Immunological and adrenal function in children with CHARGE syndrome

Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of
growth and/or development, Genital abnormalities, Ear abnormalities and
deafness (CHARGE) syndrome is caused by a de novo dominant mutation in the CHD7
gene. Truncating mutations in the CHD7 gene are, in general, associated with a
more severe phenotype compared to non-truncating mutations.
CHARGE syndrome has a high morbidity and we noticed unexplained mortality in
our own CHARGE population. CHARGE syndrome shares many features with 22q11.2
deletion syndrome, a syndrome that often shows immunological dysfunction.
CHARGE syndrome also shares features, in particular hypothalamic-pituitary
hormonal disorders, with Prader-Willi syndrome. In the latter syndrome central
adrenal insufficiency has been demonstrated, a condition that influences
morbidity and mortality.
Thus, the aim of the study is to explore whether immune dysfunction and central
adrenal insufficiency are part of the complex phenotype of CHARGE syndrome, and
thus eventually may contribute to its morbidity. Since it has been noticed that
children with CHARGE syndrome due to a truncating mutation have in general a
more severe phenotype than children with a non-truncating mutation, we will
compare our immunological observations in both groups. If central adrenal
dysfunction is found, we will correlate this observation with the type of
mutation (i.e. dysfunction is more frequently seen in children with truncating
versus non-truncatng mutations). The results of this study will enable us to
indicate whether future studies are needed to underpin evidence*based
guidelines for appropriate diagnostic immunological and adrenal function
testing and surveillance or treatment in patients with CHARGE syndrome.

Our primary objectives are:
- to estimate the prevalence of central adrenal insufficiency , defined as a
plasma cortisol response <500 nmol/l in the low-dose ACTH test (see paragraph
8.3.5 of the protocol).
- to describe immune dysfunction, i.e. whether individual immunological
parameters deviate from normal and if so, which parameters
- to estimate the prevalence of immune dysfunction
in children with CHARGE syndrome due to a CHD7 mutation.

Secondary, we want
- to describe whether there is a relation between the immunological laboratory
outcomes and
o the presence or absence of clinical signs of immune dysfunction based on
a questionnaire
o the genotype, i.e. truncating versus non-truncating mutation in CHD7
in children with CHARGE syndrome.
- to correlate central adrenal insufficiency with type of CHD7 mutation, i.e.
whether central adrenal indufficiency is more often seen in children with
CHARGE syndrome due to a truncating mutation than due to a non-truncating
mutation
- to indicate whether future studies are needed to underpin evidence-based
guidelines for appropriate diagnostic testing and surveillance or treatment of
immune and adrenal function disorders in patients with CHARGE syndrome.
.

The study is an observational cross sectional study. For some of the
immunological testing a case-control design will be used.

Children with CHARGE syndrome may benefit from the immunological and adrenal
function tests as timely diagnosis of insufficient immunological and adrenal
function may result in prevention of complications. The risk and burden
associated with the study can be considered negligible and minimal,
respectively. All participants will have to visit the hospital for half a day.
Study participants will have to fill-out a structured questionnaire (15-20
minutes). They will undergo a short physical examination. An intravenous
peripheral catheter will be inserted (total blood sampling 12-15 ml). The
healthy control group will have to fill-out a simplified questionnaire (5-10
minutes). Only height and weight will be measured. A single venous puncture of
3 ml blood will be performed. Both the adrenal function test and the
immunological tests are validated tests and are used in routine patient
diagnostics. Appropriate medical care and surveillance will be offered to all
participants with abnormal study results. This study can only be performed in
children with CHARGE syndrome as explained in the rationale. A control group is
needed to significantly increase the reliability of the outcome parameters in
the study participants.