Naoko Amano1,2, Satoshi Narumi1,3, Mie Hayashi1, Masaki Takagi1,4, Kazuhide Imai5, Toshiro Nakamura6, Rumi Hachiya1,4, Goro Sasaki1,7, Keiko Homma8, Tomohiro Ishii1, Tomonobu Hasegawa1. 1. Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. 2. Department of Pediatrics, Tokyo Saiseikai Central Hospital, Tokyo, Japan. 3. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. 4. Department of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan. 5. Department of Pediatrics, Nishibeppu National Hospital, Oita, Japan. 6. Department of Pediatrics, Kumamoto Chuo Hospital, Kumamoto, Japan. 7. Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan. 8. Clinical Laboratory, Keio University Hospital, Tokyo, Japan.
Abstract
CONTEXT: Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings. OBJECTIVE: To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients. METHODS: We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics. RESULTS: We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency. CONCLUSIONS: Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.
CONTEXT: Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings. OBJECTIVE: To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients. METHODS: We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics. RESULTS: We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency. CONCLUSIONS: Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.
Authors: Fernanda Gutierrez-Rodrigues; Sushree S Sahoo; Marcin W Wlodarski; Neal S Young Journal: Best Pract Res Clin Haematol Date: 2021-06-27 Impact factor: 3.670
Authors: Sushree S Sahoo; Victor B Pastor; Charnise Goodings; Rebecca K Voss; Emilia J Kozyra; Amina Szvetnik; Peter Noellke; Michael Dworzak; Jan Starý; Franco Locatelli; Riccardo Masetti; Markus Schmugge; Barbara De Moerloose; Albert Catala; Krisztián Kállay; Dominik Turkiewicz; Henrik Hasle; Jochen Buechner; Kirsi Jahnukainen; Marek Ussowicz; Sophia Polychronopoulou; Owen P Smith; Oksana Fabri; Shlomit Barzilai; Valerie de Haas; Irith Baumann; Stephan Schwarz-Furlan; Marena R Niewisch; Martin G Sauer; Birgit Burkhardt; Peter Lang; Peter Bader; Rita Beier; Ingo Müller; Michael H Albert; Roland Meisel; Ansgar Schulz; Gunnar Cario; Pritam K Panda; Julius Wehrle; Shinsuke Hirabayashi; Marta Derecka; Robert Durruthy-Durruthy; Gudrun Göhring; Ayami Yoshimi-Noellke; Manching Ku; Dirk Lebrecht; Miriam Erlacher; Christian Flotho; Brigitte Strahm; Charlotte M Niemeyer; Marcin W Wlodarski Journal: Nat Med Date: 2021-10-07 Impact factor: 87.241
Authors: Federica Buonocore; Avinaash Maharaj; Younus Qamar; Katrin Koehler; Jenifer P Suntharalingham; Li F Chan; Bruno Ferraz-de-Souza; Claire R Hughes; Lin Lin; Rathi Prasad; Jeremy Allgrove; Edward T Andrews; Charles R Buchanan; Tim D Cheetham; Elizabeth C Crowne; Justin H Davies; John W Gregory; Peter C Hindmarsh; Tony Hulse; Nils P Krone; Pratik Shah; M Guftar Shaikh; Catherine Roberts; Peter E Clayton; Mehul T Dattani; N Simon Thomas; Angela Huebner; Adrian J Clark; Louise A Metherell; John C Achermann Journal: J Endocr Soc Date: 2021-05-11