1) To perform gene mutation analysis in family members of patients carrying a proven mutation in the candidate gene.2) To determine the clinical, biochemical and radiological characteristics of carriers of a mutation in the candidate gene.3) To…
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) The genetic sequence of the TBL1X gene in patients with central
hypothyroidism.
2) The presence of the same TBL1X-mutation in first- and second degree
relatives of patients with a newly discovered TBL1X-mutation.
3) Clinical, biochemical and radiological characteristics of hemizygous (males)
and heterozygous (female) carriers of a mutation in the TBL1X gene:
a. Medical history, including a developmental/psychosocial history and
attention to hearing impairment.
b. Physical examination, including height and weight, pubertal development and
thyroid gland size.
c. Biochemical assessment of the HP/adrenal axis (plasma cortisol and ACTH),
the HP-growth hormone/IGF-1 axis (serum IGF-1 and IGFBP-3), the HP/gonadal
axis (plasma LH, FSH + testosterone in males and serum estradiol in females),
and the HP-lactotroph axis (plasma prolactin).
d. Biochemical assessment of liver function (ALAT, ASAT, gamma-GT, glucose,
platelet count and albumin).
4)
a. Biochemical assessment of the hypothalamo/pituitary (HP)/thyroid axis,
including plasma FT4, TSH, T4, T3, rT3, TBG, Tg and TSH bioactivity.
b. Hearing assessment by tone audiometry.
c. Thyroid gland and testicular size measured by ultrasound.
Secondary outcome
None
Background summary
Congenital central hypothyroidism is characterized by insufficient production
of thyroid hormone (TH) due to inadequate stimulation by thyroid stimulating
hormone (TSH) of an otherwise normal thyroid gland. TH is essential for the
growth and development of the brain until the age of 3 years. Untreated
congenital central hypothyroidism can lead to irreversible brain damage.
Using Sanger sequencing, a presently unknown gene mutation has been discovered
in patients with unexplained congenital central hypothyroidism. The fact that
the affected gene plays an important role in the central regulation of the
thyroid, makes this gene a likely candidate causative gene of central
hypothyroidism. The phenotype in patients with this gene mutations is
incomplete. It is unknown whether these mutations lead to more hormonal
deficiencies. The expectation is that more patients with congenital central
hypothyroidism are carriers of mutations in this gene. Relatives of these
patients are at risk of carrying mutations in this gene, which makes them
potential undiagnosed central hypothyroidism patients.
Hypothesis: via a still unknown mechanism mutations in this gene disrupt the
central regulation of the thyroid, leading to a phenotype of biochemical
central hypothyroidism.
Study objective
1) To perform gene mutation analysis in family members of patients carrying a
proven mutation in the candidate gene.
2) To determine the clinical, biochemical and radiological characteristics of
carriers of a mutation in the candidate gene.
3) To compare endocrine, radiological and auditory characteristics of
carriers of a mutation in TBL1X to those of their first- and second degree
relatives without a mutation in TBL1X.
Study design
Prospective descriptive design
Study burden and risks
TRH test: intravenous administration of the hormone may induce nausea, urinary
urgency or a strange taste in the mouth. This will pass in minutes.
GH-test (adults): intravenous administration of the hormone may induce
sweating, drowsiness, palpitations or nausea. In patients with heart disease or
epilepsy, an arginin/GHRH test will be performed in stead of a GH-test.
Clonidine (children): intravenous administration of the hormone may induce
dizziness, drowsiness and dryness of the mouth.
All mentioned procedures are performed as standard patient care and have a
direct therapeutical benefit for all patients.
Placement of an intravenous cannula and withdrawal of blood carries a risk of
bleeding or bruising.
The procedures specifically for research (including those performed in non
affected relatives) are minimally or non-invasive and have little to no risks.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Congenital central hypothyroidism.
- First- or second-degree relative of a patient with congenital central hypothyroidism.
Exclusion criteria
Carriers of other genetic defects known to cause congenital central hypothyroidism.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL47462.018.13 |