Tsh resistance syndrome

1. Dr.HAIFA ELSHWIKH

3. RTSH is broadly defined as
high serum TSH (hyperthyrotropinemia) of normal
biological activity in the absence of goitre.
Affected individuals have normal or hypoplastic thyroid
glands, high serum TSH concentrations, and normal or low
serum T4 and T3 concentrations.
They are often identified at birth through neonatal
screening for congenital hypothyroidism ( with normally
located thyroid gland)

4. TSH is the predominant regulator of thyroid growth and T4
and T3 synthesis and secretion. These actions are mediated
through TSH-binding to the TSH receptor located on the
plasma membrane of thyroid follicular cells.
Activation of the TSH receptor results in activation of G
proteins and then of the adenylyl cyclase-cyclic AMP
pathway of signal transduction The result is stimulation of
thyroid follicular-cell growth and function

6. two genetic causes of RTSH have been so far identified.
1-Inactivating mutations in the TSH receptor
The inheritance is recessive
2-Defect in the long arm of chromosome 15
The defect is inherited in an autosomal dominant
manner.

7. Fully compensated defect — The impaired response to
TSH is compensated by hypersecretion of TSH; this
overcomes the resistance, resulting in euthyroid
hyperthyrotropinemia.
Partially compensated defect — This occurs when
the high serum TSH cannot fully compensate for the
defect; affected individuals have mild hypothyroidism
("Subclinical hypothyroidism".)
Uncompensated defect — Complete lack of TSH
receptor function results in severe hypothyroidism.
This most often occurs when both alleles carry
mutant TSH receptors with complete lack of function

8. RTSH should be suspected in patients, particularly infants,
who have high serum TSH concentrations, normal or low
serum free T4 and T3 concentrations, and a normally located
thyroid gland.
The differential diagnosis includes all those conditions that
impair thyroid secretion. Because of the important role of
TSH in promoting thyroid growth, RTSH is unlikely if the
patient has a goiter or ectopically located thyroid tissue.

9. Individuals with fully compensated RTSH are euthyroid and
need no treatment. There is no evidence that in the absence
of other risk factors, persistent elevation of serum TSH
levels produces pituitary TSHomas or thyroid neoplasia.
Individuals with partially compensated or uncompensated
RTSH should be treated with L-T4, like any other
hypothyroid patient.
Because these individuals have normal responsiveness to
thyroid hormone, the goal is to normalize their serum TSH
concentration.

10. Resistance to TSH (RTSH) is broadly defined as high serum TSH
(hyperthyrotropinemia) of normal biological activity in the
absence of goiter.
Affected individuals have normal or hypoplastic thyroid glands,
high serum TSH concentrations, and normal or low serum T4
and T3 concentrations
RTSH should be suspected in patients, particularly infants, who
have high serum TSH concentrations, normal or low serum free
T4 and T3 concentrations, and a normally located thyroid
gland.
In patients with RTSH who are euthyroid (the impaired
response to TSH is fully compensated by hypersecretion of
TSH), we suggest NOT treating with thyroid hormone) (Fully
compensated defect)' , If the high serum TSH cannot fully
compensate for the defect (partially compensated or
uncompensated defects), the individual is hypothyroid and
should be treated with thyroid hormone, like any other
hypothyroid patient

12. is an inherited syndrome characterized by reduced
responsiveness of target tissues to TH.
The disorder is characterized by high serum concentrations of
free T4 and usually free T3, accompanied by normal or slightly
high serum TSH concentrations.
The diagnosis of RTH is confirmed if supra-physiologic doses of T4
or T3 are required to reduce the TSH secretion.

13. RTH has been detected in 1 of 40,000 live births
and it occurs with equal frequency in both sexes.
it is inherited as an autosomal dominant trait.

14. Thyroid hormone receptor mutations:
There are two TRs, alpha and beta, which are encoded by
separate genes located on chromosomes 17 and 3,
respectively. The receptors have structural and sequence
similarities

In approximately 85 percent of cases, RTH is due to
mutations in the TR beta gene. One hundred and twenty-four
different mutations have been identified so far among 343
unrelated families. Most of the mutations are located in the
T3-binding domain of the TR
They interfere with the function of the normal TR (dominant
negative effect)
. No mutations in the TR alpha gene have been identified in
humans
.

16. nonTR-RTH
In 15 percent of families, RTH is not caused by a TR beta
gene mutation; this is known as "nonTR-RTH". It is clinically
and biochemically indistinguishable from RTH with TR beta
gene mutations

17. In RTH, resistance of the pituitary thyrotrophs to TH raises
TSH secretion, which increases the synthesis and secretion
of T4 and T3 from the thyroid gland.
The elevated levels of these thyroid hormones fail to
downregulate the hypothalamic-pituitary-thyroid axis as
they would in an individual without RTH, As a result, these
patients have high levels of T4 and T3, and normal or high
levels of TSH..

18. Because of this apparent dissociation between serum TH and
TSH concentrations, the syndrome has been called
"inappropriate secretion of TSH". However, TSH secretion is
not really inappropriate because the response of the
thyrotrophs to TH is reduced; to the contrary, it is
compensatory and appropriate for the level of TH action
mediated through the defective TR beta
The TSH secreted by these patients is rich in sialic acid and
has increased bioactivity, as compared with normal TSH ,This
explains why patients with RTH have goiter and high serum
T4 and T3 concentrations even though their serum
immunoreactive TSH concentrations are normal or only
slightly high.

19. Because increased TH secretion compensates for TH
resistance, most patients with RTH are clinically euthyroid,
although the completeness of compensation varies in
different patients and in different tissues in the same
patient .

20. The hallmark of RTH is the paucity of symptoms and signs
of thyroid dysfunction despite the presence of high serum
T4 and T3 concentrations
Among all clinical findings, goiter is by far the most
common (65 to 95 percent), followed by hyperactivity (33
to 68 percent) and tachycardia (33 to 75 percent)

These abnormalities usually lead to evaluation of thyroid
function. The subsequent finding of high serum T4 and T3
concentrations often results in the erroneous diagnosis of
hyperthyroidism.
.

21. Patients with RTH may have some symptoms or signs of
hypothyroidism or hyperthyroidism, but these are variable
and, when present, often inconstant .
If hypothyroidism is present, clinical features may include
growth retardation, delayed bone maturation, learning
disabilities, mental retardation, sensorineural deafness, and
nystagmus.
Patients with symptoms of hyperthyroidism may have
tachycardia, hyperactivity, and increased basal metabolic
rate. Overt hypothyroidism is more common in these
patients because of erroneous diagnosis of hyperthyroidism,
they received ablative or antithyroid treatment to reduce
their TH level

22. Freqency and
persentage
finding
66_95%goiterThyroid gland
33_75%tachycardiaheart
60%Emotional disturbancesNervous system
33_68%Hyperkinetic behavior
40_60%Attention deficit
hyperactivity disorder
30%Learning disability
4_16%Mental retardation
10_22%Hearing loss
18_25%Short statureGrowth & development
29_47%Delayed bone age
33%Low body mass index

23. a high serum free T4 concentration and non-suppressed TSH
are essential requirements for the diagnosis of RTH. Serum
levels of T3 and rT3 are usually also high.
The concentration of thyroglobulin (the protein within which
T3 and T4 are synthesized and stored) tends to be high,
reflecting the level of TSH-induced thyroid gland
hyperactivity.
The abnormalities should be confirmed by repeat
measurements several weeks later.

24. Determine if there are mutations in the TR beta gene by
direct sequencing. Several commercial laboratories offer
sequencing of the TR beta gene. This test provides a means
to confirm the diagnosis, to obtain prenatal diagnosis, and to
prevent inappropriate anti-thyroid treatment of patients with
high serum levels of free TH.

The response of TSH to TSH-releasing hormone is normal or
exaggerated, depending on the baseline TSH level. The
suppressive effect of administered TH on TSH, cholesterol
and creatine kinase is blunted. Similarly, the stimulatory
effect of TH on sex-hormone binding globulin and ferritin is
attenuated.

26. All causes of high serum T4 and T3 concentrations in
association with normal to high serum TSH levels should be
considered in the differential diagnosis
1- T4-binding globulin excess TBG
2- transthyretin excess TTR
3- familial dysalbuminemic hyperthyroxinemia FDH
4-TSH-producing pituitary adenoma TSHoma
5-nonthyroidal illness NTI

27. The following steps are appropriate to establish the diagnosis
of RTH
To exclude abnormalities of TH binding in serum, including
familial dysalbuminemic hyperthyroxinemia, hereditary and
acquired thyroxine binding globulin excess, and transthyretin
excess, measure serum free T4 and T3 by equilibrium dialysis.
Normal values suggest a defect of TH binding in serum that
could be confirmed by measurement of the specific protein or
by genetic analysis.
To exclude a TSH-producing pituitary adenoma, measure the
alpha subunit of TSH , A high ratio of alpha subunit to whole
TSH is pathognomonic of TSH-secreting tumor. This disorder is
associated with a similar TH profile to RTH but most, if not
all, patients are hyperthyroid .

29. There is no treatment that will correct the defect of TR
beta function in subjects with RTH.
Fortunately, in most patients, the hyposensitivity to TH
seems to be adequately compensated by the increase in
secretion of T4 and generation of T3. Thus, treatment is
usually not needed.

30. ablative treatment should be avoided. Large glands have
been successfully treated by the administration of a single
high dose of L-T3 given every other day.
Symptoms of thyrotoxicosis, more specifically tachycardia
and tremor, respond to the administration of the beta
adrenergic blocker, atenolol.
Attention deficit hyperactivity disorder should be treated as
indicated using drugs available for the treatment of this
disorder independently from RTH.

31. In some patients with RTH, several peripheral tissues may be
relatively more resistant than the thyrotrophs. Thus, the
compensation for the hormonal resistance in these tissues is
incomplete and judicious administration of a dose of T4
higher than that needed to restore TSH secretion to normal
may be indicated. The dose must be individually determined
by assessing tissue responses..
In children, this should be done by regular assessment of
growth, bone maturation, and mental development.
Levothyroxine should be given in incremental doses, and the
basal metabolic rate, nitrogen balance, and serum sex
hormone-binding globulin should be measured after
treatment for four to six weeks before the dose is changed;
bone age and growth should be followed on a longer-term
basis. Development of a catabolic state is an indication of
overtreatment.

32. Management of pregnancies in mothers with RTH who are
carrying unaffected fetuses may warrant judicious use of anti-
thyroid medication, depending on the wellbeing of the fetus .
In such mothers, free T4 should be maintained not higher than
20 percent above the upper limit of normal. This can be
achieved by judicious use of propylthiouracil, taking care to
avoid inducing hypothyroidism.
There is no basis for regular treatment of normal mothers
carrying affected fetuses unless the fetus is found to have a
large goiter or be in distress, in which case the only treatment
alternative is intraamniotic infusion of LT-4, although this has
not been reported. Further studies are needed before general
recommendations can be made.

33. Resistance to thyroid hormone (RTH) is an inherited syndrome
characterized by reduced responsiveness of target tissues to thyroid
hormone (TH).
the disorder is characterized by high serum concentrations of free T4
and usually also free T3, accompanied by normal or slightly high
serum TSH concentration.
The hallmark of RTH is the paucity of symptoms and signs of thyroid
dysfunction despite the presence of high serum T4 and T3
concentrations. Clinical features include goiter, hyperactivity, and
tachycardia.
The clinical disease is usually mild because the hyposensitivity to TH
is adequately compensated by the increase in secretion of T4 and
generation of T3.
In approximately 85 percent of cases, RTH is due to mutations in the
TH receptor beta gene. In approximately 15 percent of cases, RTH is
caused by yet undetermined genetic abnormalities.
Diagnosis of RTH depends on characteristic elevations in TH and
exclusion of other causes of hyperthyroxinemia, When RTH is
suspected, the diagnosis should be confirmed by direct sequencing of
the TR beta gene to identify mutation.