Primary objective1) To study the frequency of mutations in this gene in patients with central hypothyroidism and their first- and second-degree relativesSecondary objective: 2) To determine the clinical, biochemical and radiological consequences of…
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) The frequency of mutations of this gene in patients with central
hypothyroidism and their first- and second-degree relatives
Secondary outcome
2) Clinical, biochemical and radiological consequences of mutations in this
gene for hemizygous (males) and heterozygous (female) carriers:
a. Medical history, including a developmental/psychosocial history
b. Physical examination, including height and weight, pubertal development and
thyroid gland size.
c. Biochemical assessment of the HPT axis, including plasma FT4, TSH, T4, T3,
rT3, TBG, Tg, TSH bioactivity and a TRH stimulation test.
d. 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). Pituitary stimulation tests will be
performed when indicated.
e. Analysis of pulsatile TSH release
f. Oral glucose tolerance test (OGTT) and homeostatic model assessment (HOMA)
g. Thyroid gland and testicular size measured by ultrasound.
h. Hypothalamus and pituitary morphology assessed by MRI (if possible without
any form of anesthesia).
i. Hearing assessment by tone audiometry.
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 whole exome sequencing, a presently unknown gene mutation has been
discovered in patients with unexplained congenital central hypothyroidism. The
fact that the product of the affected gene plays an important role stimulating
the production of thyroid hormone supports our conclusion that mutations in
this gene cause congenital central hypothyroidism.
The phenotype in patients with this gene mutations is incompletely known. 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.
Study objective
Primary objective
1) To study the frequency of mutations in this gene in patients with central
hypothyroidism and their first- and second-degree relatives
Secondary objective:
2) To determine the clinical, biochemical and radiological consequences of
mutations in this gene in hemizygous (males) and heterozygous (female)
carriers.
Study design
Prospective descriptive design
Study burden and risks
Placement of an intravenous cannula and withdrawal of blood (procedures 2e, f)
carries a risk of bleeding or bruising. For procedures 2e and 2f subjects will
be admitted to the hospital for several hours. The withdrawal of all thyroid
hormone replacement during 24 hours may cause fatigue and constipation. All
other procedures are either part of standard patient care, or are non-invasive
without further 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
Carrier 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 | NL52353.018.15 |