CHARGE syndrome: moleculair diagnosis, clinical aspects and its overlap with Kallmann syndrome

PhD ceremony: Ms. J.E.H. van Kammen-Bergman, 16.15 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: CHARGE syndrome: moleculair diagnosis, clinical aspects and its overlap with Kallmann syndrome

Promotor(s): prof. C.M.A. van Ravenswaaij-Arts, prof. R.M.W. Hofstra

Faculty: Medical Sciences

The focus of the thesis is on two rare hereditary syndromes: CHARGE syndrome and Kallmann syndrome. Patients with these syndromes may present with a smell deficit and absent pubertal maturation. CHARGE syndrome is caused by mutations in the CHD7 gene, but the genetics of Kallmann syndrome is still largely unknown. We developed a database containing all known CHD7 mutations (www.CHD7.org). In addition, a classification system was created to predict whether certain ‘mild’ CHD7 variants cause the disease. We showed that a smell deficit, genital anomalies, and decreased fertility are present in some mice with CHARGE syndrome. In patients with CHARGE syndrome, we demonstrated that a smell deficit is always correlated with absent pubertal maturation. A smell test can therefore predict whether a child with CHARGE syndrome will enter puberty spontaneously, providing the opportunity for timely hormone replacement therapy. Furthermore, we identified risk factors for sudden death in CHARGE syndrome and developed recommendations to prevent premature demise. We showed that some patients with a CHD7 mutation have very few features of CHARGE syndrome, whereas others have many/severe anomalies. A guideline was compiled indicating in which patients CHD7 analysis is useful. Also, we proposed recommendations for follow-up and treatment of patients with a CHD7 mutation. We showed that some patients with Kallmann syndrome carry a CHD7 mutation. These patients often had additional features of CHARGE syndrome.