardation. The syndrome is known to be caused by mutations in HSD17B4 or HARS2 until now but few patients were reported. We report on two sporadic Korean patients of Perrault syndrome with ovarian dysgenesis and sensorineural deafness. Patient 1 : A 14 year-6 month female patient presented with delayed puberty. She had bilateral sensorineural hearing impairment. Her neurological findings were normal and She had no mental retardation. She had normal karyotype (46, XX) and hypergonadotropic hypogonadism. Pelvic ultrasound showed a small uterus and ovaries. Brain MRI was normal. Patient 2 : A 16 year-11 month female presented with delayed puberty and neurologic manifestations. She had ataxia, dyspraxia and weakness. She had no mental retardation and brain MRI was normal. She had multiple Cafe au lait spots and long slender fingers but no Marfanoid features. Laboratory tests revealed hypergonadotropic hypogonadism and normal female karyotype (46, XX). Pelvic ultrasound examination showed a hypoplastic uterus and small ovaries. Because Perrault syndrome has clinical variability and genetically heterogeneous, we have to inspect additional findings and neurological abnormalities. And further studies will be required to ascertain the common causative mutation of this syndrome.

Acknowledgements to Reviewers

Badenhoop, K., Frankfurt am Main Bang, P., Stockholm Baron, J., Bethesda, Md. Barreca, A., Genoa Barrios, V., Madrid Bartalena, L., Varese Bartrons, R., L’Hospitalet Baudin, E., Villejuif Bauer, K., Hannover Baumgartner, A., Berlin Baxter, R., St. Leonards Beauvillain, J.C., Lille Beck, M., Mainz Beck-Peccoz, P., Milan Ben-Shlomo, A., Los Angeles, Calif. Bettendorf, M., Heidelberg Bianchi, G., Bologna Bland, M.L., San Francisco, Calif. Blasi Cabus, J.M., Barcelona Böhm, B., Ulm Brabant, G., Hannover Brain, C.F., London Brämswig, J.H., Münster Breckwoldt, M., Freiburg i. Br. Brucker, C., Ulm Buchanan, C., London Burbach, J.P., Utrecht Buyse, M., Paris Buyukgebiz, A.B., Izmir Carel, J.-C., Paris Chaussain, J.-L., Paris Chiarelli, F., Chieti Chrousos, G.P., Bethesda, Md. Clark, A.J.L., London Coerper, S., Tübingen Cohen, L.E., Boston, Mass. Cohen, M.M., Halifax Cole, T.J., London Corry, D.B., Sylmar, Calif. Cowell, C.T., Westmead Crofton, P.M., Edinburgh Cutfield, W., Auckland Czernichow, P., Paris

Contents Vol. 60, 2003

Anne Marcovich: Quelles missions pour les médecins de campagne du XIX siècle français? Soigner, éduquer, civiliser. Le rapport d’un médecin cantonal du Haut-Rhin (Alsace) en 1849 [Which Tasks for Countryside Physicians in 19th Century France? To Heal, to Educate, to Civilise the People.A Country Physician’s Report from the French Department of the Haut-Rhin in 1849] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170