Research on the occurrence of CHARGE syndrome features and CHD7 mutations in patients with Kallmann syndrome

Kallmann syndrome is characterised by hypogonadotropic hypogonadism and 
an/hyposmia. These two clinical features are also frequently seen in CHARGE 
syndrome. In addition, multiple other congenital malformations can be present 
in CHARGE syndrome, e.g. heart, eye, renal and ear anomalies. CHARGE syndrome 
can be very mild and this makes it very difficult to distinguish from Kallmann 
syndrome.

CHARGE syndrome is caused by mutations in the CHD7 gene. Kallmann syndrome is 
genetically very heterogeneous and several genes are known that together 
account for 30% of all cases. The two most important genes are KAL1, 
responsible for X-linked and FGFR1 involved in autosomal dominant Kallmann 
syndrome.

In a pilot study we demonstrated a mutation in CHD7 in three out of 33 Kallmann 
syndrome patients of North-American and Japanese descent. Careful re-evaluation 
of these three patients showed that one of them fulfilled the clinical criteria 
for CHARGE syndrome. In the current study we will investigate the 
etiological/embryological overlap between these two syndromes.

To investigate the occurrence of undiagnosed CHARGE syndrome in patients 
diagnosed with (atypical) Kallmann syndrome and to define criteria for CHD7 
analysis in patients with Kallmann syndrome.

All Dutch (paediatric) endocrinologists will be addressed both by letter and at 
the meeting of paediatric endocrinologists (autumn 2007) about this part of the 
study. They will receive extensive information on CHARGE syndrome and its 
overlap with Kallmann syndrome. They will receive two information letters (for 
themselves and for the patients, E1), a medical questionairre (F1) and a 
consent form (E2). If the patient/his parents give consent, the questionairre 
and a copy of the CHD7 analysis results will be sent to Groningen for 
evaluation. CHD7-positive patients will be offered a visit to the outpatient 
clinic in Groningen.

The burden and risks associated with this study are minimal. For participation 
in this study a single bloodsample might be necessary. The study is beneficial 
for the patient and his parents.