Universitätsklinikum Carl Gustav Carus Dresden, Klinik für Kinder- und Jugendmedizin, Fachbereich Endokrinologie und Diabetologie
Genetics of the primary adrenal insufficiency (PAI) in children and adults
Primary adrenal insufficiency (PAI) is a rare but potentially life-threatening disease. Genetic defects are the main cause for PAI in children whereas acquired forms such as autoimmune adrenalitis are predominant in adults. In recent years, the spectrum of genetic defects of many rare forms of PAI was extended. However, in almost 20 % of the patients the underlying genetic condition remains unclear. Making a specific diagnosis might have implications for the management of the patients, for detecting associated features as well as for counselling families about the risk of recurrence. The goal of my research is to contribute to the continuous progress in detecting genetic defects causing PAI offering a better care for affected patients in the long-term. Therefore, we are internationally looking for patients with PAI of unknown cause.
Firstly, we examined an 18 year old female with PAI and premature ovarian insufficiency from consanguineous parents. Whole exome sequencing revealed a novel homozygous missense mutation in the growth regulation by estrogen in breast cancer 1 (GREB1) gene which is highly expressed in fetal adrenal glands and adult ovaries and therefore seemed to be a promising target for dysfunction in PAI. However, genetic analysis of the siblings showed the same homozygous mutation in the unaffected sister and following extensive endocrinological workup did not proof adrenal insufficiency in her. Consequently, GREB1 was ruled out as a hot candidate for PAI.
Secondly, we initiated whole exome sequencing in three male patients aged 5, 15 and 24 years that were referred to us from the mother and childcare hospital Belgrad (Serbia) presenting with congenital glucocorticoid and mineralocorticoid deficiency. We detected a X-chromosal mutation in the CACNA1F gene in the youngest patient which encodes an L-type calcium channel that is expressed in the adrenal gland. As this channel possibly supports the modulation of hormone secretion we are planning to assess the role of CACNA1F in the adrenal cortex.
Thinking outside the box and getting deeper into rare syndromes in endocrinology we investigated a family with severe disproportionate short stature and acromely. Whole exome sequencing revealed a novel heterozygous missense variant in the transforming growth factor beta 5 domain of the fibrillin-1 (FBN1) gene causing a new mild phenotype of acromicric dysplasia which is an extremely rare skeletal dysplasia.
Tschaidse L, Quitter F, Hübner A, Reisch N. Langzeitmorbidität beim adrenogenitalen Syndrom. Internist (Berl). 2022;63:43-50. https://doi.org/10.1007/s00108-021-01223-6
Steenblock C, Hassanein M, Khan E, Yaman M, Kamel M, Babir M, Lorke D, Everett D, Bejtullah S, Lohmann T, Lindner U, Tahirukaj E, Soliman S, Quitter F, Bornstein S: Obesity and COVID-19: What are the consequences? Hormone and Metabolic Research 2022 (accepted 4th April 2022).
Schubert T, Reisch N, Naumann R, Reichardt I, Landgraf D, Quitter F, Thirumalasetty SR, Heninger AK, Sarov M, Peitzsch M, Huebner A, Koehler K. CYP21A2 gene expression in a humanized 21-hydroxylase mouse model does not affect adreno-cortical morphology and function. Journal of the Endocrine Society (2022) (accepted 8th of April 2022).
Dumic K, Heinrichs C, Koehler K, Huebner A, Dumic M, Kusec V, Dusek T, Quitter F. Fertility in patients with triple A syndrome. Experimental and Clinical Endocrinology and Diabetes (submitted).
Quitter F, Flury M, Waldmueller S, Schubert, T, Köhler K, Huebner A. Acromicric Dysplasia due to a novel missense mutation in the fibrillin 1 gene in a three-generation family. Journal of Pediatric Endocrinology and Metabolism.
Conference contributions 2020-2022:
Poster ESPE 2022: Palm K, Bechthold-Dalla Pozza S, De Sousa SB, Högler W, Hoyer- Kuhn H, Hübner A, Keller A, Mohnike K, Muschol N, Nader S, Pfäffle R, Quitter F, Rohrer T, Rutsch F, Schnabel D, Semler J, Völkl T, Wechsung K, Weigel J, Wölfle J, Lausch E. “Real-world data in children with achondroplasia after licensing of Vosoritide”
Poster ESPE 2022: Reichardt S, Mayer B, Quitter F, Hübner A. “Nephrolithiasis and hypoparathyroidism with normocalcemia – detecting a new mutation solves the mystery”