TY - JOUR A1 - Zopf, Kathrin A1 - Frey, Kathrin R. A1 - Kienitz, Tina A1 - Ventz, Manfred A1 - Bauer, Britta A1 - Quinkler, Marcus T1 - \(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency JF - Endocrine Connections N2 - Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR). Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH. Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented. Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)). Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC. KW - medicine KW - adrenal crisis KW - adrenal insufficiency KW - cortisol KW - hydrocortisone KW - polyglandular autoimmune syndrome Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173276 VL - 6 IS - 8 ER - TY - JOUR A1 - Vona, Barbara A1 - Maroofian, Reza A1 - Bellacchio, Emanuele A1 - Najafi, Maryam A1 - Thompson, Kyle A1 - Alahmad, Ahmad A1 - He, Langping A1 - Ahangari, Najmeh A1 - Rad, Abolfazl A1 - Shahrokhzadeh, Sima A1 - Bahena, Paulina A1 - Mittag, Falk A1 - Traub, Frank A1 - Movaffagh, Jebrail A1 - Amiri, Nafise A1 - Doosti, Mohammad A1 - Boostani, Reza A1 - Shirzadeh, Ebrahim A1 - Haaf, Thomas A1 - Diodato, Daria A1 - Schmidts, Miriam A1 - Taylor, Robert W. A1 - Karimiani, Ehsan Ghayoor T1 - Expanding the clinical phenotype of IARS2-related mitochondrial disease JF - BMC Medical Genetics N2 - Background: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. Methods: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. Results: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. Conclusions: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia. KW - adrenal insufficiency KW - CAGSSS KW - cataracts KW - growth hormone deficiency KW - IARS2 KW - sensory neuropathy KW - sensorineural hearing loss KW - type II esophageal achalasia KW - skeletal dysplasia Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176620 VL - 19 IS - 196 ER - TY - JOUR A1 - Nowotny, Hanna A1 - Ahmed, S. Faisal A1 - Bensing, Sophie A1 - Beun, Johan G. A1 - Brösamle, Manuela A1 - Chifu, Irina A1 - Claahsen van der Grinten, Hedi A1 - Clemente, Maria A1 - Falhammar, Henrik A1 - Hahner, Stefanie A1 - Husebye, Eystein A1 - Kristensen, Jette A1 - Loli, Paola A1 - Lajic, Svetlana A1 - Reisch, Nicole T1 - Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis JF - Endocrine N2 - Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives. KW - adrenal insufficiency KW - congenital adrenal hyperplasia KW - adrenal crisis KW - glucocorticoid replacement KW - hydrocortisone KW - stress instructions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308769 SN - 1355-008X SN - 1559-0100 VL - 71 IS - 3 ER -