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TSH resistance (OMIM #275200) is a condition of thyroid refractoriness
to TSH stimulation. The first description dates back to 1968 (1)
when a child with congenital hypothyroidism, in situ thyroid gland
of normal volume, and no increase of iodine uptake after exogenous
TSH administration was reported. Since then, a number of other cases
have been described. Beginning from the early reports, alterations
of TSH receptor (TSHR), Gsα or other downstream signaling elements
were considered as possible causes of this particular disorder.
However, it was only after the cloning of TSHR gene (2) that loss-of-function
TSHR mutations were recognized as the molecular defect in most familial
cases of TSH resistance (3-6). This review will focus on the clinical
presentation, differential diagnosis and molecular genetics of this
Clinical and biochemical features of TSH resistance
High levels of serum TSH, normal/reduced levels of serum thyroid
hormone and normal/hypoplastic thyroid gland characterize TSH resistance.
Depending on the degree of TSH insensitivity, the presentation may
be extremely variable, ranging from severe congenital hypothyroidism
to only mild elevations of TSH in the absence of signs and symptoms
Table I. Clinical and biochemical phenotypes associated with
inactivating mutations of TSHR depend on the degree of impairment
in receptor function.
As TSH is the major physiological stimulus of both thyrocyte function
and proliferation, a profound reduction of thyroid sensitivity to
TSH, as observed in patients with complete TSH resistance, leads
to severe hypothyroidism with a hypoplastic thyroid gland. Because
of reduced thyroid hormone feedback, TSH is markedly elevated. Such
cases are typically diagnosed at the neonatal screening for congenital
hypothyroidism. In the first description by Abramowicz et al. (4),
thyroid hypoplasia was so profound and radioiodine uptake so impaired
that thyroid agenesia was diagnosed at scintigraphy. However detectable
serum Tg levels disclosed the presence of thyroid tissue.
When thyroid refractoriness to TSH is incomplete, a condition known
as partial TSH resistance, TSH elevation can somewhat compensate
for the reduced sensitivity of the thyroid and milder forms of hypothyroidism
are seen. Patients typically have a thyroid gland of normal/reduced
size, high TSH levels, but concentrations of free thyroid hormones
in the normal range (3,5,6).
More recently, we described three families with only mild elevations
of TSH levels and a normal thyroid gland, in which the defect was
caused by heterozygous inactivating TSHR mutations (see below) (7).
Similar alterations can be found in some heterozygous relatives
of patients with homozygous TSHR mutations (8). Although such cases
can be positive at neonatal TSH screening (7), they are generally
diagnosed later on in life, when they can be easily confounded with
the more prevalent condition of subclinical hypothyroidism due to
autoimmune thyroid disease (AIT).
The occurrence of elevated TSH serum levels in the presence of low/normal
free T4 concentration and thyroid volume is rather frequent in the
general population. However, only a minority of these patients is
affected with TSH resistance. So, the diagnostic workup should exclude
other potential causes such as AIT, defects in TSH molecule (particularly
those due to TSH beta gene mutation) and TSH biological activity
or other forms of congenital primary hypothyroidism, including abnormalities
in thyroid transcription factors (6).
Differential diagnosis with AIT, by far the most frequent cause
of TSH elevations in the adult population, is based on clinical
history, biochemical evaluation of anti-thyroid antibodies (anti-TPO
and anti-thyroglobulin) and thyroid ultrasound (7). The positivity
of anti-thyroid antibodies and/or the presence of the typical heterogeneous
hypoechoic pattern at thyroid ultrasound are strongly suggestive
of AIT. Other elements in favor of AIT are diagnosis reached in
adult/advanced age as well as progressive evolution from subclinical
toward overt disease. The only exception is the very rare association
of TSH resistance with AIT (9).
Some patients with central hypothyroidism may present with elevated
serum TSH levels. These alterations are generally found in patients
with hypothalamic (tertiary) hypothyroidism (10,11), but can also
occur in the presence of TSH? gene mutations (12). In the former
situation, despite high serum concentrations of the immunoreactive
hormone, TSH biological activity is reduced, which explains the
condition of hypothyroidism. In these cases, the presence of hypothalamic-pituitary
disorders supports the diagnosis of central hypothyroidism and prompts
to test the biological activity of circulating TSH molecules in
Complete TSH resistance due to loss-of-function TSHR mutations can
lead to congenital hypothyroidism with thyroid gland in situ. Other
known causes are defects in thyroid transcription factors, such
as NKX2.1 (also named TITF1) or PAX8 (13). Due to the expression
of these transcription factors in tissues other then the thyroid,
complex phenotypes have been reported in these cases. Patients with
NKX2.1 mutations may have neurological (choreoathetosis) and pulmonary
alterations, while PAX8 mutations can be suspected in the presence
of kidney abnormalities. NKX2.1 and PAX8 mutations can be excluded
by genetic analysis.
TSH resistance can also occur in the context of the multiple hormone
resistance syndrome (Albright’s Hereditary Osteodystrophy)
caused by inactivating mutations of the gene encoding Gsα protein.
The presence of high PTH levels associated with hypocalcemia and
hyperphosphatemia, as well as typical clinical features are suggestive
of this disorder.
The congenital/childhood occurrence and the frequent family setting
of TSH resistance suggest the genetic origin of the disorder. Therefore,
after its cloning in 1989 (2), TSHR became the more obvious candidate
gene. Shortly after, inactivating TSHR mutations were identified
in a family with recessive transmission of elevated TSH levels and
normal thyroid hormone secretion (3). Since then, 23 different TSHR
loss-of-function mutations have been documented to be responsible
for TSH resistance (5,6). An updated database of TSHR mutations
can be found on the web (14). However, some cases of TSH resistance
not associated with TSHR or GNAS (Gsα) mutations have been reported,
suggesting the probable involvement of other not identified genes
In the earlier studies, in which only probands with large TSH elevations
were screened for mutations, the disease was linked to homozygous
or compound heterozygous mutations and was described to follow a
recessive pattern of inheritance. More recently, we described patients
with a mild form of partial TSH resistance due to heterozygous TSHR
mutations. In these cases, the defect had a dominant pattern of
inheritance (7). Such genetic heterogeneity is well reflected by
diversity of clinical presentation (Table I).
Natural mutations leading to resistance to TSH action are distributed
all along the receptor backbone and affect either the extracellular
or transmembrane domains. Almost all types of alterations (missense
or nonsense mutations, deletions, insertions or alterations in intron-exon
boundaries) have been reported. However, missense P162A and C41S
mutations appear to be relatively more frequent. All of these mutations
are associated with a defective cAMP response to TSH stimulation.
This was shown by in vitro functional assays using different end
points, such as determination of cAMP concentrations or using reporter
genes (e.g., luciferase) under cAMP regulation.
The molecular mechanisms responsible for the loss of receptor function
are probably multiple (5,6). Lack of receptor expression on the
plasma membrane, ligand binding or coupling with G-proteins may
be expected in case of mutations causing the synthesis of a truncated
receptor. Similarly, the skipping of exon 6 as reported in two patients,
which causes the deletion of one leucine-rich repeat in the aminoterminal
hormone binding domain, is expected to impair TSH receptor binding.
Initially, all missense mutations located in the extracellular domain
were thought to alter ligand binding. However, several exceptions
to this rule have now been reported (7,18). For instance, mutations
C41S and I167N lead to a profound alteration of TSHR native conformation
with hampers receptor targeting to the cell membrane (7,18). Another
interesting exception is represented by mutation R310C which is
instead associated with a unexpected increase in ligand-independent
activity, possibly contributing to the euthyroidism observed in
the affected patients. In contrast, mutations located in the transmembrane
domain may result either in defective transmission of the stimulatory
signal or in deranged routing of mutant TSHR to the cell plasma
membrane. The mechanism of TSH resistance in patients with heterozygous
TSHR mutations is less obvious. We recently demonstrated the presence
of an in vitro dominant negative effect exerted by some of these
mutants (C41S, L467P, C600R) at the level of wild-type receptor
maturation and routing to the cell membrane. In fact, in cells co-transfected
with wild-type and mutant TSHRs, we observed a reduction of both
basal and TSH-stimulated cAMP production as compared to that of
cell transfected with wild-type receptor alone.
Figure. Dominant negative effect of TSH receptor L467P
mutant. Plasmids encoding wild-type TSHR or L467P mutant
were either single- or co-transfected in Cos-7 cells. A mutant to
wild-type DNA ratio of 3:1 was used to enhance the effect of L467P.
Cells were then stimulated with increasing concentrations of bovine
TSH (bTSH). No cAMP acumulation was seen in cells transfected with
L467P mutant. A partial impairment of cAMP production was observed
in cells co-expressing wild-type and mutant receptor as compared
to cells expressing wild-type receptor. Similar results were obtained
with C41S and C600R mutants.
In addition, the co-expression of mutant TSHRs caused intracellular
entrapment, mainly in the endoplasmic reticulum, of wild-type receptor.
Finally, we documented, by fluorescence resonance energy transfer
and co-immunoprecipitation, the existence of a physical interaction
between wild-type and mutant receptors. Based on these data, the
occurrence of TSH resistance in these cases appears to be due to
a reduction of the amount of wild-type TSHR present at the cell
membrane caused by oligomerization with intracellularly retained
TSHR mutants (8).
Several issues about TSH resistance remain to be addressed. First,
some well-documented cases are not associated with mutations in
TSHR coding regions. However, introns and 5’ or 3’ flanking
regions of TSHR gene have not been thoroughly analyzed so far. In
addition, other genes could be involved, as recently shown by a
linkage analysis study (17).
Another debated point is whether to treat or not patients with apparently
well-compensated (i.e. partial) TSH resistance. Indeed, clinical
evidence suggests that treatment may not be necessary. In fact,
several of these patients were diagnosed in childhood or adult age
and had quite a normal somatic and neurological development despite
untreated since neonatal age. Moreover, one patient reported by
our group was diagnosed at neonatal TSH screening, but was not treated
with L-thyroxine because of thyroid hormone levels close to the
upper limit of the normal range. He is also doing quite well without
L-thyroxine supplementation. However, no general rule can be derived
from these limited observations and a decision about starting or
not therapy should be made in every single patient. In case no therapy
is established, we advise a close clinical and biochemical follow-up,
including pituitary MRI. In fact, conditions in which thyroid hormone
needs are increased, such as puberty or pregnancy, as well as any
insult to the thyroid, e.g. AIT, may easily turn euthyroid hyperthyrotropinemia
into mild or even overt hypothyroidism.