The prevalence of the IGSF-1 mutation in children who develop central hypothyroidism after starting Growth Hormone treatment.

In children with suspected isolated GH deficiency (GHD), the free thyroxine
(FT4) concentrations may fall after starting with hormone (GH) treatment. This
central hypothyroidism could be the result of unmasking an already existing
(mild) central hypothyroidism by giving GH. Consequently, this could indicate
the existence of (congenital) multiple anterior pituitary insufficiency rather
than an isolated GHD. With this in mind, we hypothesized that children who
develop central hypothyroidism after starting GH, already had lower thyroxine
concentrations at birth compared to children with true isolated GHD. To confirm
this hypothesis, a previous study was performed (2011_371): 'The thyroid
hormones after starting Growth Hormone treatment in children.

The aim of this study was to compare the T4 concentrations of children with a
'real' isolated GHD, measured during the neonatal screening, compared with
children who developed central hypothyroidism after starting GH.
For this purpose written informed consent was received from 369 children
diagnosed with GHD in 41 national medical centers. Of these 369 children
information was retrieved from the RIVM and the Foundation for Child and Growth.
This information showed that 27 children after starting with GH were treated
with thyroxine. Moreover, we found that children who did not receive thyroxine
after start with GH have an higher T4 average at the neonatal screening than
children with central hypothyroidism (- 0.31 SD (n = 127) versus -1.3 SD (n =
5)). These data are clinically relevant because these children probably already
have an congenital central hypothyroidism and may benefit with earlier
detection and treatment.
Recently, a new gene is discovered, the IGSF-1 gene, which may be responsible
for the existence of a central hypothyroidism. In these children GHD can also
be present.

1) Follow-up study of project 2011_371:
To determine whether the 27 children found in this study actually had a central
hypothyroidism, by complementing the existing data with details from the
medical records. The data used in the first study were obtained from the
database of the Foundation for Child and Growth. These data were provided by
the treating pediatricians to the Foundation and are measured at baseline,
after 1 year and 2 years of GH therapy. We included all children in the group
if a decrease in FT4 was seen in the period from 0 to 2 years after starting GH
treatment. However, the exact moment of decline in FT4 concentrations is
unknown to us. we are also not informed on the precise laboratory data just
before starting T4 . Our hypothesis that the growth velocity in children who
need thyroxine after starting with GH is lower than children who don't need
thyroxine is not answered by the lack of sufficient data.
For this reason, further research is needed in medical files; firstly to
definitively establish that these 27 children started with thyroxie for
diagnosing central hypothyroidism (indicating the precise laboratory values **
at the time of start GH). Also, it is necessary to collect data for confirming
the hypothesis that these children had a slower growth rate from the moment of
starting GH due to co-existing ypothyroidism, compared to children who don't
need thyroxine treatment. From the parents of these 27 children, currently only
informed consent was asked and received for the retrieval of information known
to the Foundation for Child and Growth and the RIVM where neonatal screening
results are saved, but not to gather data from the medical files of the
corresponding hospital.

2) The prevalence of the mutation in the IGSF-1 gene in children who develop
central hypothyroidism after starting with GH.
In response to the article "Loss-of-function mutations in IGSF1 cause an
X-linked syndrome of central hypothyroidism and testicular enlargement ', we
would like to do a follow-up study with the 27 cases from our previous study
(after confirmation of the fact that there was a central hypothyroidism and not
a thyroidal hypothyroidism). The neonatal screening results of these children
show that the 27 children treated with T4 after starting with GH already had
low-normal values of their thyroid function during neonatal screening. This
confirms that there is actually a (mild)congenital central hypothyroidism, with
later in life developing (or discovering) of GHD. In this recently published
study a corresponding loss of function mutation in the IGSF-1 gene is
discovered in different families. This gene causes central hypothyroidism
discovered at different ages and in some cases, is accompanied with a GHD. The
researchers noticed also testicular enlargement and variable prolactin values**.
The purpose of this second part of the study is to investigate the prevalence
of the IGSF-1 gene mutation in the 27 children known with central
hypothyroidism after starting with GH.

(1) Follow-up study of project 2011_371: To determine whether the 27 children
had central hypothyroidism with additional data from the medical records.
After receiving informed consent, information from the medical records will be
gathered upon the laboratory values **before and during treatment with
thyroxine and about the growth velocity before and after starting thyroxine.
The burden for the patient in this case is minimal. For this information, the
treating pediatricians will be contacted.

(2) Prevalence of IGSF-1 mutation
The 27 children all use growth hormone and thyroxine. For this reason they have
to visit their treating pediatrician every 4 to 6 months . During this visit
blood samples are also collected to check the thyroid values**. Testing for the
presence of the IGSF-1 mutation may therefore occur during a routine blood
collection.
Informed consent will be asked to draw an additional blood sample for testing
the presence of an IGSF-1 mutation.

The burden for the patients is very low. Data collection from the medical file
will be done anonymous and does not harm the patient.
The determination of the possible presence of the IGSF-1 mutation is not
considered a burden for the patient, because this will be determined in a blood
sample that is already collected for routine patient care.